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Experimental and Theoretical Investigation of Chiral Separation by Crystallisation

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Experimental and Theoretical Investigation of Chiral Separation by Crystallisation Experimental and theoretical investigation of chiral separation by crystallisation Miguel Ardid Candel A thesis submitted to University College London in partial fulfilment of the requirements for the degree of Doctor of Philosophy University College London 2013 Department of Chemical Engineering University College London Torrington Place London, WC1E 7JE United Kingdom 1 Declaration I, Miguel Ardid Candel, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Acknowledgements I would like to sincerely thank my supervisors Professor Alan Jones and Professor Sally Price for all their help, encouragement and continued support throughout my research studies. Sally’s help and encouragement over the last year has been invaluable. She has always had time to discuss my work with me and to help me clarify my thoughts and has kept me going with the writing up. Without her help arriving to this point would not have been possible. I am very grateful to everyone in Sally’s group who I had the chance to meet and work with for they are an incredible group of scientists and everyone has at some point had some useful advice that has helped develop this work. I am especially indebted to Dr Doris Braun, for her guidance and assistance with experimental work, and for the numerous discussions we had during lunch breaks that helped me find my way so often during my studies. I am also extremely grateful to Dr Louise Price for helping me with the diastereomeric salt searches presented in Chapter 6 and for having so much patience with me, helping to figure out mistakes in the input files. I was lucky to meet Dr’s Sharmarke Mohamed and Nizar Issa before they were done with their PhD’s and must thank them for their invaluable advice at the start of my research studies and for showing me how to use the X-ray diffractometer. Dr Emiliana D’Oria first taught me how to use the programmes used in Chapter 6 and Dr Matthew Habgood was there at the end to assist me with my problems and for that I thank them too. I am grateful to Martin Vickers for teaching me how to use the powder X-ray diffractometer and assisting me whenever I had problems with it. Thanks also to Ogaga Uzoh, Jean-Baptiste Arlin, Rajni Miglani, Sarah Barnett, Professor Derek Tocher and Bob Lancaster. I am also really grateful to Dr.Simon Gaisford at the London School of Pharmacy for letting me use his solution and differential scanning calorimeters, without which I would not have been able to complete this work. I would also like to thank his group, especially Ms (probably Dr by now) Asma Buanz, for being so welcoming and making work in their lab so enjoyable. In the Chemical Engineering Department I am very thankful to Dr Han Wu and Olga Narducci. Although not for academic matters, I am also grateful to other friends and colleagues at the department of Chemical Engineering with whom I used to pop down for a beer and a chat on a Friday evening for much needed unwinding: Alberto Cantu Perez, Melanie Ramirez Jaramillo, Eleftheria Polykarpou, Alberto Hernandez and Shane Morrin. Dr Luca Mazzei, Damiano Rossi and Luigi Gargiulo, with whom I’ve been working with over the last year, have also been incredibly helpful and encouraging. Luigi also proved to be amazing with all matters Word. Last but not least I must thank Adamma for putting up with my grumpiness over some difficult times and helping me get through this tough experience. 3 Abstract Chiral molecules often show different pharmacological and toxicological properties, making their separation crucial for pharmaceutical companies. The resolution of racemic mixtures is often achieved via crystallisation methods. The lack of experimental data has been a major constraint in validating proposed computational methods for aiding the design of crystallisation processes for chiral resolution. This thesis provides both structural and thermodynamic data, and uses it to assess the limitations of current computer modelling methods. Progress in computational methods might eventually result in the design of resolving agents and hence reduce production costs of drugs and fine chemicals. Previous studies of naproxen have concentrated on the marketed enantiopure form of this anti-inflammatory drug. A crystallisation screen was conducted to identify all possible crystal phases of racemic and enantiopure naproxen. No polymorphs were detected and the crystal structure of the racemic compound was solved from powder X-ray diffraction data. The nature of the racemic species was confirmed with thermal methods, and differential scanning calorimetric and solubility measurements were used to estimate the enthalpy difference between the crystals at 156 °C and in the range of 10 to 40 °C. These data were used to test the different approximations involved in determining the energy differences between the racemic and enantiopure crystals. An extensive crystallisation screen was also performed for (1R,2S)-ephedrine 2- phenylpropionate salts. The crystal structure of the least soluble salt and three polymorphs of the most soluble salt were determined by low temperature single crystal X-ray diffraction or powder X-ray diffraction. Solubility measurements and differential scanning calorimetry were used to determine the relative stability of the salt pairs and polymorphs. These results showed the inadequacies of lattice energy calculations of the diastereomeric salt pair and their polymorphs. Experimental work on related diastereomeric salt pairs emphasised the difficulty in fully structurally and thermodynamically characterising these systems. 4 Table of Contents EXPERIMENTAL AND THEORETICAL INVESTIGATION OF CHIRAL SEPARATION BY CRYSTALLISATION ................................................................................................................. 1 DECLARATION ......................................................................................................................... 2 ACKNOWLEDGEMENTS ......................................................................................................... 3 ABSTRACT ............................................................................................................................... 4 Table of Contents .................................................................................................................... 5 List of Figures .......................................................................................................................... 8 List of Tables .......................................................................................................................... 15 CHAPTER 1 INTRODUCTION TO CHIRALITY AND RESOLUTIONS ................................. 17 1.1 Background to Stereochemistry and Research motivation ........................................ 17 1.2 Classification of Enantiomers: the Cahn-Ingold-Prelog rule ...................................... 19 1.3 Biological activity of enantiomers ................................................................................. 21 1.4 Production of Enantiomerically Pure Compounds ...................................................... 23 1.5 The search for Conglomerates ....................................................................................... 33 1.6 Efficiency of Classical Resolution ................................................................................. 36 1.7 Thesis Outline .................................................................................................................. 65 CHAPTER 2 CRYSTALLISATION FROM SOLUTION .......................................................... 67 2.1 Introduction ...................................................................................................................... 67 2.2 Supersaturation ............................................................................................................... 67 2.3 Nucleation ........................................................................................................................ 69 2.4 Crystal Growth ................................................................................................................. 74 2.5 Polymorphism .................................................................................................................. 77 5 2.6 Crystallisation of Racemic Mixtures .............................................................................. 80 CHAPTER 3 EXPERIMENTAL AND COMPUTATIONAL METHODS .................................. 85 3.1 Introduction ...................................................................................................................... 85 3.2 Crystallisation Screening Method .................................................................................. 85 3.3 Crystal Form Analysis ..................................................................................................... 87 3.4 Computational Methodology .......................................................................................... 91 CHAPTER 4 RACEMIC NAPROXEN: A MULTIDISCIPLINARY STRUCTURAL AND THERMODYNAMIC COMPARISON WITH THE ENANTIOPURE FORM ............................. 94 4.1 Introduction ...................................................................................................................... 94 4.2 Objectives ........................................................................................................................
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