国家药品抽检中硫酸沙丁胺醇吸入气雾剂有关物质研究  

Research on related substances of salbutamol sulfate inhalation aerosol in national drug sampling and testing

作　　者：张连义 李文馨 李铁军 牛冲 杨书娟 王文心 窦艳丽 郑静 潘相蜜 徐玉文 ZHANG Lian-yi;LI Wen-xin;LI Tie-jun;NIU Chong;YANG Shu-juan;WANG Wen-xin;DOU Yan-li;ZHENG Jing;PAN Xiang-mi;XU Yu-wen(Shandong Institute for Food and Drug Control,NMPA Key Laboratory for Research and Evaluation of Generic Drugs,Shandong Research Center of Engineering and Technology for Consistency Evaluation of Generic Drugs,Industrial Technology Foundation Public Service Platform,Jinan 250101,China;Shandong Jewim Pharmaceutical Co.,Ltd.,Taian 271000,China;The Fifth People's Hospital of Jinan,Jinan 250022,China)

机构地区：[1]山东省食品药品检验研究院、国家药品监督管理局仿制药研究与评价重点实验室、山东省仿制药一致性评价工程技术研究中心产业技术基础公共服务平台,济南250101 [2]山东京卫制药有限公司,泰安271000 [3]济南市第五人民医院,济南250022

出　　处：《药物分析杂志》2024年第12期2078-2087,共10页Chinese Journal of Pharmaceutical Analysis

基　　金：泰山产业领军人才工程专项经费(tscx202306073)。

摘　　要：目的:对国家药品抽检品种硫酸沙丁胺醇吸入气雾剂的有关物质进行探索性研究,比较各企业样品之间含有杂质的情况,以评价药品质量。方法:采用HPLC外标法同时测定硫酸沙丁胺醇吸入气雾剂中有关物质A、B、C、D、E、F、G、H、I、J、N及其他未知杂质含量。采用Thermo Syncronis C_(8)(250 mm×4.6 mm,5μm)色谱柱;以庚烷磺酸钠溶液-乙腈为流动相,进行线性梯度洗脱;流速1.0 mL·min^(-1);柱温40℃;检测波长220 nm;进样体积20μL。结合强制降解试验探讨杂质来源,并采用毒性预测软件进行杂质毒性评估。结果:经方法验证,方法专属性良好,各杂质峰之间分离度均>1.5;精密度试验的RSD为0.30%~1.7%(n=6);线性范围在0.050~5.000μg·mL^(-1)(r=0.9999);定量限在0.025~0.200μg·mL^(-1),检测限在0.008~0.070μg·mL^(-1);原料药重复性的RSD为0.80%~3.8%,平均回收率95.2%~104.8%;吸入气雾剂重复性的RSD为1.2%~2.9%,回收率98.7%~102.8%。强制降解试验表明,杂质D、F、I、J、N均为降解杂质。对抽检的110批次样品进行检测,有关物质结果均符合规定。各企业样品中,杂质C、D、F、N检出频次较高,杂质E、G、H均未检出,杂质J仅检出1批次。其中杂质D的QSAR软件预测ICH M7(R2)分类为2级。结论:建立的方法灵敏准确,可准确地对硫酸沙丁胺醇气雾剂的有关物质含量进行定量测定,能为科学监管提供有效的技术支持。应对杂质D进行进一步的毒性研究,并确定合理的限度。Objective:To study the related substances in salbutamol sulfate inhalation aerosol during national drug sampling and testing,and to compare the impurity content and evaluate the quality between samples from various enterprises.Methods:HPLC external standard method was utilized to simultaneously determine the content of related substances A,B,C,D,E,F,G,H,I,J,N,and other unknown impurities in salbutamol sulfate inhalation aerosol.Thermo Synchronis C_(8) chromatography column(250 mm×4.6 mm,5μm)was used.Sodium heptane sulfonate solution-acetonitrile was used as the mobile phase.Linear gradient elution was performed and the flow rate was 1.0 mL·min^(-1).Column temperature was 40℃and detection wavelength was 220 nm.Injection volume was 20μL.The sources of impurities through forced degradation experiments were explored.Toxicity prediction software for impurity toxicity assessment was applied.Results:After method validation,the specificity of the method was good,and the separation degree between each impurity peak was greater than 1.5.RSDs of precision test were 0.30%-1.7%(n=6);mass concentrations of linear range were from 0.050 to 5.000μg·mL^(-1)(r=0.9999).Limit of quantitative was in the range of 0.025-0.200μg·mL^(-1),limit of detection was in the range of 0.008-0.070μg·mL^(-1).The repeatability RSD of raw materials was 0.80%-3.8%,and the recovery rate was 95.2%-104.8%.The repeatability RSD of inhaled aerosol was 1.2%-2.9%,and the recovery rate was 98.7%-102.8%.The forced degradation test showed that impurities D,F,I,J,and N were all degradation impurities.110 batches of samples were checked and the results of the relevant substances met the regulations.In the samples of diverse enterprises,impurities C,D,F,and N were detected more frequently,while impurities E,G,and H were not detected.Impurity J was only detected in one batch.The predicted impurity D by QSAR software falls to ICH M7(R2)level 2.Conclusion:The established method is sensitive and accurate,and can accurately quantify the content of related su

关 键 词：国家药品抽检 探索性研究 硫酸沙丁胺醇吸入气雾剂 有关物质 杂质来源 破坏试验 相对校正因子 高效液相色谱法 定量构效关系 

分 类 号：R917[医药卫生—药物分析学]