Chemistry of N-Nitroso Ivacaftor

1500 ng/day AI for N-Nitroso Ivacaftor is listed in the list provided by USFDA. Structure of Ivacaftor has a disubstituted phenol, which may lead to formation of Aromatic nitro product instead of Nitrosamine. Also, the-NH group is in present in a conjugated system which makes it difficult to form Nitrosamine.
Requesting Insights from the group.

Thank You.

I agree with your assessment. I don’t think it is straightforward to obtain the N-nitroso derivative - not by direct nitrosation. May it form during the manufacturing process?
In a few circumstances, we ordered the material listed by the nitrosamine standard supplier and ended up by getting a written declaration that it cannot be obtained.
It may be also tested by using recommended standardized nitrosation procedures and assess if N-nitrosamine is obtained.
Inclusion in the FDA list may be just theoretical (kind of - not a real assessment) as specified by themselves “inclusion of an API on the list is not confirmation that an NDSRI is present in a drug product containing that drug substance”.

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Ivacaftor is containing secondary amine functional group and lone-pair of electron on secondary amine undergo delocalization of electron density from nitrogen to the oxygen atom of the ring due to keto-enol tautomerism and do not undergo nitrosation. Therefore, there is no risk of forming N-Nitroso Ivacaftor.

I agree with you and it is been observed for many similar molecules