Introduction to Pharmaceutical Chemical Analysis

Preface xv 1 Introduction to Pharmaceutical Analysis 1 1.1 Applications and Definitions 1 1.2 The Life of Medicines 4 1.3 The Quality of Medical Products 8 1.4 Summary 11 2 International Pharmacopoeias, Regulations and Guidelines 13 2.1 Overview of Legislation 13 2.2 Legislation and Regulations for Industrial Production 14 2.3 Life Time of Drugs and Drug Substances 17 2.4 Pharmacopoeias 18 2.5 International Harmonization 19 2.6 Legislation and Regulations for Pharmacy Production 20 2.7 Summary 21 3 Fundamental Chemical Properties, Buffers and pH 23 3.1 pH and pKa 23 3.2 Partition 25 3.3 Stereochemistry 28 3.4 Stability Testing 29 3.5 Summary 30 4 Fundamentals of Pharmaceutical Analysis 33 4.1 What is a Pharmaceutical (Chemical) Analysis? 33 4.2 How to Specify Quantities and Concentrations? 35 4.3 Basic Laboratory Equipment 37 4.4 How to Make Solutions and Dilutions 47 4.5 Calibration of Analytical Methods 49 4.6 Errors, Accuracy, and Precision 50 4.7 Statistics 52 4.8 Some Words and Concepts 62 5 Titrimetric Methods 65 5.1 Introduction 65 5.2 Acid-Base Titrations 72 5.3 Acid-Base Titrations in Non-Aqueous Media 75 5.4 Redox Titrations 78 5.5 Other Principles of Titration 81 5.6 Summary 82 6 Introduction to Spectroscopic Methods 83 6.1 Electromagnetic Radiation 83 6.2 Molecules and Electromagnetic Radiation 85 6.3 Atoms and Electromagnetic Radiation 86 6.4 Summary 88 7 UV Spectrophotometry 89 7.1 Principle of Quantitative Determination 89 7.2 Principle of Identification 94 7.3 Which Substances Have Strong UV Absorbance? 95 7.4 Instrumentation 95 7.5 Practical Work and Method Development 99 7.6 Areas of Usage and Performance 101 7.7 System Testing 101 7.8 Summary 102 8 IR Spectrophotometry 103 8.1 IR Spectrophotometry 103 8.2 Instrumentation 106 8.3 Scope 109 8.4 Instrument Calibration 109 8.5 NIR Spectrophotometry 110 8.6 Applications 112 8.7 Summary 114 9 Atomic Spectrometry 115 9.1 Atomic Absorption Spectrometry 115 9.2 Instrumentation 118 9.3 Applications and Performance 121 9.4 Practical Work and Method Development 122 9.5 Atomic Emission Spectrometry 123 9.6 Instrumentation 124 9.7 Summary 124 10 Chromatography 127 10.1 General Principles 127 10.2 Retention 131 10.3 Column Efficiency 133 10.4 Selectivity 135 10.5 Peak Symmetry 136 10.6 Resolution 138 10.7 Chromatographic Techniques 140 10.8 Summary 140 11 Chromatographic Separation Principles 141 11.1 General Introduction 141 11.2 Normal Phase Chromatography 142 11.3 Reversed Phase Chromatography 148 11.4 Hydrophilic Interaction Chromatography 156 11.5 Chiral Separations 156 11.6 Size Exclusion Chromatography 158 11.7 Ion Exchange Chromatography 160 12 Thin-Layer Chromatography 163 12.1 Introduction 163 12.2 Apparatus 164 12.3 TLC Plates 166 12.4 Stationary Phases 166 12.5 Mobile Phases 167 12.6 Chromatographic Development 168 12.7 Detection 169 12.8 Applications of TLC 169 12.9 Quantitative Analysis and Instrumentation 170 12.10 Summary 171 13 High Performance Liquid Chromatography 173 13.1 Introduction 173 13.2 The Chromatographic Separation Process 175 13.3 The Column 177 13.4 Pumps 180 13.5 Detectors 182 13.6 Injectors 187 13.7 Mobile Phases 188 13.8 Solvents for Sample Preparation 189 13.9 Reporting the Results 189 13.10 Summary 190 14 Gas Chromatography 191 14.1 Introduction 191 14.2 Apparatus 192 14.3 Temperature 193 14.4 Carrier Gas 195 14.5 Stationary Phases 