AAPS PharmSciTech

, Volume 10, Issue 1, pp 235–242 | Cite as

Quercetin/β-Cyclodextrin Solid Complexes Prepared in Aqueous Solution Followed by Spray-drying or by Physical Mixture

  • Greice S. Borghetti
  • Ivana S. Lula
  • Ruben D. Sinisterra
  • Valquiria L. Bassani
Research Article


The present study was designed to investigate the influence of operating conditions (temperature, stirring time, and excess amount of quercetin) on the complexation of quercetin with β-cyclodextrin using a 23 factorial design. The highest aqueous solubility of quercetin was reached under the conditions 37°C/24 h/6 mM of quercetin. The stoichiometric ratio (1:1) and the apparent stability constant (Ks = 230 M−1) of the quercetin/β-cyclodextrin complex were determined using phase-solubility diagrams. The semi-industrial production of a 1:1 quercetin/β-cyclodextrin solid complex was carried out in aqueous solution followed by spray-drying. Although the yield of the spray-drying process was adequate (77%), the solid complex presented low concentration of quercetin (0.14%, w/w) and, thus, low complexation efficiency. The enhancement of aqueous solubility of quercetin using this method was limited to 4.6-fold in the presence of 15 mM of β-cyclodextrin. Subsequently, an inclusion complex was prepared via physical mixture of quercetin with β-cyclodextrin (molar ratio of 1:1 and quercetin concentration of 23% (w/w)) and characterized using infrared spectroscopy, differential scanning calorimetry, nuclear magnetic resonance spectroscopy, and scanning electron microscopy analyses. The enhancement of aqueous solubility of quercetin using this method was 2.2-fold, similar to that found in the complex prepared in aqueous solution before the spray-drying process (2.5-fold at a molar ratio of 1:1, i.e., 6 mM of quercetin and 6 mM of β-cyclodextrin).

Key words

β-cyclodextrin complexation physical mixture quercetin solubility 



The authors are grateful to Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and to Fundação de Amparo ao Estado de Minas Gerais (FAPEMIG) for the financial support and scholarships.


