Laboratory of Analytical Pharmaceutical Chemistry, Dept. of Pharmaceutical Sciences, CIRM, University of Liege, CHU, B36, B-4000 Liege, Belgium.
Laboratory of Analytical Pharmaceutical Chemistry, Dept. of Pharmaceutical Sciences, CIRM, University of Liege, CHU, B36, B-4000 Liege, Belgium.
J Chromatogr A. 2014 Oct 10;1363:178-82. doi: 10.1016/j.chroma.2014.06.082. Epub 2014 Jul 1.
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.
伏立康唑滴眼剂（(2R,3S)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇）由含有磺丁基醚-β-环糊精钠盐（Vfend）作为辅料的注射液制成，用于治疗真菌性角膜炎。成功开发了一种使用极性有机流动相和涂覆在硅胶上的纤维素三（4-氯-3-甲基苯基碳酸酯）作为手性固定相的液相色谱（LC）方法，以评估滴眼剂的手性稳定性。流动相（含乙腈作为主要溶剂）中的甲醇（MeOH）的百分比显著影响伏立康唑及其对映体（(2S,3R)-2-(2,4-二氟苯基)-3-(5-氟嘧啶-4-基)-1-(1H-1,2,4-三唑-1-基)丁-2-醇）的保留和分离。优化的流动相由乙腈/甲醇/二乙胺/三氟乙酸（80/20/0.1/0.1；v/v/v/v）组成。该方法不仅对伏立康唑的对映体具有选择性，而且对欧洲药典专论中描述的特定杂质也具有选择性。然后，根据总测量误差和准确度概况，使用基于该策略对手动方法进行了充分验证。在选定的条件下，可以进行 0.1%伏立康唑对映体的测定。最后，使用经过验证的 LC 方法进行了滴眼剂的稳定性研究。
