The extent and mode of solubility enhancement exerted by the cyclodextrins (alpha-, beta-, gamma-, and HP-beta-CDs) on loratadine (Lort) have been experimentally measured under controlled conditions in buffered aqueous solutions. Rigorous nonlinear regression analysis of the phase solubility diagrams obtained in 0.1 mol center dot L-1 phosphate buffer at pH = 7.0 and 25 degrees C revealed the following: neutral Lort (pK(a) = 4.6) tends to form soluble 1: 1 and 1:2 Lort/CD complexes with all four of the examined CDs, where complex stability follows the decreasing order -CD > HP-P-CD > gamma-CD > alpha-CD. The hydrophobic character of Lort constitutes about 66% of the driving force for complex formation whereas specific interactions contribute 11.2 kJ center dot mol(-1) towards the stability of the complexes. Thermodynamic studies showed that Lort/CD complex formation was favored by large enthalpic contributions but was impeded by negative entropic changes. Dissolution studies indicate that the dissolution rate of Lort from the freeze-dried Lort/beta-CD complex is significantly higher than that of the corresponding physical mixture. Both DSC studies and molecular mechanical modeling of Lort/beta-CD interactions were carried out to explore the possible formation of inclusion complexes.