  1. 1.
    T. Loftsson, D. Hreinsdóttir, and M. Másson. Evaluation of cyclodextrin solubilization of drugs. Intern J Pharm. 302:18–28 (2005).CrossRefGoogle Scholar
  2. 2.
    M. E. Brewster, and T. Loftsson. Cyclodextrins as pharmaceutical solubilizers. Adv Drug Del Rev. 59:645–666 (2007).CrossRefGoogle Scholar
  3. 3.
    E. M. M. Del Valle. Cyclodextrins and their uses: a review. Proc Biochem. 39:1033–1046 (2004).CrossRefGoogle Scholar
  4. 4.
    I. Erlund. Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability and epidemiology. Nutr Res. 24:851–874 (2004).CrossRefGoogle Scholar
  5. 5.
    E. R. C. Vinadé, and P. R. Petrovick. Influência da adição de polissorbato 80 e de β-ciclodextrina sobre a solubilidade de quercetina. Rev Port Farm. XLVIII:149–152 (1998).Google Scholar
  6. 6.
    K. Azuma, K. Ippoushi, H. Ito, H. Higashio, and J. Terao. Combination of lipids and emulsifiers enhances the absorption of orally administered quercetin in rats. J Agric Food Chem. 50:1706–1712 (2002).PubMedCrossRefGoogle Scholar
  7. 7.
    M. R. Lauro, M. L. Torre, L. Maggi, F. Simone, U. Conte, and R. P. Aquino. Fast- and slow-release tablets for oral administration of flavonoids: rutin and quercetin. Drug Devel Ind Pharm. 28:371–379 (2002).CrossRefGoogle Scholar
  8. 8.
    A. Saija, A. Tomaino, D. Trombetta, M. L. Pellegrino, B. Tita, C. Messina, F. P. Bonina, C. Rocco, G. Nicolosi, and F. Castelli. “In vitro” antioxidant and photoprotective properties and interaction with model membranes of three new quercetin esters. Eur J Pharm Biopharm. 56:167–174 (2003).PubMedCrossRefGoogle Scholar
  9. 9.
    A. Bertrand, S. Morel, F. Lefoulon, Y. Rolland, P. Monsan, and M. Remaud-Simeon. Leuconostoc mesenteroides glucansucrase synthesis of flavonoid glucosides by acceptor reactions in aqueous-organic solvents. Carb Res. 341:855–863 (2006).CrossRefGoogle Scholar
  10. 10.
    L. Montenegro, C. Carbone, C. Maniscalco, D. Lambusta, G. Nicolosi, C. A. Ventura, and G. Puglisi. In vitro evaluation of quercetin-3-O-acyl esters as topical prodrugs. Intern J Pharm. 336:257–262 (2007).CrossRefGoogle Scholar
  11. 11.
    M. L. Calabrò, S. Tommasini, P. Donato, D. Raneri, R. Stancanelli, P. Ficarra, R. Ficarra, C. Costa, S. Catania, C. Rustichelli, and G. Gamberini. Effects of α- and β-cyclodextrin complexation on the physico-chemical properties and antioxidant activity of some 3-hydroxyflavones. J Pharm Biomed Anal. 35:365–377 (2004).PubMedCrossRefGoogle Scholar
  12. 12.
    T. Pralhad, and K. Rajendrakumar. Study of freeze-dried quercetin-cyclodextrin binary systems by DSC, FT-IR, X-ray diffraction and SEM analysis. J Pharm Biomed Anal. 34:333–339 (2004).PubMedCrossRefGoogle Scholar
  13. 13.
    Y. Zheng, I. S. Haworth, Z. Zuo, M. S. S. Chow, and A. H. L. Chow. Physicochemical and structural characterization of quercetin-beta-cyclodextrin complexes. J Pharm Sci. 94:1079–1089 (2005).PubMedCrossRefGoogle Scholar
  14. 14.
    M. C. Bergonzi, A. R. Bilia, L. Bari, G. Mazzi, and F. F. Vincieri. Studies on the interactions between some flavonols and cyclodextrins. Bioorg Med Chem Let. 17:5744–5748 (2007).CrossRefGoogle Scholar
  15. 15.
    C. Jullian, L. Moyano, C. Yañez, and C. Olea-Azar. Complexation of quercetin with three kinds of cyclodextrins: an antioxidant study. Spectr Acta Part A: Mol Biomol Spectrosc. 67:230–234 (2007).CrossRefGoogle Scholar
  16. 16.
    K. V. Sri, A. Kondaiah, J. V. Ratna, and A. Annapurna. Preparation and characterization of quercetin and rutin cyclodextrin inclusion complexes. Drug Dev Ind Pharm. 33:245–253 (2007).PubMedCrossRefGoogle Scholar
  17. 17.
    C. Lucas-Abellán, I. Fortea, J. A. Gabaldón, and E. Núnez-Delicado. Encapsulation of quercetin and myricetin in cyclodextrins at acidic pH. J Agric Food Chem. 56:255–259 (2008).PubMedCrossRefGoogle Scholar
  18. 18.
    E. Alvarez-Parrilla, L. A. La Rosa, F. Torres-Rivas, J. Rodrigo-Garcia, and G. A. González-Aguilar. Complexation of apple antioxidants: chlorogenic acid, quercetin and rutin by β-cyclodextrin (β-CD). J Incl Phenom Macr Chem. 53:121–129 (2005).CrossRefGoogle Scholar
  19. 19.
    K. M. Krishna, A. Annapurna, G. S. Gopal, C. R. V. Chalam, K. Madan, V. K. Kumar, and G. J. Prakash. Partial reversal by rutin and quercetin of impaired cardiac function in streptozotocin-induced diabetic rats. Can J Physiol Pharmacol. 83:343–355 (2005).PubMedCrossRefGoogle Scholar
