The Inclusion Complexes of beta-cyclodextrin with Tricyclic Drugs: An X-ray Diffraction, NMR and Molecular Dynamics Study

Cyclobenzaprine HCI and Amitriptyline HCl are tertiary amine tricyclic drugs extensively used in the pharmaceutical industry. These molecules represent excellent model compounds to investigate the relationship between intermolecular i nteractions and structure of the inclusion complex with cyclodextrins (CD), both in the crystal and in solution. The guest molecules Cyclobenzaprine and Amitriptyline show a large aromatic ring system able to interact with CD cavity and a polar ammonium group with affinity for the OH groups of CD and the water environment. Moreover, Cyclobenzaprine and Amitriptyline show different conformational flexibility due to the structure of the seven-membered ring. Finally, although Cyclobenzaprine and Amitriptyline have no stereocenters, they are both not-planar and without symmetry elements and thus they tum out to be chiral. Title compounds were found to fom1 inclusion complexes with CD in the sol id state and in water solution. The structures of Cyclobenzaprine /BetaCD and Amitriptyline/BetaCD complexes were obtained via single crystal X-ray diffraction. The 1:1 complexes are packed in head-to-tail columnar arrangement along the b axis. Intermolecular H-bonds between one guest molecule with the primary OHs of CD in adjacent position, along with usual CD-CD hydrogen bonds, are stabilizing factors of the complexes in the solid state. The NMR spectra of the complex Cyclobenzaprine/BetaCD clearly showed the presen ce of two diastereomeric complexes due to chiral recognition of both enantiomers of Cyclobenzaprine. 2D ROESY spectra gave details of the geometry of inclusion in solution, pointing out significant similarities with the complex in the crystal state. Conversely, NMR spectra of the complex Amitriptyline/BetaCD did not show any evidence of chiral discrimination, possibly due to enhanced conformationa l flexi bility of Amitriptyline with respect to Cyclobenzaprine. The dynamic behavior of Cyclobenzaprine /BetaCD and Amitriptyline/BetaCD complexes was simulated by using the computational protocol proposed by some of us. Simulations were carried out both in vacuo to study the most stable inclusion compound for a comparison with the crystallographic results, and in explicit water to study the families of stable conformers populated at room temperature and explain more thoroughly the NMR data in solution.