Hai Expert Team
I have a question on assessment of NDSRI for the product with multi-amine groups. In the case of Pyrathiazine theocolate, there are six tert-amine functions. How to address NDSRI in this case, please advise?
Do you mean the combination of 8-chlorotheophylline and pyrathiazine?
Then there are four tertiary amines, one imidazole-type nitrogen, and one secondary amine. In theory, the secondary amine should be the most vulnerable per se, so that would be the first one to check.
It’s worthwhile to check whether any significant amount of impurities are detected during stability testing that indicate a desalkylation reaction has occurred. Some of the tertiary amines are likely quite stable, as they are part of the aromatic system.
As a quick measure, you could also check if any reference standards for potential nitrosoamines are available.
Regards,
Philipp
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In addition to what Phil already shared, you can easily assess Nitrosamine formation for this compound with in silico degradation tools like Zeneth. But in general, tertiary amines will be less likely to form nitrosamines compared to secondary, because of the need to dealkylate it first. Still highly likely though.
You also need to understand your product and manufacturing process properties, to assess the risk specific to your case.
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Based on the structure of pyrathiazine theocolate, possible nitrosamines are N-Nitroso phenothaizine, N-Nitroso pyrrolidine and any possible secondary amine intermediate in API route of synthesis. I am least bothered about imidazole since aromatic nitrosamines do not have sufficient carcinogenicity data as well as CPCA does not apply to such nitrosamine impurity.
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