title: Chiral separation of asenapine enantiomers by capillary electrophoresis and characterization of cyclodextrin complexes by NMR spectroscopy, mass spectrometry and molecular modeling.
abstract: The enantiomers of asenapine maleate (ASN), a novel antipsychotic against schizophrenia and mania with bipolar I disorder have been separated by cyclodextrin (CD) modified capillary zone electrophoresis for the first time. 15 different CDs were screened as complexing agents and chiral selectors, investigating the stability of the inclusion complexes and their enantiodiscriminating capacities. Although initially, none of the applied chiral selectors gave baseline separation, β-CD proved to be the most effective chiral selector. In order to improve resolution, an orthogonal experimental design was employed, altering the concentration of background electrolyte, organic modifier, pH, capillary temperature and applied voltage in a multivariate manner. The developed method (160 mM TRIS-acetate buffer pH 3.5, 7 mM β-CD, at 20 °C, applying 15 kV) was successful for baseline separation of ASN enantiomers (R(s)=2.40±0.04). Our method was validated according to ICH guidelines and proved to be sensitive, linear, accurate and precise for the chiral separation of ASN. Properties of the inclusion complexes, such as stoichiometry, atomic level intermolecular host-guest connections are proposed on the basis of ROESY NMR measurement, ESI-MS spectrometry and molecular modeling studies. It was found that the ASN-β-CD complex is of 1:1 composition, and either of the aromatic rings can be accommodated in the β-CD cavity.
authors.affiliation: Faculty of Pharmacy, University of Medicine and Pharmacy of Tîrgu Mureș, Romania.
authors.forename: Zoltán-István
authors.initials: ZI
authors.lastname: Szabó
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.
authors.forename: Gergő
authors.initials: G
authors.lastname: Tóth
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.
authors.forename: Gergely
authors.initials: G
authors.lastname: Völgyi
authors.affiliation: Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Komjáti
authors.affiliation: Faculty of Pharmacy, University of Medicine and Pharmacy of Tîrgu Mureș, Romania.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Hancu
authors.affiliation: Cyclolab Cyclodextrin Research & Development Laboratory Ltd, Budapest, Hungary.
authors.forename: Lajos
authors.initials: L
authors.lastname: Szente
authors.affiliation: Cyclolab Cyclodextrin Research & Development Laboratory Ltd, Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Sohajda
authors.affiliation: Department of Pharmacognosy, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Béni
authors.affiliation: Faculty of Pharmacy, University of Medicine and Pharmacy of Tîrgu Mureș, Romania.
authors.forename: Daniela-Lucia
authors.initials: DL
authors.lastname: Muntean
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary. Electronic address: noszal.bela@pharma.semmelweis-univ.hu.
authors.forename: Béla
authors.initials: B
authors.lastname: Noszál
mesh_terms: D003505:Cyclodextrins / Q000032:analysis / Q000737:chemistry*; D003986:Dibenzocycloheptenes; D019075:Electrophoresis, Capillary / Q000379:methods; D006576:Heterocyclic Compounds, 4 or More Rings / Q000032:analysis / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D013058:Mass Spectrometry / Q000379:methods; D008958:Models, Molecular; D013237:Stereoisomerism; D047392:beta-Cyclodextrins / Q000032:analysis / Q000737:chemistry*
chemical_list: D003505:Cyclodextrins; D003986:Dibenzocycloheptenes; D006576:Heterocyclic Compounds, 4 or More Rings; D047392:beta-Cyclodextrins; C522667:asenapine; C031215:betadex
keywords: Antipsychotic; Enantioseparation; Experimental design; Saphris(®); Sycrest(®); Validation