title: Enantioseparation and impurity determination of ambrisentan using cyclodextrin-modified micellar electrokinetic chromatography: Visualizing the design space within quality by design framework.
abstract: A capillary electrophoresis method for the simultaneous determination of the enantiomeric purity and of impurities of the chiral drug ambrisentan has been developed following the Quality by Design principles. The selected separation system consisted of a micellar pseudostationary phase made by sodium dodecyl sulphate with the addition of γ-cyclodextrin. The effects of critical process parameters (capillary length, temperature, voltage, borate concentration, pH, sodium dodecyl sulphate concentration, γ-cyclodextrin concentration) on enantioresolution of ambrisentan and analysis time were extensively investigated by multivariate strategies involving a screening phase and Response Surface Methodology. The Design Space was defined with a desired probability level π≥90%, and the working conditions, with the limits of the Design Space, corresponded to the following: capillary length, 64.5cm; temperature, 22°C; voltage, 30kV (26-30kV); background electrolyte, 100mM borate buffer pH 9.20 (8.80-9.60), 100mM sodium dodecyl sulphate, 50mM (43-50mM) γ-cyclodextrin. A Plackett-Burman design was applied for robustness testing, and a method control strategy was established. The method was fully validated according to the International Conference on Harmonisation guidelines and was applied to ambrisentan coated tablets.
authors.affiliation: Department of Chemistry "U. Schiff", University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Orlandini
authors.affiliation: Department of Chemistry "U. Schiff", University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Pasquini
authors.affiliation: Department of Chemistry "U. Schiff", University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Caprini
authors.affiliation: Department of Chemistry "U. Schiff", University of Florence, Via della Lastruccia 3-13, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Del Bubba
authors.affiliation: Zentiva, k.s. Praha, a Sanofi Company, U Kabelovny 130, 102 37 Praha 10, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Douša
authors.affiliation: Department of Chemistry "U. Schiff", University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pinzauti
authors.affiliation: Department of Chemistry "U. Schiff", University of Florence, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: sandra.furlanetto@unifi.it.
authors.forename: S
authors.initials: S
authors.lastname: Furlanetto
mesh_terms: D001881:Borates / Q000737:chemistry; D002021:Buffers; D002138:Calibration; D020374:Chromatography, Micellar Electrokinetic Capillary / Q000379:methods; D003505:Cyclodextrins; D004340:Drug Contamination; D006863:Hydrogen-Ion Concentration; D010666:Phenylpropionates / Q000032:analysis* / Q000737:chemistry; D011724:Pyridazines / Q000032:analysis* / Q000737:chemistry; D011786:Quality Control; D015203:Reproducibility of Results; D012967:Sodium Dodecyl Sulfate; D013237:Stereoisomerism; D013607:Tablets / Q000032:analysis
chemical_list: D001881:Borates; D002021:Buffers; D003505:Cyclodextrins; D010666:Phenylpropionates; D011724:Pyridazines; D013607:Tablets; D012967:Sodium Dodecyl Sulfate; C467894:ambrisentan
keywords: Ambrisentan; Capillary electrophoresis; Chiral separation; Experimental design; Impurities; Quality by design