曲格列汀琥珀酸盐的质量控制及杂质研究

发布时间：2018-05-27 17:02

  本文选题：曲格列汀琥珀酸盐 + 有关物质　； 参考：《成都学院》2017年硕士论文

【摘要】：曲格列汀琥珀酸盐(Trelagliptin succinate)是日本制药巨头武田(Takeda)公司开发研制的II型糖尿病治疗的新型药物,于2015年3月26日由日本卫生劳动福利部(MHLW)批准上市,其商品名为Zafatek,为口服片剂。迄今为止,本品的质量标准仍未被载入各国药典及药品标准,其质量控制方法仍处于新药研究阶段。本课题依据国家食品药品监督管理局相关指导原则、2015版《中国药典》及ICH指导原则的要求,对曲格列汀琥珀酸盐原料药进行系统、深入的质量研究,包括结构研究、理化性质、有关物质检查、含量测定及原料药稳定性考察。按照2015版中国药典第四部,对曲格列汀琥珀酸盐的外观、溶解度、引湿性、吸光系数、熔点及比旋度等理化常数进行检测,根据本品结构特点建立适合的鉴别方法,并对其进行氯化物、炽灼残渣、重金属等一般杂质检查和有机残留溶剂检查。建立适合曲格列汀琥珀酸盐有关物质检查及含量测定的方法,并进行方法学验证。根据2015《中国药典》稳定性试验指导原则对曲格列汀琥珀酸盐进行原料药稳定性研究。最后,采用UV、LC-MS、NMR等波谱技术、热分析技术及X射线粉末衍射技术对本品进行结构及晶型研究,并结合合成工艺对其主要杂质进行结构研究。结果表明,曲格列汀琥珀酸盐为白色粉末,无引湿性,比旋度为+16.5°~+17.1°,在二甲基亚砜及水中易溶、在甲醇中略溶,熔点为186~189℃,水溶液中吸收系数为286.1;确立了红外吸收光谱、紫外吸收光谱、氟离子特征反应及琥珀酸盐特性反应的鉴别方法;其一般杂质及有机残留溶剂检查结果均符合2015年中国药典的限度要求。建立了曲格列汀琥珀酸盐有关物质检查及含量测定的反相高效液相色谱方法,色谱条件为:采用Phenomenex Gemini C18 110A(250×460nm,5μm),以醋酸盐缓冲液(醋酸铵3.9g,三乙胺3ml,水980ml,冰醋酸调pH值至4.00)-乙腈(90:10)为流动相A,以醋酸盐缓冲液-乙腈(45:55)为流动相B,梯度洗脱,流速为1.0ml/min,柱温30℃,检测波长为278nm,进样体积20μl;方法学验证结果显示,该方法准确、简便、专属性强、灵敏度高。稳定性试验结果表明本品含量稳定,无降解现象。经结构研究,确定本品为目标化合物曲格列汀琥珀酸盐的A晶型,主要杂质为曲格列汀的去氰基化合物及氰基水解产物,其主要碱降解杂质之一为2-氨基甲基-4-氟-苄腈。本课题开发的鉴定及检测方法适用于曲格列汀琥珀酸盐的质量控制,为曲格列汀琥珀酸盐原料药质量标准的制定及工艺优化提供了依据。
[Abstract]:Trelagliptin succinateis a new type of drug for the treatment of type II diabetes developed by Japanese pharmaceutical giant Takeda. It was approved by MHLW, Japan's Ministry of Health, Labor and Welfare, on March 26, 2015. It is called Zafatek. it is an oral tablet. Up to now, the quality standard of this product has not been included in the national pharmacopoeia and drug standard, and its quality control method is still in the new drug research stage. According to the requirements of the relevant guidelines of the State Food and Drug Administration (SFDA), the Chinese Pharmacopoeia and the ICH guidelines, a systematic and in-depth study on the quality of triglutin succinate raw materials, including structural studies, physicochemical properties, was carried out. Examination of related substances, determination of content and stability of raw materials. According to the fourth part of Chinese Pharmacopoeia 2015, the physical and chemical parameters of triglutin succinate, such as appearance, solubility, hygroscopicity, absorptivity, melting point and specific curl, were determined, and a suitable identification method was established according to the structural characteristics of the product. General impurities such as chloride, incandescent residue, heavy metal and organic residual solvents were examined. To establish a suitable method for the determination and determination of the related substances of traglutin succinate, and to verify the methodology. The stability of traglutin succinate was studied on the basis of the 2015 Chinese Pharmacopoeia stability test. Finally, the structure and crystal structure of the product were studied by means of UVX LC-MS NMR spectroscopy, thermal analysis and X-ray powder diffraction, and the structure of the main impurity was studied in combination with the synthesis process. The results show that triglutin succinate is a white powder with no moisture, and its specific curl is 16.5 掳~ 17.1 掳. It is easy to dissolve in dimethyl sulfoxide and water, dissolves slightly in methanol, and the melting point is 186 ~ 189 鈩，

本文编号：1943017