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

The beta-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 beta-CD O2-H/O3-H-side and are kept in position by C5-H pi interactions, yielding thermodynamically favorable complexes. In the beta-CD cavity, NRT and AMT are less open as their butterfly angles are similar to 10 degrees 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'HClH-O26 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 beta-CD-TCA complexes. This study provides a rigorous crystallographic evidence for the beta-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.