Capillary electrophoresis is a powerful technique for the analysis of polar chiral compounds and has been widely accepted for analytical enantioseparations of drug compounds in pharmaceuticals and biological media. In addition, many mechanistic studies have been conducted in an attempt to rationalize enantioseparations in combination with spectroscopic and computational techniques. The present review will focus on recent examples of mechanistic aspects and summarize recent applications of stereoselective pharmaceutical and biomedical analysis published between January 2017 and November 2020. Various separation modes including electrokinetic chromatography in combination with several detection modes including laser-induced fluorescence, mass spectrometry and contactless conductivity detection will be discussed. A general trend also observed in other analytical techniques is the application of quality by design principles in method development and optimization.
Dextromethorphan is a centrally acting antitussive drug, while its enantiomer levomethorphan is an illicit drug with opioid analgesic effects. As capillary electrophoresis has been proven as an ideal technique for enantiomer analysis, the present study was conducted in order to develop a capillary electrophoresis-based limit test for levomethorphan. The analytical target profile was defined as a method that should be able to determine levomethorphan with acceptable precision and accuracy at the 0.1 % level. From initial scouting experiments, a dual selector system consisting of sulfated β-cyclodextrin and methyl-α-cyclodextrin was identified. The critical process parameters were evaluated in a fractional factorial resolution IV design followed by a central composite face-centered design and Monte Carlo simulations for defining the design space of the method. The selected working conditions consisted of a 30/40.2 cm, 50 μm id fused-silica capillary, 30 mM sodium phosphate buffer, pH 6.5, 16 mg/mL sulfated β-cyclodextrin, and 14 mg/mL methyl-α-cyclodextrin at 20°C and 20 kV. The method was validated according to ICH guideline Q2(R1) and applied to the analysis of a capsule formulation. Furthermore, the apparent binding constants between the enantiomers and the cyclodextrins as well as complex mobilities were determined to understand the migration behavior of the analytes.
Dexmedetomidine is a selective α -adrenergic agonist used for patient sedation, while its enantiomer levomedetomidine has no sedative effects. As CE has been shown to be a powerful technique for enantiomer analysis, the aim of the study was the quality by design-based development of a CE-based limit test for the enantiomeric impurity levomedetomidine. The analytical target profile was defined that the method should be able to determine levomedetomidine with acceptable precision and accuracy at the 0.1% level. From initial scouting experiments, sulfated β-cyclodextrin was selected as chiral selector. The critical process parameters were identified in a fractional factorial resolution V+ design, while a central composite face centered design and Monte Carlo simulations were used for defining the design space of the method. The selected working conditions were a 21.3/31.5 cm, 50 μm id fused-silica capillary, a 50 mM sodium phosphate buffer, pH 6.5, containing 40 mg/mL sulfated β-cyclodextrin, a capillary temperature of 17°C and an applied voltage of 10 kV. Validation according to the ICH guideline Q2(R1) demonstrated repeatability and intermediate precision of content and migration time between 9.3 and 4.2% with accuracy in the range of 92.0 and 98.9%.
The metabolic syndrome (MetS) is a constellation of cardiovascular and metabolic symptoms involving insulin resistance, steatohepatitis, obesity, hypertension, and heart disease, and patients suffering from MetS often require polypharmaceutical treatment. PPARγ agonists are highly effective oral antidiabetics with great potential in MetS, which promote adipocyte browning and insulin sensitization. However, the application of PPARγ agonists in clinics is restricted by potential cardiovascular adverse events. We have previously demonstrated that the racemic dual sEH/PPARγ modulator RB394 (3) simultaneously improves all risk factors of MetS in vivo. In this study, we identify and characterize the eutomer of 3. We provide structural rationale for molecular recognition of the eutomer. Furthermore, we could show that the dual sEH/PPARγ modulator is able to promote adipocyte browning and simultaneously exhibits cardioprotective activity which underlines its exciting potential in treatment of MetS.
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