Abstract
Chirality is a property of asymmetry which determines the pharmacokinetic and pharmacological profiles of optically active pharmaceuticals. Verapamil (VER), a calcium channel blocker phenylalkylamine derivative used in the treatment of cardio-vascular diseases, is a chiral compound, marketed as a racemate, although differences between the pharmacokinetic and pharmacological attributes of the enantiomers have been reported. The aim of our study was to develop a new chiral separation method for VER enantiomers by capillary electrophoresis (CE) using cyclodextrins (CDs) as chiral selectors (CSs). After an initial screening, using different native and derivatized CDs, at four pH levels, heptakis 2,3,6-tri-O-methyl-β-CD (TM-β-CD), a neutral derivatized CD, was identified as the optimum CS. For method optimization, a preliminary univariate approach was applied to characterize the influence of analytical parameters on the separation followed by a Box–Behnken experimental design to establish the optimal separation conditions. Chiral separation of enantiomers was achieved with a resolution of 1.58 in approximately 4 min; the migration order was R-VER followed by S-VER. The method analytical performance was evaluated in terms of precision, linearity, accuracy, and robustness (applying a Plackett–Burnam experimental design). The developed method was applied for the determination of VER enantiomers in pharmaceuticals. Finally, a computer modelling of VER–CD complexes was used to describe host–guest chiral recognition.
Highlights
It is known that symmetry and chirality have particular meanings in chemistry, especially when characterizing optically active pharmaceutical substances
It acts as a calcium channel blocking agent, being characterized by high selectivity for myocardial calcium channels and lower for the ones located in the vessels [2]
The following CDs were used as chiral selectors (CSs) in the screening process: neutral natural CDs α-CD, β-CD, and γ-CD (Cyclolab, Budapest, Hungary); neutral derivatized CDs hydroxypropyl-β-CD (HP-β-CD) (Sigma-Aldrich, Taufkirchen, Germany), methylated β-CD (M-βCD) (Cyclolab, Budapest, Hungary), heptakis(2,6-di-O-methyl)-β-CD (DM-β-CD), and heptakis(2,3,6-tri-O-methyl)-β-CD (TM-β-CD) (Sigma-Aldrich, Taufkirchen, Germany); and ionizable derivatized anionic CDs carboxymethyl-β-CD (CM-β-CD), sulphated β-CD (S-β-CD) (Sigma-Aldrich, Taufkirchen, Germany), and sulphobutylter-β-CD (SBE-β-CD) (Cydex Pharmaceuticals, San Diego, CA, USA)
Summary
It is known that symmetry and chirality have particular meanings in chemistry, especially when characterizing optically active pharmaceutical substances. The differences between the pharmacokinetic and pharmacological profiles of the enantiomers in the case of many chiral substances are already established, as some are used in therapy as pure enantiomers and others as racemic mixtures [1]. Verapamil (VER) [R,S-2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-ylpentanenitrile] is a phenylalkylamine derivative commonly used in the treatment of supraventricular and ventricular arrhythmias, hypertension, and angina pectoris. It acts as a calcium channel blocking agent, being characterized by high selectivity for myocardial calcium channels and lower for the ones located in the vessels [2]. VER is administered in therapy as a racemate containing equivalent amounts of the Sand R-VER. S-VER is more potent as an antiarrhythmic than R-VER, but it is metabolized
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