Crystal Morphology and Associated Face-Specific Growth Kinetics of Tolfenamic Acid as a Function of Its Solution Crystallization Environment

The crystal morphology and face-specific growth kinetics of tolfenamic acid (TFA) forms I and II are investigated through an integrated molecular modeling and experimental approach. Morphology predictions based on attachment energy calculations are consistent with experimental observations, with needle-like habits for both forms, although with some subtle differences in the capping faces formed, which can be attributed to the variations in intermolecular packing and surface chemistry. The solvent polarity is found to significantly influence the crystal growth of both forms: for instance, polar solvents, such as ethanol, promote higher aspect ratios by disrupting hydrogen bonding at prismatic faces, while nonpolar solvents, such as toluene, are found to hinder elongation of the crystal habit by providing strong solute/solvent aromatic stacking interactions at the capping faces. Examination of the measured growth rates for form I in ethanolic solutions reveals markedly slower growth rates (0-0.02 μm/s) on the prismatic faces (e.g., {0 1 1}) when compared to the capping faces e.g., {1 0 0} (0.044-0.555 μm/s), consistent with the lower surface intermolecular unsaturation and limited solute binding on the former faces. Examination shows that the facet crystal growth rates of form II (at a supersaturation of 0.3) are higher than that for form I for both capping and prismatic faces, consistent with the ease of crystallization of form II in ethanolic solutions. Analysis of the growth rate data for form I as a function of supersaturation reveals a good fit using a BCF model, with the surface integration at the crystal/solution interface rather than solute mass transfer in the bulk solution being identified as the rate-limiting step for the prismatic faces. This is in contrast to the capping faces, which is found to be less well-defined with mass transfer and surface integration being more balanced depending on the degree of solution supersaturation. The interplay between solvent-dependent surface interactions and intermolecular packing with the crystal face-specific growth kinetics is highlighted, contributing well toward the development of a predictive framework for the design and control of the solid-form properties of organic materials.