Reading a recent post from Dr. Teasdale (@AndyTeasdale) got me thinking… Can we build together a list of impossible to synthesized nitrosamine impurities? I believe this information can be extremely useful to the entire community, especially those dealing with drug-substance-related Nitrosamines (NDSRIs). There is nothing proprietary about sharing if you were not able to produce a particular nitrosamine impurity in the lab!
The key point here and one that aligns to the EMA Q&A document is that if it is impossible to synthesize the N-Nitrosamine then it is assumed that it cannot be formed in vivo. A good example is within the Nitroso-Derivatives of Dihydropyridine Calcium Channel Blockers (CCBs) - Dr. Teasdale
We are planning as part of the OPR&D Nitrosamines special edition to address this in terms of the specific conditions to use to attempt to form a specific Nitrosamine - we can as part of this look to identify those compounds that cannot be synthesised
@AndyTeasdale I am assuming it will be by looking at the reactivity of the amine group to the nitrosation reaction, correct?
Those findings can be validated to a degree by contributions from all the community members responsible for synthesizing nitrosamines compounds for their organizations.
@trust_user_a@trust_user_b Can you share nitroso-compounds that in your experience were ‘impossible’ to synthesize? Thanks in advance…
Many of the compounds which have primary and secondary amine groups will fall in this category. Eons back, I had a really tough time trying to make a nitrosamine, where there was a beta- amino group. Had to go all around protection and deprotection and the yield was poor. But it would be good to have a list of these, as you said. Do we want to make some kind of a repository and as an when we hear that people could not make a particular nitrosamine, we could add it there.
A number of APIs have been tested for the formation of N-Nitroso compounds (NOCs), and nitrosamines were not always detected. I would mention:
Schmidtsdorff et al. (2022 - DOI: 10.1002/ardp.202100435) tested 67 compounds in a forced degradation study performed with a four‐fold molar excess of sodium nitrite, relative to the drug substance, at pH 3–4 for 4 h at 37°C
Brambilla et al. (2007 - DOI: 10.1016/j.mrrev.2006.09.003) reviewed data on 182 drugs for their ability to react with nitrite in various experimental conditions
Gillat et al. (1984 - DOI: 10.1016/0278-6915(84)90005-x)