目的: 根据ICH Q3D元素杂质指导原则,建立了电感耦合等离子体质谱法（ICP-MS法）同时测定药用辅料琥珀酸钠中10种元素杂质含量的方法,为全面评价其潜在风险提供依据。方法: 根据注射给药途径需风险评估的元素种类和每日允许暴露量（PDE）,采用单组分限度计算法,以10 g · d-1作为最大日剂量,计算琥珀酸钠中各元素的限度和控制阈值。采用iCAP RQ 电感耦合等离子体质谱仪,样品前处理采用直接溶解法,建立了以锗（Ge）、铟（In）、铋（Bi）为内标可同时测定琥珀酸钠中10种元素杂质残留量的分析方法。结果: 各元素杂质均呈良好的线性关系（r>0.99）,镉（Cd）、铅（Pb）、砷（As）、汞（Hg）、钴（Co）、钒（V）、镍（Ni）、锂（Li）、锑（Sb）和铜（Cu）的检测限分别为0.27、19.22、8.86、16.63、0.12、0.28、1.48、6.91、0.35、9.26 ng · g-1,高、中、低浓度点的回收率（n=3）范围为82.4%~130.9%,重复性试验的RSD（n=6）≤ 7.1%,均满足方法学验证的要求。琥珀酸钠样品中各元素杂质的含量均低于PDE的30%,表明琥珀酸钠中的元素杂质对药品无潜在的安全性风险。结论: 该方法样品前处理简便,灵敏度高,准确性良好,适用于琥珀酸钠中元素杂质的监测和风险评估,有利于质量控制,同时为其他品种元素杂质的测定提供参考。
Objective: To establish an inductively coupled plasma mass spectrometry (ICP-MS) method to determine the contents of 10 elemental impurities in the pharmaceutical excipients sodium succinate according to the ICH Q3D elemental impurity guideline, and to provide a basis for the comprehensive evaluation of potential risks. Methods: According to the types of elements that needed to risk assessment and the permitted daily exposure (PDE) of the injection route, the single-component limit calculation method was used to calculate the limit and control threshold of each element in sodium succinate with 10 g · d-1 as the maximum daily dose. Samples were preprocessed by direct dissolution and the iCAP RQ ICP-MS was used for the simultaneous determination of the residual amounts of 10 impurities in sodium succinate, using Ge, In and Bi as the internal standards. Results: All elemental impurities showed good linear relationship (r>0.99). The limits of detection of Cd, Pb, As, Hg, Co, V, Ni, Li, Sb and Cu were 0.27,19.22,8.86,16.63,0.12,0.28,1.48,6.91,0.35,9.26 ng · g-1, respectively. The recoveries (n=3) of each concentration were between 82.4% and 130.9%, and the RSD (n=6) of the repeatability test was not more than 7.1%, with all findings meeting the requirements for methodological validation. The content of elemental impurities in sodium succinate was less than 30% of the PDE, indicating that the elemental impurities in sodium succinate had no potential safety risk with the medicinal product. Conclusion: The method is simple in sample pretreatment, with high sensitivity and good accuracy. It is suitable for monitoring and risk assessment of elemental impurities in sodium succinate, which is conducive to the quality control. It also provides a reference for the determination of elemental impurities in other products. Keywords: sodium succinate; ICH Q3D; inductively coupled plasma mass spectrometry (ICP-MS); elemental impurities; permitted daily exposure（PDE）;content determination;internal standard method;risk assessment
[1] 陈蕾,张阳洋,郑爱萍,等.我国药用辅料产业高质量发展的思考[J].中国药事,2021,35(9):972
CHEN L,ZHANG YY,ZHENG AP,et al.Thoughts on the high quality development of pharmaceutical excipients industry in China[J].Chin Pharm Aff,2021,35(9):972
[2] 朱俐,赵瑜,尹利辉,等.电感耦合等离子体原子发射光谱法和电感耦合等离子体质谱法检测药品中元素杂质的研究进展[J].理化检验-化学分册,2022,58(3):361
ZHU L,ZHAO Y,YIN LH,et al.Research process of determination of elemental impurities in drugs by ICP-AES and ICP-MS[J].Phys Test Chem Anal Part B:Chem Anal,2022,58(3):361
[3] 朱俐,赵瑜,姚尚辰,等.药物中元素杂质检测技术研究最新进展[J].分析测试学报,2020,39(4):547
