Introduction to Pharmaceutical Chemical Analysis

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1 Introduction to Pharmaceutical Chemical Analysis Hansen, Steen ISBN-13: Table of Contents Preface xv 1 Introduction to Pharmaceutical Analysis Applications and Definitions The Life of Medicines The Quality of Medical Products Summary 11 2 International Pharmacopoeias, Regulations and Guidelines Overview of Legislation Legislation and Regulations for Industrial Production Life Time of Drugs and Drug Substances Pharmacopoeias International Harmonization International Conference on Harmonization Pharmacopoeial Discussion Group Legislation and Regulations for Pharmacy Production Summary 21 3 Fundamental Chemical Properties, Buffers and ph ph and pka Partition Stereochemistry Stability Testing Summary 30 4 Fundamentals of Pharmaceutical Analysis What is a Pharmaceutical (Chemical) Analysis? How to Specify Quantities and Concentrations? Basic Laboratory Equipment The Analytical Balance Pipettes Volumetric Flasks Burettes How to Make Solutions and Dilutions Calibration of Analytical Methods Errors, Accuracy, and Precision 50

2 4.6.1 Systematic and Random Errors Accuracy and Precision Statistics Mean Value and Standard Deviation Confidence Intervals Comparison of Means with a t-test Q-Test to Reject Outliers Linear Regression with the Method of Least Squares How to Present an Analytical Result Some Words and Concepts Analysis and Determination Sample Replicates and Measuring Replicates Interference Blind Samples 62 5 Titrimetric Methods Introduction Acid Base Titrations Acid Base Titrations in Non-Aqueous Media Redox Titrations Other Principles of Titration Summary 82 6 Introduction to Spectroscopic Methods Electromagnetic Radiation Molecules and Electromagnetic Radiation Atoms and Electromagnetic Radiation Summary 88 7 UV Spectrophotometry Principle of Quantitative Determination Principle of Identification Which Substances Have Strong UV Absorbance? Instrumentation Practical Work and Method Development Areas of Usage and Performance System Testing Summary IR Spectrophotometry IR Spectrophotometry Instrumentation 106

3 8.3 Scope Instrument Calibration NIR Spectrophotometry Applications Summary Atomic Spectrometry Atomic Absorption Spectrometry Instrumentation Applications and Performance Practical Work and Method Development Atomic Emission Spectrometry Instrumentation Summary Chromatography General Principles Retention Column Efficiency Selectivity Peak Symmetry Resolution Chromatographic Techniques Summary Chromatographic Separation Principles General Introduction Normal Phase Chromatography Silica Interactions Order of Elution Other Stationary Phases Mobile Phases Summary of Normal Phase Chromatography Reversed Phase Chromatography Stationary Phases Retention Mechanisms Mobile Phases Ion-Pair Chromatography Summary of Reversed Phase Chromatography Hydrophilic Interaction Chromatography Chiral Separations 156

4 11.6 Size Exclusion Chromatography Principle Summary of SEC Ion Exchange Chromatography Thin-Layer Chromatography Introduction Apparatus TLC Plates Stationary Phases Mobile Phases Chromatographic Development Detection Applications of TLC Quantitative Analysis and Instrumentation Summary High Performance Liquid Chromatography Introduction The Chromatographic Separation Process The Column Pumps Detectors UV detector Fluorescence Detector Electrochemical Detector Refractive Index, Evaporative Light Scattering and Corona Discharge Detectors Combination of Detectors Injectors Mobile Phases Solvents for Sample Preparation Reporting the Results Summary Gas Chromatography Introduction Apparatus Temperature Carrier Gas Stationary Phases Selectivity in GC Columns 198

5 Capillary Columns Packed Columns Injection Systems Injection Systems for Capillary Columns Injection Systems for Packed Columns Detectors Flame Ionization Detector Nitrogen Phosphorus Detector Thermal Conductivity Detector Electron Capture Detector Mass Spectrometry Detector Derivatization Silylation Alkylation Acylation The Uses of GC More Advanced GC techniques Summary Capillary Electrophoresis Principle and Theory Electroosmotic Flow Instrumentation The Capillary Sample Introduction Capillary Zone Electrophoresis; an Example Micellar Electrokinetic Chromatography Chiral Separations Coated Capillaries Non-Aqueous CE Summary Mass Spectrometry Introduction Basic Theory Electron Ionization Identification using Electron Ionization Spectra Characterization of Totally Unknowns using Electron Ionization Spectra Chemical Ionization Electrospray Ionization Atmospheric Pressure Chemical Ionization 247

