Additive-mediated Crystallization of Metastable Fluxapyroxad Polymorph: Characterization, Structure, and Theoretical Insights

Surface-induced nucleation has received much attention in the discovery of new drug polymorphs and the modulation of metastable polymorphs. It has emerged as an increasingly important strategy for crystal structure control. In this study, we employed a heterogeneous surface design strategy based on molecular functionality to screen additives and induce the growth of new polymorphs of Fluxapyroxad (FLU), a potent succinate dehydrogenase inhibitor. Three new polymorphs were successfully obtained, named as F3, F4, and F5. These polymorphs were characterized through single-crystal X-ray diffraction and thermal analysis. Their intermolecular interactions and stacking patterns were more accurately elucidated by single-crystal structure analysis. Additionally, Hirshfeld surface analysis and the BFDH model morphological prediction were performed. Theoretical calculations further clarified the formation mechanism of the new polymorphs. In summary, the additives demonstrated the effectiveness of inducing novel FLU polymorphs, confirming the potential of a surface-induced nucleation strategy for polymorphs discovery.