Download - Lecture 2 - Disperse Systems
1
Pharmaceutics 356C
Chapter 14
Disperse Systems(Suspensions Emulsions Surfactants and Aerosols)
2
Disperse or Polyphase Systemsbull Definition A dispersion is a system containing one
or more constituents distributed throughout a homogeneous medium
bull Can classify dispersions into three categories based on particle size ndash True Solutionsmdashless than 0001 micron ndash Colloidsmdash0001 to 05 microns ndash Coarse Dispersionsmdashgreater than 05 microns
(Much overlapping in such a classification)
3
Disperse or Polyphase Systemsbull True Solutions
ndash Molecular dispersions ndash Particles are invisible even with the electron microscope and
pass through filter paper and semi- permeable membranes bull Colloidal Dispersions (Sols)
ndash An intermediate state between true solutions and suspensions ndash Particles cannot be seen with an ordinary microscope but can
be seen with the electron microscope ndash In addition while the particles of a colloidal dispersion will still
pass through filter paper they will not pass through semi-permeable membranes
ndash Very high surface areandash Particles diffuse more slowly than those of a true solution
4
Disperse or Polyphase Systems
bull Coarse Dispersions ndash The systems we know as emulsions or
suspensionsndash Particles (dispersed phase) are often visible with
the naked eye (unaided)ndash Will not pass through filter paper or semi-
permeable membranesndash Particles seldom diffuse ndash Are used extensively in pharmaceutical products
5
Types of Colloidal Systems
bull There can be many types of colloidal dispersions bull Each phase may be a solid liquid or gas bull The most important colloidal pharmaceutical
preparations include ndash 1 Foams ndash 2 Aerosolsndash 3 Emulsions ndash 4 Suspensions ndash 5 Ointments ndash 6 Gels ndash 7 Magmas and Mucilages
6
Basis of Classification
bull In general colloids may be divided into three main groups
bull This division is made on the basis of how the colloidal particles react with the dispersion medium
7
Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)
bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic
ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines
(+)ndash Cellulose Derivatives (and charge)
raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)
raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)
raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)
8
Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)
bull Low attraction to dispersion mediummdashmust put a lot of energy into system
bull Requires special method to manufacture ndash Particle size reduction or particle condensation by
aggregation
ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of
molecule)bull Decrease surface tension (surfactants)
9
Preparation of Colloids
bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods
bull Hydrophobic colloidal dispersionsndash Ultrasonic generators
bull gt20000 Hzndash Colloid mills
bull Less efficient broad particle size distribution
10
Colloid Mill
11
Properties of Colloids
bull Kinetic Propertiesndash Brownian movement
bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by
molecules of dispersion medium
12
Properties of Colloids
bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced
Tyndall effect than hydrophobic colloids
13Light through mist from ultrasonic nebulizer
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
2
Disperse or Polyphase Systemsbull Definition A dispersion is a system containing one
or more constituents distributed throughout a homogeneous medium
bull Can classify dispersions into three categories based on particle size ndash True Solutionsmdashless than 0001 micron ndash Colloidsmdash0001 to 05 microns ndash Coarse Dispersionsmdashgreater than 05 microns
(Much overlapping in such a classification)
3
Disperse or Polyphase Systemsbull True Solutions
ndash Molecular dispersions ndash Particles are invisible even with the electron microscope and
pass through filter paper and semi- permeable membranes bull Colloidal Dispersions (Sols)
ndash An intermediate state between true solutions and suspensions ndash Particles cannot be seen with an ordinary microscope but can
be seen with the electron microscope ndash In addition while the particles of a colloidal dispersion will still
pass through filter paper they will not pass through semi-permeable membranes
ndash Very high surface areandash Particles diffuse more slowly than those of a true solution
4
Disperse or Polyphase Systems
bull Coarse Dispersions ndash The systems we know as emulsions or
suspensionsndash Particles (dispersed phase) are often visible with
the naked eye (unaided)ndash Will not pass through filter paper or semi-
permeable membranesndash Particles seldom diffuse ndash Are used extensively in pharmaceutical products
5
Types of Colloidal Systems
bull There can be many types of colloidal dispersions bull Each phase may be a solid liquid or gas bull The most important colloidal pharmaceutical
preparations include ndash 1 Foams ndash 2 Aerosolsndash 3 Emulsions ndash 4 Suspensions ndash 5 Ointments ndash 6 Gels ndash 7 Magmas and Mucilages
6
Basis of Classification
bull In general colloids may be divided into three main groups
bull This division is made on the basis of how the colloidal particles react with the dispersion medium
7
Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)
bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic
ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines
(+)ndash Cellulose Derivatives (and charge)
raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)
raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)
raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)
8
Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)
bull Low attraction to dispersion mediummdashmust put a lot of energy into system
bull Requires special method to manufacture ndash Particle size reduction or particle condensation by
aggregation
ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of
molecule)bull Decrease surface tension (surfactants)
9
Preparation of Colloids
bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods
bull Hydrophobic colloidal dispersionsndash Ultrasonic generators
bull gt20000 Hzndash Colloid mills
bull Less efficient broad particle size distribution
10
Colloid Mill
11
Properties of Colloids
bull Kinetic Propertiesndash Brownian movement
bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by
