β-Cyclodextrin Inclusion Complexation With Tricyclic Antidepressants Desipramine and Imipramine: A Structural...

Single-crystal X-ray diffraction and DFT calculation have been carried out for an atomic-level understanding of β-cyclodextrin (β-CD) inclusion complexation with 2 tricyclic antidepressants (TCAs), desipramine and imipramine. X-ray analysis discloses that the A-C-rings are buried in the β-CD cavity and the side chain is mostly outside the cavity, nearby the O2-H/O3-H side. Hence, the inclusion structures of both complexes are stabilized by host-guest C5-H∙∙∙π interaction and N5'-H∙∙∙O5/O6 H-bonds of twofold-screw-symmetry-related molecules, which are similar to those of the reported complexes of nortriptyline and amitriptyline. The DFT full-geometry optimization in the gas phase reveals an alternative inclusion scenario with the TCA side chain that is embedded in the β-CD cavity and stabilized by intermolecular O6-H∙∙∙N5' H-bond and O2-H/O3-H∙∙∙π interactions. The β-CD encapsulation of the TCA side chain is more energetically stable by 10.76 and 4.70 kcal mol^-1 than that of the aromatic moiety for the respective complexes of DPM and IPM, based on the relative stabilization energies (ΔΔE_stb). This suggests the existence of the bimodal β-CD-TCA inclusion complexes as spectroscopically observed in solution, thus explaining the controversy in the inclusion mode and the improvement of TCA therapeutic effect by CD encapsulation.