Advertisement

Thermodynamic enthalpy–entropy compensation effects observed in the complexation of basic drug substrates with β-cyclodextrin

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

Abstract

Measurement of the variation of inherent drug solubility (S o) and 1:1 drug/cyclodextrin complex formation constants (K 11) with temperature were used to estimate the thermodynamic parameters (ΔH o, ΔS o and ΔGo). A plot of TΔS o against ΔH o indicates the extent of enthalpy–entropy compensation; that is, how much of the enthalpic gain is cancelled by entropy loss or vice versa (the slope indicates the fraction of conformational change contribution to enthalpy gain that is cancelled by an accompanying entropy loss). The remaining fraction of enthalpy gain contributes to complex formation. The intercept is the inherent contribution to complex stability, which is due to desovation. Extensive phase solubility studies combined with rigorous analysis were conducted in the temperature range 20–45°C for the following basic drugs complexing with β-cyclodextrin (β-CD): astemizole (Astm), cisapride (Cisp), dipyridamole (Dipy), ketotifen (Keto), pizotifen (Pizo), terfenadine (Terf), fexofenadine (Fexo), sildenafil (Sild), and celecoxib (Celox). The results indicate that inherent drug solubility is accompanied by unfavorable conformational changes to the extent of 86%, which are counterbalanced by opposite favorable entropy changes. Only 14% of the favorable enthalpy change contributes to drug solubility. The extent of solvation (hydration) accompanying solubility amounts to −30 kJ/mol, which retards solubility as an unfavorable entropy change. In contrast, 1:1 drug/β-CD complex formation is accompanied by favorable conformational changes to the extent of 94%, which are counterbalanced by unfavorable entropy changes. Only about 6% of enthalpy changes contribute to complex stability. However, the extent of favorable entropy change (desolvation) accompanying complex formation amounts to 26 kJ/mol.

Keywords

Basic drug cyclodextrin complexation Enthalpy–entropy compensation Phase solubility diagrams Thermodynamics 

References

  1. 1.
    Ventura, P., Chiesi, P., Pasini, M., Redenti, E., Szejtli, J., Vikmon, M.: US Patent 5855916, Chiesi Farmaceutici SPA. Co. (1995)Google Scholar
  2. 2.
    Badwan, A.A., Abu-Malooh, A., Haddadin, M., Ibrahim, H.: US Patent 5646131, Arab company for Drug Industries and Medical appliances (ACDIMA) (1997)Google Scholar
  3. 3.
    Al Omari, M.M., Zughul, M.B., Davies, J.E.D., Badwan, A.A.: US Patent EP1570862 Al, Application No. EP 2004- 4227 20040225 (2005)Google Scholar
  4. 4.
    Ilium, L., Watts, P.J., Cheng, Y.: Patent W020000215l0, Application No. W099-GB3396 19991012 (2000)Google Scholar
  5. 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)CrossRefGoogle Scholar
  6. 6.
    Torri, G., Naggi, A., Fregnan, G.B., Trebbi, A.: Dipyridamole-β-cyclodextrin complex: preparation and characterization. Pharmazie. 45(3), 193–195 (1990)Google Scholar
  7. 7.
    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)CrossRefGoogle Scholar
  8. 8.
    Bacchi, A., Pelizzi, G., Sheidrick, G.M., Amari, G., Deicanale, M., Redenti, E.: The molecular structure and crystal organization of Rac-terfenadine/β-cyclodextrin/tartaric acid multicomponent inclusion complex. Supramol. Chem. 14(1), 67–74 (2002)CrossRefGoogle Scholar
  9. 9.
    Tong, W.Q., Lach, J.L., Chin, T.F., Guillory, J.K.: Structural effects on the binding of amine drugs with the diphenylmethyl functionality to cyclodextrins. I. A micro-calorimetric study. Pharm. Res. 8(7), 951–957 (1991)CrossRefGoogle Scholar
  10. 10.
    Tong, W.Q., Lach, J.L., Chin, T.F., Guillory, J.K.: Microcalorimetric investigation of the complexation between 2-hydroxypropyl-beta-cyclodextrin and amine drugs with the diphenylmethyl functionality. J. Pharm. Biomed. Anal. 9(10–12), 1139–1146 (1991)CrossRefGoogle Scholar
  11. 11.
    Choi, H., Lee, B., Han, J., Lee, M., Park, K., Yong, C., Rhee, J., Kim, Y., Kim, C.: Terfenadine-β-cyclodextrin inclusion complex with antihistaminic activity enhancement. Drug Dev. Ind. Pharm. 27(8), 857–862 (2001)CrossRefGoogle Scholar
  12. 12.
    Redenti, E., Pasini, M., Ventura, P., Spisni, A., Vikmon, M., Szejtli, J.: The terfenadine/β-cyclodextrin inclusion complex. J. Incl. Phenom. Mol. Recog. Chem. 15(3), 281–292 (1994)CrossRefGoogle Scholar
  13. 13.
    Rawat, S., Jain, S.K.: Solubility enhancement of celecoxib using β-cyclodextrin inclusion complexes. Eur. J. Pharm. Biopharm. 57, 263–267 (2004)CrossRefGoogle Scholar
  14. 14.
    Reddy, M.N., Rehana, T., Ramakrishna, S., Chowdary, K.P.R., Diwan, P.V.: β-Cyclodextrin complexes of celecoxib: molecular-modeling, characterization, and dissolution studies. AAPS Pharm. Sci. 6(1), Article 7 (http://www.aapspharmsci.org (2004)
  15. 15.
    Sinha, V.R., Anitha, R., Ghosh, S., Nanda, A., Kumria, R.: Complexation of celecoxib with β-cyclodextrin: characterization of the interaction in solution and in solid state. J. Pharm. Sci. 94(3), 676–687 (2005)CrossRefGoogle Scholar
  16. 16.
    Rao, G.C.S., Kumar, M.S., Mathivanan, N., Rao, M.E.B.: Improvement of physical stability and dissolution rate of celecoxib suspensions by complexation with β-cyclodextrins. Pharmazie, 59(8), 627–630 (2004)Google Scholar
  17. 17.
    Rekharsky, M.V., Inoue, Y.: Complexation thermodynamics of cyclodextrins. Chem. Rev. 98(5), 1875–1918 (1998)CrossRefGoogle Scholar
  18. 18.
    Liu, L., Guo, Q-X.: The driving forces in the inclusion complexation of cyclodextrins. J. Incl. Phenom. Macrocyc. Chem. 42(1–2), 1–14 (2002)CrossRefGoogle Scholar
  19. 19.
    Higuchi, T., Connors, K.A.: Phase-solubility techniques. Advan. Anal. Chem. Instr. 4, 117–212 (1965)Google Scholar
  20. 20.
    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)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2007

Authors and Affiliations

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

Personalised recommendations