molecules of dispersion medium
12
Properties of Colloids
bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced
Tyndall effect than hydrophobic colloids
13Light through mist from ultrasonic nebulizer
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
3
Disperse or Polyphase Systemsbull True Solutions
ndash Molecular dispersions ndash Particles are invisible even with the electron microscope and
pass through filter paper and semi- permeable membranes bull Colloidal Dispersions (Sols)
ndash An intermediate state between true solutions and suspensions ndash Particles cannot be seen with an ordinary microscope but can
be seen with the electron microscope ndash In addition while the particles of a colloidal dispersion will still
pass through filter paper they will not pass through semi-permeable membranes
ndash Very high surface areandash Particles diffuse more slowly than those of a true solution
4
Disperse or Polyphase Systems
bull Coarse Dispersions ndash The systems we know as emulsions or
suspensionsndash Particles (dispersed phase) are often visible with
the naked eye (unaided)ndash Will not pass through filter paper or semi-
permeable membranesndash Particles seldom diffuse ndash Are used extensively in pharmaceutical products
5
Types of Colloidal Systems
bull There can be many types of colloidal dispersions bull Each phase may be a solid liquid or gas bull The most important colloidal pharmaceutical
preparations include ndash 1 Foams ndash 2 Aerosolsndash 3 Emulsions ndash 4 Suspensions ndash 5 Ointments ndash 6 Gels ndash 7 Magmas and Mucilages
6
Basis of Classification
bull In general colloids may be divided into three main groups
bull This division is made on the basis of how the colloidal particles react with the dispersion medium
7
Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)
bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic
ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines
(+)ndash Cellulose Derivatives (and charge)
raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)
raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)
raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)
8
Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)
bull Low attraction to dispersion mediummdashmust put a lot of energy into system
bull Requires special method to manufacture ndash Particle size reduction or particle condensation by
aggregation
ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of
molecule)bull Decrease surface tension (surfactants)
9
Preparation of Colloids
bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods
bull Hydrophobic colloidal dispersionsndash Ultrasonic generators
bull gt20000 Hzndash Colloid mills
bull Less efficient broad particle size distribution
10
Colloid Mill
11
Properties of Colloids
bull Kinetic Propertiesndash Brownian movement
bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by
molecules of dispersion medium
12
Properties of Colloids
bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced
Tyndall effect than hydrophobic colloids
13Light through mist from ultrasonic nebulizer
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
4
Disperse or Polyphase Systems
bull Coarse Dispersions ndash The systems we know as emulsions or
suspensionsndash Particles (dispersed phase) are often visible with
the naked eye (unaided)ndash Will not pass through filter paper or semi-
permeable membranesndash Particles seldom diffuse ndash Are used extensively in pharmaceutical products
5
Types of Colloidal Systems
bull There can be many types of colloidal dispersions bull Each phase may be a solid liquid or gas bull The most important colloidal pharmaceutical
preparations include ndash 1 Foams ndash 2 Aerosolsndash 3 Emulsions ndash 4 Suspensions ndash 5 Ointments ndash 6 Gels ndash 7 Magmas and Mucilages
6
Basis of Classification
bull In general colloids may be divided into three main groups
bull This division is made on the basis of how the colloidal particles react with the dispersion medium
7
Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)
bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic
ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines
(+)ndash Cellulose Derivatives (and charge)
raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)
raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)
raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)
8
Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)
bull Low attraction to dispersion mediummdashmust put a lot of energy into system
bull Requires special method to manufacture ndash Particle size reduction or particle condensation by
aggregation
ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of
molecule)bull Decrease surface tension (surfactants)
9
Preparation of Colloids
bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods
bull Hydrophobic colloidal dispersionsndash Ultrasonic generators
bull gt20000 Hzndash Colloid mills
bull Less efficient broad particle size distribution
10
Colloid Mill
11
Properties of Colloids
bull Kinetic Propertiesndash Brownian movement
bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by
molecules of dispersion medium
12
Properties of Colloids
bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced
Tyndall effect than hydrophobic colloids
13Light through mist from ultrasonic nebulizer
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
5
Types of Colloidal Systems
bull There can be many types of colloidal dispersions bull Each phase may be a solid liquid or gas bull The most important colloidal pharmaceutical
preparations include ndash 1 Foams ndash 2 Aerosolsndash 3 Emulsions ndash 4 Suspensions ndash 5 Ointments ndash 6 Gels ndash 7 Magmas and Mucilages
6
Basis of Classification
bull In general colloids may be divided into three main groups
bull This division is made on the basis of how the colloidal particles react with the dispersion medium
7
Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)
bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic
ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines
(+)ndash Cellulose Derivatives (and charge)
raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)
raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)
raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)
8
Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)
bull Low attraction to dispersion mediummdashmust put a lot of energy into system
