【摘要】：本論文在對注射用泮托拉唑鈉進行專題調(diào)研、文獻檢索后,結(jié)合該品種原輔料、生產(chǎn)工藝、質(zhì)量標準、說明書等方面,進一步開展了與藥品安全性有關(guān)的有關(guān)物質(zhì)、配伍溶液對泮托拉唑鈉穩(wěn)定性影響、降解雜質(zhì)結(jié)構(gòu)分析及金屬螯合劑EDTA二鈉的添加量等4個方面的探索研究。國外藥典中收載的注射用泮托拉唑鈉有關(guān)物質(zhì)方法基本一致,僅限度略有差異,但與中國藥典收載方法差異較大。因此,分別采用中國藥典方法與國外藥典方法對該品種有關(guān)物質(zhì)的測定方法開展探索性研究,考察該品種在兩種色譜條件下檢出雜質(zhì)的種類及含量。結(jié)果證明現(xiàn)有的有關(guān)物質(zhì)色譜條件及測定方法(中國藥典2015版方法),能完全分離并有效檢出歐洲藥典已經(jīng)明確的各已知雜質(zhì)。并且現(xiàn)有方法與歐洲藥典方法中各雜質(zhì)相對保留時間基本一致,雜質(zhì)含量測定結(jié)果無差別。泮托拉唑鈉為強堿性藥物,在堿性溶液中保持穩(wěn)定,國內(nèi)外企業(yè)說明書中均明確注明:本品需用0.9%氯化鈉注射液溶解后,在一定時間內(nèi)注射完。在合格范圍內(nèi)的不同p H值的氯化鈉注射液對泮托拉唑鈉穩(wěn)定性影響不容忽視,因此對其進行了探索性研究。經(jīng)研究,隨著放置時間的增加,泮托拉唑鈉含量顯著降低,雜質(zhì)增加;在相同放置時間的條件下,隨著溶劑氯化鈉注射液p H值降低,泮托拉唑鈉降解率隨之增大。根據(jù)上述研究,為配伍溶液的選擇提供了建議。實驗發(fā)現(xiàn)注射用泮托拉唑鈉溶液放置過程中會產(chǎn)生明顯的降解。藥品中雜質(zhì)的存在會嚴重影響藥物的品質(zhì),甚至伴隨嚴重的不良反應(yīng),對人體產(chǎn)生危害。因此,研究注射用泮托拉唑鈉放置過程中產(chǎn)生的主要降解雜質(zhì)具有重要意義。在原有關(guān)物質(zhì)檢查方法的基礎(chǔ)上,經(jīng)反復(fù)優(yōu)化,建立了適合液質(zhì)聯(lián)用分析的色譜條件,采用梯度洗脫法將降解雜質(zhì)有效分離,利用高效液相色譜-四級桿飛行時間質(zhì)譜推定了四個降解雜質(zhì)的結(jié)構(gòu),并嘗試用液核聯(lián)用分析進行確證,分析了供試品溶液中主要降解雜質(zhì)的來源。為了提高注射液的穩(wěn)定性,一些企業(yè)選擇在注射用泮托拉唑鈉中加入EDTA二鈉。但攝入的EDTA二鈉會與人體中的鈣離子形成水溶性螯合物,被排出體外,過多的攝入可能會導(dǎo)致低血鈣癥或骨鈣流失,因此對制劑中EDTA二鈉添加情況開展探索性研究。建立了HPLC絡(luò)合顯色法測定EDTA的方法,并對測定結(jié)果進行了綜合評價。
[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.
【學(xué)位授予單位】：浙江工業(yè)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：O657.7;TQ460.7

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