Theoretical estimation of the conversion of a tertiary amine to nitrosamine

Dear all,

There are different scientific publications to theoretically estimate the conversion of a tertiary amine to nitrosamine (Ashworth et al., 2023; Moser et al., 2023). However, there is no long-term conversion data. Would anyone have experience with the actual conversion of a tertiary amine to a nitrosamine over the shelf life of the product? (the excipients would be the source of nitrites)
Thank you all for your collaboration!!
Victoria

Hi all, I would also like to highlight the topic here. Also, it is interesting to see for ex. in EMA Appendix 1 that an increasing number of demethylated nitrosamines (coming from tertiary amines) are started to be detected and falling into CPCA Category 1.

I am wondering that even if based on literature that says that the rate of formation of tertiary amines is likely 200 to 1000 times slower when you put into the equation a 18 ng/day limit, nonethelss, you will get a non-negligible amount as you are in ppb levels territory.

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Hi Diego,

A general answer is not easy, because the demethylated API may be a synthesys by-product, not only a degradation product (or it may be both).
We already know one case where the demethylated API is a specified impurity with a limit of 0.15% (i.e. 1500 ppm) and average values around 0.2% (200 ppm). In contact with nitrites, this amount may easily generate some ppm of the N-nitroso demethylated API.
Even when the demethylated API is not a specified impurity, it may be an unspecified impurity (generally below 0.10%).
Moreover, also tertiary amines with one or two ethyl groups may be easily oxidized, giving acetaldehyde and the deethylated API.
In my opinion, only a stress test on the API (better on the drug product also) focused on the research of the demethylad API could exclude its formation as degradation product. And only the knowledge of the route of synthesis could exclude the the demethylad API as synthesis by-product.

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Hai Sir,

Can we use the NAP procedure or are there any other means of doing the stress test?

very accurate and reasonable justification as usual!!

Hi,

NAP procedure and stress test of drugs are different procedures and they give different information.
A traditional stress test of drug subtances and products indicates:

  1. if your analytical method(s) is(are) enough specific to detect nearly all the degradation products
  2. the main degradation products under different degradation conditions (Thermal, hydrolytic, photodegradation, oxidants, etc)
    In this case, such stress test may indicate if the precursor (i.e. the demethylad API) may be formed in significant amount (i.e. 0.1% or more) and in which degradation process.
    There not is a standardized procedure, because any API is more or less sensitive, so the conditions shoul be adapted case by case.
    Here you can find some useful articles:

Development of forced degradation and stability indicating studies of drugs—A review

Forced degradation studies: Practical approch-overview of regulatory guidance and literature for the drug products and drug substances

Pharmaceutical Forced Degradation (Stress Testing) Endpoints: A Scientific Rationale and Industry Perspective

The NAP test is a different thing; it is a specific procedure to check if a substance may be nitrosated in presence of nitrites and favorable conditions.

In other words, the NAP test indicates in the nitroso-API (or in this cas, the N-nitroso demethylad API) may be formed or not.
A stress test on the drug product with a very sensitive method (generally HPLC-MS) focused on the research of the N-nitroso demethylad API indicates if it may be really formed in your drug product with the nitrite traces generally presents in all the excipents.

I hope I was clear in my explanation,
kind regards

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I would remark that while the discussion is on the conversion of a tertiary amine API to nitrosamine, the problem is normally approached theoretically from the perspective of the conversion of nitrite, which is the limiting reagent.

Moser’s paper cited by @victoria contains relevant data regarding nitrite conversion in case of model APIs having different structures. For 1-Me-4-PhP-4-ol (Tertiary amine) as HCl salt,
image
the maximum conversion of the nitrite was found to plateau around 0.5% at 60°C.

Simple NAP test to check potential conversion!

Thank you for the time and the explanation provided.