Evidence for the 2:1 molecular recognition and inclusion behaviour between β- and γ-cyclodextrins and cinchonine

Cinchonine (Cin) is the primary drug of choice in the treatment of malaria, but its poor solubility has restricted its use via the oral route. Cyclodextrins (CDs) form inclusion complexes with cinchonine to form soluble complexes. This interaction was investigated by solubility studies, electrospray ionization mass spectrometry (ESI-MS), and molecular modeling. ESI-MS evaluated successfully the nature of the solution-phase inclusion complexes. The experimental results showed that not only 1:1, but also stable 2:1 inclusion complexes can be formed between CDs and Cin. Multi-component complexes of β-CD–Cin–β-CD (1:1:1), γ-CD–Cin–γ-CD (1:1:1), and β-CD–Cin–γ-CD (1:1:1) were found in equimolar β- and γ-CD mixtures with Cin. The formation of 2:1 and multi-component 1:1:1 non-covalent CD–Cin complexes indicates that β- and γ-CD are able to form sandwich-type inclusion complexes with Cin in high concentrations. The phase-solubility diagram showed non-linear type Ap profile, indicating that more than one cyclodextrin molecule is involved in the complexation of one guest molecule. Molecular modeling calculations have been carried out to rationalize the experimental findings and predict the lowest energy molecular structure of inclusion complex.