Ab initio simulation of molecular crystal regrowth of paracetamol from solution

Abstract

The morphology of molecular crystals depends strongly on both thermodynamic stability and the growth kinetics which are themselves dependent on the fine details of intermolecular interactions and challenging to model with ab initio methods. Here, the combination of density functional theory with the effective screen medium-reference interaction site model (DFT/ESM-RISM) is used to study the fast regrowth of a form I paracetamol crystal post-breakage, recently reported by [Bade et al., Mater. Horiz., 2023, 10, 1425–1430]. It is demonstrated that both the thermodynamic and the kinetic factors affecting regrowth are successfully captured by DFT/ESM-RISM with relatively low computational costs. With inclusion of all the externally observed facets, the morphology predicted from thermodynamic considerations alone is found to agree well with observation. Deviation from this morphology is predicated upon inclusion into the model of the fast-growing internal (010) plane, indicating the strong influence of kinetic effects on morphology. The paracetamol molecules at the surface are characterised by unsaturated hydrogen bonds; the resultant strong interaction with the solutes and the solvent significantly altering surface thermodynamics and the structure of the near-surface solvent. For example, the competition between ethanol and solvated paracetamol molecules for the formation of hydrogen bonds is found to reduce the growth rate due to steric hindrance. This effect becomes less prominent for the (010) surface, which presents no broken hydrogen bonds, resulting in a more uniform near-surface solvent structure that facilitates surface growth. As the first attempt to investigate the complicated solid–liquid interface of molecular crystals, this study broadens the applicability of DFT/ESM-RISM. The kinetic mechanisms underpinning the fast regrowth of form I paracetamol post-breakage are qualitatively elucidated, suggesting new strategies for efficient morphology control in molecular crystals.