Understanding Nucleation Mechanism of Mefenamic Acid: An Examination of Relation between Pre-assembly Structure in Solution and Nucleation Kinetics

Crystal nucleation from solution plays a decisive role in the formation of crystalline materials, but its mechanism at the molecular level is still unclear. Structural similarity between self-assemblies in solution and crystal synthons suggested possible mechanisms of nucleation; however, the detailed role of these solute pre-assemblies on nucleation kinetics remains elusive. Herein, we examined the relation of solution chemistry with nucleation kinetics by an array of solution IR, 1D, and 2D NMR spectroscopy, density-functional theory calculations, and statistical probability distribution analyses of the measured induction time data with mefenamic acid (MFA) as the model compound. Depending on the solvent, MFA can form different hydrogen-bonded solution assemblies. Quantification of nucleation kinetics was performed by measuring 4400 sets of induction time data. Solution chemistry and nucleation kinetics collectively reveal that pre-assemblies in solution can serve as building units for crystal nucleation, but the difficulty of nucleation apparently correlates with the effective interfacial energy, not attachment frequency. The structure link may be obscured through nucleation kinetics driven by interfacial energy.