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.

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Presentation transcript:

CHEE 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

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

CHEE 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

CHEE 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

CHEE 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

CHEE 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

CHEE 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

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

CHEE 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

CHEE 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 - ]

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

CHEE Hydrolysis of Ester u base-catalyzed degradation

CHEE 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 M of X present, determine k 2 for this reaction.

CHEE 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

CHEE 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

CHEE 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

CHEE Example u 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.

CHEE 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

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

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

CHEE 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

CHEE 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

CHEE t 90 u zero-order u first order u second order

CHEE 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 = /day). how long will it take for the drug to degrade to 90% of its original concentration?