bull Requires special method to manufacture ndash Particle size reduction or particle condensation by
aggregation
ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of
molecule)bull Decrease surface tension (surfactants)
9
Preparation of Colloids
bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods
bull Hydrophobic colloidal dispersionsndash Ultrasonic generators
bull gt20000 Hzndash Colloid mills
bull Less efficient broad particle size distribution
10
Colloid Mill
11
Properties of Colloids
bull Kinetic Propertiesndash Brownian movement
bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by
molecules of dispersion medium
12
Properties of Colloids
bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced
Tyndall effect than hydrophobic colloids
13Light through mist from ultrasonic nebulizer
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
6
Basis of Classification
bull In general colloids may be divided into three main groups
bull This division is made on the basis of how the colloidal particles react with the dispersion medium
7
Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)
bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic
ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines
(+)ndash Cellulose Derivatives (and charge)
raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)
raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)
raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)
8
Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)
bull Low attraction to dispersion mediummdashmust put a lot of energy into system
bull Requires special method to manufacture ndash Particle size reduction or particle condensation by
aggregation
ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of
molecule)bull Decrease surface tension (surfactants)
9
Preparation of Colloids
bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods
bull Hydrophobic colloidal dispersionsndash Ultrasonic generators
bull gt20000 Hzndash Colloid mills
bull Less efficient broad particle size distribution
10
Colloid Mill
11
Properties of Colloids
bull Kinetic Propertiesndash Brownian movement
bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by
molecules of dispersion medium
12
Properties of Colloids
bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced
Tyndall effect than hydrophobic colloids
13Light through mist from ultrasonic nebulizer
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
7
Basis of Classificationndash Lyophilic (or Hydrophilic Colloid)
bull Solvent lovingmdashattraction to dispersion medium (water or alcohol) ndash hydrophilic alcophilic
ndash Natural Polymers (and charge)raquo Acacia (-) Tragacanth (-) Xanthan Gum (-) Protamines
(+)ndash Cellulose Derivatives (and charge)
raquo Methylcellulose (none) Sodium Carboxymethylcellulose (-)ndash Synthetic Polymers (and charge)
raquo PVP (none) Carbomer (-)ndash Particulate Colloids (and charge)
raquo Bentonite (colloidal hydrated aluminum silicate) (-) Veegum (colloidal aluminum magnesium silicate) (-)
8
Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)
bull Low attraction to dispersion mediummdashmust put a lot of energy into system
bull Requires special method to manufacture ndash Particle size reduction or particle condensation by
aggregation
ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of
molecule)bull Decrease surface tension (surfactants)
9
Preparation of Colloids
bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods
bull Hydrophobic colloidal dispersionsndash Ultrasonic generators
bull gt20000 Hzndash Colloid mills
bull Less efficient broad particle size distribution
10
Colloid Mill
11
Properties of Colloids
bull Kinetic Propertiesndash Brownian movement
bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by
molecules of dispersion medium
12
Properties of Colloids
bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced
Tyndall effect than hydrophobic colloids
13Light through mist from ultrasonic nebulizer
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
8
Basis of Classificationndash Lyophobic (or Hydrophobic Colloid)
bull Low attraction to dispersion mediummdashmust put a lot of energy into system
bull Requires special method to manufacture ndash Particle size reduction or particle condensation by
aggregation
ndash Association Colloidsbull Amphiphilic colloids (polar and nonpolar parts of
molecule)bull Decrease surface tension (surfactants)
9
Preparation of Colloids
bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods
bull Hydrophobic colloidal dispersionsndash Ultrasonic generators
bull gt20000 Hzndash Colloid mills
bull Less efficient broad particle size distribution
10
Colloid Mill
11
Properties of Colloids
bull Kinetic Propertiesndash Brownian movement
bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by
molecules of dispersion medium
12
Properties of Colloids
bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced
Tyndall effect than hydrophobic colloids
13Light through mist from ultrasonic nebulizer
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
9
Preparation of Colloids
bull Hydrophilic colloidal dispersionsndash Spontaneously disperse no special methods
bull Hydrophobic colloidal dispersionsndash Ultrasonic generators
bull gt20000 Hzndash Colloid mills
bull Less efficient broad particle size distribution
10
Colloid Mill
11
Properties of Colloids
bull Kinetic Propertiesndash Brownian movement
bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by
molecules of dispersion medium
12
Properties of Colloids
bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced
Tyndall effect than hydrophobic colloids
13Light through mist from ultrasonic nebulizer
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
10
Colloid Mill
11
Properties of Colloids
bull Kinetic Propertiesndash Brownian movement
bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by
molecules of dispersion medium
12
Properties of Colloids
bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced
Tyndall effect than hydrophobic colloids
13Light through mist from ultrasonic nebulizer
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
11
Properties of Colloids
bull Kinetic Propertiesndash Brownian movement
bull Random movement of particles in dispersionbull Observed by SEMbull Due to bombardment of small particles by
molecules of dispersion medium
12
Properties of Colloids
bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced
Tyndall effect than hydrophobic colloids
13Light through mist from ultrasonic nebulizer
