Chiral separation of asenapine enantiomers by capillary electrophoresis and characterization of cyclodextrin complexes by NMR spectroscopy, mass spectrometry and molecular modeling

Zoltán István Szabó, Gergo Tóth, Gergely Völgyi, Balázs Komjáti, Gabriel Hancu, Lajos Szente, Tamás Sohajda, S. Béni, Daniela Lucia Muntean, B. Noszál

Research output: Contribution to journalArticle

32 Citations (Scopus)

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 (160mM TRIS-acetate buffer pH 3.5, 7mM β-CD, at 20°C, applying 15kV) was successful for baseline separation of ASN enantiomers (Rs=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.

Original languageEnglish
Pages (from-to)398-404
Number of pages7
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume117
DOIs
Publication statusPublished - Jan 5 2016

Fingerprint

Capillary electrophoresis
Molecular modeling
Enantiomers
Cyclodextrins
Capillary Electrophoresis
Nuclear magnetic resonance spectroscopy
Mass spectrometry
Mass Spectrometry
Magnetic Resonance Spectroscopy
Bipolar Disorder
Electrophoresis
Stoichiometry
Design of experiments
Spectrometry
Electrolytes
Antipsychotic Agents
Spectrum Analysis
Schizophrenia
Buffers
Acetates

Keywords

  • Antipsychotic
  • Enantioseparation
  • Experimental design
  • Saphris
  • Sycrest
  • Validation

ASJC Scopus subject areas

  • Analytical Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Spectroscopy
  • Clinical Biochemistry

Cite this

Chiral separation of asenapine enantiomers by capillary electrophoresis and characterization of cyclodextrin complexes by NMR spectroscopy, mass spectrometry and molecular modeling. / Szabó, Zoltán István; Tóth, Gergo; Völgyi, Gergely; Komjáti, Balázs; Hancu, Gabriel; Szente, Lajos; Sohajda, Tamás; Béni, S.; Muntean, Daniela Lucia; Noszál, B.

In: Journal of Pharmaceutical and Biomedical Analysis, Vol. 117, 05.01.2016, p. 398-404.

Research output: Contribution to journalArticle

Szabó, Zoltán István ; Tóth, Gergo ; Völgyi, Gergely ; Komjáti, Balázs ; Hancu, Gabriel ; Szente, Lajos ; Sohajda, Tamás ; Béni, S. ; Muntean, Daniela Lucia ; Noszál, B. / Chiral separation of asenapine enantiomers by capillary electrophoresis and characterization of cyclodextrin complexes by NMR spectroscopy, mass spectrometry and molecular modeling. In: Journal of Pharmaceutical and Biomedical Analysis. 2016 ; Vol. 117. pp. 398-404.
@article{4e88ac1a5e0748c385bd47aa4bc68284,
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 (160mM TRIS-acetate buffer pH 3.5, 7mM β-CD, at 20°C, applying 15kV) was successful for baseline separation of ASN enantiomers (Rs=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.",
keywords = "Antipsychotic, Enantioseparation, Experimental design, Saphris, Sycrest, Validation",
author = "Szab{\'o}, {Zolt{\'a}n Istv{\'a}n} and Gergo T{\'o}th and Gergely V{\"o}lgyi and Bal{\'a}zs Komj{\'a}ti and Gabriel Hancu and Lajos Szente and Tam{\'a}s Sohajda and S. B{\'e}ni and Muntean, {Daniela Lucia} and B. Nosz{\'a}l",
year = "2016",
month = "1",
day = "5",
doi = "10.1016/j.jpba.2015.09.022",
language = "English",
volume = "117",
pages = "398--404",
journal = "Journal of Pharmaceutical and Biomedical Analysis",
issn = "0731-7085",
publisher = "Elsevier",

}

TY - JOUR

T1 - Chiral separation of asenapine enantiomers by capillary electrophoresis and characterization of cyclodextrin complexes by NMR spectroscopy, mass spectrometry and molecular modeling

AU - Szabó, Zoltán István

AU - Tóth, Gergo

AU - Völgyi, Gergely

AU - Komjáti, Balázs

AU - Hancu, Gabriel

AU - Szente, Lajos

AU - Sohajda, Tamás

AU - Béni, S.

AU - Muntean, Daniela Lucia

AU - Noszál, B.

PY - 2016/1/5

Y1 - 2016/1/5

N2 - 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 (160mM TRIS-acetate buffer pH 3.5, 7mM β-CD, at 20°C, applying 15kV) was successful for baseline separation of ASN enantiomers (Rs=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.

AB - 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 (160mM TRIS-acetate buffer pH 3.5, 7mM β-CD, at 20°C, applying 15kV) was successful for baseline separation of ASN enantiomers (Rs=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.

KW - Antipsychotic

KW - Enantioseparation

KW - Experimental design

KW - Saphris

KW - Sycrest

KW - Validation

UR - http://www.scopus.com/inward/record.url?scp=84943171030&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943171030&partnerID=8YFLogxK

U2 - 10.1016/j.jpba.2015.09.022

DO - 10.1016/j.jpba.2015.09.022

M3 - Article

C2 - 26440287

AN - SCOPUS:84943171030

VL - 117

SP - 398

EP - 404

JO - Journal of Pharmaceutical and Biomedical Analysis

JF - Journal of Pharmaceutical and Biomedical Analysis

SN - 0731-7085

ER -