Interactions of fexofenadine (Fexo) with cyclodextrins (CDs: alpha- beta-, gamma-, and HP-beta-CD) were investigated by several techniques including phase solubility, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), (1)H-nuclear magnetic resonance ((1)H-NMR) and molecular mechanical modeling (MM(+)). The effects of CD type, pH, ionic strength, and temperature on complex stability were also explored. Fexo/CD complex formation follows the decreasing order: beta-CD > HP-beta-CD > gamma-CD > alpha-CD (i.e., at pH 7.0 and 30 degrees C, K(11) = 1139, 406, 130, and 104 M(-1), respectively). The linear correlation of the free energy of Fexo/beta-CD complex formation (DeltaG(11)) with the free energy of inherent Fexo solubility (DeltaG(So)), obtained from the variation of K(11) with inherent Fexo solubility (S(o)) at different pHs and ionic strengths, was used to measure the contribution of the hydrophobic character of Fexo to escape from water by including into the hydrophobic CD cavity. The hydrophobic effect (desolvation) contributes about 76% of the total driving force towards inclusion complex formation, while specific interactions contribute -7.7 kJ/mol. Moreover, Zwitterionic Fexo/beta-CD complex formation appears to be driven both by favorable enthalpy (DeltaH degrees = -23.2 kJ/mol) and entropy (DeltaS degrees = 15.2 J/molxK) changes at pH 7.0. (1)H-NMR and MM(+) studies indicate multimodal inclusion of the piperidine, carboxypropylphenyl, and phenyl moieties into the beta-CD cavity. MM(+) computations indicate that the dominant driving force for complexation is Van der Waals force with very little electrostatic contribution. (1)H-NMR, DSC, and XRPD studies indicate the formation of inclusion complex in aqueous solution and the solid state.