Research Progress in Nitrosamine Drug Substance-Related Impurity Synthesis

doi:10.19803/j.1672-8629.20260290

Abstract

Abstract: Objective To introduce the synthetic methods of various nitrosamine drug substance-related impurities (NDSRIs) in order to provide a reference for the preparation of their reference standards for the development of analytical methods, evaluation of genetic toxicity, and for setting better limits. Methods The synthetic methods of and research progress in NDSRIs were outlined based on related literature and synthetic experiments. Results There were relatively few literature reports on the synthetic methods of NDSRIs, and many technological difficulties and challenges persisted. In this article, direct and indirect synthetic methods as well as multiple synthetic strategies were classified and summarized while solutions to the synthesis of some of the difficult-to-synthesize NDSRIs were recommended. Conclusion The technical challenges facing the synthesis of some NDSRIs require the availability of reference standards needed for the inspection and testing of the corresponding APIs and their preparations so as to facilitate the regulation of drugs.

Key words: Nitrosamine Drug Substance-Related Impurities (NDSRIs), Genotoxicity, Synthesis, Drug Regulation, Research Progress

CLC Number:

JIN Longlong, WEN Hairuo, YANG Huiying, WANG Qing, SHAO Changjun, WU Xianfu. Research Progress in Nitrosamine Drug Substance-Related Impurity Synthesis[J]. Chinese Journal of Pharmacovigilance, 2026, 23(5): 500-505.

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References

[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] FDA. Drug Recalls[EB/OL]. (2025-08-29)[2026-04-08]. https://www.fda.gov/drugs/drug-safety-and-availability/drug-recalls.
[4] Health Canada. Nitrosamine Impurities in Medications:Recalls[EB/OL]. (2025-03-31)[2026-04-08]. https://www.canada.ca/en/health-canada/services/drugs-health-products/comp-liance-enforcement/information-health-product/drugs/nitrosamine-impurities/recalls.html.
[5] ICH. M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk[EB/OL]. (2023-07-18)[2026-04-08]. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-m7r2-guideline-assessment-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit_en.pdf.
[6] FDA. Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) Guidance for Industry[EB/OL]. (2023-08-07)[2026-04-08]. https://www.fda.gov/media/170794/download.
[7] FDA. Control of Nitrosamine Impurities in Human Drugs:Guidance for Industry[EB/OL]. (2024-09-05)[2026-04-08]. https://www.fda.gov/media/141720/download.
[8] EMA. Questions and Answers for Marketing Authorisation Holders/Applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 Referral on Nitrosamine Impurities in Human Medicinal Products[EB/OL]. (2023-10-02)[2026-04-08]. https://www.ema.europa.eu/en/documents/referral/nitrosamines-emeah-a53-1490-questions-answers-marketing-authorisationholders/applicants-chmp-opinion-article-53-regulation-ec-no-726/2004-referral-nitrosamine-impurities-human-medicinalproducts_en.pdf.
[9] Anhui Jinding Pharmaceutical Co., Ltd. Preparation of gliclazide intermediate 3-amino-3-azabicyclo[3.3.0]octane hydrochloride (一种格列齐特中间体氨基杂环盐酸盐的制备工艺及制备系统). CN116283719A[P].2023-06-23.
[10] Zakrytoe Aktsionernoe Obshchestvo Gruppa Kompanii“Epidbiomed”. Method of producing N-(2-chloroethyl)-N'-cyclohexyl-M-nitrosourea:RU2797412 C1[P].2023-06-05.
[11] GRAHEK R, DREV M, ZUPANCIC B, et al.Stability and Degradation Pathways of N-nitroso-hydrochlorothiazide and the Corresponding Aryl Diazonium Ion[J]. Organic Process Research & Development, 2023, 27(10):1792-1811.
[12] ZHANG S, POWELL ML, NELSON WL, et al.Derivatives of β-Adrenergic Antagonists. N-nitrosopropranolol and N-hydroxypropranolol and Its Aldonitrone[J]. Journal of Medicinal Chemistry, 1983, 26(3):455-458.
[13] Southern Medical University, Shenzhen University, Guangzhou Kelang Medical Technology Co., Ltd. Preparation of Aryl Chloroethyl Nitrosourea Compounds and Its Application in Anti-Tumor Agent (一种含芳基的氯乙基亚硝基脲类化合物及其制备方法和应用). CN117486761 A[P].2024-02-02.
[14] WEST SP, BISAI A, SARPONG R, et al.Total Synthesis of (+)-Lyconadin A and Related Compounds via Oxidative C-N Bond Forma-tion[J]. Journal of the American Chemical Society, 2009, 131(31):11187-11194.
[15] CORPAS J, CALDORA HP, TOMMASO EM Di, et al.A General Strategy for the Amination of Electron-Rich and Electron-Poor Heteroaromatics by Desaturative Catalysis[J]. Nature Catalysis, 2024, 7(5):593-603.
[16] BELLINGHAM RK, CAREY JS, HUSSAIN N, et al.A Practical Synthesis of a Potent δ-Opioid Antagonist:Use of a Modified Knorr Pyrrole Synthesis[J]. Organic Process Research & Development, 2004, 8(2):279-282.
[17] Rib-X Pharmaceuticals, Inc. Preparation of Macrolide Aminodeoxy Glycosides Useful as Antiinfective, Antiproliferative, Antiinflammatory,Prokinetic Agents:WO2008143729 A2[P].2008-11-27.
[18] MOHANARANGAM S, KARRA SK, PADI PR, et al.Impurity Profile Study of Venlafaxine Hydrochloride, an Antipsychotic Drug Substance[J]. Synthetic Communications, 2010, 40(13):1880-1886.
[19] MARTELLI A, ROBBIANO L, GROSSI S, et al.Formation of DNA-damaging N-nitroso Compounds from the Interaction of Calcium-channel Blockers with Nitrite[J]. Toxicology, 2007, 238(2-3):211-215.
[20] Zhuhai Rundu Pharmaceutical Co., Ltd. Preparation of Amlodipine Nitrosamine Impurity(一种氨氯地平亚硝胺类杂质的制备方法). CN118255709 A[P].2024-06-28.
[21] WU ZL, WANG B, LOU JF, et al.Study on N-nitrosamine Impurities in Dipine Drugs[J]. Chinese Journal of New Drugs(中国新药杂志), 2025, 34(5):541-552.
[22] Chongqing Shenghuaxi Pharmaceutical Co., Ltd., Chongqing Changjie Pharmaceutical Co., Ltd. Cost-Effective Preparation Method of Benidipine Nitrosamine Impurity Using Acetoacetyl Methyl Ester and 3-Aminocrotonic Acid Methyl Ester as Raw Materials(贝尼地平亚硝胺杂质的制备方法). CN118993993 A[P].2024-11-22.