Skip to main content

Advertisement

SpringerLink
Log in

Studies of curcumin and curcuminoids. XXXVI. The stoichiometry and complexation constants of cyclodextrin complexes as determined by the phase-solubility method and UV–Vis titration

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

Abstract

Cyclodextrin (CD) complex stoichiometry and complexation constant with two symmetric curcuminoids and two unsymmetric curcuminoid-like compounds were investigated and compared by two independent methods, the phase-solubility method and ultraviolet-visible absorption spectroscopy (UV–Vis) titration. Two different methods were applied in an effort to increase the apparent intrinsic solubility of the compounds and make the investigation of stoichiometry and complexation constants possible. The intrinsic solubility could be determined for all four compounds in aqueous 10% (v/v) ethanolic solutions. Higher order complexation or solubilization through complex aggregation was observed for the symmetric molecules, while 1:1 complexation was observed for the unsymmetric molecules in the phase-solubility diagram. The UV–Vis investigation showed 1:1 complexation for all compounds, with some indication of higher order complexation for the symmetric molecules. Thus the stoichiometry found with the two methods correlated well for the unsymmetric, but not for the symmetric compounds where the phase-solubility investigations clearly indicated higher order complexation and possible aggregation of complexes. There was also a difference between the 1:1 complexation constants found with the two methods, especially for the compounds with low intrinsic solubility (i.e. the symmetric curcuminoids). However, they agree in the ranking of complexes according to the strength of the association. The 1:2 complexation constant observed with the phase-solubility method was more than 100 times the complexation constant found with the UV–Vis method, which explains why solubility is poorly predicted from the UV–Vis data. This discrepancy may be explained by solubilization by aggregation of complexes or some phenomena other than inclusion complexation.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Supardjan, A.M.: Chemical content of turmeric curcumin and its derivatives. Majalah Farmasi Indones. 12(3), 115–119 (2001)

    CAS  Google Scholar 

  2. Lauro, G.J., Francis, F.J.: Natural Food Colorants: Science and Technology. Marcel Dekker, Chicago (2000)

    Google Scholar 

  3. Tønnesen, H.H., Arrieta, A.F., Lerner, D.: Studies on curcumin and curcuminoids. Part XXIV. Characterization of the spectroscopic properties of the naturally occurring curcuminoids and selected derivatives. Pharmazie 50(10), 689–693 (1995)

    Google Scholar 

  4. Tønnesen, H.H., Grislingaas, A.L., Karlsen, J.: Studies on curcumin and curcuminoids. Part 19. Evaluation of thin-layer chromatography for the quantitation of curcumin and curcuminoids. Z. Lebensm.-Unters. Forsch. 193(6), 548–550 (1991)

    Article  Google Scholar 

  5. Banerji, A., Chakrabarti, J., Mitra, A., Chatterjee, A.: Effect of curcumin on gelatinase A (MMP-2) activity in B16F10 melanoma cells. Cancer Lett. (Amsterdam, Netherlands) 211(2), 235–242 (2004)

    CAS  Google Scholar 

  6. Syng-ai, C., Kumari, A.L., Khar, A.: Effect of curcumin on normal and tumor cells: role of glutathione and bcl-2. Mol. Cancer Ther. 3(9), 1101–1108 (2004)

    CAS  Google Scholar 

  7. Adams, B.K., Ferstl, E.M., Davis, M.C., Herold, M., Kurtkaya, S., Camalier, R.F., Hollingshead, M.G., Kaur, G., Sausville, E.A., Rickles, F.R., Snyder, J.P., Liotta, D.C., Shoji, M.: Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents. Bioorg. Med. Chem. 12(14), 3871–3883 (2004)

    Article  CAS  Google Scholar 

  8. Duvoix, A., Blasius, R., Delhalle, S., Schnekenburger, M., Morceau, F., Henry, E., Dicato, M., Diederich, M.: Chemopreventive and therapeutic effects of curcumin. Cancer Lett. 223(2), 181–190 (2005)

