Separation Methods in Drug Synthesis and Purification

by Valko, Klara

• ISBN13: 9780444500076
• ISBN10: 0444500073
• Edition: 1st
• Format: Hardcover
• Copyright: 2000-10-01
• Publisher: Elsevier Science Ltd

Table of Contents

Editor's Preface	v
Series Editor's Preface	ix
List of Contributors	xi
Comparison of various modes and phase systems for analytical HPLC	1	(72)
P. Jandera
Fundamentals of HPLC	1	(7)
Characteristics of HPLC separation	1	(1)
Elution development and chromatographic peaks	2	(1)
Basic characteristics of chromatographic separation	3	(2)
Retention factor and thermodynamic aspects of chromatography	5	(1)
Hydrodynamic (kinetic) aspects of chromatography, band broadening and column efficiency	6	(2)
Chromatographic column and column packing particles	8	(5)
HPLC column	8	(2)
Packing materials for HPLC	10	(3)
Separation modes in HPLC	13	(22)
Normal-phase chromatography	13	(1)
Stationary phases and retention mechanism	13	(1)
Retention behaviour in normal-phase chromatography	14	(1)
The mobile phase in normal-phase chromatography	15	(3)
Reversed-phase chromatography	18	(1)
Stationary phases in reversed-phase chromatography	19	(3)
Retention behaviour in reversed-phase chromatography	22	(1)
The mobile phase in reversed-phase chromatography	23	(1)
Retention behaviour of non-ionic solutes in reversed-phase chromatography	24	(2)
Reversed-phase chromatography of ionic compounds	26	(3)
Ion-pair chromatography	29	(2)
Micellar chromatography	31	(1)
Ion-exchange chromatography	32	(3)
Method development and optimisation of conditions in isocratic HPLC	35	(14)
Selection of the separation mode	35	(1)
Effects of experimental HPLC conditions on chromatographic resolution	36	(3)
Control of the separation efficiency	39	(1)
Effect of the temperature on separation	40	(1)
Adjustment of the composition of binary mobile phases	40	(1)
Selectivity control using ternary or more complex mobile phases	41	(4)
Computer-assisted optimisation of HPLC methods	45	(4)
Development of gradient-elution separations	49	(20)
Gradient-elution versus other HPLC programming techniques	49	(3)
Theory of HPLC with binary gradients	52	(1)
Gradient elution versus ioscratic elution - effects of the gradient profile on separation	53	(3)
Gradient elution in reversed-phase systems	56	(1)
Gradient elution in normal-phase and ion-exchange systems	57	(1)
Gradient-elution method development	58	(4)
Ternary gradients in HPLC	62	(6)
Sources of errors in prediction of retention in gradient-elution chromatography	68	(1)
Acknowledgements	69	(1)
References	69	(4)
Fast Generic HPLC methods	73	(14)
I.M. Mutton
Introduction	73	(1)
Theory	74	(1)
Production of fast gradients	74	(1)
Strategy for production of fast gradients	75	(7)
General strategy for standard bore columns	75	(4)
Production of fast gradients with small bore columns	79	(3)
Fast gradients in practice	82	(3)
References	85	(2)
Application of standard methods in capillary electrophoresis for drug analysis	87	(20)
K. Altria
Introducton to capillary electrophoresis	87	(2)
Analysis of pharmaceuticals by CE	89	(1)
Low-pH buffer for analysis of basic drugs	90	(2)
High-pH buffer for analysis of acidic drugs	92	(1)
Micellar electrokinetic chromatography (MEKC) for neutral and/or charged drugs	93	(2)
Microemulsion electrokinetic chromatography (MEEKC) for neutral and/or charged drugs	95	(2)
Indirect UV detection method for analysis of inorganic anions	97	(3)
Indirect UV detection method for analysis of simple organic acids	100	(1)
Indirect UV detection method for analysis of metal ions	101	(1)
Non-aqueous CE for analysis of acidic and basic drugs	102	(1)
Benefits of adopting standard CE methods	103	(2)
References	105	(2)
Chapillary electrochromatography (CEC)	107	(20)
C.J. Paterson
R.J. Boughflower
Introduction	107	(1)
Basic principles of capillary electrochromatography	108	(5)
Electroendosmotic flow	108	(1)
Factors that influence electroendosmotic flow (EOF)	109	(1)
Dispersion	110	(2)
Thermal effects in CEC	112	(1)
Mobile phase composition	113	(1)
Stationary phases used in CEC	113	(4)
Operational characteristics of CEC	117	(5)
Sampling	117	(1)
Detection	118	(4)
Gradient and pressure-assisted (pseudo) CEC	122	(1)
Conclusions	123	(1)
Glossary of symbols	123	(1)
References	124	(3)
Coupled chromatography-mass spectrometry techniques for the analysis of combinatorial libraries	127	(36)
S. Lane
Introduction	127	(3)
Lc/MS analysis of high-throughout parallel synthesis libraries	130	(10)
Development of walk-up open-access LC/UV/MS systems	132	(2)
System components	134	(6)
Example for monitoring the rehearsal phase of the synthesis of a solid-phase library	140	(4)
