B. Amsden CHEE 440
Suspensions
• coarse dispersion in which insoluble solid particles (10-50 µm) are dispersed in a liquid medium
• routes of administration : oral, topical (lotions), parenteral (intramuscular), some
ophthalmics• used for drugs that are unstable in solution (ex. antibiotics).• allow for the development of a liquid dosage form containing
sufficient drug in a reasonably small volume
B. Amsden CHEE 440
Oral Suspensions
• for elderly, children etc., liquid drug form is easier to swallow• liquid form gives flexibility in dose range• majority are aqueous with the vehicle flavored and sweetened.• supplies insoluble, distasteful substance in form that is pleasant
to taste • examples
antacids, tetracycline HCl, indomethacin
B. Amsden CHEE 440
Topical Suspension (Lotions)
• most often are aqueous• intended to dry on skin after application (thin coat of medicianl
component on skin surface)• label stating “to be shaken before use” and “for external use only”• examples :
calamine lotion (8% ZnO, 8% ZnOFeO) hydrocortisone 1 - 2.5 % betamethasone 0.1%
B. Amsden CHEE 440
Ophthalmics
used to increase corneal contact time (provide a more sustained action)
B. Amsden CHEE 440
Intramuscular
• formation of drug depots (sustained action)
examples : Procaine penicillin G Insulin Zinc Suspension
• addition of ZnCl2
• suspended particles consist of a mixture of crystalline and amorphous zinc insulin (intermediate action)
Extended Insulin Zinc Suspension• solely zinc insulin crystals longer action
contraceptive steroids
B. Amsden CHEE 440
Disadvantages
• uniformity and accuracy of dose - not as good as tablet or capsule adequate particle dispersion
• sedimentation, cake formation• product is liquid and bulky• formulation of an effective suspension is more difficult than for
tablet or capsule
B. Amsden CHEE 440
Formulation Criteria
1. slow settling and readily dispersed when shaken
2. constant particle size throughout long periods of standing
3. pours readily and easily OR flows easily through a needle
specific to lotions :
1. spreads over surface but doesn’t run off
2. dry quickly, remain on skin, provide an elastic protective film containing the drug
3. acceptable odor and color
common : therapeutic efficacy, chemical stability, esthetic appeal
B. Amsden CHEE 440
Settling
Fb =43πro
3g ρs −ρo( )
Ff =6πroηov
Ffriction
Fbuoyancy
B. Amsden CHEE 440
Settling Cont’d
eventually Ff = Fb and reach terminal velocityStokes’ Law
v = terminal velocity (cm/s)d = diameter (cm)
ρs = density of dispersed phase
ρo = density of continuous phase
ηo = viscosity of continuous phase (Pa s)
v =d2 ρs −ρo( )g
18ηo
B. Amsden CHEE 440
Example
How fast will a 50 m particle of density 1.3 g/cm3 settle in water (η = 1.0 cP)? How fast will it settle in a 2 w/v% methylcellulose solution of viscosity = 120 cP? How fast will it settle if you reduce its particle size to 10 m?
