亚硝胺类药物相关杂质检测方法研究进展

doi:10.19803/j.1672-8629.20260288

摘要/Abstract

摘要： 目的总结近年来亚硝胺类药物相关杂质（NDSRIs）的分析检测方法,为相关药物的质量控制提供参考。方法通过梳理国内外药品监管机构推荐的检测方法以及近5 年文献报道的关于NDSRIs 的分析检测方法,归纳分析其方法来源和应用特点。结果基于NDSRIs的结构特殊性和监管机构的严格限度要求,使得当前关于NDSRIs检测方法的文献报道相对较少。现有的检测方法主要以（超）高效液相色谱-串联质谱为主,因其具有较高的灵敏度、特异性和准确度,在NDSRIs检测方面得到了广泛应用。结论部分NDSRIs的检测仍面临着诸多技术难题和挑战,亟需开发更多种类药物的NDSRIs分析检测方法。

关键词: 亚硝胺类药物相关杂质, 遗传毒性, 检测方法, 质量控制

Abstract: Objective To summarize the recent advancements in methods used to detect the nitrosamine drug substance-related impurities (NDSRIs) in order to provide a reference for quality control of drug products potentially containing NDSRIs. Methods By reviewing the recommendations issued by international drug regulatory authorities and the analytical methods for NDSRIs reported in the literature over the past five years, the related detection approaches and their applications were summarized. Results Due to the unique structure of NDSRIs and the stringent AI limit requirements set by regulatory agencies, there are relatively few literature reports on the detection methods of NDSRIs. The existing detection methods mainly rely on (U)HPLC-MS/MS, which has been widely applied in the detection of NDSRIs due to its high sensitivity, specificity and accuracy. Conclusion The detection of some NDSRIs still facing many technical challenges, more analytical methods for such impurities remains urgently developing.

Key words: Nitrosamine Drug Substance-Related Impurities (NDSRIs), Genotoxicity, Detection Methods, Quality Control

中图分类号:

靳龙龙, 文海若, 陈忠兰, 杨会英, 王青, 邵长军, 吴先富. 亚硝胺类药物相关杂质检测方法研究进展[J]. 中国药物警戒, 2026, 23(5): 506-512.

JIN Longlong, WEN Hairuo, CHEN Zhonglan, YANG Huiying, WANG Qing, SHAO Changjun, WU Xianfu. Research Progress in Detection Methods of Nitrosamine Drug Substance-Related Impurities[J]. Chinese Journal of Pharmacovigilance, 2026, 23(5): 506-512.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://zgywjj.magtechjournal.com/CN/10.19803/j.1672-8629.20260288

