LC/MS Applications in Drug Development

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.

"…a comprehensive primer and will appeal to laboratory scientists and instructors in the pharmaceutical field…" (Analytical Chemistry, November 2002) "...describes...applications in each phase of drug development...provides perspective on changes in strategies for pharmaceutical analysis..." (SciTech Book News, Vol. 26, No. 2, June 2002)"...useful not only for students and scholars of analytical chemistry, but also for managers and other scientists...another fine addition to the Wiley-InterScience Series on Mass Spectrometry, it should be in the collections of all research libraries." (The Chemist, Summer 2003)

• Preface ixAcknowledgments xi1. Introduction 1Emerging Analytical Needs 1Integration of LC/MS into Drug Development 3Partnerships and Acceptance 6Overview 102. Drug Development Overview 11Analysis Perspectives 11The Four Stages of Drug Development 12Drug Discovery 14Preclinical Development 15Clinical Development 16Manufacturing 173. Accelerated Drug Development 19Accelerated Development Strategies 20Quantitative and Qualitative Process Elements 20Quantitative Process Pipeline 24Qualitative Process Pipeline 25Motivating Factors 27Analysis Opportunities for Accelerated Development 28Full-Time Equivalent 28Sample Throughput Model 29Elimination Model 29Rate-Determining Event Model 31Accelerated Development Perspectives 334. LC/MS Development 34The Elements of LC/MS Application 34HPLC 35Mass Spectrometry 35LC/MS Interface 36LC/MS Growth 385. Strategies 41Standard Methods 43Template Structure Identification 46Databases 49Screening 50Integration 53Miniaturization 55Parallel Processing 56Visualization 58Automation 61Summary 636. LC/MS Applications 65Drug Discovery 65Proteomics 68Protein Expression Profiling 70Quantitation 76Glycoprotein Mapping 78Natural Products Dereplication 83Lead Identification Screening 88Bioaffinity Screening 89Combinatorial Library Screening 92Open-Access LC/MS 96Structure Confirmation 97High Throughput 100Purification 102Combinatorial Mixture Screening 103In Vivo Drug Screening 106Pharmacokinetics 109In Vitro Drug Screening 115Metabolic Stability Screening 118Membrane Permeability 119Drug-Drug Interaction 121Metabolite Identification 122Preclinical Development 123Metabolite Identification 125Impurity Identification 132Degradant Identification 140Clinical Development 145Quantitative Bioanalysis—Selected Ion Monitoring 148Quantitative Bioanalysis—Selected Reaction Monitoring 152Quantitative Bioanalysis—Automated Solid-Phase Extraction 156Quantitative Bioanalysis—Automated On-Line Extraction 162Metabolite Identification 165Degradant Identification 168Manufacturing 171Impurity Identification Using Data-Dependent Analysis 173Peptide Mapping in Quality Control 176Patent Protection 1787. Future Applications and Prospects 183Workstations 183Multidimensional Analysis 186Miniaturization 187Information Management 189Strategic Outsourcing 190Summary 1918. Perspectives on the Future Growth of LC/MS 1929. Conclusions 195Glossary 197References 205Index 235