Investigating polymorphism in small molecules using three-dimensional electron diffraction

Sammanfattning: For scientific, regulatory and intellectual property reasons, the discovery and characterisation of polymorphic systems is an integral aspect of the development process of any solid-formulated drug product. Yet, these studies are often hindered by crystal quality and size, poor yields and the generation of mixtures of phases. Three-dimensional electron diffraction (3D ED) is a technique capable of structure determination from individually selected, nanometre-sized crystals. In this thesis, 3D ED is applied to investigate polymorphism in small molecules. The unique advantages of the method are highlighted across numerous studies to demonstrate how 3D ED can broaden the scope of polymorphism discovery and characterisation in the screening and selection of pharmaceutical crystal forms. 3D ED is first applied to reveal that two crystallisation methods believed for 47 years to produce Form δ of the pharmaceutical compound indomethacin result in two different polymorphs, highlighting the power of the method for polymorphism discovery. The polymorphic crystal structures of a small molecule are then determined directly from melt-grown compact spherulites for the first time to show how 3D ED can widen the application of melt crystallisation in polymorph screening, where polycrystalline spherulites are common products. Furthermore, 3D ED is combined with on-the-grid crystallisation and plunge freezing to follow the polymorph evolution of glycine during crystallisation from an aqueous solution to demonstrate the ability of the method to monitor crystallisation processes in situ. The final part of the thesis explores how a high-throughput method combining 3D ED data collection in batch mode with semi-automated data processing can be applied for the phase analysis of complex melt crystallisation products to improve the efficiency and accuracy of polymorph screening.