N-Nitrosamines andN-nitrosoimines

Challis, Brian C.; Challis, J. A.

doi:10.1002/9780470771679.ch11

Cited by 28 publications

(30 citation statements)

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“…The reactions of nitrous acid and species derived from it with amines have been extensively studied, and the observed kinetics has been shown to vary with the acidity of the reaction solution and the concentration of nitrous acid. A thorough rationalization of these observations was provided by Ridd, and wide-ranging reviews of the field of nitrosation have been compiled by Turney and Wright and Challis and Challis . More recently, monographs by Williams , have provided significant coverage of the kinetics and mechanism of nitrosation.…”

Section: Nitrosation Of Amines In Watermentioning

confidence: 99%

“…A more focused overview of the formation of N -nitroso compounds with relevance to their potential formation in vivo was provided by Mirvish . Additionally, their formation and presence in foods, the environment, , and their formation in cosmetics and skincare products have been reviewed. , Nitrosation of amines may also occur in organic solvents with organic soluble nitrosating agents such as dinitrogen trioxide, dinitrogen tetroxide, nitrosyl chloride, and alkyl nitrites being effective reagents . Nitrosation in organic solvents has been excluded from the scope of this review.…”

Section: Nitrosation Of Amines In Watermentioning

confidence: 99%

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Potential for the Formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water

Ashworth

Dirat

Teasdale

et al. 2020

Org. Process Res. Dev.

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Regulatory requests that marketing authorization holders for chemically synthesized active substances risk assess their medicines for the potential presence of N-nitrosamines have led to a renewed interest in amine nitrosation. We have used published mechanistic and kinetic studies of amine nitrosation to assess the risk that traces of nitrite in the water used during active pharmaceutical ingredient (API) manufacturing could give rise to significant levels of N-nitrosamines. We conclude that the levels of nitrite typically found in water used for API manufacture are very low (<0.01 mg/L) and will not give rise to significant levels of N-nitrosamines through reaction with basic secondary amines (pK a > 9.5) in the majority of cases. The use of less basic amines, elevated processing temperatures, or low pH conditions in combination with elevated levels of nitrite have the potential to generate levels of N-nitrosamines that could lead to significant quantities being present in the isolated API if the downstream processing does not provide an adequate purge. The kinetic models described may be used to risk assess specific situations or processes. For example, the addition of traces of dimethylamine to a nitrosation reaction is predicted to lead to the rapid, quantitative formation of N-nitroso dimethylamine. Simple tertiary alkylamines can nitrosate via a dealkylative process, which is significantly slower than secondary amine nitrosation. Therefore, they do not represent a risk of N-nitrosamine formation under conditions where there is no significant risk of secondary amine nitrosation.

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Section: Nitrosation Of Amines In Watermentioning

confidence: 99%

Section: Nitrosation Of Amines In Watermentioning

confidence: 99%

Potential for the Formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water

Ashworth

Dirat

Teasdale

et al. 2020

Org. Process Res. Dev.

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“…A nitrosating agent can be regarded as a nitrosonium ion carrier ([NO + ]), of electrophilic character, which is subjected to nucleophilic attack by an amino compound (Scheme ). , …”

Section: N–n Bond Formationmentioning

confidence: 99%

Pathways for N-Nitroso Compound Formation: Secondary Amines and Beyond

López‐Rodríguez

McManus

Murphy

et al. 2020

Org. Process Res. Dev.

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Recent drug recalls (e.g., valsartan and ranitidine) linked to the discovery of nitrosamine impurities have led to increased regulatory scrutiny in the manufacturing process of marketed medicines, notably for determining any sources of risk for nitrosamine (or related N-nitroso compound) formation within the manufacturing process. This review seeks to aid the risk assessment process through identifying known conditions and reactants through which N-nitroso compounds can be formed.

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“…Concerning AMPNO, it is known from aqueous-phase chemistry that nitrosamines from primary amines are very unstable 58 and that they quickly react (acid-catalyzed) to the corresponding alcohols: (R–NHNO (aq) ⇆ R–N=NOH (aq) ; R–N=NOH (aq) + H (aq) + ⇆ R–N= N OH 2(aq) + → R (aq) + + N 2 + H 2 O → ROH (aq) + N 2 + H (aq) + ). The theoretical calculations, however, predict AMPNO to be thermally stable in the gas phase and indicate a lifetime of around 500 s in the chamber experiments, see the Supporting Information .…”

Section: Resultsmentioning

confidence: 99%

Atmospheric Chemistry of 2-Amino-2-methyl-1-propanol: A Theoretical and Experimental Study of the OH-Initiated Degradation under Simulated Atmospheric Conditions

et al. 2021

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The OH-initiated degradation of 2-amino-2-methyl-1-propanol [CH 3 C(NH 2 )(CH 3 )CH 2 OH, AMP] was investigated in a large atmospheric simulation chamber, employing time-resolved online high-resolution proton-transfer reaction-time-of-flight mass spectrometry (PTR-ToF-MS) and chemical analysis of aerosol online PTR-ToF-MS (CHARON-PTR-ToF-MS) instrumentation, and by theoretical calculations based on M06-2X/aug-cc-pVTZ quantum chemistry results and master equation modeling of the pivotal reaction steps. The quantum chemistry calculations reproduce the experimental rate coefficient of the AMP + OH reaction, aligning k ( T ) = 5.2 × 10 –12 × exp (505/ T ) cm 3 molecule –1 s –1 to the experimental value k exp,300K = 2.8 × 10 –11 cm 3 molecule –1 s –1 . The theoretical calculations predict that the AMP + OH reaction proceeds via hydrogen abstraction from the −CH 3 groups (5–10%), −CH 2 – group, (>70%) and −NH 2 group (5–20%), whereas hydrogen abstraction from the −OH group can be disregarded under atmospheric conditions. A detailed mechanism for atmospheric AMP degradation was obtained as part of the theoretical study. The photo-oxidation experiments show 2-amino-2-methylpropanal [CH 3 C(NH 2 )(CH 3 )CHO] as the major gas-phase product and propan-2-imine [(CH 3 ) 2 C=NH], 2-iminopropanol [(CH 3 )(CH 2 OH)C=NH], acetamide [CH 3 C(O)NH 2 ], formaldehyde (CH 2 O), and nitramine 2-methyl-2-(nitroamino)-1-propanol [AMPNO 2 , CH 3 C(CH 3 )(NHNO 2 )CH 2 OH] as minor primary products; there is no experimental evidence of nitrosamine formation. The branching in the initial H abstraction by OH radicals was derived in analyses of the temporal gas-phase product profiles to be B CH 3 / B CH 2 / B NH 2 = 6:70:24. Secondary photo-oxidation products and products resulting from particle and surface processing of the primary gas-phase products were also observed and quantified. All the photo-oxidation experiments were accompanied by extensive particle formation that was initiated by the reaction of AMP with nitric acid and that mainly consisted of this salt. Minor amounts of the gas-phase photo-...

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N-Nitrosamines andN-nitrosoimines

Cited by 28 publications

References 0 publications

Potential for the Formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water

Potential for the Formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water

Pathways for N-Nitroso Compound Formation: Secondary Amines and Beyond

Atmospheric Chemistry of 2-Amino-2-methyl-1-propanol: A Theoretical and Experimental Study of the OH-Initiated Degradation under Simulated Atmospheric Conditions

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