A novel approach to improving solubility of drugs: chelation-assisted solubility enhancement (CHASE)

We explore a novel concept of metal Chelation-assisted Solubility Enhancement (CHASE). This study is based on complexation with Na⁺ or K⁺. A series of 6 compounds are studied by conjugating a hydrophobic moiety with benzo-15-crown-5. LogP values are determined in the absence and presence of Na⁺ or K⁺, respectively. The largest shift upon metal chelation is with compound 7 (a pyrenyl-crown ether conjugate), which has a logP of 3.61 in the absence of any metal ion and 0.99 and 1.45 in the presence of Na⁺ or K⁺, respectively. Such results clearly demonstrate the feasibility of the proposed approach. Beyond chelation, cation-π interactions seem to play a substantial role in determining the partitioning outcome for those with an aryl system. Such findings suggest the need for all future partition experiments to incorporate biologically relevant concentrations of metal ions. This feasibility study opens a new direction in improving drug solubility.