Introduction Clarke's Analysis of Drugs and Poisons is the new name of the well established Clarke's Isolation and Identification of Drugs. Professor E G C Clarke, who edited the first edition, designed it to be the leading text for the analysis of drugs and poisons, and this tradition is carried on in the third edition. The name has been changed to reflect the greater scope of the monographs which now include many more pesticides and other poisonous substances as well as veterinary products, drugs misused in sport and drugs of abuse. Clarke, as the book is affectionately known, has gained a worldwide reputation as a reliable source of information. Its presence on the benches of many different types of pharmaceutical and toxicological laboratories is a testament to its usefulness. A major change from the second edition is the provision of the information in this electronic version. This form of Clarke has the advantage that text searches can be performed thus aiding the reader to access relevant information more rapidly. Future electronic versions will enable combined searches on the analytical data from the same or different techniques. For example, it will be possible to identify an unknown drug or substance from a combination of its high performance liquid chromatography retention index and ultraviolet peak maximum. An electronic form also has the advantage that it can be updated far more often and easily than the conventional book form. Since the second edition was published in 1986, there have been about 800 new chemical entities brought to market. Some of these come from completely new chemical or pharmacological groups. Examples include: COX-2 inhibitors, phosphodiesterase inhibitors, proton pump inhibitors, selective serotonin re-uptake inhibitors and statins. In addition, there has been a growth of drugs misused in sport and those subject to abuse, e.g. anabolic steroids, volatile materials and phenethylamines (ecstasy and derivatives). About 400 new monographs have been added in this third edition, with priority based on the importance of the substances they cover in one of the following areas: drugs of abuse, forensic toxicology, hospital emergency toxicology, doping in sport, drugs subjected to therapeutic drug monitoring and environmental toxicology. It has been impossible to include all the new drugs and poisons available, but work is continuing to add other data in future editions. There is more need to identify and quantify drugs and poisons than ever before. Whether the reader is in a hospital toxicology laboratory, a clinical laboratory involved in therapeutic drug monitoring or a forensic toxicology laboratory, the requirement for accurate analytical methods and associated data is essential. The information in Clarke has been designed to provide methods and data to enable analysts to detect, identify, quantify and profile drugs and poisons in a wide variety of situations. In addition, information on how to interpret the analytical data is included, since often this is the most difficult part. Clarke has been planned for use not only in hospital and toxicology laboratories, but also in numerous other analytical establishments. This includes quality control laboratories, and clinical laboratories engaged in drug investigations for purposes such as therapeutic drug monitoring or research into pharmacokinetics and patterns of drug metabolism. In addition, there is much information that will be of use in certain areas of environmental toxicology, particularly the analysis of toxic metals and pesticides. The needs of students who are studying drug analysis and its applications have also been kept in mind during the every stage of this project. Those who already use Clarke will be pleased to see that the original style and form of presentation of the information has been retained from the second edition. This tried and tested format is clear, making it easy to find relevant information. Chapters: methodology and analytical techniques This part contains 31 chapters describing methodology and analytical techniques. There are new chapters on the philosophy and methodology to be used in various areas of toxicology that were not fully covered in the last edition. These areas are: drugs of abuse, alcohol and drugs in driving, workplace drug testing, postmortem toxicology, drugs in saliva, hair analysis, natural toxins, volatile substances, medicinal products and solid dosage forms. All the other chapters have been rewritten to bring them fully up-to-date. The chapter on forensic toxicology is worthy of special mention. It is dedicated to the memory of the late John Jackson who was the author of this chapter in the second edition. It has been brought up-to-date and integrated with the contents of the third edition by the editors, but with his philosophical style preserved as a tribute to John. The information contained in the chapters on analytical techniques has similarly been brought up-to-date. This reflects the great advances in instrumental design and capabilities over the last 17 years. There are new chapters on the use of near-infrared spectroscopy, Raman spectroscopy and capillary electrophoresis, each describing the applications of the technique in pharmaceutical analysis. The structure of the spectroscopic and chromatographic chapters has been formalised to ensure all the relevant information is given and in an easy-to-read form. A chapter on emerging techniques also looks at the regulatory problems involved in the introduction of new techniques and what new instrumentation might be available routinely in the future. The chromatographic systems have been extensively expanded and revised to include general screening systems as well as specialised systems for various classes of drugs and poisons. The general systems advocated for use have all been proven over the years to be rugged and give reproducible results, and are excellent for use in systematic toxicological analyses. The importance of quality control is brought out in an updated chapter to include the importance of accreditation. Finally, the chapter on pharmacokinetics and drug metabolism gives an overview of the principles and kinetics of absorption, distribution, metabolism and excretion. There is also a section in this chapter on how to interpret analytical data. In addition, each of the methodology chapters includes a relevant section to aid interpretation in that field of toxicology. Monographs: analytical and toxicological data This part contains monographs for over 1730 drugs and poisons. This includes about 400 new monographs with the retention of all the monographs from the second edition, which have been completely updated. Clarke now uses the Recommended International Nonproprietary Name (rINN) for drug names as this is now the international standard method of nomenclature. Data for compounds in colour tests, thin-layer chromatography, gas chromatography and high