Formation of Dialkyl-N-nitrosamines in Aqueous Solution: An Experimental Validation of a Conservative Predictive Model and a Comparison of the Rates of Dialkyl and Trialkylamine Nitrosation

Ashworth et all (AstraZeneca) posted a paper related to the kinetic modeling of dialkylamine nitrosation and a comparison of the rates of dialkyl and trialkylamine nitrosation.


It is an outstanding paper. But the dilemma is that while tertiary amine nitrosation is slower in aqueous phase, it seems to be quite facile in the solid state as we are seening copious amounts of desalkylnitrosamines for drugs that are tertiary amines. There is possibly a different mechanism working here. I feel that in solid phase, we should not rule out free radical reactions which may be causing these nitrosatives delakylation.

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Thank you for sharing your thoughts, @ASrinivasan. The paper which Moser et. al wrote demonstrated that tertiary amines are less reactive with nitrite in the solid state.

I think the simple tertiary amines react with nitrite in the same manner as in the aqueous phase, even in the solid state. On the other hand, for complex tertiary amines, we should consider the reaction on a case-by-case basis.

We should not ignore the risk of nitrosamine formation of tertiary amines without consideration.
I heard NOx gas in the air caused nitrosamine formation during the jet milling of secondary amine API salt. The vulnerable amines are literally “vulnerable” in some cases.

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Tertiary amines being less reactive than secondary amines, is justified very well when it comes to nitrosamines. My PhD advisor, Richard Loeppky did his PhD thesis on tertiary amine nitrosation in the 1960s. So, the concept is not new. What I was stating that the fact that we see them at the extent that we see them in solid products is still surprising. I am a proponent of looking at NOx. I worked in Larry Keefer’s lab, where we made the nitric oxide donors (NO was the superstar of chemistry then) and found nitrosamines being formed anytime the process was exposed to oxygen. I guess we will all have to reinvent the wheel now :slight_smile: Lets just hope that it is not a square wheel.

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But are we sure that in this case the formation of the nitrosamine is starting at the tertiary amine, or is there an impurity of the API that is a secondary amine which is the one reacting. Bear in mind that in most APIs any impurity below 0.1% is usually not identified, and 1000 ppm of a vulnerable amine is more than enough to lead to nitrosamine content over the TTC of 18 ng/day.

I think it is wishful thinking that tertiary amines do not nitrosate when it was shown to do so in the PHD thesis of my advisor Dr. R.N. Loepply as early as in the 60s. As Dr. Loeppky used to say, somehow people have tough time taking this. Please be assured that when the drug is a tertiary amine it undergoes nitrosative dealkylation, and it is not just secondary amine impurities in a tertiary amine drug that are giving rise to this impurities. if the product is an aromatic amine, there is also a possibility of a radical cation mediated nitrosative dealkylation reaction. Tertiary amine nitrosation in many cases is much slower than secondary amine nitrosation, but who’s in a hurry here? A tablet or a capsule is a reaction vessel where reaction can run for 2 years :slight_smile: .
Giving you information of a few old publications,

Rapid nitrosamine formation from a tertiary amine: The nitrosation of 2-(N,N-Dimethylaminomethyl)pyrrole, Rapid nitrosamine formation from a tertiary amine: The nitrosation of 2-(N,N-Dimethylaminomethyl)pyrrole - ScienceDirect


Evidence for Radical Cations in Linked Mechanisms of N,N-Dialkyl Aromatic Amine Nitration and Nitrosative Dealkylation


Thank you for sharing the information. You are right. Even if tertiary amines don’t have an aromatic ring near the amine, the slow reaction rate of tertiary amines can bring the nitrosation risk during the whole shelf life. We should evaluate the contamination risk of nitrosamines on a case-by-case basis.