Tracking Dehydration Mechanisms in Crystalline Hydrates with Molecular Dynamics Simulations

Dehydration of crystalline solids is a widespread phenomenon, yet the fundamental mechanisms by which dehydration occurs are not properly understood. This arises due to technical limitations in studying such fast processes with sufficient sensitivity; nevertheless, understanding dehydration pathways is critical for designing optimal properties for materials, particularly in the case of pharmaceutical solids. The computational methods presented here allow for accurate determination of the dehydrated species' crystal structure and to develop an understanding of the mechanism of dehydration at the molecular level. This work also highlights the critical role of explicitly taking into account the dynamical aspect of molecules using computational techniques, rather than relying on static energy minimization approaches. Specifically, the crystalline active pharmaceutical agent naproxen sodium, and its hydrates, is studied in silico using density functional theory and molecular dynamics, ultimately elucidating the face-specific dehydration mechanisms and revealing highly complex diffusion and nucleation behavior. Additionally, the results indicate that the method is a viable way to explore dehydration pathways and predict new dehydrated crystal structures.