From Solution Associates to Crystal Packing: Molecular Origins of Solvent-Dependent Polymorphism in Tecovirimat

Abstract

Abstract Solvent-dependent polymorphism remains one of the central challenges in pharmaceutical crystallization. The molecular mechanisms governing polymorph selection are often poorly understood. In the present work, molecular dynamics (MD) simulations were used to investigate the relationship between solution-phase association and polymorph formation in the antiviral drug tecovirimat. A series of atomistic models with increasing concentrations were constructed in various solvents. Principal component analysis (PCA) and conformational analysis revealed that the conformational behavior of tecovirimat molecules is largely insensitive to both concentration and solvent identity. In contrast, pronounced solvent-dependent differences were observed in the intermolecular association. Radial distribution functions (RDFs) and direct analysis of molecular associates showed that benzene solutions are enriched in inclined, parallel, and antiparallel associates, whereas ethyl acetate favors crossed hydrogen-bonded dimers and chain-like higher-order clusters composed of orthogonal molecules. Comparison with the crystal structures of the anhydrous polymorphs IV and VI revealed a close correspondence between the dominant solution associates and the packing motifs present in the respective crystalline phases. The results suggest that solvent-dependent polymorph selection in tecovirimat is governed primarily by differences in the intermolecular organization established in solution.