Investigation of Solubility Behavior of Canagliflozin Hydrate Crystals Combining Crystallographic and Hirshfeld Surface Calculations.

Canagliflozin (CG) was a highly effective, selective and reversible inhibitor of sodium-dependent glucose co-transporter 2 developed for the treatment of type 2 diabetes mellitus. The crystal structure of CG monohydrate (CG-HO) was reported for the first time while CG hemihydrate (CG-Hemi) had been reported in our previous research. Solubility and dissolution rate results showed that the solubility of CG-Hemi was 1.4 times higher than that of CG-HO in water and hydrochloric acid solution, and the dissolution rates of CG-Hemi were more than 3 folds than CG-HO in both solutions. Hirshfeld surface analysis showed that CG-HO had stronger intermolecular forces than CG-Hemi, and water molecules in CG-HO participated three hydrogen bonds, forming hydrogen bond networks. These crystal structure features might make it more difficult for solvent molecules to dissolve CG-HO than CG-Hemi. All these analyses might explain why the dissolution performance of CG-Hemi was better than CG-HO. This work provided an approach to predict the dissolution performance of the drug based on its crystal structure.