β-Cyclodextrin encapsulation of nortriptyline HCl and amitriptyline HCl: Molecular insights from single-crystal X-ray diffraction and DFT calculation.

The β-CD encapsulation of two tricyclic antidepressants (TCAs), nortriptyline (NRT) HCl and amitriptyline (AMT) HCl (most widely used TCA), has been thoroughly investigated by single-crystal X-ray diffraction and DFT calculation for insights into the inclusion complexation. X-ray analysis reveals that both drugs insert the A-ring moiety vertically from the β-CD O2H/O3H-side and are kept in position by C5H⋯π interactions, yielding thermodynamically favorable complexes. In the β-CD cavity, NRT and AMT are less open as their butterfly angles are ~10° smaller than those in free HCl salt forms and in complex with proteins. The effect of HCl salt on both complexes is evaluated by DFT full-geometry optimization. When Cl- is directly linked with the NRT NH2Me+ group, the inclusion complex formed gains stability by 3.65 kcal mol-1 through N5'H⋯Cl⋯HO26 H-bond chain, compared to the complex of NRT base. The addition of HCl to N5' of the side chain marginally affects the structures of β-CD-TCA complexes. This study provides a rigorous crystallographic evidence for the β-CD-TCA complexation and a theoretical view on the improved stability of TCA in the CD cavity, supporting the pharmacological benefit of CD encapsulation in reducing the TCA side effects.