Computational Screening and Experimental Validation on Multicomponent Crystals of a New Class of Janus Kinase (JAK) Inhibitor Drug with Improved Solubility
Yujiang Xie,
Genpei Shi,
Jie Sun,
Si Li,
Wei Gao,
Yimin Hu,
Chang Zu,
Weiwei Tang,
Junbo Gong
Affiliations
Yujiang Xie
School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Tianjin 300072, China
Genpei Shi
School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Tianjin 300072, China
Jie Sun
School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Tianjin 300072, China
Si Li
School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Tianjin 300072, China
Wei Gao
Jiangsu Hengrui Pharmaceuticals Co., Ltd., Lianyungang 222000, China
Yimin Hu
Jiangsu Hengrui Pharmaceuticals Co., Ltd., Lianyungang 222000, China
Chang Zu
Jiangsu Hengrui Pharmaceuticals Co., Ltd., Lianyungang 222000, China
Weiwei Tang
School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Tianjin 300072, China
Junbo Gong
School of Chemical Engineering and Technology, State Key Laboratory of Chemical Engineering, The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Tianjin 300072, China
Developing multicomponent crystal forms, especially cocrystals and salts, is becoming a promising pathway to improve the solubility and bioavailability of drugs. Herein, new multicomponent crystals of SHR0302, a new generation of Janus Kinase (JAK) inhibitor that suffers from poor solubility, were developed based on a cooperative approach of computational and experimental coformer screenings. Virtual screening methods, including the conductor-like screening model for realistic solvents (COSMO-RS) and molecular complementary (MC) analysis, were employed to predict the binding affinity between SHR0302 and selected coformers. The developed screening method was capable of reducing the screening database to 30 coformers from a total of 42 proposed coformers. The proof-of-concept experimental screening study was performed to demonstrate the efficiency of computational screening, wherein three new multicomponent crystalline forms were found and fully characterized by powder X-ray diffraction, thermal analysis, and IR and 1H-NMR spectroscopy. Further, the measurements of the solubility property of these new multicomponent crystal forms reveal an apparent promotion compared with the drug alone. Finally, the receiver operator characteristic (ROC) curve was used to assess the prediction performance of the COSMO-RS model. It was found that the established screening model can effectively shorten the experimental screening time and efforts.
