安全监测

UPLC-MS/MS法测定注射用头孢美唑钠中潜在亚硝胺类物质的含量*

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  • 1.南京中医药大学,南京 210023;
    2.江苏省食品药品监督检验研究院,南京 210019;
    3.国家局化学药物杂质谱研究重点实验室,南京 210019;
    4.江苏省医疗器械所,南京 210012;
    5.安捷伦科技有限公司,上海 200080;
    6.国家药典委员会,北京 100061
第一作者 宋芸峰 Tel:(010)86251141;E-mail:1421136824@qq.com
耿悦 Tel:(010)86251141;E-mail:467262949@qq.com
** 袁耀佐 Tel:(025)86251130;E-mail:yuanyaozuo@hotmail.com
裘婧 Tel:(025)69655968;E-mail:13813826429@163.com

收稿日期: 2022-01-28

  网络出版日期: 2024-06-24

基金资助

* 2021年国家药品评价性抽验资助(国药监药管[2021]1号)

Determination of potential nitrosamines in cefmetazole sodium for injection by UPLC-MS/MS*

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  • 1. Nanjing University of Traditional Chinese Medicine, Nanjing 210023, China;
    2. Jiangsu Institute of Food and Drug Administration, Nanjing 210019, China;
    3. NMPA Key Laboratory for Impurity Profile of Chemical Drugs, Nanjing 210019, China;
    4. Jiangsu Institutef of Medical Devices, Nanjing 210012, China;
    5. Agilent Technologies Inc, Shanghai 200080, China;
    6. Chinese Pharmacopoeia Commission, Beijing 100061, China

Received date: 2022-01-28

  Online published: 2024-06-24

摘要

目的:建立一种超高效液相色谱-串联质谱联用法,用于测定注射用头孢美唑钠中的13个潜在亚硝胺类基因毒性杂质的含量(NDELA、NMOR、NPYR、NMPhA、NEPhA、NDiBA、NDBzA、NDBA、NDMA、NDEA、NPIP、NDiPA和NDPA)。方法:使用ACQUITY UPLC BEH C8(100 mm×2.1 mm,1.7 μm)色谱柱和Agilent Infinity Lab Poroshell120 Bonus-RP(100 mm×3.0 mm,2.7 μm)色谱柱,流动相为0.1%甲酸(A)-甲醇(B),梯度洗脱,流速0.4 mL·min-1,采用APCI离子源,在多反应监测模式(MRM)下,对全国20个生产厂家以及国外原研厂家的样品进行分析。结果:该方法能同时测定13个亚硝胺类基因毒性杂质。其线性范围、灵敏度、精密度、回收率均满足分析要求。在21批注射用头孢美唑钠中,10批检出了NPIP,但均小于定量限。结论:注射用头孢美唑钠中存在亚硝胺类基因毒性杂质的风险可控;所建立的方法高效灵敏,性能优异,专属性强,可为以四氮唑环为结构特征的抗生素中亚硝胺类基因毒性杂质控制方法提供参考,也可用于胶塞中N-亚硝胺类基因毒性杂质迁移量的检测,为监管部门提供技术储备和数据支持。

本文引用格式

宋芸峰, 耿悦, 孙春业, 王志军, 姚卫峰, 张锦琳, 裘婧, 袁耀佐 . UPLC-MS/MS法测定注射用头孢美唑钠中潜在亚硝胺类物质的含量*[J]. 药物分析杂志, 2022 , 42(7) : 1186 -1194 . DOI: 10.16155/j.0254-1793.2022.07.11

Abstract

Objective: To establish an ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) method for the simultaneous determination of 13 potential nitrosamine genotoxic impurities (NDELA, NMOR, NPYR, NMPhA, NEPhA, NDiBA, NDBzA, NDBA, NDMA, NDEA, NPIP, NDiPA and NDPA) in cefmetazole sodium for injection. Methods: This assay was performed on chromatographic column ACQUITY UPLC BEH C8(100 mm×2.1 mm, 1.7 μm) and chromatographic column Agilent Infinity Lab Poroshell120 Bonus-RP(100 mm×3.0 mm, 2.7 μm) with mobile phase 0.1% formic acid (A)-methanol (B) by gradient elution at a flow rate of 0.4 mL·min-1. Multiple reaction monitoring (MRM) was performed on a triple quadripole mass spectrometer with an APCI source to analyze samples from 20 manufacturers in China and a foreign original manufacturer. Results: 13 kinds of nitrosamine genotoxic impurities were detected simultaneously by this method. The linear range, sensitivity, precision, and recovery of 13 compounds met the analysis requirements. Among 21 batches of cefmetazole sodium for injection, NPIP was detected in 10 batches, but all were less than the limit of quantification. Conclusion: The risk of nitrosamines genotoxic impurities in cefmetazole sodium for injection is controllable. The established method is efficient and sensitive, and has excellent performance and strong specificity. It can be used as a method for controlling nitrosamine genotoxic impurities in antibiotics with a tetrazolium ring as the structural feature. It can also be used for the detection of N-nitrosamine genotoxic impurities migration in rubber stoppers, and provide technical reserves and data support for regulatory authorities.

