Thermodynamic mechanism of selective cocrystallization explored by MD simulation and phase diagram analysis

Abstract The thermodynamic mechanism of selective cocrystallization was investigated by combination of molecular dynamics (MD) simulations and phase diagram analysis, using system of urea and cresol isomers as model compounds. Hansen solubility parameters (HSPs) models were utilized to predict miscibility and cocrystal formation. Thermodynamic phase diagrams of cresol isomers and urea were measured with the help of process analysis technology. MD simulations were performed to investigate the intermolecular interactions between m ‐ and/or p ‐cresol and urea, by calculating the solvation free energies (SFEs) and analysing radial distribution functions (RDFs). The simulation and experimental results indicate that the solubility data of urea are apparently affected by the SFEs, which are linearly related with the concentration of urea. Moreover, it was also found that the type of O‐H···O=C hydrogen bond plays a critical role in the contribution of intermolecular interactions and is also a key factor for selective cocrystallization.