N-Nitrosamine impurity of heterocyclic aromatic ring

[ghanshyam.joshi]

Can heterocyclic aromatic ring form N-nitrosamine impurity?

[Diego_HM]

Yes, under the right conditions it can be formed.

[Naiffer_Host]

@ghanshyam.joshi Do you have any specific example that you would like to share?

[David]

Do you mean a pyrrole-type nitrogen, c1cccn1N=O ? These can definitely nitrosate but are not expected to undergo the a-hydroxylation mechanism that leads to concern, since cleavage of the aromatic ring to form the diazonium is very unlikely.
There is an alternative mechanism of mutagenicity/carcinogenicity, reduction via nitroreductases to form the hydroxylamine and thence a nitrenium ion - and comparable adducts to aromatic amines - but I would not expect them to be CoC.

Nitrosated heteroaromatic amines, e.g. c1nccnc1N(C)N=O, are expected to behave similarly to nitrosomethylaniline, and thus need to be treated as CoC.

[paliog]

Here you can find some examples of Nitrosamine drug substance-related impurities (NDSRIs) or other impurities where the tetrazole ring contains a N-nitroso group:

Nitroso Olmesartan

N-Nitroso Olmesartan Impurity

Valsartan Tetrazole nitrosamine impurity

Also in this case, there is any alfa-hydrogen, so they are not expected to undergo the alfa-hydroxylation mechanism. However, we should consider that the tautomerism of tetrazoles may complicate the framework.

[ghanshyam.joshi]

Phenothiazine and diphenylamine

[Naiffer_Host]

Phenothiazine
SMILES: c1ccc2c(c1)Nc3ccccc3S2

Diphenylamine
SMILES: c1ccc(cc1)Nc2ccccc2

[Yosukemino]

Nitrosoirbesartan is free from nitrosation in ordinary.

Lupin Pharmaceuticals issues nationwide recall of Irbesartan Tablets

According to the recent studies, the reaction of Irbesartan with nitrous acid produces Irbesartan oxime derivatives, rather than N -Nitrosoirbesartan. Though I’m not sure the details of the recall, it’s helpful to understand nitrosamine risk assessment. [image]