Inclusion complexes of loratadine with (3-cyclodextrin and its derivatives in solution. Integrated spectroscopic, thermodynamic and computational studies

The low aqueous solubility of drugs like loratadine (LOR) can be increased by the formation of inclusion complexes with cyclodextrins. The complexation of LOR by (3-cyclodextrin ((3-CD) and its derivatives (hydroxypropyl (3-CD (HP-(3-CD), randomly methylated (3-CD (RM-(3-CD) and sulfobutylether (3-CD sodium salt (SBE-(3-CD)) in water and simulated biorelevant media was thoroughly studied by means of an integrated approach comprising phase solubility experiments, ITC, MS, NMR spectroscopy, and computational methods. The addition of all investigated cyclodextrins considerably increased the LOR solubility, the most effective being RM-(3-CD. The formation of 1:1 and 1:2 (LOR:CD) inclusion complexes was observed for all derivatives, and the corresponding reactions were thermodynamically characterized by determining and discussing the complex stability constants (and derived standard reaction Gibbs energies), standard reaction enthalpies and entropies. The structures of (3-CD complexes with non-protonated and protonated (LORH+) loratadine forms were elucidated by comprehensive 1D and 2D NMR spectroscopy. Additional information regarding the structures as well as the energetic and thermodynamic stabilities of LOR and LORH+ complexes was obtained by carrying out the DFT calculations, which corroborated the experimental results. It was found that protonation had minor effect on the complex stability.