1 Modern Pharmaceutical Analysis: An Overview
SATINDER AHUJA
I. Identity and Purity Requirements 2
II. Bioavailability/Dissolution Requirements 4
III. Regulatory Considerations 5
IV. Regulatory Compliance 8
V. International Conference on Harmonization 9
VI. Global CMC NDA 9
VII. Highlights of Modern Pharmaceutical Analysis 10
References 22
2 Combinatorial Chemistry and High-Throughput
Screening in Drug Discovery and Development
KEN APPELL, JOHN J. BALDWIN, AND WILLIAM J. EGAN
I. Introduction 24
II. Combinatorial Methods 25
v
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vi CONTENTS
III. Methods for Structural Assignment 26
IV. Diversity 28
V. Druglikeness 28
VI. Designing Combinatorial Libraries with Optimal ADME Properties 28
VII. Existing Computational Methods for ADME Properties 30
VIII. Optimization Philosophy 35
IX. Applying Existing ADME Models to Combinatorial Library Design 37
X. The Future of ADME Modeling 38
XI. High-Throughput Screening and Combinatorial Chemistry 39
XII. Assay Plate Formats: Move to Miniaturization 40
XIII. Nonseparation or Homogeneous Assays 43
XIV. Identification of Receptor Antagonists for Chemokine Receptor and
Bradykinin-1 by Screening a 150,000-Member Combinatorial
Library 44
XV. Structure-based Design of Somatostatin Agonists 47
XVI. Conclusions 48
References 49
3 Solid-State Analysis
HARRY G. BRITTAIN
I. Introduction 57
II. Properties Associated with the Molecular Level 58
III. Properties Associated with the Particulate Level 65
IV. Properties Associated with the Bulk Level 73
V. Summary 81
References 81
4 Degradation and Impurity Analysis for Pharmaceutical
Drug Candidates
KAREN M. ALSANTE, ROBERT C. FRIEDMANN, TODD D. HATAJIK, LINDA L. LOHR,
THOMAS R. SHARP, KIMBERLY D. SNYDER, AND EDWARD J. SZCZESNY
I. Residual Solvents and Water 86
II. Purposeful Degradation Studies 95
III. Isolation and Identification of Impurities/Degradants 119
IV. Mass Spectrometry in Identification of Impurities 127
V. Role of NMR 147
VI. Reference Standards 166
VII. Summary 168
References 168
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