| Summary: | Depression is a global threat. Tricyclic antidepressants (TCAs) are still efficacious in treating depression, albeit with more side effects. Cyclodextrins (CDs) with a suitable nanocavity are potential drug carriers and can enhance the drug bioavailability. Aiming for an atomistic understanding of the CD encapsulation facilitating the improvement of drug stability and the reduction of side effects, a comprehensive study series of the β-CD–TCA inclusion complexes through single crystal X-ray diffraction and density functional theory (DFT) calculation was undertaken. This work reports the supramolecular complexes of β-CD with two pivotal TCAs, clomipramine (CPM; <b>1</b>) and doxepin (DXP; <b>2</b>). The different inclusion topologies of the β-CD–TCA complexes were notable. X-ray analysis revealed that, in <b>1,</b> the CPM B-ring (without chloro group) was entrapped in the β-CD cavity, whereas, in <b>2,</b> the <i>E</i>-DXP A-ring and the <i>Z</i>-DXP B-ring were disordered in the cavity, yielding energetically favorable complexes primarily maintained by intermolecular C–H<b>⋯</b>π interactions, as indicated by DFT calculation. Because both wings of TCAs were similar, an alternative inclusion scenario of the A-ring was evidenced crystallographically in four other TCA complexes. The enhanced TCA thermodynamic stabilities via CD inclusion complexation helped to reduce the side effects and to increase the bioavailability. Moreover, the scrutinization of six TCAs in different lattice circumstances revealed the greater TCA structural flexibilities for their optimum pharmacological activity while binding with proteins.
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