Separation Methods in Drug Synthesis and Purification

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1 HANDBOOK OF ANALYTICAL SEPARATIONS - VOLUME 1 Separation Methods in Drug Synthesis and Purification Edited by KLARA VALKO Physical Sciences, Glaxo Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts. SGI 2NY, United Kingdom 2000 ELSEVIER Amsterdam - Lausanne - New York - Oxford - Shannon - Singapore - Tokyo

2 xm Contents Editor's Preface Series Editor's Preface List of Contributors V IX XI Chapter 1. Comparison of various modes and phase systems for analytical HPLC P. Jandera Fundamentals of HPLC Characteristics of HPLC separation Elution development and chromatographic peaks Basic characteristics of chromatographic separation Retention factor and thermodynamic aspects of chromatography Hydrodynamic (kinetic) aspects of chromatography, band broadening and column efficiency Chromatographic column and column packing particles HPLC column Packing materials for HPLC Separation modes in HPLC Normal-phase chromatography Stationary phases and retention mechanism Retention behaviour in normal-phase chromatography The mobile phase in normal-phase chromatography Reversed-phase chromatography Stationary phases in reversed-phase chromatography Retention behaviour in reversed-phase chromatography The mobile phase in reversed-phase chromatography Retention behaviour of non-ionic solutes in reversed-phase chromatography Reversed-phase chromatography of ionic compounds Ion-pair chromatography Micellar chromatography Ion-exchange chromatography Method development and optimisation of conditions in isocratic HPLC Selection of the separation mode Effects of experimental HPLC conditions on chromatographic resolution Control of the separation efficiency Effect of the temperature on separation 40

3 XIV Contents Adjustment of the composition of binary mobile phases Selectivity control using ternary or more complex mobile phases Computer-assisted optimisation of HPLC methods Development of gradient-elution separations Gradient-elution versus other HPLC programming techniques Theory of HPLC with binary gradients Gradient elution versus isocratic elution effects of the gradient profile on separation Gradient elution in reversed-phase systems Gradient elution in normal-phase and ion-exchange systems Gradient-elution method development Ternary gradients in HPLC Sources of errors in prediction of retention in gradient-elution chromatography Acknowledgements References 69 Chapter 2. Fast generic HPLC methods I.M. Mutton Introduction Theory Production of fast gradients Strategy for production of fast gradients General strategy for standard bore columns Production of fast gradients with small bore columns Fast gradients in practice References 85 Chapter 3. 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 charged drugs Microemulsion electrokinetic chromatography (MEEKC) for neutral and/or charged 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 105

4 Contents XV Chapter 4. Capillary electrochromatography (CEC) C.J. Paterson and R.J. Boughtflower Introduction Basic principles of capillary electrochromatography Electroendosmotic flow Factors that influence electroendosmotic flow (EOF) Dispersion Thermal effects in CEC Mobile phase composition Stationary phases used in CEC Operational characteristics of CEC Sampling Detection Gradient and pressure-assisted (pseudo) CEC Conclusions Glossary of symbols References 124 Chapter 5. Coupled chromatography-mass spectrometry techniques for the analysis of combinatorial libraries S. Lane Introduction LC/MS analysis of high-throughput parallel synthesis libraries Development of walk-up open-access LC/UV/MS systems System components 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 Purity profile for phenyl analogue (Fig. 5.14) Purity profile for carboxy analogue (Fig. 5.15) Purity profile for cyano analogue (Fig. 5.16) Assisted automated LC/MS analysis The analysis of split-pool combinatorial libraries Conclusions and future References 160 Chapter 6. Optimization strategies for HPLC and CZE Y. Vander Heyden, C. Perrin and D.L. Massart Introduction Responses and response functions Univariate optimization strategies Factorial methods Full factorial designs Screening designs Response surface designs 183

5 XVI Contents Classical symmetrical designs Non-symmetrical designs Models Mixture designs Robustness/ruggedness The simplex sequential approach Automating the whole process: expert systems and knowledge based systems References 210 Chapter 7. Strategies for the development of process chromatography as a unit operation for the pharmaceutical industry A.M. Katti Introduction The process development cycle Process discovery, development and implementation Organizational issues Chromatographic unit operations development Discovery experiment stage Limiting impurity Separation factor Column saturation capacity Relationship between flow rate and plate count Development stage Experimental development and modeling Modes of chromatography Optimum loading factor Optimum column length Optimum flow rate Required number of plates Regeneration and equilibration Analytical methods Equipment design Pumps Piping, valves and pressure relief Pulse dampeners Filtration and guard columns Columns Detectors Scale-up Economics Numerical solutions Economies of scale Pressure Column saturation capacity Particle size 259

6 Contents XVII Separation factor (a) Retention factor (if) Crude costs ($/g) Solvent costs ($/g) Purity Diffusivity Safety and environmental Regulatory and compliance Flow rate Temperature Composition of mobile phase, regeneration solution and load solution Packing efficiency Load concentration or volume Cut point location strategy List of symbols Acknowledgements References 289 Chapter 8. The development and industrial application of automated preparative HPLC T. Underwood, R.J. Boughtflower and K.A. Blinded Introduction Instrumental considerations Hardware configuration Stationary phase selection Operating principles and gradient details A worked example Analytical scale investigation Preparative scale-up and sample introduction considerations Validation of the preparative chromatography The autoprep purification Practical considerations and 'calibrated' methods Problems with the initial generic approach The 'calibrated' method for hydrophilic compounds 'Calibrated' methods and the advantages of their application Additional system developments Mass directed autoprep The addition of a mass spectrometer Mass spectrometer considerations and chromatography adjustments Instrumental layout and software demands MS-prep system refinements Conclusion Acknowledgements 336

