Molecular and Thermodynamic Drivers of Hydrate Formation: Framework and Insights from Plosaracetam

Hydrate formation risk for Plosaracetam was rigorously evaluated using combined experimental screening and advanced computational modeling. Plosaracetam is a neuropsychiatric drug candidate exhibiting multiple features associated with high hydrate propensity, including multiple exposed hydrogen bond acceptors, moderate molecular complexity, and a highly negative multidifferential hydrogen bond propensity score. Despite over 300 diverse solid form screening experiments, only the anhydrous Form I was observed, with no hydrates detected under any thermodynamic or kinetic conditions. Computational workflows incorporating crystal structure prediction, topological hydrate mapping, and ab initio water activity phase diagrams consistently identified Form I as the global thermodynamic minimum, with all predicted hydrates remaining energetically disfavored. Mechanistic insight from molecular dynamics simulations and density functional theory energies of formation revealed that a cooperative network of π–π stacking and robust halogen bonding uniquely stabilizes the anhydrous lattice, while incorporation of water disrupts this network and results in less favorable hydrogen bonds─particularly under aqueous conditions. For Plosaracetam, these findings demonstrate that the unique cooperative network of π–π stacking and halogen bonding in the anhydrous lattice effectively overrides molecular and network-based hydrate risk indicators, and only through comprehensive integration of experimental and atomistic modeling approaches was the true hydrate risk confidently resolved.