196 14.6 Selectivity in GC 197 14.7 Columns 198 14.8 Injection Systems 200 14.9 Detectors 203 14.10 Derivatization 206 14.11 The Uses of GC 208 14.12 More Advanced GC techniques 209 14.13 Summary 209 15 Capillary Electrophoresis 211 15.1 Principle and Theory 211 15.2 Electroosmotic Flow 213 15.3 Instrumentation 214 15.4 The Capillary 217 15.5 Sample Introduction 218 15.6 Capillary Zone Electrophoresis; an Example 221 15.7 Micellar Electrokinetic Chromatography 222 15.8 Chiral Separations 224 15.9 Coated Capillaries 225 15.10 Non-Aqueous CE 229 15.11 Summary 229 16 Mass Spectrometry 231 16.1 Introduction 231 16.2 Basic Theory 233 16.3 Electron Ionization 236 16.4 Identification using Electron Ionization Spectra 237 16.5 Characterization of Totally Unknowns using Electron Ionization Spectra 239 16.6 Chemical Ionization 244 16.7 Electrospray Ionization 246 16.8 Atmospheric Pressure Chemical Ionization 247 16.9 High-Resolution Mass Spectrometry 248 16.10 Instrumentation 250 16.11 Chromatography Coupled with Mass Spectrometry 253 16.12 Quantitative GC-MS and LC-MS 256 16.13 Areas of Usage and Performance 257 16.14 Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry 257 16.15 Inductively Coupled Plasma Mass Spectrometry 258 16.16 Summary 259 17 Miscellaneous Chemical Techniques 261 17.1 Potentiometric Determination of Ions using Ion-Selective Electrodes 261 17.2 Paper Chromatography 263 17.3 Supercritical Fluid Chromatography 264 17.4 Gel Electrophoresis 265 17.5 Iso-Electric Focusing 267 17.6 Nuclear Magnetic Resonance Spectrometry 268 17.7 Raman Spectrometry 270 18 Sample Preparation 273 18.1 Why is Sample Preparation Required? 273 18.2 Main Strategies 274 18.3 Recovery and Enrichment 276 18.4 Protein Precipitation 278 18.5 Liquid-Liquid Extraction 279 18.6 Solid-Liquid Extraction 287 18.7 Solid Phase Extraction 287 18.8 Summary 298 19 Analytical Chemical Characteristics of Selected Drug Substances 299 19.1 Amitriptyline and Mianserin 299 19.2 Morphine and Codeine 301 19.3 Ibuprofen and Naproxen 302 19.4 Furosemide 304 19.5 Paracetamol (Acetaminophen) 306 19.6 Neutral Drugs 307 20 Quantification and Quality of Analytical Data 309 20.1 Peak Height and Peak Area 309 20.2 Calibration Methods 310 20.3 Validation 314 20.4 System Suitability 325 21 Chemical Analysis of Drug Substances 327 21.1 What is a Pharmaceutical Raw Material, how is it Produced and why must it be Controlled? 327 21.2 The Pharmacopoeias - the Basis for Control of Pharmaceutical Raw Materials 330 21.3 Which Contaminants are Found in Raw Materials, What are the Requirements in a Maximum Content and Why? 337 21.4 How to Check the Identity of Pharmaceutical Raw Materials 344 21.5 How to Test for Impurities in Pharmaceutical Raw Materials 359 21.6 How to Determine the Purity of Pharmaceutical Raw Materials 389 21.7 How to Control Compounds for Which no Pharmacopoeia Monograph Exists 402 21.8 How are Ph.Eur. and USP Updated? 402 22 Chemical Analysis of Final Pharmaceutical Products 405 22.1 Quality Control of Final Pharmaceutical Products 405 22.2 Monographs and Chemical Testing 406 22.3 Identification of the Active Pharmaceutical Ingredient 412 22.4 Assay of the Active Pharmaceutical Ingredient 427 22.5 Chemical Tests for Final Pharmaceutical Products 446 23 Analysis of Drugs in Biological Fluids 453 23.1 Introduction 453 23.2 The Biological Matrix 458 23.3 Bioanalytical Methods 460 23.4 Examples 466 Index 477