Characterization of Impurities and Degradants

The book highlights the current practices and future trends in structural characterization of impurities and degradants. It begins with an overview of mass spectrometry techniques as related to the analysis of impurities and degradants, followed by studies involving characterization of process related impurities (including potential genotoxic impurities), and excipient related impurities in formulated products. Both general practitioners in pharmaceutical research and specialists in analytical chemistry field will benefit from this book that will detail step-by-step approaches and new strategies to solve challenging problems related to pharmaceutical research.

BIRENDRA N. PRAMANIK is a Distinguished Fellow at Merck Research Laboratories, where he directs spectroscopy programs covering mass spectrometry and NMR efforts. He was previously a distinguished fellow at Schering-Plough Research Institute. He received his PhD in organic chemistry under the late Professor Ajay K. Bose from Stevens Institute of Technology in 1977.

MIKE S. LEE is President of Milestone Development Services, a provider of consulting services specializing in pharmaceutical analysis and accelerated drug discovery and development strategies in Newtown, Pennsylvania. He previously directed program research at Bristol-Myers Squibb, Pharmaceutical Research Institute in New Brunswick, New Jersey.

GUODONG CHEN is Principal Scientist in Bioanalytical and Discovery Analytical Sciences at Bristol-Myers Squibb in Princeton, New Jersey. He heads a mass spectrometry group in support of drug discovery as well as development programs in small molecule pharmaceuticals and biologics. He received his PhD in analytical chemistry from Purdue University under the direction of Professor R. Graham Cooks.

Preface
Contributors
Methodology
Introduction to Mass Spectrometry
History
Ionization Methods
Mass Spectrometer Types
Tandem Mass Spectrometry
Separation Techniques Coupled to Mass Spectrometry
Prospects for Mass Spectrometry
LC Method Development and Strategies
Introduction
Column, pH and Solvent Screening
Gradient and Temperature Optimization
Orthogonal Screening
High Efficiency Separation
Conclusions
Rapid Analysis of Drug Related Substances Using Desorption Electrospray Ionization and Direct Analysis in Real Time Ionization Mass Spectrometry
Introduction
Ionization Apparatus, Mechanisms and General Performance
Drug Analysis in Biological Matrices Using DESI and DART
High Throughput Analysis
Chemical Imaging and Profiling
Future Perspectives
Orbitrap High Resolution Applications
Historical Anecdote
General Description of Orbitrap Operating Principles
The Orbitrap is a "Fourier Transform" Device
Performing Experiments in Trapping Devices
Determining Elemental Compositions of "Unknowns" Using an Orbitrap
Orbitrap Figures of Merit in Mass Measurement
HPLC Orbitrap MS - Accurate Mass Demonstration and Differentiation of Small Molecule Formulas Very Proximate in Mass/Charge Ratio Space
Determination of Trace Contaminant Compositions by Simple Screening HPLC-MS and Infusion Orbitrap MS
Determining Sub-structures - Orbitrap Tandem Mass Spectrometry (MSn)
Multi-Analyzer (Hybridized) System - the Linear Ion Trap / Orbitrap for MS/MS and Higher Order MSⁿ, n>2
Mass Mapping to Discover Impurities
The Current Practice of Orbitrap Mass Spectrometry
Conclusion
Structural Characterization of Impurities and Degradation Products in Pharmaceuticals Using High Resolution LC/MS and On-line Hydrogen/Deuterium Exchange Mass Spectrometry
Introduction
Characterization of Impurities
Characterization of Degradation Products
Conclusions
Isotope Patten Recognition on Molecular Formula Determination for Structural Identification of Impurities
Introduction
Three Basic Approaches to Isotope Pattern Recognition
The Importance of Line-Shape Calibration
Spectral Accuracy
Formula Determination with Quadrupole MS
Formula Determination with High Resolution MS
Conclusions and Future Directions
Application
Practical Application of Very-High Pressure Liquid Chromatography across the Pharmaceutical Development / Manufacturing Continuum
Introduction
Theory and Benefits of VHPLC
VHPLC Method Development
Other Practical Considerations
VHPLC Method Validation
Summary
Impurity Identification for Drug Substances
Introduction
Case Studies
Conclusions
Impurity Identification in Process Chemistry by Mass Spectrometry
Introduction
Experimental
Applications
Concluding Remarks
Structure Elucidation of Pharmaceutical Impurities and Degradants in Drug Formulation Development
Importance of Drug Degradation Studies in Drug Development
Drug Degradation Studies in Formulation Development
Complexity of Impurity Identification in Drug Development
Strategy for Structure Elucidation
Hyphenated Analytical Techniques
Case Studies
Investigation of Degradation Products and Extractables in Developing Topical OTC (Over the Counter) and NCE (New Chemical Entity) Consumer Healthcare Medication Products
Introduction
Oxidatively Induced Coupling of Miconazole Nitrate with Butylated Hydroxytoluene in a Topical Ointment
Extractables from Rubber Closures of a Pre-filled Semisolid Drug Applicator
New Degradation Products and Pathways of Vitamin D and Its Analogues
Reductive Degradation of a 1,2,4-Thiadiazolium Derivative
Conclusions
Characterization of Impurities and Degradants in Protein Therapeutics by Mass Spectrometry
Introduction to Therapeutic Proteins
Recent Advances in Mass Spectrometry
Impurities
Degradation Products
Conclusions
Identification and Quantification of Degradants and Impurities in Antibodies
Introduction to Antibodies and Protein Drugs
Overview of Degradations and Impurities in Protein Drugs and Antibodies
Methods to Identify and Quantitate Degradations and Impurities
Conclusions
Table of Contents provided by Publisher. All Rights Reserved.

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Characterization of Impurities and Degradants Using Mass Spectrometry

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