發(fā)布時間：2018-04-14 17:38

  本文選題：布洛芬 + 布洛芬乙酯��； 參考：《山東大學》2014年碩士論文

【摘要】：本文研究的主要對象——布洛芬乙酯是布洛芬原料藥生產(chǎn)、檢驗過程中發(fā)現(xiàn)的一種未知雜質(zhì)。在布洛芬原料藥有關(guān)物質(zhì)檢測過程中,這一雜質(zhì)成為布洛芬有關(guān)物質(zhì)超出限度的最主要的來源。各國藥典、相關(guān)文獻均未收錄這一雜質(zhì),更沒有合適的分析方法對它進行定量分析,因此,對該雜質(zhì)進行深入的研究,對提高布洛芬質(zhì)量、保障用藥安全具有重要的意義。 本文首先利用制備色譜對該雜質(zhì)進行制備,接著對它進行結(jié)構(gòu)解析和確證,然后探索雜質(zhì)的分析方法,通過對檢測波長、色譜柱、流動相等色譜條件的篩選,找出最佳的色譜條件,并進行了全面的方法學驗證。在上述工作的基礎(chǔ)上,進一步探明了布洛芬乙酯的生成原理和來源,并對該雜質(zhì)的消除和降低工藝進行了深入的探索,通過對布洛芬精制工藝過程中的相關(guān)關(guān)鍵工藝參數(shù)的優(yōu)化,達到了有效的、簡便的控制布洛芬中布洛芬乙酯含量的目的。 首先通過制備色譜制備出布洛芬乙酯,接著通過紅外光譜、紫外光譜、質(zhì)譜、核磁共振等方法手段對該雜質(zhì)進行結(jié)構(gòu)解析和確證。然后摸索出高效液相色譜測定方法的關(guān)鍵色譜條件,包括檢測波長、色譜柱、流動相梯度組成等內(nèi)容,最后確定了最佳色譜條件。為了驗證該分析方法的適用性和有效性,對專屬性、準確度、重復性、中間精密度、線性、檢測限及定量限、溶液穩(wěn)定性進行了方法學驗證和考察。得出了最佳高效液相色譜法條件：檢測波長214nm；色譜柱：YMC-pack ODS-A C18(4.6×150mm,5μm);流動相：流動相A：乙腈—水=340：660(用磷酸調(diào)pH為3.0),流動相B：乙腈,并確定了最佳的流動相梯度組成。通過方法學驗證,結(jié)果表明,該分析方法的專屬性測試中相鄰峰的分離度均1.5,重復性中布洛芬峰面積的RSD=1.0%,中間精密度兩組測定結(jié)果間沒有差異,布洛芬乙酯的檢測限為1.1001μg/ml、定量限為0.5005μg/ml,線性測試中布洛芬的R=0.99998、布洛芬雜質(zhì)B的R=0.99999、布洛芬乙酯的R=0.99999,準確度測試中回收率均在95.0%-105.0%之間,方法學驗證均符合要求,具有靈敏度高、簡便及準確特點,適合布洛芬中布洛芬乙酯及其他有關(guān)物質(zhì)的檢測,為布洛芬成品的質(zhì)量控制發(fā)揮了重要作用。 論文接著對布洛芬粗品精制過程進行了研究,通過對粗品、成品的分析,對脫色時間、脫色溫度、乙醇溶媒濃度、回收乙醇中布洛芬乙酯含量的分析,確定了布洛芬乙酯生產(chǎn)的原理和來源,找到了布洛芬乙酯含量的影響因素。 最后根據(jù)酯化反應(yīng)的原理,對控制布洛芬乙酯含量的工藝參數(shù)進行了篩選,確定了最佳的工藝參數(shù),達到了有效控制布洛芬中布洛芬乙酯含量的目的。
[Abstract]:Ibuprofen ethyl ester, the main object of this study, is an unknown impurity found in the production of ibuprofen raw material.In the detection of ibuprofen related substances, this impurity is the main source of ibuprofen related substances.The impurity is not included in the pharmacopoeia of all countries and there is no suitable analytical method for quantitative analysis. Therefore, it is of great significance to improve the quality of ibuprofen and ensure the safety of drug use.In this paper, the impurity was prepared by preparative chromatography, then the structure of the impurity was analyzed and confirmed, then the analytical method of impurity was explored, and the detection wavelength, chromatographic column, mobile chromatographic conditions were screened.The optimum chromatographic conditions were found and the comprehensive methodology was verified.On the basis of the above work, the formation principle and source of ibuprofen ethyl ester were further investigated, and the process of removing and reducing the impurity was explored.By optimizing the key process parameters in the process of ibuprofen refining, the purpose of controlling the content of ibuprofen ethyl ester in ibuprofen was achieved.Firstly, ibuprofen ethyl ester was prepared by preparation chromatography, and then the structure of the impurity was elucidated and confirmed by IR, UV, MS, NMR and other methods.The key chromatographic conditions of the method were found out, including detection wavelength, chromatographic column, gradient composition of mobile phase and so on. Finally, the optimum chromatographic conditions were determined.In order to verify the applicability and effectiveness of the method, the specificity, accuracy, repeatability, intermediate precision, linearity, detection limit and quantitative limit, solution stability were investigated.The optimum HPLC conditions were obtained as follows: detection wavelength: 214nm; column: YMC-pack ODS-A C184.6 脳 150mm-1 5 渭 m; mobile phase: mobile phase A: acetonitrile-water 340660 (pH 3.0 with phosphoric acid, mobile phase B: acetonitrile), and the optimum mobile phase gradient composition was determined.The results of methodology verification showed that the separation degree of adjacent peaks was 1.5, the RSD 1.0 of ibuprofen peak area in reproducibility was not different between the two groups.The detection limit of ibuprofen ethyl ester is 1.1001 渭 g / ml, and the quantitative limit is 0.5005 渭 g / ml. In linear test, ibuprofen is 0.99998, ibuprofen impurity B is 0.99999, ibuprofen ethyl ester is 0.999999.The recoveries of ibuprofen ethyl ester are between 95.0and 105.0%.It is simple and accurate, suitable for the detection of ibuprofen ethyl ester and other related substances in ibuprofen, and plays an important role in the quality control of ibuprofen.Then, the refining process of ibuprofen crude product was studied. The decolorization time, decolorization temperature, ethanol solvent concentration and the content of ibuprofen ethyl ester in ethanol were analyzed through the analysis of crude product and finished product.The principle and source of ibuprofen ethyl ester production were determined, and the influencing factors of ibuprofen ethyl ester content were found.Finally, according to the principle of esterification reaction, the technological parameters for controlling the content of ibuprofen ethyl ester were screened, and the optimum process parameters were determined, which achieved the purpose of effectively controlling the content of ibuprofen ethyl ester in ibuprofen.
【學位授予單位】：山東大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R927.2
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本文編號：1750384