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Introduction to Pharmaceutical Chemical Analysis

ISBN: 978-0-470-66122-2
510 pages
December 2011
Introduction to Pharmaceutical Chemical Analysis (0470661224) cover image
This textbook is the first to present a systematic introduction to chemical analysis of pharmaceutical raw materials, finished pharmaceutical products, and of drugs in biological fluids, which are carried out in pharmaceutical laboratories worldwide.

In addition, this textbook teaches the fundamentals of all the major analytical techniques used in the pharmaceutical laboratory, and teaches the international pharmacopoeias and guidelines of importance for the field. It is primarily intended for the pharmacy student, to teach the requirements in “analytical chemistry” for the 5 years pharmacy curriculum, but the textbook is also intended for analytical chemists moving into the field of pharmaceutical analysis.

  • Addresses the basic concepts, then establishes the foundations for the common analytical methods that are currently used in the quantitative and qualitative chemical analysis of pharmaceutical drugs
  • Provides an understanding of common analytical techniques used in all areas of pharmaceutical development
  • Suitable for a foundation course in chemical and pharmaceutical sciences
  • Aimed at undergraduate students of degrees in Pharmaceutical Science/Chemistry Analytical Science/Chemistry, Forensic analysis
  • Includes many illustrative examples

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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

2.5.1 International Conference on Harmonization 20

2.5.2 Pharmacopoeial Discussion Group 20

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

4.3.1 The Analytical Balance 37

4.3.2 Pipettes 41

4.3.3 Volumetric Flasks 44

4.3.4 Burettes 47

4.4 How to Make Solutions and Dilutions 47

4.5 Calibration of Analytical Methods 49

4.6 Errors, Accuracy, and Precision 50

4.6.1 Systematic and Random Errors 50

4.6.2 Accuracy and Precision 51

4.7 Statistics 52

4.7.1 Mean Value and Standard Deviation 52

4.7.2 Confidence Intervals 54

4.7.3 Comparison of Means with a t-Test 55

4.7.4 Q-Test to Reject Outliers 56

4.7.5 Linear Regression with the Method of Least Squares 57

4.7.6 How to Present an Analytical Result 58

4.8 Some Words and Concepts 62

4.8.1 Analysis and Determination 62

4.8.2 Sample Replicates and Measuring Replicates 62

4.8.3 Interference 62

4.8.4 Blind Samples 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

11.2.1 Silica 142

11.2.2 Interactions 143

11.2.3 Order of Elution 144

11.2.4 Other Stationary Phases 145

11.2.5 Mobile Phases 146

11.2.6 Summary of Normal Phase Chromatography 147

11.3 Reversed Phase Chromatography 148

11.3.1 Stationary Phases 148

11.3.2 Retention Mechanisms 150

11.3.3 Mobile Phases 152

11.3.4 Ion-Pair Chromatography 155

11.3.5 Summary of Reversed Phase Chromatography 155

11.4 Hydrophilic Interaction Chromatography 156

11.5 Chiral Separations 156

11.6 Size Exclusion Chromatography 158

11.6.1 Principle 158

11.6.2 Summary of SEC 160

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

13.5.1 UV detector 182

13.5.2 Fluorescence Detector 184

13.5.3 Electrochemical Detector 186

13.5.4 Refractive Index, Evaporative Light Scattering and Corona Discharge Detectors 186

13.5.5 Combination of Detectors 187

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

14.7.1 Capillary Columns 198

14.7.2 Packed Columns 199

14.8 Injection Systems 200

14.8.1 Injection Systems for Capillary Columns 200

14.8.2 Injection Systems for Packed Columns 202

14.9 Detectors 203

