Nitrosamine Risk in Trospium chloride tablets

N-nitrosamines Chemistry
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Dear nitrosamines exchange community,

I am currently conducting a risk assessment for trospium chloride film-coated tablets and have a few questions that you may be able to help me with.
I do not consider trospium chloride itself to be a risk because it is a quaternary ammonium compound and would first have to be dealkylated.
I see the starting material for trospium chloride synthesis—nortropine—and the related impurity B (benzyl acid nortropine ester) as more problematic. Both of these substances are secondary amines. Benzyl acid nortropine ester is actually always < 100 ppm, and I don’t have any analysis values for nortropine itself. However, I actually assume that it is completely converted during API synthesis and therefore does not pose a risk. When I categorize the NDSRI of benzyl acid nortropine ester (see picture below) using the CPCA approach, I end up in potency category 5 because there is only 1 alpha-hydrogen on each side of the N-nitroso group. Have I assessed this correctly? How do you view the general risk posed by this nitrosamine contamination? Based on various publications (Moser et al., 2023 – N-Nitrosamine Formation in Pharmaceutical Solid Drug Products: Experimental Observations; Carloni et al., 2023 – Solid State Kinetics of Nitrosation Using Native Sources of Nitrite) on nitrosamine formation in the solid state, a low single-digit conversion rate is to be expected.

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dear KWL,

i think that your approach is very good and you have targeted the most ‘‘suspicious’’ molecule.

Furthermore, the AI you have estimated for this NDSRI, according to the CPCA rules, is right.

And, finally Moser article is one of the most important and useful tool for risk assessment reports.

good luck!!

Christos

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Dr. Richard Loeppky has papers where he has addressed the nitrosation of molecules where N is at a bridgehead. You are right in that if you creat the 3D model, it will show how difficult it is to nitrosate. you can may be look at those and create a justification.

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