Abstract
Phase solubility techniques were used to obtain the complexation parameters of cisapride (Cisp) with β-cyclodextrin (β-CD) in aqueous 0.05 M citrate buffer solutions. From the UV absorption spectra and the pH solubility profile, two basic pK as 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+·citrate1− salt at low pH (pK sp = 3.0). Cisp forms soluble 1:1 and 1:2 Cisp/β-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/β-CD complex formation (ΔG 11 = −RT ln K 11 < 0) with that of the inherent solubility of Cisp \((\Delta G_{S_{\hbox{o}} } = - RT\,{\hbox{ln}}\,S_{\hbox{o}} > {\hbox{0}})\). 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/β-CD complex formation at pH 6.0 is driven by favorable enthalpy (ΔH° = −9 kJ/mol) and entropy (ΔS° = 51 J/mol K) changes. In contrast, inherent Cisp solubility is impeded by unfavorable enthalpy (ΔH° = 12 kJ/mol) and entropy (ΔS° = 90 J/mol K) changes. 1H-NMR spectra in D2O and molecular mechanical studies indicate the formation of inclusion complexes. The dominant driving force for neutral Cisp/β-CD complexation in vacuo was predominantly van der Waals with very little electrostatic contribution.
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Al Omari, M.M., Zughul, M.B., Davies, J.E.D. et al. Cisapride/β-cyclodextrin complexation: stability constants, thermodynamics, and guest–host interactions probed by 1H-NMR and molecular modeling studies. J Incl Phenom Macrocycl Chem 57, 511–517 (2007). https://doi.org/10.1007/s10847-006-9242-7
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DOI: https://doi.org/10.1007/s10847-006-9242-7