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Fejos I.,Semmelweis University | Kazsoki A.,Semmelweis University | Sohajda T.,Cyclolab Cyclodextrin Research and oDevelopment Laboratory Ltd. | Marvanyos E.,Chemical Research Division | And 3 more authors.
Journal of Chromatography A | Year: 2014

The single isomer drug R,R-tadalafil (Cialis®) contains two chiral centers thus four stereoisomers (R,R-, S,S-, S,R- and R,S-tadalafil) exist, however, only the most potent inhibitor, the R,R-tadalafil is in clinical use.In our study, over 20 charged cyclodextrin (CD) derivatives were studied for enantiospecific host-guest type interactions in CD-modified capillary electrophoresis. Tadalafil stereoisomers are non-charged; therefore, their electrophoretic separation poses a challenge. Several candidates of both positively and negatively charged hosts were found to be effective for the enantioseparation. Eight out of the beta derivatives and three of alpha derivatives (including sulfated, sulfoalkylated, carboxyalkylated and amino derivatives) resolved all four stereoisomers partially or completely. Cavity size-dependent absolute enantiomer migration order (EMO) reversals were observed in the case of sulfopropyl-alpha (EMO: R,S; S,R; R,R; S,S) and sulfopropyl-beta (S,S; R,R; S,R; R,S) derivatives, while substituent-dependent partial EMO reversals were detected for sulfobutyl-ether-alpha (R,S; S,R; S,S; R,R) and sulfated-alpha-CD (R,R; S,S; R,S; S,R) selectors. Complexation-induced 1H NMR chemical shift changes reflected that the benzodioxole moiety plays a major role in cavity size-dependent EMO reversal.Sulfobutyl-ether-alpha-CD was the only selector that provided the desired EMO in which the clinically applied eutomer R,R-tadalafil migrates last. Finally, an electrophoretic method applying a background electrolyte (BGE) containing 75. mM Tris-acetic acid buffer (pH 4.75) and 7. mM sulfobutyl-ether-alpha-CD was developed for the baseline resolution of all isomers at 25. °C and +25. kV applied voltage. © 2014 Elsevier B.V.

Szabo Z.-I.,Victor Babes University of Medicine and Pharmacy Timisoara | Toth G.,Semmelweis University | Volgyi G.,Semmelweis University | Komjati B.,Budapest University of Technology and Economics | And 6 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2016

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. © 2015 .

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