头孢唑肟钠有关物质的研究  

Study on related substances in ceftizoxime sodium

作　　者：孟君 林顺权 蒲含林[3] 李金菊 袁晓 Meng Jun;Lin Shun-quan;Pu Han-lin;Li Jin-ju;Yuan Xiao(Zhuzhou Qianjin Pharmaceutical Co.,Ltd.,Zhuzhou 412000;Guangzhou PI&PI Biotech,Inc.Guangzhou 510663;Department of Cell Biology,College of Life Science and Technology,Jinan University,Guangzhou 510632;Wuhan Botanical Garden of Chinese Academy of Sciences,Wuhan 430074)

机构地区：[1]株洲千金药业股份有限公司,株洲412000 [2]广州牌牌生物科技有限公司,广州510663 [3]暨南大学生命科学与技术学院细胞生物学系,广州510632 [4]中国科学院武汉植物园,武汉430074

出　　处：《中国抗生素杂志》2022年第7期682-690,共9页Chinese Journal of Antibiotics

摘　　要：目的采用液相色谱法和液相色谱-质谱联用法对不同批次的头孢唑肟钠粉针中的杂质进行全面深入研究。方法对头孢唑肟钠进行加速稳定性试验,采用液相色谱、液质联用仪检测头孢唑肟钠中的杂质类型,采用制备型液相色谱制备有关杂质,经波普分析确定各杂质的结构。结果共检出12种杂质,其中2种为新检出的杂质,且在制剂中含量较高,本次报道的杂质为B(6R,7R)-7-((Z)-2-(2-氨基噻唑-4-基)-2-(甲氧基亚氨基)乙酰胺-8-氧代-5-噻-1-氮杂双环[4,2,0]辛-3-烯-2-羧酸,C 2-(R)-(Z)-2-(2-氨基噻唑-4-基)-2-(甲氧基亚氨基)乙酰胺(羧基)甲基)-3,6-二氢-2H-1,3-噻嗪-4-羧酸,D 2-((R)-(Z)-2-(2-氨基噻唑基)-2-(甲氧基亚氨基)乙酰胺(羧基)甲基)-3,6-二氢-2H-1,3-噻嗪-4-羧酸,F(Z)-2-((2-(2-氨基噻唑-4-基)-2-(甲氧基亚氨基)乙酰胺)甲基)-3,6-二氢-2H-1,3-噻嗪-4-羧酸,G 2-((R)-((E)-2-(2-氨基噻唑-4-基)-2-(甲氧基亚氨基)乙酰胺基(羧基)甲基)-3,6-二氢-2H-1,3-噻嗪-4-羧酸,H 2-(R)-(E)-2-(2-氨基噻唑-4-基)-2-(甲氧基亚氨基)乙酰胺基(羧基)甲基)-3,6-二氢-2H-1,3-噻嗪-4-羧酸,I(6R,7R)-7-((E)-2-(2-氨基噻唑-4-基)-2-(甲氧基亚氨基)乙酰胺基)-8-氧基-5-噻-1-氮杂双环[4,2,0]辛-3-烯-2-羧酸,J(6R)-7-(Z)-2-(2-氨基噻唑-4-基)-2-(甲氧基亚氨基)乙酰胺)-8-氧代-5-噻-1-氮杂双环[4,2,0]辛-2-烯-2-羧酸。结论本文报道的分析方法能较好的检测分析头孢唑肟钠中的各种可能的常见杂质,本实验室开发的分离纯化方法能够分离得到纯度合乎结构确证要求的杂质,用NMR、HRMS、NOE和CD等分析方法能准确推测这些杂质的结构。Objective To study the impurities in different batches of ceftizoxime sodium by HPLC and LC-MS.Methods The accelerated stability test of ceftizoxime sodium was carried out.The impurities in ceftizoxime sodium were detected by HPLC and LC-MS.The related impurities were prepared by preparative HPLC.The structure of each impurity was determined by pop analysis.Results A total of 12 impurities were detected,of which 2 were newly reported for the first time,and the content was high in the preparation.The impurities reported in this report are B(6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-3-ene-2-carboxylicacid,C 2-(R)-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)(carboxy)methyl)-3,6-dihydro-2H-1,3-thiazine-4-carboxylic acid,D 2-((R)-((Z)-2-(2-aminothiazoyl)-2-(methoxyimino)acetamido)(carboxyl)methyl)-3,6-dihydro-2H-1,3-thiazine-4-carboxylic acid,F(Z)-2-((2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)methyl)-3,6-dihydro-2H-1,3-thiazine-4-carboxylicacid,G 2-((R)-((E)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)(carboxy)methyl)-3,6-dihydro-2H-1,3-thiazine-4-carboxylic acid,H 2-((R)-((E)-2-(2-amino-thiazol-4-yl)-2-(methoxyimino)acetamido)(carboxy)methyl)-3,6-dihydro-2H-1,3-thiazine-4-carboxylic acid,I(6R,7R)-7-((E)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-3-ene-2-carboxylic acid,and J(6R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid.Conclusion The analytical method reported in this paper can detect and analyze all kinds of possible common impurities in ceftizoxime sodium.The separation and purification method developed by our laboratory can separate the impurities with purity meeting the requirements of structure confirmation.The structures of these impurities can be accurately characterized by NMR,HRMS,NOE,CD and other analytical methods.

关 键 词：头孢唑肟钠 杂质分析检测 结构分析 

分 类 号：R978.1[医药卫生—药品]