氨甲苯酸注射液中20种元素杂质的含量测定及相容性考察

Content Determination of 20 Element Impurities in Aminomethylbenzoic Acid Injections and Its Compatibility Investigation

目的:建立测定氨甲苯酸注射液中20种元素杂质含量的方法,并考察该注射液在低硼硅玻璃安瓿中的相容性。方法:样品以5%硝酸溶液稀释后,分别以钪、铟、铋为内标,采用电感耦合等离子体质谱法测定各元素杂质。载气(氩气)流量为0.92 L/min,碰撞气(氦气)流量为4.5 L/min,射频功率为1 895 W,等离子气流量为18 L/min,泵速为40 r/min,进样延迟时间为65 s;测量模式为碰撞模式,数据采样模式为跳峰模式,重复次数为3次。样品于70℃条件放置1、3个月后进行加速试验,通过比较元素杂质含量的变化趋势进行相容性考察。结果:钒、钴、铬、砷、镉、锑、汞、铊、铅检测质量浓度的线性范围均为0.01~20μg/L,镁、铝、铁、镍、铜、锌、钡检测质量浓度的线性范围均为0.1~200μg/L,硼、硅、钾、钙检测质量浓度的线性范围均为1~2 000μg/L(r≥0.9998);精密度、中间精密度、稳定性(8 h)、重复性试验的RSD均小于6%;定量限为0.000 7~2.986 3μg/L,检测限为0.000 2~0.8959μg/L;平均加样回收率为88.50%~111.00%(RSD为0.52%~2.33%,n=9)。8家企业的氨甲苯酸注射液中20种元素杂质的含量最低值均小于检测限,最大值分别为3 835.9μg/L(0个月)、10 448.4μg/L(1个月)、17 261.2μg/L(3个月)。20种元素杂质中,除硼、铝、镁、硅、钙、钾未有限度规定外,其余元素杂质含量均小于分析评价阈值。相容性考察结果显示,硼、铝、硅、钾、锌、砷、钡等7种元素杂质含量有增大趋势,1个月和3个月加速样品中硅浓度、硅/铝及硅/硼浓度比值较0个月样品均有较大变化。结论:所建方法灵敏度高、重复性和准确度均较好,可用于氨甲苯酸注射液中20种元素杂质的含量测定;低硼硅安瓿与氨甲苯酸注射液相互作用较为明显。

OBJECTIVE:To establish a method to determine the contents of 20 elements impurities in Aminomethylbenzoic acid injection,and to investigate its compatibility in low-borosilicate glass ampoules.METHODS:The sample was diluted with5%nitric acid solution,and then determined by ICP-MS using scandium,indium and bismuth as internal standards.The nebulizer flow(argon)was 0.92 L/min,collision gas flow(helium)was 4.5 L/min,RF power was 1895 W,plasma flow was 18 L/min,pump speed was 40 r/min,injection delay time was 65s.The collision mode was used as measurement mode,the data sampling adopted peak skipping mode,and repeated for 3 times.The accelerated test was carried out after sample was stored at 70℃for 1 and 3 months,and the compatibility was investigated by comparing the change trend of element impurity content.RESULTS:The linear range of vanadium,cobalt,chromium,arsenic,cadmium,antimony,mercury,thallium and lead were 0.01-20μg/L;those of magnesium,aluminium,ferrum,nickel,copper,zinc,barium were 0.1-200μg/L;those of boron,silicon,potassium and calcium were 1-2000μg/L(r≥0.9998).RSDs of precision,intermediate precision,stability(8 h)and repeatability test were all lower than 6%.The limits of quantitation were 0.0007-2.9863μg/L;the limits of detection were 0.0002-0.8959μg/L.The average recoveries were 88.50%-111.00%(RSDs were 0.52%-2.33%,n=9).The minimum content of 20 element impurities was less than detection limits,the maximum contents were 3835.9μg/L(0 month),10448.4μg/L(1 month),17261.2μg/L(3 month)in Aminomethylbenzoic acid injection from 8 manufacturers.Among the 20 elements impurities,except that boron,aluminum,magnesium,silicon,calcium and potassium were not specified,the contents of other elements were less than the threshold.The research of compatibility showed that the impurity contents of seven elements such as boron,aluminum,silicon,potassium,zinc,arsenic and barium showed an increasing trend.The silicon concentration,silicon/aluminum concentration ratio and silicon/boron concentration ratio in the accelerated samples after stored for one and three months were significantly different from those stored for 0 month.CONCLUSIONS:The established method is sensitive,reproducible and accurate,and can be used for the content determination of 20 element impurities in Aminomethylbenzoic acid injection.The interaction between low-borosilicate ampoule and Aminomethylbenzoic acid injection is obvious.