B. Amsden CHEE 440
Physical Stability
• the large surface area of dispersed particles results in high surface free energy G = SL A
• thermodynamically unstable
• can reduce SL by using surfactants but not often can one reach G = 0
• particles tend to come together
B. Amsden CHEE 440
Interfacial Phenomena
flocculation or caking determined by forces of attraction (van der Waals)
versus forces of repulsion (electrostatic)
deflocculated repulsion> attraction affected by [electrolytes]
flocculated attraction > repulsion
B. Amsden CHEE 440
Electrical Properties
particles may become charged by adsorption of ionic species present in sol’n or preferential
adsorption of OH-
ionization of -COOH or -NH2 group
------
solid
++++++ hydroxyl ion
B. Amsden CHEE 440
Electric Double Layer
------
++++++
+-+
+-
+ - -++
-+
-- ++ - +
+
gegenion
Nernst potential
zeta potential
tightlybound
diffuse
electroneutralbulk
B. Amsden CHEE 440
Electrical Prop’s cont’d
Nernst potential potential difference between the actual solid surface and the
electroneutral bulk
Zeta potential potential difference between the tightly bound layer and the
bulk governs electrostatic force of repulsion between solid
particles
B. Amsden CHEE 440
DLVO Theory
0
+
-
distancebetweenparticles
repulsion
attraction
tota
l pot
enti
al e
nerg
y of
inte
ract
ion
B. Amsden CHEE 440
DLVO Theory
0
+
-
distancebetweenparticles
repulsion
attraction
tota
l pot
enti
al e
nerg
y of
inte
ract
ion
[electrolyte]
B. Amsden CHEE 440
Deflocculated Condition
• repulsion energy is high • particles settle slowly• particles in sediment compressed over time to form a
cake (aggregation)• difficult to re-suspend caked sediment by agitation• forms a turbid supernatant
B. Amsden CHEE 440
Flocculated Condition• weakly bonded to form fluffy conglomerates• 3-D structure (gel-like)• settle rapidly but will not form a cake - resist close-
packing• easily re-suspended• forms a clear supernatant
B. Amsden CHEE 440
Gels
2-phase gels ex. bentonite (hydrated aluminum silicate)
single phase gels entangled polymer chains in solution if increase concentration or decrease hydration of polymer
chain, then form a gel factors influencing gel formation
• temp., concentration, mol. wt.
B. Amsden CHEE 440
Rheology of Suspensions
flocculated particles in concentrated suspensions exhibit pseudoplastic or plastic flow
• system resists flow until a yield stress is reached
• below substance is a solid
deflocculated systems exhibit Newtonian behavior
B. Amsden CHEE 440
Thixotropy
slow recovery of viscosity lost through shearing applies only to shear thinning materials gel-sol-gel transformation (hysteresis)
thixotropy is desirable because : gel state resists particle settling becomes fluid on shaking and then readily dispensed
stre
ss,
shear rate
B. Amsden CHEE 440
Viscosity
other considerations : increasing viscosity decreases rate of drug
absorption extent of absorption is unaffected, but may reduce
effectiveness of drugs with a low therapeutic window
B. Amsden CHEE 440
Formulation of Suspensions
2 common approaches :
1. use of a structured vehicle caking still a problem
2. flocculation no cake formation
less common approach is to combine above
B. Amsden CHEE 440
Controlled Flocculation
electrolytes most widely used reduce zeta potential
• decrease force of repulsion change pH bridge formation
alcohol reduction in zeta potential
surfactants form adsorbed monolayers on particle surface efficacy is dependent on charge, concentration
B. Amsden CHEE 440
Controlled Flocculation
polymers adsorb to particle surface bridging viscosity, thixotropy protective colloid action most effective
B. Amsden CHEE 440
Structured Vehicles
• pseudoplastic or plastic dispersion medium • examples
methylcellulose, bentonite• negatively charged• increase viscosity
B. Amsden CHEE 440
Combined Approach
possibility of incompatibilities of suspending agent and flocculating agent
structured vehicles have negative charge incompatible if particle carries a negative charge
B. Amsden CHEE 440
Preparation of Suspensions
• reduce drug powder to desired size• add drug and wetting agent to solution• prepare solution of suspending agent• add other ingredients
electrolytes, color, flavor• homogenize medium• package
B. Amsden CHEE 440
Evaluating Suspensions
two parameters
sedimentation volume, F = Vu/Vo
• Vu = final sediment volume
• Vo = initial dispersion volume
• want F =1
degree of flocculation, = Vu/Vu
• Vufinal sediment volume of deflocculated
suspension
other parameters : redispersibility, particle size, zeta potential,
rheology
B. Amsden CHEE 440
Other Considerations
temperature raising T often causes flocculation of sterically stabilised
suspensions freezing may result in cake formation fluctuations in T may cause crystal growth