托伐普坦的晶型研究

Polymorphs of tolvaptan

目的 研究低钠血症治疗药物托伐普坦的晶型特征。方法 采用蒸发结晶、溶析结晶、研磨转晶等方法对托伐普坦进行晶型制备筛选；采用粉末X射线衍射分析（PXRD）、差示扫描量热分析（DSC）、红外光谱分析（IR）、热重–差热分析（TG-DTA）以及单晶X射线衍射分析（SXRD）技术对制备得到的托伐普坦晶型样品进行表征；采用研磨、加热、加压和混悬方法对无水晶型进行转晶行为研究；此外，还对各种晶型进行了溶解性质研究。结果 通过上述制备方法获得了托伐普坦的4种晶型状态Ⅰ、Ⅱ、Ⅲ和Ⅳ型。其中Ⅰ型为无水晶型，Ⅱ型为溶剂化物，Ⅲ型为半水合物，Ⅳ型为无定型。Ⅰ、Ⅳ型在特定的条件下可以相互转化。结论 采用PXRD、DSC和TG-DTA技术可实现4种晶型的直观、快速、准确鉴别。Ⅰ～Ⅳ型托伐普坦的理化性质及稳定性存在明显差异，其中Ⅳ型为热力学不稳定晶型，溶解性最好，而Ⅰ型最稳定。

Objective To study the polymorphic characteristics of tolvaptan for the treatment of hyponatremia. Methods Polymorph screening of the compound was carried out in this study. Polymorphs of tolvaptan were prepared by evaporative crystallization, antisolvent crystallization and other polymorph transformation methods such as grinding, and were characterized by powder X ray diffraction （PXRD）, differential scanning calorimetry （DSC）, infrared spectrometry （IR）, thermogravimetric analysis coupled with differential thermal analysis （TG-DTA） and single crystal X ray diffraction analysis （SXRD）. Grinding, heating, pressurizing and suspension methods were selected for studying polymorph transformation behavior of type I, and the dissolution properties of different polymorphs were also studied. Results It was found that tolvaptan obtained by the above methods existed four kinds of polymorphic state types I-IV. Among which, type I was anhydrous, type II was solvate, type III was semi-hydrate and type IV was amorphous. Types I and IV could be transformed into each other under certain conditions. Conclusion This study indicates that PXRD, DSC and TG-DTA could be used to identify the four kinds of tolvaptan polymorphs intuitively, rapidly and accurately. There are obvious differences in physicochemical properties and stability of different polymorphs, wherein type IV is thermodynamically unstable polymorph with best solubility, while type I is the most stable one.