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Pharmaceutical Analysis

De
384 pages
The use of analytical sciences in the discovery, development and manufacture of pharmaceuticals is wide-ranging. From the analysis of minute amounts of complex biological materials to the quality control of the final dosage form, the use of analytical technology covers an immense range of techniques and disciplines.


This book concentrates on the analytical aspects of drug development and manufacture, focusing on the analysis of the active ingredient or drug substance. It provides those joining the industry or other areas of pharmaceutical research with a source of reference to a broad range of techniques and their applications, allowing them to choose the most appropriate analytical technique for a particular purpose.

The volume is directed at analytical chemists, industrial pharmacists, organic chemists, pharmaceutical chemists and biochemists.

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Contents
Contributors Preface
1
Quality control and regulation C.J. MOORES
1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9
Introduction The quality of medicines 1.2.1 The meaning of quality 1.2.2 Medicines are special 1.2.3 Endproduct testing General quality system requirements 1.3.1 ISO 9000 1.3.2 UKAS 1.3.3 NAMAS Good laboratory practice (GLP) 1.4.1 Organisation for economic cooperation and development (OECD) GLP guide 1.4.2 Principles of GLP Good manufacturing practice (GMP) 1.5.1 USA GMP regulations 1.5.2 EU/UK GMP requirements 1.5.3 USA/EU GMP differences 1.5.4 International GMPs International harmonisation of quality standards Quality control, quality assurance and regulatory filings 1.7.1 Preclinical development 1.7.2 Early phase development (Phases I/II) 1.7.3 Late phase development (Phase III) 1.7.4 Commercial manufacture Regulatory inspection key areas 1.8.1 Inspection of analytical test facilities 1.8.2 Computerised systems (21 CFR part 11) 1.8.3 Outofspecification (OOS) test results 1.8.4 System audits Conclusions and the future of regulatory scrutiny References
xiii xiv
1
1 2 2 3 3 4 6 7 8 9
9 10 11 11 13 14 16 16 17 18 19 20 20 21 21 24 26 28 29 30
vi
2
CONTENTS
Development of achiral separation methods in pharmaceutical analysis GEORGE N. OKAFO and JOHN K. ROBERTS
2.1
2.2
2.3
2.4
2.5
Introduction 2.1.1 Historical perspective of separation methods and their uses in pharmaceutical analysis 2.1.2 Regulatory considerations for separation methods in pharmaceutical analysis General guidance for method development in separation sciences 2.2.1 Separation goals/objectives 2.2.2 Nature of the sample 2.2.3 Choosing the separation technique 2.2.4 Sample pretreatment and detection 2.2.5 Developing the separation High performance liquid chromatography (HPLC) 2.3.1 Brief historical perspective of HPLC 2.3.2 Different modes of HPLC 2.3.3 Key developments in HPLC 2.3.3.1 Stationary phase and column technology 2.3.3.2 Instrumentation 2.3.3.3 Microcolumn liquid chromatography 2.3.3.4 Combined HPLC methods Gas chromatography (GC) 2.4.1 Brief historical perspective 2.4.2 GC in pharmaceutical analysis 2.4.3 Key developments in GC 2.4.3.1 Sensitivity enhancement with large volume injection 2.4.3.2 Thermally labile samples 2.4.3.3 Analytes in complex matrices 2.4.3.4 Detection systems 2.4.3.5 Efficiency increases in GC 2.4.3.6 Automation Capillary electrophoretic techniques 2.5.1 Brief historical perspective 2.5.2 Developments in detection modes in CE 2.5.3 Different modes and method development options in CE 2.5.3.1 Capillary zone electrophoresis 2.5.3.2 Micellar electrokinetic chromatography 2.5.3.3 Microemulsion electrokinetic chromatography 2.5.3.4 Capillary electrochromatography
31
31
32
34
34 35 38 39 41 43 44 44 44 45 45 47 48 48 49 49 50 52
52 52 52 53 53 54 54 54 55
55 55 57 57 57
3
4
CONTENTS
