Organic chemistry of drug degradation [electronic resource] / Min Li.
- Li, Min, 1962-
- Cambridge, U.K. : RSC Publishing, 
- Copyright Date:
- Physical Description:
- 1 online resource (xvii, 287 pages) : illustrations
- RSC Drug Discovery Series ; no. 29
- Machine generated contents note: ch. 1 Introduction -- 1.1.Drug Impurities, Degradants and the Importance of Understanding Drug Degradation Chemistry -- 1.2.Characteristics of Drug Degradation Chemistry and the Scope of this Book -- 1.3.Brief Discussion of Topics that are Outside the Main Scope of this Book -- 1.3.1.Thermodynamics and Kinetics of Chemical Reactions -- 1.3.2.Reaction Orders, Half-lives and Prediction of Drug Product Shelf-lives -- 1.3.3.Key Elements in Solid State Degradation -- 1.3.4.Role of Moisture in Solid State Degradation and pH in the Microenvironment of the Solid State -- 1.4.Organization of the Book -- References -- ch. 2 Hydrolytic Degradation -- 2.1.Overview of Hydrolytic Degradation -- 2.2.Drugs Containing Functional Groups/Moieties Susceptible to Hydrolysis -- 2.2.1.Drugs Containing an Ester Group -- 2.2.2.Drugs Containing a Lactone Group -- 2.2.3.Drugs Containing an Amide Group -- 2.2.4.β-Lactam Antibiotics -- 2.2.5.Carbamates -- 2.2.6.Phosphates and Phosphoramides -- 2.2.7.Sulfonamide Drugs -- 2.2.8.Imides and Sulfonylureas -- 2.2.9.Imines (Schiff Bases) and Deamination -- 2.2.10.Acetal and Hemiacetal Groups -- 2.2.11.Ethers and Epoxides -- 2.3.Esterification, Transesterification and Formation of an Amide Linkage -- References -- ch. 3 Oxidative Degradation -- 3.1.Introduction -- 3.2.Free Radical-mediated Autooxidation -- 3.2.1.Origin of Free Radicals: Fenton Reaction and Udenfriend Reaction -- 3.2.2.Origin of Free Radicals: Homolytic Cleavage of Peroxides by Thermolysis and Heterolytic Cleavage of Peroxides by Metal Ion Oxidation -- 3.2.3.Autooxidative Radical Chain Reactions and Their Kinetic Behavior -- 3.2.4.Additional Reactions of Free Radicals -- 3.3.Non-radical Reactions of Peroxides -- 3.3.1.Heterolytic Cleavage of Peroxides and Oxidation of Amines, Sulfides, and Related Species -- 3.3.2.Heterolytic Cleavage of Peroxides and Formation of Epoxides -- 3.4.Carbanion/enolate-mediated Autooxidation (Base-catalyzed Autooxidation) -- 3.5.Oxidation Pathways of Drugs with Various Structures -- 3.5.1.Allylic- and Benzylic-type Positions Susceptible to Hydrogen Abstraction by Free Radicals -- 3.5.2.Double Bonds Susceptible to Addition by Hydroperoxides -- 3.5.3.Tertiary Amines -- 3.5.4.Primary and Secondary Amines -- 3.5.5.Enamines and Imines (Schiff Bases) -- 3.5.6.Thioethers (Organic Sulfides), Sulfoxides, Thiols and Related Species -- 3.5.7.Examples of Carbanion/enolate-mediated Autooxidation -- 3.5.8.Oxidation of Drugs Containing Alcohol, Aldehyde, and Ketone Functionalities -- 3.5.9.Oxidation of Aromatic Rings: Formation of Phenols, Polyphenols, and Quinones -- 3.5.10.Oxidation of Heterocyclic Aromatic Rings -- 3.5.11.Miscellaneous Oxidative Degradations -- References -- ch. 4 Various Types and Mechanisms of Degradation Reactions -- 4.1.Elimination -- 4.1.1.Dehydration -- 4.1.2.Dehydrohalogenation -- 4.1.3.Hofmann Elimination -- 4.1.4.Miscellaneous Eliminations -- 4.2.Decarboxylation -- 4.3.Nucleophilic Conjugate Addition and Retro-nucleophilic Conjugate Addition -- 4.4.Aldol Condensation and Retro-aldol -- 4.4.1.Aldol Condensation -- 4.4.2.Retro-aldol Reaction -- 4.5.Isomerization and Rearrangement -- 4.5.1.Tautomerization -- 4.5.2.Racemization -- 4.5.3.Epimerization -- 4.5.4.Cis-trans Isomerization -- 4.5.5.N,O-Acyl Migration -- 4.5.6.Rearrangement via Ring Expansion -- 4.5.7.Intramolecular Cannizzaro Rearrangement -- 4.6.Cyclization -- 4.6.1.Formation of Diketopiperazine (DKP) -- 4.6.2.Other Cyclization Reactions -- 4.7.Dimerization/Oligomerization -- 4.8.Miscellaneous Degradation Mechanisms -- 4.8.1.Diels--Alder Reaction -- 4.8.2.Degradation via Reduction or Disproportionation -- References -- ch. 5 Drug--Excipient Interactions and Adduct Formation -- 5.1.Degradation Caused by Direct Interaction between Drugs and Excipients -- 5.1.1.Degradation via the Maillard Reaction -- 5.1.2.Drug--Excipient Interaction via Ester and Amide Linkage Formation -- 5.1.3.Drug--Excipient Interaction via Transesterification -- 5.1.4.Degradation Caused by Magnesium Stearate -- 5.1.5.Degradation Caused by Interaction between API and Counter Ions and between Two APIs -- 5.1.6.Other Cases of Drug--Excipient Interactions -- 5.2.Degradation Caused by Impurity of Excipients -- 5.2.1.Degradation Caused by Hydrogen Peroxide, Formaldehyde, and Formic Acid -- 5.2.2.Degradation