Separation Methods in Drug Synthesis and Purification

Edited by

  • K. Valkó, Physical Sciences, GlaxoWellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.

The new technologies in drug research such as combinatorial chemistry, high throughput screening, and robotics have made it possible to synthesise millions of molecules for thousands of screens. This volume presents the theory and applications of a wide range of separation methods used in the early stages of drug synthesis, purification and characterisation.
The topics covered are high performance liquid chromatography, capillary electrophoresis, capillary electro-chromatography, enantioseparations, preparative chromatography, and thin-layer chromatography. The separation methods used for the determination of physical-chemical properties together with the quantitative structure–retention relationship studies are also reviewed. The academic contributors provide a detailed description of the basic principles while the industrial contributors give real life examples of their application. The book not only reviews the major achievements in the field but also contains methods which have never been published before but are frequently used in pharmaceutical research.
To avoid the lengthy process of method development for every compound going through quality control, generic methods have been developed using fast gradient reversed-phase chromatography. Generic methods developed for high-throughput quality information generation are presented. The most important factors influencing column selection and gradient conditions are compared with the information gained, time and cost.
Similarly, generic methods can be developed for capillary electrophoresis in drug analysis. The recently emerged separation technique, capillary electro-chromatography, has received great attention in the pharmaceutical industry and is discussed in this volume. The various hyphenated analytical separation techniques widely applied in combinatorial assays for the identification of molecules available only in very small quantities are also presented.
The most stimulating section of this volume is the presentation of completely automated methods and technologies that can handle the analysis of hundreds of compounds weekly. A unique feature of the book is a demonstration of how separation sciences can contribute to the high throughput physical chemical profiling of the compounds, and how it can help in quantitative studies of structure–activity relationships. The optimisation strategies for process scale chromatography and process chromatography are also reviewed.
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For chemists and pharmaceutical chemists in pharmaceutical companies, research development analytical laboratories of government and industry, and universities.


Book information

  • Published: October 2000
  • Imprint: ELSEVIER
  • ISBN: 978-0-444-50007-6


"...this well written and thoroughly edited volume brings the reader up to date on a wide range of subjects pertaining to separation methods in pharmaceutical industry, with a special emphasis on HPLC...This volume will be a useful reference for anyone interested in analysis and purification of drugs."
A. Nezlin, The Alchemist, 2002

Table of Contents

Editor's Preface. Series Editor's Preface. List of Contributors. Comparison of various modes and phase systems for analytical HPLC (P. Jandera). Fundamentals of HPLC. Chromatographic column and column packing particles. Separation modes in HPLC. Method development and optimisation of conditions in isocratic HPLC. Development of gradient-elution separations. Acknowledgements. References. Fast generic HPLC methods (I.M. Mutton). Introduction. Theory. Strategy for production of fast gradients. Fast gradients in practice. References. Application of standard methods in capillary electrophoresis for drug analysis (K. Altria). Introduction to capillary electrophoresis. Analysis of pharmaceuticals by CE. Low-pH buffer for analysis of basic drugs. High-pH buffer for analysis of acidic drugs. Micellar electrokinetic chromatography (MEKC) for neutral and=or chargeddrugs. Microemulsion electrokinetic chromatography (MEEKC) for neutral and=orcharged drugs. Indirect UV detection method for analysis of inorganic anions. Indirect UV detection method for analysis of simple organic acids. Indirect UV detection method for analysis of metal ions. Non-aqueous CE for analysis of acidic and basic drugs. Benefits of adopting standard CE methods. References. Capillary electrochromatography (CEC) (C.J. Paterson, R.J. Boughtflower). Introduction. Basic principles of capillary electrochromatography. Mobile phase composition. Stationary phases used in CEC. Operational characteristics of CEC. Gradient and pressure-assisted (pseudo) CEC. Conclusions. Glossary of symbols. References. Coupled chromatography-mass spectrometry techniques forthe analysis of combinatorial libraries (S. Lane). Introduction. LC=MS analysis of high-throughput parallel synthesis libraries. Example for monitoring the rehearsal phase of the synthesis of a solid-phase library. LC=UV=MS as a pre-screen for autoprep-solution phase. Assisted automated LC=MS analysis. The analysis of split-pool combinatorial libraries. Conclusions and future. References. Optimization strategies for HPLC and CZE (Y. Vander Heyden et al.). Introduction. Responses and response functions. Univariate optimization strategies. Factorial methods. Mixture designs. Robustness=ruggedness. The simplex sequential approach. Automating the whole process: expert systems and knowledge based systems. References. Strategies for the development of process chromatography as a unit operation for the pharmaceutical industry (A.M. Katti). Introduction. The process development cycle. Chromatographic unit operations development. Discovery experiment stage. Development stage. Economics. Safety and environmental. Regulatory and compliance. List of symbols. Acknowledgements. References. The development and industrial application of automated preparative HPLC (T. Underwood et al.). Introduction. Instrumental considerations. Operating principles and gradient details. A worked example. Practical considerations and 'calibrated' methods. Additional system developments. Mass directed autoprep. Conclusion. Acknowledgements. References. Recent developments in liquid chromatographicenantioseparation (M. Lämmerhofer, W. Lindner). Introduction. Direct enantioseparation by liquid chromatography with chiral stationary phases (CSPs) - chiral selectors and chiral recognition mechanisms. Some aspects of preparative enantioseparation methods. Other enantioselective liquid-phase separation techniques. General conclusion. Addendum to literature -books on chiral discrimination. References. Basis and pharmaceutical applications of thin-layer chromatography (H. Kalász, M. Báthori). Planar chromatography. The components of the planar stationary phase. Mobile phases for thin-layer chromatography. The chambers. Detection. Quo vadis thin-layer chromatography. Acknowledgements. References. Recent advances in quantitative structure-retention relationships (QSRR) (R. Kaliszan). Introduction. Strategy of QSRR research. Retention prediction. Molecular mechanism of retention in view of QSRR. Chromatographic methods of determination of hydrophobicity. Applications of QSRR in molecular pharmacology and rational drug design. Concluding remarks. References. Measurements of physical properties for drug design in industry (K. Valkó). Introduction. Measurements of compound lipophilicity using chromatography. Measurements of membrane transport by immobilised artificial membrane (IAM) HPLC. Measurements of drug-protein binding constants using chromatography. Measurements of solubility by HPLC. Measurements of acid-base character (pKa) by HPLC. Measurements of H-bond acidity, basicity and polarisability-dipolarity byHPLC. Conclusion. References. Subject Index.