Quantifying molecular interactions linking disordered and ordered phases to predict crystallisation

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Even though crystallisation is one of the most used unit processes in the chemical and pharmaceutical industries, it is still impossible to predict the crystallisation outcome without conducting an experiment. The current practice of crystallisation screening costs industry between 50K and 120K Euros per compound in time and manpower. Streamlining this approach with the help of computational crystal structure prediction is currently curbed by computing power and the missing link between the predicted structures and the experimental conditions needed to produce them. Current attempts to investigate solution-state aggregation and its influence on the crystallisation outcome show varying success, are isolated, and do not allow for investigation to yield generalised insights.The aim of this project is to elucidate the molecular interactions in pre-crystallisation states and to link these with crystallisation outcomes. Using a combination of spectroscopic and total scattering techniques, I will extract strength and structure of homomeric interactions from the single component phase (melt or glass), solute-solvent interactions from solution, and the impact of binary solvent microheterogeneity and solvent-solvent interface on aggregation insolution. This approach will yield the fundamental understanding to enable the prediction of the crystallisation behaviour of compounds not investigated in this study. In addition, I will translate this fundamental knowledge into scale bars of interaction strength and easy-to-use rules comparable to Lipinski's 'Rule of Five' or the Biopharmaceutical Classification System allowing the application of the fundamental insights of this project in the everyday work of crystallisation scientists. This will lead to a step-change in how the community approaches crystallisation and enable a tailored and controlled approach to replace the current brute-force screening.