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
12
Properties of Colloids
bull Optical propertiesndash Tyndall effect ndash light scatteringndash True solution ndash no visible conendash Colloid ndash visible cone due to light scatteringndash Hydrophilic colloids have less pronounced
Tyndall effect than hydrophobic colloids
13Light through mist from ultrasonic nebulizer
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
13Light through mist from ultrasonic nebulizer
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
14
Light through colloidal dispersion of silver
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
15
Properties of Colloidsbull Diffusion
ndash Movement of particles from areas of high concentration to areas of low concentration to establish equilibrium ndash Fickrsquos First Law
ndash dQ = -DA (dcdx) dtndash Amount (dQ) of substance diffusing in time (dt) across
plane of area (A) is directly proportional to change in concentration (dc) with distance traveled (dx)
ndash D influenced by diffusant properties solvent properties temperature ndash is not constant but depends on conditions
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
16
Properties of Colloids
bull Sedimentationndash Stokersquos Law v = 2r2 g ( ndash o) 9ndash Where
v is rate of sedimentationr is radius of particleis viscosity of dispersion mediumg gravitation constant is particle densityo is density of dispersion medium
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
17
Properties of Colloidsbull Viscosity
ndash Measure of resistance of a liquid to flow the more viscous the liquid the greater force required to make it flow at a particular rate
ndash Liquid composed of parallel ldquolayersrdquo or platesndash FA = dvdx
bull FA is shear stress (F applied to area A)bull dvdx is shear rate (velocity of shear distance between
platesbull Often plotted dvdx = 1 (FA)
(fluidity)
ndash Unit of viscosity ndash centipoise (cPs)
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
18
Shearing force required to produce velocity gradient between parallel
plates of a block material
F
dx
A
dv
Top plane moves at constant velocity (dv) ndash each lower layer moves atVelocity proportional to its distance from the fixed bottom layer (dx) ndash Result is shear of liquid
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
19
Properties of Colloids - Flowndash Newtonian Flow
ndash Rate of shear linearly related shearing stressndash Influence of temperaturendash Examples
raquo Castor oilraquo Ethyl alcoholraquo Glycerinraquo Olive oilraquo Waterraquo Milkraquo Sugar Solutionraquo Mineral Oil
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
20
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
21
Properties of Colloids - Flowndash Non-Newtonian Flow
bull Plastic Flowndash Apparent viscosity decreases with increasing rates of
shearndash Van der Waals attractive forces must be overcome for
flow to startndash Yield value ndash material begins to flow when forces
between attractive particles is overcome is elastic before then behaves like Newtonian liquid after yield value is reached
ndash Yield value indicates force of flocculation between particles (gt degree of flocculation = higher yield value)
ndash Flocculated particles in suspension are characteristic of plastic flow
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
22
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
23
Properties of Colloids
ndash Non-Newtonian Flowbull Pseudoplastic Flow
ndash Shear thinning materialsndash No yield valuendash Increasing rates of shear will decrease viscosityndash Examples are polymer dispersions (eg Tragacanth
Sodium Alginate Methylcellulose Sodium CMC)ndash Polymers in solution with shear stress long chain
molecules begin to align themselves in direction of flow to reduce internal resistance
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
24
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
25
Properties of Colloids
ndash Non-Newtonian Flowbull Dilatant
ndash Shear thickening materialsndash Increased resistance to flow as the shear rate is
increased with agitationndash Examples include dispersions with gt50 solids of small
deflocculated particles pastes
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
26
FA = (dvdx)dvdx = 1 (FA) (slope = fluidity or 1 viscosity)
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
27
Properties of Colloidsndash Thixotropy
bull Isothermal and slow recovery on standing of a consistency lost through shearing
bull Asymetric particles form loose 3-dimensional structure that when lost takes time to reform
bull Hysteresis loop ndash measure of thixotropic breakdown the larger the hysteresis loop the more thixotropic the liquid is
bull Useful property to formulate liquids to control settlingbull Examples include Bentonite Magma
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
28
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
29
Approximate Viscosities of Gels at RT (mPa s or cPs)
bull Acacia 30 100bull Alginic acid 05 20bull Guar gum1 2000bull HPMC E42 4000bull HPMC K100 2 100000bull MC A4 2 4000bull Starch 2 13bull Xanthan gum 1 1400
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
30
Properties of Colloidsbull Electrical Properties of Colloids
ndash Zeta potential ndash governs degree of repulsion or attraction between adjacent like charged dispersed particles
ndash Difference in potential between the surface of a tightly bound layer and the electroneutral region of the solution
ndash Hydrophobic colloids have critical zeta potentialbull above critical zeta potential ndash repulsive forces gt attractive forcesbull below critical zeta potential ndash attractive forces gt repulsive forces
(controlled flocculation)ndash Manipulate zeta potential
bull Oppositely charged electrolytes to lower zeta potentialbull Add another colloid with opposite charge to lower zeta potential
ndash Zeta potential ndash gives indication of stability of a colloidal systemndash WE WANT controlled flocculation or reduction of repulsion in
order to stabilize dispersion
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
31
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
32
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
33
Properties of Colloids
bull Protective Colloidsndash Hydrophobic colloids are difficult to stabilize
due to large surface area and large free surface energy particles will flocculate to reduce energy
