b. amsdenchee 440 suspensions coarse dispersion in which insoluble solid particles (10-50 µm) are...

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