14.9.1 Flame Ionization Detector 203

14.9.2 Nitrogen–Phosphorus Detector 203

14.9.3 Thermal Conductivity Detector 204

14.9.4 Electron Capture Detector 204

14.9.5 Mass Spectrometry Detector 206

14.10 Derivatization 206

14.10.1 Silylation 206

14.10.2 Alkylation 207

14.10.3 Acylation 207

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

18.5.1 Fundamentals 279

18.5.2 A Closer Look at the Theory 279

18.5.3 Extraction Solvents 282

18.5.4 Calculation of Recovery 283

18.5.5 Multiple Extractions 285

18.5.6 LLE with Back-Extraction 286

18.6 Solid–Liquid Extraction 287

18.7 Solid Phase Extraction 287

18.7.1 Fundamentals 287

18.7.2 The SPE Column 288

18.7.3 Conditioning 289

18.7.4 Equipment 290

18.7.5 Reversed-Phase SPE 290

18.7.6 Secondary Interactions 292

18.7.7 Ion Exchange SPE 293

18.7.8 Mixed-Mode SPE 295

18.7.9 Normal-Phase SPE 297

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

20.2.1 External Standard Method 310

20.2.2 Internal Standard Method 313

20.2.3 Standard Addition 314

20.2.4 Normalization 314

20.3 Validation 314

20.3.1 Analytical Procedure 317

20.3.2 Accuracy 317

20.3.3 Precision 318

20.3.4 Specificity 320

20.3.5 Detection Limit 320

20.3.6 Quantification Limit 321

20.3.7 Linearity and Range 321

20.3.8 Robustness 323

20.3.9 Test Methods in the European Pharmacopeia 325

20.4 System Suitability 325

20.4.1 Adjustment of Chromatographic Conditions 326

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

21.3.1 Well Defined Chemical Compounds 339

21.3.2 Mixtures of Organic Compounds 343

21.4 How to Check the Identity of Pharmaceutical Raw Materials 344

21.4.1 Overview of the Identification Procedures 344

21.4.2 Techniques used for the Identification of Well Defined Chemical Compounds 344

21.4.2.1 Infrared Absorption Spectrophotometry 344

21.4.2.2 Ultraviolet and Visible Absorption Spectrophotometry 347

21.4.2.3 Thin-Layer Chromatography 351

21.4.2.4 Melting Point 352

21.4.2.5 Polarimetry 353

21.4.2.6 High Performance Liquid Chromatography 356

21.4.2.7 Chloride and Sulfate Identification 359

21.5 How to Test for Impurities in Pharmaceutical Raw Materials 359

21.5.1 Main Purity Tests for Well Defined Chemical Compounds 359

21.5.1.1 Appearance of Solution 361

21.5.1.2 Absorbance 364

21.5.1.3 Acidity/Alkalinity 365

21.5.1.4 Optical Rotation 365

21.5.1.5 Related Substances 366

21.5.1.6 Solvent Residues 372

21.5.1.7 Foreign Anions 372

21.5.1.8 Cationic Impurities 376

21.5.1.9 Loss on Drying 378

21.5.1.10 Determination of Water 379

21.5.2 Purity Tests for Raw Materials of the Type of Mixtures of Organic Compounds 382

21.5.2.1 Oxidizing Substances 383

21.5.2.2 Acid Value 383

21.5.2.3 Hydroxyl Value 384

21.5.2.4 Iodine Value 384

21.5.2.5 Peroxide Value 385

21.5.2.6 Saponification Value 385

21.5.2.7 Unsaponifiable Matter 386

21.5.2.8 Other Tests 386

21.5.3 Identification of the Raw Materials of the Type of Mixtures of Organic Compounds 388

21.6 How to Determine the Purity of Pharmaceutical Raw Materials 389

21.6.1 Acid–Base Titration in Aqueous Environment 389

21.6.2 Acid–Base Titration in a Non-Aqueous Environment 393

21.6.3 Redox Titrations 396

21.6.4 High Performance Liquid Chromatography 396

21.6.5 UV spectrophotometry 401

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

22.5.1 Test for Related Substances 446

22.5.2 Uniformity of Content 449

22.5.3 Dissolution 451

23 Analysis of Drugs in Biological Fluids 453

23.1 Introduction 453

23.1.1 Drug Development 453

23.1.2 Therapeutic Drug Monitoring 455

23.1.3 Forensic and Toxicological Analysis 456

23.1.4 Doping Control Analysis 457

23.2 The Biological Matrix 458

23.3 Bioanalytical Methods 460

