Continuing the discussion from Formation of Nitroso-Omeprazole:
During assessment of Omeprazole, i just found that the supplier had used Dichloromethane which’s known as a source of Nitrite and acetic acid acidic condition encouraging the nitrosation of Omeprazole .
(my reference is;
Nitrosation reactions catalyzed by nitrite in DCM
So my two questions are;
Do i request from the supplier to provide me with the proper nitrite content in DCM to be sure that its levels are below detection limits?
The limit of N-nitroso Omeprazole will be controlled according to Canadian guidance ; acc to AI 18.0 ng/day ?
It is unlikely that Omeprazole could undergo nitrosation reaction on the benzimidazole ring.
In general non-basic and basic aromatic rings are chemically not amines as the nitrogen atom is contained within the aromatic system and hence cannot form nitrosamines1. Nitrosation of basic aromatic rings can only be achieved by excess of the strong nitrosating agent nitrosonium tetrafluoroborate, whereas an excess of the ring leads to its cleavage2.
Whereas nitrosation occurs of non-basic aromatic rings, such as quinolone, an N-nitro-hetero-aromatic compound is formed. Whilst these compounds may be mutagenic, the mechanism will not rely on α-hydroxylation and C-N cleavage as this would require breaking the aromaticity of the ring. The α-hydroxylation pathway requires the cleavage of the C−N bond after initial metabolic oxidation. However, subsequent C−N bond cleavage would require disruption of the aromatic system and is not reported to occur3.
The aromatic N-nitroso compounds are sensitive to TA98 and TA100 with and without S9, a strain profile that is comparable to that of the aromatic amines. This sub-class follows a different non-cohort-of-concern mechanism.
The carcinogenic potency categorization approach suggested by EMA does not apply to N-nitrosamines where the N-nitroso group is within an aromatic ring (e.g., nitrosated indole). https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-marketing-authorisation-holders/applicants-chmp-opinion-article-53-regulation-ec-no-726/2004-referral-nitrosamine-impurities-human-medicinal-products_en.pdf
1 Joerg Schlingemann, Michael J. Burn et al. The Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals, Redirecting
2 Olah GA, Olah JA, Overchuk NA. Aromatic substitution. XXIII.1 nitration and nitrosation of pyridine with nitronium and nitrosonium tetrafluoroborate. isolation of N-nitro- and N-nitrosopyridinium tetrafluoroborates. J Org Chem. 1965;30 (10):3373–3376.
3 David J Ponting, Robert S Foster, Drawing a Line: Where Might the Cohort of Concern End? https://doi.org/10.1021/acs.oprd.3c00008
I am still wondering, when they say it does not apply to nitrogens included in aromatic rings, what do they mean, are they out of the cohort of concern, or just they cannot be categorized and have to be treated as potentially of high concern and be limited to 18 ng/day?
I would say they are out of the cohort - potentially mutagenic and thus need control under M7, yes, but they definitely can’t lead to a diazonium which is the mechanism that places nitrosamines in the cohort. See my paper linked at the bottom of @Muzaffar 's excellent answer for more details.
I would be comfortable in saying your control limit should be 1500 ng/day (unless you have a negative Ames, of course…)