Insights into the Formation Mechanism of <i>p</i> -Hydroxybenzoic Acid Solvates Based on Experiments and Molecular Simulations

In pharmaceutical development and manufacturing, uncontrolled solvate formation of active pharmaceutical ingredients (APIs) poses a fundamental challenge, potentially compromising process robustness, inducing batch-to-batch variability, and risking patient safety. p-Hydroxybenzoic acid (PHBA) is a widely used compound in pharmaceuticals, food preservation, and cosmetics, yet its common hydrate form exhibits instability during processing. In this study, the formation mechanism of PHBA solvates and its possible transition were systematically investigated through integrated experimental and molecular simulation approaches. Three distinct solvate forms (A, B, and C) were successfully prepared using 1,4-dioxane, N,N-dimethylacetamide (DMA), and water as solvents, with Form B being reported for the first time. Comprehensive characterization via PXRD, thermal analysis, and spectroscopy confirmed their structural and thermal differences. Suspension crystallization experiments revealed that the final polymorph is highly dependent on solvent composition, with clear transition thresholds observed in mixed-solvent systems. Molecular dynamics simulations and radial distribution function (RDF) analyses provided molecular-level insights into the competitive solvation behavior, elucidating how local enrichment and absolute occupancy of solvent molecules govern polymorph selection. This work not only clarifies the phase transition mechanism of PHBA solvates but also offers a theoretical foundation for controlling crystal forms of PHBA in industrial applications.