Molecular mechanisms of supercritical CO2-induced interfacial softening in curcumin polymorphs

Abstract

Unique properties of supercritical CO 2 (scCO 2 ) make it one of the most interesting “green” solvents for pharmaceutical particle formation and polymorph engineering. However, due to the complexity of the scCO 2 dynamics, the molecular mechanisms by which scCO 2 alters the stability of crystal surfaces remain poorly understood. Here, all-atom molecular dynamics simulations were used to investigate the temperature-dependent evolution of the three curcumin polymorphs exposed to scCO 2 along the (100), (010), and (001) crystallographic surfaces. Layer-resolved analyses based on the ITIM method reveal that structural changes emerge at the crystal interface significantly below the bulk melting temperature, demonstrating that scCO 2 promotes an early onset of interfacial softening. The magnitude and temperature of this softening depend strongly on both the polymorph and the crystallographic surface. By combining analyses of layer expansion, positional fluctuations, molecular orientation, aromatic packing, hydrogen-bond populations, and conformational distributions, we show that the anisotropic response originates from the interplay between surface functional-group exposure and the progressive disruption of intermolecular cohesion. Surfaces exposing hydroxyl- and methoxy-rich environments soften earlier than those dominated by the more rigid β-diketone framework, while persistent aromatic and hydroxyl close contact networks delay structural disorder. These results provide a molecular picture of how scCO 2 destabilizes pharmaceutical crystal interfaces and establish interfacial softening as a key precursor to surface-mediated transformations relevant to CO 2 -assisted pharmaceutical processing.