Advancing insights on β-cyclodextrin inclusion complexes with SSRIs through lens of X-ray diffraction and DFT calculation

Depression—the global crisis hastened by the coronavirus outbreak, can be efficaciously treated by the selective serotonin reuptake inhibitors (SSRIs). Cyclodextrin (CD) inclusion complexation is a method of choice for reducing side effects and improving bioavailability of drugs. Here, we investigate in-depth the β-CD encapsulation of sertraline (STL) HCl (1) and fluoxetine (FXT) HCl (2) by single-crystal X-ray diffraction and DFT complete-geometry optimization, in comparison to the reported complex of paroxetine (PXT) base. X-ray analysis unveiled the 2:2 β-CD–STL/FXT complexes with two drug molecules inserting their halogen-containing aromatic ring in the β-CD dimeric cavity, which are stabilized by the interplay of intermolecular O2–H [Formula: see text] N1–H [Formula: see text] O3 H-bonds, C3/C5–H [Formula: see text] π and halogen [Formula: see text] halogen interactions. Similarly, the 1:1 β-CD–tricyclic-antidepressant (TCA) complexes have an exclusive inclusion mode of the aromatic ring, which is maintained by C3/C5–H [Formula: see text] π interactions. By contrast, the 2:1 β-CD–PXT complex has a total inclusion that is stabilized by host–guest O6–H [Formula: see text] N1–H [Formula: see text] O5 H-bonds and C3–H [Formula: see text] π interactions. The inherent stabilization energies of 1 and 2 evaluated using DFT calculation suggested that the improved thermodynamic stabilities via CD encapsulation facilitates the reduction of drug side effects. Moreover, the SSRI conformational flexibilities are thoroughly discussed for understanding of their pharmacoactivity.