    Article  CAS  Google Scholar 

  9. Sui, Z., Salto, R., Li, J., Craik, C., Ortiz de Montellano, P.R.: Inhibition of the HIV-1 and HIV-2 proteases by curcumin and curcumin boron complexes. Bioorg. Med. Chem. 1(6), 415–422 (1993)

    Article  CAS  Google Scholar 

  10. Mazumder, A., Raghavan, K., Weinstein, J., Kohn, K.W., Pommier, Y.: Inhibition of human immunodeficiency virus type-1 integrase by curcumin. Biochem. Pharmacol. 49(8), 1165–1170 (1995)

    Article  CAS  Google Scholar 

  11. Artico, M., Di Santo, R., Costi, R., Novellino, E., Greco, G., Massa, S., Tramontano, E., Marongiu, M.E., De Montis, A., La Colla, P.: Geometrically and conformationally restrained cinnamoyl compounds as inhibitors of HIV-1 integrase: synthesis, biological evaluation, and molecular modeling. J. Med. Chem. 41(21), 3948–3960 (1998)

    Article  CAS  Google Scholar 

  12. Vajragupta, O., Boonchoong, P., Morris, G.M., Olson, A.J.: Active site binding modes of curcumin in HIV-1 protease and integrase. Bioorg. Med. Chem. Lett. 15(14), 3364–3368 (2005)

    Article  CAS  Google Scholar 

  13. Egan, M.E., Pearson, M., Weiner, S.A., Rajendran, V., Rubin, D., Gloeckner-Pagel, J., Canny, S., Du, K., Lukacs, G.L., Caplan, M.J.: Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science (Washington, DC, United States) 304(5670), 600–602 (2004)

    Article  CAS  Google Scholar 

  14. Zeitlin, P.: Can curcumin cure cystic fibrosis? N. Engl. J. Med. 351(6), 606–608 (2004)

    Article  CAS  Google Scholar 

  15. Gao, X., Kuo, J., Jiang, H., Deeb, D., Liu, Y., Divine, G., Chapman, R.A., Dulchavsky, S.A., Gautam, S.C.: Immunomodulatory activity of curcumin: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production in vitro. Biochem. Pharmacol. 68(1), 51–61 (2004)

    Article  CAS  Google Scholar 

  16. Chueh, S.C.J., Lai, M.K., Liu, I.S., Teng, F.C., Chen, J.: Curcumin enhances the immunosuppressive activity of cyclosporine in rat cardiac allografts and in mixed lymphocyte reactions. Transplant. Proc. 35(4), 1603–1605 (2003)

    Article  CAS  Google Scholar 

  17. Gomes Denise de Castro, F., Alegrio Leila, V., Leon Leonor, L., de Lima Marco Edilson, F.: Total synthesis and anti-leishmanial activity of some curcumin analogues. Arzneimittelforschung 52(9), 695–698 (2002)

    Google Scholar 

  18. Tønnesen, H.H., de Vries, H., Karlsen, J., Beijersbergen van Henegouwen, G.: Studies on curcumin and curcuminoids. IX: Investigation of the photobiological activity of curcumin using bacterial indicator systems. J. Pharm. Sci. 76(5), 371–373 (1987)

    Article  Google Scholar 

  19. Anand, P., Kunnumakkara, A.B., Newman, R.A., Aggarwal, B.B.: Bioavailability of curcumin: problems and promises. Mol. Pharm. 4(6), 807–818 (2007)

    Article  CAS  Google Scholar 

  20. Tønnesen, H.H., Masson, M., Loftsson, T.: Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and photochemical stability. Int. J. Pharm. 244(1–2), 127–135 (2002)

    Article  Google Scholar 

  21. Tønnesen, H.H.: Solubility and stability of curcumin in solutions containing alginate and other viscosity modifying macromolecules. Studies of curcumin and curcuminoids. XXX. Pharmazie 61(8), 696–700 (2006)

    Google Scholar 

  22. Tønnesen, H.H., Karlsen, J.: Studies on curcumin and curcuminoids. V. Alkaline degradation of curcumin. Z. Lebensm.-Unters.-Forsch. 180(2), 132–134 (1985)

