注射用泮托拉唑钠中主要降解杂质的鉴定及其质量控制研究

发布时间：2019-02-21 08:15

【摘要】：本论文在对注射用泮托拉唑钠进行专题调研、文献检索后,结合该品种原辅料、生产工艺、质量标准、说明书等方面,进一步开展了与药品安全性有关的有关物质、配伍溶液对泮托拉唑钠稳定性影响、降解杂质结构分析及金属螯合剂EDTA二钠的添加量等4个方面的探索研究。国外药典中收载的注射用泮托拉唑钠有关物质方法基本一致,仅限度略有差异,但与中国药典收载方法差异较大。因此,分别采用中国药典方法与国外药典方法对该品种有关物质的测定方法开展探索性研究,考察该品种在两种色谱条件下检出杂质的种类及含量。结果证明现有的有关物质色谱条件及测定方法(中国药典2015版方法),能完全分离并有效检出欧洲药典已经明确的各已知杂质。并且现有方法与欧洲药典方法中各杂质相对保留时间基本一致,杂质含量测定结果无差别。泮托拉唑钠为强碱性药物,在碱性溶液中保持稳定,国内外企业说明书中均明确注明:本品需用0.9%氯化钠注射液溶解后,在一定时间内注射完。在合格范围内的不同p H值的氯化钠注射液对泮托拉唑钠稳定性影响不容忽视,因此对其进行了探索性研究。经研究,随着放置时间的增加,泮托拉唑钠含量显著降低,杂质增加;在相同放置时间的条件下,随着溶剂氯化钠注射液p H值降低,泮托拉唑钠降解率随之增大。根据上述研究,为配伍溶液的选择提供了建议。实验发现注射用泮托拉唑钠溶液放置过程中会产生明显的降解。药品中杂质的存在会严重影响药物的品质,甚至伴随严重的不良反应,对人体产生危害。因此,研究注射用泮托拉唑钠放置过程中产生的主要降解杂质具有重要意义。在原有关物质检查方法的基础上,经反复优化,建立了适合液质联用分析的色谱条件,采用梯度洗脱法将降解杂质有效分离,利用高效液相色谱-四级杆飞行时间质谱推定了四个降解杂质的结构,并尝试用液核联用分析进行确证,分析了供试品溶液中主要降解杂质的来源。为了提高注射液的稳定性,一些企业选择在注射用泮托拉唑钠中加入EDTA二钠。但摄入的EDTA二钠会与人体中的钙离子形成水溶性螯合物,被排出体外,过多的摄入可能会导致低血钙症或骨钙流失,因此对制剂中EDTA二钠添加情况开展探索性研究。建立了HPLC络合显色法测定EDTA的方法,并对测定结果进行了综合评价。
[Abstract]:In this paper, a special investigation of pam Tora sodium for injection was carried out. After literature retrieval, related substances related to drug safety were further developed in combination with the raw and auxiliary materials of the variety, production process, quality standard, specification and so on. The effects of compatibility solution on the stability of pam Tora sodium the structure analysis of degradation impurity and the addition of metal chelating agent EDTA disodium were studied. The methods of Pam Tora sodium for injection in the foreign pharmacopoeia are basically the same, but the limits are slightly different, but there is a great difference with the Chinese Pharmacopoeia. Therefore, the Chinese pharmacopoeia method and the foreign pharmacopoeia method were used to carry out the exploratory research on the determination of the related substances in this variety, and to investigate the kinds and contents of impurities detected under the two kinds of chromatographic conditions. The results show that the existing chromatographic conditions and determination methods (Chinese Pharmacopoeia 2015) can completely separate and effectively detect all known impurities in the European Pharmacopoeia. The relative retention time of each impurity in the existing method is basically the same as that in the European Pharmacopoeia method, and there is no difference in the determination of impurity content. Pam Tora sodium is a strong alkaline drug and is stable in alkaline solution. It is clearly stated in the instructions of enterprises at home and abroad: this product needs to be dissolved with 0.9% sodium chloride injection and injected in a certain time. The effect of different pH values of sodium chloride injection on the stability of pam Tora sodium can not be ignored. The results showed that the content of pam Tora sodium decreased and the impurity increased with the increase of storage time, and the degradation rate of pam Tora sodium increased with the decrease of pH value of the solvent sodium chloride injection at the same time. According to the above study, some suggestions are provided for the selection of compatible solution. It was found that pam Tora sodium solution for injection produced obvious degradation during the process of storage. The presence of impurities in drugs can seriously affect the quality of drugs, even with serious adverse reactions, causing harm to human body. Therefore, it is of great significance to study the main degradation impurities produced during the storage of pam Tora sodium for injection. On the basis of the original inspection methods of related substances, after repeated optimization, the chromatographic conditions suitable for liquid-mass spectrometry analysis were established, and the degradation impurities were effectively separated by gradient elution method. The structure of four degradable impurities was estimated by high performance liquid chromatography (HPLC) -time of flight mass spectrometry (TOF-MS). The main sources of degradation impurity in the sample solution were analyzed. In order to improve the stability of the injection, some enterprises choose to add EDTA disodium to pam Tora sodium for injection. However, the EDTA disodium can form a water-soluble chelate with calcium ions in human body and be expelled out of the body. Too much intake may lead to hypocalcemia or bone calcium loss. Therefore, the study on the addition of EDTA disodium in the preparation was carried out. A method for the determination of EDTA by HPLC complexing colorimetry was established, and the determination results were evaluated synthetically.
【学位授予单位】：浙江工业大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：O657.7;TQ460.7

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