AI for NDSRIs of Terbinafin hydrochloride and Impurity A

Limits of Nitrosamines
1

Hello Experts,

i am currently setting AI for the following NDSRIs by SAR to determine a limit of quantification for an analytical method:

  • N-nitroso-[(2E)-6,6-dimethylhept-2-en-4-yn-1-yl][naphthalen-1-yl)methyl]amine (NHNA)
  • N-nitroso-N-methyl-1-naphthlymethylamine (Nitrosamine of Impurity A of terbinafine hydrochloride)

image

Unfortunately, I lack expertise on which compound best compares to the above compounds in terms of structure and activity.
What do you think would be a suitable compound?

Thank you in advance,

Kevin

2

Hello Nitrosamine Community,

Here I attach Terbinafine’s structure:
image
Terbinafine
Isomeric SMILES: CC(C)(C)C#C/C=C/CN(C)CC1=CC=CC2=CC=CC=C21

What I had understand is that for tertiary amines, specific conditions were needed for nitrosative cleavage or nitrosative dealkylation, in order to be a risk for Nitrosamine Formation. What do the experts say about it?

Kind regards

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3

Hi,
As per the literature and the case studies, tertiary amines are less sensitive to nitrosamine generation as they require an additional dealkylation step. The rate of reaction with the tertiary amines is approximately 1000 times slower as compared to the secondary amines.

Please go through the recent research paper on the same point - [https://doi.org/10.1021/acs.oprd.3c00073]; A Consideration of the Extent That Tertiary Amines Can Form N‑Nitroso Dialkylamines in Pharmaceutical Products. Please ignore it if you already referred.

The above information can be used in the nitrosamine risk assessment of the drug products containing tertiary amines.

4

Regarding impurity A, it is a low molecular weight impurity and I would expect its corresponding nitrosamine to be quite potent, having a methyl group in one side next to the nitroso group and and the other side the aromatic rings. This nitrosamine precursor also has pkA around 3.2, therefore the kinetics would be quite fast.

image

The USP monograph for the tablets of the mentioned API accepts up to 0.2% of Impurity A ( N-Methyl-1-(naphthalen-1-yl) methanamine). It would be worth checking how much do we have if the impurity in release and over time, nitrosating agents presence, what kind of manuf. process is used, amonth other things.

This is just a gut feeling, but I would look first into NMPEA as a possible surrogate (N-Methyl-N-nitrosophenethylamine).

image
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5

The nitrosation is in indeed yes quite slow but for alkyl tertiary amines. The mentioned paper put some examples of exceptions structurally wise where the evaluation needs to be more carefully considered. Just as a side comment.

Nevertheless, for this case, the nitrosation reaction of Terbinafin should be really slow as already indicated.

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