ndash Coat hydrophobic colloid with hydrophillic colloid to stabilize
ndash Examples include gelatin acacia albumin tragacanth methylcellulose Na oleate
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
34
Suspensions
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
35
Suspensionbull Definition -A heterogeneous system in which the
continuous phase is a liquid or semisolid and the dispersed phase consists of a dispersed solid
bull Acceptable properties of a suspensionndash 1 Particles should not settle rapidly ndash 2 When particles settle should not form hard cake (ie be
readily dispersible) ndash 3 Product should be viscous enough so patient gets
uniform dose but not so viscous to prevent pouring or injecting
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
36
Pharmaceutical Suspensions
bull Heterodisperse systems bull Particles often gt 1 um (usually gt 10 um) bull Complex continuous phase
ndash Viscosity Inducing agents flavors etcbull Particle shapes non-spherical bull High solids content
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
37
Why Use Suspensionsbull1 No suitable solvent available to dissolve drug (ie ZnO) bull2 Mask unpleasant taste of drugsndash (ie chloramphenicol palmitate Chloromycetin Parke-Davis ) ndash garlic-like taste for chloramphenicol ndash palmitate salt masks taste ndash also more stable in gastric juices so increased blood levels ndash at pH 3-6 palmitate hydrolyzes
bull3 To increase chemical stability ndash Ex Penicillin G rapid hydrolysis in solution ndash Procaine Penicillin G no hydrolysis if decrease solubility below 15
mcgml (G = glutamate) bull4 To Control Therapeutic Responsendash InsulinmdashDifferent Release Ratendash Depot SystemsmdashSuspension Injections for time release
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
38
Stokersquos Law
bullMost important law controlling formulation of suspensionsbullIn equation
ndash V = rate of settling of the particles ndash r = radius of the particles ndash p = density of the particles ndash po= density of the mediumndash g = gravity constant ndash η = viscosity of the dispersionndash Stokes Law assumes
bull Particles are sphericalbull Suspensions are dilute (lt2 wv)bull Particles do not flocculatebull No Brownian movementbull No electrical effects
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
39
Stokersquos Law Applications
bull Pharmaceutically we can control suspensions by1) Radius of the particles (r)V α r2 (Decrease radius then increase SA and increase surface energy)-a high surface energy leads to aggregate formation so use a peptizing agent (Na+ citrate in calamine lotion) to place surface charge on the particles so they do not aggregate and the surface charge repels the particles - aggregates form to reduce (minimize) surface energy
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
40
Stokersquos Law Applicationsbull Pharmaceutically we can control suspensions by
2) Viscosity (η) of the mediummdashSuspending Agents--Rate of settling is inversely proportional to viscosity Examples of suspending agents -acacia tragacanth ndash In too sticky for Ex-Carboxymethylcellulose (CMC) ndashIn or Ex -Veegum (montmorrilonite clays) -use hydrated In or Ex -Carbopol -a gum use in pH range 5-10 In or Ex--Viscosity inducing agents -swell in water to increase viscosity
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
41
Methods of Preparation of Suspensions
bull A Dispersion Method -add dispersion medium to finely divided particles
ndash 1 Diffusible powdersmdashno suspending agent required will remain suspended long enough for uniform dosebull Ex Kaolin Mg Carbonate Mg Oxide Quinine sulfate and
Bismuth subcarbonatemdashCompletely insoluble2 Indiffusable powdersmdashsuspending agent required does not
remain suspended long enough for patientbull Ex Aspirin sulfa drugs sulfur in topical preps Salicylic acid
Phenobarbital
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
42
General Method of Preparationbull 1 Material must be finely dividedbull 2 Add small amount of vehicle to make smooth lump free
paste bull 3 Slowly dilute with remainder of vehicle with constant stirring
(34 volume of prep) in mortarbull 4 Add through gauze to pre-calibrated bottle rinse mortar
with remainder of vehicle into cylinder bull 5 qs to volume with rinse in cylinder
bull NOTE If suspension is thick use calibrated bottle to qs with bull NOTE With soluble solids add as solution AFTER forming
initial dispersion (same with tinctures) If add before aggregates will form
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
43
Fritsch Planetary Micro Mill
For reducing particle size downTo colloidal size range dry or in suspension
For mixing and homogenizing of emulsions suspensions pastes
Uses grinding balls for high impactenergy
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
44
Methods of Preparation of Suspensions
bull 1 Chemical interaction (Lotio Alba White Lotion) sulfurated potash + zinc sulfate
(stink) + (zinc) K2S + ZnSO4 K2SO4 + ZnS
bull prepare as separate solutions filter add stink to the zinc slowly with stirring obtain fine white ppt (zinc polysulfides)
bull used as astringent (acne) bull 2 Alteration of solvent
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
45
Interfacial Properties of Suspended Particles
bull Thermodynamically unstable--Flocculate--light fluffy conglomerates held by weak Van der Waals forces --Aggregates--caking ndashstronger forces to form solid aggregate (Trying to overcome free surface energy in suspension)
F = SL A
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
46
Interfacial Properties of Suspended Particles
bull To approach a thermodynamically stable systemΔF = O by reduce interfacial tensionndashUse
surfactant reduce interfacial areamdashControl flocculation (Using Zeta Potential)
--Flocculated particles weakly bonded settle rapidly no cake re-suspend
--Deflocculated particles settle slowly sediment difficult to re-
suspend
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
47
Sedimentation Volumes
bull Sedimentation volumes produced by adding varying amounts of flocculating agent
bull Examples b and c are pharmaceutically acceptable
F = Sedimentation Volume
F = Vu = Final Volume of Susp Sediment
Vo Original Volume of Susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
48
Caking Diagram
bull Demonstrating the flocculation of a bismuth subnitrate (+ charged) suspension by means of the flocculating agent monobasic potassium phosphate
