Stability of Drugs and Dosage Forms Sumie Yoshioka

Contents
1. Introduction ............................................................. 1
2. Chemical Stability of Drug Substances .................................... 3
2.1. Pathwaysof Chemical Degradation ................................... 4
2.1.1. Hydrolysis ................................................. 5
2.1.1.1. Esters ............................................ 5
2.1.1.2. Amides ........................................... 10
2.1.1.3. Barbiturates, Hydantoins, and Imides ............... 12
2.1.1.4. Schiff Base and Other Reactions Involving
Carbon-Nitrogen Bond Cleavage ................... 15
2.1.1.5. OtherHydrolysisReactions ......................... 17
2.1.2. Dehydration ............................................... 18
2.1.3. IsomerizationandRacemization ............................ 18
2.1.4. Decarboxylation and Elimination ........................... 22
2.1.5. Oxidation ................................................ 24
2.1.6. Photodegradation ......................................... 28
2.1.7. Drug-Excipientand Drug-Drug Interactions ................. 29
2.1.7.1. Reactions of Bisulfite, an Antioxidant ............ 30
2.1.7.2. Reaction of Amines with Reducing Sugars .......... 30
2.1.7.3. Transesterification Reactions ..................... 33
2.2. Factors Affecting Chemical Stability ................................... 34
2.2.1. Basic Kinetic Principles ..................................... 34
2.2.2. The Role of MolecularStructure ............................. 37
2.2.3. Rate Equations and Kinetic Models .......................... 38
2.2.3.1. Kinetic Models to Describe Drug Degradation
inSolution ........................................ 39
2.2.3.2. Kinetic Models Describing Chemical Drug
Degradationin the Solid State ..................... 52
2.2.3.3. Calculationof Rate Constants byFittingtoKineticModels 61
2.2.4. Temperature ............................................... 61
2.2.4.1. General Principles .................................. 61
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