本文選題：恩雜魯胺原料藥 + 質(zhì)量研究��； 參考：《上海醫(yī)藥工業(yè)研究院》2017年碩士論文

【摘要】：恩雜魯胺為雄激素受體拮抗劑,于2012年8月在美國上市,用于治療去勢抵抗性前列腺癌。本文對恩雜魯胺原料藥進(jìn)行全面的質(zhì)量研究,為其質(zhì)量標(biāo)準(zhǔn)的制定提供依據(jù)。同時進(jìn)行苯的兩種測定方法比較,為分析工作者選擇苯的定量分析方法提供參考。研究工作共包括兩部分。1、恩雜魯胺原料藥的質(zhì)量研究1)恩雜魯胺原料藥的結(jié)構(gòu)確證、理化性質(zhì)、鑒別和一般檢查項本文通過紫外(UV)、紅外(IR)、核磁共振譜(1H-NMR、13C-NMR、HSQC和HMBC等)和高分辨質(zhì)譜,對恩雜魯胺原料藥進(jìn)行結(jié)構(gòu)確證;考察其外觀、熔點、溶解度等理化性質(zhì);建立了UV、IR和高效液相色譜-紫外檢測器法(HPLC-UV)三種鑒別方法;對其水分、熾灼殘渣、重金屬進(jìn)行了檢查和限度的確定。2)恩雜魯胺原料藥的有關(guān)物質(zhì)研究本文對恩雜魯胺原料藥工藝過程和降解產(chǎn)生的共13個雜質(zhì)進(jìn)行研究,其中分別采用LC-MS/MS法、雜質(zhì)對照品峰位對比法和核磁共振法鑒定由降解產(chǎn)生的4個雜質(zhì)。通過方法的選擇優(yōu)化及系統(tǒng)的方法驗證,最終建立了專屬性強、靈敏度高、準(zhǔn)確、穩(wěn)定的HPLC-UV法進(jìn)行本品有關(guān)物質(zhì)的測定。同時計算各雜質(zhì)相對于主峰的校正因子,采用加校正因子的主成分自身對照法進(jìn)行了13個雜質(zhì)的定量測定。3)恩雜魯胺原料藥的殘留溶劑檢查建立了氣相色譜-氫火焰離子化檢測器法(GC-FID)分離分析恩雜魯胺原料藥中的5種殘留溶劑(乙醇、異丙醇、二甲亞砜、乙酸異丙酯和四氫呋喃),并對建立的方法進(jìn)行了系統(tǒng)的方法驗證,采用外標(biāo)法對5種殘留溶劑進(jìn)行了定量測定。4)恩雜魯胺原料藥的含量測定建立了恩雜魯胺含量測定的HPLC-UV法,對所建立的方法進(jìn)行了系統(tǒng)的方法驗證,采用外標(biāo)法進(jìn)行恩雜魯胺原料藥的含量測定。同時,通過定量核磁方法驗證了HPLC-UV法的準(zhǔn)確性。2、苯的兩種測定方法比較研究以氯卡色林為模型藥,分別建立氣相色譜串聯(lián)質(zhì)譜法和頂空-氣相色譜法定量測定原料藥中的殘留苯,并對兩種定量測定方法進(jìn)行了系統(tǒng)的對比研究。1)氣相色譜串聯(lián)質(zhì)譜法的建立通過選擇合適的定量離子,采用選擇離子模式,建立氣相色譜串聯(lián)質(zhì)譜法定量測定原料藥中的殘留苯;對方法進(jìn)行系統(tǒng)的驗證,確定方法定量限可達(dá)到10.7ng/m L。2)頂空-氣相色譜法的建立采用頂空進(jìn)樣的方式,通過優(yōu)選合適的溶樣溶劑,提高苯在氣相色譜法中的響應(yīng)值,建立頂空-氣相色譜法定量測定原料藥中的殘留苯;對方法進(jìn)行系統(tǒng)的驗證,確定方法的定量限可達(dá)到20.34 ng/m L。3)對苯的兩種定量測定方法進(jìn)行系統(tǒng)的比較研究,確定方法的適用情況,為選擇苯的定量方法提供了參考。通過上述研究,已完成恩雜魯胺原料藥的系統(tǒng)質(zhì)量研究,為其藥物申報奠定了扎實的基礎(chǔ);進(jìn)行苯的2種測定方法的比較研究,為分析工作者選擇苯的定量方法提供了有益的參考。
[Abstract]:Enclamine, an androgen receptor antagonist, was listed in the United States in August 2012 for the treatment of castrated resistant prostate cancer. In this paper, a comprehensive quality study was conducted to provide the basis for the formulation of its quality standards. At the same time, two methods for the determination of benzene were compared, and the quantitative analysis method of benzene was selected for the analysis workers. The research work includes two parts of.1, the quality study of the API 1) the structural confirmation, physicochemical properties, identification and general examination of the drug of etguramine. The structure of the drug was confirmed by UV (UV), infrared (IR), nuclear magnetic resonance (1H-NMR, 13C-NMR, HSQC and HMBC) and high resolution mass spectrometry. The physical and chemical properties of its appearance, melting point and solubility were investigated. Three identification methods of UV, IR and high performance liquid chromatography - ultraviolet detector (HPLC-UV) were established. The water, burning residue, heavy metals were examined and the limits were determined.2). The related substances of the drug of eapluamines were studied in this paper. A total of 13 impurities were studied. Among them, LC-MS/MS method was used, 4 impurities were identified by the peak position contrast method and nuclear magnetic resonance method, respectively. Through the selection and