Solid-State NMR Elucidation of Intermolecular Interactions in Venetoclax-Fumaric Acid Cocrystal

Cocrystallization is of fundamental importance in active pharmaceutical ingredients in order to enhance their physicochemical properties, particularly solubility, stability, and bioavailability, without altering the pharmacological activity. While crystal engineering has provided key principles for designing cocrystals, detailed experimental insights into the specific intermolecular interactions governing cocrystallization remain important for structurally complex APIs. We investigate the cocrystallization of an antileukemia drug, venetoclax, with fumaric acid as a coformer. The formation of a new cocrystalline phase is confirmed through powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Solid-state nuclear magnetic resonance (NMR) spectroscopy provides key insights into the cocrystallization mechanism, revealing specific hydrogen-bonding interactions between the aromatic amine and pyrrole groups of venetoclax and the carboxylic groups of fumaric acid. These results not only demonstrate a successful case of cocrystallization but also highlight the value of complementary solid-state characterization techniques, PXRD, DSC, and solid-state NMR, in probing cocrystal formation and elucidating the underlying supramolecular interactions in complex pharmaceutical systems.