Solvates and polymorphs of rebamipide: Preparation, characterization, and physicochemical analysis

Abstract

This study aimed to investigate the solid forms of the peptic ulcer agent rebamipide (RBM). Four RBM solvates, including dimethyl sulfoxide solvate (RBM/DMSO), dichloromethane solvate (RBM/CH2Cl2), hydrate (RBM/H2O), and hemiethanol hemihydrate, were prepared via solvent crystallization. Single crystals of RBM/DMSO and RBM/CH2Cl2 were successfully obtained at 4 °C. These solid forms were both monoclinic with the space group P21/c. Hirshfeld surface and 2D fingerprint plot analyses indicated that RBM/DMSO and RBM/CH2Cl2 showed similarities in hydrogen bonds but exhibited differences in subtle intermolecular interactions. RBM/CH2Cl2 transformed into a novel solid form (form 3) after solvent removal and transformed into another solid form (form 4) when heated at 220 °C. RBM/H2O was converted to form 5 after dehydration. Forms 3-5 were RBM polymorphs. The stability results indicated that RBM/H2O, form 3, and form 4 showed good stability at 40 °C and 75% relative humidity. Furthermore, the three solid forms displayed higher solubility than commercial RBM (form 1) in both water and phosphate buffer solution (PBS). Compared with form 1, RBM/H2O and form 4 showed a comparable and faster dissolution rate in water and PBS, respectively.