Separation Methods in Drug Synthesis and Purification

, by Valko, Klara

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ISBN: 9780444500076 | 0444500073
Cover: Hardcover
Copyright: 10/1/2000

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Supplemental Materials

Editor's Preface

Series Editor's Preface

List of Contributors

Comparison of various modes and phase systems for analytical HPLC

(72)

P. Jandera

Fundamentals of HPLC

(7)

Characteristics of HPLC separation

(1)

Elution development and chromatographic peaks

(1)

Basic characteristics of chromatographic separation

(2)

Retention factor and thermodynamic aspects of chromatography

(1)

Hydrodynamic (kinetic) aspects of chromatography, band broadening and column efficiency

(2)

Chromatographic column and column packing particles

(5)

HPLC column

(2)

Packing materials for HPLC

(3)

Separation modes in HPLC

(22)

Normal-phase chromatography

(1)

Stationary phases and retention mechanism

(1)

Retention behaviour in normal-phase chromatography

(1)

The mobile phase in normal-phase chromatography

(3)

Reversed-phase chromatography

(1)

Stationary phases in reversed-phase chromatography

(3)

Retention behaviour in reversed-phase chromatography

(1)

The mobile phase in reversed-phase chromatography

(1)

Retention behaviour of non-ionic solutes in reversed-phase chromatography

(2)

Reversed-phase chromatography of ionic compounds

(3)

Ion-pair chromatography

(2)

Micellar chromatography

(1)

Ion-exchange chromatography

(3)

Method development and optimisation of conditions in isocratic HPLC

(14)

Selection of the separation mode

(1)

Effects of experimental HPLC conditions on chromatographic resolution

(3)

Control of the separation efficiency

(1)

Effect of the temperature on separation

(1)

Adjustment of the composition of binary mobile phases

(1)

Selectivity control using ternary or more complex mobile phases

(4)

Computer-assisted optimisation of HPLC methods

(4)

Development of gradient-elution separations

(20)

Gradient-elution versus other HPLC programming techniques

(3)

Theory of HPLC with binary gradients

(1)

Gradient elution versus ioscratic elution - effects of the gradient profile on separation

(3)

Gradient elution in reversed-phase systems

(1)

Gradient elution in normal-phase and ion-exchange systems

(1)

Gradient-elution method development

(4)

Ternary gradients in HPLC

(6)

Sources of errors in prediction of retention in gradient-elution chromatography

(1)

Acknowledgements

(1)

References

(4)

Fast Generic HPLC methods

(14)

I.M. Mutton

Introduction

(1)

Theory

(1)

Production of fast gradients

(1)

Strategy for production of fast gradients

(7)

General strategy for standard bore columns

(4)

Production of fast gradients with small bore columns

(3)

Fast gradients in practice

(3)

References

(2)

Application of standard methods in capillary electrophoresis for drug analysis

(20)

K. Altria

Introducton to capillary electrophoresis

(2)

Analysis of pharmaceuticals by CE

(1)

Low-pH buffer for analysis of basic drugs

(2)

High-pH buffer for analysis of acidic drugs

(1)

Micellar electrokinetic chromatography (MEKC) for neutral and/or charged drugs

(2)

Microemulsion electrokinetic chromatography (MEEKC) for neutral and/or charged drugs

(2)

Indirect UV detection method for analysis of inorganic anions

(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

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Separation Methods in Drug Synthesis and Purification

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