https://zgywjj.magtechjournal.com/CN/Y2026/V23/I5/506

参考文献

[1] HUANG P,CATALANO A.Changes in Secondary Structure of DNA of Rat Embryos Following Treatment with 1,2-Diethylhydrazine and Dimethylnitrosamine in vivo[J]. Teratog Carcinog Mutagen, 1994, 14(2):53-64.
[2] IWAKUMA T, SAKUMI K, NAKATSURU Y, et al.High Incidence of Nitrosamine-Induced Tumorigenesis in Mice Lacking DNA Repair Methyltransferase[J]. Carcinogenesis, 1997, 18(8):1631-1635.
[3] SNODIN DJ, TREJO-MARTIN A, PONTING DJ, et al.Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency[J]. Chemical Research in Toxicology, 2024, 37(2):181-198.
[4] NUDELMAN R, KOCKS G, MOUTON B, et al.The Nitrosamine “Saga”:Lessons Learned from Five Years of Scrutiny[J]. Organic Process Research & Development, 2023, 27(10):1719-1735.
[5] FDA. Recommended Analytical Testing Methods[EB/OL]. (2024-02-23)[2026-04-08]. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits#testing.
[6] Official Medicines Control Laboratories. Methods for Determination of Nitrosamine Drug Substance-Related Impurities (NDSRIs) and Intermediate-Related Contaminants[EB/OL].[2026-04-08]. https://www.edqm.eu/en/nitrosamine-testing-activities-of-the-omcl-network.
[7] Health Sciences Authority. Nitrosamine Impurities in Medicines[EB/OL]. (2022-5-20)[2026-04-08]. https://www.hsa.gov.sg/therapeutic-products/medicines-quality-and-compliance-monitoring/nitrosamine-impurities-in-medicines/test-methods.
[8] HUANG HW, YUAN S, ZHANG QS, et al.Determination of Genotoxic Impurity N-nitroso-propranolol in Propranolol Hydrochloride Sustained-Release Tablets by UHPLC-MS/MS[J]. Journal of Pharmaceutical Research(药学研究), 2023, 42(7):481-484.
[9] GUO CC, WEN SS, XU YW, et al.Determination of Trace N-nitroso-propranolol in Propranolol Hydrochloride Sustained Release Tablets by UHPLC-Q-Orbitrap HRMS[J]. Herald of Medicine(医药导报), 2025, 44(4):628-633.
[10] TWOHIG M, WAGH P, BARTLETT A.Quantitation of N-nitroso-propranolol in Drug Substance Using LC-MS/MS[G]. Abstracts of Papers, ACS Fall Meeting, 2024.
[11] FUKUDA S, NAKASE Y, IMAGAKI K, et al.Simple and Practical Method for the Quantitative High-Sensitivity Analysis of N-nitroso Duloxetine in Duloxetine Drug Products Utilizing LC-MS/MS[J]. ACS Omega, 2024, 9(11):13440-13446.
[12] BOPPANA SSSK, CHAGARLAMUDI KK, DAMARAPURAPU R, et al.High-Sensitivity LC-MS/MS Approach for Accurate Quantification of N-nitroso Duloxetine in Duloxetine Pharmaceutical Formulations[J]. Biomedical Chromatography, 2025, 39(6):e70101.
[13] GANESH P, RAJU BVN, RAO BM, et al.Characterization and Quantitation of N-nitroso Duloxetine Impurity in Duloxetine Hydrochloride Drug Substance[J]. Asian Journal of Chemistry, 2023, 35(11):2789-2796.
[14] JAYAVARAPU NC, SENGUPTA S, BAPATU HR, et al.Development and Validation of RP-HPLC Method for the Detection of N-nitroso Meglumine in Pharmaceutical Products[J]. Biomedical Chromatography, 2025, 39(6):e70064.
[15] RAGHUVARAN G, SATLA SR.A Highly Sensitive Green Analytical UHPLC-MS/MS Method for the Quantification of Trace Level of N-nitroso Meglumine Impurity in Tafamidis Meglumine Applying the Quality by Design[J]. Asian Journal of Chemistry, 2025, 37(8):1949-1958.
[16] THAKKAR K, SOLANKI R, PATEL R.Ultrasensitive Liquid Chromatography Triple Quadrupole Mass Spectrometry Detection and Quantification of N-nitroso-meglumine in Tafamidis Meglumine Capsules Using Electrospray Ionization[J]. Separation Science Plus, 2025, 8(8):e70091.
[17] WANG YX, YUAN S, CHEN H, et al.Synthesis and Detection of Potential Genotoxic Impurities in Nebivolol Hydrochloride[J]. Chinese Journal of New Drugs(中国新药杂志), 2025, 34(1):73-79.
[18] HAN JR, XU YM, HAO LJ, et al.Determination of Potential Genotoxic Impurities in Labetalol Hydrochloride by HPLC-MS/MS Method[J]. Journal of Hebei University of Science and Technology(河北科技大学学报), 2024, 45(3):277-282.
[19] WANG L, CAO L, FAN YL, et al.Determination of Nitrosamine Impurities in Bevantolol Hydrochloride by HPLC-MS/MS[J]. Tianjin Pharmacy(天津药学), 2025, 37(5):526-545.
[20] KWON S, AHN SH, CHANG YH, et al.Development and Validation of a Sensitive LC-MS/MS Method for the Determination of N-nitroso-atenolol in Atenolol-Based Pharmaceuticals[J]. Separations, 2025, 12(5):122.
[21] YUAN S, CHEN H, ZHANG QS, et al.Determination of Potential Genotoxic Impurity in Enalaoril Hydrochlorothiazide Preparation by UHPLC-MS/MS Method[J]. Journal of Pharmaceutical Research(药学研究), 2023, 42(8):579-583.
