Making a drug crystal in the right shape currently costs industry up to 120K Euros per compound in trial-and-error experiments, and researchers still cannot predict the outcome without running those tests. This project tackles a fundamental gap in chemistry: no one knows exactly how molecules cluster together in solution before they crystallise. Without that knowledge, pharmaceutical companies must brute-force test hundreds of conditions to find the right crystal form, wasting time and money. The researcher will use spectroscopic and total scattering techniques to measure the strength and structure of interactions between identical molecules, between solute and solvent, and across solvent-solvent interfaces in mixtures. If successful, the work will produce simple, practical rules—comparable to Lipinski’s ‘Rule of Five’—that crystallisation scientists can apply without running complex simulations. That would replace costly brute-force screening with a tailored, controlled approach, accelerating drug development and reducing manufacturing waste. This is fundamental science with a clear industrial payoff: a deeper understanding of molecular behaviour before crystals form, translated directly into everyday lab practice.
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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 in solution. 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.
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