1. CHEE 440 1 Suspensions u coarse dispersion in which insoluble solid particles (10-50 µm) are dispersed in a liquid medium u routes of administration : ä oral, topical (lotions), parenteral (intramuscular), some ophthalmics u used for drugs that are unstable in solution (ex. antibiotics). u allow for the development of a liquid dosage form containing sufficient drug in a reasonably small volume

2. CHEE 440 2 Oral Suspensions u for elderly, children etc., liquid drug form is easier to swallow u liquid form gives flexibility in dose range u majority are aqueous with the vehicle flavored and sweetened. u supplies insoluble, distasteful substance in form that is pleasant to taste u examples ä antacids, tetracycline HCl, indomethacin

3. CHEE 440 3 Topical Suspension (Lotions) u most often are aqueous u intended to dry on skin after application (thin coat of medicianl component on skin surface) u label stating “to be shaken before use” and “for external use only” u examples :  calamine lotion (8% ZnO, 8% ZnO  FeO) ä hydrocortisone 1 - 2.5 % ä betamethasone 0.1%

4. CHEE 440 4 Opthalmics u used to increase corneal contact time (provide a more sustained action)

5. CHEE 440 5 Intramuscular u formation of drug depots (sustained action) u examples : ä Procaine penicillin G ä Insulin Zinc Suspension »addition of ZnCl 2 »suspended particles consist of a mixture of crystalline and amorphous zinc insulin (intermediate action) ä Extended Insulin Zinc Suspension »solely zinc insulin crystals  longer action ä contraceptive steroids

6. CHEE 440 6 Disadvantages u uniformity and accuracy of dose - not as good as tablet or capsule ä adequate particle dispersion u sedimentation, cake formation u product is liquid and bulky u formulation of an effective suspension is more difficult than for tablet or capsule

7. CHEE 440 7 Formulation Criteria u slow settling and readily dispersed when shaken u constant particle size throughout long periods of standing u pours readily and easily OR flows easily through a needle lotions : u spreads over surface but doesn’t run off u dry quickly, remain on skin, provide an elastic protective film containing the drug u acceptable odor and color common : therapeutic efficacy, chemical stability, esthetic appeal

8. CHEE 440 8 Settling F friction F buoyancy

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

10. CHEE 440 10 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. CHEE 440 11 Physical Stability  the large surface area of dispersed particles results in high surface free energy  G =  SL  A u thermodynamically unstable  can reduce  SL by using surfactants but not often can one reach  G = 0 u particles tend to come together

12. CHEE 440 12 Interfacial Phenomena u flocculation or caking ä determined by forces of attraction (van der Waals) versus forces of repulsion (electrostatic) u deflocculated ä repulsion> attraction ä affected by [electrolytes] u flocculated ä attraction > repulsion

13. CHEE 440 13 Electrical Properties u particles may become charged by ä adsorption of ionic species present in sol’n or preferential adsorption of OH - ä ionization of -COOH or -NH 2 group - - - - - - solid + + + + + + hydroxyl ion

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

15. CHEE 440 15 Electrical Prop’s cont’d u Nernst potential ä potential difference between the actual solid surface and the electroneutral bulk u Zeta potential ä potential difference between the tightly bound layer and the bulk ä governs electrostatic force of repulsion between solid particles

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

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

18. CHEE 440 18 Deflocculated Condition u repulsion energy is high u particles settle slowly u particles in sediment compressed over time to form a cake (aggregation) u difficult to re-suspend caked sediment by agitation u forms a turbid supernatant

19. CHEE 440 19 Flocculated Condition u weakly bonded to form fluffy conglomerates u 3-D structure (gel-like) u settle rapidly but will not form a cake - resist close-packing u easily re-suspended u forms a clear supernatant

20. CHEE 440 20 Gels u 2-phase gels ä ex. bentonite (hydrated aluminum silicate) u single phase gels ä entangled polymer chains in solution ä if increase concentration or decrease hydration of polymer chain, then form a gel ä factors influencing gel formation »temp., concentration, mol. wt.

21. CHEE 440 21 Rheology of Suspensions u flocculated particles in concentrated suspensions ä exhibit pseudoplastic or plastic flow »system resists flow until a yield stress is reached »below  substance is a solid u deflocculated systems exhibit Newtonian behavior

22. CHEE 440 22 Thixotropy u slow recovery of viscosity lost through shearing ä applies only to shear thinning materials ä gel-sol-gel transformation (hysteresis) u thixotropy is desirable because : ä gel state resists particle settling ä becomes fluid on shaking and then readily dispensed stress,  shear rate

23. CHEE 440 23 Viscosity u other considerations : ä increasing viscosity decreases rate of drug absorption ä extent of absorption is unaffected, but may reduce effectiveness of drugs with a low therapeutic window

24. CHEE 440 24 Formulation of Suspensions 2 common approaches : u use of a structured vehicle ä caking still a problem u flocculation ä no cake formation less common approach is to combine above

25. CHEE 440 25 Controlled Flocculation u electrolytes ä most widely used ä reduce zeta potential »decrease force of repulsion ä change pH ä bridge formation u alcohol ä reduction in zeta potential u surfactants ä form adsorbed monolayers on particle surface ä efficacy is dependent on charge, concentration

26. CHEE 440 26 Controlled Flocculation u polymers ä adsorb to particle surface ä bridging ä viscosity, thixotropy ä protective colloid action ä most effective

27. CHEE 440 27 Structured Vehicles u pseudoplastic or plastic dispersion medium u examples ä methylcellulose, bentonite u negatively charged u increase viscosity

28. CHEE 440 28 Combined Approach u possibility of incompatibilities of suspending agent and flocculating agent ä structured vehicles have negative charge ä incompatible if particle carries a negative charge

29. CHEE 440 29 Preparation of Suspensions u reduce drug powder to desired size u add drug and wetting agent to solution u prepare solution of suspending agent u add other ingredients ä electrolytes, color, flavor u homogenize medium u package

30. CHEE 440 30 Evaluating Suspensions u two parameters ä 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 u other parameters : ä redispersibility, particle size, zeta potential, rheology

31. CHEE 440 31 Other Considerations u temperature ä raising T often causes flocculation of sterically stabilised suspensions ä freezing may result in cake formation ä fluctuations in T may cause crystal growth ä allow suspension stored in fridge to come to room T before redispersing u don’t dilute ä reduces palatability, effectiveness of flocculating & suspending agents ä change in pH (stability) ä manufacturer will no longer accept legal responsibility for consequences