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Stability

This guide explores the stability of pharmaceutical products, detailing the extent to which they maintain their original properties during storage and use. It covers various degradation mechanisms, such as hydrolysis, oxidation, photo-degradation, and isomerization, along with the role of pH, temperature, and formulation interactions. The document also discusses the impact of catalysts, such as acids and bases, on drug stability, and introduces strategies for drug stabilization, including the use of antioxidants. Additionally, it explains shelf-life determination and key concepts in pharmaceutical kinetics.

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

  6. 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

  7. 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

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

  9. 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

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

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

  12. Effect of T • Arrhenius CHEE 440

  13. 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

  14. 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

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

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

  17. 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

  18. 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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