App
aren
t Zet
a Po
tent
ial
F = Sedimentation Volume
F = Vu = Final Volume of susp Sediment
Vo Original Volume of susp
Bismuth Subnitrate (+)Monobasic Potassium Phosphate (-)
05
10
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
49
Examples of Official Suspensions
1 Chloramphenicol Palmitate Oral Suspension USP
(Chloromycetin Palmitate Suspension Parke-Davis)
-Derivative increases stability and masks taste -palmitate deriv is hydrolyzed off in GI tract
and chloramphenicol is absorbed -for eye and ear drops derivative not
necessary because acid stability or taste are not problems
USE against gm (-) and gm (+) bacteria Caution -blood dyscrasias (bone marrow
depression)
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
50
Examples of Official Suspensions
bull B EXTERNAL SUSPENSIONS1 Calamine Lotion USP
8 ZnO + 8 Calamine (calamine consists of 98 ZnO + 2 Fe203)
-powders are levigated with glycerin then paste is diluted with Bentonite Magma + calcium
hydroxide USE protectant relieves itching sunburn pain poison
ivy 2 Phenolated Calamine Lotion USP
Calamine Lotion USP + 1 Phenol 3 White Lotion NF -see previous notes
-must add ldquostink to the zinc in order to obtain fine particles as the precipitate
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
51
Suspending Agents
bull Categorize by ndash Rheologic Behaviorndash Ionic Chargendash Amount usedndash Internal or Externalndash Stable pH rangendash Any incompatibilities
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
52
Examples of Suspending Agents
bull Gums and Derivativesndash Acaciandash Tragacanthndash Pectinndash Carbopol
bull Claysndash Bentonitendash Veegum
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
53
Examples of Suspending Agents
bull Cellulose Derivativesndash Methylcellulosendash Carboxymethyl Cellulose Sodiumndash HPMCndash HPC
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
54
Emulsions
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
55
Emulsions
bull Definition -system of 2 immiscible materials one of which is dispersed in globular form throughout the other
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
56
Emulsions
bull Termsndash Dispersed PhasemdashVarious droplets
discontinuous phasendash Continuous PhasemdashCarries the dispersed
dropletsndash OW EmulsionmdashOil is the dispersed phase
water the continuous phasendash WO EmulsionmdashWater is the dispersed
phase oil is the continuous phase
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
57
Why Use Emulsionsbull 1 Permits administration of liquid drug in form of
tiny globules rather than in bulk bull 2 0W emulsion if oil tastes offensive bull 3 Irritating medicinal agents to be applied externally
onto the skin (ie lotion or cream)mdashkeep in friendly environment
bull 4 0W vs W0 for topical preparationsWOmdashSpreads more evenly on unbroken but
damaged skin to protect (ie Water-proof
sunscreen)OWmdashEasily removed from skin
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
58
To Maintain a Stable Emulsionbull 1 Reduce interfacial tension between the 2
immiscible liquids by using SAA (wetting agent)bull 2 Emulsifying agent must be amphiphilic (SAA)bull 3 There must be a high interaction energy between
the non-polar portions These London attractive forces increase the tensile strength of the film making it more difficult to break (tough and pliable)
--SAA forms a film at interface a prevents coalescence of the droplets
of oil b stabilizes the emulsion
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
59
Nonpolar tail
Interface
Polar head
London dispersion forces
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
60
Emulsions for Internal Use
bull Use OW typebull Acacia is best emulsifying agent for internal usebull Desirable properties of an emulsifying agent
(Amphiphilic)ndash Non-toxic (GRAS listed)ndash NO therapeutic activityndash Amphiphilic structurendash High HLB value (ie 8 to 18)
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
61
Emulsions for External Use
bull OW or WO typesbull Use soaps as the emulsifying agents
ndash Monovalent soapsbull Na+ and K+ mdash Water soluble Forms OW
ndash Divalent soaps Ca++ soaps or long chain fatty acids mdash
Water insoluble Forms WO
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
62
Stability of Emulsions
bull Stability is characterized by 1 Absence of coalescencemdashNo forming of one droplet from two droplets2 Absence of creaming (Phase separation)3 Nice color 4 Pleasant odor 5 Esthetic appearance
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
63
Stability of Emulsionsbull 1 Flocculation and Creaming (Measure of Stability)
- flocculation and concentration of globules - reversible ndash shake or agitate - related by Stokes Law ndashDensity difference viscosity important a) upward creamingmdashOW b) downward creamingmdashWO
bull 2 Coalescence and Breaking --irreversiblemdashpoor formulation possibly increase emulsifier --physicalKey is to prevent breakingmdashdictated by proper choice and level of emulsifying agent(s)
bull 3 Phase Inversion --must be controlled ndash often results in finer dispersed phase--OW to WO (Internal Phase becomes External Phase)
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
64
Stability of Emulsions
bull Na Stearate (ow) + CaCl2
bull Ca Stearate (wo)
bull What is the emulsifying agent
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
65
o o
Flocculation
o o
Coalescence
o
w
w
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
66
Preservation of Emulsionsbull Growth of microorganisms cause
--Physical phase separation mdash Partitioning --Discoloration mdash Turns white or brown--Gas emission (possibly)--Odor formation--Changes in rheological properties
bull Microorganisms degrade the emulsifying agentbull Use Preservatives -- Essential
--ie Methylparaben and Propylparaben
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
67
Emulsion Technologybull Industrial Homogenizers
--In pharmacy practice use mortar amp pestlebull Continental (Dry Gum) Method
Emulsifying agent + OilmdashThen add water [General Rule 421 (OilWaterGum)]-- Acacia + Oil triturate then add all water amp mix-- Use ceramic MampPmdashMore friction generated -- Requires about 3 minutes-- Can use electric mixer or blender
bull English (Wet Gum) Method Emulsifying Agent + WatermdashThen add oil(A thicker preparationmdashAdd oil slowly)
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
68
High shear homogenizer
Hand homogenizer
