作　　者： (李进）; (张培培）; (崇小萌）; (姚尚辰）; (胡昌勤）;

机构地区： 中国食品药品检定研究院,北京100050

出　　处： 《药物分析杂志》 2017年第8期1430-1440,共11页

摘　　要： 目的:建立阿莫西林克拉维酸钾复方制剂中聚合物杂质的分析方法。方法:采用使用TSK-gel G2500PWxl色谱柱的高效凝胶排阻色谱法(HPSEC)进行色谱分离,采用二维高效液相色谱法(2D-HPLC法)对其分离的聚合物杂质进行定性,评价色谱系统的专属性;同时使用中国药典2015年版的RP-HPLC有关物质测定方法,通过扩展洗脱梯度范围进行聚合物分析;并比较2种分析方法对阿莫西林钠克拉维酸钾聚合物混合溶液中聚合物杂质的分离情况,确定理想的分析方法。结果:HPSEC法分析阿莫西林克拉维酸钾系统适用性对照品,共检出7个色谱峰;2D-HPLC法证明在HPSEC色谱图中阿莫西林开环二聚体与克拉维酸共出峰,阿莫西林闭环二聚体在阿莫西林主峰后出峰;HPSEC法分析实际样品,聚合物杂质峰展宽严重,无法准确进行定量分析。优化后的RP-HPLC法分析聚合物混合溶液,保留时间最长的聚合物杂质经LC-MS解析推断为阿莫西林闭环四聚体,各类聚合物杂质均在中国药典2015年版规定的梯度范围内被洗脱。结论:HPSEC法不能对阿莫西林克拉维酸钾中的聚合物杂质进行有效质控,中国药典2015年版二部收载的RP-HPLC有关物质方法分析聚合物杂质准确,专属性强。 Objective： To establish a method for determination of polymer impurities in co-amoxicillin and potassium clavulanate preparations. Methods： Using TSK-gel G2500PWxl column, a high performance size exclusion chromatography （ HPSEC ） method was setup. Polymer impurities separated by HPSEC method were identified by two-dimensional HPLC （ 2D-HPLC ） method and the specificity of HPSEC method was assessed. On the basis of related substance method in Chinese pharmacopoeia 2015 edition, an optimized RP-HPLC method was obtained by extending the elution gradient range. The separation performance on polymer impurities of the two RP- HPLC methods was compared in order to establish an effective analysis method for polymers. Results： Seven peaks were detected in the amoxicillin clavulanate potassium systematic suitability standard by HPSEC method. It was proved by 2D-HPLC method that amoxicillin open ring dimer was co-eluted with clavulanic acid, and amoxicillin closed-loop dimer was eluted after amoxicillin peak. The polymer impurity peaks in real samples were broadened too severely to be analyzed quantitatively. It was verified that all the polymer impurities detected in the polymer mixed solutions by optimized RP-HPLC method could be eluted by the related substance method loaded in Part 1I, Chinese pharmacopoeia 2015 version. The polymer impurity with the longest retention time was identified as amoxicillin tetrapolymer by column switching LC-MS method. Conelusion： HPSEC method is not suitable for the quality control of polymer impurities in amoxicillin and clavulanate potassium, while the RP-HPLC related substance method loaded in the Chinese pharmacopoeia 2015 edition is accurate and specific, which can effectively control the polymer impurities.

关 键 词： 内酰胺抗生素 阿莫西林克拉维酸钾 聚合物杂质 柱切换 液相色谱质谱联用技术 二维高效液相色谱法 高效凝胶排阻色谱法