恩杂鲁胺原料药质量研究及苯测定方法的比较

发布时间：2018-06-15 01:21

本文选题：恩杂鲁胺原料药 + 质量研究　；参考：《上海医药工业研究院》2017年硕士论文

【摘要】：恩杂鲁胺为雄激素受体拮抗剂,于2012年8月在美国上市,用于治疗去势抵抗性前列腺癌。本文对恩杂鲁胺原料药进行全面的质量研究,为其质量标准的制定提供依据。同时进行苯的两种测定方法比较,为分析工作者选择苯的定量分析方法提供参考。研究工作共包括两部分。1、恩杂鲁胺原料药的质量研究1)恩杂鲁胺原料药的结构确证、理化性质、鉴别和一般检查项本文通过紫外(UV)、红外(IR)、核磁共振谱(1H-NMR、13C-NMR、HSQC和HMBC等)和高分辨质谱,对恩杂鲁胺原料药进行结构确证;考察其外观、熔点、溶解度等理化性质;建立了UV、IR和高效液相色谱-紫外检测器法(HPLC-UV)三种鉴别方法;对其水分、炽灼残渣、重金属进行了检查和限度的确定。2)恩杂鲁胺原料药的有关物质研究本文对恩杂鲁胺原料药工艺过程和降解产生的共13个杂质进行研究,其中分别采用LC-MS/MS法、杂质对照品峰位对比法和核磁共振法鉴定由降解产生的4个杂质。通过方法的选择优化及系统的方法验证,最终建立了专属性强、灵敏度高、准确、稳定的HPLC-UV法进行本品有关物质的测定。同时计算各杂质相对于主峰的校正因子,采用加校正因子的主成分自身对照法进行了13个杂质的定量测定。3)恩杂鲁胺原料药的残留溶剂检查建立了气相色谱-氢火焰离子化检测器法(GC-FID)分离分析恩杂鲁胺原料药中的5种残留溶剂(乙醇、异丙醇、二甲亚砜、乙酸异丙酯和四氢呋喃),并对建立的方法进行了系统的方法验证,采用外标法对5种残留溶剂进行了定量测定。4)恩杂鲁胺原料药的含量测定建立了恩杂鲁胺含量测定的HPLC-UV法,对所建立的方法进行了系统的方法验证,采用外标法进行恩杂鲁胺原料药的含量测定。同时,通过定量核磁方法验证了HPLC-UV法的准确性。2、苯的两种测定方法比较研究以氯卡色林为模型药,分别建立气相色谱串联质谱法和顶空-气相色谱法定量测定原料药中的残留苯,并对两种定量测定方法进行了系统的对比研究。1)气相色谱串联质谱法的建立通过选择合适的定量离子,采用选择离子模式,建立气相色谱串联质谱法定量测定原料药中的残留苯;对方法进行系统的验证,确定方法定量限可达到10.7ng/m L。2)顶空-气相色谱法的建立采用顶空进样的方式,通过优选合适的溶样溶剂,提高苯在气相色谱法中的响应值,建立顶空-气相色谱法定量测定原料药中的残留苯;对方法进行系统的验证,确定方法的定量限可达到20.34 ng/m L。3)对苯的两种定量测定方法进行系统的比较研究,确定方法的适用情况,为选择苯的定量方法提供了参考。通过上述研究,已完成恩杂鲁胺原料药的系统质量研究,为其药物申报奠定了扎实的基础;进行苯的2种测定方法的比较研究,为分析工作者选择苯的定量方法提供了有益的参考。
[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.
【学位授予单位】：上海医药工业研究院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R927.1

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