N-nitroso Des-methyl Dapoxetine

It was found that Desmethyl Dapoxetine as an impurity of Dapoxetine in presence of acidic conditions and source of nitrite can encourage N-nitroso Desmethyl dapoxetine.

Is there any Recommended limit to control of N-nitroso Desmethyl Dapoxetine or It can be controlled as mentioned in Canadian guidance ; 18 ng/day.

2D structure of N-nitroso desmethyl Dapoxetine

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Hi, this is only a speculative hypothesis or you really found it?
If you found it, it is was presente in API, tablets or both?

We do not tested yet in our product but due to the possibility of demethylation and formation of Desmethyl impurity, so this impurity can be carried over and in presence of acidic conditions and nitrite source in the synthetic procedure provided by the supplier in its drug master file section 3.2.S.2.2, so i posted this question that came into my mind about this possibility especially that i have found the N-nitroso Desmethyl Dapoxetine in many supplier offering analytical standards.

There is no recommended limit to control of N-nitroso Desmethyl Dapoxetine; you should apply the default limit (18 ng/day), or (only for EU countries) the temporary limit (max for one year) of 178 ng/day.

Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products

Consider that this impurity may be formed also in the tablets, by reaction with nitrites presents in the excipents (typically in cellulose)

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Isn’t this molecule prone rather to form NDMA, as a benzylic tertiary amine?
e.g., Loeppky RN, Outram JR, Tomasik W, Faulconer JM. Rapid Nitrosamine Formation from a Tertiary Amine: The Nitrosation of 2-(N,N-Dimethylaminomethyl)Pyrrole. Tetrahedron Lett. 1983, 24, 4271−4274.
Lhasa Poster: “In silico prediction of N-nitrosamine degradants in APIs that possess a secondary or tertiary amine functional group”, dr Ash Ali, Science of Stability Conference 2021
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Theoretically nearly all is possible. In Dapoxetine we have a dimethylamino moiety linked to a benzylic carbon. however this structure is very different from the example mentioned in the poster (pirrole ring), because the benzene ring is much more stable.:
image
It is very difficult to break the aromaticity of a benzene ring; in my opinion, the mechanism in the poster is not applicable to Dapoxetine.
In any case, two years ago we tested some batches of Dapoxetine tablets for NDMA and we didn’t find it.

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YOu are right. My PhD advisor always recommended that if we needed a model compound, to choose a nitrosamine with a benzene ring of one side, as it makes the nitrosamine less carcinogenic and also it helps focus of the nitrosation mechanism. But sadly we dont have a lot of data on such nitrosmines. I myself worked on N-phenyl-N-nitroso-2-hydroxyethylamine a lot, but being a chemist, did not bother to make sure that better work was done on determining the TD50.

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Yes, my PhD advisor Dr. Loeppky and Vitig (Tomasik), who was a post doc in the team basically showed that tertiary amines can undergo facile nitrosation. I still thing that NDMA may be formed here with the nitroso-nordopoxetine. A surrogate study is called for.

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You are not breaking the aromaticity of the benzene ring is this case, this is not a Phenylamine but a benzylamine. the benzylnitrosamines are quite potent.

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In the article: “Nitrosative Cleavage of Tertiary Amines, Smith & Loeppky, J. Am. Chem. Soc. 1967, 89, 5, 1147–1157”, the nitrosation of benzyldiethylamine was studied, among other tertiary amines, and the main reaction products isolated were CH3CHO and C6H5CH2N(Et)NO, while diethylnitrosamine was not reliably recovered. A cleavage ratio benzyl/ethyl of 21/79 is indicated.
This appears to confirm that the reaction does not follow the mechanism of rapid nitrosation mentioned above.

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I run the structure through Zeneth, and confirm Hydrolysis of amine (Water, pH) + Nitrosation of the secondary amine (NDMA) in addition to the oxidation of alcohol to carbonyl compound + dehydration of alcohol

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This was expected based on Lhasa poster

Hi Naiffer,
I understand your concern, however Zeneth is only a software. It may be useful to make theoretical prediction when we do not have any experimental data. As I wrote before, we tested about 20 batches Dapoxetine tablets (both 30 and 60 mg dosages) and we didn’t find NDMA (detection limit < 0,03 ppm). Of course the possible formation of N-nitroso-desmethyldapoxetine is another issue which should be investigated.

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