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”.
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
similar molecules like ?
Hi,
I think that reactivity amine group of Ivacaftor is simialr to those in dihydopyridines CCB.
Please see: https://www.efpia.eu/media/677167/position-paper-for-nitroso-dihydropyridine-ccbs-20feb2023.pdf