Suspensions

1. 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 CHEE 440

2. 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 CHEE 440

3. 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% CHEE 440

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

5. 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 CHEE 440

6. 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 CHEE 440

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

8. Settling Fbuoyancy Ffriction CHEE 440

9. Settling Cont’d • eventually Ff = Fb 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) CHEE 440

10. Example • How fast will a 50 mm particle of density 1.3 g/cm3 settle in water (h = 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 mm? CHEE 440

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

12. 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 CHEE 440

13. 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 + - + - + - + - + - + hydroxyl ion - solid CHEE 440

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

15. 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 CHEE 440

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

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

18. 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 CHEE 440

19. 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 CHEE 440

20. 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. CHEE 440

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

22. 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, s shear rate CHEE 440

23. 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 CHEE 440

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

25. 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 CHEE 440

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

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

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

29. 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 CHEE 440

30. 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 • Vufinal sediment volume of deflocculated suspension • other parameters : • redispersibility, particle size, zeta potential, rheology CHEE 440

31. 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 CHEE 440