Did anyone calculate NDSRI limits for a molecule with multiple secondary amine groups within the same molecule? There is a potential for multiple NDSRIs from the same molecule based on the site of nitrosation at one site or multiple sites. Can anyone suggest a model molecule?
Hi Vinay,
If you have more than one secondary amines in the same molecules, you have to consider all possible nitrosamines forming from mono-nitrosation, calculate the corresponding CPCA limits, and perform confirmatory testing.
It could occur that reactivity is favoured on one of the amines rather than the rest.
Even if more than one nitrosamine is found, I would personally not go after di-nitrosation products since statistically speaking they are going to be irrelevant, unless a huge excess of nitrosating agent is used (normally not the case in drug products). If you have 1% of your molecules mono-nitrosated, you have a 99:1 chance of the next reaction taking place on a non-nitrosated molecule (Assuming reactivity remains the same)
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Hi Javier,
Thank you for the answer. I was also looking at NDSRI AI info listed by FDA. For the parent compound Colistin, they listed about 5 NDSRIs which are mono-nitrosated. Adding to the formation of di-or tri-nitrosated molecule, what will be the steric bulk or other factors not favoring multi-nitrosation with in the same molecule.? You have already explained about this in your reply. Thank you!