title: Development and validation of a liquid chromatographic method for the stability study of a pharmaceutical formulation containing voriconazole using cellulose tris(4-chloro-3-methylphenylcarbamate) as chiral selector and polar organic mobile phases.
abstract: The ophthalmic solution of voriconazole, i.e. (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol, made from an injection formulation which also contains sulfobutylether-β-cyclodextrin sodium salt as an excipient (Vfend), is used for the treatment of fungal keratitis. A liquid chromatographic (LC) method using polar organic mobile phase and cellulose tris(4-chloro-3-methylphenylcarbamate) coated on silica as chiral stationary phase was successfully developed to evaluate the chiral stability of the ophthalmic solution. The percentage of methanol (MeOH) in the mobile phase containing acetonitrile (ACN) as the main solvent significantly influenced the retention and resolution of voriconazole and its enantiomer ((2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol). The optimized mobile phase consisted of ACN/MeOH/diethylamine/trifluoroacetic acid (80/20/0.1/0.1; v/v/v/v). The method was found to be selective not only regarding the enantiomer of voriconazole but also regarding the specified impurities described in the monograph from the European Pharmacopoeia. The LC method was then fully validated applying the strategy based on total measurement error and accuracy profiles. Under the selected conditions, the determination of 0.1% of voriconazole enantiomer could be performed. Finally, a stability study of the ophthalmic solution was conducted using the validated LC method.
authors.affiliation: Laboratory of Analytical Pharmaceutical Chemistry, Dept. of Pharmaceutical Sciences, CIRM, University of Liege, CHU, B36, B-4000 Liege, Belgium. Electronic address: acservais@ulg.ac.be.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Servais
authors.affiliation: Laboratory of Analytical Pharmaceutical Chemistry, Dept. of Pharmaceutical Sciences, CIRM, University of Liege, CHU, B36, B-4000 Liege, Belgium.
authors.forename: Radu
authors.initials: R
authors.lastname: Moldovan
authors.affiliation: Laboratory of Analytical Pharmaceutical Chemistry, Dept. of Pharmaceutical Sciences, CIRM, University of Liege, CHU, B36, B-4000 Liege, Belgium.
authors.forename: Elena
authors.initials: E
authors.lastname: Farcas
authors.affiliation: Laboratory of Analytical Pharmaceutical Chemistry, Dept. of Pharmaceutical Sciences, CIRM, University of Liege, CHU, B36, B-4000 Liege, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: Crommen
authors.affiliation: Hospital Pharmacy, CHU, B-4000 Liege, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Roland
authors.affiliation: Laboratory of Analytical Pharmaceutical Chemistry, Dept. of Pharmaceutical Sciences, CIRM, University of Liege, CHU, B36, B-4000 Liege, Belgium.
authors.forename: Marianne
authors.initials: M
authors.lastname: Fillet
mesh_terms: D002482:Cellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D002853:Chromatography, Liquid / Q000379:methods*; D048448:Phenylcarbamates / Q000737:chemistry*; D013237:Stereoisomerism; D065819:Voriconazole / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D048448:Phenylcarbamates; D047392:beta-Cyclodextrins; C552444:cellulose tris(4-chloro-3-methylphenylcarbamate); C093196:SBE4-beta-cyclodextrin; D002482:Cellulose; D065819:Voriconazole
keywords: Chiral stability; Chiral stationary phase; Liquid chromatography; Validation; Voriconazole