Extending the Search Space for Novel Physical Forms of Pharmaceuticals and Biomolecules using High-Pressure Techniques

Abstract

This thesis, which is divided into two parts, describes the use of non-ambient crystallisation techniques, in particular high-pressure, to explore on one hand inclusion complex formation of cyclodextrins with drug molecules (part 1), and on the other hand the solid-state behaviour of imidazolium-based ionic liquids (part 2). Much of this thesis is devoted to establishing detailed crystallisation protocols for the compounds studied and to reporting full structural analysis of the resulting crystals, which have been investigated by single-crystal X-ray diffraction using both laboratory and synchrotron sources. This work shows that the application of pressure has different effects on cyclodextrin-based inclusion complexes. When water is used as pressure transmitting medium, cyclodextrins undergo dissolution as function of increasing pressure, regardless of the inclusion state. Upon further pressurisation three events have been observed to take place: no crystallisation, crystallisation of host and guest molecules as separate entities or crystallisation of inclusion complexes. It has not been possible to rationalise the observed behaviour or predict which of the three events is most likely to occur for a given system. During the course of this work, novel inclusion complexes for α- and β- cyclodextrin have been obtained at both ambient- and high-pressure conditions; full structural characterisation has enabled to identify two novel packing motifs. As demonstrated for imidazolium-based ionic liquids, high-pressure is a powerful external factor for triggering crystal formation and phase transitions in this class of compounds. The solid-state behaviour of ionic liquids at high pressure has been correlated with the one at low temperature, proving that a thorough understanding and exploration of the crystallisation diagrams necessitates the use of both non-ambient techniques. The studies performed in this thesis demonstrate the importance of characterising crystalline phases by single-crystal X-ray diffraction methods. Thanks to the availability of accurate structural data it has been possible to unravel the elusive polymorphism of the most widely studied imidazolium-based ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate, which had been the subject of much debate and speculation in the literature. For 1-decyl-3-methylimidazolium chloride, structural data have enabled to distinguish between three distinct packing types of this ionic liquid in its hydrated forms, and to pin point subtle but important structural differences between the different crystalline phases.