参考文献

[1] LIJINSKY W, REUBER MD, SAAVEDRA JE, et al. Carcinogenesis in F344 rats by N-nitrosomethyl-n-propylamine derivatives[J].J Natl Cancer Inst, 1983, 70(5):959
[2] THOMAS BJ, KOVATCH RM, LIJINSKY W. The induction of bladder tumors in F344 rats by intravesicular administration of some nitrosamines[J].Jpn J Cancer Res, 1988, 79(3):309
[3] 蔡鲁峰, 李娜, 杜莎, 等. N-亚硝基化合物的危害及其在体内外合成和抑制的研究进展[J].食品科学, 2016, 37(5): 271
CAI LF, LI N, DU S, et al. Progress in hazards, synthesis and inhibition of N-nitroso compounds in vitro and in vivo[J].Food Sci, 2016, 37(5):271
[4] SEDLO I, KOLONIC' T, TOMIC' S. Presence of nitrosamine impurities in medicinal products[J].Arh Hig Rada Toksikol, 2021, 72(1): 1
[5] ICH M7(R1) Current Step 5 Version:Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk[S].2018
[6] TUESUWAN B, VONGSUTILERS V. Nitrosamine contamination in pharmaceuticals: threat, impact, and control[J].J Pharm Sci, 2021, 110(9): 3118
[7] MILLS AL, ALEXANDER M. N-nitrosamine formation by cultures of several microorganisms[J].Appl Environ Microbiol, 1976, 31(6): 892
[8] ROUX JL, GALLARD H, CROUÉ JP, et al. NDMA formation by chloramination of ranitidine: kinetics and mechanism[J].Environ Sci Technol, 2012, 46(20): 11095
[9] ELDER DP, JOHNSON GE, SNODIN DJ. Tolerability of risk: a commentary on the nitrosamine contamination issue[J].J Pharm Sci, 2021, 110(6):2311
[10] EADS AV. Pharmacists are key in interpreting clinical implications of N-nitrosodimethylamine contamination in medications[J].J Am Pharm Assoc, 2020, 60(6):100
[11] BENIGNI R, BOSSA C. Mechanisms of chemical carcinogenicity and mutagenicity: a review with implications for predictive toxicology[J].Chem Rev, 2011, 111(4):2507
[12] 张静, 翟小语, 张贝贝, 等. 关于医药包装弹性体中亚硝胺的综述[J].中国医药工业杂志, 2021, 52(10):1313
ZHANG J, ZHAI XY, ZHANG BB, et al. A review on nitrosamines in medical packaging elastomers[J].Chin J Pharm, 2021, 52(10):1313
[13] 吴兆伟, 杜凯, 王琳, 等. GC-MS法测定缬沙坦中的N-亚硝基二甲胺[J].中国新药杂志, 2019, 28(20):2478
WU ZW, DU K, WANG L, et al. Determination of the contents of N-nitrosodimethylamine in valsartan by GC-MS[J].Chin J New Drugs, 2019, 28(20):2478
[14] 姜俊, 邹韵, 孙丽鹏, 等. 顶空气相色谱质谱联用测定厄贝沙坦中遗传毒性杂质N-亚硝基二甲胺和N-亚硝基二乙胺[J].分析试验室, 2020, 39(2):245
JIANG J, ZOU Y, SUN LP, et al. Determination of N-nitrosodimethylamine and N-nitrosodiethylamine in irbesartan using headspace gas chromatography mass spectrometry[J].Chin J Anal Lab, 2020, 39(2): 245
[15] 侯金凤, 李珉, 寇晋萍, 等. 超高效液相色谱串联质谱法测定缬沙坦原料中4种亚硝胺类基因毒性杂质[J].中国药学杂志, 2021, 56(10):842
HOU JF, LI M, KOU JP, et al. Determination of four nitrosamine genotoxic impurities in valsartan by UPLC-MS /MS method[J].Chin Pharm J, 2021, 56(10):842
[16] 张岩琛, 王玲娜, 刘晓强. LC-MS/MS法测定厄贝沙坦中基因毒性杂质N-亚硝基二甲胺和N-亚硝基二乙胺[J].中国新药杂志, 2021, 30(6): 569
ZHANG YC, WANG LN, LIU XQ. Determination of N-nitrosodimethylamine and N-nitrosodiethylamine in irbesartan by liquid chromatography-tandem mass spectrometry[J].Chin J New Drugs, 2021, 30(6):569
[17] 徐艳梅, 韩彬, 闫凯, 等. 高效液相色谱-串联质谱法同时检测厄贝沙坦原料药及其片剂中3种N-亚硝胺类基因毒性杂质[J].药物分析杂志, 2021, 41(4): 720
XU YM, HAN B, YAN K, et al. Simultaneous detection of 3 N-nitrosamine genotoxic impurities in irbesartan[J].Chin J Pharm Anal, 2021, 41(4): 720
[18] 郭常川, 杨书娟, 刘琦, 等. 超高效液相色谱-静电场轨道阱高分辨质谱法测定法莫替丁及其制剂中的痕量N-亚硝基二甲胺[J].分析测试学报, 2020, 39(9):1079
GUO CC, YANG SJ, LIU Q, et al. Determination of trace N-nitrosodimethylamine in famotidine and its preparations by ultra-high performance liquid chromatography-orbitrap high resolution mass spectrometry[J].J Instrum Anal, 2020, 39(9):1079
[19] 张岩琛, 刘晓强, 黄海伟, 等. 采用不同方法评估二甲双胍原料药及其制剂中N-亚硝胺二甲胺含量[J].药物分析杂志, 2021, 41(6): 1036
ZHANG YC, LIU XQ, HUANG HW, et al. Different methods to evaluate the content of N-nitrosodimethylamine in metformin and its preparations[J].Chin J Pharm Anal, 2021, 41(6): 1036
[20] PARK JE, SEO JE, LEE JY, et al. Distribution of seven N-nitrosamines in food[J].Toxicol Res, 2015, 31(3):279
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