Caused by Residual Impurities in Polymeric Excipients -- 5.3.Degradation Caused by Degradants of Excipients -- 5.4.Degradation Caused by Impurities from Packaging Materials -- References -- ch. 6 Photochemical Degradation -- 6.1.Overview -- 6.2.Non-oxidative Photochemical Degradation -- 6.2.1.Photodecarboxylation: Photodegradation of Drugs Containing a 2-Arylpropionic Acid Moiety -- 6.2.2.Photoisomerization -- 6.2.3.Aromatization of 1,4-Dihydropyridine Class of Drugs -- 6.2.4.Dehalogenation of Aryl Halides -- 6.2.5.Cyclization in Polyaromatic Ring Systems -- 6.2.6.Photochemical Elimination -- 6.2.7.Photodimerization and Photopolymerization -- 6.2.8.Photochemistry of Ketones: Norris Type I and II Photoreactions -- 6.3.Oxidative Photochemical Degradation -- 6.3.1.Type I Photosensitized Oxidation: Degradation via Radical Formation and Electron Transfer -- 6.3.2.Type II Photosensitized Oxidation: Degradation Caused by Singlet Oxygen -- 6.3.3.Degradation Pathways via Reaction with Singlet Oxygen -- References -- ch. 7 Chemical Degradation of Biological Drugs -- 7.1.Overview -- 7.2.Chemical Degradation of Protein Drugs -- 7.2.1.Hydrolysis and Rearrangement of Peptide Backbone Caused by the Asp Residue -- 7.2.2.Various Degradation Pathways Caused by Deamidation and Formation of Succinimide Intermediate -- 7.2.3.Hinge Region Hydrolysis in Antibodies -- 7.2.4.Oxidation of Side Chains of Cys, Met, His, Trp, and Tyr -- 7.2.5.Oxidation of Side Chains of Arg, Pro, and Lys -- 7.2.6.β-Elimination -- 7.2.7.Crosslinking, Dimerization, and Oligomerization -- 7.2.8.The Maillard Reaction -- 7.2.9.Degradation via Truncation of a N-Terminal Dipeptide Sequence through DKP Formation -- 7.2.10.Miscellaneous Degradation Pathways -- 7.3.Degradation of Carbohydrate-based Biological Drugs -- 7.4.Degradation of DNA and RNA Drugs -- 7.4.1.Hydrolytic Degradation of Phosphodiester Bonds -- 7.4.2.Oxidative Degradation of Nucleic Acid Bases -- References -- ch. 8 Strategies for Elucidation of Degradant Structures and Degradation Pathways -- 8.1.Overview -- 8.2.Practical Considerations of Employing LC-MSn for Structural Elucidation of Degradants at Trace Levels -- 8.2.1.Conversion of MS-unfriendly HPLC Methods to LC-MS Methods -- 8.2.2.Nomenclature, Ionization Modes and Determination of Parent Ions -- 8.2.3.Fragmentation and LC-MSn Molecular Fingerprinting -- 8.3.Brief Discussion of the Use of Multi-dimensional NMR in Structure Elucidation of Trace Level Impurities -- 8.4.Performing Meaningful Stress Studies -- 8.4.1.Generating Relevant Degradation Profiles -- 8.5.Effective Use of Mechanism-based Stress Studies in Conjunction with LC-MSn Molecular Fingerprinting in Elucidation of Degradant Structures and Degradation Pathways: Case Studies -- 8.5.1.Outline of General Strategy -- 8.5.2.Proposing Type of Degradation Based on LC-MSn Analysis -- 8.5.3.Design of Stress Studies According to Presumed Degradation Type -- 8.5.4.Tracking and Verification of Unknown Degradants Generated in Stress Studies Using LC-MSn Molecular Fingerprinting -- 8.5.5.Case Study 1: Elucidation of a Novel Degradation Pathway for Drug Products Containing Betamethasone Dipropionate and Similar Corticosteroidal 17,21-Diesters -- 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 -- 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 -- References -- ch. 9 Control of Drug Degradation -- 9.1.Overview -- 9.2.Degradation Controlling Strategies Versus Multiple Degradation Pathways and Mechanisms -- 9.3.Design and Selection of a Drug Candidate Considering Drug Degradation Pathways and Mechanisms -- 9.4.Implication of the Udenfriend Reaction and Avoidance of a Formulation Design that may Fall into the "Udenfriend Trap" -- 9.5.Control of Oxygen Content in Drug Products -- 9.6.Use of Antioxidants and Preservatives -- 9.7.Use of Chelating Agents to Control Transition Metal Ion-mediated Autooxidation -- 9.8.Control of Moisture in Solid Dosage Forms -- 9.9.Control of pH -- 9.10.Control of Photochemical Degradation Using Pigments, Colorants, and Additives -- 9.11.Variability of Excipient Impurity Profiles -- 9.12.Use of Formulations that Shield APIs from Degradation -- 9.13.Impact of Manufacturing Process on Drug Degradation -- 9.14.Selection of Proper Packaging Materials -- 9.15.Concluding Remarks -- References.
- "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."--
- 9781849735360 (electronic bk.)
1849735360 (electronic bk.)
- AVAILABLE ONLINE TO AUTHORIZED PSU USERS.
- Bibliography Note:
- Includes bibliographical references and index.
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