title: Origin of non-linearity in phase solubility: solubilisation by cyclodextrin beyond stoichiometric complexation.
abstract: The low solubility of drugs, which poses a serious problem in drug development, can in part be overcome by the use of cyclodextrins (CDs) and their derivatives. Here, the key to solubilisation is identified as the formation of inclusion complexes with the drug molecule. If inclusion complexation were the only contribution to drug solubility, it would increase linearly with CD concentration (as per the Higuchi-Connors model); this is because inclusion complexation is a 1 : 1 stoichiometric process. However, solubility curves often deviate from this linearity, whose mechanism is yet to be understood. Here we aim to clarify the origin of such non-linearity, based on the Kirkwood-Buff and the McMillan-Mayer theories of solutions. The rigorous statistical thermodynamic theory shows that non-linearity of solubilisation can be rationalised by two contributions: CD-drug interaction and the drug-induced change of CD-CD interaction.
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5DD, UK. seishi.shimizu@york.ac.uk.
authors.forename: Thomas W J
authors.initials: TW
authors.lastname: Nicol
authors.affiliation: Division of Chemical Engineering, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka 560-8531, Japan and Elements Strategy Initiative for Catalysts and Batteries, Kyoto University, Katsura, Kyoto 615-8520, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matubayasi
authors.affiliation: York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5DD, UK. seishi.shimizu@york.ac.uk.
authors.forename: Seishi
authors.initials: S
authors.lastname: Shimizu