Chiral Liquid Chromatography

ISBN-13: 9789401068758 / Angielski / Miękka / 2011 / 280 str.

W. Lough

Opis

While working as a chromatographer in the pharmaceutical industry, it became apparent to the editor that there was a pressing need for a comprehensive reference text for analysts working on the resolution of enantiomers by liquid chromatography (LC). This need arises from the fact that, whereas previously it was very difficult to determine enantiomers by direct means, there is now a wide choice of direct LC methods. At the same time, regulatory authorities have been changing their attitudes towards the administration of pharmaceuticals as racemates, partly because it is now possible to study the individual enantiomers. Clearly this abundance of new information needs to be rationalized. More importantly, the chiral LC systems which are commercially available or readily accessible to the practising chromatographer needed to be reviewed and, to a much greater extent than in existing reviews or books, discussed in terms of their practical application. Accordingly this book is very much orientated towards the practical aspects of these commercially available and readily accessible chiral LC systems. To this end, it is written for practising chromatographers by a team of practising, experienced chromatographers who have spent many years tackling the problems presented by resolving enantiomers by LC. The practical aspects of common chiral LC systems cannot be fully understood if discussed in isolation.

Spis treści

1 Introduction.- 1 Molecular asymmetry.- 1.1 Chirality.- 1.2 Chiroptical properties.- 1.3 Asymmetric centres.- 1.4 Twisted structures.- 1.4.1 Cumulenes.- 1.4.2 Spiro compounds.- 1.5 Hindered rotation.- 1.5.1 Atropisomers.- 1.5.2 Ansa compounds.- 1.6 Molecular overcrowding.- References.- 2 The importance of enantiomer separations.- 2.1 Introduction.- 2.2 Enantiomers versus racemates: questions of efficacy and safety.- 2.3 Enantiomers versus racemates: questions of pharmacokinetics.- 2.4 Experimental considerations for investigation of pure enantiomers.- 2.5 Conclusion.- References.- 3 Chiral liquid chromatography: past and present.- 3.1 Historical perspectives.- 3.2 Three-point rule.- 3.3 Development of commercially-available or easily accessible direct chiral resolution methods.- 3.3.1 Chiral ligand exchange chromatography.- 3.3.2 Synthetic multiple-interaction CSPs.- 3.3.3 Protein CSPs.- 3.3.4 Cyclodextrin CSPs.- 3.3.5 Cellulose CSPs.- 3.3.6 Synthetic polymer CSPs.- 3.3.7 Chiral ion-pair chromatography.- 3.3.8 Other direct chiral resolution methods.- 3.4 Present status of chiral liquid chromatography.- References.- 2 Chiral Derivatization.- 4 Chiral derivatization.- 4.1 Introduction.- 4.2 Diastereomer formation.- 4.3 Reagents.- 4.3.1 Acylating reagents.- 4.3.2 Amine reagents.- 4.3.3 Isocyanates and activated carbamates.- 4.3.4 Isothiocyanates.- 4.3.5 Chloroformates.- 4.3.6 Reagents based on o-phthalaldehyde and chiral thiols.- 4.3.7 Other reagents.- 4.4 Separation mechanisms.- 4.5 Detection.- 4.6 Applications.- 4.6.1 Resolution of l-isopropyl-amino-2-propanols (?-blockers).- Acknowledgements.- References.- 3 Direct Chiral Resolution.- 5 Chiral ligand exchange chromatography.- 5.1 Introduction.- 5.2 Immobilized metal coordinating ligands.- 5.3 Metal coordinating ligands as mobile phase additives.- 5.4 Ligand exchange mechanism.- 5.5 Enantiomeric resolution of d and l amino acids.- 5.5.1 Free amino acids.- 5.5.2 Dansyl amino acids.- 5.5.3 Imino acids.- 5.6 Parameters affecting ligand exchange.- 5.6.1 Metal ion.- 5.6.2 Metal to ligand ratio.- 5.6.3 Concentration of metal complex.- 5.6.4 Eluent pH.- 5.6.5 Elution order.- 5.6.6 Organic modifier.- 5.6.7 Stereoselectivity.- 5.7 Conclusion.- References.- 6 Synthetic multiple-interaction chiral bonded phases.- 6.1 Introduction.- 6.2 Survey of multiple-interaction CSPs.- 6.2.1 Historical development.- 6.2.2 Survey.- 6.2.3 Preparation of CSPs.- 6.2.4 General chromatographic considerations.- 6.3 Resolutions of enantiomeric solutes.- 6.3.1 Survey.- 6.3.2 Derivatization of solutes.- 6.3.3 Limitations.- 6.4 Special applications.- 6.4.1 Preparative separations.- 6.4.2 Enantiomeric trace analysis.- 6.4.3 Elution order and configuration.- 6.5 Conclusion.- References.- 7 Immobilized proteins as HPLC chiral stationary phases.- 7.1 Introduction.- 7.2 The AGP-CSP.- 7.2.1 Preparation of the CSP.- 7.2.2 Solute selectivity.- 7.2.3 Mobile phase effects.- 7.2.4 Effect of pH.- 7.2.5 Effect of mobile phase modifiers.