2.6 Other separation techniques 2.6.1 Thin layer chromatography 2.6.2 Supercritical fluid chromatography 2.7 Hyphenated separation techniques 2.8 Use of automated approaches to method development in chromatography 2.8.1 Separation optimisation programmes 2.8.2 Column switching devices 2.9 Use of chemometric approaches to method development Abbreviations References
Chiral analysis of pharmaceuticals W. JOHN LOUGH
3.1 Significance of chirality in pharmaceutical R&D 3.2 Evolution of methodologies for chiral resolution 3.3 Recent developments in commercial CSP for LC 3.3.1 Polysaccharidebased CSP 3.3.2 Macrocyclic antibiotic CSP 3.3.3 Synthetic multipleinteraction CSP 3.4 Role ofhistoricalCSP 3.5 Chiral drug bioanalysis 3.6 Preparative chiral separations 3.7 Present and future perspectives 3.7.1 Alternatives to chiral LC 3.7.2 Fit for intended purpose? 3.7.3 The future Ancillary reading References Commercial literature
Nuclear magnetic resonance spectroscopy in pharmaceutical analysis RICHARD J. SMITH and ANDREW J. EDWARDS
4.1 4.2
Introduction Structure elucidation 4.2.1 Background and historical perspective 4.2.2 The move to higher fields 1 4.2.3 Modern H NMR experiments 4.2.4 Nuclei other than the proton 13 4.2.4.1 C 19 4.2.4.2 F
vii
58 58 59 59
61 61 63 66 67 68
74
74 79 87 87 88 90 92 95 96 98 98 101 102 103 103 104
105
105 106 106 107 112 115 117 119
viii
5
CONTENTS
31 4.2.4.3 P 17 4.2.4.4 O 15 4.2.4.5 N 4.2.5 Computerassisted structure determination 4.2.5.1 Computerassisted interpretation 4.2.5.2 Computerassisted structure elucidation 4.3 Online separations 4.3.1 LC/NMR 4.3.1.1 Chromatographic considerations 4.3.1.2 NMR mode 4.3.1.3 Solvent suppression in LC/NMR 4.3.1.4 Applications of LC/NMR 4.3.1.5 LC/NMR/MS 4.3.1.6 Capillary LC/NMR 4.3.2 Hyphenation to other separation techniques 4.4 Quantitation 4.4.1 The basics of quantitation 4.4.2 Optimising the experimental parameters 4.4.3 Quantitative impurity determinations 4.4.4 Summary of experimental considerations 4.4.5 Method validation 4.5 Solid state NMR 4.5.1 Introduction 4.5.2 Basic theory of solid state NMR 4.5.3 Methods of assignment of solid state NMR spectra 4.5.3.1 Onedimensional editing methods 4.5.3.2 Twodimensional solid state methods 4.5.4 Distance measurements in the solid state – recoupling 4.5.4.1 Heteronuclear recoupling 4.5.4.2 Homonuclear recoupling 4.5.5 Application of solid state NMR to pharmaceuticals Acknowledgements References
Mass spectrometry in pharmaceutical analysis NEVILLE HASKINS
5.1 5.2
Introduction Mass spectrometry 5.2.1 Sample introduction systems 5.2.2 Ionisation techniques 5.2.2.1 Electron ionisation 5.2.2.2 Chemical ionisation
119 122 122 125 125 126 127 127 128 130 135 135 137 137 138 139 139 140 144 145 145 148 148 148 150 150 151 152 152 153
153 157 157
165
165 166 167 168 168 169
6
CONTENTS
5.2.2.3 Electrospray 5.2.2.4 Nanospray 5.2.2.5 Atmospheric pressure chemical ionisation (APCI) 5.2.3 Analysers 5.2.3.1 Sectors 5.2.3.2 Quadrupole analysers 5.2.3.3 Quadrupole ion traps 5.2.3.4 Time of flight analysers 5.2.3.5 Ion cyclotron resonance mass spectrometers 5.2.3.6 Hybrid instruments 5.2.4 Ion detection systems 5.2.4.1 Conversion dynode and electron multiplier 5.2.4.2 Conversion dynode and photon multipliers 5.2.5 Data acquisition and processing Strategies for structural elucidation 5.3.1 Determination of molecular weight n 5.3.2 Collisionally induced decomposition and MS 5.3.3 Accurate mass measurement Structural confirmation 5.4.1 Library searches n 5.4.2 Using MS techniques 5.4.3 Process monitoring Quantitation 5.5.1 Development of an assay 5.5.2 The calibration process 5.5.3 Use of stable isotopically labelled substance 5.5.4 Use of double labelling Using the data system 5.6.1 Automation 5.6.2 Data processing 5.6.3 Data mining References
5.3 5.4 5.5 5.6
Vibrational spectroscopy in pharmaceutical analysis CLARE L. ANDERTON
6.1
Introduction 6.1.1 Molecular motion 6.1.2 Infrared spectroscopy 6.1.2.1 Instrumentation for infrared spectroscopy 6.1.2.2 Sample preparation for infrared spectroscopy
ix
