Dear all,
in the light of the addition of new nitroso-compounds in the EMA guideline, i would like to discuss the upcoming (?) threat for metformin final products.
As metformin is a guanidine type API, relevant risk is anticipated to be raised apart the presence of NDMA for the starting material cyano-guanidine and the impurities (at least) as well :
(4,6-diamino-1,3,5-triazin-2-yl) guanidine, EP imp B (an aromatic guanidine)
1-methyl guanidine, EP imp E (an alkyl guanidine).
Do you think that the risk is reasonable?
I would appreciate very much the feedback of anyone on this case.
thank you
Christos
dear Christos
at least for cyanoguanidine please consider the below:
Based on the findings of two long-term feeding studies DCD exerts no carcinogenic potential in rats when administered for up to two years under the applied conditions at doses up to 50000 ppm (equals 1740 mg/kg bw/day in males and 2424 mg/kg bw/day in females, respectively, based on compound consumption in week 104).
hope this helps.
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Eleni thank you very much lot for your very fast and valuable information.
The problem would be the nitroso-derivative of the DCD (1-nitroso-cyano guanidine) and not the DCD it self, same case with NDMA and DMA.
The same and for the other two impurities, B & E.
Personally i beleive that the 1-nitroso-cyano guanidine is very difficult to be formed due to the presence of the cyano group in alpha position but for the other two guanidines i cannot guess.
christos
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i was about to correct the comment because i revisited your initial question. so correct. it is not about dcd
Hi Christos
for the 1-nitroso-cyano guanidine we may now refer to 1-Nitroso Cyano Guanidine: Synthesis Attempts and Failure Report - Veeprho
thanks Yosukemino for sharing.
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thanks a lot for the information Eleni!!
Hi Christos,
From our personal experience, the only possible nitrosamine from Metformin is NMDA which can be easily controlled by controlling the levels of the other starting material, i.e. Dimethylamine (hydrochloride).
There seems to be no risk of nitrosation of, (a) (4,6-diamino-1,3,5-triazin-2-yl) guanidine and (b) cyano-guanidine as they lack the essential secondary amine. Besides, they are highly basic in nature and therefore likely to be protonated at acidic pH (necessary for nitrosation) rendering the nitrosation impossible.
Nitrosation of methyl-guanidine does not seem to be equally possible.
I am reproducing an interesting statement from Mirvish article:
“Nitrosation of methylguanidine gave a 35% yield of methylnitrosourea”
Sidney S Mirvish, Kinetics of Nitrosamide Formation From Alkylureas, N-Alkylurethans, and Alkylguanidines: Possible Implications for the Etiology of Human Gastric Cancer, https://doi.org/10.1093/jnci/46.6.1183
Hope this helps 
Muzaffar
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Dear Muzaffar,
i totally agree with you.
Recently we received a relevant justification letter for the non-possible synthesis of those nitrosamines.
My question was more to investigate if we have any ‘‘surprise’’ in our community 
To be honest, i am afraid that the synthesis of several of N-nitroso guanidines and amides have been characterized as ‘‘feasible’’ just from a signal in the MS spectra without any isolation of the compound which could be proved impossible due, for example, to its instability.
Last, before a month ago, one impurity supplier informed us that he has the N-nitroso metformin in-stock!! The relevant characterization data which have been send did not prove the structure
thank you for the answer,
kind regards
Christos
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Dear Christos,
Thank you for the clarification.
You nailed the problem. We ourselves have several examples where the suppliers claimed availability of NDSRI standards without proper characterization. You can easily end-up with C or O-nitroso analogues or other compounds with the same m/z as the N-nitroso compounds. Unfortunately many organizations fall prey and end up testing the drug product using these “so called” NDSRI standards. In my opinion, complete and adequate characterization (of the NDSRI standards) should precede any confirmatory testing.
If an NDSRI cannot form under the conditions recommended by EFPIA (https://www.efpia.eu/media/tkbnsicy/efpia-nitrosamines-risk-management-workflows-jun-24-udpate.pdf) in all probability, it is unlikely to form under real-time manufacturing/storage conditions. To me this remains the gold-standard for evaluating the risk of nitrosamine formation from an industry perspective. We don’t have to be innovative in synthesizing the NDSRIs if they are not going to form in real-time manufacturing conditions.
Best regards,
Muzaffar
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