LC/UV/MS as a pre-screen for autoprep-solution phase	144	(7)
Purity profile for phenyl analogue (Fig 5.14)	144	(1)
Purity profile for carboxy analogue (Fig 5.15)	145	(6)
Purity profile for cyano analogue (Fig. 5.16)	151	(1)
Assisted automated LC/MS analysis	151	(1)
The analysis of split-pool combinatorial libraries	152	(7)
Conclusions and future	159	(1)
References	160	(3)
Optimization strategies for HPLC and CZE	163	(50)
Y. Vander Heyden
C. Perrin
D.L. Massart
Introduction	163	(2)
Responses and response functions	165	(5)
Univariate optimization strategies	170	(2)
Factorial methods	172	(25)
Full factorial designs	172	(5)
Screening designs	177	(6)
Response surface designs	183	(1)
Classical symmetrical designs	184	(4)
Non-symmetrical designs	188	(4)
Models	192	(5)
Mixture designs	197	(4)
Robustness/ruggedness	201	(2)
The simplex sequential approach	203	(6)
Automating the whole process: expert systems and knowledge based systems	209	(1)
References	210	(3)
Stragegies for the development of process chromatography as a unit operation for the pharmaceutical industry	213	(80)
A.M. Katti
Introduction	213	(4)
The process development cycle	217	(8)
Process discovery, development and implementation	217	(5)
Organizational issues	222	(3)
Chromatographic unit operations development	225	(1)
Discovery experiment stage	225	(7)
Limiting impurity	228	(1)
Separation factor	228	(2)
Column saturation capacity	230	(1)
Relationship between flow rate and plate count	231	(1)
Development stage	232	(11)
Experimental development and modeling	233	(1)
Modes of chromatography	234	(1)
Optimum loading factor	235	(1)
Optimum column length	236	(1)
Optimum flow rate	237	(1)
Required number of plates	237	(1)
Regeneration and equilibration	238	(1)
Analytical methods	238	(1)
Equipment design	238	(1)
Pumps	239	(1)
Piping, valves and pressure relief	239	(1)
Pulse dampeners	240	(1)
Filtration and guard columns	240	(1)
Columns	241	(1)
Detectors	241	(1)
Scale-up	241	(2)
Economics	243	(32)
Economies of scale	248	(4)
Pressure	252	(3)
Column saturation capacity	255	(4)
Particle size	259	(2)
Separation factor(α)	261	(2)
Retention factor(k')	263	(4)
Crude costs ($/g)	267	(1)
Solvent costs ($/g)	267	(5)
Purity	272	(1)
Diffusivity	273	(2)
Safety and environmental	275	(7)
Regulatorya and compliance	282	(6)
Flow rate	284	(1)
Temperature	285	(1)
Composition of mobile phase, regeneration solution and local solution	285	(1)
Packing efficiency	286	(1)
Load concentration or volume	287	(1)
Cut point location strategy	287	(1)
List of symbols	288	(1)
Acknowledgements	289	(1)
References	289	(4)
The development and industrial application of automated preparative HPLC	293	(44)
T. Underwood
R.J. Boughflower
K.A. Brinded
Introduction	293	(3)
Instrumental considerations	296	(3)
Hardware configuration	296	(1)
Stationary phase selection	297	(2)
Operating principles and gradient details	299	(1)
A worked example	300	(11)
Analytical scale investigation	300	(1)
Preparative scale-up and sample introduction considerations	301	(2)
Validation of the preparative chromatography	303	(6)
The autoprep purification	309	(2)
Practical considerations and `calibrated' methods	311	(16)
Problems with the initial generic approach	311	(4)
The `calibrated' method for hydrophilic compounds	315	(5)
`Calibrated' methods and the advantages of their application	320	(7)
Additional system developments	327	(2)
Mass directed autoprep	329	(6)
The addition of a mass spectrometer	329	(1)
Mass spectrometer considerations and chromatography adjustments	330	(2)
Instrumental layout and software demands	332	(1)
MS-prep system refinements	333	(2)
Conclusion	335	(1)
Acknowledgements	336	(1)
References	336	(1)
Recent developments in liquid chromatographic enantioseparation	337	(102)
M. Lammerhofer
W. Lindner
Introduction	337	(11)
Impact of stereochemistry on drug development	337	(1)
Historical background of modern liquid-phase enantioseparation	338	(1)
Scope and aims of this chapter	339	(1)
Mechanism of chiral recognition and enantioseparation	339	(9)
Direct enantioseparation by liquid chromatography with chiral stationary phases (CSPs) - chiral selectors and chiral recognition mechanisms	348	(71)
Polymeric type selectors and chiral stationary phases	350	(1)
Polymeric type CSPs primarily operated in the non-aqueous mobile phase mode	350	(15)
Protein type CSPs - representing a class of polymeric type CSPs which can be used with aqueous mobile phases	365	(8)
CSPs with macrocyclic, oligomeric and/or intermediate molecular size selectors	373	(1)
Cylodextrin derived CSPs	373	(8)
CSPs with macrocyclic glycopeptide antibiotics as selectors	381	(11)
Crown-ether type CSPs	392	(3)
Low molecular weight selectors	395	(1)
