Nucleation of Conformational Polymorphs: A Computational Study of Tolfenamic Acid by Explicit Solvation

The nucleation mechanism of polymorph formation remains poorly understood. For conformational polymorphism, the nature and strength of molecular interactions influence the conformation of a molecule, and such interplay between conformation and intermolecular interaction likely plays out through the self-assembling process of nucleation governing the outcome of resultant crystal structures. This study investigates molecular interactions and structural properties of a conformationally flexible molecule, tolfenamic acid, in explicit solvent by means of molecular dynamics and combined quantum mechanics and molecular mechanics methods. The results point out that tolfenamic acid prefers to take a relatively flat conformation, stabilized by intermolecular interactions between the solute and solvent molecules. Tolfenamic acid molecules can also adopt a more twisted conformation in a homodimeric state which exhibits lower solvation energy but greater stability. The computational work unravels the important influence by intermolecular interactions—between the solute and solvent or between the solute and solute—on stabilizing the conformation of solute molecules and, thus, highlights the underlying cooperation between a molecule’s conformation and its intermolecular interaction leading to the nucleation of distinct polymorphic structures.