Abstract/Summary

Determination of structural information from diffraction patterns of crystalline materials can enable and enhance many ‘high impact’ areas of chemistry including the development of materials for photovoltaics, hydrogen storage cells and battery materials. In this thesis, drug discovery and drug development is explored with respect to their use of structural information. Given that these processes utilise conformational and packing information to enhance all stages of their development; from lead identification to formulation. The earlier conformational information is obtained within these processes, the greater potential impact on the direction of a project within these areas. Furthermore, in many cases, it is not feasible to grow single crystals, large enough what they are suitable for single crystal X-ray diffraction (SCXRD). Powder X-ray diffraction is the best alternative but unfortunately, a standard powder diffraction set up requires at least 10 mg of sample, which is simply not available at the early stages of drug development programmes. In this thesis, a trial of 81 small organic compounds found that, after multiple recrystallisations, 25 compounds produced one or more samples that were crystalline but were unsuitable for SCXRD. This thesis presents a method for the routine powder diffraction data collection using an in-house single crystal diffractometer with < 0.1 mg of polycrystalline sample. The process of optimising of a single crystal diffractometer for optimal powder data collection is described. This method combines the use of powder diffraction data collected on a standard, lab-based single crystal diffractometer (SDPD-SX) using DASH, an open-source global optimisation structure solution approach. The applicability of the method is also demonstrated through a wide range of molecular and crystallographic complexity, with particular focus on compounds of pharmaceutical interest. SDPD-SX enabled the crystal structure determination from limited samples of a range of known and novel crystal structures. Novel structures were validated using DFT-D energy minimisation.