Venlafaxine Chiral Separation by Capillary Electrophoresis Using Cyclodextrin Derivatives as Chiral Selector and Experimental Design Method Optimization

Abstract

Venlafaxine (VFX) is a modern antidepressant from the serotonin and norepinephrine reuptake inhibitor (SNRI) class. It is a chiral substance used in therapy as a racemate, but differences between the pharmacological properties of the two enantiomers have been reported. The current article presents the development of a simple capillary electrophoresis (CE) method for the rapid chiral separation of VFX enantiomers. A complex cyclodextrin (CD) screening at four different pH levels was carried out to establish the optimum chiral selector; carboxymethyl-β-CD (CM-β-CD) at pH 2.5 was selected for further method development. An initial “one factor at time” (OFAT) screening strategy was used to establish the influence of analytical parameters on the separation, followed by a face centered central composite design (FCCD) for the optimization process. The analytical performances of the newly developed method were verified in terms of accuracy, linearity, precision, repeatability, and sensitivity. The method was used for the determination of VFX enantiomer ratio in pharmaceutical forms. Finally, computer modelling of VFX-CD complexes was undertaken to characterize host–guest chiral recognition.

From capillaries to microchips, green electrophoretic features for enantiomeric separations: A decade review (2013–2022)

“…CDs are non‐toxic to human health, have good water solubility, and are easily scaled up, and some papers report systems using native CDs as chiral selectors (α‐CD, β‐CD, and γ‐CD). The specialized literature reports the use of pure CDs for CE (especially the β‐CD, as is presented in Table 1 [56–96]). Initially, native CDs are preferred for chiral separation to obtain reproducible results (especially for the β‐CD) and to study aspects of the selector‐analyte interactions.…”

“…Thus, it is possible to separate uncharged or protonated enantiomers. As chiral drugs separated through CM‐β‐CD, it can be mentioned: meptazinol and its three synthetic intermediates (opioid‐type analgesic with mixed agonist–antagonist properties) [60]; zopiclone (used to treat sleep disorders) [65]; 16 essential chiral drugs including 10 cardiovascular agents and 6 bronchiectasis drugs [73]; methadone (a drug for the treatment of drug addiction) [74]; and venlafaxine (antidepressant) [92]. In addition, CM‐β‐CD can be used in CEKC, as in the separation of enantiomers of amlodipine (a long‐acting dihydropyridine‐type inhibitor for the slow calcium channel) [89].…”

Chiral Capillary Electrokinetic Chromatography: Principle and Applications, Detection and Identification, Design of Experiment, and Exploration of Chiral Recognition Using Molecular Modeling

“…Settling on the most relevant CMPs is usually aided by Main Effect Plots and Pareto charts, however none of the methods reported in the interval January 2016-March 2021 invested effort in this phase where many used the OFAT approach, while others did not proceed via the statistical analysis step ( Table 1 ), probably due to the established CMPs in CEKC, namely, voltage, temperature, nature and concentration of chiral modifier and buffer in the BGE. In a study by Milan et al [ 110 ], nine types of CDs were screened at four different pH values using OFAT, meaning 36 runs, which has certainly consumed an enormous time, while a nine-factor Placket Burman screening design would have needed only eight runs and proper statistical interpretation using Main Effect Plots and Pareto charts.…”

“…All computation was indeed focused on the optimization phase, where designs like full factorial, face-centered central composite designs, D-optimal designs are adopted to produce the response surfaces and generate the multivariate or least-square regression models related the significant CMPs to CMAs in addition to Monte Carlo simulations that are used for accurate definition of the DS, that enables selection of the optimal working point, robust range, or sweet spot revealed by the overlay of multiple methods operable design region (MODR). Responses in multivariate optimization in CEKC are mostly selectivity or resolution, and analysis time, where their simultaneous optimization is sometimes performed via the desirability function [ 110 , 141 ].…”

Application of Experimental Design Methodologies in the Enantioseparation of Pharmaceuticals by Capillary Electrophoresis: A Review

“…To describe host-guest chiral recognition, computer modelling of venlafaxine-CD complexes was applied. The method was validated and used for the determination of venlafaxine enantiomers in pharmaceutical formulations [ 109 ].…”