原料药SR的质量标准研究

发布时间：2018-04-13 05:26

  本文选题：SR + 质量标准　； 参考：《河南大学》2016年硕士论文

【摘要】：近年来肿瘤的靶点治疗方法得到了越来越多的发展,特别是多靶点药物,由于优越的药理活性在临床上应用广泛。SR是一种口服多激酶抑制剂,一方面SR可抑制EGFR、VEGFR,发挥抗血管生成作用;另一方面抑制Raf信号通路,从而抗细胞增殖。目前在各国药典中尚未收载其质量标准,该课题采用多种分析技术对SR原料药进行质量标准研究,并对各研究方法进行方法学验证,以制定出SR的质量标准草案。首先,该课题对SR的理化性质,包括性状、溶解度、熔点等项目进行了考察,建立了快速准确的实验方法。其次,本文对SR原料药进行了有关物质,包括基因毒性杂质检查的方法开发和方法学研究,通过考察色谱柱、流动相、稀释剂和流速、柱温等因素,分别建立了测定有关物质、检查基因毒性杂质的液相色谱条件。其中有关物质的测定方法为:Waters e2695系统,2489 UV检测器,色谱柱为Waters C18 Symmetry Shield~(TM)(5μm,4.6×150mm)色谱柱,流动相有机相为乙腈,水相为0.01 mol/L NaH_2PO_4溶液(稀磷酸调节pH至3.0),检测波长为265 nm,柱温为40℃,流速为1.0 ml/min,进样量为10 μL,并对该方法进行了方法学验证,结果表明该方法能快速准确检测SR的有关物质。三批样品的有关物质均小于0.1%。再次,本文采用气相色谱法建立了SR残留溶剂的检测方法。最佳的色谱条件为气相色谱仪为Agilent 7890A,直接进样器为Agilent G4513A,使用Agilent DB毛细管柱和FID检测器,检测器温度为250℃,柱温为程序升温,起始温度40℃维持11分钟,以每分钟10℃的升温速率升至130℃,维持12分钟,再以每分钟100℃的升温速率升至200℃,维持20 min。载气为高纯氮气,直接进样气化室温度为220℃,进样量为2 μL,对该方法进行了方法学验证。验证结果表明该方法线性良好,灵敏度高,重复性好。以内标法对三批样品进行检测,乙醇的检出量小于标准限度,其他溶剂未检出。同时对有关物质液相色谱方法的色谱条件稍作调整,建立SR原料药的含量测定方法,并进行方法学验证,结果表明该方法可以准确测定SR的含量。对SR三批样品进行测定,结果表明三批样品的含量均在98%-102%之间。最后,建立了测定对甲苯磺酸成盐比例的液相色谱方法,并对其进行方法学验证。验证结果表明该方法可用于检测对甲苯磺酸的成盐比例。对SR原料药的水分、干燥失重、炽灼残渣和重金属检查等项目进行检查,三批样品的测定结果均符合要求。使用红外光谱和液相色谱对SR原料药进行鉴别。对SR原料药的稳定性进行考察,主要进行影响因素试验,结果表明,SR原料药对强光、高湿和高温都比较稳定,性状、含量和有关物质无明显变化。上述实验为SR原料药的质量标准草案提供了依据,并为制剂工艺的研发和生产工艺的设计奠定了基础。
[Abstract]:In recent years, the target therapy of tumor has been more and more developed, especially multi-target drugs. Because of its excellent pharmacological activity, SR is a kind of oral polykinase inhibitor, which is widely used in clinic.On the one hand, SR can inhibit EGFR and exert anti-angiogenesis effect; on the other hand, SR can inhibit Raf signaling pathway and thus inhibit cell proliferation.At present, the quality standard of SR has not been collected in the pharmacopoeia of various countries. This paper studies the quality standard of SR API by using various analytical techniques, and verifies the methodology of each research method in order to work out the draft of SR quality standard.Firstly, the physical and chemical properties of SR, including properties, solubility and melting point, were investigated, and a rapid and accurate experimental method was established.Secondly, the related substances, including the method and methodology of genotoxic impurity detection, were developed and studied. The related substances were determined by investigating the chromatographic column, mobile phase, diluent and flow rate, column temperature, etc.The liquid chromatographic conditions of toxic impurities were examined.The flow rate was 1.0 ml / min and the injection amount was 10 渭 L. the results showed that the method could be used to detect SR related substances quickly and accurately.The related substances of the three batches of samples are less than 0.1.Thirdly, gas chromatography was used to establish a method for the determination of SR residual solvent.The best chromatographic conditions were Agilent 7890A, Agilent G4513A, Agilent DB capillary column and FID detector. The detector temperature was 250 鈩，

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