Physicochemical aspects and comparative analysis of Voxelotor and its salt and cocrystal

Voxelotor (VOX) is a BCS (Biopharmaceutical classification system) Class II drug (poor solubility and high permeability) and is issued for the treatment of sickle cell disease. The VOX free base, VOX-HCl salt and succinic acid (VOX-SC) cocrystals were crystallized and their crystal structures were determined by the Single Crystal X-ray diffraction technique (SCXRD). Further, solid-state characterization techniques such as Nuclear magnetic resonance (NMR) and Fourier transform Infra-red spectroscopy(FT-IR) were carried out. In all three structures, the VOX molecules exhibit an intramolecular S(6)-motif formed by O-H center dot center dot center dot O hydro-gen bond. In VOX free base, only weak C-H center dot center dot center dot O, C-H center dot center dot center dot pi and pi center dot center dot center dot pi interactions were observed, which lead to the formation of two-dimensional hydrogen-bonded sheets. In VOX-HCl salt, N-H center dot center dot center dot Cl hydrogen bond along with the C-H center dot center dot center dot pi and pi center dot center dot center dot pi interactions form a discrete dimeric unit. In VOX-SC cocrystal, the VOX and SC molecules were connected through N-H center dot center dot center dot O, O-H center dot center dot center dot O and C-H center dot center dot center dot O interactions and generate a two-dimensional hydrogen-bonded network. Thermal analysis of VOX-SC cocrystal resulted in melting points intermediate to that of API and coformer, while VOX-HCl salt yielded a higher melting point than the parent VOX. Both VOX-HCl and VOX-SC cocrystal showed better solubility compared to VOX free base. The stress analysis revealed that in VOX-SC cocrystal, no physical transformations of solid-phase was observed. Enhancement in solubility and stability was observed in the obtained VOX-SC cocrystal in comparison to the free base. (C) 2022 Elsevier B.V. All rights reserved.

Automated summary

This study investigated the crystal forms of Voxelotor using crystallographic and solid-state characterization techniques, revealing the improved solubility and stability of VOX-HCl salt and VOX-SC cocrystal.