FDA has described two NDSRI for Doxepin.
- N-nitroso-desmethyl-cidoxepin &
- N-nitroso-desmethyl-doxepin, (e)-
Which NDSRI is to be monitored for Doxepin related drug Products ???
Both. E-Doxepin is an impurity of Doxepin leading to an additional NDSRI.
I would presume that if you can keep the primary NDSRI in check that the NDSRI based on the impurity will never be over 10% of the specification. If that is shown in the confirmatory testing, you would not have to test that NDSRI on an ongoing basis.
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Hi, @jason.brown
Doxepin is a mixture of (E) and (Z) stereoisomers with an approximate ratio of 85:15, according to Wikipedia. I think both are APIs. I dare to say that Cidoxepin or Z-Doxepin is a minor component. I am sorry for pointing out the details.
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Good catch, @Yosukemino & Wikipedia. The thought may still be true. Given the lower ratio, E may remain below 10% and not have to be tested. This is just not as likely as I supposed.
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Do you think anyone could claim that as these are two different nitrosamines the limit could be different to the mono-nitrosamine?
That’s a great question. Not to mention, how the two would be separately quantified. It may be in everyone’s best interest to quantify them together & treat them as one.
As for the limit, the limit for the total reverts to the lowest individual. So, again, either way, you’re basically in the same spot.
Hi,
Maybe my grain of salt. I would also agree in considering them jointly. By the way , all alkyl nitrosamines have (E) and (Z) positional (conformational) isomers. With the isomers having very similar to equal physicochemical properties and very difficult to isolate. The ratio in this case is variable depending on the conditions (e.g., °T) and only fixed if the nitrosamine is symmetrical.
But here I understand, we have other type of stereoisomers = different properties. If the ratio is fixed, I infer it is possible to dismiss the presence of the (E) isomer based on the results of (Z).
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