I would like to share a question with you and hear your opinion regarding the potential nitrosation of bilastine API, more specifically at the piperidine ring.
Do you believe that the nitrosamine known as 1-(2-ethoxyethyl)-2-(1-nitrosopiperidin-4-yl)-1H-benzo[d]imidazole could be formed through the direct nitrosation of the API itself, or do you think its formation would be more likely associated with process-related impurities/intermediates from the synthesis?
In addition, do you think that other nitrosamines derived from the API could potentially be formed? For example, could nitrosation followed by ring opening lead to a nitrosamine in which the nitroso group and an aldehyde group are present in the same final molecule?
I have been looking for papers and other relevant information on this topic, but I have not yet been able to reach a clear conclusion. I would really appreciate hearing your thoughts and any references you may have.
The manufacturing process should be available from the supplier, at least in a schematic form in the DMF. The impurities of each synthesis steps are normally listed and for a nitrosamine risk assessment their fate is followed in the subsequent steps. If you don’t have access to enough details of the manufacturing process you may want to check the patent literature. If there is a non substituted piperidine intermediate, it is likely to be present as an impurity in the API, at a significant level from nitrosamine risk perspective, even if it is not included as a controlled impurity in the specification.
On the other hand, nitrosation and degradation followed by nitrosation of the tertiary amine may also occur. Regarding its relative importance vs the nitrosation of the hypothetical piperidine impurity, there are publications on the comparative kinetics on the reactivity of secondary and tertiary amine, e.g., N-Nitrosamine Formation in Pharmaceutical Solid Drug Products: Experimental Observations, Moser; Ashworth, Scrivens et al., J. Pharm. Sci., 2023, showing that the tertiary amine to be significantly less reactive with nitrite.
Nitrosation of the N-substituted piperidine with ring opening generating a nitrosamine compound including an aldehyde group, while theoretically would be possible, it was not reported, as far as I know, therefore this is even less probable.