An update on the current status and prospects of nitrosation pathways and possible root causes of nitrosamine formation in various pharmaceuticals

Wichitnithad, Wisut; Nantaphol, Siriwan; Noppakhunsomboon, Kachathong; Rojsitthisak, Pornchai

doi:10.1016/j.jsps.2022.12.010

Cited by 23 publications

(7 citation statements)

References 65 publications

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“…2) for the following reasons: 1) Although the formation of N-nitrosamines in pharmaceuticals is generally known to occur through the reac- tion of secondary amines with nitroso sources, such as nitrous acid, the formation of N-nitrosamine through the oxidation of hydrazine is less known. [18][19][20] 2) Inherent impurities of these pharmaceuticals are well defined, and thus N-nitrosamine formation can be assessed through the degradation reactions of these pharmaceuticals and analogues. Additionally, we predicted the degradation product formation pathways using ranitidine, a pharmaceutical known to produce NDMA.…”

Section: Resultsmentioning

confidence: 99%

In Silico Prediction of N-Nitrosamine Formation Pathways of Pharmaceutical Products

Tsuji,

Kurohara,

Shoda

et al. 2024

CHEMICAL & PHARMACEUTICAL BULLETIN

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The recent discovery of N-nitrosodimethylamine (NDMA), a mutagenic N-nitrosamine, in pharmaceuticals has adversely impacted the global supply of relevant pharmaceutical products. Contamination by N-nitrosamines diverts resources and time from research and development or pharmaceutical production, representing a bottleneck in drug development. Therefore, predicting the risk of N-nitrosamine contamination is an important step in preventing pharmaceutical contamination by DNA-reactive impurities for the production of high-quality pharmaceuticals. In this study, we first predicted the degradation pathways and impurities of model pharmaceuticals, namely gliclazide and indapamide, in silico using an expert-knowledge software. Second, we verified the prediction results with a demonstration test, which confirmed that Nnitrosamines formed from the degradation of gliclazide and indapamide in the presence of hydrogen peroxide, especially under alkaline conditions. Furthermore, the pathways by which degradation products formed were determined using ranitidine, a compound previously demonstrated to generate NDMA. The prediction indicated that a ranitidine-related compound served as a potential source of nitroso groups for NDMA formation. In silico software is expected to be useful for developing methods to assess the risk of N-nitrosamine formation from pharmaceuticals.

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Section: Resultsmentioning

confidence: 99%

In Silico Prediction of N-Nitrosamine Formation Pathways of Pharmaceutical Products

Tsuji,

Kurohara,

Shoda

et al. 2024

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Metformin hydrochloride is prepared from DMA hydrochloride and 2-cyanoguanidine in suppliers A and B (Figure ). Metformin is relatively stable and it is believed that metformin API is not the primary source of NDMA, and DMA as an impurity is the source of NDMA formation . Thus, if the finished API contains a small amount of DMA in the form of hydrochloride, it may react with a nitrosating agent under the appropriate conditions to form NDMA.…”

Section: Resultsmentioning

confidence: 99%

N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO₂

Fukuda,

Kondo,

Fukumoto

et al. 2023

Org. Process Res. Dev.

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In 2019, N-nitrosodimethylamine (NDMA) exceeding the maximum allowable intake (96 ng/day) was detected in metformin drug products in Singapore, and since then, many of the drug products have been voluntarily recalled globally for the same reason. In our company, the analysis of the metformin drug products showed that small batches (1.9%) of products contained the excessive level of NDMA, so we investigated the root cause of NDMA formation. As a result, we found that dimethylamine (DMA) in the active pharmaceutical ingredient (API) used in the manufacturing process and nitrogen dioxide (NO 2 ) in the atmosphere had considerable influence on the formation of NDMA in metformin drug products. The results of a model experiment simulating a fluidized bed granulator also supported the hypothesis that atmospheric NO 2 introduced into the granulator Nnitrosated DMA in the API to form NDMA.

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“…Environmental Contamination: External environmental factors such as air pollution or cross-contamination in the manufacturing facility can lead to the introduction of nitrosamine impurities into final product. [18] Reactions during Storage: Some drug products, particularly those containing certain drug classes e.g. angiotensin receptor blockers -ARBs, have been found to form nitrosamines during long-term storage under specific conditions, such as exposure to light, heat or humidity.…”

Section: Sources Of Nitrosamine Impuritiesmentioning

confidence: 99%

Nitrosamine impurities in pharmaceutical dosage forms: Current challenges and mitigation strategies

Monali Rushi Dakhole,

Krishna Radheshyam Gupta,

Milind Janrao Umekar

2023

Int. J. Front. Chem. Pharm. Res.

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Nitrosamine impurities have been detected in various pharmaceutical products in nowadays. These impurities are classified as probable human carcinogens and can be found in a wide range of products including pharmaceuticals, industrial chemicals and food. This review paper provides a comprehensive analysis of nitrosamine impurities in Pharmaceutical dosage forms. It covers the formation and sources of nitrosamine impurities, allowable daily intake impurities limit (ng/day), the analytical methods employed for their detection. Various methods including LC-MS, GC-MS and HPLC for nitrosamine impurities, regulatory guidelines, notable incidents, case studies and the impact of nitrosamine impurities contamination on the pharmaceutical landscape and additionally, case studies of previous incidents involving nitrosamine-contaminated pharmaceutical products. Furthermore, this overall review provides outlines the current mitigation strategies, risk assessment, future directions and challenges adopted by pharmaceutical companies to ensure Drug safety and regulatory compliance in worldwide also provides a comprehensive examination of the current state of knowledge regarding nitrosamine impurities in pharmaceutical dosage forms.

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An update on the current status and prospects of nitrosation pathways and possible root causes of nitrosamine formation in various pharmaceuticals

Cited by 23 publications

References 65 publications

<i>In Silico</i> Prediction of <i>N</i>-Nitrosamine Formation Pathways of Pharmaceutical Products

<i>In Silico</i> Prediction of <i>N</i>-Nitrosamine Formation Pathways of Pharmaceutical Products

N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO₂

Nitrosamine impurities in pharmaceutical dosage forms: Current challenges and mitigation strategies

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An update on the current status and prospects of nitrosation pathways and possible root causes of nitrosamine formation in various pharmaceuticals

Cited by 23 publications

References 65 publications

<i>In Silico</i> Prediction of <i>N</i>-Nitrosamine Formation Pathways of Pharmaceutical Products

<i>In Silico</i> Prediction of <i>N</i>-Nitrosamine Formation Pathways of Pharmaceutical Products

N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO2

Nitrosamine impurities in pharmaceutical dosage forms: Current challenges and mitigation strategies

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Product

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N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO₂