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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 1 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 CHEE 440 antacids, tetracycline HCl, indomethacin 2 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 : CHEE 440 calamine lotion (8% ZnO, 8% ZnOFeO) hydrocortisone 1 - 2.5 % betamethasone 0.1% 3 Opthalmics used to increase corneal contact time (provide a more sustained action) CHEE 440 4 Intramuscular formation of drug depots (sustained action) examples : CHEE 440 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 5 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 6 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 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 7 Settling 4 Fb ro3gs o 3 Fbuoyancy Ff 6roov Ffriction CHEE 440 8 Settling Cont’d eventually Ff = Fb and reach terminal velocity Stokes’ Law d 2 s o g v 18o CHEE 440 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) 9 Example fast will a 50 mm particle of density 1.3 g/cm3 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 mm? How CHEE 440 10 Physical Stability the large surface area of dispersed particles results in high surface free energy DG = SL DA thermodynamically unstable can reduce SL by using surfactants but not often can one reach DG = 0 particles tend to come together CHEE 440 11 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 CHEE 440 attraction > repulsion 12 Electrical Properties particles may become charged by adsorption of ionic species present in sol’n or preferential adsorption of OHionization of -COOH or -NH2 group ++++++ - hydroxyl ion solid CHEE 440 13 Electric Double Layer tightly bound diffuse +- + ++ - - + + +- ++ + - + + +- + ++ + electroneutral bulk gegenion zeta potential Nernst potential CHEE 440 14 Electrical Prop’s cont’d Nernst potential difference between the actual solid surface and the electroneutral bulk Zeta CHEE 440 potential potential potential difference between the tightly bound layer and the bulk governs electrostatic force of repulsion between solid particles 15 DLVO Theory total potential energy of interaction repulsion + 0 distance between particles - attraction CHEE 440 16 total potential energy of interaction repulsion + 0 distance between particles - attraction CHEE 440 [electrolyte] 17 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 18 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 19 Gels 2-phase gels single phase gels CHEE 440 ex. bentonite (hydrated aluminum silicate) 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. 20 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 21 Thixotropy slow recovery of viscosity lost through shearing applies only to shear thinning materials gel-sol-gel transformation (hysteresis) thixotropy gel state resists particle settling becomes fluid on shaking and then readily dispensed stress, s is desirable because : shear rate CHEE 440 22 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 23 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 24 Controlled Flocculation electrolytes most widely used reduce zeta potential » decrease force of repulsion change pH bridge formation alcohol reduction in zeta potential surfactants CHEE 440 form adsorbed monolayers on particle surface efficacy is dependent on charge, concentration 25 Controlled Flocculation polymers adsorb to particle surface bridging viscosity, thixotropy protective colloid action most effective CHEE 440 26 Structured Vehicles pseudoplastic or plastic dispersion medium examples methylcellulose, bentonite negatively charged increase viscosity CHEE 440 27 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 28 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 29 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 CHEE 440 parameters : redispersibility, particle size, zeta potential, rheology 30 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 allow suspension stored in fridge to come to room T before redispersing don’t CHEE 440 dilute reduces palatability, effectiveness of flocculating & suspending agents change in pH (stability) manufacturer will no longer accept legal responsibility for consequences 31