Exploring mechanochemistry of pharmaceutical cocrystals: effect of incident angle on molecular mixing during simulated indentations of two organic solids

Abstract

The solid-state reaction of the active pharmaceutical ingredient theophylline with citric acid is a well-established example of a mechanochemical reaction, leading to a model pharmaceutical cocrystal. Here, classical force field molecular dynamics was employed to investigate the molecular mixing and structural distortion that take place on the mechanically driven indentation of a citric acid nanoparticle on a slab of crystalline theophylline. Through non-equilibrium molecular dynamics simulations, a 6 nm diameter nanoparticle of citric acid was introduced onto an open (001) surface of a theophylline crystal, varying both the angle of incidence of the nanoparticle between 15° and 90° and the indentation speed between 1 m s⁻¹ and 16 m s⁻¹. This theoretical study enabled the evaluation of how these two parameters promote molecular mixing and overall structural deformation upon the mechanical contraction of theophylline and citric acid, both of which are important parameters underlying mechanochemical cocrystallisation. The results show that the angle of incidence plays a key role in the molecular transfer ability between the two species and in the structural disruption of the initially spherical nanoparticles. Changing the indentation speed, however, did not lead to a discernible trend in molecular mixing, highlighting the importance of the incident angle in mechanochemical events in the context of supramolecular chemistry, such as the disruption of the crystal structure and molecular transfer between molecular crystals.