Development of a Near-Infrared Spectroscopic Method for the Determination of Water in Prozac

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MSc Analytical Chemistry - N. Blakiston 1 FACULTY OF SCIENCE MSc DEGREE IN Analytical Chemistry Neil Blakiston K0429387 Development of a Near-Infrared Spectroscopic Method for the Determination of Water in Prozac September 2007 Supervisor: Dr R. J. Singer MSc Analytical Chemistry - N. Blakiston 2 Acknowledgements First, I would like to thank my Supervisors, Dr Richard Singer and Dr Steve Barton whose support, encouragement and feedback on both practical and written work was invaluable to
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  MSc Analytical Chemistry - N. Blakiston1 FACULTY OF SCIENCE MSc DEGREEINAnalytical Chemistry Neil Blakiston K0429387 Development of a Near-InfraredSpectroscopic Method for theDetermination of Water in ProzacSeptember 2007 Supervisor: Dr R. J. Singer   MSc Analytical Chemistry - N. Blakiston2 Acknowledgements First, I would like to thank my Supervisors, Dr Richard Singer and Dr Steve Bartonwhose support, encouragement and feedback on both practical and written work wasinvaluable to the completion of this thesis.My gratitude also goes to Amanda Hibberd for her assistance and training on the NIR spectrophotometer, to Jim Martindale, Ian Anderson, Yousuf Jeetoo, Ian Ross, AndyFirth, Russell Freeman and Teresa Coyle for their review and input to the technicalreports and authorisation of the practical work.I am also grateful to Eli Lilly & Co. Ltd. for their financial support and Jon Markswhom supported my application, gave encouragement and technical guidance.Finally, I would like to thank my family, especially my wife Jane, daughtersHermione and Hannah for their continued encouragement and patience throughout allof my studies.  MSc Analytical Chemistry - N. Blakiston3 Abstract The application of near-infrared (NIR) spectroscopy as an alternative analytical procedure for analysis has been a controversial subject with both the analyticalcommunity and regulatory authorities. This is due, in part, to the belief that theInternational Conference on Harmonisation (ICH) Guidelines on the Validation of Analytical Procedures could not be applied to NIR spectroscopy.In this study Prozac was chosen to determine if NIR spectroscopy could replace themore time consuming, costly and hazardous method of water determination byvolumetric Karl Fischer Titration (reference method).This work demonstrated that a NIR method for determination of water was not onlyfeasible, but with only a few data points could produce results statistically comparableto the existing method. During investigation the reference method requireddevelopment due to its unforeseen poor performance.The guidelines of the International Conference on Harmonisation (ICH) for thesubmission requirements of the pharmaceutical industry regulatory approval are alsodiscussed in relation to NIR methods.The method proved suitable for the measurement of water concentrations fromapproximately 2 to 9 % H 2 O with a maximum absolute error of 1.2 % H 2 O from theaverage replicate value of the reference method. This is of a similar magnitude to theerror between replicate analysis by the reference method.  MSc Analytical Chemistry - N. Blakiston4 Contents Page FACULTY OF SCIENCE ..............................................................................................1Acknowledgements ........................................................................................................2Abstract ..........................................................................................................................3Contents of Figures ........................................................................................................7Contents of Tables and Attachments ..............................................................................8Abbreviations ................................................................................................................9General Introduction .................................................................................................... 10Aims and Objectives ................................................................................................ 10Background .............................................................................................................. 10Water Determination ................................................................................................ 12Definition: ............................................................................................................ 12Methods for the determination of water ............................................................... 13Choosing a Suitable Method ........................................................................................ 16The Product of Choice ..............................................................................................16The Method of Choice ..............................................................................................17Introduction to the drug product PROZAC® ...............................................................18Sample Source ..............................................................................................................20Introduction to Karl Fischer Volumetric Titration ....................................................... 21Karl Fischer Titration - History and Development .................................................. 21Conditions for Karl Fischer Titration .......................................................................25Hydranal® Composite 5 Titrant ...............................................................................26Solvent ......................................................................................................................27 pH ............................................................................................................................. 28Standard Sodium Tartrate Dihydrate ........................................................................29Automated Analysis ................................................................................................. 29Orion Turbo2TM Volumetric Karl Fisher Titrator .................................................. 31Limitations of KF ..................................................................................................... 34An introduction to Near-infrared spectroscopy ............................................................36 NIR Spectroscopy - History and Development ........................................................36Theory ...................................................................................................................... 38Instrumentation .........................................................................................................44Mathematical Pre-Treatment and Processing ...........................................................46Bruker Opus NIR Spectroscopic Quant-Software ................................................... 46Theoretical Background ........................................................................................... 47Mulitvariate Calibration ........................................................................................... 48Cross Validation ....................................................................................................... 49Processing the Data .................................................................................................. 50Experimental Analysis Karl Fischer ............................................................................ 52Chemical Safety (CoSHH, Risk and MSDS) ........................................................... 52Sample Preparation .................................................................................................. 53Loss on Drying Determination ................................................................................. 54Good Manufacturing Practice (GMP) Requirements ...............................................54Execution of Technical Reports ............................................................................... 55QCL-TR-014: Loss on Drying of Prozac Powder Blend ..................................... 55QCL-TR-015: Water Determination on Dried Prozac Powder Blend by KarlFischer Titration and Near-Infrared ..................................................................... 56Investigation of Failed Execution: QCL-TR-015 .....................................................56
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