Organic Chemistry of Drug Degradation (Drug Discovery, Volume 29)

The Vast Majority Of Drugs Are Organic Molecular Entities. A Clear Understanding Of The Organic Chemistry Of Drug Degradation Is Essential To Maintaining The Stability, Efficacy, And Safety Of A Drug Product Throughout Its Shelf-life. During Analytical Method Development, Stability Testing, And Pharmaceutical Manufacturing Troubleshooting Activities, One Of The Frequently Occurring And Usually Challenging Events Would Be The Identification Of Drug Degradants And Understanding Of Drug Degradation Mechanisms And Pathways. This Book Is Written By A Veteran Of The Pharmaceutical Industry Who Has First-hand Experience In Drug Design And Development, Drug Degradation Mechanism Studies, Analytical Development, And Manufacturing Process Troubleshooting And Improvement.^ The Author Discusses Various Degradation Pathways With An Emphasis On The Mechanisms Of The Underlying Organic Chemistry, Which Should Aid Greatly In The Efforts Of Degradant Identification, Formulation Development, Analytical Development, And Manufacturing Process Improvement. Organic Reactions That Are Significant In Drug Degradation Will First Be Reviewed And Then Illustrated By Examples Of Drug Degradation Reported In The Literature. The Author Brings The Book To A Close With A Final Chapter Dedicated To The Strategy For Rapid Elucidation Of Drug Degradants With Regard To The Current Regulatory Requirements And Guidelines. One Chapter That Should Be Given Special Attention Is Chapter 3, Oxidative Degradation. Oxidative Degradation Is One Of The Most Common Degradation Pathways But Perhaps The Most Complex One. This Chapter Employs More Than Sixty Drug Degradation Case Studies With In-depth Discussion In Regard To Their Unique Degradation Pathways.^ With The Increasing Regulatory Requirements On The Quality And Safety Of Pharmaceutical Products, In Particular With Regard To Drug Impurities And Degradants, The Book Will Be An Invaluable Resource For Pharmaceutical And Analytical Scientists Who Engage In Formulation Development, Analytical Development, Stability Studies, Degradant Identification, And Support Of Manufacturing Process Improvement. In Addition, It Will Also Be Helpful To Scientists Engaged In Drug Discovery And Development As Well As In Drug Metabolism Studies.-- Min Li. Includes Bibliographical References And Index. Mode Of Access: World Wide Web. Cover......Page 1 Copyright......Page 5 Contents......Page 12 1.1 Drug Impurities, Degradants and the Importanceof Understanding Drug Degradation Chemistry......Page 20 1.2 Characteristics of Drug Degradation Chemistryand the Scope of this Book......Page 22 1.3.1 Thermodynamics and Kinetics of Chemical Reactions......Page 24 1.3.2 Reaction Orders, Half-lives and Prediction of DrugProduct Shelf-lives......Page 26 1.3.3 Key Elements in Solid State Degradation......Page 28 1.3.4 Role of Moisture in Solid State Degradation and pH inthe Microenvironment of the Solid State......Page 29 1.4 Organization of the Book......Page 30 References......Page 33 2.1 Overview of Hydrolytic Degradation......Page 35 2.2.1 Drugs Containing an Ester Group......Page 39 2.2.2 Drugs Containing a Lactone Group......Page 42 2.2.3 Drugs Containing an Amide Group......Page 43 2.2.4 b-Lactam Antibiotics......Page 45 2.2.5 Carbamates......Page 49 2.2.6 Phosphates and Phosphoramides......Page 51 2.2.7 Sulfonamide Drugs......Page 53 2.2.8 Imides and Sulfonylureas......Page 54 2.2.9 Imines (Schiff Bases) and Deamination......Page 55 2.2.10 Acetal and Hemiacetal Groups......Page 59 2.2.11 Ethers and Epoxides......Page 60 2.3 Esterification, Transesterification and Formationof an Amide Linkage......Page 62 References......Page 63 3.1 Introduction......Page 67 3.2.1 Origin of Free Radicals: Fenton Reaction and Udenfriend Reaction......Page 68 3.2.2 Origin of Free Radicals: Homolytic Cleavage of Peroxides by Thermolysis and Heterolytic Cleavage of Peroxides by Metal Ion Oxidation......Page 72 3.2.3 Autooxidative Radical Chain Reactions and Their Kinetic Behavior......Page 73 3.2.4 Additional Reactions of Free Radicals......Page 75 3.3.1 Heterolytic Cleavage of Peroxides and Oxidation of Amines, Sulfides, and Related Species......Page 76 3.3.2 Heterolytic Cleavage of Peroxides and Formation of Epoxides......Page 78 3.4 Carbanion/enolate-mediated