Insight into the formation of N-nitrosodimethylamine in metformin products

Jireš, Jakub; Kalášek, Stanislav; Gibala, Petr; Rudovský, Jakub; Douša, Michal; Kubelka, Tomáš; Hrubý, Ján; Řezanka, Pavel

doi:10.1016/j.jpba.2020.113877

Cited by 23 publications

(6 citation statements)

References 12 publications

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“…Additionally, the use of recycled and/or contaminated raw and starting materials, carryover or cross‐contamination of NA intermediates, degradation processes generating, for example, nitrosyl or oxime functionalities, and the use of certain packaging materials (e.g., nitrocellulose lidding foil) or any other nitrosating agents in the presence of secondary or tertiary amines were discussed as a source of NAs. [ 12–15 ]…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, the use of recycled and/or contaminated raw and starting materials, carryover or cross-contamination of NA intermediates, degradation processes generating, for example, nitrosyl or oxime functionalities, and the use of certain packaging materials (e.g., nitrocellulose lidding foil) or any other nitrosating agents in the presence of secondary or tertiary amines were discussed as a source of NAs. [12][13][14][15] Recently, mainly organic solvents and short-chain aliphatic amines (e.g., dimethylamine, diethylamine, or N-methyl-2-pyrrolidone) have been considered to be the precursors of nitrosamines, but as the varenicline case shows, nitrosation should also be considered for APIs.…”

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confidence: 99%

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Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development

Schmidtsdorff

Neumann

Schmidt³

et al. 2022

Archiv der Pharmazie

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Since June 2018, thousands of drug products from around the world had to be recalled due to the unexpected presence of nitrosamines (NAs). Starting with the pharmaceutical group of sartans, antidiabetic drugs, antihistamines, and antibiotics also became the subject of investigation. The occurrence of NAs has shown that pharmaceutical companies and regulatory agencies did not focus on these substances in the past during drug development. In this study, we incorporated a nitrosation assay procedure into highresolution supercritical fluid chromatography (SFC)-mass spectrometry screening to test the potential of direct nitrosation of active pharmaceutical ingredients (APIs). The forced degradation study was performed with a four-fold molar excess of sodium nitrite, relative to the drug substance, at pH 3-4 for 4 h at 37°C. Chromatographic separation was performed on a porous graphitic carbon column by SFC. The mass analysis then focused on direct N-nitrosation or N-nitroso compounds (NOCs) formed after dealkylation. Substances (n = 67) from various pharmaceutical classes were evaluated and 49.3% of them formed NOCs, of which 21.2% have not yet been reported in the literature. In addition, for two APIs, which are known to form an unidentified NOC, the structure could be identified. A few substances also showed multiple NOCs and even N,N'-dinitroso-species.As NAs are carcinogens, they have to be eliminated or at least limited to prevent cancer in patients, who rely on these drugs. This study contributes a procedure that can be implemented in preapproval drug development and postapproval risk assessment to prevent unexpected findings in the future.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development

Schmidtsdorff

Neumann

Schmidt³

et al. 2022

Archiv der Pharmazie

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“…Contamination of these pharmaceuticals by NDMA is attributed to three main factors: (1) manufacturing process of the pharmaceutical (e.g., sartan), 1) (2) degradation of the pharmaceutical (e.g., ranitidine), 6) and (3) chemical reactions between the pharmaceutical or its degradation products and ingredients in the container or packaging (e.g., metformin). 7,8) In the case of sartans, NDMA is believed to form through the reaction between nitrite and dimethylamine (DMA), which is generated during the decomposition of dimethylformamide (DMF), a solvent used in the manufacturing process. 9) Although the source of ranitidine contamination has not been completely elucidated, NDMA can form even from ranitidine alone, leading to the hypothesis that NDMA arises from the dimethyl and nitro groups in the ranitidine molecule.…”

Section: Introductionmentioning

confidence: 99%

<i>In Silico</i> Prediction of <i>N</i>-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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“…The nitrosamine impurity production is mainly determined by the kind of reagent, structure, and concentration of the nitrosating agent. (Jireš, 2021) Empagliflozin is a selective inhibitor of sodium-glucose cotransporter two approved for type 2 diabetes (NCBI, Pubchem, 2021) Fig. 1.…”

Section: Introductionmentioning

confidence: 99%

validated LC-MS method for the estimation of genotoxic nitroso amines impurities in empagliflozin

Mohammed¹,

Gandhimathi²

2022

ijhs

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Background: Nitrosamine impurities are known to be mutagenic and carcinogenic, and even minor exposure to these impurities can result in genotoxicity. Objective: The objective of this study was to develop and validate simple, robust and accurate Liquid Chromatography coupled with Mass spectroscopy (LC-MS) method for estimation of nitroso amine impurities [N-nitroso dimethyl amine (NDMA), N-nitroso diethylamine (NDEA), N-nitroso ethyl isopropylamine (NEIA), N- Nitroso diisopropylamine (NDIPA)] in empagliflozin. Method & Results: Aqueous ammonia buffer (0.10%) in a mixture of methanol (5:95 v/v), flow rate, and injection volume were 0.4mL/min, 20µL, respectively. Linearity was observed in the concentration range of 0.05-0.5 ppm (r2 =1). The retention time of NDMA, NDEA, NEIA and NDIPA were 6.412, 7.172, 7.486 and 7.719, respectively. The method was validated according to ICH guidelines with good reproducibility, and the limits of detection were 0.03 ppm for NDMA, NEIA and NDIPA and 0.02 ppm for NDEA, respectively. The limit of quantitation for NDMA, NEIA and NDIPA was 0.09 ppm and 0.06 ppm for NDEA, respectively. Conclusion: The proposed method is helpful for the best analysis of nitrosamine impurities in dosage forms of empagliflozin within a shorter duration of time.

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Insight into the formation of N-nitrosodimethylamine in metformin products

Cited by 23 publications

References 12 publications

Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development

Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development

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

validated LC-MS method for the estimation of genotoxic nitroso amines impurities in empagliflozin

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