CSPs based on chiral selectors related to the Pirkle concept	395	(10)
Chiral ion exchangers	405	(9)
Ligand-exchange type CSPs	414	(4)
Summary on CSPs	418	(1)
Some aspects of preparative enantioseparation methods	419	(3)
Other enantioselecgtive liquid-phase separation techniques	422	(3)
General conclusion	425	(1)
Addendum to literature - books on chiral discrimination	425	(1)
References	426	(13)
Basis and pharmaceutical applications of thin-layer chromatography	439	(64)
H. Kalasz
M. Bathori
Planar chromatography	439	(9)
Historical overview	440	(1)
Basic formulas for TLC	441	(1)
Advantages of planar chromatography	442	(1)
Solvent propagation	443	(2)
Elution, frontal and displacement modes	445	(1)
Planar vs. column chromatography	446	(1)
Advances in thin-layer chromatography	447	(1)
Multidimensional planar chromatography	448	(1)
The components of the planar stationary phase	448	(8)
Stationary phases for chromatography	448	(1)
Silica gels	448	(2)
Inert stationary phase containing silicium dioxides	450	(1)
Aluminas	450	(1)
Magnesia (magnesium oxide, magnesium hydroxide)	451	(1)
Celluloses	451	(1)
Polyamides	451	(1)
Sephadex and BioGel P gels	452	(1)
Chemically modified stationary phases	452	(1)
Ion exchangers	453	(1)
Methods and stationary phases for enantiomeric separations	453	(1)
Mixed stationary phases	454	(1)
Special additives to the stationary phase	454	(1)
Binders	454	(1)
UV indicators	455	(1)
Precoated plates	455	(1)
Mobile phases for thin-layer chromatography	456	(2)
Optimisation of solvent systems	457	(1)
The chambers	458	(6)
Simple chambers	458	(1)
Chambers in instrumental TLC	459	(1)
Centrifugal thin-layer chromatography	459	(1)
High-speed thin-layer chromatography	459	(1)
Automated multiple development (AMD)	459	(1)
Forced-flow thin-layer chromatography (FF-TLC)	460	(4)
Detection	464	(7)
Monitoring	464	(1)
Non-destructive detections	465	(2)
Detection of TLC with on-line coupled spectroscopic methods other than UV and/or visible monitoring	467	(1)
HPTLC-FTIR on-line coupling	467	(1)
TLC-MS coupling	468	(1)
TLC-NMR coupling	469	(1)
X-ray detection	469	(1)
Electrochemical detection	469	(1)
Destructive detection	470	(1)
Colour reagents	470	(1)
Flame-ionisation detector (FID)	471	(1)
Application of TLC in pharmaceutical and forensic analysis	471	(23)
Analysis of drugs and metabolities	471	(21)
Application of TLC in the study of lipophilicity	492	(2)
Quo vadis thin-layer chromatography	494	(4)
Acknowledgements	498	(1)
References	498	(5)
Recent advances in quantitative structure-retention relationships (QSRR)	503	(32)
R. kaliszan
Intruction	503	(2)
Strategy of QSRR research	505	(8)
Retention data for QSRR	506	(3)
Chemometic methodology	509	(2)
Structural descriptors for QSRR	511	(2)
Retention prediction	513	(5)
Molecular mechanisms of retention in view of QSRR	518	(4)
Chromatographic methods of determination of hydrophobicity	522	(2)
Applications of QSRR in molecular pharmacology and rational drug design	524	(5)
Conclujding remarks	529	(1)
References	530	(5)
Measurements of physical properties for drug design in industry	535	(50)
K. Valko
Introduction	535	(1)
Measurements of compound lipophilicity using chromatography	536	(13)
Measurements of liquid-liquid partition	536	(6)
Measurements of chromatographic partition	542	(1)
Application of gas chromatography	542	(1)
Applicationof thin-layer chromatography (TLC)	543	(1)
Application of reversed-phase high-performance liquid chromatography (RP-HPLC)	543	(6)
Measuremenrts of members transport by immobilised artificial membrane (IAM) HPLC	549	(3)
Measurements of drug-protein binding constants using chromatography	552	(5)
Measurements of solubility by HPLC	557	(2)
Concentration determination by HPLC for solubility measurements	557	(1)
Partition coefficient determination for solubility estimation	558	(1)
Measurements of acid-base character (pKa) by HPLC	559	(5)
pH dependence of lipophilicity and solubility	559	(2)
pH dependence of chromatographic retention	561	(1)
Estimation of lipophility of pKa by gradient reversed-phase chromatography	562	(2)
Measurements of H-bond acidity, and polarisability-dipolarity by HPLC	564	(16)
The importance of H-bond acidity, basicity and polarisability-dipolarity in describing various partition processes and solubility	564	(1)
Description of various lipophilicity scales by molecular descriptors (solvation equations)	564	(3)
Description of various chromatographic lipophilicity scales by the molecular descriptors	567	(1)
Description of solubility by the molecular descriptors	568	(1)
Determination of molecular descriptors by chromatography	569	(11)
Conclusion	580	(1)
References	580	(5)
Subject Index	585