6 16.9 High-Resolution Mass Spectrometry Instrumentation Chromatography Coupled with Mass Spectrometry Quantitative GC-MS and LC-MS Areas of Usage and Performance Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Inductively Coupled Plasma Mass Spectrometry Summary Miscellaneous Chemical Techniques Potentiometric Determination of Ions using Ion-Selective Electrodes Paper Chromatography Supercritical Fluid Chromatography Gel Electrophoresis Iso-Electric Focusing Nuclear Magnetic Resonance Spectrometry Raman Spectrometry Sample Preparation Why is Sample Preparation Required? Main Strategies Recovery and Enrichment Protein Precipitation Liquid Liquid Extraction Fundamentals A Closer Look at the Theory Extraction Solvents Calculation of Recovery Multiple Extractions LLE with Back-Extraction Solid Liquid Extraction Solid Phase Extraction Fundamentals The SPE Column Conditioning Equipment Reversed-Phase SPE Secondary Interactions Ion Exchange SPE Mixed-Mode SPE 295

7 Normal-Phase SPE Summary Analytical Chemical Characteristics of Selected Drug Substances Amitriptyline and Mianserin Morphine and Codeine Ibuprofen and Naproxen Furosemide Paracetamol (Acetaminophen) Neutral Drugs Quantification and Quality of Analytical Data Peak Height and Peak Area Calibration Methods External Standard Method Internal Standard Method Standard Addition Normalization Validation Analytical Procedure Accuracy Precision Specificity Detection Limit Quantification Limit Linearity and Range Robustness Test Methods in the European Pharmacopeia System Suitability Adjustment of Chromatographic Conditions Chemical Analysis of Drug Substances What is a Pharmaceutical Raw Material, how is it Produced and why must it be Controlled? The Pharmacopoeias the Basis for Control of Pharmaceutical Raw Materials Which Contaminants are Found in Raw Materials, What are the Requirements in a Maximum Content and Why? Well Defined Chemical Compounds Mixtures of Organic Compounds How to Check the Identity of Pharmaceutical Raw Materials Overview of the Identification Procedures Techniques used for the Identification of Well Defined Chemical Compounds Infrared Absorption Spectrophotometry Ultraviolet and Visible Absorption Spectrophotometry 347

8 Thin-Layer Chromatography Melting Point Polarimetry High Performance Liquid Chromatography Chloride and Sulfate Identification How to Test for Impurities in Pharmaceutical Raw Materials Main Purity Tests for Well Defined Chemical Compounds Appearance of Solution Absorbance Acidity/Alkalinity Optical Rotation Related Substances Solvent Residues Foreign Anions Cationic Impurities Loss on Drying Determination of Water Purity Tests for Raw Materials of the Type of Mixtures of Organic Compounds Oxidizing Substances Acid Value Hydroxyl Value Iodine Value Peroxide Value Saponification Value Unsaponifiable Matter Other Tests Identification of the Raw Materials of the Type of Mixtures of Organic Compounds How to Determine the Purity of Pharmaceutical Raw Materials Acid Base Titration in Aqueous Environment Acid Base Titration in a Non-Aqueous Environment Redox Titrations High Performance Liquid Chromatography UV spectrophotometry How to Control Compounds for Which no Pharmacopoeia Monograph Exists How are Ph.Eur. and USP Updated? Chemical Analysis of Final Pharmaceutical Products Quality Control of Final Pharmaceutical Products Monographs and Chemical Testing Identification of the Active Pharmaceutical Ingredient 412

9 22.4 Assay of the Active Pharmaceutical Ingredient Chemical Tests for Final Pharmaceutical Products Test for Related Substances Uniformity of Content Dissolution Analysis of Drugs in Biological Fluids Introduction Drug Development Therapeutic Drug Monitoring Forensic and Toxicological Analysis Doping Control Analysis The Biological Matrix Bioanalytical Methods Sampling Sample Preparation Protein Precipitation Liquid Liquid Extraction Solid-Phase Extraction Separation Detection Calibration and Quantification Examples Sample Preparation Sample Preparation Procedure by LLE Comments to the Procedure Sample Preparation Procedure by LLE and Back Extraction Comments to the Procedure Sample Preparation Procedure by SPE Comments to the Procedure Sample Preparation Procedure by Protein Precipitation Comments to the Procedure Quantitative Determination Quantitative Determination of Amitriptyline in Serum by LC-MS Comments to the Procedure Determination of Valproic Acid in Serum by GC-MS Comments to the Procedure Identification Sample Preparation Procedure for Unknown Screening by Mixed Mode Cation Exchange Comments to the Procedure 472

10 GC-MS Procedure for Unknown Screening Comments to the Procedure LC-MS-MS Procedure for Unknown Screening Comments to the Procedure 475 Index 477

CHROMATOGRAPHY. The term "chromatography" is derived from the original use of this method for separating yellow and green plant pigments.

CHROMATOGRAPHY. The term chromatography is derived from the original use of this method for separating yellow and green plant pigments. CHROMATOGRAPHY The term "chromatography" is derived from the original use of this method for separating yellow and green plant pigments. THEORY OF CHROMATOGRAPHY: Separation of two sample components in