Inclusion complexes of β-cyclodextrin with tricyclic drugs: an X-ray diffraction, NMR and molecular dynamics study

Area of Science:

• Supramolecular Chemistry
• Drug Delivery Systems
• Molecular Recognition

Background:

• Cyclobenzaprine and amitriptyline are tricyclic compounds with therapeutic applications.
• Beta-cyclodextrin (β-CD) is a cyclic oligosaccharide known for forming inclusion complexes.
• Understanding drug-host interactions is crucial for developing effective drug delivery systems.

Purpose of the Study:

• To investigate the formation and structural characteristics of 1:1 inclusion complexes between cyclobenzaprine and β-CD.
• To compare the inclusion behavior of cyclobenzaprine with that of amitriptyline, a structurally related drug.
• To elucidate the molecular interactions governing these supramolecular assemblies.

Main Methods:

• Formation and characterization of inclusion complexes in both solid state and aqueous solution.
• Rotating Frame Overhauser Effect spectroscopy (ROESY) to determine inclusion geometry.
• Molecular Dynamics (MD) simulations to model complex behavior in solution.
• Single-crystal X-ray diffraction to analyze solid-state structures.

Main Results:

• Both cyclobenzaprine/β-CD and amitriptyline/β-CD formed stable 1:1 inclusion complexes.
• ROESY experiments and MD simulations showed consistent inclusion geometry: aromatic rings entered the β-CD cavity via the wide rim, with the alkylammonium chain extending outwards.
• X-ray diffraction confirmed this inclusion mode in the solid state.
• MD simulations accurately reproduced experimental observations, including conformational flexibility in aqueous solution.

Conclusions:

• The study elucidates the precise mode of inclusion for cyclobenzaprine and amitriptyline within β-CD.
• The findings highlight the potential of β-CD as a host molecule for these drugs, impacting formulation and delivery.
• Molecular dynamics simulations serve as a powerful tool to complement experimental structural data.