瑞舒伐他汀钙的质量控制及杂质研究

发布时间：2018-04-10 04:31

  本文选题：瑞舒伐他汀钙　切入点：有关物质　出处：《成都学院》2017年硕士论文

【摘要】：瑞舒伐他汀钙是一种新一代的选择性HMG-CoA还原酶抑制剂,该药由阿斯利康公司开发研制,于2003年8月经美国FDA批准上市,主要用于高胆固醇血症、单纯高甘油三酯血症以及血脂代谢紊乱症的治疗[1]。经查阅文献后发现有印度药典(2010版)、欧洲药典(8.8版)和英国药典(2016版)收载该品种。本论文对一种利用绿色工艺合成的瑞舒伐他汀钙产品进行了全面的质量控制和杂质研究,建立适宜的质量标准及其起始原料和关键中间体的内控标准,为终产品的质量可控提供了保障。首先本文针对瑞舒伐他汀钙进行了全面、深入的质量控制研究。结合本品的合成工艺路线,对本品理化常数进行了检测,根据相关标准建立适宜的鉴别方法,并对含钙量、水分、重金属、氯化物等一般杂质进行了检查,研究建立了有关物质、残留溶剂、残留氧化物(起始原料)的检查方法,建立了光学异构体及含量测定的检查方法,并对上述方法进行了方法学验证。有关物质检查方法采用C18色谱柱,以水-乙腈-1%三氟乙酸水溶液(64:35:1)为流动相A,水-乙腈-1%三氟乙酸水溶液(24:75:1)为流动相B进行梯度洗脱;波长242nm,流速1m L/min,柱温40℃。异构体检查采用CHIRALPAK AD-H色谱柱,流动相为正己烷-乙醇-三氟乙酸(85:15:0.1),检测波长244nm,流速0.5 m L/min,柱温30℃。以两种气相色谱方法测定本品的残留溶剂和起始原料,采用顶空进样法测定乙醇、乙腈、乙酸乙酯、四氢呋喃的含量,采用直接进样法测定DMSO及残留氧化物的含量。含量测定方法为HPLC外标法,采用C18色谱柱,以水-乙腈-1%三氟乙酸溶液(62:37:1)为流动相,检测波长为242nm,流速为0.8m L/min,柱温40℃。上述方法均经过方法学验证,可用于瑞舒伐他汀钙的检查与含量测定。本文根据样品有关物质检查的杂质情况,结合合成工艺路线和降解试验结果,对样品中的杂质进行了归属研究。结果表明,样品中最大的杂质为瑞舒伐他汀钙的非对映异构体(杂质B),样品中除各已知杂质外,还含有微量未知杂质。为保证药品使用安全性,本文通过MS、NMR等技术对未知杂质进行了研究,推测了杂质K结构为:双[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰基-氨基)-嘧啶-5-基]-(3R,5S)-2,2-二甲基-1-二氧己环-4-乙酸]钙盐(2:1),推断杂质L为瑞舒伐他汀钙异构体。最后对合成工艺中的起始原料(母核、氧化物)及关键中间体(骨架)进行了系统的质量控制研究,分别进行了理化常数测定及一般检查项的检查,建立了有关物质检查方法及含量测定方法,并进行了相关方法学验证。结合合成工艺与终产品的质量制订相应的内控标准对其质量进行控制,为工艺稳定性和终产品的质量可控性提供有效保障。
[Abstract]:Risuvastatin calcium is a new generation of selective HMG-CoA reductase inhibitors developed by AstraZeneca, which was approved for sale by FDA in the United States in August 2003 and is mainly used for hypercholesterolemia.Treatment of hypertriglyceridemia and dyslipidemia [1].It is found that there are Indian Pharmacopoeia (2010), European Pharmacopoeia (8.8) and British Pharmacopoeia (2016).In this paper, the quality control and impurity of a kind of rosuvastatin calcium product synthesized by green process were studied, and the suitable quality standard and the internal control standard of the starting material and the key intermediate were established.For the final product quality control provides a guarantee.Firstly, the quality control of rosuvastatin calcium was studied in detail.The physical and chemical constants of the product were determined, the suitable identification method was established according to the relevant standards, and the general impurities, such as calcium content, water content, heavy metal, chloride and so on, were examined.A method for the detection of related substances, residual solvents and residual oxides (starting raw materials) was established. The method for the determination of optical isomers and their contents was established, and the above methods were validated.The related substances were detected on C18 column with water acetonitrile-1% trifluoroacetic acid aqueous solution (64: 35: 1) as mobile phase A and water acetonitrile-1% trifluoroacetic acid aqueous solution as mobile phase B for gradient elution at a wavelength of 242 nm at a flow rate of 1m L / min and column temperature at 40 鈩，

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