Is there any possibility to generate the N-Desmethyl Tramadol in formulation?

Limits of Nitrosamines
1

Dear All.
is there any possibility to generate the N-Desmethyl Tramadol Impurity in formulation?
if yes, how to control the generation of Desmehylation of Tramadol.
Thank you in advance.

2

Dear Harshad,
although is consider difficult to have demethylation in a solid form, you cannot exclude this. We have seen a demethylation to one of our products during stability (not tramadol, other API). So, you should perform a confirmatory test in your formulation, at least at ACC conditions for the identification of N-nitrosodesmethyl tramadol. If its quantity is <10% of the specification limit, then you will not have to worry about the demethylation process.
If you want to control the demethylation, i would propose to take care from oxidative or photolytic factors, as demethylation is usually result of oxidation or photodegradation.

Christos

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3

Thank you for your response.

4

suggest conducting confirmatory testing

5

Yes, there are chances of formation of this impurity. Its a two step reaction where first desmethyl Tramadol will form which will further react with nitrite ions to form N Nitroso desmethylTramodol. The best way to control this impurity is by using nitrite free or low nitrite grade excipient in the formulation. Non-aq approach will be more suitable. Just check out FD studies on API and formulation samples to understand if desmethylTramodol imp is forming, The LOQ should be near the expected LOQ of its nitrosamine imp. That will help you and formulator to control this impurity, if its really forming or increasing during stability,

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6

There is a theoretical possibility…confirmatory testing is required