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Evaluation of potential genotoxic impurities in prasugrel intermediate by HPLC chromatography

Marcin Cybulski 1Elżbieta Lipiec-Abramska 1Adam Formela 1Piotr Cmoch 1,2Wioleta Maruszak 1

1. Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland
2. Polish Academy of Science, Institute of Organic Chemistry, Kasprzaka 44/52, Warszawa 01-224, Poland


The residual impurities for active pharmaceutical ingredient may stem from starting materials, reagents, intermediates, solvents, side reactions and API degradation processes.  Some impurities possess genotoxic and carcinogenic potential, therefore the determination of their acceptable limits is essential  to avoid patient risk and guarantee therapeutic safety.  In the course of our studies on prasugrel hydrochloride synthesis, the literature search associated with its genotoxicity was performed. Although EMEA Assessment Report discloses that prasugrel (antiplatelet drug) do not exhibit genotoxic properties when tested in a battery of standard in vitro and in vivo assays, the recent patent application suggests that the particular intermediate impurity i.e. dibrominated by-product (PU1BZ) can be finally transformed, in API synthetic sequence, to generate prasugrel-like potential genotoxic impurity. According to Muller classification which was accepted as a background to establish ICH  M7 guideline proposal, above cited impurities match the group with alerting structure (primary halides), unrelated to the structure of the API and with unknown genotoxic potential.

Since our prasugrel synthetic route uses secondary alkyl halide derivative, 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone as a key intermediate to generate the basic skeleton of prasugrel, we synthetized and NMR characterized both revealed impurities. In further studies the HPLC chromatography was applied to examine  the presence of potential genotoxic impurities  in substrate and final prasugrel samples.

This work was supported by the EU - “Innovative technologies of cardio-vascular medicines of special therapeutic and social importance”UDA-POIG.01.03.01-14-062/09.


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Submitted: 2014-03-13 08:33
Revised:   2014-04-29 11:32