Improving the equilibrium solubility of Nateglinide by synthesizing a novel Nateglinide co-crystal with a single-crystal structure

•NTG is a BCS class II drug, almost insoluble in water, with limited oral bioavailability.•NTG-INA co-crystal prepared through solvent evaporation with ultrasound.•Co-crystals were characterized via DSC, FTIR, XRPD, SEM, and SCXRD.•Equilibrium solubility of the co-crystal was more than twice that of NTG. Nateglinide (NTG) is clinically used to treat type II diabetes. NTG is a Biopharmaceutics Classification System class II drug and is thus almost insoluble in water, limiting its oral bioavailability. The solubility of drugs can be increased through various methods; however, these methods have several limitations. Therefore, this study used solvent evaporation combined with the ultrasonic method to prepare an NTG-isonicotinamide (INA) co-crystal to improve the solubility of NTG and characterized the co-crystal using scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction, single-crystal X-ray diffraction (SCXRD), and Fourier transform infrared spectroscopy. The SCXRD results demonstrate that the newly formed crystal material belongs to the P21 monoclinic crystal system. A single crystal was formed by NTG and INA in a stoichiometric ratio of 2:2; the crystallographic information is as follows: a = 8.9552 Å, b = 12.6413 Å, c = 21.5877 Å, α=90°, β=98.463 (6)°, γ=90°, Z = 4, R1=0.0712, and wR2=0.1284. The equilibrium solubility of the co-crystal was more than twice that of NTG, suggesting that it is suitable for further research on its bioavailability and improvement in clinical application. [Display omitted]