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Stability

Stability. The extent to which a product retains, within specified limits, and throughout its period of storage and use, the same properties and characteristics it possessed when manufactured. Types chemical physical microbiologic therapeutic toxicologic. Degradation Mechanisms.

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Stability

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  1. Stability • The extent to which a product retains, within specified limits, and throughout its period of storage and use, the same properties and characteristics it possessed when manufactured. • Types • chemical • physical • microbiologic • therapeutic • toxicologic CHEE 440

  2. Degradation Mechanisms • Hydrolysis • cleavage of bonds by action of water • esters • procaine, atropine, aspirin • amides • chloramphenicol, penicillin, cephalosporins • Oxidation • molecule gains O or loses H • susceptible compounds • phenols, aromatic amines, aldehydes, ethers, unsaturated aliphatic compounds • examples • epinephrine, vitamin A, ascorbic acid CHEE 440

  3. Degradation Mechanisms • photo-degradation • light energy provides energy of activation • reaction rate is independent of T • photo-oxidation • catalyzed by light • nifedipine, colchicine, chlorpromazine, riboflavin • isomerisation • conversion of a drug into its optical isomer • enantiomers often have significantly different ADME and pharmacological action • often catalyzed by acid or a base • ex. tetracycline, pilocarpine, cephalosporin esters CHEE 440

  4. Degradation Mechanisms • Interactions between formulation compounds • buffers • general acid-base catalysts • formation of amides • benzocaine and citric acid • accelerated photodecomposition • riboflavin in presence of nonionic or anionic surfactant CHEE 440

  5. Kinetics • rates and orders of reactions • use • more stable dosage forms • storage conditions • prediction of shelf life • factors • concentration • temperature • light • catalysts CHEE 440

  6. Factors governing stability • Liquids • pH • temperature • ionic strength • solvent • oxygen • Solids • excipients CHEE 440

  7. Effect Of pH • Catalyst • substance that influences rate of reaction but is not changed chemically • either accelerates or inhibits reaction • does not change position of equilibrium • no change in DGo • forms a complex with reactant • decomposes to form product + catalyst CHEE 440

  8. Acid-Base Catalysis • accelerated decomposition in presence of acid or base • often buffered therefore catalyzed • specific acid-base catalysis • rate law contains [H3O+] or [OH-] CHEE 440

  9. Hydrolysis of Ester • acid-catalyzed degradation • ester = S • water = W • product = P • base-catalyzed degradation CHEE 440

  10. Example • Drug X degrades by a base-catalyzed process in a buffer of pH 9 at room T. If the initial concentration of X was 0.1 M and after 4 days there was 0.099 M of X present, determine k2 for this reaction. CHEE 440

  11. Solvent catalysis • indicated by minimum region of k versus pH plot • can occur along with both acid and base catalyzed degradation CHEE 440

  12. General Acid-Base Catalysis • catalysis in buffered solution by other than H+ or OH- • kobs vs pH diagram deviates from expected behavior • streptozotocin in phosphate buffer CHEE 440

  13. Effect of T • Arrhenius CHEE 440

  14. Example • The rate constant for the decomposition of expensinin at 120 °C is 1.173 hr-1 and at 140 °C is 4.86 hr-1. Calculate the activation energy and the Arrhenius factor for this reaction. CHEE 440

  15. Other Influences • Solvent • polar solvents increase the rate of reaction where the products are more polar than the reactants • nonpolar solvents increase the rate of reaction where the products are more nonpolar than the reactants • Ionic strength, m • influences rate constant CHEE 440

  16. Solid Dosage Forms • Stability concerns • moisture • hygroscopic excipients • excipient catalyzed reactions • ex. Mg stearate lubricant CHEE 440

  17. Drug Stabilization • primarily hydrolysis • strategies • optimum pH, buffer, solvent • refrigeration • complexation agent • dosage form • emulsion, suspensions • oxidation • antioxidants • undergo oxidation faster • sodium bisulfite, ascorbic acid • ascorbyl palmitate, butylated hydroxytoluene (BHT), vitamin E CHEE 440

  18. Shelf-Life • effective period of storage and use • t90 • time required to degrade 10% of the drug • 90% drug still active • determined by reaction kinetics zero order first order 2nd order CHEE 440

  19. Example • An ophthalmic solution has a mydriatic drug present at a 5 mg/ml concentration. The drug degrades by first order kinetics (k1 = 0.0005/day).What is its shelf life? CHEE 440

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