Organic Chemistry of Drug Degradation

Transcription

1 Organic Chemistry of Drug Degradation Li New Jersey Publishing

2 Contents Chapter 1 Introduction Drug Impurities, and the Importance of Understanding Drug Chemistry 1 Characteristics of Degradation Chemistry and the Scope of this Book Brief Discussion of that are Outside the Main Scope of this Book Thermodynamics Kinetics of Chemical Reactions Reaction Orders, Half-lives Prediction of Drug Product Shelf-lives Key Elementii in Solid State Degradation Role of Solid State Degradation PH the the Solid State 10 Organization of the References 14 Chapter 2 Degradation Overview of Hydrolytic Drugs Containing Groups/Moieties Susceptible to Hydrolysis Drugs Containing an Ester Group Drugs Containing Lactone Group Drugs Containing Amide Group p-lactam Carbamates 30 RSC Drug Discovery Series No. 29 Organic Chemistry of Drug Degradation By Min Li Min Li 2012 Published by the Royal Society of Chemistry,

3 xii Contents Phosphates and Sulfonamide Drugs Imides and Sulfonylureas Imines (Schiff Bases) and Acetal and Groups Ethers and Epoxides and Formation of an Amide Linkage 43 References 44 Chapter 3 Oxidative Degradation Introduction Free Radical-mediated Autooxidation Origin of Free Radicals: Fenton Reaction and Udenfriend Reaction Origin of Free Radicals: Homolytic Cleavage of Peroxides by Thermolysis and Heterolytic Cleavage of Peroxides by Metal Ion Oxidation Autooxidative Radical Chain Reactions and Their Kinetic Behavior Additional Reactions of Free Radicals Non-radical Reactions of Peroxides 57 Heterolytic Cleavage of Peroxides and Oxidation of Amines, Sulfides, and Related Species Heterolytic Cleavage of Peroxides and Formation of Epoxides Carbanion/enolate-mediated Autooxidation (Base-catalyzed Autooxidation) Oxidation Pathways of Drugs with Various Structures Allylic- and Positions Susceptible to Hydrogen Abstraction by Free Radicals Double Bonds Susceptible to Addition by Hydroperoxides Tertiary Amines Primary and Secondary Amines and Imines Bases) Thioethers (Organic Sulfides), Sulfoxides, Thiols and Related Species Examples of Carbanion/enolate-mediated Autooxidation Oxidation of Drugs Containing Alcohol, Aldehyde, and Ketone Functionalities 87

4 Contents Oxidation of Aromatic Rings: Formation of Phenols, Polyphenols, and Quinones Oxidation of Heterocyclic Aromatic Rings References Miscellaneous Oxidative Degradations 99 g \ Chapter 4 Various Types and Mechanisms of Degradation Reactions 4.1 Elimination Dehydration Dehydrohalogenation Hofmann Elimination Miscellaneous Eliminations 4.2 Decarboxylation 4.3 Nucleophilic Conjugate Addition and Conjugate Addition 4.4 Aldol Condensation and Retro-aldol 124 Aldol Condensation Retro-aldol Reaction 4.5 Isomerization and Rearrangement Tautomerization Racemization Epimerization Cis-trans Isomerization Migration Rearrangement via Ring Expansion Intramolecular Cannizzaro Rearrangement 4.6 Cyclization Formation of Diketopiperazine (DKP) Other Cyclization Reactions Dimerization/Oligomerization Miscellaneous Degradation Mechanisms Reaction Degradation via Reduction or Disproportionation 145 References Chapter 5 Drug-Excipient Interactions and Adduct Formation Degradation Caused by Direct Interaction between Drugs and Excipients Degradation via the Maillard Reaction Drug-Excipient Interaction via Ester and Amide Linkage Formation

