Behaviour of Tetrabenazine in Acid Medium: Reassessment and Impact on Formulation

Laurent Ettouati (1) , Zoé Senta-Loys (2) , Sandrine Bourgeois (2, 3) , Bernard Fenet (4, 5) , Marc Le Borgne (1) , Hatem Fessi (2)

1 B2MC - Molécules bioactives et chimie médicinale
2 LAGEP - Laboratoire d'automatique et de génie des procédés
3 UCBL ISPB - Université Claude Bernard Lyon 1 - Institut des Sciences Pharmaceutiques et Biologiques
4 UCBL - Université Claude Bernard Lyon 1
5 CCRMN - Centre Commun de Résonance Magnétique Nucléaire, Université Lyon1

Thorough studies of previous analytical stress data of tetrabenazine, a dopamine depleting agent, showed a potential susceptibility to acidic conditions. Hence, the behavior of tetrabenazine acidic solutions was studied by LC-MS and NMR spectroscopy. Reverse-phase LC-MS analysis of tetrabenazine acidic aqueous solutions consistently showed a main lipophilic impurity in a proportion of 15 to 20%. NMR spectroscopy studies did not allow to completely ascertain its structure. However, we hypothesize an interconversion of trans-tetrabenazine with its unstable cis isomer via an open isoquinolinium intermediate. Evaluation of tetrabenazine integrity in orodispersible films was reassessed in light of these observations after formulation and during stability study. Even if interconversion of trans-tetrabenazine with its cis isomer was observed in orodispersible films containing tetrabenazine, this phenomenon seems not to have any consequences for the overall tetrabenazine bioavailability.

Mots clés: synthesis; deuterated tetrabenazine; deuteration; tetrabenazine; acid medium; degradation impurities; stability; LC-MS; orodispersible film

Domaines: Médicaments; Chimie thérapeutique

Laurent Ettouati, Zoé Senta-Loys, Sandrine Bourgeois, Bernard Fenet, Marc Le Borgne, et al.. Behaviour of Tetrabenazine in Acid Medium: Reassessment and Impact on Formulation. Pharmaceutics, 2019, 11 (1), pp.44. ⟨10.3390/pharmaceutics11010044⟩. ⟨hal-01987081⟩