Study On Polymorphism And Cocrystal Of SGLT-2 Inhibitor Empagliflozin

Empagliflozin,a SGLT2 inhibitor,is a kind of hypoglycemic drug which can regulate the blood glucose concentration by inhibiting the renal reabsorption of glucose.Empagliflozin has great development potential,which has attracted wide attention of pharmaceutical companies.At present,empagliflozin has one crystal form and one hydrate,which has few solid forms and lacks systematically researches.Therefore,in order to explore a new solid form with better physicochemical propertie,this work systematically studies the polymorphism and cocrystal of empagliflozinFirstly,the crystallization thermodynamics of empagliflozin is studied.Solubility of empagliflozin was measured in four kinds of pure solvent((ethanol,formamide,methanol,acetonitrile)and one binary solvent system(formamide + water)from278.15 K to 318.15 K by the dynamic method.The NRTL model,the modified Apelblat equation and the λh equation were used to correlate the experimental solubility data of empagliflozin in four pure solvent system and the experimental solubility results in binary solvent systems were correlated by the NRTL model,the CNIBS/R-K model and the Jouyban-Acree model.In addition,the mixing and dissolution thermodynamic properties of empagliflozin in the tested systems were also calculated and discussed by using the NRTL model and the solubility data.Then,the polymorphs of empagliflozin were screened,and a new solvate of empagliflozin was successfully developed by solution crystallization method.And in order to characterize and analyze the obtained solvate of empagliflozin,several means including polarizing microscope,PXRD,TGA,DSC,FTIR and Raman were applied.The single crystal of form of empagliflozin was achieved by slow evaporation method and anti-solvent crystallization method.With the method of in situ monitoring by Raman spectroscopy and off-line sampling,the solvent-mediated transformation between form Ⅰ and solvation has been investigated qualitatively.The rate-determining step of transformation process is determined.Based on the crystal engineering principles,the appropriate ligands for empagliflozin cocrystal were screened by grinding method and cooling crystallization method.The products were characterized and analyzed by means of DSC and PXRD,and two kinds of cocrystals were successfully obtained.The method of preparing empagliflozin-nicotinamide cocrystal was developed by selecting suitable solvent,ratio of material and crystallization method.Cocrystals were characterized by DSC,PXRD,TGA,FTIR,Raman,microscopy,and ESP potential distributions in Gaussian simulations to validate the formation of co-crystal and how the hydrogen bonds are formed.