Attached is a poster we made for AAPS from a study we did on selecting the optimal inhibitor and concentration. This study was designed to inform the formulator’s next steps as they try the most promising strategies identified.
Nitrosamine Mitigation Case Study Poster.pdf (518.4 KB)
Hi Jason. Many thanks for sharing this - really interesting work and ties in with a lot of my thoughts.
A couple of quick questions, if I may?
Why did you try the addition of sodium benzoate alongside the vitamin C? Sodium amino benzoic acid would give the primary amine functionality similar to PABA, but I haven’t seen anything utilising sodium benzoate as a scavenger molecule. It may explain some of my observations though!
In terms of PABA itself, it is a named impurity, with controlled permitted levels in Benzocaine, and propyl paraben as well from memory. If it is a controlled impurity in the monographs then are the levels tried acceptable from an overall perspective?
Many thanks, Mark
Great questions, Mark.
I regard to using benzoic acid, honestly, this was a suggestion from a colleague who is an organic chemist. We were a bit skeptical ourselves, but felt it was worth the look given their experience.
With regard to the allowable concentration of PABA, as you mention, it is not an approved excipient. We were not aware of these limits but knew that discussions would be necessary.
The important context to this study is that it was designed to give the most comprehensive list of inhibitors and concentrations possible to the formulator. So, we did not want to prematurely rule anything out. Even ascorbic acid has some hurdles that could be called out in the next step, which should be lab scale batches put on stability.
Many thanks for the reply Jason.
I wouldn’t rule Benzoic acid out as a possibility yet, although your initial results seem to suggest no real impact. As you state in the poster, all nitrosamines are individual, and what doesn’t work for one may work for others. Also, it may be that it works better in a liquid formulation compared to a tablet.
The results for some of the scavengers are still impressive, and I would think that in a full tablet they could be even more so, depending on the manufacturing process and the stage at which the scavenger is introduced into that process.
Thanks for the feedback, Mark. I agree. The last thing we wanted to do was prematurely move off of something that may work. The beauty of this study is the breadth accomplished in a matter of weeks.
Para-amino benzoic acid is commonly known as vitamin B10. It is a white crystalline chemical found in the folic acid vitamin and also in several foods such as whole grains, eggs, brewer’s yeast, milk, organ meat, mushrooms, spinach and many others.
4-Aminobenzoic acid is listed in the Ph.Eur. monographs (No. 1687).
It is not listed in USP as is, but sodium Aminobenzoate is listed.
The fact that it is also a Benzocaine impurity is not relevant.
