Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

STEP 1:
Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

MENDELEY PAIRING EXPIRED
Your Mendeley pairing has expired. Please reconnect
ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Figure 1Loading Img

A Consideration of the Extent That Tertiary Amines Can Form N-Nitroso Dialkylamines in Pharmaceutical Products

Cite this: Org. Process Res. Dev. 2023, 27, 10, 1714–1718
Publication Date (Web):April 19, 2023
https://doi.org/10.1021/acs.oprd.3c00073
Copyright © 2023 American Chemical Society

    Article Views

    4461

    Altmetric

    -

    Citations

    LEARN ABOUT THESE METRICS
    Other access options

    Abstract

    Abstract Image

    Most secondary amines have the potential to undergo nitrosation in the presence of nitrite under certain conditions, particularly at low pH, to generate N-nitrosamines. Tertiary amines are generally considered to be less prone to nitrosamine formation as they require an additional dealkylation step. A review of the published literature combined with recently generated experimental data from nitrosation experiments carried out on several trialkyl amines further informs on the extent that tertiary amines can form N-nitrosamines by reaction with trace levels of nitrite, which may be present during drug substance or drug product manufacture. Simple trialkylamines, amines containing no additional heteroatoms, have been demonstrated to react via a nitrosative dealkylation mechanism that slowly generates a dialkylamine, which in turn nitrosates. This sequence of reactions to generate a N-nitrosamine is approximately 1000-fold slower than the simple nitrosation of a secondary amine of comparable pKa. Therefore, the formation of N-nitrosamines from simple trialkylamines in pharmaceutical products is typically not considered to be a risk. Dialkylanilines are able to access alternative reaction mechanisms and may undergo dealkylative nitrosation with greater ease than simple trialkylamines and therefore require a more focused risk assessment. Finally, certain structurally complex tertiary amines may contain functional groups that can facilitate the formation of N-nitrosamines through resonance and/or inductive electronic effects. Therefore, structures containing highly functionalized tertiary amines require a thorough, compound-specific assessment to determine the level of risk of nitrosamine generation. Note that in situations where higher amounts of nitrosating agents are present, such as when nitrosation chemistry is used during the drug substance manufacturing process, simple trialkylamines should be considered for N-nitrosamine generation during the risk assessment.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.

    Recommended

    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Cited By

    This article is cited by 2 publications.

    1. Samir Diab, Andrew P. Dominey, Paola Ferrini, John Hayler, Stephen Hermitage, Michael W. Urquhart, Matthew P. Whiting, James Wickens. Formation of N-Nitrosamines by Reaction of Secondary Dialkylamines with Trace Levels of Nitrite in Aqueous Solution: An Automated Experimental and Kinetic Modeling Study Using Di-n-butylamine. Organic Process Research & Development 2024, 28 (1) , 293-304. https://doi.org/10.1021/acs.oprd.3c00404
    2. Raphael Nudelman, Grace Kocks, Bruno Mouton, David J. Ponting, Joerg Schlingemann, Stephanie Simon, Graham F. Smith, Andrew Teasdale, Anne-Laure Werner. The Nitrosamine “Saga”: Lessons Learned from Five Years of Scrutiny. Organic Process Research & Development 2023, 27 (10) , 1719-1735. https://doi.org/10.1021/acs.oprd.3c00100