(560h) Solvent-Mediated Polymorphic Phase Transformation Prediction in Melts Using Digital Mechanistic Tools: The Case Study of Flufenamic Acid

This work demonstrates synthonic engineering approaches integrating molecular-scale models and systematic workflows to investigate how interacting functional groups and their associated energies drive polymorphic phase transformations in organic crystals. The case study examines the transformation of Flufenamic Acid from form III to Form I under varying temperature and pressure conditions in presence of a polymer melt (polyethylene glycol),^1,2 acting as a solvent.³ The results are validated with experimental data.^1,2

Intermolecular interactions at the interface of solute and solvent are characterized to identify key interactions promoting the phase transformation, their correlation with the surface chemistry and topology of the crystal habit planes. Other critical process parameters, such as temperature, were also considered for the study. A modified attachment energy model explicitly accounts for solute-solvent interactions, enabling accurate simulations of polymorphic phase transformation that reflect anisotropic interactions between crystals and their solvent (melt) environment.

The developed workflow and insights presented here provide a generalizable approach applicable to other polymorphic organic materials, enhancing the understanding of their transformation behavior and impact of solvents/melts and critical process parameters.

(1) Reyes, F.; Hernández, J.R.; Hernández, M.H.; López, V.; Stelzer, T. Polymorphic Phase Transformations in Crystalline Solid Dispersions: The Combined Effect of Pressure and Temperature. Cryst. Growth Des. 2022, 22 (5), 2903–2909.

(2) Reyes, F.; Hernández, J.R.; Manivel, S.; Yu, L.; Zhang, G..; López, V.; Stelzer, T. Process Controlled Polymorphic Phase Transformation in Crystalline Solid Dispersions: Impact of Temperature, Pressure, and Shear Stress. Cryst. Growth Des. 2024, 24 (21), 8866–8875.

(3) Hernández, J.R.; Toro, V.; Yao, X.; Yu, L.; Lopéz, V.; Stelzer, T. Solvent-Mediated Polymorphic Transformations in Molten Polymers: The Account of Acetaminophen. Mol. Pharm. 2022, 19 (7), 2183–2190.