Is N-Nitroso abemacicib reported anywhere in Literature or is it available anywhere. We tried to synthesize by using regular process like sodium nitrite in acidic pH, also we tried Tert butyl nitrile. But, we were not able to synthesize it. Can someone please help to understand the possibility of its formation.
Thank You
Sachin
Dear Sachinb,
this impurity is in the e-list of some impurity vendors but check for its in-stock availability.
Looking at its structure, i think that its synthesis could be quite difficult-due to the resonance with the aromatic rings-but not impossible.
The nice thing with this nitrosamine (if finally you find a ref, standard) is that you could try to ask for the limit of N-nitroso diphenylamine (78000ng/day!!) which have similar structure.
best regards
Christos
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Dear Chrischar,
Thank you so much for your response. Yes this impurity is there in list of many vendors, but it is not in stock with anyone i.e never synthesized by any vendor yet.
Thank You
Sachin
Regarding nitroso-abemaciclib, which nitrogen are we referring to? One can imagine at least four potential nitrosamine structures - desethyl-nitroso-abemaciclib, two nitroso-abemaciclib structures resulting from piperazine ring opening, and what we might call the 2-aminopyrimidine nitrogen, which is unlikely to undergo nitrosation due to its low nucleophilicity.
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this would be the desethyl-
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dear Naiffer,
i think that the question of Sachinb was for the below molecule
The desethyl-abemaciclib is anticipated to be synthesized quite easily, as it is a typical piperazine-type compound.
kind regards
Christos
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Dear Chrischar,
Thank you.
Yes it is the Target nitrosamine.
Regards
Sachin
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Dear Naiffer,
This could be one of the non nitroso impurity and further a nitroso can be formed on the nitrogen of piperazine Nitrogen.
Thanks
Sachin
Hello Chrischar,
Can we extrapolate Des-ethyl Abemaciclib limit using N-nitroso-piperazine (NPZ) as surrogate with an AI 1300 ng/day mentioned in FDA website? Any views from team?
Hallo swathi,
first of all the N-nitrosopiperazine in EMA and FDA lists has an AI of 400ng/day.
It is not necessary to extrapolate anything, the CPCA rules for the N-nitroso Des-ethyl Abemaciclib resulted to a AI of 400ng/day.
hope it helps
Christos
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Hello Christos,
Thanks for the quick response. Please note that in FDA data base it is 1300 ng for N-nitrosopiperazine. as there is an option to extrapolate based on surrogate, this can be considered as surrogate. Please opine.
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ok sorry, you are right!! i was looking at the below two piperazine-type nitrosamines
well, you can try a shot but i am not sure about the possibility to be acceptable from the authorities.
I would recommend to be also prepared for the AI of 400ng/day as well.
Christos
Hello, are you ultimately studying the deethylated or non-deethylated nitrosamine impurities?
Hello dear all,
Based on the assessment performed by an API supplier, the potential nitrosamine is expected to be N-Nitroso Desethyl Abemaciclib. However, when searching for commercially available reference standards, I can find N-Nitroso Abemaciclib from several suppliers, but I have not been able to find N-Nitroso Desethyl Abemaciclib.
Does anyone have information or experience regarding which nitrosamine is actually expected to form from Abemaciclib: N-Nitroso Abemaciclib or N-Nitroso Desethyl Abemaciclib?
One of the nitrosamines expected is N-Nitroso Desetyl Abemaciclib, due to traces of piperazine in ethylpiperazine used in the synthesis or due to degradation of Abemaciclib by dealkylation or direct dealkylative nitrosation. This appears to be available at Veeprho N-Nitroso Desethyl Abemaciclib - Veeprho. Nitroso Abemacicilib is not a probable compound for reasons mentioned above by 1nsect. A comprehensive risk assessment would be required to evaluate all potential sources of nitrosamine contamination, and possibly suported by nitrosation experiments.
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