    Article  Google Scholar 

  23. Tønnesen, H.H., Karlsen, J., van Henegouwen, G.B.: Studies on curcumin and curcuminoids. VIII. Photochemical stability of curcumin. Z. Lebensm.-Unters.-Forsch. 183(2), 116–122 (1986)

    Article  Google Scholar 

  24. Tønnesen, H.H.: Studies of curcumin and curcuminoids, XXVIII. Solubility, chemical and photochemical stability of curcumin in surfactant solutions. Pharmazie 57(12), 820–824 (2002)

    Google Scholar 

  25. Loftsson, T., Magnusdottir, A., Masson, M., Sigurjonsdottir, J.F.: Self-association and cyclodextrin solubilization of drugs. J. Pharm. Sci. 91(11), 2307–2316 (2002)

    Article  CAS  Google Scholar 

  26. Loftsson, T., Hreinsdottir, D., Masson, M.: Evaluation of cyclodextrin solubilization of drugs. Int. J. Pharm. 302(1–2), 18–28 (2005)

    Article  CAS  Google Scholar 

  27. Loftsson, T., Masson, M., Brewster, M.E.: Self-association of cyclodextrins and cyclodextrin complexes. J. Pharm. Sci. 93(5), 1091–1099 (2004)

    Article  CAS  Google Scholar 

  28. Loftsson, T., Duchene, D.: Cyclodextrins and their pharmaceutical applications. Int. J. Pharm. 329(1–2), 1–11 (2007)

    Article  CAS  Google Scholar 

  29. Duan, M.S., Zhao, N., Oessurardottir, I.B., Thorsteinsson, T., Loftsson, T.: Cyclodextrin solubilization of the antibacterial agents triclosan and triclocarban: formation of aggregates and higher-order complexes. Int. J. Pharm. 297(1–2), 213–222 (2005)

    CAS  Google Scholar 

  30. Tomren, M.A., Masson, M., Loftsson, T., Tønnesen, H.H.: Studies on curcumin and curcuminoids. XXXI. Symmetric and asymmetric curcuminoids: stability, activity and complexation with cyclodextrins. Int. J. Pharm. 338(1–2), 27–34 (2007)

    Article  CAS  Google Scholar 

  31. Szente, L., Mikuni, K., Hashimoto, H., Szejtli, J.: Stabilization and solubilization of lipophilic natural colorants with cyclodextrins. J. Inclusion Phenom Mol. Recognit. Chem. 32(1), 81–89 (1998)

    Article  CAS  Google Scholar 

  32. Baglole, K.N., Boland, P.G., Wagner, B.D.: Fluorescense enhancement of curcumin upon inclusion into parent and modified cyclodextrins. J. Photochem. Photobiol. A 173, 230–237 (2005)

    Article  CAS  Google Scholar 

  33. Swaroop, S., Mishra, B., Priyadarsini, K.I.: Studies on b-cyclodextrin inclusion complex of curcumin. Proc. Natl. Acad. Sci. India Sect. B Biol. Sci. 77(3), 205–211 (2007)

    Google Scholar 

  34. Tang, B., Ma, L., Wang, H.Y., Zhang, G.Y.: Study on the supramolecular interaction of curcumin and beta-cyclodextrin by spectrophotometry and its analytical application. J. Agric. Food Chem. 50, 1355–1361 (2002)

    Article  CAS  Google Scholar 

  35. Qi, A.D., Li, L., Liu, Y.: The binding ability and inclusion complexation behavior of curcumin with natural alpha-, beta-, gamma-cyclodextrins and organoselenium-bridged bis (beta-cyclodextrin)s. J. Chin. Pharm. Sci. 12(1), 15–20 (2003)

    CAS  Google Scholar 

  36. Tønnesen, H.H., Karlsen, J., Adhikary, S.R., Pandey, R.: Studies on curcumin and curcuminoids. Part 17. Variation in the content of curcuminoids in Curcuma longa from Nepal during one season. Z. Lebensm.-Unters. Forsch. 189(2), 116–118 (1989)

    Article  Google Scholar 

  37. Hegge, A.B., Màsson, M., Kristensen, S., and Tønnsen, H.H.: Investigation of curcumin-cyclodextrin inclusion complexation in aqueous solutions containing various alcoholic co-solvents and alginates using an UV–VIS titration method: studies on curcumin and curcuminoids XXXV. Pharmazie 64(6), 382–389 (2009)

