1. B. AmsdenCHEE 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

2. B. AmsdenCHEE 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

3. B. AmsdenCHEE 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% ZnO  FeO)  hydrocortisone 1 - 2.5 %  betamethasone 0.1%

4. B. AmsdenCHEE 440 Ophthalmics used to increase corneal contact time (provide a more sustained action)

5. B. AmsdenCHEE 440 Intramuscular formation of drug depots (sustained action) examples :  Procaine penicillin G  Insulin Zinc Suspension addition of ZnCl 2 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

6. B. AmsdenCHEE 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

7. B. AmsdenCHEE 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

8. B. AmsdenCHEE 440 Settling F friction F buoyancy

9. B. AmsdenCHEE 440 Settling Cont’d eventually F f = F b and reach terminal velocity Stokes’ Law v = terminal velocity (cm/s) d = diameter (cm)  s = density of dispersed phase  o = density of continuous phase  o = viscosity of continuous phase (Pa s)

10. B. AmsdenCHEE 440 Example How fast will a 50  m particle of density 1.3 g/cm 3 settle in water (  = 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?

11. B. AmsdenCHEE 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

12. B. AmsdenCHEE 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

13. B. AmsdenCHEE 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 -NH 2 group - - - - - - solid + + + + + + hydroxyl ion

14. B. AmsdenCHEE 440 Electric Double Layer - - - - - - + + + + + + + - + + - + - - + + - + - - + + - + + gegenion Nernst potential zeta potential tightly bound diffuse electroneutral bulk

15. B. AmsdenCHEE 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

16. B. AmsdenCHEE 440 DLVO Theory 0 + - distance between particles repulsion attraction total potential energy of interaction

17. B. AmsdenCHEE 440 DLVO Theory 0 + - distance between particles repulsion attraction total potential energy of interaction [electrolyte] 

18. B. AmsdenCHEE 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

19. B. AmsdenCHEE 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

20. B. AmsdenCHEE 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.

21. B. AmsdenCHEE 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

22. B. AmsdenCHEE 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 stress,  shear rate

23. B. AmsdenCHEE 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

24. B. AmsdenCHEE 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

25. B. AmsdenCHEE 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

26. B. AmsdenCHEE 440 Controlled Flocculation polymers  adsorb to particle surface  bridging  viscosity, thixotropy  protective colloid action  most effective

27. B. AmsdenCHEE 440 Structured Vehicles pseudoplastic or plastic dispersion medium examples  methylcellulose, bentonite negatively charged increase viscosity

28. B. AmsdenCHEE 440 Combined Approach possibility of incompatibilities of suspending agent and flocculating agent  structured vehicles have negative charge  incompatible if particle carries a negative charge

29. B. AmsdenCHEE 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

30. B. AmsdenCHEE 440 Evaluating Suspensions two parameters  sedimentation volume, F = V u /V o V u = final sediment volume V o = initial dispersion volume want F =1  degree of flocculation,  = V u /V u  V u   final sediment volume of deflocculated suspension other parameters :  redispersibility, particle size, zeta potential, rheology

31. B. AmsdenCHEE 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