Novel Pharmaceutical Cocrystal of Voxelotor, a Hemoglobin Oxygen Affinity Modulator: Synthesis, Crystal Structure, and Physicochemical Properties

Voxelotor (VOX), a small-molecule BCS class-II drug, is used for the treatment of sickle cell disease. The USFDA granted accelerated approval for this drug molecule in 2019 as a first-in-class medication. A novel 1:0.5 cocrystal of voxelotor with a pharmaceutically acceptable coformer, oxalic acid (OA), has been identified to ameliorate the aqueous solubility of the drug and characterized using various solid-state techniques such as PXRD, DSC, TGA, and Fourier transform infrared spectroscopy. Further, single crystals were successfully generated for both the voxelotor-OA cocrystal (VOX-OA) and the VOX free base (Form-II) to have structural insights. Crystal structure analysis has been performed to understand the torsional/interplanar angles, hydrogen bonds, packing of the molecules, and other weak interactions for both the forms (cocrystal and Form-II) using single-crystal XRD studies. In addition, Hirshfeld surface analysis has been performed to delineate the intermolecular interactions quantitatively. The equilibrium solubility revealed that VOX-OA exhibited superior performances compared to VOX Form-II (marketed form) at pH conditions of 4.5 and 6.8. The hemi-OA cocrystal of voxelotor is stable enough under formulation stress conditions such as drying, milling, 10 ton pressure, open exposure, and humidity exposure. The cocrystal was found to be stable in the excipient compatibility study as no polymorphic transformation of the cocrystal is observed.

Automated summary

Voxelotor (VOX), a small-molecule BCS class-II drug, has been used to treat sickle cell disease. A novel cocrystal of voxelotor with oxalic acid (OA) has been identified to improve the drug's solubility and exhibit better performance compared to the marketed form. The stability of the cocrystal has been demonstrated under various stress conditions.