performance liquid chromatography are given from which to choose systems that will separate and identify drugs, poisons and their metabolites. Full mass spectra now join the full ultraviolet and infra-red spectra in the monographs together with the listings of the major peaks to assist further in identifying compounds. References to published methods for separating, identifying and quantifying drugs and their metabolites are given in each monograph wherever possible. The section entitled Disposition in the Body gives data on therapeutic concentration, toxicity, bioavailability, half-life, volume of distribution, clearance, distribution in blood, plasma:saliva ratio and protein binding to enable analytical data to be interpreted in the context of a given case. In addition, abstracts from published clinical studies and case histories are included. Review articles have also been included where relevant. Indexes to analytical data This part contains indexes of analytical data, including all the data for colour tests, chromatography, ultraviolet spectrophotometry, infra-red spectroscopy and mass spectrometry, together with indexes of CAS number, molecular formula, therapeutic class, molecular weight, melting point, colour tests, and a medical glossary. In addition, a list of excipient ‘E’ numbers is included. A list of reagents and proprietary test materials mentioned in the analytical procedures in the chapters and the monographs is also provided. Preparation of this edition A very large team has been involved in putting this edition together, and we are particularly grateful to Tamsin Cousins, Linda Horrell, Louise McIndoe, Siân Owen, and John Wilson of the Pharmaceutical Press. They have been ably assisted by Emma Brightwell, Kelly Davey, Millie Davis, Eileen Laughton, Anjana Patel and Sue Shankie who wrote and revised many of the monographs. A dedicated team of freelances worked on editing, proof checking and indexing. Our special thanks are to Laurent Galichet and Paul Weller who have been primarily responsible for co-ordinating the project and have worked with unfailing patience and good humour to maintain its momentum. Without the enthusiasm and commitment of all these individuals this work would not have been published. The Editorial Board members have also given freely of their time to suggest authors, referee manuscripts and provide data from their own laboratories. They and the authors have done a great job in providing up-to-date information in an easily accessible and readable manner. Many people have given specific assistance in different ways to make this book a success and these are listed in the Acknowledgements section. In addition, we would like to thank all those who gave physico-chemical data for inclusion in the chapters and monographs. In particular, members of the International Association of Forensic Toxicologists, many of whom ran drugs through analytical systems in their own laboratories to provide spectra and chromatographic data for our use. A C Moffat M D Osselton B Widdop September 2003 Foreword It is a great pleasure for me to join in the celebration of the third edition and electronic version of Clarke's Analysis of Drugs and Poisons. A full revision and expansion of this text is a monumental, but highly necessary, task. We work in a rapidly changing world with ever-increasing quantities of information and data. Data that we, as toxicologists, require to improve our measurement of concentrations of drugs, poisons and their metabolites in an expanding repertoire of biological fluids and tissues. Hundreds of new drugs are introduced each year. High potency and selective pharmacotherapies may reduce unwanted side-effects and drug interactions, yet many make our job more difficult by requiring quantification following ever-decreasing therapeutic dosages. On the other hand, increased analytical sensitivity and specificity facilitate measurement of lower and lower concentrations of drugs in smaller and smaller sample volumes with each new technological advance. But what is the significance of these findings? Interpretation of toxicological results has been and continues to be the greatest challenge. We operate under new rules of evidence, requiring our data and our opinions to be accepted by the general scientific community. Comparison of our limited case data to larger scientific databases is necessary. Each of us has the responsibility to contribute to this database, whether our professional area of interest is analytical toxicology, clinical toxicology, workplace drug testing, postmortem toxicology, research, pharmacy or other related field. In this complex world, we are all specialists with limited access and exposure to the broad spectrum of compounds of toxicological interest, methods and instruments for their analysis, and research into the pharmacokinetics and pharmacodynamics of drug action. By combining our knowledge and experience, we can create a scientific database to aid interpretation and to make more informed decisions. The larger and more complete the database, the greater our ability to cope with difficult issues such as intra- and interindividual variability, postmortem redistribution, drug interactions, tolerance, routes of drug administration and differences in absorption, distribution, metabolism and excretion due to age-, sex-, race- or disease-related changes. There are several areas where our collective knowledge is especially lacking: our ability to correlate drug concentrations to ongoing pharmacodynamic events, including performance impairment; and the significance of drug concentrations in alternate matrices including oral fluid, hair, sweat and meconium. If the basic pharmacokinetic and pharmacodynamic research is not performed, informed interpretation of drug concentrations in these alternate specimens will not be possible. Our ability to cope with the increasing volume and complexity of data requires that we have means of filtering out unreliable and inconsequential information and access to databases of collated accurate information. We need reliable, current reference material; information that has been validated by independent sources. There are few toxicologists around the world who have not referred to Clarke on a regular basis for dependable information. This new edition of Clarke's Analysis of Drugs and Poisons addresses many of the emerging and critical issues in toxicology including testing of alternate matrices, use of liquid chromatography tandem mass spectrometry, interpretation of analytical results and performance impairment. In mentoring young professionals in the field we stress, not the need to memorize volumes of facts, but the ability to access needed information in a timely manner. We work in a valuable, interesting and highly complicated field. One that requires us to continually learn and extend our capabilities. I urge each of you to publish your findings to add to our