Autooxidation (Base-catalyzed Autooxidation)......Page 80 3.5.1 Allylic- and Benzylic-type Positions Susceptible to Hydrogen Abstraction by Free Radicals......Page 81 3.5.2 Double Bonds Susceptible to Addition by Hydroperoxides......Page 87 3.5.3 Tertiary Amines......Page 90 3.5.4 Primary and Secondary Amines......Page 95 3.5.5 Enamines and Imines (Schiff Bases)......Page 98 3.5.6 Thioethers (Organic Sulfides), Sulfoxides, Thiols and Related Species......Page 99 3.5.7 Examples of Carbanion/enolate-mediated Autooxidation......Page 102 3.5.8 Oxidation of Drugs Containing Alcohol, Aldehyde, and Ketone Functionalities......Page 106 3.5.9 Oxidation of Aromatic Rings: Formation of Phenols, Polyphenols, and Quinones......Page 111 3.5.10 Oxidation of Heterocyclic Aromatic Rings......Page 115 3.5.11 Miscellaneous Oxidative Degradations......Page 118 References......Page 120 4.1.1 Dehydration......Page 129 4.1.2 Dehydrohalogenation......Page 133 4.1.3 Hofmann Elimination......Page 135 4.1.4 Miscellaneous Eliminations......Page 136 4.2 Decarboxylation......Page 137 4.3 Nucleophilic Conjugate Addition and Retro-nucleophilic Conjugate Addition......Page 140 4.4.1 Aldol Condensation......Page 143 4.4.2 Retro-aldol Reaction......Page 145 4.5.1 Tautomerization......Page 146 4.5.2 Racemization......Page 147 4.5.4 Cis-trans Isomerization......Page 148 4.5.5 N,O-Acyl Migration......Page 151 4.5.6 Rearrangement via Ring Expansion......Page 152 4.5.7 Intramolecular Cannizzaro Rearrangement......Page 155 4.6.1 Formation of Diketopiperazine (DKP)......Page 156 4.6.2 Other Cyclization Reactions......Page 157 4.7 Dimerization/Oligomerization......Page 158 4.8.1 Diels–Alder Reaction......Page 163 4.8.2 Degradation via Reduction or Disproportionation......Page 164 References......Page 165 5.1.1 Degradation via the Maillard Reaction......Page 169 5.1.2 Drug–Excipient Interaction via Ester and Amide Linkage Formation......Page 172 5.1.4 Degradation Caused by Magnesium Stearate......Page 173 5.1.5 Degradation Caused by Interaction between API and Counter Ions and between Two APIs......Page 175 5.1.6 Other Cases of Drug–Excipient Interactions......Page 176 5.2.1 Degradation Caused by Hydrogen Peroxide, Formaldehyde, and Formic Acid......Page 177 5.2.2 Degradation Caused by Residual Impurities in Polymeric Excipients......Page 178 5.3 Degradation Caused by Degradants of Excipients......Page 179 5.4 Degradation Caused by Impurities from Packaging Materials......Page 180 References......Page 181 6.1 Overview......Page 184 6.2 Non-oxidative Photochemical Degradation......Page 185 6.2.1 Photodecarboxylation: Photodegradation of Drugs Containing a 2-Arylpropionic Acid Moiety......Page 186 6.2.2 Photoisomerization......Page 189 6.2.3 Aromatization of 1,4-Dihydropyridine Class of Drugs......Page 193 6.2.4 Dehalogenation of Aryl Halides......Page 195 6.2.5 Cyclization in Polyaromatic Ring Systems......Page 199 6.2.6 Photochemical Elimination......Page 201 6.2.7 Photodimerization and Photopolymerization......Page 203 6.2.8 Photochemistry of Ketones: Norris Type I and II Photoreactions......Page 204 6.3 Oxidative Photochemical Degradation......Page 206 6.3.1 Type I Photosensitized Oxidation: Degradation via Radical Formation and Electron Transfer......Page 207 6.3.2 Type II Photosensitized Oxidation: Degradation Caused by Singlet Oxygen......Page 208 6.3.3 Degradation Pathways via Reaction with Singlet Oxygen......Page 209 References......Page 213 7.1 Overview......Page 217 7.2.1 Hydrolysis and Rearrangement of Peptide Backbone Caused by the Asp Residue......Page 218 7.2.2 Various Degradation Pathways Caused by Deamidation and Formation of Succinimide Intermediate......Page 221 7.2.4 Oxidation of Side Chains of Cys, Met, His, Trp, and Tyr......Page 223 7.2.5 Oxidation of Side Chains of Arg, Pro, and Lys......Page 228 7.2.6 b-Elimination......Page 230 7.2.7 Crosslinking, Dimerization, and Oligomerization......Page 232 7.2.8 The Maillard Reaction......Page 233 7.2.10 Miscellaneous Degradation Pathways......Page 234 7.3 Degradation of Carbohydrate-based Biological Drugs......Page 235 7.4.1 Hydrolytic Degradation of Phosphodiester Bonds......Page 237 7.4.2 Oxidative Degradation of Nucleic Acid Bases......Page 239 References......Page 241 8.1 Overview......Page 246 8.2 Practical Considerations of Employing LC-MSn for Structural Elucidation