Capillary electrophoresis methods for chiral drug analysis and cyclodextrin-guest complexation mechanisms

The stereochemistry of the drugs plays in important in their pharmacological effects since the enantiomers of chiral drugs interact in a stereoselective way with the targets, which may lead to different activity or even undesirable effects. In the presented work, three methods were developed for the determination of the enantiomeric purity of three drug substances ambrisentan, dextromethorphan and dexmedetomidine using cyclodextrin-mediated capillary electrophoresis (CE), following QbD methodology for method development, optimization and validation. The three methods enabled the determination of the enantiomeric with acceptable precision and accuracy at 0.1 %. The analysis run time less than 10 minutes of for ambrisentan and dexmedetomidine, and ca. 5 minutes for dextromethorphan. The mechanism of the chiral separation of dextromethorphan and its enantiomer was studied by CE in order to explain the role of the dual selector system in the separation method. Moreover, the role of the cavity size and the substitution pattern of the cyclodextrins in the migration order of medetomidine enantiomers in the presence of cyclodextrins (CDs) was investigated. This involved the opposite migration order in the presence of β-CD and γ-CD as well as S-β-CD and HS-β-CD, which was observed during the screening of various CDs as possible chiral selectors. The apparent complexation constants and complex mobilities of the diastereomeric CDanalyte complexes were determined by CE. Additionally, the complexation was studied in detail by NMR spectroscopy and molecular modeling. An unusual complexation behavior of γ-CD and daclatasvir (DCV), that is two peaks with a plateau in between was observed in CE. This phenomenon was studied by NMR and mass spectroscopy in addition to CE methods. The simultaneous formation of DCV- γ-CD inclusion complexes with 1:1 and 2:1 stoichiometry was proved by NMR and mass spectrometry.



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