5 xiv Contents Interaction via Transesterification Degradation Caused by Magnesium Stearate Degradation Caused by Interaction between API and Counter Ions and between Two APIs Other Cases of Drug-Excipient Interactions 5.2 Degradation Caused by Impurity of Excipients Degradation Caused by Hydrogen Peroxide, Formaldehyde, and Formic Acid Degradation Caused by Residual Impurities in Polymeric Excipients 5.3 Degradation Caused by Degradants of Excipients Degradation Caused by Impurities from Packaging 161 References Chapter 6 Photochemical Degradation Overview Non-oxidative Photochemical Degradation 166 Photodecarboxylation: Photodegradation of Drugs Containing a Acid Moiety Photoisomerization of Class of Drugs Dehalogenation of Halides Cyclization in Ring Systems Photochemical Elimination Photodimerization and Photochemistry of Ketones: Norris Type I and II Photoreactions Oxidative Photochemical Degradation Type I Photosensitized Oxidation: Degradation via Radical Formation and Electron Transfer Type II Photosensitized Oxidation: Degradation Caused by Singlet Oxygen Degradation Pathways via Reaction with Singlet Oxygen 190 References 194

6 Contents Chapter 7 Chemical Degradation of Biological Drugs Overview 7.2 Chemical Degradation of Protein Drugs Hydrolysis and Rearrangement of Peptide Backbone Caused by the Asp Residue Various Degradation Pathways Caused by and Formation of Succinimide Intermediate Hinge Region Hydrolysis in Antibodies Oxidation of Side Chains of Cys, Met, His, Trp, and Tyr Oxidation of Side Chains of Arg, Pro, and Lys Crosslinking, Dimerization, and Oligomerization The Maillard Reaction Degradation via Truncation of a Dipeptide Sequence through DKP Formation Miscellaneous Degradation Pathways Degradation of Carbohydrate-based Biological Drugs Degradation of DNA and RNA Drugs Hydrolytic Degradation of Phosphodiester Bonds Oxidative Degradation of Nucleic Acid Bases 220 References 222 Chapter 8 Strategies for Elucidation of Degradant Structures and Degradation Pathways 227 Overview Practical Considerations of Employing LC-MS" for Structural Elucidation of Degradants at Trace Levels 229 Conversion of HPLC Methods to LC-MS Methods Nomenclature, Ionization Modes and Determination of Parent Ions Fragmentation and LC-MS" Molecular Fingerprinting Brief Discussion of the Use of Multi-dimensional NMR in Structure Elucidation of Trace Level Impurities 239

7 9.1 Overview Degradation Controlling Strategies Versus Multiple Degradation Pathways and Mechanisms Design and Selection of a Drug Candidate Considering Drug Degradation Pathways and Mechanisms Implication of the Udenfriend Reaction and Avoidance of a Formulation Design that may Fall into the "Udenfriend Trap" Control of Oxygen Content in Drug Products Use of Antioxidants and Preservatives Use of Chelating Agents to Control Transition Metal Ion-mediated Autooxidation Contents 8.4 Performing Meaningful Stress Studies Generating Relevant Degradation Profiles Effective Use of Mechanism-based Stress Studies in Conjunction with LC-MS" Molecular Fingerprinting in Elucidation of Degradant Structures and Degradation Pathways: Case Studies Outline of General Strategy Proposing Type of Degradation Based on LC-MS" Analysis Design of Stress Studies According to Presumed Degradation Type Tracking and Verification of Unknown Degradants Generated in Stress Studies Using LC-MS" Molecular Fingerprinting Case Study 1: Elucidation of a Novel Degradation Pathway for Drug Products Containing Betamethasone Dipropionate and Similar Corticosteroidal Case Study 2: Rapid Identification of Three Betamethasone Sodium Phosphate Isomeric Degradants - Use of Enzymatic Transformation When a Direct MS" Fingerprint Match is not Available Case Study 3: Identification of an Impurity in Betamethasone Drug Substance Structure Prediction When an Exact MS" Fingerprint Match is not Available 256 References 258 Chapter 9 Control of Drug Degradation 262

8 Contents 9.8 Control of Moisture in Solid Dosage Forms Control of ph Control of Photochemical Degradation Using Pigments, Colorants, and Additives Variability of Excipient Impurity Profiles Use of Formulations that Shield APIs from Degradation Impact of Manufacturing Process on Drug Degradation Selection of Proper Packaging Materials Concluding Remarks 273 References 274 xvii Subject Index 278