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