Computational Insights into Glycine Crystallisation in Structured Ternary Fluids

This thesis develops a molecular simulation framework to investigate glycine behaviour in the octanol/water/ethanol (OWE) ternary mixture, with the overarching aim of understanding polymorph control mechanisms in structured ternary fluids (STFs).

STFs, often called surfactant-free microemulsions or ultra-flexible microemulsions, consist of small amphiphilic hydrotropes that enhance the miscibility of two otherwise immiscible components. Experimentally, the OWE ternary mixture has been found to act as a nanocrystal incubator, where the soft nanoconfinement of glycine within aqueous domains enables high nucleation rates and slow crystal growth. This allows selective crystallisation of γ-glycine and, by adjusting the composition and glycine supersaturation, enables access to all three ambient pressure polymorphs.

Initial benchmarking of glycine force fields reveals the challenge of identifying a single model capable of accurately reproducing both solution and crystal properties across all three polymorphs. A multi-objective Bayesian optimisation procedure is devised to refine the non-bonded parameters of selected models, improving crystal-phase properties. To contextualise supersaturation levels in STF mixtures, a robust workflow is applied to calculate the solubility of glycine polymorphs in the pure OWE components using a modified Einstein crystal approach and alchemical free energy methods.

The nanostructure and phase behaviour of the OWE system are characterised using both atomistic and coarse-grained molecular dynamics simulations. Atomistic models reproduce expected composition-dependent STF morphologies and two-phase boundaries. After a systematic bead remapping, a coarse-grained model is developed that preserves this STF nanostructuring at larger length and time scales.

Finally, simulations of glycine in OWE mixtures reveal preferential localisation within water-rich domains. Calculations of transport properties confirm its restricted mobility in octanol-rich compositions, while clustering analysis indicates enhanced aggregation. Together, these results provide molecular-level insight into how STF nanostructuring modulates glycine pre-nucleation behaviour, helping to rationalise experimental observations of polymorph control and build a foundation for future work elucidating nucleation mechanisms in this system.