Molecular Insights into Water-Activity Effects on Nucleation and Polymorph Selection of Flufenamic Acid

Polymorph control is critical for robust crystallization production, yet the solvent-composition effects on polymorphic nucleation remain poorly understood. By integrating rapid cooling crystallization experiments with molecular dynamics simulations, this study systematically investigates the role of the water content in directing polymorphic nucleation within methanol–water solvent systems. Experimental results demonstrate that increasing water activity shifts the nucleation preference of flufenamic acid (FFA) from form III to form I (xw ≥ 0.4–0.6) at both 298 and 313 K. Molecular simulations further reveal that water progressively displaces methanol in the first solvation shell of the carboxyl group and weakens aromatic solvation when increasing the water fraction, which thus promotes π···π stacking. Furthermore, water also alters the conformation distributions in solutions from thermodynamically stable conformer III to form I-associated conformer I. This work elucidates the molecular mechanism by which water activity governs polymorph selection in FFA and provides a rational strategy for the crystal form control of conformationally flexible organic molecules.