Skip to main content
Log in

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

  • Original Article
  • Published:
Journal of Inclusion Phenomena and Macrocyclic Chemistry Aims and scope Submit manuscript


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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others


  1. Loftsson, T., Brewster, M.E.: Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. J. Pharm. Sci. 85(10), 1017–1025 (1996)

    Article  CAS  Google Scholar 

  2. Stella, V.J., Rajewski, R.A.: Cyclodextrins: their future in drug formulation and delivery. Pharm. Res. 14(5), 556–567 (1997)

    Article  CAS  Google Scholar 

  3. Menard, F.A., Dedhiya, M.G., Rhodes, C.T.: Physicochemical aspects of the complexation of some drugs with cyclodextrins. Drug Dev. Ind. Pharm. 16(1), 91–113 (1990)

    CAS  Google Scholar 

  4. Backensfeld, T., Muller, B.W., Kolter, K.: Interaction of NSA with cyclodextrins and hydroxypropyl cyclodextrin derivatives. Int. J. Pharm. 74(2–3), 85–93 (1991)

    Article  CAS  Google Scholar 

  5. Al Omari, M.M., Zughul, M.B., Davies, J.E.D., Badwan, A.A.: Effect of buffer species on the inclusion complexation of acidic drug celecoxib with cyclodextrin in solution. J. Incl. Phenom. Macrocyc. Chem. 55(3–4), 247–254 (2006)

    Article  Google Scholar 

  6. Al Omari, M.M., Zughul, M.B., Davies, J.E.D., Badwan, A.A.: Sildenafil/cyclodextrin complexation: stability constants, thermodynamics, and guest-host interactions probed by 1H-NMR and molecular modeling studies. J. Pharm. Biomed. Anal. 41(3), 857–865 (2006)

    Article  CAS  Google Scholar 

  7. Rekharsky, M.V., Goldberg, R.N., Schwarz, F.P., Tewari, Y.B., Ross, P.D., Yamashoji, Y., Inoue, Y.: Thermodynamic and nucler magnetic resonance study of the interactions of alpha- and beta-cyclodextrin with model substances: phenethylamine, ephedrines, and related substances. J. Am. Chem. Soc. 117, 8830 (1995)

    Article  CAS  Google Scholar 

  8. Muller, B.W., Albers, E.: Complexation of dihydropyridine derivatives with cyclodextrins and 2-hydroxypropyl-β-cyclodextrin in solution. Int. J. Pharm. 79(2–3), 273–288 (1992)

    Article  Google Scholar 

  9. Esclusa-Diaz, M.T., Gayo-Otero, M., Perez-Marcos, M.B., Vila-Jato, J.L., Torres-Labandeira, J.J.: Preparation and evaluation of ketoconazole-β-cyclodextrin multicomponent complexes. Int. J. Pharm. 142(2), 183–187 (1996)

    Article  CAS  Google Scholar 

  10. Higuchi, T., Connors, K.A.: Phase-solubility techniques. Advan. Anal. Chem. Instr. 4, 117–212 (1965)

    CAS  Google Scholar 

  11. Zughul, M.B., Badwan, A.A.: SL2 type phase solubility diagrams, complex formation and chemical speciation of soluble species. J. Incl. Phenom. Mol. Recog. Chem. 31(3), 243–264 (1998)

    Article  CAS  Google Scholar 

  12. El-Barghouthi, MI., Masoud, N.A., Al-Kafawein, J.K., Zughul, M.B., Badwan, A.A.: Hostguest interactions of risperidone with natural and modified cyclodextrins: phase solubility, thermodynamics and molecular modeling studies. J. Incl. Phenom. Macrocyc. Chem. 53(1–2), 15–22 (2005)

    Article  CAS  Google Scholar 

  13. Dewar, M.J.S., Zoebisch, E.G., Healy, E.F., Stewart, J. J.P.: Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model. J. Am. Chem. Soc. 107(13), 3902–3909 (1985)

    Article  CAS  Google Scholar 

  14. Puliti, R., Mattia, C.A., Paduano, L.: Crystal structure of a new alpha-cyclodextrin hydrate form. Molecular geometry and packing features: disordered solvent contribution. Carbohydr. Res. 310(1–2), 1–8 (1998)

    Article  CAS  Google Scholar 

  15. Linder, K., Saenger, W.: Topography of cyclodextrin complexes. Part XVII. Crystal and molecular structure of cycloheptaamylose dodecahydrate. Carbohydr. Res. 99(2), 103–115 (1982)

    Article  Google Scholar 

  16. Saenger, W., Jacob, J., Gessler, K., Steiner, T., Hoffman, D., Sanbe, H., Koizumi, K., Smith, S.M., Takaha, T.: Structures of the common cyclodextrins and their larger analogues-beyond the doughnut. Chem. Rev. 98(5), 1787–1802 (1998)

    Article  CAS  Google Scholar 

  17. Harata, K.: The structure of the cyclodextrin complex. XX. Crystal structure of uncomplexed hydrated β-cyclodextrin. Bull. Chem. Soc. Jpn. 60(8), 2763–2767 (1987)

    Article  CAS  Google Scholar 

  18. Tong, W., Lach, J.L., Chin, T., Guillory, J.K.: Structural effects on the binding of amine drugs with the diphenylmethyl functionality to cyclodextrins. II. A molecular modeling study. Pharm. Res. 8(10), 1307–1312 (1991)

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to M. B. Zughul.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: