N-nitroso Torasemide Impurity formation and control

Dear Respected members,

During my review and assessment of Torasemide API , i have found * N nitroso Torasemide* as shown in the figure Structure of N-nitroso impurity

however in the drug master file, the manufacturing process did not reveal any tendency for its formation

I just need to confirm if there’s a raising worry about its formation to finalize my risk assessment?.

I doubt that can be formed by oxidation- Phase one metabolism, but i am not quite sure.

Waiting for your valuable discussions!.

My regards,

In my experience… they will always ask you for batch analysis to verify with “facts”. Then you can apply 10% or 30% of the specification if you are below this limit.
Any theoretical justification is welcome but insufficient by regulatory agencies.
I have no experience as to whether the nitrosation process is favored , but if it is a low-dose medication, the daily limit of nitrosamine will go up quite a bit.
Cheer up. :slight_smile:

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So, there’s a lot to discuss here.

  1. NDSRIs are rarely formed during the API manufacturing process. This is normally formed in the drug product on stability.

  2. I would advise specific evaluation of every secondary and dimethyl tertiary amine, which you are doing. The first real step of this in the lab should be confirming that the nitrosamine can be formed. If you find an FDA limit and a standard from a reputable source, one can presume that it can be formed. Neither are the case here. Additionally, this paper ( Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development - Schmidtsdorff - 2022 - Archiv der Pharmazie - Wiley Online Library) shows another lab that has tried to form the resulting nitrosamine without success. This work can be done in the lab or in-silico.

  3. If and only if you prove that the nitrosamine can be formed will you proceed to confirmatory testing of old stability/retain samples.


First of all, thank you so much for sharing this publication. very fruitful

I have worries to be formed in our FP.

I have checked this publication and concluded that no success for determing N-nitroso torasemide, but the fact is when i purchase working standard ,what limit can i go for it to control or decide whether its below 10% or 30% of limit?

My assessment is: depending on the attached route of synthesis purified water _nitrite content in presence of acidic conditions favored by acetic acid and 2ry amino group on p-tolyl ring favor its formation.

I need to exclude my worries to predict what we will do in our labs.

Hope my point is explained.

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So i go for asking the supplier for batch analysis of N-nitroso torasemide to decide whether they are below 10% or 30% of limit.

So, the problem you’re running into is that there are a number of companies trying to sell all kinds of nitrosamine standards, even though they cannot make that nitrosamine.

You need to determine if the nitrosamine can be formed. There are a number of resources in the forum to perform the NAP test or a modified NAP test. Don’t just presume that since someone wants to sell you N-nitroso-torasemide that it can actually form. They will take your money and will not provide you anything you need to help your cause.

If you don’t have an LC-MS or the in-silico tools, you will need to contract out this work.


If you are their client, ask them for information about it. They will already be working on this issue. I work at API and ours clients constantly ask us for MS analysis and risks evaluations.
What Mr. Brown tells you is true. But the bureaucracy is not scientific and they ask you for evidence beyond paper data. At least in my experience… or is it that we have very bad luck :slight_smile:
Another thing that Mr. Brown says is the issue of impurities… Well here you need someone serious. There are many Jack Sparrows. Ideally, you have an experienced MS lab and an experienced synthesis company. Another option is to look for a university in your area if they work in chemical synthesis and analysis…
Good luck.


Totally agree with you!. From my humble experience as an analytical chemist:
The issue of impurities is drawing the attention of many pirates :pirate_flag:. But the fault also lies with the authorities. They ALWAYS ask for proof. It’s up to me to search (LC MS analysis) even though it is materially impossible.
I also meet a lot with MS method developers (external lab :parrot:)… there is nothing like homemade. :slight_smile:


A paper that you always have to have on hand :clap:

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Greatly explained.

Only one comment though, although NDSRI are not usually formed during synthesis of API, beware of the stability of the API!
We have observed OOS just in APIs - which also leads to, we are always very focused on nitrite levels on excipients, but sometimes we should not forget that the API itself can have low ppm nitrites


We have LC-MS in our Labs.

I got the idea of performing N-nitrosation of the API and to be injected in the LC-MS against our Torasemide product and see if there detectable or not in our FPP.

But concerning the limits; we got the issue of not establishing yet by any regulatory authorities.

Is this idea can be helpful and alternative to expensive in-silico assessment?

I will contact the supplier for this finding.

For LC-MS we have it in our labs, we can go on an organic chemistry journey Nitrosation of the API and regarded it as secondary standard and injected against our FPP and see what the result reveals, but we will have the issue for the control limit to see if the results are below detection limits or not?.

Don’t forget the lessons learned from Valsartan, nitrites salts are sometime used in the synthesis or the reagents can bring nitrites impurities as well.


Limits-wise, there’s only one secondary amine in torasemide, between the aromatic rings. Assuming this is the site of nitrosation rather than the sulphonylurea, the nitrosamine formed is a clear cat 5 by CPCA (1500 ng/day) and even a good substrate for read-across to nitrosodiphenylamine (limit 78000 ng/day based on the lower confidence interval of available carcinogenicity studies) as has been performed for mefenamic acid by the EMA…

If you do do the nitrosation studies, please properly characterise the product; I would guess it will be on the amine but it would be good to confirm it is not on the urea. All N-nitroso compounds are cohort of concern, including nitrosoureas, but the CPCA does not apply to them so additional work may be needed if it is there!


just for information, anyone purchased and/or synthetized a valid standard of N-nitroso Torasemide? We received from a contract lab a report with detailed sinthesis tentatives. They never obtained N-nitroso Torasemide, but always other products.