of Degradants at Trace Levels......Page 248 8.2.2 Nomenclature, Ionization Modes and Determination of Parent Ions......Page 249 8.2.3 Fragmentation and LC-MSn Molecular Fingerprinting......Page 252 8.3 Brief Discussion of the Use of Multi-dimensional NMR in Structure Elucidation of Trace Level Impurities......Page 258 8.4 Performing Meaningful Stress Studies......Page 259 8.4.1 Generating Relevant Degradation Profiles......Page 260 8.5.2 Proposing Type of Degradation Based on LC-MSn Analysis......Page 264 8.5.3 Design of Stress Studies According to Presumed Degradation Type......Page 266 8.5.5 Case Study 1: Elucidation of a Novel Degradation Pathway for Drug Products Containing Betamethasone Dipropionate and Similar Corticosteroidal 17,21-Diesters......Page 267 8.5.6 Case Study 2: Rapid Identification of Three Betamethasone Sodium Phosphate Isomeric Degradants – Use of Enzymatic Transformation When a Direct MSn Fingerprint Match is not Available......Page 270 8.5.7 Case Study 3: Identification of an Impurity in Betamethasone 17-Valerate Drug Substance – Structure Prediction When an Exact MSn Fingerprint Match is not Available......Page 275 References......Page 277 9.2 Degradation Controlling Strategies Versus Multiple Degradation Pathways and Mechanisms......Page 281 9.3 Design and Selection of a Drug Candidate Considering Drug Degradation Pathways and Mechanisms......Page 282 9.4 Implication of the Udenfriend Reaction and Avoidance of a Formulation Design that may Fall into the ‘‘Udenfriend Trap’’......Page 284 9.5 Control of Oxygen Content in Drug Products......Page 286 9.7 Use of Chelating Agents to Control Transition Metal Ion-mediated Autooxidation......Page 287 9.8 Control of Moisture in Solid Dosage Forms......Page 288 9.10 Control of Photochemical Degradation Using Pigments, Colorants, and Additives......Page 289 9.12 Use of Formulations that Shield APIs from Degradation......Page 290 9.14 Selection of Proper Packaging Materials......Page 291 9.15 Concluding Remarks......Page 292 References......Page 293 Subject Index......Page 297 "The vast majority of drugs are organic molecular entities. A clear understanding of the organic chemistry of drug degradation is essential to maintaining the stability, efficacy, and safety of a drug product throughout its shelf-life. During analytical method development, stability testing, and pharmaceutical manufacturing troubleshooting activities, one of the frequently occurring and usually challenging events would be the identification of drug degradants and understanding of drug degradation mechanisms and pathways. This book is written by a veteran of the pharmaceutical industry who has first-hand experience in drug design and development, drug degradation mechanism studies, analytical development, and manufacturing process troubleshooting and improvement. The author discusses various degradation pathways with an emphasis on the mechanisms of the underlying organic chemistry, which should aid greatly in the efforts of degradant identification, formulation development, analytical development, and manufacturing process improvement. Organic reactions that are significant in drug degradation will first be reviewed and then illustrated by examples of drug degradation reported in the literature. The author brings the book to a close with a final chapter dedicated to the strategy for rapid elucidation of drug degradants with regard to the current regulatory requirements and guidelines. One chapter that should be given special attention is Chapter 3, Oxidative Degradation. Oxidative degradation is one of the most common degradation pathways but perhaps the most complex one. This chapter employs more than sixty drug degradation case studies with in-depth discussion in regard to their unique degradation pathways. With the increasing regulatory requirements on the quality and safety of pharmaceutical products, in particular with regard to drug impurities and degradants, the book will be an invaluable resource for pharmaceutical and analytical scientists who engage in formulation development, analytical development, stability studies, degradant identification, and support of manufacturing process improvement. In addition, it will also be helpful to scientists engaged in drug discovery and development as well as in drug metabolism studies."-- Provided by publisher