B. AmsdenCHEE 440 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

B. AmsdenCHEE 440 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

B. AmsdenCHEE 440 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

B. AmsdenCHEE 440 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

B. AmsdenCHEE 440 Factors governing stability Liquids  pH  temperature  ionic strength  solvent  oxygen Solids  excipients

B. AmsdenCHEE 440 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  G o  forms a complex with reactant decomposes to form product + catalyst

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

B. AmsdenCHEE 440 Hydrolysis of Ester acid-catalyzed degradation  ester = S  water = W  product = P base-catalyzed degradation

B. AmsdenCHEE 440 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 M of X present, determine k 2 for this reaction.

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

B. AmsdenCHEE 440 General Acid-Base Catalysis catalysis in buffered solution by other than H + or OH - k obs vs pH diagram deviates from expected behavior  ex. streptozotocin in phosphate buffer

B. AmsdenCHEE 440 Effect of T  Arrhenius

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

B. AmsdenCHEE 440 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,   influences rate constant

B. AmsdenCHEE 440 Solid Dosage Forms Stability concerns  moisture  hygroscopic excipients  excipient catalyzed reactions ex. Mg stearate lubricant

B. AmsdenCHEE 440 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

B. AmsdenCHEE 440 Shelf-Life effective period of storage and use t 90  time required to degrade 10% of the drug  90% drug still active  determined by reaction kinetics first order2nd orderzero order

B. AmsdenCHEE 440 Example An ophthalmic solution has a mydriatic drug present at a 5 mg/ml concentration. The drug degrades by first order kinetics (k 1 = /day). What is its shelf life?