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

## TL;DR

This study explores how the crystal shape and growth of tolfenamic acid depend on the solvent used, combining modeling and experiments to understand how different solvents affect crystal formation.

## Contribution

The study introduces a predictive framework for controlling crystal morphology and growth kinetics based on solvent-solute interactions and intermolecular packing.

## Key findings

- Polar solvents like ethanol increase crystal aspect ratios by disrupting hydrogen bonding at prismatic faces.
- Nonpolar solvents like toluene hinder elongation due to strong aromatic stacking at capping faces.
- Form II of tolfenamic acid shows higher growth rates than form I, especially in ethanolic solutions.

## Abstract

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.