ZHU L,ZHAO Y,YAO SC,et al.Research progress on detection techniques for elemental impurities in drugs[J].J Instrum Anal,2020,39(4):547
[4] 孙佳敏,杨美玲,杜颖,等.药品质量标准中杂质的限度确定方式探讨[J].中国新药杂志,2023,32(21):2129
SUN JM,YANG ML,DU Y,et al.Discussion on the determination of impurity limits in drug specification[J].Chin J New Drugs,2023,32(21):2129
[5] ICH Q3D.Guidline For Elemental Impurities[S].2022
[6] 李智明,卢日刚,邓鸣,等.电感耦合等离子体质谱法检测药品中重金属及其他元素的研究进展[J].理化检验-化学分册,2022,58(12):1477
LI ZM,LU RG,DENG M,et al.Research process of determination of heavy metal and other elements in drugs by ICP-MS[J].Phys Test Chem Anal Part B:Chem Anal,2022,58(12):1477
[7] USP43-NF 38[S].2023:935
[8] 张芸,王亚敏.基于ICH Q3D(R2)解读药品元素杂质研究的基本考虑[J].中国新药杂志,2023,32(17):1719
ZHANG Y,WANG YM.General considerations for the evaluation of elemental impurities in drug products based on ICH Q3D9(R2)[J].Chin J New Drugs,2023,32(17):1719
[9] 中华人民共和国药典2020年版.四部[S].2020:236,305,524,620
ChP2020.Vol Ⅳ[S].2020:236,305,524,620
[10] da Silva,CS,Pinheiro,FC,do Amaral,CDB,et al.Determination of As,Cd,Hg and Pb in continuous use drugs and excipients by plasma-based techniques in compliance with the United States Pharmacopeia requirements[J].Spectrochim Acta Part B Atom Spectrosc,2017,138:14
[11] 钟思伟. ICP-MS法测定左氧氟沙星注射液中10种元素杂质的含量[J].药物分析杂志,2023,43(11):1914
ZHONG SW.Determination of 10 elemental impurities in levofloxacin injection by ICP-MS[J].Chin J Pharm Anal,2023,43(11):1914
[12] 屠哲玮,吴杨,林成祥.盐酸伐昔洛韦中元素杂质钯电感耦合等离子体发射光谱法的含量测定[J].抗感染药学,2021,18(9):1249
TU ZW,WU Y,LIN CX.Determination of palladium in valaciclovir hydrochloride by inductively coupled plasma atomic emission spectrometry[J].Anti Infect Pharm,2021,18(9):1249
[13] 张璐. ICP-OES法测定甘油磷酸钠注射液中的钠和磷的含量[J].中国药品标准,2023,24(2):149
ZHANG L.The content of sodium and phosphorus in sodium glycerophosphate injection was determined by ICP-MS[J].Drug Stand China,2023,24(2):149
[14] 齐艳菲,贾菲菲,王颖,等.盐酸氨溴索注射液玻璃安瓿包装中20种元素迁移量的测定与风险评估[J].中南药学,2024,22(1):194
QI YF,JIA FF,WANG Y,et al.Migration determination and risk assessment of 20 elements in ambroxol hydrochloride injection in glass ampoule packaging[J].Cent South Pharm,2024,22(1):194
[15] 张凤妹,陈丹丹,顾霄,等.注射用头孢美唑钠中10种ICH控制元素测定方法的建立[J].药物分析杂志,2023,43(8):1446
ZHANG FM,CHEN DD,GU X,et al.A method for the determination of 10 elemental impurities in cefmetazole sodium for injection according to ICH requirement[J].Chin J Pharm Anal,2023,43(8):1446
[16] 郭雅娟,王彩媚,胡淑君,等.ICP-MS法检测甘露醇中元素杂质的残留量[J].药物分析杂志,2023,43(5):804
GUO YJ,WANG CM,HU SJ,et al.Determination of elemental impurities in mannitol by ICP-MS[J].Chin J Pharm Anal,2023,43(5):804
[17] 张军红. 消除ICP-MS测定汞的记忆效应[J].济源职业技术学院学报,2015,14(2):23
ZHANG JH.Eliminating the memory effect of determining mercury by ICP-MS[J].J Jiyuan Vocat Tech Coll,2015,14(2):23
[18] 李耀磊,金红宇,韩笑.电感耦合等离子体质谱测定法中汞元素记忆效应与稳定性研究[J].中国药学杂志,2019,54(1):53
LI YL,JIN HY,HAN X.Determination of the memory effect and stability of mercury by ICP-MS[J].Chin Pharm J,2019,54(1):53
[19] 王玉,郑淑凤,贾艾玲,等.ICP-MS法检测富马酸亚铁中7种元素杂质[J].药物分析杂志,2023,43(8):1423
WANG Y,ZHENG SF,JIA AL,et al.ICP-MS determination of 7 kinds of elementalimpurities in ferrous fumarate[J].Chin J Pharm Anal,2023,43(8):1423
