1. CHEE 440 1 Stability u 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 u types ä chemical ä physical ä microbiologic ä therapeutic ä toxicologic

2. CHEE 440 2 Degradation Mechanisms u Hydrolysis ä cleavage of bonds by action of water ä esters »procaine, atropine, aspirin ä amides »chloramphenicol, penicillin, cephalosporins

3. CHEE 440 3 Degradation Mechanisms u Oxidation ä molecule gains O or loses H ä susceptible compounds »phenols, aromatic amines, aldehydes, ethers, unsaturated aliphatic compounds ä examples »epinephrine, vitamin A, ascorbic acid

4. CHEE 440 4 Degradation Mechanisms u photodegradation ä light energy provides energy of activation ä reaction rate is independent of T ä photo-oxidation »catalyzed by light »nifedipine, colchicine, chlorpromazine, riboflavin

5. CHEE 440 5 Degradation Mechanisms u isomerisation ä conversion of a drug into its optical isomer ä enantiomers often have significantly different ADME and pharmacological action ä often catalyzed by acid or a base ä ex. tetracycline, pilocarpine, cephalosporin esters

6. CHEE 440 6 Degradation Mechanisms u Interactions between formulation compounds ä buffers »general acid-base catalysts »formation of amides u benzocaine and citric acid ä accelerated photodecomposition »riboflavin in presence of nonionic or anionic surfactant

7. CHEE 440 7 KINETICS u rates and orders of reactions u use ä more stable dosage forms »storage conditions ä prediction of shelf life u factors ä concentration ä temperature ä light ä catalysts

8. CHEE 440 8 Factors governing stability u Liquids ä pH ä temperature ä ionic strength ä solvent ä oxygen u Solids ä excipients

9. CHEE 440 9 EFFECT OF PH u Catalyst ä substance that influences rate of reaction but is not changed chemically ä either accelerates or inhibits ä does not change position of equilibrium  no change in  G o ä form a complex with reactant ä decomposes to form product + catalyst

10. CHEE 440 10 Acid-Base Catalysis u accelerated decomposition in presence of acid or base u often buffered therefore catalyzed u specific acid-base catalysis ä rate law contains [H 3 O + ] or [OH - ]

11. CHEE 440 11 Hydrolysis of Ester u in acidic solution ä ester = S ä water = W ä product = P

12. CHEE 440 12 Hydrolysis of Ester u base-catalyzed degradation

13. CHEE 440 13 Example u 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 k 2 for this reaction.

14. CHEE 440 14 Solvent catalysis u indicated by minimum region of k versus pH plot u can occur along with both acid and base catalyzed degradation log k obs pH

15. CHEE 440 15 General Acid-Base Catalysis u catalysis in buffered solution by other than H + or OH - u k obs vs pH diagram deviates from expected behavior ä streptozotocin in phosphate buffer

16. CHEE 440 16 Effect of T u any change in conditions produces different k ä Arrhenius ä A = Arrhenius factor »frequency of collisions ä E a = activation energy »minimum energy required per collision ä used in accelerated stability testing

17. CHEE 440 17 Example u 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.

18. CHEE 440 18 Effect of Solvent u affects rate constant ä polar solvents increase the rate of reaction where the products are more polar than the reactants ä nonpolar solvents increase the rate of reaction where the products are more nonpolar than the reactants

19. CHEE 440 19 Effect of Ionic Strength  ionic strength,  u influences rate constant

20. CHEE 440 20 Solid Dosage Forms u Stability concerns ä moisture ä hygroscopic excipients ä excipient catalyzed reactions »ex. Mg stearate lubricant

21. CHEE 440 21 Drug Stabilization u primarily hydrolysis ä strategies »optimum pH, buffer, solvent »refrigeration »complexation agent »dosage form u micelles, suspensions u oxidation ä antioxidants »undergo oxidation faster u sodium bisulfite, ascorbic acid u ascorbyl palmitate, butylated hydroxytoluene (BHT), vitamin E

22. CHEE 440 22 Shelf-Life u effective period of storage and use u t 90 ä time required to degrade 10% of the drug ä 90% drug still active ä determined by reaction kinetics

23. CHEE 440 23 t 90 u zero-order u first order u second order

24. CHEE 440 24 Example u An ophthalmic solution has a mydriatic drug present at a 5 mg/ml concentration. The drug degrades by first order kinetics (k 1 = 0.0005/day). how long will it take for the drug to degrade to 90% of its original concentration?