optimization of the methods and the system method verification, a specific, sensitive, accurate and stable HPLC-UV method was established for the determination of the related substances. At the same time, the correction factors of each impurity relative to the main peak were calculated. The quantitative determination of 13 impurities was carried out by the principal component self control method adding the correction factor.) the residual solvent of the raw material of ehruramine was examined by the method of gas chromatography hydrogen flame ionization detector (GC-FID) for the separation and analysis of 13 residual solvents in the raw material of ehruramine (b). Alcohol, isopropanol, two methyl sulfoxide, isopropyl acetate and tetrahydrofuran, and a systematic method verification, the quantitative determination of 5 residual solvents by external standard method.4) the determination of the content of eismisamines was established by the determination of the HPLC-UV method for the determination of the content of eisrallamide. At the same time, the accuracy of the HPLC-UV method was verified by the quantitative NMR method.2, and the two methods for the determination of benzene were compared and studied with chlorapeol as the model drug. The quantitative determination of residual benzene in the raw materials by gas chromatography tandem mass spectrometry and headspace gas chromatography was established. A systematic contrast study of two quantitative determination methods.1) gas chromatography tandem mass spectrometry (GC MS) was established to determine the residual benzene in the raw materials by selecting the appropriate quantitative ions, using the selective ion mode, and setting up a gas chromatography tandem mass spectrometry to determine the residual benzene in the drug. The method is verified by a systematic method, and the quantitative limit of the method can reach 10.7ng/m L.2). Headspace gas chromatography (headspace gas chromatography) was established by headspace sampling to improve the response value of benzene in gas chromatography, and to establish a headspace gas chromatography for quantitative determination of residual benzene in raw materials. The method was verified by a systematic method, and the quantitative limit of the method could reach 20.34 ng/m L.3) and two kinds of benzene were determined. A systematic comparative study of the measurement method is carried out to determine the application of the method, which provides a reference for the selection of the quantitative method of benzene. Through the above study, the system quality of the raw material of EH has been studied, and a solid foundation for its drug application is laid. 2 methods for the determination of benzene have been compared and selected for the analysis workers to choose benzene. The quantitative method provides a useful reference.
【學(xué)位授予單位】：上海醫(yī)藥工業(yè)研究院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R927.1

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