Structural elucidation of two photolytic degradation products of tetrabenazine.
During solution formulation study of tetrabenazine (TBZ), a dopamine depleting agent, used in chorea associated with Huntington's disease and symptomatic treatment of hyperkinetic movement disorder it was observed a strong discoloration upon storage. We investigated this physico-chemical behavior by implementing forced degradation studies. It was observed yellowing only under Suntest(®) light exposure of TBZ solution. LC-MS (liquid chromatography coupled to mass spectrometer detection) analysis of light exposed TBZ samples allowed us to propose 1,11b-dedihydrotetrabenazine (DTBZ) and 1,3,4,11b-detetrahydrotetrabenazine (TTBZ) as the main TBZ impurities. Synthesis and complete structural determination of DTBZ and TTBZ·HCl by NMR and X-ray crystallography were carried out. They were identical in LC-MS with polar impurities found in light exposed TBZ samples. However, even if these TBZ degradation products are correlated with discoloration of TBZ solution there is no evidence they are directly responsible of it.
Université de Lyon, Université Lyon 1, LAGEP, UMR 5007, CNRS, CPE, 43 bd du 11 novembre, 69100 Villeurbanne, France.
Zouaoui
Z
Bourezg
Université de Lyon, Université Lyon 1, Faculté de Pharmacie - ISPB, EA 4446 Biomolécules Cancer et Chimiorésistances, SFR Santé Lyon-Est CNRS UMS3453 - INSERM US7, 8 avenue Rockefeller, F-69373 Lyon Cedex 8, France.
Nathalie
N
Cartiser
Université de Lyon, Université Lyon 1, Faculté de Pharmacie - ISPB, EA 4446 Biomolécules Cancer et Chimiorésistances, SFR Santé Lyon-Est CNRS UMS3453 - INSERM US7, 8 avenue Rockefeller, F-69373 Lyon Cedex 8, France. Electronic address: laurent.ettouati@univ-lyon1.fr.
Laurent
L
Ettouati
Université de Bordeaux, UFR des Sciences Pharmaceutiques, INSERM U869, Laboratoire ARNA, 146 rue Léo Saignat, F-33076 Bordeaux Cedex, France.
Jean
J
Guillon
ISM - CNRS UMR 5255, Université de Bordeaux, 351 cours de la Libération, F-33405 Talence Cedex, France.
Aline
A
Lacoudre
ISM - CNRS UMR 5255, Université de Bordeaux, 351 cours de la Libération, F-33405 Talence Cedex, France.
Noël
N
Pinaud
Université de Lyon, Université Lyon 1, Faculté de Pharmacie - ISPB, EA 4446 Biomolécules Cancer et Chimiorésistances, SFR Santé Lyon-Est CNRS UMS3453 - INSERM US7, 8 avenue Rockefeller, F-69373 Lyon Cedex 8, France.
Marc
M
Le Borgne
Université de Lyon, Université Lyon 1, LAGEP, UMR 5007, CNRS, CPE, 43 bd du 11 novembre, 69100 Villeurbanne, France.
Hatem
H
Fessi
D002853:Chromatography, Liquid / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D004340:Drug Contamination; D008027:Light; D013058:Mass Spectrometry / Q000379:methods; D010782:Photolysis; D013747:Tetrabenazine / Q000737:chemistry*
D013747:Tetrabenazine
Crystallography; Degradation impurities; LC–MS; Stability; Tetrabenazine