布洛芬中布洛芬乙酯及其分析方法的研究

发布时间：2018-04-14 17:38

  本文选题：布洛芬 + 布洛芬乙酯　； 参考：《山东大学》2014年硕士论文

【摘要】：本文研究的主要对象——布洛芬乙酯是布洛芬原料药生产、检验过程中发现的一种未知杂质。在布洛芬原料药有关物质检测过程中,这一杂质成为布洛芬有关物质超出限度的最主要的来源。各国药典、相关文献均未收录这一杂质,更没有合适的分析方法对它进行定量分析,因此,对该杂质进行深入的研究,对提高布洛芬质量、保障用药安全具有重要的意义。 本文首先利用制备色谱对该杂质进行制备,接着对它进行结构解析和确证,然后探索杂质的分析方法,通过对检测波长、色谱柱、流动相等色谱条件的筛选,找出最佳的色谱条件,并进行了全面的方法学验证。在上述工作的基础上,进一步探明了布洛芬乙酯的生成原理和来源,并对该杂质的消除和降低工艺进行了深入的探索,通过对布洛芬精制工艺过程中的相关关键工艺参数的优化,达到了有效的、简便的控制布洛芬中布洛芬乙酯含量的目的。 首先通过制备色谱制备出布洛芬乙酯,接着通过红外光谱、紫外光谱、质谱、核磁共振等方法手段对该杂质进行结构解析和确证。然后摸索出高效液相色谱测定方法的关键色谱条件,包括检测波长、色谱柱、流动相梯度组成等内容,最后确定了最佳色谱条件。为了验证该分析方法的适用性和有效性,对专属性、准确度、重复性、中间精密度、线性、检测限及定量限、溶液稳定性进行了方法学验证和考察。得出了最佳高效液相色谱法条件：检测波长214nm；色谱柱：YMC-pack ODS-A C18(4.6×150mm,5μm);流动相：流动相A：乙腈—水=340：660(用磷酸调pH为3.0),流动相B：乙腈,并确定了最佳的流动相梯度组成。通过方法学验证,结果表明,该分析方法的专属性测试中相邻峰的分离度均1.5,重复性中布洛芬峰面积的RSD=1.0%,中间精密度两组测定结果间没有差异,布洛芬乙酯的检测限为1.1001μg/ml、定量限为0.5005μg/ml,线性测试中布洛芬的R=0.99998、布洛芬杂质B的R=0.99999、布洛芬乙酯的R=0.99999,准确度测试中回收率均在95.0%-105.0%之间,方法学验证均符合要求,具有灵敏度高、简便及准确特点,适合布洛芬中布洛芬乙酯及其他有关物质的检测,为布洛芬成品的质量控制发挥了重要作用。 论文接着对布洛芬粗品精制过程进行了研究,通过对粗品、成品的分析,对脱色时间、脱色温度、乙醇溶媒浓度、回收乙醇中布洛芬乙酯含量的分析,确定了布洛芬乙酯生产的原理和来源,找到了布洛芬乙酯含量的影响因素。 最后根据酯化反应的原理,对控制布洛芬乙酯含量的工艺参数进行了筛选,确定了最佳的工艺参数,达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.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R927.2
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本文编号：1750384