Polymorphism Of Rivaroxaban

Polymorphism of drugs is related to the physicochemical and mechanical properties,stability,bioavailability,quality of preparations and efficacy of drugs,which drawed an increasing of attention of pharmaceutical researchers in recent years,polymorphism screening has become an indispensable link in drug development process.In this study,the anticoagulant drug rivaroxaban possesses polymorphism and is used as object drug.The thermodynamic and kinetics of forms I and II of rivaroxaban were studied systematically.The main contents are as follows:(1)Both forms of rivaroxaban were characterized by densimeter,Fourier transform infrared spectroscopy(FTIR),powder X-ray diffraction(PXRD),differential scanning calorimetry(DSC)and thermogravimetric analysis(TGA),in addition,the calibration curve for quantitative analysis between forms I and II was set up by FTIR;(2)A dynamic dissolution method was used to determine the solubility of both forms in acetonitrile,1,4-dioxane,methyl acetate,acetone,2-butanone,3-pentanone and 2-hexanone.Meanwhile,such semiempirical thermodynamic models based on local composition concept as Wilson,nonrandom two-liquid(NRTL)and universal quasi chemical(UNIQUAC)equations with the correlation between model parameters and temperature were employed to model the studied solid-liquid equilibrium.According to the thermodynamic data,the transformation behavior and relative stability were obtained,which was used as theoretical foundation for the solution-mediated phase transformation and crystallization process of optimization of rivaroxaban;(3)The apparent solubility of forms I and II of rivaroxaban was measured in 0.1 M hydrochloric acid solution(pH = 1.0)and 0.2 M phosphate buffer solution(pH = 6.8).The influence of temperature,slurry density and stirring speed on the rate of solution-mediated phase transformation was explored simultaneously.The phase transformation process was simulated by the appropriate kinetic model.In addition,the activation energy of phase transformation was calculated;(4)The effect of crystallization temperature and the addition rate of anti-solvent on the crystallization process of form II was investigated to obtain the optimum crystallization process parameters.The above studies provide an important theoretical basis for the screening of new crystal forms and polymorphic industrial production of rivaroxaban.