Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 eventually Ff = Fb and reach terminal velocity Stokes’ Law d 2 (rs - ro )g v= 18ho 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) B. Amsden 4 3 F = Fbuoyancy b 3 pro g(rs - ro ) CHEE 440 Ffriction Ff = 6pro ho v 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 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 + + + + + + - hydroxyl ion solid B. Amsden CHEE 440 Electric Double Layer tightly bound + + + + + + - diffuse - - + - + + + + + - + - + + zeta potential Nernst potential B. Amsden CHEE 440 + + electroneutral bulk 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 Debye-Huckel length: B. Amsden æ ee RT =ç 2 o k ç F å ci Zi è 1 ( CHEE 440 ) ö ÷ ÷ ø 1 2 total potential energy of interaction DLVO Theory repulsion + 0 VT = VA +VR - VA = - attraction B. Amsden Aa 12H VR = 2p aeeoyo2 exp (-k H ) CHEE 440 Distance (H) between particles total potential energy of interaction DLVO Theory repulsion + 0 distance between particles attraction B. Amsden [electrolyte] 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 closepacking • 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 s 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) stress, s thixotropy is desirable because : gel state resists particle settling becomes fluid on shaking and then readily dispensed 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 B. Amsden CHEE 440