23.3.1 Sampling 460

23.3.2 Sample Preparation 461

23.3.3 Protein Precipitation 462

23.3.4 Liquid–Liquid Extraction 463

23.3.5 Solid-Phase Extraction 463

23.3.6 Separation 464

23.3.7 Detection 464

23.3.8 Calibration and Quantification 465

23.4 Examples 466

23.4.1 Sample Preparation 466

23.4.1.1 Sample Preparation Procedure by LLE 466

23.4.1.2 Comments to the Procedure 466

23.4.1.3 Sample Preparation Procedure by LLE and Back Extraction 467

23.4.1.4 Comments to the Procedure 467

23.4.1.5 Sample Preparation Procedure by SPE 467

23.4.1.6 Comments to the Procedure 468

23.4.1.7 Sample Preparation Procedure by Protein Precipitation 468

23.4.1.8 Comments to the Procedure 468

23.4.2 Quantitative Determination 468

23.4.2.1 Quantitative Determination of Amitriptyline in Serum by LC-MS 468

23.4.2.2 Comments to the Procedure 469

23.4.2.3 Determination of Valproic Acid in Serum by GC-MS 471

23.4.2.4 Comments to the Procedure 471

23.4.3 Identification 472

23.4.3.1 Sample Preparation Procedure for Unknown Screening by Mixed Mode Cation Exchange 472

23.4.3.2 Comments to the Procedure 472

23.4.3.3 GC-MS Procedure for Unknown Screening 473

23.4.3.4 Comments to the Procedure 473

23.4.3.5 LC-MS-MS Procedure for Unknown Screening 475

23.4.3.6 Comments to the Procedure 475

Index 477

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Steen Hansen is professor in analytical chemistry at the Faculty of Pharmaceutical Sciences at Copenhagen University (Denmark), and has extensive experience in the teaching of analytical chemistry for pharmacy students. His main research interests are in basic separation sciences (primarily HPLC and CE), in particular on separation mechanisms, but also extend into hyphenated techniques using NMR and ICP-MS besides conventional detection techniques. He has authored and/or coauthored more than 240 papers in international peer-review journals. For 20 years, he was the President of the Scandinavian Section of The Chromatographic Discussion Group until this was renamed the Separation Sciences Foundation of which he is President.

Knut Einar Rasmussen is professor in pharmacy at the School of Pharmacy at University of Oslo (Norway) and has similarly long experience in teaching of drug analysis for Pharmacy students. He has published extensively and his main research areas are focused on the development of innovative state-of-the-art miniaturized methods in separation science combined with detection and structure determination of drugs, naturally occurring biomolecules/biomarkers and environmental biomarkers.

Stig Pedersen-Bjergaard is professor at at the School of Pharmacy, University of Oslo (Oslo, Norway) as well as in 2008, being appointed as full Professor (part time) at Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen (Copenhagen, Denmark). SPB has specialized in analytical micro extraction technologies, on development and applications of artificial liquid membranes, and on electrokinetic separation methods. SPB has published more than 90 papers in international journals, given more than 65 presentations at international symposia, authored 6 patent applications, and is a member of the Editorial board for Analytica Chimica Acta and International Journal of Analytical Chemistry.

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"It is teaches the fundamentals of all the major analytical techniques and their application in pharmaceutical laboratories, and it is valuable resource for pharmacy students and analytical chemists working in pharmaceutical analysis."  (Analytical and Bioanalytical Chemistry, 1 August 2012)

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