Enantioseparation of novel COX‐2 anti‐ inflammatory drugs by capillary electrophoresis using single and dual cyclodextrin systems

Abstract

A capillary electrophoresis method was developed for the enantioseparation of three novel cyclooxygenase-2 (COX-2) inhibitor drugs (E-6259, E-6036 and E-6087) with anti-inflammatory and analgesic activities using sulfobutyl ether-beta-cyclodextrin (SBE-beta-CD) as a chiral selector. The use of 50 mM sodium tetraborate at pH 9.2 with 30% v/v methanol, containing 7.1 mM SBE-beta-CD, as a background electrolyte (BGE) allowed the complete enantioseparation of the three neutral racemic mixtures (resolution = 2.4, 3.0 and 8.7, respectively) and their corresponding metabolites (oxidation products) in a single run. Migration times were shortened with some loss of enantioresolution by adding 1.75 mM dimethyl-beta-cyclodextrin (DM-beta-CD) to the previous BGE (dual CD system). The reversal of the migration order of E-6259 enantiomers in the dual CD system was also studied. Furthermore, the addition of DM-beta-CD to the BGE introduced a new chemoselectivity in the system that allowed E-6259 to be separated from the structurally similar compound E-6036.

Cyclooxygenase-independent inhibitory effects on T cell activation of novel 4,5-dihydro-3 trifluoromethyl pyrazole cyclooxygenase-2 inhibitors

“…E-6087 is a racemic mixture of two stereoisomers that can be separated by preparative HPLC with a chiral column to obtain enantiomerically pure compounds, R(+)E-6087 (E-6231) and S(-)E-6087 (E-6232) [36]. From these two stereoisomers, relevant pharmacological activity as COX inhibitor could be ascribed only to the S(-) enantiomer E-6232 both by in vitro and in vivo assays.…”

“…The novel 4,5-dihydropyrazole drugs used in this study, E-6087, a racemic mixture of two enantiomers S(−) E-6232 and R(+) E-6231, E-6036 and E-6259 ( Fig. 1) have been previously shown to display anti-inflammatory, analgesic and antipyretic activities in animal models [34][35][36][37][38]. COX-2 selectivity of these compounds was determined by in vitro assays with purified COX-1 and COX-2 enzymes (Table 1) as well as by in vivo assays in rats analyzing PGE 2 production in inflammatory exudates and in gastric mucosa (Table 2).…”

An overview of the recent developments in analytical methodologies for determination of COX-2 inhibitors in bulk drugs, pharmaceuticals and biological matrices

“…Enantioseparation of noval COX-2 inhibitors by capillary electrophoresis using sulphabutyl ether cyclodextrin systems as chiral selector using 50 mM sodium tetraborate buffer at pH 9.2 was reported [172]. A capillary GC-MS for the detection of COX-2 inhibitors in human plasma was discussed [173].…”

Determination of enantiomeric purity of a novel COX‐2 anti‐inflammatory drug by capillary electrophoresis using single and dual cyclodextrin systems

“…The enantiomeric separation of E-6087 and other related compounds (E-6259 and E-6036) was studied in a previous work [21]. In that study, the MeOH content in the BGE proved to be a critical parameter to achieve a suitable enantioresolution, in order to perform enantiomeric purity determinations.…”

“…This compound possesses a stereogenic center and its pharmacological activity is mainly due to the S(2)-enantiomer (E-6232), whereas the R(1)-enantiomer (E-6231) becomes an impurity whose content should be determined. In a previous paper [21], a CE method was developed for the enantioseparation of E-6087 and other COX-2 inhibitor compounds belonging to the same chemical series. E-6232 is the most advanced compound in the COX-2 series, so it is necessary not only to achieve a good enantiomeric resolution but also to avoid interferences from related impurities or degradation products.…”