Cisapride/β-cyclodextrin complexation:: stability constants, thermodynamics, and guest-host interactions probed by 1H-NMR and molecular modeling studies

Phase solubility techniques were used to obtain the complexation parameters of cisapride (Cisp) with beta-cyclodextrin (beta-CD) in aqueous 0.05 M citrate buffer solutions. From the UV absorption spectra and the pH solubility profile, two basic pK (a)s were estimated: pK (a(1+)) = 8.7 and pK (a(2+)) < 2. The inherent solubility (S (o)) of Cisp was found to increase as pH decreases, but is limited by the solubility product of the CispH(+)center dot citrate(1-) salt at low pH (pK (sp) = 3.0). Cisp forms soluble 1:1 and 1:2 Cisp/beta-CD complexes. A quantitative measure of the hydrophobic effect (desolvation) contribution to 1:1 complex formation was obtained from the linear variation of free energy of 1:1 Cisp/beta-CD complex formation (Delta G(11) = -RT ln K-11 < 0) with that of the inherent solubility of Cisp (Delta DG(So) = -RTln S-o > 0). The results show that the hydrophobic character of Cisp contributes about 35% of the total driving force to 1:1 complex formation (slope = -0.35), while other factors, including specific interactions, contribute -10.6 kJ/mol (intercept). Protonated 1:1 Cisp/beta-CD complex formation at pH 6.0 is driven by favorable enthalpy (Delta H degrees = -9 kJ/mol) and entropy (Delta S degrees = 51 J/mol K) changes. In contrast, inherent Cisp solubility is impeded by unfavorable enthalpy (Delta H = 12 kJ/mol) and entropy (Delta S degrees = 90 J/mol K) changes. H-1-NMR spectra in D2O and molecular mechanical studies indicate the formation of inclusion complexes. The dominant driving force for neutral Cisp/beta-CD complexation in vacuo was predominantly van der Waals with very little electrostatic contribution.