Unusual complexation behavior between daclatasvir and γ-Cyclodextrin. A multiplatform study.

Area of Science:

• Analytical Chemistry
• Separation Science
• Chiral Separations

Background:

• Daclatasvir (DCV) is an antiviral medication requiring chiral separation for purity assessment.
• Cyclodextrins (CDs) are commonly used as chiral selectors in capillary electrophoresis (CE).
• Unusual separation phenomena can provide insights into molecular interactions.

Purpose of the Study:

• To investigate the chiral separation of daclatasvir (DCV) and its enantiomer using cyclodextrins (CDs) in capillary electrophoresis (CE).
• To elucidate the cause of an observed unusual separation pattern involving two peaks and a plateau with gamma-cyclodextrin (γ-CD).

Main Methods:

• Capillary electrophoresis (CE) was employed for chiral separation.
• Nuclear magnetic resonance (NMR) spectroscopy, including Nuclear Overhauser effect (NOE) methods, was used to determine molecular conformation.
• Mass spectrometry (MS) was utilized to confirm complex stoichiometry.
• CE-MS was used to analyze the migration behavior of complexes.

Main Results:

• An unusual two-peak separation with a plateau was observed for DCV using γ-CD, indicative of complex interactions.
• NMR studies revealed that DCV adopts a folded conformation in solution, with valine side chains oriented towards aromatic rings.
• NMR and MS confirmed the simultaneous formation of both 1:1 and 2:1 DCV-γ-CD inclusion complexes, where DCV maintained a folded structure.
• CE-MS demonstrated that both DCV-γ-CD complexes comigrated as a single peak, distinct from non-complexed DCV.

Conclusions:

• The observed two-peak separation with a plateau in the chiral separation of DCV using γ-CD is attributed to the simultaneous formation of two distinct inclusion complexes (1:1 and 2:1 stoichiometry).
• DCV's inherent folded conformation plays a crucial role in its complexation with γ-CD.
• This study highlights the complex binding equilibria that can occur between chiral selectors and analytes, impacting separation outcomes.