Unveiling the Critical Roles of Aromatic Interactions in the Crystal Nucleation Pathway of Flufenamic Acid

Abstract

There has been growing interest in investigating the role of solvents played in nucleation pathways; nevertheless, the nucleation mechanism is still poorly understood. In this work, flufenamic acid (FFA) was selected as model compound to investigate the relationship between solvent and nucleation kinetics. Over 1000 induction time experiments were conducted. Solution IR spectroscopy and molecular dynamic simulations were used to explore the solvent–solute interaction and conformation distribution in solutions. Given the same driving force, the order of nucleation rate of FFA was found following acetonitrile > methanol > toluene, in which dimers are significantly distributed in toluene solutions. The observation cannot support the previously proposed hypothesis that the breakage of solvent–solute hydrogen bonds and dimerization determine the nucleation rate. Through crystal growth experiment and detailed discussions, we have reached an interesting conclusion that the weak C–H···π interactions play a vital ...