7 XVIII Contents 8.10 References 336 Chapter 9. Recent developments in liquid chromatographic enantioseparation M. Lammerhofer and W. Lindner Introduction Impact of stereochemistry on drug development Historical background of modern liquid-phase enantioseparation Scope and aims of this chapter Mechanism of chiral recognition and enantioseparation Direct enantioseparation by liquid chromatography with chiral stationary phases (CSPs) chiral selectors and chiral recognition mechanisms Polymeric type selectors and chiral stationary phases Polymeric type CSPs primarily operated in the non-aqueous mobile phase mode Protein type CSPs representing a class of polymeric type CSPs which can be used with aqueous mobile phases CSPs with macrocyclic, oligomeric and/or intermediate molecular size selectors Cyclodextrin derived CSPs CSPs with macrocyclic glycopeptide antibiotics as selectors Crown-ether type CSPs Low molecular weight selectors CSPs based on chiral selectors related to the Pirkle concept Chiral ion exchangers Ligand-exchange type CSPs Summary on CSPs Some aspects of preparative enantioseparation methods Other enantioselective liquid-phase separation techniques General conclusion Addendum to literature books on chiral discrimination References 426 Chapter 10. Basis and pharmaceutical applications of thin-layer chromatography H. Kalasz and M. Bathori Planar chromatography Historical overview Basic formulas for TLC Advantages of planar chromatography Solvent propagation Elution, frontal and displacement modes Planar vs. column chromatography Advances in thin-layer chromatography 447

8 Contents XIX Multidimensional planar chromatography The components of the planar stationary phase Stationary phases for chromatography Silica gels Inert stationary phase containing silicium dioxides Aluminas Magnesia (magnesium oxide, magnesium hydroxide) Celluloses Polyamides Sephadex and BioGel P gels Chemically modified stationary phases Ion exchangers Methods and stationary phases for enantiomeric separations Mixed stationary phases Special additives to the stationary phase Binders UV indicators Precoated plates Mobile phases for thin-layer chromatography Optimisation of solvent systems The chambers Simple chambers Chambers in instrumental TLC Centrifugal thin-layer chromatography High-speed thin-layer chromatography Automated multiple development (AMD) Forced-flow thin-layer chromatography (FF-TLC) Detection Monitoring Non-destructive detections Detection of TLC with on-line coupled spectroscopic methods other than UV and/or visible monitoring HPTLC-FTIR on-line coupling TLC-MS coupling TLC-NMR coupling X-ray detection Electrochemical detection Destructive detection Colour reagents Flame-ionisation detector (FID) Application of TLC in pharmaceutical and forensic analysis Analysis of drugs and metabolites Application of TLC in the study of lipophilicity Quo vadis thin-layer chromatography 494

9 XX Contents 10.8 Acknowledgements References 498 Chapter 11. Recent advances in quantitative structure-retention relationships (QSRR) R. Kaliszan Introduction Strategy of QSRR research Retention data for QSRR Chemometric methodology Structural descriptors for QSRR 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 530 Chapter 12. Measurements of physical properties for drug design in industry K. Valko Introduction Measurements of compound lipophilicity using chromatography Measurements of liquid-liquid partition Measurements of chromatographic partition Application of gas chromatography Application of thin-layer chromatography (TLC) Application of reversed-phase high-performance liquid chromatography (RP-HPLC) Measurements of membrane transport by immobilised artificial membrane (IAM) HPLC Measurements of drug-protein binding constants using chromatography Measurements of solubility by HPLC Concentration determination by HPLC for solubility measurements Partition coefficient determination for solubility estimation Measurements of acid-base character (pa" a ) by HPLC ph dependence of lipophilicity and solubility ph dependence of chromatographic retention Estimation of lipophilicity and pk 3 by gradient reversed-phase chromatography Measurements of H-bond acidity, basicity and polarisability-dipolarity by HPLC The importance of H-bond acidity, basicity and polarisabilitydipolarity in describing various partition processes and solubility

10 Contents XXI Description of various lipophilicity scales by molecular descriptors (solvation equations) Description of various chromatographic lipophilicity scales by the molecular descriptors Description of solubility by the molecular descriptors Determination of molecular descriptors by chromatography Conclusion References 580 Subject Index 585

HPLC COLUMNS WILEY-VCH. Theory, Technology, and Practice. Uwe D. Neue with a contribution from M. Zoubair El Fallah

HPLC COLUMNS WILEY-VCH. Theory, Technology, and Practice. Uwe D. Neue with a contribution from M. Zoubair El Fallah HPLC COLUMNS Theory, Technology, and Practice Uwe D. Neue with a contribution from M. Zoubair El Fallah WILEY-VCH New York Chichester Weinheim Brisbane Singapore Toronto CONTENTS Preface ix 1 Introduction