collective wisdom, and if you are lucky, to be immortalised in the next edition of Clarke. We are fortunate to have such a valuable reference to aid us in our work. Marilyn A Huestis, PhD President, The International Association of Forensic Toxicologists Editorial Advisory Board Professor Rolf Aderjan Institute of Legal Medicine and Traffic Medicine, University of Heidelberg, Heidelberg, Germany Dr Robin A Braithwaite Regional Toxicology Laboratory, City Hospital NHS Trust, Birmingham, UK Professor David A Cowan Drug Control Centre, King's College London, UK Dr Alastair G Davidson Visiting Professor, Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow, UK Dr Sheila Dawling Diagnostics Laboratories, Vanderbilt University Medical Centre, Nashville, USA Dr Raphael de la Torre Institut Municipal d'Investigació Mèdica, Barcelona, Spain Professor Frederik A de Wolff Toxicology Laboratory, Leiden University Medical Centre, The Netherlands Dr Olaf H Drummer Victorian Institute of Forensic Medicine, Melbourne, Australia Professor Santo Ferrara Centre for Behavioural and Forensic Toxicology, University of Padova, Padova, Italy Dr Robert J Flanagan Medical Toxicology Unit, Guy's and St Thomas' Hospital Trust, London, UK Dr Robert Forrest Department of Forensic Pathology, Medico-Legal Centre, Sheffield, UK Dr Carol Foster Forensic Sciences Laboratory, Chepstow, UK Dr Jan Piet Franke Department of Bioanalysis and Toxicology, University Centre of Pharmacy, Groningen, The Netherlands Mr Laurent Y Galichet Royal Pharmaceutical Society of Great Britain, London, UK Dr Bruce Goldberger College of Medicine, University of Florida, Gainesville, USA Professor Terry Gough Forensic Science Unit, King's College London, UK Dr Stephen Hammond Pfizer Ltd, Sandwich, UK Dr Ed Houghton HFL, Fordham, UK Dr Marilyn Huestis Intramural Research Program, National Institute of Drug Abuse, Baltimore, USA Dr Allan Jamieson Lothian and Borders Police Forensic Science Laboratory, Edinburgh, UK Dr Wayne Jeffery Forensic Laboratory, Royal Canadian Mounted Police, Vancouver, Canada Dr Graham Jones Office of Chief Medical Examiner, Edmonton, Canada Dr Les A King Formerly, Drugs Intelligence Unit, Forensic Science Service, London, UK Dr Pascal Kintz Institut de Médecine Légale, Strasbourg, France Dr Barry K Logan Washington State Toxicology Laboratory, Seattle, USA Professor Robert Maes Department of Human Toxicology, Institute of Pharmaceutical Sciences, Utrecht, The Netherlands Professor Hans Maurer Institute of Experimental and Clinical Pharmacology and Toxicology, University of Saarland, Homburg, Germany Professor Manfred Moeller Institute of Legal Medicine, University of Saarland, Homburg, Germany Professor Anthony C Moffat Royal Pharmaceutical Society of Great Britain, and The School of Pharmacy, University of London, London, UK Dr Christine Moore US Drug Testing Laboratories, Des Plaines, USA Dr John Oliver Department of Forensic Medicine and Science, University of Glasgow, Glasgow, UK Dr M David Osselton Forensic Science Service, London, UK Miss Siân C Owen Royal Pharmaceutical Society of Great Britain, London, UK Dr Cathy Petts Development Laboratories, Merck Sharp and Dohme, Hoddesdon, UK Dr John Ramsey Division of Cardiological Sciences, St George's Hospital Medical School, London, UK Professor Jordi Segura Institut Municipal d'Investigació Mèdica, Barcelona, Spain Dr Vina Spiehler Newport Beach, California, USA Dr Rick Treble Laboratory of the Government Chemist, Teddington, UK Professor Donald R A Uges Laboratory for Clinical and Forensic Toxicology and Drug Analysis, University Hospital Groningen and University Centre of Pharmacy, Groningen, The Netherlands Dr David Watson Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow, UK Mr Paul J Weller Royal Pharmaceutical Society of Great Britain, London, UK Professor Robert Wennig Division de Toxicologie, Laboratoire National de Santé, Luxembourg, Luxembourg Professor Douglas Westerlund Analytical Pharmaceutical Chemistry, Uppsala University Biomedical Centre, Uppsala, Sweden Dr Mike Whitehouse Forensic Science Service, London, UK Dr Brian Widdop Formerly, Medical Toxicology Unit, Guy's and St Thomas' Hospital Trust, London, UK Professor Ikuo Yamamoto Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan Editorial Staff Emma Brightwell Kelly Davey Dr Millie Davis Laurent Y Galichet Linda Horrell Dr Eileen Laughton Louise M E McIndoe Siân C Owen Dr Anjana Patel Dr Susan Shankie Paul J Weller Contributors Dr Robin A Braithwaite Regional Toxicology Laboratory, City Hospital NHS Trust, Birmingham, UK Dr Robert K Bramley Forensic Science Service, Birmingham, UK Dr David E Bugay SSCI Inc., West Lafayette, USA Dr David G Bullock Wolfson EQA Laboratory, Birmingham, UK Dr Jan Cordonnier Chemiphar n.v., Brugge, Belgium Professor David A Cowan Drug Control Centre, King's College London, UK Dr Alastair G Davidson Visiting Professor, Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow, UK Dr Sheila Dawling Diagnostics Laboratories, Vanderbilt University Medical Centre, Nashville, USA Professor Frederik A de Wolff Toxicology Laboratory, Leiden University Medical Center, Leiden, The Netherlands Dr Alex Drake The School of Pharmacy, King's College, University of London, UK Dr Olaf H Drummer Victorian Institute of Forensic Medicine, Melbourne, Australia Dr Robert J Flanagan Medical Toxicology Unit, Guy's and St Thomas' Hospital Trust, London, UK Mr José R Garcia Pharmaceutical Division, BovisLendLease, USA Dr Rodney G Gullberg Washington State Toxicology Laboratory, Seattle, USA Mr Mike Hallworth Department of Clinical Biochemistry, Royal Shrewsbury Hospital, Shrewsbury, UK Dr Chris Hand Cozart Bioscience Limited, Abingdon, UK Dr Matthias Herzler Institute of Legal Medicine, Humboldt University, Germany Dr Ed Houghton HFL, Fordham, UK Dr Roger D Jee The School of Pharmacy, University of London, UK Dr Wayne Jeffery Forensic Laboratory, Royal Canadian Mounted Police, Vancouver, Canada Dr Graham Jones Office of Chief Medical Examiner, Edmonton, Canada Dr Maria Kaℓa Department of Forensic Toxicology, Institute of Forensic Research, Crakow, Poland Dr Les A King Formerly, Drugs Intelligence Unit, Forensic Science Service, London, UK Dr Pascal Kintz Institut de Médecine Légale, Strasbourg, France Dr Thomas Kupiec Analytical Research Laboratories, Oklahoma City, USA Professor John C Lindon Division of Biomedical Sciences, Imperial College of Science, Technology and Medicine, London, UK Dr Barry K Logan Washington State Toxicology Laboratory, Seattle, USA Dr Pamela A Martoglio Smith SSCI Inc., West Lafayette, USA Dr Sean D McDermott Drugs Intelligence Unit, Forensic Science Laboratory, Dublin, Ireland Professor Anthony C Moffat Royal Pharmaceutical Society of Great Britain, and The School of Pharmacy, University of London, London, UK Professor Jeremy K Nicholson Division of Biomedical Sciences, Imperial College of Science, Technology and Medicine, London, UK