头孢噻肟钠原料的聚合物杂质分析  

Analysis of polymer impurities in cefotaxime sodium raw materials

作　　者：李进[1] 姚尚辰[1] 尹利辉[1] 许明哲[1] 胡昌勤[1] Li Jin;Yao Shang-chen;Yin Li-hui;Xu Ming-zhe;Hu Chang-qin(National Institutes for Food and Drug Control,Beijing 102629)

机构地区：[1]中国食品药品检定研究院,北京102629

出　　处：《中国抗生素杂志》2020年第9期883-892,共10页Chinese Journal of Antibiotics

摘　　要：目的建立头孢噻肟钠原料中聚合物杂质的分析方法。方法采用浓溶液降解法制备头孢噻肟钠降解溶液;采用高效凝胶色谱法(TSK G2000 SWxl)和柱切换-LC/MSn法对头孢噻肟钠降解溶液中的聚合物杂质进行分离和结构推定;采用Agilent ZORBAX SB-C18型色谱柱,以0.05mol/L磷酸盐缓冲液-甲醇为流动相,进行梯度洗脱,建立头孢噻肟钠聚合物的RP-HPLC分析方法,采用二维液相色谱法和柱切换-LC/MSn法对该方法的专属性进行分析;进行方法学验证。结果在头孢噻肟钠降解物中推定出头孢噻肟二聚体及其异构体、三聚体、四聚体;高效凝胶色谱法分离头孢噻肟钠聚合物杂质时,部分聚合物杂质在与主峰共出峰和在主峰后出峰,定量准确性差;RP-HPLC法分析头孢噻肟钠聚合物杂质时,在30~50min范围内检出6个聚合物杂质峰;主要二聚体杂质的定量限为6.3×10-5μg,最低检测限为2.0×10-5μg。结论高效凝胶色谱法不能对头孢噻肟钠原料中聚合物杂质进行有效质控,反相色谱法分析头孢噻肟钠聚合物杂质时专属性良好、灵敏度高、方法耐用性好,可用于头孢噻肟钠原料的聚合物杂质质控;头孢噻肟钠降解溶液可作为分析头孢噻肟钠聚合物的系统适用性溶液。Objective To establish a method for determination of polymer impurities in cefotaxime sodium raw materials.Methods A concentrated solution was maintained for four days to prepare the cefotaxime sodium degradation solution;the High Performance Size Exclusion Chromatography method(HPSEC,using TSK-gel G2000SWxl column)and the Column-Switching LC/MSn method were applied to separate and identify the poor retention impurities in cefotaxime sodium degradation solution;a new RP-HPLC method for cefotaxime sodium polymer was established with an Agilent ZORBAX SB-C18 column,using a mobile phase with gradient elution by 0.05mol/L phosphate buffer and methanol.The specificity of RP-HPLC method was assessed by a two dimensional chromatography method and the Column-Switching LC/MSn method,and other validation experiments were also done.Results A series of polymer impurities in cefotaxime sodium degradation solution were deduced including cefotaxime dimers and their isomers,trimers,and tetramers.Partial polymer impurities were eluted in and after the main peak,which made poor quantification accuracy.Six cefotaxime polymers were detected within the retention time from 30.0~50.0min when using the RP-HPLC method to separate cefotaxime degradation solution.The LOQ and LOD of main dimer were 6.3×10-5μg and 2.0×10-5μg respectively.Conclusion The HPSEC method is not suitable for the quality control of polymer impurities in cefotaxime raw materials,while the new established RP-HPLC method is specific,sensitive,and robust,which can effectively control the polymer impurities.Cefotaxime degradation solution can be used to identify polymer peaks as the system suitability solution.

关 键 词：头孢噻肟钠 聚合物 杂质 柱切换-LC/MSn 高效凝胶色谱 二维色谱 Β-内酰胺抗生素 

分 类 号：R978.1[医药卫生—药品]