PhD project title and outline, including interdisciplinary dimension:
Pre-nucleation aggregates in amorphous pharmaceuticals

This project will investigate the amorphous structure of pharmaceutical drug compounds towards an understanding of the factors leading to multiple crystal forms (polymorphism). Polymorphism is one of the bottlenecks of formulation of any new drug entity, as different crystal forms have varying physicochemical characteristics, and pharmaceutical companies spend billions of US$ each year to circumvent this problem. Instead of the currently used time and cost intensive crystallisation screening, we are aiming to understand the factors leading to multiple crystal forms by investigating the phases before crystallisation. By applying X-ray and neutron total scattering techniques, the student will extract data related to the local ordering in the amorphous samples before crystallisation. This data can then be modelled by Monte-Carlo simulations to give a 3D structural model of the phase, which can be further interrogated towards strong intermolecular interactions (hydrogen bonds, halogen bonds, pi-stacking). By comparing these interactions with those found in the crystal structure of the resulting crystal form, we will be able to relate the two phases and extract structure guiding factors for the crystallisation process.

The topic of crystallisation and crystal polymorphism is an integral part of pharmaceutical pre-formulation studies and thus the pharmaceutical formulation process. The approach of this project to gain information about the factors driving the appearance of different crystal forms lies on the border between Pharmacy, Chemistry and Physics, and is thus inherently multi-disciplinary. This project will run in collaboration with ISIS Neutron and Muon Source as non-HEI partner organisation, who will host the student for placements. During this time, the student will be trained in the theoretical aspects of neutron total scattering, will conduct experiments and model the obtained data under supervision of Dr Silvia Imberti, as well as participate in the wide range of training courses in transferrable skills. Additional collaboration is planned with the Institut Laue-Langevin in France as second neutron source and Pfizer Ltd, the world-leading pharmaceutical company.

Primary supervisor: Dr Katharina Edkins  (Pharmacy)
Secondary supervisor: Dr John Holbrey  (Chemistry and Chemical Engineering)
External Partner/Organisation: Rutherford Appleton Laboratory (RAL)