Dr M David Osselton Forensic Science Service, London, UK Dr Mike Peat Quest Diagnostics Inc., Houston, USA Professor David Perrett Department of Medicine, St Bartholomew's Hospital, London, UK Professor Colin F Poole Department of Chemistry, Wayne State University, Detroit, USA Professor Fritz Pragst Institute of Legal Medicine, Humboldt University, Berlin, Germany Dr John Ramsey Division of Cardiological Sciences, St George's Hospital Medical School, London, UK Dr Manuel Sanchez-Felix Eli Lilly, Minneapolis, USA Dr Johan Schaep Chemiphar n.v., Brugge, Belgium Dr Matt Slawson Department of Pharmacology & Toxicology, University of Utah, Utah, USA Dr Vina Spiehler Newport Beach, California, USA Professor Donald A Uges Laboratory for Clinical and Forensic Toxicology and Drug Analysis, University Hospital Groningen and University Centre of Pharmacy, Groningen, The Netherlands Dr David Watson Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow, UK Dr Brian Widdop Formerly, Medical Toxicology Unit, Guy's and St Thomas' Hospital Trust, London, UK About the Editors Professor Anthony C Moffat BPharm, PhD, DSc, CChem, FRSC, FRPharmS, FCPP Professor Anthony C Moffat is currently Chief Scientist at the Royal Pharmaceutical Society of Great Britain. In addition, he is the Royal Pharmaceutical Society Professor at The School of Pharmacy, University of London, where he heads the Centre for Pharmaceutical Analysis. He has over 200 publications including the co-authorship of 7 books. Previously he worked for the Forensic Science Service for 23 years as Research Coordinator (Birmingham Laboratory), Resources Manager (Huntingdon Laboratory), Head of Quality Management (HQ, London) Assistant Director (Huntingdon Laboratory) and Head of the Drugs and Toxicology Division at the Home Office Central Research Establishment, Aldermaston. He has also been a Superintendent Pharmacist in a community pharmacy, Assistant Professor of Biochemistry, Baylor College of Medicine, Houston, Texas, and Chief Pharmacist, St Leonards Hospital, London. An active member of many professional and learned bodies, his memberships include the Royal Pharmaceutical Society, the Royal Society of Chemistry, the International Pharmaceutical Federation, the International Association of Forensic Toxicologists, the Forensic Science Society, the College of Pharmacy Practice and the Society for Medicines Research. Dr M David Osselton BSc, PhD, CChem, FRSC, RFP Dr M David Osselton is currently a Consultant Forensic Toxicologist and Professional Lead in toxicology for the UK Forensic Science Service. With over 28 years' experience in forensic toxicology, Dr Osselton has extensive experience in both casework and research. He is also an author/co-author of over 70 published scientific papers/book chapters. After gaining experience working in the Central Research and Support Establishment, Aldermaston, and the Forensic Science laboratories in Aldermaston, Nottingham and Huntingdon, he was appointed Head of Drugs and Toxicology Research in 1984, and later Head of Toxicology for the FSS. Dr Osselton also acts in an advisory capacity to the Home Office on Drug Testing and as Lead Assessor in Toxicology for the Council for the Registration of Forensic Toxicologists. He has also been a member of a number of national and international committees concerned with the drafting and publication of laboratory guidelines for toxicology including the UK Guidelines for Urine Drug Testing. He is a member of the International Association of Forensic Toxicologists, the American Society of Forensic Toxicologists (SOFT), the Forensic Science Society and the London Toxicology Group. Dr Brian Widdop BSc, PhD, SRCS, CChem, FRSC, FRCPath Dr Brian Widdop was Director of the Medical Toxicology Unit Laboratory at Guy's Hospital, London, from 1997 until 2002. Dr Widdop is a Speciality Assessor for the Council for the Registration of Forensic Practitioners, a member of the WHO IPCS Working Group on Analytical Toxicology, Chief Adviser to the South East Asia Regional Office of the WHO on analytical toxicology and was, until recently, a Director of the Board of the UK Horseracing Forensic Science Laboratory. From 1997 to 2001, he was joint co-ordinator of the European Proficiency Testing Scheme for Drugs of Abuse. Dr Widdop has published over 80 papers on various aspects of clinical and analytical toxicology and has spoken at many international meetings. He is also a member of the editorial board of the Journal of Analytical Toxicology. Dr Widdop belongs to several international scientific societies and has been a member of TIAFT for 36 years. He was also a founder member of the London Toxicology Group. Acknowledgements Acknowledgements are gratefully made to the following individuals, and manufacturers for the provision of analytical data, spectra or samples: R A de Zeeuw, R Cordero, S Patterson, C Peclet, L Dehaut, A Mozayani, T Mills, A Elian, J Hughes, J Hudson, J Castorena, G Jones, C Kay, C Hawkins, S Stroud, P Bottomley, P Jones, N Kolassa, L-P Haahr, R Lewis, V Zingel, B Renger, S Bentley, D White, S McDonald, J O'Boyle, A Davy, J-P Paris, J Gilbart, M Weiss, K Haines, D James, C Jestey, J Legiski, B Kay, L De Santis, M Reynolds, S McClain, R Blanke, W Mann, J Penning, S Wallaser, N Watts, L Strangeways, A Gadd, D Brockwell, A Allan, M McMullin, W Dunn, R Middleberg, K Pfleger, H H Maurer, A Weber, R K Waters, R A Watt, S Dawling, G Maylin, C Roberson, W H Wall, K L Lothridge, W D McDougall, M W Gilbert, J P Franke, J Hartstra, F Degel, G Machbert, H Schütz, J Wijsbeek, B S Finkle, G Jones, M R Möeller, R K Müller, R Wennig, J Bäumler, H Brandenberger, J Büttner, M von Clarmann, M Geldmacher-von Mallinckrodt, H J Gibitz, A N P van Heijst, G Machata, R Maes, H Moll, M Oellerich, D Stamm, M Stoeppler, H Wisser, C Schneider, W Fabricius, J M H Conemans, C C Pijnenburg, R C A Philipse, C G J Barella, A M J A Duchateau, M Bogusz, H Huizer, D Anderson, D Brougham, S Hammond, M Heinrich, P J Houghton, D C Lee, A Taylor. AstraZeneca, Bristol-Myers Squibb, Aventis, Exelgyn, Boehringer Ingelheim, Myogen, Pantheon, Baxter, Eisai, Alcon, Schwartz Pharma, Bayer, Abbott, Novo Nordisk, Novartis, Sanofi-Synthélabo, Orion Pharma, Eli Lilly, Byk Gulden, Agilent, British Pharmacopoeia Laboratories, Beckman Coulter. Special mention is made to F Pragst, M Herzler, S Herre, B-T Erxleben, and M Rothe for giving permission to reproduce a large number of ultraviolet spectra from UV Spectra of Toxic Compounds, 2001, Verlag Dr Dieter Helm, Heppenheim. Furthermore, thanks are given to M Masters and M Paylor from Dionex for providing ultraviolet spectra from the Summitox library, developed by S Elliott, Regional Toxicology Laboratory, Birmingham. General Notices The following explanatory notes are provided so that the reader can interpret and use the information in Clarke correctly and efficiently. They should be studied before using the data given in the