    CAS  Google Scholar 

  38. Gibson, M.: Pharmaceutical Preformulation and Formulation A Practical guide from Candidate Drug Selection to Commercial Dosage Form. CRC Press LLC, Boca Raton (2004)

    Google Scholar 

  39. Pabon, H.J.J.: Synthesis of curcumin and related compounds. Recueil Des Travaux Chimiques Des Pays-Bas. J. R. Neth. Chem. Soc. 83(4), 379–386 (1964)

    CAS  Google Scholar 

  40. Babu, K.V.D., Rajasekharan, K.N.: Simplified condition for synthesis of curcumin I and other curcuminoids. Org. Prep. Proced. Int. 26(6), 674–677 (1994)

    Article  CAS  Google Scholar 

  41. Venkateswarlu, S., Ramachandra, M.S., Subbaraju, G.V.: Synthesis and biological evaluation of polyhydroxycurcuminoids. Bioorg. Med. Chem. 13(23), 6374–6380 (2005)

    Article  CAS  Google Scholar 

  42. Masuda, T., Matsumura, H., Oyama, Y., Takeda, Y., Jitoe, A., Kida, A., Hidaka, K.: Synthesis of (+–)-Cassumunins A and B, new curcuminoid antioxidants having protective activity of the living cell against oxidative damage. J. Nat. Prod. 61(5), 609–613 (1998)

    Article  CAS  Google Scholar 

  43. Masuda, T., Hidaka, K., Shinohara, A., Maekawa, T., Takeda, Y., Yamaguchi, H.: Chemical studies on antioxidant mechanism of curcuminoid: analysis of radical reaction products from curcumin. J. Agric. Food Chem. 47(1), 71–77 (1999)

    Article  CAS  Google Scholar 

  44. Quideau, S., Ralph, J.: Facile large-scale synthesis of coniferyl, sinapyl, and p-coumaryl alcohol. J. Agric. Food Chem. 40(7), 1108–1110 (1992)

    Article  CAS  Google Scholar 

  45. Jovanovic, S.V., Steenken, S., Boone, C.W., Simic, M.G.: H-atom transfer is a preferred antioxidant mechanism of curcumin. J. Am. Chem. Soc. 121(41), 9677–9681 (1999)

    Article  CAS  Google Scholar 

  46. Tønnesen, H.H., Karlsen, J.: Studies on curcumin and curcuminoids. VI. Kinetics of curcumin degradation in aqueous solution. Z. Lebensm.-Unters. -Forsch. 180(5), 402–404 (1985)

    Article  Google Scholar 

  47. Bernabe-Pineda, M., Ramirez-Silva, M.T., Romero-Romo, M., Gonzalez-Vergara, E., Rojas-Hernandez, A.: Determination of acidity constants of curcumin in aqueous solution and apparent rate constant of its decomposition. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 60A(5), 1091–1097 (2004)

    Article  CAS  Google Scholar 

  48. Dietze, F., Arrieta, A.F., Zimmer, U.: pKa stability constants and UV/VIS spectral behavior of selected curcumin analogs. Pharmazie 52(4), 302–306 (1997)

    CAS  Google Scholar 

  49. Borsari, M., Ferrari, E., Grandi, R., Saladini, M.: Curcuminoids as potential new iron-chelating agents: spectroscopic, polarographic and potentiometric study on their Fe(III) complexing ability. Inorg. Chim. Acta 328, 61–68 (2002)

    Article  CAS  Google Scholar 

  50. Wang, Y.-J., Pan, M.-H., Cheng, A.-L., Lin, L.-I., Ho, Y.-S., Hsieh, C.-Y., Lin, J.-K.: Stability of curcumin in buffer solutions and characterization of its degradation products. J. Pharm. Biomed. Anal. 15(12), 1867–1876 (1997)