172 173 173 173 173 174 175 176
177 181 182 182 183 183 183 184 186 191 192 193 194 195 195 196 197 198 198 199 199 201 201 202
203
203 203 204 204
204
x
7
CONTENTS
6.1.3 Raman spectroscopy 6.1.3.1 Instrumentation for Raman spectroscopy 6.1.3.2 Sample preparation for Raman spectroscopy 6.1.4 Applications 6.2 Vibrational spectroscopy to investigate molecular structure 6.2.1 Introduction 6.2.2 Techniques in structural elucidation and specialist applications 6.2.2.1 Tautomerism 6.2.2.2 Hydrogen bonding 6.2.2.3 Chirality 6.2.2.4 Contaminant analysis 6.2.2.5 Products from combinatorial chemistry 6.2.2.6 Theoretical calculations 6.2.3 Routine chemical identification 6.3 Vibrational spectroscopy of polymorphs, hydrates and solvates 6.3.1 Introduction 6.3.2 Identifying structural differences between solidstate forms 6.3.2.1 Polymorphs 6.3.2.2 Hydrates and solvates 6.3.2.3 Amorphous material 6.3.3 Quantifying solidstate forms in drug substance 6.3.4 Identifying the solidstate form in formulated product 6.4 Vibrational spectroscopy for in situ characterisation 6.4.1 Investigating solid phase transformations 6.4.1.1 Variable temperature spectroscopy 6.4.1.2 Combining spectroscopy with other solidstate techniques 6.4.2 Monitoring chemical reactions and processes 6.4.3 Chromatography detection 6.5 Summary Acknowledgements References
Solidstate analysis and polymorphism ULRICH J. GRIESSER and JOSEPH G. STOWELL
7.1 7.2
Introduction Solidstate properties of drug compounds 7.2.1 Determinant levels of solidstate properties
205 208 209 210 211 211
211 211 211 212 212 213 214 216
216 216
218 218 220 222 224
226 228 228 228
231 231 234 236 236 236
240
240 242 242
8
CONTENTS
7.2.2 Types and properties of pharmaceutical solids 7.2.2.1 Crystalline solids 7.2.2.2 Amorphous solids 7.2.2.3 Regulatory aspects and quality control 7.3 Methods of solidstate analysis 7.3.1 Xray diffraction and crystallography 7.3.2 Spectroscopy 7.3.2.1 Ultravioletvisible diffuse reflectance spectroscopy 7.3.2.2 Infrared spectroscopy 7.3.2.3 Raman spectroscopy 7.3.2.4 Solidstate NMR 7.3.3 Thermal analysis and calorimetry 7.3.3.1 Thermomicroscopy (hotstage microscopy) 7.3.3.2 Differential thermal analysis and differential scanning calorimetry 7.3.3.3 Thermogravimetry 7.3.3.4 Thermomechanical analysis 7.3.3.5 Dielectric analysis 7.3.3.6 Microcalorimetry 7.3.4 Vapour pressure determination of solids 7.3.5 Micromeritic measurements 7.3.5.1 Particlesize analysis 7.3.5.2 Particle shape 7.3.5.3 Specific surface area 7.3.5.4 Porosity 7.3.5.5 Density 7.3.6 Other technologies 7.3.6.1 Atomic force microscopy 7.4 Summary References
Microscopy and imaging in pharmaceutical analysis ROBERT A. CARLTON
8.1 8.2
Introduction Solidstate analysis 8.2.1 Early stage solidstate analysis (polymorph discovery) 8.2.1.1 Optical crystallography 8.2.1.2 Solvent recrystallization experiments 8.2.1.3 Thermal microscopy 8.2.2 Late stage solidstate analysis (polymorph relationships) 8.2.3 Summary
xi
244 247 250 251 253 254 260
260 261 266 269 273 275
276 281 282 283 283 283 284 284 286 287 287 287 288 288 289 289
295
295 295 297 298 298 300 304 307
xii
9
CONTENTS
8.3 Particle size and morphology 8.3.1 Particle morphology 8.3.2 Particle size analysis/image analysis 8.3.3 Summary 8.4 Contaminant identification 8.5 Conclusion References
Process analysis in the pharmaceutical industry MARTIN WARMAN and STEVE HAMMOND
9.1 Introduction 9.2 Pharmaceutical manufacturing 9.2.1 Drug substance manufacture 9.2.1.1 Raw material testing 9.2.1.2 Reaction mixture 9.2.1.3 Reaction monitoring 9.2.1.4 Crystallisation monitoring 9.2.1.5 Dryer monitoring 9.2.1.6 Monitoring the milling process 9.2.1.7 Cleaning monitoring 9.2.2 Drug product manufacturing 9.2.2.1 Raw material monitoring 9.2.2.2 Formulation monitoring 9.2.2.3 Tablet cores 9.2.2.4 Tablet coating 9.2.2.5 Packaging 9.3 Conclusions References
Index
307 309 313 317 319 321 322
324
324 325 326 326 328 328 338 340 341 343 344 345 348 353 355 355 355 356
357