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Stability of Zopiclone in Whole Blood Studies from a Forensic Perspective

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Stability of Zopiclone in Whole Blood Studies from a Forensic Perspective Linköping Studies in Health Sciences, Thesis No. 113 Stability of zopiclone in whole blood ‐ Studies from a forensic perspective Gunnel Nilsson Division of Drug Research Department of Medical and Health Sciences Linköping University, Sweden Linköping 2010 Supervisors Robert Kronstrand, Associate Professor Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Sweden Johan Ahlner, Professor Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Sweden Fredrik C. Kugelberg, Associate Professor Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Sweden Gunnel Nilsson, 2010 Published article has been reprinted with permission of the copyright holder. Paper I © 2010 Elsevier, Forensic Science International Printed in Sweden by LiU‐Tryck, Linköping, Sweden, 2010 ISBN 978‐91‐7393‐339‐1 ISSN 1100‐6013 Dala‐Gård Ring the bells that still can ring Forget your perfect offering There is a crack in everything That’s how the light gets in Anthem by Leonard Cohen Contents CONTENTS ABSTRACT ............................................................................................................................. 1 POPULÄRVETENSKAPLIG SAMMANFATTNING..................................................... 3 LIST OF PAPERS ................................................................................................................... 5 ABBREVIATIONS ................................................................................................................. 6 INTRODUCTION.................................................................................................................. 7 Pre‐analytical conditions............................................................................................... 7 Drug stability................................................................................................................... 7 Design and evaluation of stability experiments....................................................... 9 Stability investigations of drugs................................................................................ 10 Zopiclone........................................................................................................................ 11 Pharmacokinetics .................................................................................................... 12 Pharmacodynamics................................................................................................. 13 Forensic cases........................................................................................................... 14 Analytical methods ................................................................................................. 16 Biological specimens............................................................................................... 17 AIMS OF THESIS ................................................................................................................ 19 Specific aims.................................................................................................................. 19 Paper I....................................................................................................................... 19 Paper II...................................................................................................................... 19 MATERIALS AND METHODS........................................................................................ 21 Study designs ................................................................................................................ 21 Long‐ and short‐term stability .............................................................................. 21 Freeze‐thaw stability............................................................................................... 22 Processed stability................................................................................................... 22 Degradation ............................................................................................................. 22 Influence of pre‐analytical conditions.................................................................. 22 Contents Ethical considerations.................................................................................................. 23 Equipment...................................................................................................................... 23 Chemicals and solutions ............................................................................................. 24 Analytical methods....................................................................................................... 24 Gas chromatography .............................................................................................. 24 Liquid chromatography ......................................................................................... 26 Quality controls ....................................................................................................... 26 Clinical chemical analysis ...................................................................................... 27 Statistical analysis ........................................................................................................ 27 RESULTS................................................................................................................................ 29 Paper I ............................................................................................................................. 29 Long‐ term and short‐term stability ..................................................................... 29 Freeze‐thaw stability............................................................................................... 31 Processed stability................................................................................................... 32 Degradation products............................................................................................. 32 Quality control samples ......................................................................................... 32 Paper II............................................................................................................................ 33 Authentic and spiked stability samples............................................................... 33 Quality control samples ......................................................................................... 35 GENERAL DISCUSSION................................................................................................... 37 Stability investigations................................................................................................ 37 Pre‐analytical aspects ................................................................................................... 40 Methodological aspects ............................................................................................... 40 CONCLUDING REMARKS............................................................................................... 43 Paper I ............................................................................................................................. 43 Paper II............................................................................................................................ 43 FUTURE PERSPECTIVES .................................................................................................. 45 ACKNOWLEDGEMENTS ................................................................................................. 47 REFERENCES........................................................................................................................ 49 APPENDIX (PAPERS I–II).................................................................................................. 59 Abstract ABSTRACT Bio‐analytical results are influenced by in vivo factors like genetic, pharmacological and physiological conditions and in vitro factors like specimen composition, sample additives and storage conditions. The knowledge of stability of a drug and its major metabolites in biological matrices is very important in forensic cases for the interpretation of analytical results. Many drugs are unstable and undergo degradation during storage. Zopiclone is a short‐acting hypnotic drug, introduced as a treatment for insomnia in the 1980s. However, this drug is also subject to abuse and can be found in samples from drug‐impaired drivers, recreational drug users and forensic autopsy cases. Zopiclone is analyzed in biological materials using different analytical methods. It is unstable in certain solvents and depending on storage conditions unstable in biological fluids. The aim of this thesis was to investigate the stability of zopiclone in human whole blood and to compare stability between authentic and spiked samples. Interpretation of zopiclone concentrations in whole blood is important in forensic toxicology. The following investigations were performed to study the stability of zopiclone in both spiked and authentic human blood. First, different stability tests were performed. Spiked blood samples were stored at –20°C, 5°C and 20°C and the degradation of zopiclone was investigated in long‐ and short‐term stability. Authentic and spiked blood samples were stored at 5°C and differences in zopiclone stability were studied. Processed sample stability and effect of freeze/thaw
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