monographs. Health and safety This work is intended to be used by appropriately qualified and experienced scientists. Processes and tests described should be performed in suitable premises by personnel with adequate training and equipment. Care should be taken to ensure the safe handling of all chemical or biological materials, and particular attention should be given to the possible occurrence of allergy, infection, fire, explosion or poisoning (including inhalation of toxic vapours). Cautionary notes have been included in a number of monograph entries, but the possibility of danger should always be kept in mind when handling biological samples, and medicinal or other chemical substances. Classification At the head of each monograph, an indication is given of the classification of the compound according to its therapeutic or commercial use, its pharmacological action and/or its chemical group. The substance may, of course, have other uses or actions in addition to that stated. Nomenclature Monograph titles The main titles of the monographs are the Recommended International Non-Proprietary Names (rINNs), this includes both drugs and pesticides. For drugs of abuse, the most common chemical names or abbreviations have been used. It is worth noting that for rINNs and chemical nomenclature, it is now general policy to use ‘f’ for ‘ph’ (e.g. in sulpha), ‘t’ for ‘th’ and ‘i’ for ‘y'. For this reason, entries in alphabetical lists and indexes should be sought in alternative spellings if the expected spellings are not found. The main title of a monograph is generally that of the free acid or base as this is the form in which the compound will usually be isolated in an analysis; details of the commonly available salts are included in subsidiary paragraphs within the monograph. The following abbreviated names for radicals and groups are used in the titles. Recommended name Chemical name acetonide (isopropylidenedioxy) aceturate N-acetylglycinate amsonate 4,4′-diaminostilbene-2,2′-disulfonate besilate camsilate caproate cipionate closilate edetate edisilate eglumine embonate enantate erbumine esilate gluceptate hibenzate isetionate lauril laurilsulfate meglumine mesilate metilsulfate mofetil napadisilate napsilate octil pivalate steaglate tebutate teoclate tosilate xinafoate benzenesulfonate camphorsulfonate hexanoate cyclopentanepropionate p-chlorbenzenesulfonate ethylenediaminetetraacetate 1,2-ethanedisulfonate N-ethylglucamine 4,4′-methylenebis (3-hydroxy-2-naphthoate) (=pamoate) heptanoate tert-butylamine ethane sulfonate glucoheptonate o-(4-hydroxybenzoyl)benzoate 2-hydroxyethanesulfonate n-dodecyl n-dodecylsulfate N-methylglucamine methanesulfonate methylsulfate 2-morpholinoethyl 1,5-naphthalenedisulfonate 2-naphthalenesulfonate octyl trimethylacetate steroyl-glycolate tert-butylacetate 8-chlorotheophyllinate p-toluenesulfonate 1-hydroxy-2-naphthoate Chemical names The nomenclature generally follows the definitive rules issued by IUPAC, 1993. Proprietary names and synonyms A selection of proprietary names have been included in the monographs. These can generally be applied to the UK, USA, Japan and a selection of African, Asian and European countries. Comprehensive lists of proprietary names worldwide, can be found in Martindale, The Extra Pharmacopoeia, 33rd Edn, London, The Pharmaceutical Press, 2002. Only single-substance preparations have been included except in the case of certain major classes of drugs for which the names of some compound preparations have been added. Some proprietary names that are not in current use have been retained. Names under the heading ‘Synonyms’ include alternative names, common titles, abbreviations and drug trial numbers. CAS registry numbers Chemical Abstract Service (CAS) registry numbers are provided, where available, in the monographs to assist readers to refer to other information databases. Molecular weights Molecular weights have been calculated using the table of Atomic Weights as revised in 2001 by the Commission on Atomic Weights, IUPAC General Assembly, and based on the C scale. Molecular weights have been corrected to one decimal place and are listed in 12 ascending order in the index of Molecular Weights. Physical characteristics Dissociation constants Numerous methods can be used for the determination of dissociation constants, and there are often differences in the various values reported in the scientific literature. The pKa values given in the monographs have been taken from published data and should be regarded only as approximate. The temperature at which the determination was made is given where known. Information on the theory, measurement and evaluation of dissociation constants is given in The Pharmaceutical Codex, 12th Edn, London, The Pharmaceutical Press, 1994. Melting points The melting points recorded in the individual monographs are listed in ascending order in the index of Melting Points. Partition coefficients Values for log P are given in a number of monographs. Where the pH of the aqueous phase is stated, the values given are apparent coefficients at that pH (not ion-corrected). Where no pH is stated for the aqueous phase, it can be assumed that log P is for the neutral form of the substance even though it is potentially ionisable. The values given are approximates only but they serve to indicate the characteristics of the substance when it is submitted to an extraction process. For a comprehensive collection of partition coefficients for drugs see C. Hansch et al., Exploring QSAR: Hydrophobic, Electronic and Steric Constants, Washington, American Chemical Society, 1995. Information on the theory of partition coefficients can also be found in J. Sangster, Octanol-Water Partition Coefficients: Fundamentals and Physical Chemistry, New York, John Wiley, 1997. Solubility The solubilities given in the monographs, unless otherwise stated, apply at ordinary room temperature. They have been obtained from various sources and should not be regarded as precise because of variations depending on the method and condition of determination. In general, approximate values are given when a substance is soluble in less than 1000 parts of solvent. Where no figure is given, the usual solubility terms have been adopted: Very soluble 1 part in less than 1 Freely soluble 1 part in 1–10 Soluble 1 part in 10–30 Sparingly soluble 1 part in 30–100 Slightly soluble 1 part in 100–1000 Very slightly soluble 1 part in 1000–10000 Practically insoluble or insoluble 1 part in more than 10000 In the solubility statements, the word ‘water’ refers to purified water, the word ‘ether’ refers to diethyl ether and the word ‘ethanol', without qualification, refers to ethanol (95%). Temperature Temperatures are expressed throughout the text in degrees Celsius (centigrade). Analytical data All analytical data in the monographs apply to the form of the substance described in the main title of the monograph, unless otherwise