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
The one possible reason, I can think of, why N-Nitroso Ivacaftor is listed in FDA, EMA and Health Canada guidance document since few suppliers mentioned it as available.
https://www.simsonpharma.com/product/n-nitroso-ivacaftor
I strongly believe that aromatic nitrosation competes the N-nitrosation which pose a challenge to nitrosate Ivacaftor directly. However, it is possible to synthesis this impurity (one possible route is nitrosating the secondary amine before aromatization) and then appending the ditertiary butyl phenol motifs.
Though it is synthetically attainable target, it is impossible to form or present in a drug product. I wonder whether is it worth to test in a drug product?
Hi Krishna,
Suppliers have listed N-Nitroso Ivacaftor, but Impurity is not available with them. On Enquiry, its denied.