Study of pre-nucleation clusters of liquid benzoic acid by molecular dynamics simulations

The properties of crystalline drugs and materials are strongly dependent on the specific polymorph of a substance. Polymorphs can exhibit notably distinct interaction modes, reminiscent of the initial step of crystallization: nucleation. A deep understanding of the nucleation process is crucial, yet the direct observation of the formation of a crystal nucleus remains a challenging task, leaving the nucleation mechanism largely unclear. Despite its merits, Classical Nucleation Theory has demonstrated limitations in certain systems. In response, Multi-Step Nucleation Theories have emerged, that take into account non-classical mechanisms. One of them is the Pre-Nucleation Clusters pathway, which suggest that small, disordered and highly dynamic clusters may initially form, subsequently evolving into dense liquid droplets that act as precursors to crystal nuclei. In this study, we employ molecular dynamics simulations conducted with the MiCMoS platform, to provide an atomistic perspective of what is happening before nucleation, in liquid benzoic acid. The only known crystal structure of benzoic acid crystallises in the P21/c group and is made of cyclic dimers, as basic principles of crystal engineering would predict in presence of a carboxylic group. However, our analysis reveals that cyclic dimers are not the predominant cluster type in the liquid phase. In addition, larger clusters are also present, consisting in tens of molecules arranged in a catemeric configuration instead of a dimeric one. All the clusters are here analysed in terms of cohesive energy, shape, branching, size and temporal persistence.