specified. In all lists or indexes of chromatographic data, a dash indicates that the value is not known, not that the substance does not elute. Extraction It has not been possible to give direct information on the best method for extracting individual substances from various biological samples. However, useful information can be gained from the data on solubility, dissociation constant and partition coefficient. The best solvent can be chosen by reference to solubility, the pH for extraction is indicated by the pKa value, and the partition coefficient gives a quantitative measure of the phase volume ratios needed for a successful extraction. Colour tests Where colour tests are given in the monographs, the names of the tests are printed with initial capitals. These names refer to the tests described under Colour Tests where complete tables of colours are provided. Reference should be made to this chapter for an explanation of the system used for describing the colours. The reagents used for the colour tests are also listed within the list of reagents and additional colour reaction data for approximately 250 compounds is also presented. Colour tests applicable to biological fluids are described under the Hospital Toxicology Chapter. Thin-layer chromatography The thin-layer chromatographic systems referred to in the monographs are described in the TLC chapter on together with lists of data for drugs in important chemical and pharmacological classifications. General screening systems (systems TA to TF and systems TL, TAD, TAE, TAF, TAJ, TAK and TAL), which include over 1500 drugs and metabolites, are provided (see Chapter 27 for system details and references). In order to clarify the presentation of values, the data are expressed in terms of Rf×100. Complete lists of data, in ascending order, are given in the index of Thin-layer Chromatographic Data. Gas chromatography The gas chromatographic systems referred to in the monographs are described in the GC chapter, together with lists of retention data for drugs in important chemical and pharmacological classifications. A general screening system (system GA), which includes over 1500 drugs and metabolites, is provided. An alternative screening system (system GB) is also included (see Chapter 28 for system details and references). For most of the systems, the data are given in terms of Retention Index. Retention times or relative retention times are used in a few systems. Complete lists of retention data, in ascending order, are given in the indexes of Gas Chromatographic Data. High performance liquid chromatography The HPLC systems referred to in the monographs are described in the HPLC chapter, together with lists of retention data for drugs in important chemical and pharmacological classifications. Six general screening systems (systems HA, HX, HY, HZ, HAA and HBK) covering between 400 and 1600 drugs are provided (please note that values for system HBK have not been included within monographs and can only be found in the index) (see Chapter 29 for system details and references). The data are given in terms of Retention Index, retention time, relative retention time and column capacity ratio k (see Chapter 29). Complete lists of retention data, in ascending order, are given in the indexes of High Performance Liquid Chromatographic Data. Ultraviolet absorption The wavelengths of principal and subsidiary peaks are recorded in each monograph for acid, alkaline and neutral solution, where available. These are generally listed from 230 nm. Values in neutral solution are given for compounds for which values in acid or alkaline solution are not available or when the values in neutral solution differ significantly from those in acid or alkaline solution. In many monographs, the ultraviolet spectrum is reproduced. In these spectra, the following notation is used: ------------------ acid solution ……………… alkaline solution ------neutral solution Where more than one curve is shown, they do not necessarily relate to the same concentration and, consequently, points where the curves cross cannot be taken as true isosbestic points. The wavelengths of peaks in a few of the spectra may differ very slightly from those stated in the text. Where there is doubt, the values given in the text should be used. In monographs where the spectrum is reproduced, the A11 value for each peak is stated, if available. The A values apply to the form of the substance described in the main title of the monograph, unless otherwise stated. The A11 values are divided into three categories in order to provide an indication of reliability: • The letter ‘a’ after a figure indicates that the value is a mean value based on several reported figures, all of which lie within a range of ±10% of the mean. • The letter ‘b’ after a figure indicates that the value is a single reported value of unknown reliability. • The letter ‘c’ after a figure indicates that the value is a mean value based on several reported figures, some of which lie outside ±10% of the mean. The phrase ‘no significant absorption’ indicates that no peaks are found at the concentrations normally used. The A11 values quoted in the monographs may be useful in identification, and may help in determining the strength of a solution which is required to obtain a curve within the instrumental range of absorption. They may also be useful to give an approximate indication of the amount of drug in a solution. However, because of instrumental differences and the possible effect of solvent and pH, A11 values are subject to considerable variation and the values quoted should not be used when an accurate assay is required. In this case, a reference specimen should be examined at the same time as the sample. The wavelengths of main peaks are listed for acid, alkaline and neutral solution from 230 nm in the index of Ultraviolet Absorption Maxima. Infra-red absorption The wavenumbers of the six major peaks in the range 2000 to 650 cm−1 (5 to 15 μm), in descending order or amplitude, are recorded in the monographs. In many cases, the infrared spectrum is also reproduced. When selecting the six principal peaks, those which are in the region where Nujol absorbs (1490 to 1320 cm−1, 6.7 to 7.6 μm) have been omitted. Corrections for calibration errors have been applied where these are known. The six principal peaks, in ascending order of the main peak, are listed in the index of Infra-red Peaks. Mass spectrum The m/z values of the eight most abundant ions, in descending order of intensity, are included in many monographs. Where dashes occur in the listing, this indicates that less than eight ions have been observed. The eight principal ions, in ascending order of the main peak, are listed in the index of Mass Spectral Data of Drugs. A separate index for pesticides can also be found. The full mass spectra for the majority of the listed compounds are displayed within the monographs. Quantification The methods referred