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
69
Examples of Official Emulsions
bull Castor Oil EmulsionmdashLaxativebull Hexachlorophene Cleansing
Emulsionbull Mineral Oil EmulsionmdashLaxativebull Simethicone EmulsionmdashGas
Flatulence
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
70
Other Emulsifying Agents
bull Anionicndash Alkali Soaps (RCOO- + monovalent)ndash Metallic Soaps ((RCOO)2 + di or tri valent)ndash Soaps of Organic Aminesndash Sulfated Compounds (R-OSO3Na)
ndash Sulfonates (R-SO3Na)
bull Cationicndash Quaternary ammonium compounds
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
71
Other Emulsifying Agentsbull Non-Ionic (generally esters ndash R-COOR1)
ndash Polyethylene glycol 400 monostearatendash Sorbitan monopalmitate (Span 40)ndash Sorbitan monooleate (Span 80)ndash Polyoxyethylene sorbitan monooleate (Tween 80)ndash Polyoxyethylene sorbitan monolaurate (Tween 20)ndash Silicones
bull Low MW have surfactant propertiesbull High MW have antifoaming action
bull Natural and Modified Naturalndash Alginatesndash Cellulose derivativesndash Gums (Acacia Tragacanth Pectin)ndash Lipids (Lecithin)
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
72
Surface Tension and Surfactants
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
73
Surface Tensionbull Surface Tension is the
ndash inward force or stress or tension that tends to pull molecules into the liquid
ndash force per unit area at the surface of the liquid which opposes expansion of the surface (dynecm or erg)
bull Surface Tension is the term used when we have an interface of a liquid or solid with air
bull Surface Active AgentsmdashConcentrate at the surface and reduce the ST of the liquid(Note Electrolytes (NaCl KCl) tend to concentrate in the bulk of the medium and cause an increase in ST)
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
74
Surface Tension Examplebull Surface tension and interfacial tension
are important considerations in pharmaceutical technology
bull Consider a beaker of liquid as being a beaker-full of molecules Molecules at the surface behave differently than those in the interior of the liquid
bull Molecule A in the interior is completely surrounded by identical molecules
bull These molecules are oriented in such a way that there are no residual forces
bull Molecules surrounding A exert equal forces in all direction and there is no tendency for molecules to be pulled one way or the other
bull With molecule B at the surface the situation is different
bull The molecules in the interior of the liquid tend to pull B into the interior
AB
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
75
Surface Active Agents - Basic Characteristics
bull Amphiphilic Molecules ndash Contain polar and non-polar portionsndash Are oriented at the surface and significantly
effect ST ndash Are not completely hydrophobic or hydrophilicndash Soluble in water and in oilndash Must be a balance between the polar and non-
polar moieties for the molecule to be an effective SAA
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
76
Sodium Lauryl Sulfate
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
77
Interfacial Tension
bull Definition The force per unit length at the interface between 2 immiscible liquids (Usually an emulsion in pharmacy)
bull Force measured with the Du Nuoy Tensiometer (dynescm)bull An INTERFACE is a boundary between two phasesbull ITmdashDetermines miscibility of liquidsbull Examples
ndash Waterliquid paraffinmdashIT = 57 dynescm (completely immiscible)ndash WaterethermdashIT = 107 dynescm (partially miscible)ndash WateralcoholmdashIT = 0 dynescm (completely miscible)THUS To improve miscibility of systems we must lower the ITHOW Use Surface Active Agents (Surfactants)
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
78
Surfactants at the interface
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
79
Schematic of a Surface Active Agent
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
80
Properties of Surfactants
bull Surfactants may be described variously by a number of different titles depending upon how they are used
bull 1 Detergents bull 2 Wetting Agents bull 3 Solubilizers bull 4 Emulgents
bull See Examples of Surfactants Given Earlier
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
81
The HLB Systembull Developed for and is important in surfactant selection
for emulsions etcbull The Hydrophilic-Lipophilic Balance System (HLB) bull System is based on the knowledge that all surfactants combine both
lipophilic and hydrophilic groups in the moleculebull The proportion of the weight percentages of these two portions will
determine the physical behavior of the surfactant bull Particularly applies to non-ionic surfactants bull The ratio determines their relative oil-soluble and water-soluble tendencies bull The balance between these two tendencies is the Hydrophilic-Lipophilic
Balance bull Indicates the relative size and strength of the two portions of the molecule bull In the HLB system each surfactant is assigned a numerical value which is
known as its HLB
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
82
HLB Systembull In general
--Empirical Scale(1-20 or 1-30) to describe the properties of non-ionic surfactants--Below 9mdashLipophilic--Above 11mdashHydrophilic
bull FunctionHLB1 -3 Antifoaming 4 -6 WO emulgent 7 -9 Wetting agent 8 -18 OW emulgent 13 -15 Detergent 10- 18 Solubilizer
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
83
Solubilizationbull The ability of surfactants to increase the solubility of substances
which normally only have limited solubility in the dispersion medium bull Surfactants are usually non-ionic and dispersion medium is water bull Known as micellar solubilization bull Used to bring into aqueous dispersion a wide range of substances
which are normally considered to be water insoluble
bull Mechanism of Solubilization bull Non-ionic surfactants act as solubilizing agents because of their
ability to form micelles bull Micelles are also formed by ionic surfactants as well but these are less
extensively used in solubilization (pharmaceutically) bull We showed earlier that when we add a surfactant to water it forms a
monomolecular layer on the surface of the water bull That is it concentrates at the interface because it is surface-active
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
84
Mechanism of Solubilization cont