  20. 20.
    T. Higuchi, and K. A. Connors. Phase-solubility techniques. Adv Anal Chem Instr. 4:117–212 (1965).Google Scholar
  21. 21.
    International Conference on Harmonization. (ICH). Validation of analytical procedures, ICH, Geneva, 2005.Google Scholar
  22. 22.
    US Pharmacopoeia (USP). Validation of compendial methods, 31rd ed., USP, Rockville, 2008.Google Scholar
  23. 23.
    V. J. Stella, V. M. Rao, E. A. Zannou, and V. Zia. Mechanisms of drug release from cyclodextrin complexes. Adv Drug Deliv Rev. 36:3–16 (1999).PubMedCrossRefGoogle Scholar
  24. 24.
    N. Sauerwald, M. Schwenk, J. Polster, and E. Bengsch. Spectrometric pK determination of daphnetin, chlorogenic acid and quercetin. Zeitschrift für Naturforschung. 53:315–321 (1998).Google Scholar
  25. 25.
    V. Kuntic, N. Pesic, S. Micic, D. Malesev, and Z. Vujic. Determination of dissociation constants of quercetin. Pharmazie. 58:439–440 (2003).PubMedGoogle Scholar
  26. 26.
    H. A. Milane, G. Ubeaud, T. F. Vandamme, and L. Jung. Isolation of quercetin’s salts and studies of their physicochemical properties and antioxidant relationships. Bioorg Med Chem. 12:3627–3635 (2004).PubMedCrossRefGoogle Scholar
  27. 27.
    R. Challa, A. Ahuja, J. Ali, and R. K. Khar. Cyclodextrins in drug delivery: an update review. AAPS PharmSciTech. 6:E329–E351 (2005).PubMedCrossRefGoogle Scholar
  28. 28.
    G. S. Borghetti, I. M. Costa, P. R. Petrovick, V. P. Pereira, and V. L. Bassani. Characterization of different samples of quercetin in solid-state: indication of polymorphism occurrence. Pharmazie. 61:802–804 (2006).PubMedGoogle Scholar
  29. 29.
    M. Petry, G. S. Borghetti, and V. L. Bassani. Influência de ciclodextrinas e polímero hidrofílico sobre a hidrossolubilidade de diferentes formas polimórficas de quercetina. Lat Am J Pharm. 26:831–836 (2007).Google Scholar
  30. 30.
    I. M. Costa. Estudo de pré-formulação com composto polifenólico utilizando como modelo a quercetina. Dissertation. Universidade Federal do Rio Grande do Sul (2005).Google Scholar
  31. 31.
    J. Zhou, L.-F. Wang, J.-Y. Wang, and N. Tang. Synthesis, characterization, antioxidative and antitumor activities of solid quercetin rare earth (III) complexes. J Inorg Biochem,. 83:41–48 (2001).CrossRefGoogle Scholar
  32. 32.
    R. F. V. Souza, and W. F. Giovani. Synthesis, spectral and electrochemical properties of Al (III) and Zn (II) complexes with flavonoids. Spectr Acta Part A: Mol Biomol Spectrosc. 61:1985–1990 (2005).CrossRefGoogle Scholar
  33. 33.
    E. G. Ferrer, M. V. Salinas, M. J. Correa, L. Naso, D. A. Barrio, S. B. Etcheverry, L. Lezama, T. Rojo, and P. A. M. Williams. Synthesis, characterization, antitumoral and osteogenic activities of quercetin vanadyl (IV) complexes. J Biol Inorg Biochem. 11:791–801 (2006).CrossRefGoogle Scholar
  34. 34.
    K. Dias, S. Nicolaou, and W. F. Giovani. Synthesis and spectral investigation of Al(III) catechin/β-cyclodextrin and Al(III) quercetin/β-cyclodextrin inclusion compounds. Spectr Acta Part A: Mol Biomol Spectrosc. 70:154–161 (2008).CrossRefGoogle Scholar
  35. 35.
    S. B. Bukhari, S. Memon, M. Mahroof-Tahir, and M. I. Bhanger. Synthesis, characterization and antioxidant activity copper-quercetin complex. Spectr Acta Part A: Mol Biomol Spectrosc. 715:1901–1906 (2008).Google Scholar
  36. 36.
    L. S. Koester, P. Mayorga, V. P. Pereira, C. L. Petzhold, and V. L. Bassani. Carbamazepine/betaCD/HPMC solid dispersions: physical characterization. Drug Devel Ind Pharm. 29:145–154 (2003).CrossRefGoogle Scholar
  37. 37.
    S. Olejniczak, and M. J. Potrzebowski. Solid state NMR studies and density functional theory (DFT) calculations of conformers of quercetin. Org Biomol Chem. 2:2315–2322 (2004).PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2009

Authors and Affiliations

  • Greice S. Borghetti
    • 1
  • Ivana S. Lula
    • 2
  • Ruben D. Sinisterra
    • 2
  • Valquiria L. Bassani
    • 1
  1. 1.Universidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Universidade Federal de Minas GeraisBelo HorizonteBrazil

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