药学学报, 2021, 56(6): 1683-1688
引用本文:
赵敬丹, 刘浩*, 张含智. 由硫酸卡那霉素注射液中杂质的变化探讨处方和灭菌工艺的合理性[J]. 药学学报, 2021, 56(6): 1683-1688.
ZHAO Jing-dan, LIU Hao*, ZHANG Han-zhi. Formulation and sterilization assessment of kanamycin sulfate injection based on impurity profiles[J]. Acta Pharmaceutica Sinica, 2021, 56(6): 1683-1688.

由硫酸卡那霉素注射液中杂质的变化探讨处方和灭菌工艺的合理性
赵敬丹, 刘浩*, 张含智
上海市食品药品检验研究院, 上海 201203
摘要:
通过硫酸卡那霉素注射液中主药卡那霉素和功能性辅料枸橼酸钠的相容性研究,对制剂处方进行评价,探讨处方中枸橼酸钠添加浓度和该处方条件下灭菌工艺的合理性。采用经优化的高效液相色谱-蒸发光散射检测系统(HPLC-ELSD)分别测定原研药和国产制剂中枸橼酸钠的含量和杂质谱;采用新建的柱后衍生化-HPLC-荧光检测系统(FLD)分析某些特定杂质的量和枸橼酸钠含量的相关性;结合特定杂质的质谱(MS)裂解规律,探讨处方及灭菌工艺的合理性。结果显示:国产注射液中枸橼酸钠的含量是原研药的近40倍;通过系列加速对比实验(121℃),提示某些未知杂质和枸橼酸钠的含量相关;结合其质谱裂解规律,推测上述杂质主要为卡那霉素和枸橼酸钠的反应产物。因此,国内药品生产企业在处方筛选时应关注处方的合理性,并结合主药和辅料的理化特性选择适当的灭菌工艺,保证临床用药的安全性。同时,对于主药结构中含有伯氨基的药物,在处方设计中应关注辅料的相容性问题。
关键词:    卡那霉素      枸橼酸钠      辅料相容性      杂质谱      衍生化     
Formulation and sterilization assessment of kanamycin sulfate injection based on impurity profiles
ZHAO Jing-dan, LIU Hao*, ZHANG Han-zhi
Shanghai Institute for Food and Drug Control, Shanghai 201203, China
Abstract:
The compatibility of kanamycin with sodium citrate for the formulation of kanamycin sulfate injection was determined, including optimization of the amount of sodium citrate in the injection and the sterilization process. An HPLC coupled with an evaporative light scattering detector (ELSD) was used to measure the amount of sodium citrate and the impurity profiles. A validated post-column derivatization HPLC coupled with a fluorescence detector (FLD) was used to determine the correlation between specific impurities in a domestic factory and sodium citrate, and then the formulation was evaluated by HPLC coupled with mass detector (MS) characterization of degradation products. The results show that the amount of sodium citrate in kanamycin sulfate injection from a domestic factory is about 40 times higher than that of the Meiji formulation. Several specific impurities can be detected in solutions heated under simulated sterilization conditions (121 ℃), which were correlated with the amount of sodium citrate. Impurities were characterized by HPLC-MS/MS, and data showed that the identified impurities were interaction products of kanamycin and sodium citrate. These results indicate that greater attention should be directed at formula optimization in domestic factories, as it is crucial to the safety and efficacy of the preparations. Drug-excipient chemical compatibility should also be evaluated in the development of pharmaceutical dosages forms especially when the active pharmaceutical ingredients have a primary amine group.
Key words:    kanamycin    sodium citrate    drug-excipient chemical compatibility    impurity profile    derivatization   
收稿日期: 2021-01-18
DOI: 10.16438/j.0513-4870.2021-0104
基金项目: 2019年国家药品标准提高项目(2019H02).
通讯作者: 刘浩,Tel:13788965965-6202,E-mail:liuhao1968@hotmail.com
Email: liuhao1968@hotmail.com
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