双嘧达莫无定形药物体系动力学稳定性评价

Evaluation of kinetic stability of dipyridamole amorphous drug system

目的本研究制备双嘧达莫无定形药物体系,并研究其晶化动力学稳定性和热分解动力学稳定性。方法通过熔融-冷却-复融的方法成功制备了双嘧达莫无定形药物体系,并用粉末X-射线衍射(PXRD)和温度调制差式扫描量热(TMDSC)进行了表征,高效液相色谱(HPLC)及氢核磁(1HNMR)技术对样品进行了纯度分析及结构确证。采用动态差示扫描量热分析方法研究样品的非等温晶化动力学性质,采用多速率无模型方法评估样品热分解动力学稳定性,并对其贮存有效期进行推断。结果双嘧达莫晶化机理为三维生长的体积析晶,热分解机理函数为G(a)=[-ln(1-a)]^(3/4),属于随机成核和随后生长机理(n=3/4),贮存有效期约为4~5年。结论双嘧达莫无定形药物体系容易晶化,但热稳定性较高。本研究为双嘧达莫无定形药物体系的进一步临床应用提供理论基础,也为其它无定形药物体系动力学稳定性研究提供参考。

Objective To prepare the dipyridamole amorphous drug system,and study its kinetic stability of crystallization and thermal decomposition.Methods The dipyridamole amorphous drug system was successfully prepared by melting-cooling-remelting method.It was verified by powder X-ray diffraction(PXRD)and temperature modulated differential scanning calorimetry(TMDSC),and its purity and chemical structure were analyzed by high performance liquid chromatography(HPLC)and hydrogen nuclear magnetic resonance(~1HNMR)techniques.Dynamic different scanning calorimetry analysis was used to study the non-isothermal crystallization kinetics of the sample.The kinetic stability of thermal decomposition of samples was evaluated by multi-rate model-free method,and the shelf life was deduced.Results The crystallization mechanism of amorphous dipyridamole was three-dimensional growth volume crystallization and thermal decomposition mechanism function was G(a)=[-ln(1-a)]^(3/4),which belonged to random nucleation and subsequent growth mechanism(n=3/4);The shelf life of dipyridamole would be about 4~5 years.Conclusions Dipyridamole amorphous drug system tends to crystallize easily but has high thermal stability.This study provides a theoretical basis for the further clinical application of dipyridamole amorphous drug system,and also provides a reference for the study of kinetic stability of other amorphous drug systems.