bull Once the surface of the water has been covered by this monomolecular film the bulk of the solution then becomes saturated with the surfactant When saturation has been achieved the surfactant which up to this time has been in the monolayer form begins to form molecular aggregates
bull That is as the concentration of the surfactant is increased the surface becomes covered then the solution becomes saturated and finally molecular aggregates begin to form
bull These colloidal aggregates are known as micelles bull The molecules making up the micelles may be arranged in either a
spherical or in a laminar or palisade form bull All micelles have a hydrophobic core and hydrophilic exterior bull Micelles are separate and distinct entities from the dispersion
medium
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
85
Schematic of Micelle
Surfactant placed in water hydrophilic heads orient to outer water phase and longchain hydrophobic tails orient together
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
86
Critical Micelle Concentrationbull Definition The concentration of the surfactant at which the
micelles begin to form bull The CMC is usually characterized by a distinct change in the
physical properties of the solution bull For example
ndash 1 Surface tension ndash 2 Conductivity ndash 3 Osmotic pressure
bull Have a change in these parameters as a function of concentration bull A surfactant or surface active agent will concentrate at the surface
of liquid and reduce the surface tension of the liquid bull As the concentration of SAA is increased there is a steady
reduction in S T until the CMC is reached (See illustration) bull At this point with further increases in concentration there is no
further reduction in surface tension bull THUS the point of lowest surface tension is the CMC When no
more molecules of surfactant can align themselves on the surface there is no further reduction in surface tension Further addition of surfactant will result in the formation of micelles
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
87
Surface Tension and CMC
bull At CMC surface tension does not decrease anymorebull ST is experimentally determined by a Du Nuoy Tensiometer
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
88
Solubilization
bull SOLUBILIZATION bull Since the micelle core is essentially a paraffin-like
region it is capable of dissolving oil-soluble substances
bull The process of dissolving water-insoluble substances into solution by incorporating them into micelles is known as solubilization
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
89
Applications of Solubilizationbull To improve chemical stability
ndash Vitamin A less readily oxidized in the solubilized formndash The polar or hydrophilic head of the micelle provides protection
by preventing the OH- ion which catalyzes oxidation or hydrolysis from reaching the chemical to be protected
bull To improve drug absorptionndash Improvement orally and through the skin
bull To improve solubilityndash Vitamin A and D can be solubilized to give a water-dispersible
mixture that can be added to childrenrsquos formulasbull To reduce irritation
ndash Preparation of Iodophorsbull A solution of iodine in a surfactant (decreased irritation odor)
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
90
Wetting Agent
bull A surfactant that when dissolved in water lowers the advancing contact angle and aids in displacing air from surface with liquid phase (complete wetting vs insufficient wetting)
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
91
Natural Surfactants
bull In the GI Tractndash Bile salts
bull Deoxycholic Acidbull Chenodeoxycholic Acidbull Hyodeoxycholic Acidbull Cholic Acid
ndash Purpose
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
92
Natural Surfactants
bull In the lungndash Mixture of phospholipids proteins and lipidsndash Purpose
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
93
Exosurf Neonatal is a protein-free synthetic lung surfactant that dramatically reduces mortality and morbidity in premature infants suffering from or at risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency Exosurf Neonatal is effective in the treatment of premature infants suffering from or at the risk of Respiratory Distress Syndrome (RDS) due to surfactant deficiency (GSK)
Each 10mL vial containsDPPC 108mgCetyl Alcohol 12mgTyloxopol 8mgNaCl 47mgHClNaOH to adjust pH
Reconstitute with 8mL SWFIpH = 5-7Osm = 185 mOsmL
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-
94
Natural Surfactants
bull In the Eyendash Cornea ndash Tear Interface
ndash Aqueous Tear Film
ndash Surface of Tear Film
ndash Tear Film
- Pharmaceutics 356C
- Disperse or Polyphase Systems
- Slide 3
- Slide 4
- Types of Colloidal Systems
- Basis of Classification
- Basis of Classification
- Slide 8
- Preparation of Colloids
- Colloid Mill
- Properties of Colloids
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Shearing force required to produce velocity gradient between parallel plates of a block material
- Properties of Colloids - Flow
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Approximate Viscosities of Gels at RT (mPa s or cPs)
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Suspensions
- Suspension
- Pharmaceutical Suspensions
- Why Use Suspensions
- Stokersquos Law
- Stokersquos Law Applications
- Slide 40
- Methods of Preparation of Suspensions
- General Method of Preparation
- Slide 43
- Slide 44
- Interfacial Properties of Suspended Particles
- Slide 46
- Sedimentation Volumes
- Caking Diagram
- Examples of Official Suspensions
- Slide 50
- Suspending Agents
- Examples of Suspending Agents
- Slide 53
- Emulsions
- Emulsions
- Slide 56
- Why Use Emulsions
- To Maintain a Stable Emulsion
- Slide 59
- Emulsions for Internal Use
- Emulsions for External Use
- Stability of Emulsions
- Slide 63
- Slide 64
- Slide 65
- Preservation of Emulsions
- Emulsion Technology
- Slide 68
- Examples of Official Emulsions
- Other Emulsifying Agents
- Slide 71
- Surface Tension and Surfactants
- Surface Tension
- Surface Tension Example
- Surface Active Agents - Basic Characteristics
- Slide 76
- Interfacial Tension
- Surfactants at the interface
- Schematic of a Surface Active Agent
- Properties of Surfactants
- The HLB System
- HLB System
- Solubilization
- Mechanism of Solubilization cont
- Schematic of Micelle
- Critical Micelle Concentration
- Surface Tension and CMC
- Slide 88
- Applications of Solubilization
- Wetting Agent
- Natural Surfactants
- Slide 92
- Slide 93
- Slide 94
-