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.
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.
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
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…
Totally agree with you!. From my humble experience as an analytical chemist:
The issue of impurities is drawing the attention of many pirates . 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 )… there is nothing like homemade.
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
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?.
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.