Inclusion complexes of tricyclic drugs and β-cyclodextrin: Inherent chirality and dynamic behaviour

Abstract

Amitriptyline (AMT) and cyclobenzaprine (CBZ) are tricyclic drugs used as antidepressant and muscle relaxant, respectively. They show inherently chirality, i.e. they are chiral due to the lack of any symmetry element. As they are used as racemic mixture, diastereomeric inclusion complexes are formed via encapsulation in homochiral βCD. In this work we show that a suitable combination of NMR methods easily provides details on the chiral recognition, geometry of complexation, rotational dynamics and spatial proximity of selected atom pairs. In particular, we show that ¹³C NMR can be used to unambiguously assess chiral recognition, demonstrating a higher performance over ¹H NMR. The mole fraction of the bound drug and the association constant can be worked out through diffusion experiments, whereas the combination of non-selective, selective and bi-selective relaxation spectra gave insights into the rotational motion of the complexed drug and the spatial proximity of selected proton pairs. The toolkit here proposed provides a thorough characterization of CD/drug inclusion complexes from a physicochemical point of view. This can constructively complement the conventional pharmacological and pharmacokinetic experiments, and can shed light on the understanding of CD/drug formulations.

Keywords: Chiral recognition; Dynamics; Host-guest complex; NMR spectroscopy; Tricyclic drugs.