【摘要】：甾體激素是一類具有環(huán)戊烷多氫菲母核結(jié)構(gòu)的四環(huán)脂肪烴化合物,廣泛存在于人和動(dòng)物體內(nèi),對(duì)人體內(nèi)新陳代謝、內(nèi)環(huán)境的穩(wěn)定、生長(zhǎng)發(fā)育以及生殖行為有重要的調(diào)節(jié)作用。一般情況下,甾體激素在人體內(nèi)維持正常范圍,過(guò)高或過(guò)低容易造成內(nèi)分泌功能紊亂,引發(fā)各種疾病。因此,內(nèi)源性甾體激素的測(cè)定對(duì)疾病的預(yù)防、診斷和治療有重要意義。藥品作為一種特殊商品,其質(zhì)量與人們的身體健康及生命安全息息相關(guān),因此,對(duì)其質(zhì)量的控制必須貫穿藥品研發(fā)、生產(chǎn)、流通及儲(chǔ)存各個(gè)階段。藥品雜質(zhì)的研究是藥品質(zhì)量控制的一項(xiàng)重要內(nèi)容。通過(guò)對(duì)藥品相關(guān)雜質(zhì)的分析檢測(cè)對(duì)藥品的生產(chǎn)工藝的優(yōu)化及質(zhì)量控制提供依據(jù)。本文綜述部分首先介紹了甾體激素的種類和作用,展開敘述了國(guó)內(nèi)外甾體激素的分析檢測(cè)方法。其次對(duì)藥品雜質(zhì)的分類及來(lái)源做了簡(jiǎn)要介紹,重點(diǎn)闡述了藥品雜質(zhì)的檢測(cè)方法以及高效液相色譜-質(zhì)譜聯(lián)用技術(shù)(HPLC-MS)在雜質(zhì)分析中的應(yīng)用。實(shí)驗(yàn)部分分為兩部分,第一部分選擇一種甾體激素的衍生試劑,優(yōu)化了衍生反應(yīng)條件及質(zhì)譜條件;第二部分分析替比培南復(fù)雜中間體側(cè)鏈和母核(MAP)的相關(guān)雜質(zhì),優(yōu)化了分析條件,通過(guò)質(zhì)譜數(shù)據(jù)、二級(jí)碎片信息推測(cè)了幾種可能雜質(zhì)。具體研究?jī)?nèi)容及結(jié)果包括以下兩個(gè)方面:1.首先選擇本校藥學(xué)院合成的10種肼類化合物與睪酮進(jìn)行衍生反應(yīng),通過(guò)ESI-MS檢測(cè),發(fā)現(xiàn)各個(gè)肼類化合物衍生效果不理想,然后選擇市售的相對(duì)分子質(zhì)量較小的7種肼類化合物與睪酮反應(yīng),結(jié)果顯示水楊酰肼衍生效果最好。以水楊酰肼作為衍生試劑,與孕酮、孕烯醇酮、雌酮、脫氫表雄酮和雙氫睪酮五種甾體激素標(biāo)準(zhǔn)品進(jìn)行衍生反應(yīng),優(yōu)化了反應(yīng)溶劑、反應(yīng)溫度、反應(yīng)時(shí)間、反應(yīng)pH和水楊酰肼的用量等衍生反應(yīng)的條件。該方法簡(jiǎn)單快速、靈敏度高,水楊酰肼與甾體激素反應(yīng)條件簡(jiǎn)單、高效,可以作為甾體激素的衍生試劑來(lái)檢測(cè)甾體激素的含量。2.對(duì)合成替比培南的復(fù)雜中間體側(cè)鏈和母核進(jìn)行雜質(zhì)分析,確立了HPLC-MS條件,優(yōu)化了流動(dòng)相和洗脫程序,實(shí)現(xiàn)了20 min內(nèi)對(duì)藥品雜質(zhì)的分析檢測(cè)。根據(jù)藥品的合成工藝信息、液相色譜保留時(shí)間、液相色譜圖對(duì)應(yīng)的質(zhì)譜圖以及二級(jí)裂解碎片信息,推測(cè)了雜質(zhì)的可能結(jié)構(gòu),并分析推測(cè)了雜質(zhì)的裂解途徑,為替比培南新藥研發(fā)及質(zhì)量控制提供參考依據(jù)。
[Abstract]:Steroid hormones are a class of tetracyclic fatty hydrocarbons with the nuclear structure of cyclopentane polyhydrophenanthrene which widely exist in human and animal bodies and play an important role in regulating metabolism stability of internal environment growth and development as well as reproductive behavior. In general, steroid hormones in the human body maintain a normal range, too high or too low prone to endocrine disorders, leading to various diseases. Therefore, the determination of endogenous steroid hormones is of great significance in the prevention, diagnosis and treatment of diseases. As a special commodity, the quality of drugs is closely related to people's health and life safety. Therefore, the quality control must run through all stages of drug development, production, circulation and storage. The study of drug impurity is an important content of drug quality control. The analysis and detection of drug related impurities provide basis for the optimization of drug production process and quality control. In the part of review, the types and functions of steroid hormones are introduced, and the analytical methods of steroid hormones at home and abroad are described. Secondly, the classification and source of drug impurity are briefly introduced, and the detection method of drug impurity and the application of high performance liquid chromatography-mass spectrometry (HPLC-MS) in impurity analysis are emphasized. The experiment is divided into two parts. In the first part, a steroid hormone derivative reagent is selected to optimize the derivatization reaction conditions and mass spectrometry conditions, and the second part is to analyze the related impurities in the side chain and mother nuclear (MAP) of the complex intermediate of tibipenem. The analysis conditions were optimized and several possible impurities were inferred by mass spectrometry data and secondary fragment information. The specific research contents and results include the following two aspects: 1. Firstly, 10 kinds of hydrazine compounds synthesized in our school of pharmacy were selected for derivatization reaction with testosterone. By ESI-MS detection, it was found that the derivative effect of each hydrazine compound was not satisfactory. Seven hydrazine compounds with relatively small molecular weight were selected to react with testosterone. The results showed that salicylic hydrazide derivatives were the best. Salicylic hydrazide was used as derivatization reagent. The reaction solvent, reaction temperature and reaction time were optimized by derivatization reaction with five steroidal hormone standard compounds, progesterone, pregnenolone, estradione, dehydroepiandrosterone and dihydrotestosterone. The reaction conditions such as the amount of pH and salicylic hydrazide were obtained. The method is simple, rapid and sensitive. The reaction condition of salicylhydrazide with steroid hormone is simple and efficient. It can be used as the derivative reagent of steroid hormone to detect the content of steroid hormone. 2. The side chain and mother nucleus of the complex intermediate of tibipenem were analyzed, the HPLC-MS conditions were established, the mobile phase and elution procedure were optimized, and the analysis and detection of drug impurities within 20 min were realized. According to the synthetic process information of drugs, retention time of liquid chromatography, mass spectrogram corresponding to liquid chromatogram and information of secondary pyrolysis fragment, the possible structure of impurity was deduced, and the pathway of impurity cracking was analyzed. To provide a reference for the R & D and quality control of new drugs of tibipenem.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R927.1

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