to in the references quoted under the heading ‘Quantification’ in the monographs are not intended to be recommended methods. These references are intended to be used as a guide to the literature on the particular subject. Reagents Reagents required for specific tests or methods are generally described fully in the appropriate place in the text. However, certain common reagents that are used throughout the book are described in the list of Reagents and Proprietary Test Materials. Reagent solutions are made in purified water unless otherwise specified. When ethanol, without qualification, is stated to be used, this refers to ethanol (95%). Unless otherwise stated, solutions of solids in liquids are expressed as percentage w/v, and solutions of liquids in liquids as percentage v/v. When acids of various strengths are specified, e.g. 50% sulfuric acid, this implies the appropriate dilution by volume of the strong acid in water. Disposition in the body Many of the monographs contain a section with the heading ‘Disposition in the Body’. The information in these statements has been obtained from a detailed survey of published papers and other reference sources. Certain monographs have a single reference at the end of the statement, and this indicates that all the disposition information has been obtained from that source. Wherever possible, information is included on absorption, distribution, metabolism, excretion, therapeutic concentration, toxicity and pharmacokinetic parameters. Entry to the literature is provided by the inclusion of abstracts of published papers on clinical studies or case histories. These abstracts include details of drug concentrations in plasma or other body fluids or tissues; in these data a dash means that the particular value was not determined, and ND or 0 means that the substance was not detected. Concentrations in body fluids or tissues are expressed in mg/L or μg/g. In some monographs, the information is incomplete, the amount of detail being dependent upon that available in the literature searched. It should not be assumed that the statements presented reflect the only significant factors in the disposition of the drug concerned. Therapeutic concentration This is the concentration range usually observed after therapeutic doses, as reported in clinical studies and other research projects. It should not be interpreted as the concentration range required for optimum therapeutic effects. Toxicity This statement may include drug concentrations in blood or other body fluids or tissues, which have been reported to be associated with toxic or lethal effects. Because of intersubject variations or other variable factors, the reported toxic or lethal concentrations may occasionally lie close to or within the therapeutic range. In some monographs, the toxic or lethal blood concentrations are stated in the form 60 to 89 to 150 mg/L. These figures have been obtained from a survey of a number of reported cases and represent the maximum concentrations found in 10%, 50% and 90% of the subjects, respectively. Maximum permitted concentrations in air (8-hour exposure limit) are those recommended by the Health and Safety Executive in Occupational Exposure Limits 2002, Guidance Note EH40/2002 Supplement, London, HMSO, 2003. Volume of distribution This relates to plasma concentrations after intravenous administration, unless otherwise stated. Values are based in a body-weight of 70 kg. Clearance This usually refers to the total plasma clearance (or total whole blood clearance) after intravenous administration. In some instances, the total clearance after an oral dose has been included if the drug is known to be well absorbed and is not subject to significant first-pass metabolism. Numerous factors and inter-subject variations may affect the absorption, distribution, metabolism and excretion of drugs. These include age, sex and disease states such as renal impairment. In addition, results of analyses may be subject to unavoidable analytical inaccuracies. Consequently, there may be considerable variations in the observed drug concentrations and in values for pharmacokinetic parameters in individual cases. Hence, the values given in the monographs should be used only as a guide and should not be taken as absolute values. Dose The dose recorded under this heading in the monographs indicates the usual daily dose (oral unless otherwise stated) that may be administered for therapeutic purposes. It is intended solely as a guide in deciding whether the amount taken by an individual falls within the normal dosage range and should not be taken as a recommendation for treatment. More detailed information on doses in different conditions and age groups may be found in Martindale, The Extra Pharmacopoeia, 33rd Edn, London, The Pharmaceutical Press, 2002; The British National Formulary, latest edition; or in the manufacturers’ data sheets for the products. Comments This edition of Clarke could not have been completed without the comments on the second and the first editions, and the contribution of analytical data from many scientists involved in the analysis of drugs. In order to assist in the preparation of the next edition, the reader is invited to send any constructive comments and relevant new data concerning the analysis of drugs in biological materials to the Editor, Clarke's Analysis of Drugs and Poisons, The Royal Pharmaceutical Society of Great Britain, 1 Lambeth High Street, London SE1 7JN, UK. In this way, future editions will be improved to the benefit of all of those who use it. Deletions The following substances which were included in Volumes 1 and 2* of the 1st and 2nd Editions are not included in this edition: Acetyldihydrocodeine Adrenalone Allantoin Allylprodine Alphameprodine Alphamethadol Aminometradine Aminopentamide Amisometradine Amolanone Amopyroquine *Amotriphene Amprotropine Amydricaine Amylocaine Apoatropine Azacosterol Azamethonium Bromide Benzalkonium Bromide Benzamine Benzathine Penicillin Benzethidine Betameprodine Betaprodine *Brocresine Butallylonal Butethamine Butoxamine Cetoxime Chlorisondamine Chloride Citronella Oil Clamoxyquin Clonitazene *Cloponone Codeine N-Oxide Cyclamic Acid Cyprenorphine Demecolcine Demeton-O Desomorphine Diampromide Dibutoline Sulphate *Diethylaminoethyl Diphenylpropionate Dimenoxadole *Dimethocaine Dimethylthiambutene *Dimophebumine Dioxaphetyl Butyrate Dioxathion *Dioxyamidopyrine *Diphenazoline Dithiazanine Iodide Embramine Erythrityl Tetranitrate *Ethylisobutrazine Ethylmethylthiambutene *Ethylpiperidyl Benzilate Etonitazene Etoxeridine Etymide Fenimide *Fenmetramide Furethidine Hydromorphinol Hydroxypethidine *Imidocarb *Iminodimethylphenylthiazolidine *Iopydol *Iopydone Isobutyl Aminobenzoate *Isometamidium Isomethadone Laudexium Methylsulphate Leucinocaine Levomethorphan Levomoramide Levophenacylmorphan Lucanthone Metabutethamine Metabutoxycaine Metazocine *Methadone Intermediate Methaphenilene