Nucleation behaviors of p-coumaric acid in four solvents from induction time and metastable zone width: Experiments and simulations

The study of nucleation behaviors during crystallization is important for understanding the drug crystallization process. The induction time of p-coumaric acid (p-CA) was measured in four solvents at various levels of supersaturation. The kinetic parameters of nucleation (interfacial energy, critical nucleation radius, and critical Gibbs free energy) were estimated using the classical nucleation theory (CNT). The results showed that the nucleation difficulty of p-CA in the four solvents was in the order of ethyl acetate > acetone > ethanol > methanol. In addition, the metastable zone width (MSZW) of p-CA was determined in four solvents. The nucleation behaviors of p-CA were further expounded using self-consistent Nývlt-like model and modified Sangwal’s model. The results were consistent with those of CNT. To further reveal the impact of interactions between solvent and solute molecules on the nucleation behaviors of p-CA, molecular electrostatic potential surfaces (MEPs), Hirshfeld Surfaces (HS), and the radial distribution function (RDF) were performed. The investigation revealed that the intensity of solvent–solute interactions depended primarily on the strength of hydrogen bonding interactions. The RDF results showed that the magnitude of hydrogen bonding interactions of p-CA in the four solvents was in the following order: ethyl acetate > acetone > ethanol > methanol. As the hydrogen bonding interactions between p-CA and solvent molecules became stronger, the dissociation of solute molecules from solvent molecules became more difficult, leading to a wider MSZW and a lower nucleation rate.