[22] YUAN S, CHEN H, ZHANG QS, et al.Determination of Potential Genotoxic Impurity N-nitrosovarenicline in Varenicline Tartrate by UPLC-MS/MS[J]. Chinese Journal of Modern Applied Pharmacy(中国现代应用药学), 2023, 40(9):1219-1223.
[23] YUAN S, LIU Y, ZHANG QS, et al.Determination of Genotoxic Impurity NTTP in Sitagliptin Phosphate by UPLC-MS/MS[J]. Journal of Pharmaceutical Research(药学研究), 2023, 42(12):1000-1004.
[24] CHAO RR, CHEN KR, HANG TJ, et al.Determination of N-nitroso-Trimetazidine as the Potential Genotoxic Impurity in Hydrochloride Trimetazidine by HPLC-MS/MS[J]. Pharmaceutical and Clinical Research(药学与临床研究), 2025, 33(3):227-230.
[25] ZENG Y, TEO J, LIM JQ, et al.Determination of N-nitroso Folic Acid in Folic Acid and Multivitamin Supplements by LC-MS/MS[J]. Food Additives & Contaminants:Part A, 2024, 41(1):1-8.
[26] MANDAPAKA MK, BODDU V.Identification and Quantification of Potential Genotoxic Impurity N-nitroso Isoproterenol in Bradycardia Drug Isoproterenol Hydrochloride by LC-MS/MS Technique[J]. Analytical Chemistry Letters, 2024, 14(6):935-950.
[27] YADAV AD, ALASPURE AC, LODHA SR, et al.Ultrasensitive LC-MS/MS Quantitation of the N-nitroso-dabigatran Etexilate Impurity in Dabigatran Etexilate Mesylate Using an Electrospray Ionization Technique[J]. Analytical Methods, 2025, 17(8):1797-1803.
[28] CHITRA P, PREMAKUMARI KB, ARUN B.An Efficient LC-MS/MS Method for Determining N-nitroso Tofacitinib Toxicity in the Tablet Form[J]. Current Analytical Chemistry, 2025, 21(5):521-534.
[29] WEI MY, HUANG B, LIU SZ, et al.Determination of N-nitrosoprimaquine Genotoxic Impurity in Primaquine Phosphate API by UPLC-MS/MS[J]. Guangdong Chemical Industry(广东化工), 2025, 52(16):117-119.
[30] GUO CC, CHENG CL, XU YW, et al.Determination of Genotoxic Impurity N-nitroso Atomoxetine in Atomoxetine Hydrochloride Capsules by Ultra High-Performance Liquid Chromatography-Q-Orbitrap High-Resolution Mass Spectrometry[J]. Chinese Journal of Pharmaceutical Analysis(药物分析杂志), 2025, 45(12):2107-2115.
[31] UPPALA R, PRABHU RC, MARUTHAPILLAI A, et al.Development of an UPLC-MS/MS Approach to Detect and Quantify N-nitroso Mirabegron in Mirabegron[J]. Rapid Communications in Mass Spectrometry, 2024, 38(22):e9911.
[32] RALLIS GN, PAPAKANAKI VN, GKATZIOU DG, et al.A Compre-hensive UPLC-MS/MS Method for the Determination of N-nitroso Metamizole EP Impurity C in Metamizole Drug Products[J]. Journal of Liquid Chromatography & Related Technologies, 2025, 48(6-10):159-167.
[33] VELE VT, MORE K, MOHAN A, et al.LC-MS/MS Method for the Determination and Quantification of a N-nitroso-dorzolamide in the Dorzolamide Hydrochloride Active Pharmaceutical Ingredient[J]. European Journal of Biomedical and Pharmaceutical Sciences, 2024, 11(3):149-154.
[34] KUMAR V, BALTHU L, PEPAKAYALA S, et al.N-nitroso-vildagliptin, a New N-nitrosamine Drug Substance Related Impurity (NDSRI) of Vildagliptin-An Antidiabetic Drug:Synthesis, Characterization and Development of Sensitive LC-MS/MS Method[J]. Chromatographia, 2025, 88(10):791-799.
[35] NAKKA S, KATARI NK, MUCHAKAYALA SK, et al.Synthesis and Trace-Level Quantification of Mutagenic and Cohort-of-Concern Ciprofloxacin Nitroso Drug Substance-Related Impurities (NDSRIs) and Other Nitroso Impurities Using UPLC-ESI-MS/MS-Method Optimization Using I-Optimal Mixture Design[J]. ACS Omega, 2024, 9(8):8773-8788.
[36] LI SH, DONG LX, LIN HQ, et al.Simultaneous and Trace Level Quantification of Two Potential Genotoxic Impurities in Valsartan Drug Substance Using UPLC-MS/MS[J]. Journal of Pharmaceutical and Biomedical Analysis, 2022, 212:114630.
[37] MANDAPAKA MK, BODDU V.A Simple and Rapid Analytical Method to Detect and Quantify the N-nitroso Desmethyl Diltiazem Impurity by Liquid Chromatography-Tandem Mass Spectrometry in Diltiazem Hydrochloride[J]. Separation Science Plus, 2025, 8:e70065.
[38] VALLAMKONDA B, YARGUNTLA SR, CHALLA RR.Development and Validation of a Highly Sensitive LC-MS/MS Method for Quantification of Mutagenic N-nitroso Desmethyl Citalopram in Drug Formulations[J]. Separation Science Plus, 2025, 8:e70011.
[39] RAJANA N, BALAJI SKK.Quantitative LC-MS/MS Method for Simultaneous Quantification of N-nitroso-Berotralstat and N-nitroso-Boc-Berotralstat in Berotralstat·HCl[J]. Separation Science Plus, 2025, 8(5):e70046.
[40] CHAGARLAMUDI K, DAMARAPURAPU R, MANGLIGE VK, et al.High-Sensitivity LC-MS/MS Method for Precise Quantification of N-nitroso Sertraline in the Antidepressant Sertraline Drug Products[J]. Separation Science Plus, 2025, 8(5):e70048.