Breakthroughs in combinatorial chemistry and molecular biology, as well as an overall industry trend toward accelerated development, mean the rate of sample generation now far exceeds the rate of sample analysis in the pursuit of producing new and better pharmaceuticals. LC/MS is an analytical tool that helps the researcher identify the most promising sample early in the selection process, effectively creating a shortcut to finding new drugs. This book is the first to describe LC/MS applications within the context of drug development, including the discovery, preclinical, clinical, and manufacturing phases.
In addition to the thorough technical analysis of this tool,
LC/MS Applications in Drug Development provides perspective on the significant changes in strategies for pharmaceutical analysis. A process overview of drug development from an analytical point of view is provided along with essential data required to successfully bring a drug to market. The incorporation of LC/MS is illustrated from target to product. Chapters pertaining to the discovery process itself include:ProteomicsGlycoprotein MappingNatural Products DereplicationLead Identification ScreeningOpen-Access LC/MSIn Vitro Drug Screening
Written for both the analytical chemist who uses LC/MS applications and the pharmaceutical scientist who works with the drugs they produce,LC/MS Applications in Drug Development is the premier reference on the subject.
MIKE S. LEE, PhD, is President of Milestone Development Services, a consulting firm specializing in pharmaceutical analysis and drug development strategies. He lives in Newtown, Pennsylvania.
Preface ix
Acknowledgments xi
1. Introduction 1
Emerging Analytical Needs 1
Integration of LC/MS into Drug Development 3
Partnerships and Acceptance 6
Overview 10
2. Drug Development Overview 11
Analysis Perspectives 11
The Four Stages of Drug Development 12
Drug Discovery 14
Preclinical Development 15
Clinical Development 16
Manufacturing 17
3. Accelerated Drug Development 19
Accelerated Development Strategies 20
Quantitative and Qualitative Process Elements 20
Quantitative Process Pipeline 24
Qualitative Process Pipeline 25
Motivating Factors 27
Analysis Opportunities for Accelerated Development 28
Full-Time Equivalent 28
Sample Throughput Model 29
Elimination Model 29
Rate-Determining Event Model 31
Accelerated Development Perspectives 33
4. LC/MS Development 34
The Elements of LC/MS Application 34
HPLC 35
Mass Spectrometry 35
LC/MS Interface 36
LC/MS Growth 38
5. Strategies 41
Standard Methods 43
Template Structure Identification 46
Databases 49
Screening 50
Integration 53
Miniaturization 55
Parallel Processing 56
Visualization 58
Automation 61
Summary 63
6. LC/MS Applications 65
Drug Discovery 65
Proteomics 68
Protein Expression Profiling 70
Quantitation 76
Glycoprotein Mapping 78
Natural Products Dereplication 83
Lead Identification Screening 88
Bioaffinity Screening 89
Combinatorial Library Screening 92
Open-Access LC/MS 96
Structure Confirmation 97
High Throughput 100
Purification 102
Combinatorial Mixture Screening 103
In Vivo Drug Screening 106
Pharmacokinetics 109
In Vitro Drug Screening 115
Metabolic Stability Screening 118
Membrane Permeability 119
Drug-Drug Interaction 121
Metabolite Identification 122
Preclinical Development 123
Metabolite Identification 125
Impurity Identification 132
Degradant Identification 140
Clinical Development 145
Quantitative BioanalysisSelected Ion Monitoring 148
Quantitative BioanalysisSelected Reaction Monitoring 152
Quantitative BioanalysisAutomated Solid-Phase Extraction 156
Quantitative BioanalysisAutomated On-Line Extraction 162
Metabolite Identification 165
Degradant Identification 168
Manufacturing 171
Impurity Identification Using Data-Dependent Analysis 173
Peptide Mapping in Quality Control 176
Patent Protection 178
7. Future Applications and Prospects 183
Workstations 183
Multidimensional Analysis 186
Miniaturization 187
Information Management 189
Strategic Outsourcing 190
Summary 191
8. Perspectives on the Future Growth of LC/MS 192
9. Conclusions 195
Glossary 197
References 205
Index 235
