200+ USP Monograph w/ Tertiary amines

by @ASrinivasan

Another victim of the demon, that we call nitrosamine. The recall of Orphenadrine Citrate ER Tablets, though not surprising, is not pleasant. My Ph.D. Advisor, Dr. Richard Loeppky spend most of his life taking about facile nitrosation of some tertiary amines. However, it has always been tough for people to accept it, as it will lead to re-evaluaiton of significant number of drugs. My evaluation of USP monographs show that about 200 or more of the monographed products are tertiary amines, which may undergo nitrosation in mildly acidic conditions. I guess if we consider other approved products, which are not in USP or EP, the list will be unending. It is high time, Agencies look more into endogenous nitrosation to better understand if these impurities are worth controlling at the levels being proposed, when these are already being formed possibly in our GI track. Afterall, stomach is the perfect round bottomed flask for nitrosation reaction. We also need a pathway to establish if these larger nitrosamines are really carcinogenic. Is this a scenario where twigs are being mistaken as venomous snakes? I think this is equally risky as mistaking a snake as dry branch. Possibly time for Agencies to pause and take a good look at what lies ahead and the consequences of moving on the current path.

Dont forget Quinapril/HCTZ which is being recalled too right after Orphenadrine. Nitrosamine of HCTZ is known for quite some time and it is a difficult molecule. Also, there are literally hundreds of products, if we include the generics, that are combination of HCTZ, an established diuretic with other drugs, mostly cardiovascular. Quinapril, is a secondary amine and thus a sitting duck, when it comes to nitrosation.


Because nitrosamines are regulated on a mass basis rather a molar basis, larger nitrosamines are subject to tighter limits relative to the actual concentration of nitrosamine functional groups. This is convenient but not valid.