索拉非尼无定形体系结晶动力学稳定性评价及结晶抑制剂筛选

Evaluation of Crystallization Kinetic Stability of Sorafenib Amorphous System and Screening of Crystallization Inhibitors

目的制备索拉非尼无定形体系,评价其结晶动力学稳定性,探讨聚合物对无定形的抑制结晶效应。方法旋转蒸发法制备索拉非尼无定形态,非等温多速率差式扫描量热分析法研究无定形形成能力和结晶动力学稳定性,溶解度和体外溶出实验考察聚合物对无定形的抑制结晶效应。结果动力学脆性指数48,玻璃化转变温度与熔融温度之比0.8,降低结晶温度0.51,结晶活化能152.15 kJ·mol^(-1),Avrami指数约为2,含有50μg·mL^(-1)甲基纤维素M450溶液,无定形体系溶解度与累积溶出度分别提高1.43和2.17倍。结论索拉非尼无定形具有较高的动力学稳定性,甲基纤维素可延长无定形体系过饱和时间。

Objective To prepare an amorphous sorafenib system,to evaluate its crystallization dynamic stability,and to discuss the inhibition effect of polymers on amorphous crystallization.Methods Amorphous sorafenib was prepared by the rotary evaporation method.The amorphous forming ability and crystallization kinetics stability of amorphous sorafenib were studied by non-isothermal multi-rate differential scanning calorimetry.The inhibitory effects of polymers on amorphous sorafenib crystallization were investigated by solubility and dissolution experiments in vitro.Results The kinetic fragility index was 48.The ratio of glass transition temperature to melting temperature was about 0.8.The reduced crystallization temperature was 0.51.The crystallization activation energy was 152.15 kJ·mol^(-1).Avrami index was about 2.In 50μg·mL^(-1) methyl cellulose solution,the solubility and cumulative dissolution of the amorphous system were 1.43 and 2.17 times that of the pure amorphous drug,respectively.Conclusion Amorphous sorafenib has high crystallization dynamic stability.Methyl cellulose prolongs the supersaturation time of amorphous sorafenib.