Crystal structure and solid-state conformational analysis of active pharmaceutical ingredient venetoclax

Abstract

Venetoclax is an orally bioavailable, B-cell lymphoma-2 selective inhibitor used for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma, and acute myeloid leukemia. Venetoclax’s crystal structure was until now determined only when it was bound to a B-cell lymphoma-2 (BCL-2) protein, while the crystal structure of this active pharmaceutical ingredient alone has not been reported yet. Herein, we present the first successful crystallization, which provided crystals of venetoclax suitable for X-ray diffraction analysis. The crystal structure of venetoclax hydrate was successfully determined. The asymmetric unit is composed of two crystallographically independent molecules of venetoclax and two molecules of interstitial water. Intramolecular N– H· · · O hydrogen bonding is present in both molecules, and a molecular overlay shows differences in their molecular conformations, which is also observed in respect to venetoclax molecules from known crystal structures of BCL-2:venetoclax complexes. A supramolecular structure is achieved through various N–H· · · N, O–H· · · O, C–H· · · O, C–H· · · π, C–Cl· · · π, ONO· · · π, and π· · · π interactions. The obtained crystals were additionally characterized with spectroscopic techniques, such as IR and Raman, as well as with thermal analysis.