    Article  CAS  Google Scholar 

  51. Strickley, R.G.: Solubilizing excipients in oral and injectable formulations. Pharm. Res. 21(2), 201–230 (2004)

    Article  CAS  Google Scholar 

  52. FDA. Inactive Ingredient Guide. http://www.fda.gov/cder/drug/iig/inact1.pdf (2008). Accessed 15 Dec 2008

  53. Connors, K.A.: The stability of cyclodextrin complexes in solution. Chem. Rev. (Washington, D C) 97(5), 1325–1357 (1997)

    CAS  Google Scholar 

  54. Mrozek, J., Guzow, K., Szabelski, M., Karolczak, J., Wiczk, W.: Influence of methanol and cyclodextrin cavity size on stoichiometry and binding constant of 3-[2-(9-anthryl)benzoxazol-5-yl]-alanine. J. Photochem. Photobiol. A 153(1–3), 121–128 (2002)

    Article  CAS  Google Scholar 

  55. Pitha, J., Hoshino, T.: Effects of ethanol on formation of inclusion complexes of hydroxypropyl cyclodextrins with testosterone or with methyl orange. Int. J. Pharm. 80(2–3), 243–251 (1992)

    Article  CAS  Google Scholar 

  56. Màsson, M., Sigurdardòttir, B.V., Matthìasson, K., Loftsson, T.: Investigation of drug -cyclodextrin complexes by a phase-distribution method: some theoretical and practical considerations. Chem. Pharm. Bull. 53(8), 958–964 (2005)

    Article  Google Scholar 

  57. Connors, K.A.: Solubility measurement. In: Connors, K.A. (ed.) Binding Constants: The measurements of molecular complex stability, pp. 261–281. John Wiley and sons, Madison (1987)

    Google Scholar 

  58. Bender, M.L., Komiyama, M.: Cyclodextrin Chemistry. Springer-Verlag, Berlin; New York (1978)

    Google Scholar 

  59. Connors, K.A.: Determination of Stoichiometry. In: Connors, K.A. (ed.) Binding Constants: The measurement of molecular complex stability, pp. 24–28. John Wiley and Sons, Madison (1987)

    Google Scholar 

  60. Nelson, G., Patonay, G., Warner, I.M.: The utility of time-resolved emission spectroscopy in the study of cyclodextrin-pyrene inclusion complexes. Talanta 36(1–2), 199–203 (1989)

    Article  CAS  Google Scholar 

  61. Connors, K.A.: Optical absorption spectroscopy. In: Connors, K.A. (ed.) Binding Constants: The Measurement of Molecular Complex Stability, pp. 141–188. John Wiley and Sons, Madison (1987)

    Google Scholar 

Download references

Acknowledgements

The authors thank Ragnhild Haugse for the phase-solubility diagrams of curcumin and bisdemethoxycurcumin in CD formulations without ethanol, Hoai T.N. Aas from the Department of Pharmaceutics, University of Oslo, for the solubility determination of bisdemethoxycurcumin in ethanol and phase-solubility diagram of diketone in HPγCD and 10% (v/v) ethanol, and Tove Larsen, also from the Department of Pharmaceutics, University of Oslo, for the assistance with the calorimetric measurements. We thank the University of Iceland Research fund for financial support.

Author information

Authors and Affiliations

  1. School of Pharmacy, Department of Pharmaceutics, University of Oslo, P.O. Box 1068, Blindern, 0316, Oslo, Norway

    Ravinder Singh & Hanne Hjorth Tønnesen

  2. Faculty of Pharmaceutical Sciences, University of Iceland, Hagi, Hofsvallagata 53, IS-107, Reykjavik, Iceland

    Stine Byskov Vogensen, Thorsteinn Loftsson & Már Másson

Authors
  1. Ravinder Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hanne Hjorth Tønnesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stine Byskov Vogensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thorsteinn Loftsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Már Másson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Már Másson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Singh, R., Tønnesen, H.H., Vogensen, S.B. et al. Studies of curcumin and curcuminoids. XXXVI. The stoichiometry and complexation constants of cyclodextrin complexes as determined by the phase-solubility method and UV–Vis titration. J Incl Phenom Macrocycl Chem 66, 335–348 (2010). https://doi.org/10.1007/s10847-009-9651-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10847-009-9651-5

Keywords

Search

Navigation