Development an enantioseparation method for montelukast by capillary electrophoresis applied to quality control

FLOR S; ESTEVEZ PABLO; SCIOSCIA S.,; IGLESIAS M.; TRIPODI V.; LUCANGIOLI S.

Buenos Aires

Simposio; 18 th Latin-American Symposium on Biotechnology, Biomedical, Biopharmaceutical and Industrial Applications of Capillary Electrophoresis and Microchip Technology; 2012

LACE

In the field of optical isomerism, pharmaceutical industry has become vital importance in recent years, since about 60% of the drugs included in the pharmacopoeias are racemates composed of equimolar mixtures of two enantiomers. The importance is that the enantiomers are chemical entities independent with different pharmacokinetic, pharmacodynamic and toxicological properties.Montelukast is a drug used in the treatment of chronic asthma, in preventing exercise-induced bronchospasm and in allergic rhinitis. The main inflammatory mediators involved in this process are the leukotrienes. Therefore, various leukotrienes modulatory agents have been developed like montelukats.Montelukast is a molecule with a chiral carbon in its chemical structure that confers optical isomerism. It has two enantiomers, R-isomer, which corresponds to properly montelukast and S-isomer, its principal synthesis impurity. Capillary electrophoresis using cyclodextrins as pseudoestationary phases is one of the analytical methods of choice for chiral analysis due to its high separation efficiency, resolution, versatility, low sample consumption and short analysis times. The aim of this work was to develop a selective analytical method for determining the S-isomer as well as its main related impurities at very low concentrations in both raw material and finished product of montelukast.The CD-MEKC electrophoretic system consisted of 10 mM SDS with a combination of cyclodextrins (15 mM sulphobutylether-β-cyclodextrin and 10 mM hydroxypropyl-γ-cyclodextrin) in 20 mM borate buffer at pH 9.5. The separation was carried out in a fused silica capillary (60 cm x 75 µm ID), UV detection at 214 nm and the separations were achieved at temperature of 15 ºC, 15 kV of applied voltage using a pressure of 0.5 psi for 5s of sample introduction.Different cyclodextrins have been tested and the combination of sulphobutylether-β-cyclodextrin and hydroxypropyl-γ-cyclodextrin allow the complete resolution of montelukast enantiomers and its main related impurities. The results showed the separation and determination of S-isomer at 1% level and the main synthesis impuririties at 0.5 % levels. Parameters of validation were evaluated according to ICH guidelines such as specificity, linearity, LOD, LOQ, accuracy, precision and robustness.The CE developed method is fast, simple, robust and resulted to be suitable for routine quality and stability control studies applicable to the enantiomeric purity of montelukast in both raw material and finished product.