本文選題：SR + 質量標準　； 參考：《河南大學》2016年碩士論文

【摘要】：近年來腫瘤的靶點治療方法得到了越來越多的發(fā)展,特別是多靶點藥物,由于優(yōu)越的藥理活性在臨床上應用廣泛。SR是一種口服多激酶抑制劑,一方面SR可抑制EGFR、VEGFR,發(fā)揮抗血管生成作用;另一方面抑制Raf信號通路,從而抗細胞增殖。目前在各國藥典中尚未收載其質量標準,該課題采用多種分析技術對SR原料藥進行質量標準研究,并對各研究方法進行方法學驗證,以制定出SR的質量標準草案。首先,該課題對SR的理化性質,包括性狀、溶解度、熔點等項目進行了考察,建立了快速準確的實驗方法。其次,本文對SR原料藥進行了有關物質,包括基因毒性雜質檢查的方法開發(fā)和方法學研究,通過考察色譜柱、流動相、稀釋劑和流速、柱溫等因素,分別建立了測定有關物質、檢查基因毒性雜質的液相色譜條件。其中有關物質的測定方法為:Waters e2695系統(tǒng),2489 UV檢測器,色譜柱為Waters C18 Symmetry Shield~(TM)(5μm,4.6×150mm)色譜柱,流動相有機相為乙腈,水相為0.01 mol/L NaH_2PO_4溶液(稀磷酸調節(jié)pH至3.0),檢測波長為265 nm,柱溫為40℃,流速為1.0 ml/min,進樣量為10 μL,并對該方法進行了方法學驗證,結果表明該方法能快速準確檢測SR的有關物質。三批樣品的有關物質均小于0.1%。再次,本文采用氣相色譜法建立了SR殘留溶劑的檢測方法。最佳的色譜條件為氣相色譜儀為Agilent 7890A,直接進樣器為Agilent G4513A,使用Agilent DB毛細管柱和FID檢測器,檢測器溫度為250℃,柱溫為程序升溫,起始溫度40℃維持11分鐘,以每分鐘10℃的升溫速率升至130℃,維持12分鐘,再以每分鐘100℃的升溫速率升至200℃,維持20 min。載氣為高純氮氣,直接進樣氣化室溫度為220℃,進樣量為2 μL,對該方法進行了方法學驗證。驗證結果表明該方法線性良好,靈敏度高,重復性好。以內標法對三批樣品進行檢測,乙醇的檢出量小于標準限度,其他溶劑未檢出。同時對有關物質液相色譜方法的色譜條件稍作調整,建立SR原料藥的含量測定方法,并進行方法學驗證,結果表明該方法可以準確測定SR的含量。對SR三批樣品進行測定,結果表明三批樣品的含量均在98%-102%之間。最后,建立了測定對甲苯磺酸成鹽比例的液相色譜方法,并對其進行方法學驗證。驗證結果表明該方法可用于檢測對甲苯磺酸的成鹽比例。對SR原料藥的水分、干燥失重、熾灼殘渣和重金屬檢查等項目進行檢查,三批樣品的測定結果均符合要求。使用紅外光譜和液相色譜對SR原料藥進行鑒別。對SR原料藥的穩(wěn)定性進行考察,主要進行影響因素試驗,結果表明,SR原料藥對強光、高濕和高溫都比較穩(wěn)定,性狀、含量和有關物質無明顯變化。上述實驗為SR原料藥的質量標準草案提供了依據,并為制劑工藝的研發(fā)和生產工藝的設計奠定了基礎。
[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，

本文編號：1743119