Methoxypromazine Methylaminoheptane Methyldesorphine Methyldihydromorphine Methylhexaneamine Methyridine Metofoline Metopon *Moramide Intermediate Morpheridine Morphine N-Oxide Mustine Myrophine Naepaine *Naftazone Narcobarbital Nicocodine Nicomorphine *Nifuroxime Noracymethadol Norbutrine *Nordefrin *Norgestrel Norlevorphanol *Octacaine Octaverine Orthocaine Pamaquin *Panidazole *Paromomycin Pentaquin *Pethidine Intermediate A Phenadoxone Phenamidine Phenampromide *Phenatine Phenisonone Phenomorphan Phenoxypropazine Phenylpropylmethylamine *Phthivazid *Picloxydine Pipamazine Piperoxan Pipethanate Plasmocide *Proadifen Probarbital Proheptazine Properidine Pulegium Oil *Pyrrocaine Quinapyramine Chloride Racemethorphan Racemoramide *Resorantel *Rifamide *Rolicypram Stilbamidine Sulphasomizole Sulphonal *Taurolin Teclothiazide *Terodiline *Tetracosactrin *Tetraethylammonium Bromide *Thozalinone Thurfyl Nicotinate *Tiletamine Tolonium Chloride Tolycaine Triclobisonium Chloridc Tropacocaine Tropine Tymazoline Viomycin Xenysalate Abbreviations A11 specific absorbance (abbreviation of A1%1cm) AC AFID agg. AIDS API APCI Art AUC AV B.P. b.p. CAS CFTB CHF -CHNO CI CIn Cl CNS -CO2 CSF CT DMES DMF DMSO ECD ECG EDTA EI ELISA ELS ET eV FAB fg FID f.p. acetylated alkali flame ionisation detector aggregate (in botanical names), including 2 or more species which resemble each other closely acquired immunodeficiency syndrome atmospheric pressure ionisation atmospheric pressure chemical ionisation artefact area under the curve atrioventricular British Pharmacopoeia boiling point Chemical Abstracts Service 5-chloro-2′-fluoro-2-(2,2,2-trifluoroethylamino)-benzophenone congestive heart failure descarbamoyl artefact chemical ionisation colour index clearance central nervous system artefact formed by decarboxylation cerebrospinal fluid computed tomography dimethylethylsilyl dimethylformamide dimethylsulfoxide electron capture detection electrocardiogram ethylene diamine tetra-acetate electron impact enzyme-linked immunosorbent assay evaporative light-scattering ethylated electron volts fast atom bombardment femtograms flame ionisation detection freezing point FPD ft FTIR G-CSF GC GI h -HCl -HCN HIV -H2O HPLC -HY i.d. IM IR IV I.S. k λ log ln M M (OH-) M (COOH) M (nor-) M (ring) MAO mEq μg μm MID min mol m.p. MRM MS flame photometric detector foot (feet) Fourier transform infra-red granulocyte colony-stimulating factor gas chromatography gastro-intestinal hour (s) artefact formed by the elimination of hydrochloric acid artefact formed by the elimination of hydrogen cyanide human immunodeficiency virus artefact formed by dehydration of an alcohol or by rearrangement of an amino oxo compound high performance liquid chromatography acid-hydrolysed/acid hydrolysis internal diameter intramuscular infra-red intravenous internal standard column capacity ratio wavelength logarithm to the base 10 logarithm to the base e (natural logarithm) molar (moles per litre) hydroxy metabolite carboxy metabolite N-desmethyl metabolite ring compound as metabolite monoamine oxidase milliequivalent(s) microgram(s) micrometer(s) multiple ion detector minute mole melting point multiple reaction monitoring mass spectrometry m/z Me or ME ng -NH3 NIAPCI NICI nm NPD NSD P PAD PDHID PEEK PFB -PFP pg PIAPCI PICI PID PIFAB pKa ppb ppm PTFE r.d. RI RRT s SDS SIM -SO2NH sp. sp.gr. t 1/2 TBA TBAF TBSA TCD mass to charge ratio methylated nanogram(s) artefact formed by elimination of ammonia negative ion atmospheric pressure chemical ionisation negative ion chemical ionisation nanometer(s) nitrogen-phosphorus detection nitrogen-specific detector apparent partition coefficient peripheral arterial disease pulsed discharge helium ionisation detector polyether etherketone pentafluorobenzoyl pentafluoropropionylated picogram(s) positive ion atmospheric pressure chemical ionisation positive ion chemical ionisation photoionisation detector positive ion fast atom bombardment negative logarithm of the dissociation constant part(s) per billion part(s) per million polytetrafluoroethylene relative density retention index relative retention time second(s) sodium dodecyl sulfate selected ion monitoring artefact formed by elimination of the sulfonamide group species (plural spp.) specific gravity half-life tetrabutyl ammonium hydrogen sulfate tetrabutyl ammonium fluoride total body surface area thermal conductivity detector TEA -TFA TIC TLC TMS TMSTFA TOF TSD UV V var. VD Vet. Vol v/v Wt w/v w/w triethylamine trifluoroacetylated total ion current thin-layer chromatography trimethylsilyl trimethylsilyltrifluoroacetyl time of flight thermionic specific detection ultraviolet volt(s) variety volume of distribution veterinary volume(s) volume in volume weight weight in volume weight in weight Copyright © Pharmaceutical Press 2004 is a trade mark of Pharmaceutical Press All rights reserved. No part of this publication (data or software) may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without the prior written permission of the copyright holder. The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this software and cannot accept any legal responsibility or liability for any errors or omissions that may be made. Contact Us Publishers Pharmaceutical Press Publications division of the Royal Pharmaceutical Society of Great Britain 1 Lambeth High Street London SE1 7JN UK Telephone: +44 (0)20 7735 9141 Fax: +44 (0)20 7572 2509 Email: pharmpress@rpsgb.org Web: http://www.pharmpress.com/ Pharmaceutical Press 100 South Atkinson Road, Suite 206 Grayslake, Illinois 50038-7820 USA Telephone: +1 847 543 1708 Fax: +1 847 543 1768 Email: pharmpress@ameritech.net Web: http://www.pharmpress.com/ Software Developers Clinical and Biomedical Computing Ltd 2nd Floor, 32a Bridge Street Cambridge CB2 1UJ UK Telephone: +44 (0)1223 364 444 Fax: +44 (0)1223 364 444 Email: info@cbcl.co.uk Web: http://www.cbcl.co.uk/ Technical Support Brook House Telephone: +44 (0)1988 600 789 Fax: +44 (0)1988 402 567 Email: clarke@brookhouse.co.uk Web: http://pharmpress.brookpub.net/support/ Methodology & Analytical Techniques Chapters 1 Hospital Toxicology Chapters 2 Drugs of Abuse 3 Alcohol, Drugs and Driving 4 Workplace Drug Testing 5 Forensic Toxicology 6 Postmortem Toxicology 7 Drugs in Saliva 8 Hair Analysis 9 Drug Abuse in Sport 10 Therapeutic Drug Monitoring 11 Quality Control and Assessment 12 Pharmacokinetics and Metabolism 13 Natural Toxins 14 Pesticides 15 Volatile Substances 16 Medicinal Products 17 Solid Dosage Form Identification 18 Metals and Anions 19 Colour Tests Chapters 20 Immunoassays 21 Ultraviolet, Visible and Fluorescence Spectrophotometry 22 Infra–red Spectroscopy 23 Near–infrared Spectroscopy 24 Raman Spectroscopy 25 Nuclear Magnetic Resonance Spectroscopy 26 Mass Spectrometry 27 Thin–layer Chromatography 28 Gas Chromatography 29 High Performance Liquid Chromatography 30 Capillary Electrophoresis for Drug Analysis 31 Emerging Techniques
