Homogeneous Nucleation of L-Histidine from Solution: Systematic Studies of Nucleation Rates in Solvent Mixtures

Precise control of crystalline particle properties, such as polymorphic form, habit, and particle size are crucial in the pharmaceutical and wider chemical industry. A deep understanding of the molecular processes underlying nucleation and crystal growth kinetics, is crucial for rational control of the crystallisation process conditions, with a view to achieving optimal product properties. This work seeks to establish the fundamental parameters that relate the resulting particle properties to crystallisation conditions, including solvent composition, concentration/supersaturation and temperature; for different process methodologies, such as cooling, evaporative and anti-solvent crystallisations. The focus of attention must be the transition state for the crystal nucleation events, in which the properties of the crystallisation products are likely to be predetermined.

Using a transition state theory approach for interpreting nucleation rates, we can experimentally obtain activation Gibbs free energies, enthalpies and entropies associated with the formation of the transition state from nucleation rate data. The height and nature of the activation barrier has wider implications, as it determines not only the rate of nucleation but also the yield and polymorphic outcome. It is also fundamentally linked to all relevant intermolecular interactions, including solvent-solute, solute-solute and solvent-solvent interactions, and the molecular structure of the transition state.

This thesis presents a simple experimental workflow for determining the activation parameters for the dissolution and crystallisation processes of L-Histidine in binary solvent mixtures, containing water and an organic solvent in fixed volume ratio. The influence of the organic solvents on the nucleation rate was interpreted with the aim to relate the differences in molecular structure and interactions to the observed activation parameters. They were further rationalized through computational analysis, combining hydrogen bond donor and acceptor parameters, with multi-component hydrogen bond propensity calculations developed at the Cambridge Crystallographic Data Centre.