Preparation and characterization of chlorzoxazone–ascorbic acid cocrystals for enhanced solubility

Cocrystallization of chlorzoxazone (CHZ) with ascorbic acid (ASC), a nutraceutical compound as a coformer, is performed for the solubility enhancement of CHZ. The structural interactions of the CHZ-ASC coordinated complex in all possible orientations are predicted using density function theory (DFT) analysis. A binary phase diagram (BPD) is constructed for the CHZ-ASC system to identify the stoichiometric ratio. The liquid-assisted grinding (LAG) method is used to prepare CHZ-ASC cocrystals. In vitro solubility and dissolution rate studies are assessed at different pH levels. DFT analysis identifies the supramolecular heterosynthon complex formation via hydrogen bonds (bond distance of less than 2 Å) and binding energy (∆E_CHZ-ASC) of CHZ-ASC complexes. BPD confirms a “W” shape for the CHZ-ASC system, indicating the system is favorable for obtaining cocrystals at the stoichiometric ratio of 0.75: 0.25 (CHZ:ASC) reactant mixture. CHZ-ASC(CC) is prepared using LAG method and further analyzed. DSC results indicate a lower melting point, while TGA results reveal distinct mass loss behavior of CHZ-ASC(CC) when compared to CHZ and ASC, suggesting the formation of a new crystalline solid. PXRD results confirm the distinct peak, while FTIR peak shifting is attributed to the hydrogen bond (N–H–O = C) interaction, manifesting the existence of CHZ-ASC(CC). The solubility and dissolution rate of CHZ are improved by 1.3–1.8 times compared to that of the pure CHZ when released from CHZ-ASC (CC) under different pH conditions. The surface modification of CHZ with ASC via cocrystallization is found to be supportive for the solubility enhancement of CHZ.