药物利培酮的晶型表征及其热稳定性研究

目的： 建立利培酮药物A、B与E的多晶型和稳定性的研究方法，并以A晶型为例，计算和推导药物的动力学参数和热分解反应机制。 方法： 运用差示扫描量热仪、热重分析仪、X射线粉末衍射仪、傅立叶变换红外光谱仪和扫描电子显微镜对药物进行测试。同时，用Kissinger法、Flynn-Wall-Ozawa法和Vyazovkin 法计算药物的分解动力学参数，运用Achar法和Coats-Redfern法进行 分解反应机制的推导。 结果： 3种晶型药物的结构具有相似性和差异性，其热稳定性从小到大依次为：Eθ最强衍射峰分别出现在19.64°、21.18°、14.96°；A、B和E晶型药物的红外最强峰分别位于1456、1468、1455 cm^-1；利培酮A晶型的熔点为442.50 K，熔融焓为107.59 J·g^-1，热分解表观活化能为145.81 kJ·mol^-1，指前因子为19.92 s^-1；其降解动力学方程模型为dα/dt=Aexp（-E/RT）（1-α）。 结论： 热分析技术是研究药物多晶型和稳定性强有力的分析手段之一，与其他分析技术联合使用可以更加有效、准确地表征药物的晶型、形貌、稳定性和反应机理。同时，本研究也为利培酮药物的制备、检定和质量控制提供重要的数据、特征曲线谱和分析方法，具有重要的理论和实践意义。

Objective: To develop polymorphism and themostability determination methods for risperidone A,B and E,so as to investigate the thermal decomposition parameters and the thermal decomposition reaction mechanism. Methods: The drugs had been analyzed by using differential scanning calorimetry(DSC),thermal gravimetric analysis(TGA),powder X-ray diffraction(XRD),fourier transform infrared spectroscopy(FTIR)and scanning electron microscopy(SEM).Besides,the decomposition parameters had been calculated by Kissinger,Flynn-Wall-Ozawa and Vyazovkin equations.In addition,the decomposition reaction mechanism of drug had been derived by Achar and Coats-Redfern equations. Results: The crystal structure of three drugs showed both similarities and difference.The order of stability was Eθ of drug crystal A,B and E was at 19.64°,21.18°,and 14.96°,respectively.The most intense peak of infrared spectroscopy of drug crystal A,B and E was situated at 1456,1468 and 1455 cm^-1,respectively.For risperidone crystal A,the melting point was 442.50 K,the enthalpy was 107.59 J·g^-1,the apparent average activation energy 145.81 kJ·mol^-1,and frequency factor 19.92 s^-1. The kinetic equation of the thermal degradation process was dα/dt=Aexp(-E/RT)(1-α). Conclusion: Thermal analysis is one of the most powerful tools for the drug polymorphism and stability study, which can better characterize the crystal form,morphology,stability,and reaction mechanism of drug when combined with other analysis techniques.Furthermore,this study provided reference for the preparation,identification and quantity control of drug risperidone, which will be of considerable theoretical and practical significance.