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

  • M. M. Al Omari
  • M. B. Zughul
  • J. Eric D. Davies
  • A. A. Badwan
Original Article


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.


Cisapride Cyclodextrin Hydrophobic effect Thermodynamics 1H-NMR Molecular mechanical modeling 


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Copyright information

© Springer Science+Business Media, Inc. 2007

Authors and Affiliations

  • M. M. Al Omari
    • 1
  • M. B. Zughul
    • 2
  • J. Eric D. Davies
    • 3
  • A. A. Badwan
    • 1
  1. 1.The Jordanian Pharmaceutical Manufacturing CompanyNaorJordan
  2. 2.Department of ChemistryUniversity of JordanAmmanJordan
  3. 3.Deparment of Environmental ScienceLancaster UniversityLancasterEngland

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