- 7.2.6 Applications of the AGP-CSP to pharmacological studies.- 7.3 The bovine serum albumin (BSA) CSP.- 7.3.1 Preparation of the CSP.- 7.3.2 Solute selectivity.- 7.3.3 Mobile phase effects.- 7.3.4 Effect of pH.- 7.3.5 Effect of buffer concentration.- 7.3.6 Effect of mobile phase modifiers.- 7.3.7 Applications of BSA-CSP to pharmacological studies.- 7.4 Chiral phases based on enzymes and other biological polymers.- 7.4.1 Immobilized ovomucoid.- 7.4.2 Immobilized ?-chymotrypsin.- 7.5 Conclusion.- References.- 8 Cyclodextrin inclusion complexation.- 8.1 Structure of cyclodextrin.- 8.2 Mechanism of chiral separation.- 8.3 Inclusion complexes.- 8.4 Examples of chiral separations.- 8.4.1 ?-Cyclodextrin column.- 8.4.2 ?-Cyclodextrin column.- 8.4.3 ?-Acetylated cylcodextrin.- 8.4.4 Aromatic and alkyl groups and their behaviour with cyclodextrin.- 8.5 Choosing conditions for separation.- 8.5.1 Mobile phase effects.- 8.5.2 Salt and pH effects.- 8.5.3 Effect of temperature.- 8.5.4 Effect of flow rate.- 8.6 Care and use of cyclodextrin columns.- 8.7 Advantages and disadvantages.- 8.8 Use of cyclodextrins in mobile phase.- References.- 9 Binding to cellulose derivatives.- 9.1 Cellulose.- 9.2 Cellulose triacetate.- 9.3 Cellulose derivatives.- 9.3.1 Applications.- 9.3.2 Practical considerations.- 9.4 Derivatives of other polysaccharides.- References.- 10 Binding to synthetic polymers.- 10.1 Introduction.- 10.2 Helical polymethacrylates.- 10.2.1 Applications of poly(triphenylmethyl methacrylate).- 10.2.2 Practical considerations.- 10.3 Polyacrylamides and polymethylacrylamides.- 10.4 Other synthetic polymer CSPs.- References.- 11 Ion-pairing.- 11.1 Introduction.- 11.2 Retention principles.- 11.3 Desired properties of chiral counter-ions.- 11.3.1 Acid-base character of counter-ions.- 11.3.2 Kind and nature of counter-ions.- 11.3.3 Presence of functional groups suitable for tertiary interaction.- 11.3.4 Enantiomeric purity of chiral counter-ions.- 11.3.5 Other important properties of chiral counter-ions.- 11.4 Availability of chiral counter-ions.- 11.5 Separation variables.- 11.5.1 Influence of mobile-phase composition.- 11.5.2 Stationary-phase selection.- 11.5.3 Influence of concentration of chiral counter-ion and of mobile-phase additive on retention.- 11.5.4 Influence of optical antipode selection of chiral counter-ion on selectivity of separation.- 11.5.5 Influence of column temperature and flow rate.- 11.6 Problems of diastereomeric complex formation using chiral counter-ions: advantages and limitations.- 11.7 Combination of ion-pair chromatography and inclusion complex formation.- References.- 12 Other direct chiral resolution methods.- 12.1 Introduction.- 12.2 Minor variations on more common methods.- 12.3 More unusual direct chiral resolution methods.- References.- 4 Strategy for Development of LC Enantiomeric Determination Methods.- 13 Consideration of other techniques.- 13.1 Introduction.- 13.2 Measurement of optical rotation.- 13.3 Nuclear magnetic resonance spectroscopy.- 13.4 Gas chromatography.- 13.5 Other chromatographic techniques.- 13.6 Radioimmunoassays.- References.- 14 Choice of chiral LC systems.- 14.1 Reference to known examples.- 14.2 Relative merits of LC enantioseparation methods.- 14.2.1 Direct v. indirect methods.- 14.2.2 Chiral stationary phases v. mobile-phase additives.- 14.2.3 Choice of chiral stationary phase.- 14.3 Method development.- 14.4 More complex enantiomer separation problems.- 14.4.1 Preparative enantiomer separations.- 14.4.2 Sensitivity.- 14.4.3 Limited time for method development.- 14.4.4 Determination of trace enantiomers in the presence of excess of the antipode.- 14.4.5 Other typical enantiomer separation problems.- References.- 15 Optimization.- 15.1 Introduction.- 15.2 Optimization methods.- 15.2.1 Chromatographic response surface mapping.- 15.2.2 Modified sequential simplex approach.- 15.3 Comparison of methods for oxamniquine and its metabolic precursor.- 15.4 Conclusion.- References.- 5 Future Trends and Requirements.- 16 Future trends and requirements.- 16.1 Introduction.- 16.2 Hardware.- 16.2.1 Detectors.- 16.2.2 Miniaturization.- 16.2.3 Multicolumn systems.- 16.3 Trends in the development of new chiral packings.- 16.3.1 Recognition mechanisms.- 16.3.2 New types of chiral stationary phases.- 16.3.3 Use of computer-assisted modelling.- 16.3.4 Conclusions.- 16.4 Preparative liquid chromatography.- 16.4.1 Preparative chiral separations.- 16.4.2 Preparative diastereoisomer separations.- 16.4.3 Packings for preparative chiral HPLC.- References.