柠檬酸苹果酸钙25种元素杂质的含量测定  

Determination of 25 elemental impurities in calcium citrate malate

作　　者：景奕文 张巧 杨秀云 王维 张威风 朱俐[4] 肖超强 JING Yi-wen;ZHANG Qiao;YANG Xiu-yun;WANG Wei;ZHANG Wei-feng;ZHU Li;XIAO Chao-qiang(Henan Vocational University of Science and Technology,Zhoukou 466000,China;Prenatal Diagnosis Center,Beijing Haidian Maternal and Child Health Hospital,Beijing 100089,China;Shandong Dyne Marine Organism Pharmaceutical Co.,Ltd.,Weihai 264300,China;National Institutes for Food and Drug Control,Beijing 102629,China)

机构地区：[1]河南科技职业大学,周口466000 [2]北京市海淀区妇幼保健院,北京100089 [3]山东达因海洋生物制药股份有限公司,威海264300 [4]中国食品药品检定研究院,北京102629

出　　处：《药物分析杂志》2023年第7期1229-1237,共9页Chinese Journal of Pharmaceutical Analysis

基　　金：山东省自然科学基金青年基金(ZR2021QH358)。

摘　　要：目的:探索复杂基质样品电感耦合等离子体质谱(ICP-MS)分析方法的专属性考察方式,建立定量测定柠檬酸苹果酸钙中25种潜在元素杂质镉、铅、砷、汞、钴、钒、镍、铊、金、钯、铱、锇、铑、钌、硒、银、铂、锑、锂、钡、钼、铜、锡、铬和铝的ICP-MS方法。方法:取样品25 mg,置25 mL量瓶(PP)中,加硝酸1 mL和盐酸溶液0.25 mL,轻微摇晃使溶解后,用超纯水稀释。Agilent 7900 ICP-MS配合自动进样器进行样品测定,以He模式进样检测,采用同心雾化器,雾化气流速1.05 L·min^(-1),雾化室温度2℃,样品提升速度0.1 r·s^(-1),射频功率为1 550 W,采样深度10 mm,氦气流速5 mL·min^(-1),能量歧视5.0 V,内标校正的标准曲线法对样品中的元素杂质进行定量分析。以各元素杂质的同位素比值进行专属性考察,选择各元素的特征同位素(质量数),并参考USP 41<233>完成方法验证。结果:25种元素杂质的检测限为0.002~6.97μg·L^(-1),定量限为0.01~3.25μg·L^(-1),加样回收率均在70%~150%,重复性RSD不大于20%,精密度良好。依据ICH Q3D方法1通用允许浓度限度法进行评估,多批次原料和制剂样品中24种元素杂质均符合限度要求,但存在个别元素超出控制阈值(30%PDE)的情况,样品中铝风险较低。考虑原料来源的不确定性,从保证产品安全的角度,应建立方法对本品原料和制剂进行质控。结论:同位素比法是ICP-MS方法专属性研究的有效手段,所建立方法专属性强,准确度高,简便可行,可以为柠檬酸苹果酸钙及其他复杂基质中的元素杂质方法验证提供参考。本研究所建立的方法能够满足柠檬酸苹果酸钙的质控。Objective:To establish an inductively coupled plasma mass spectrometry(ICP-MS)method for the determination of 25 types of element impurities with potential risks in calcium citrate malate,include Cd,Pb,As,Hg,Co,V,Ni,Tl,Au,Pd,Ir,Os,Rh,Ru,Se,Ag,Pt,Sb,Li,Ba,Mo,Cu,Sn,Cr and Al.Methods:About 25 mg of sample was taken and placed in a 25 mL bottle(PP),and 1 mL nitric acid and 0.25 mL hydrochloric acid solution were added.The solutions were shake slightly to dissolve,and diluted with ultra-pure water.Agilent 7900 ICP-MS combined with automatic sampler was used for sample determination in He mode.Concentric atomizer was used,atomizing gas flow rate was 1.05 L·min^(-1),atomizing chamber temperature was 2℃,sample lifting speed was 0.1 r·s^(-1),RF power was 1550 W,sampling depth was 10 mm,and sample flow rate was 1.05 L·min^(-1).The helium flow rate was 5 mL·min^(-1),the energy discrimination was 5.0 V,and the elemental impurities in the samples were quantitatively analyzed by standard curve method with internal standard correction.The characteristic isotope(mass number)of each element was selected based on the isotope ratio of each element impurity,and the method was verified by reference to USP 41<233>.Results:The lower detection limits of the 25 impurity elements were 0.002-6.97μg·L^(-1),the spiked recoveries were between 70%-150%,and the repeatabilities were no more than 20%,with good precision.According to ICH Q3D method 1 General allowable concentration limit method,24 elemental impurities in multiple batches of raw materials and preparation samples all met the limit requirements,while some elements exceeded the control threshold(30%PDE),and the risk of aluminum in the samples was low.Considering the uncertainty of the source of raw materials,from the perspective of ensuring product safety,methods should be established to control the quality of raw materials and preparations.Conclusion:Isotope ratio method is an effective method to study the specificity of ICP-MS method.The established method has strong specifi

关 键 词：柠檬酸苹果酸钙 钙营养强化剂 元素杂质 风险评估 电感耦合等离子体质谱 专属性 基质效应 同位素比 

分 类 号：R917[医药卫生—药物分析学]