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Inclusion complexes of fluconazole with β-cyclodextrin: physicochemical characterization and in vitro evaluation of its formulation

Abstract

Fluconazole (FZ) is a triazole antifungal drug administered orally or intravenously. It is employed for the treatment of mycotic infections. However, the efficacy of FZ is limited with its poor aqueous solubility and low dissolution rate. One of the important pharmaceutical advantages of cyclodextrins is to improve pharmacological efficacy of drugs due to increasing their aqueous solubility. The aim of present study was to prepare an inclusion complex of FZ and β-cyclodextrin (β-CD) to improve the physicochemical and biopharmaceutical properties of FZ. The effects of β-CD on the solubility of FZ were investigated according to the phase solubility technique. Complexes were prepared with 1:1 M ratio by different methods namely, freeze-drying, spray-drying, co-evaporation and kneading. For the characterization of FZ/β-CD complex, FZ amount, practical yield %, thermal, aqueous solubility, XRD, FT-IR and NMR (1H and 13C) analysis were performed. In vitro dissolution from hard cellulose capsules containing FZ/β-CD complexes was compared to pure FZ and its commercial capsules and evaluated by f1 (difference) and f2 (similarity) factors. Paddle method defined in USP 31 together with high pressure liquid chromatographic method were used in in vitro dissolution experiments. It was found that solubility enhancement by FZ/β-CD complexes depends on the type of the preparation method. High release of active agent from hard cellulose capsules prepared with β-CD complexes compared to commercial capsules was attributed to the interactions between β-CD and active agent, high energetic amorphous state and inclusion complex formation.

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References

  1. Sweetman, S.C., Blake, P.S., Brayfield, A., McGlashan, J.M., Neathercoat, G.C., Parsons, A.V.: Martindale: The Complete Drug References, 36th edn, pp. 517–551. Pharmaceutical Press, Gurnee (2009)

    Google Scholar 

  2. Gilman, A.G., Ruddon, R.W., Molinoff, P.B., Limbird, L.E., Hardman, J.G.: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th edn, pp. 1175–1190. The McGraw Companies Inc, New York (1996)

    Google Scholar 

  3. Serajuddin, A.T.M.: Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems and recent breakthroughs. J. Pharm. Sci. 88(10), 1058–1066 (1999)

    Article  CAS  Google Scholar 

  4. Kibbe, A.H.: Handbook of Pharmaceutical Excipients Cyclodextrins, 3rd edn. Published by the American Pharmaceutical Association, pp.165–168. Pharmaceutical Press, Washington (2000)

  5. Loftsson, T.: Pharmaceutical Application of β-cyclodextrin, Pharm. Tech. pp.40-50, December (1999)

  6. USP 31(The United States Pharmacopeia), 26th ed. (NF 26), The United States Pharmacopeial Convention, pp. 2488–2490 (2008)

  7. Shabir, G.A.: Validation of high-performance liquid chromatography methods for pharmaceutical analysis understanding the differences and similarities between validation requirements of the US Food and Drug Administration, the US Pharmacopeia and the International Conference on Harmonization. J. Chromatogr. A 987, 57–66 (2003)

    Article  Google Scholar 

  8. Higuchi, T., Connors, K.A.: Phase solubility techniques. Adv. Anal. Chem. Instrum. 4, 117–210 (1965)

    CAS  Google Scholar 

  9. Bilensoy, E., Doğan, L., Şen, M., Hıncal, A.: Complexation behaviour of antiestrogen drug tamoxifen citrate with natural and modified β-cyclodextrins. J. Incl. Phenom. Macro. 57, 651–655 (2007)

    Article  CAS  Google Scholar 

  10. Demirel, M., Büyükköroğlu, G., Kalava, B.S., Yazan, Y.: Enhancement in dissolution pattern of pribedil by molecular encapsulation with β-cyclodextrin. Methods Find. Exp. Clin. Pharmacol. 28(2), 83–88 (2006)

    Article  CAS  Google Scholar 

  11. Al-Marzouqi, A.H., Elwy, H.M., Shehadi, I., Adem, A.: Physicochemical properties of antifungal drug-cyclodextrin complexes prepared by supercritical carbon dioxide and by conventional techniques. J. Pharm. Biopharm. 49, 227–233 (2009)

    CAS  Google Scholar 

  12. http-1 Dissolution Methods, http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions.cfm?PrintAll=1 (20.01.2010)

  13. Li, N., Zhang, Y.-H., Xiong, X.-L., Li, Z.-G., Jin, X.-H., Wu, Y.-N.: Study of the physicochemical properties of trimethoprim with β-cyclodextrin in solution. J. Pharm. Biomed. Anal. 38(2), 370–374 (2005)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Kang, J., Kumar, V., Yang, D., Chowdury, P.R., Hohl, R.J.: Cyclodextrin complexation: influence on the solubility, stability and citotoxicity of camptothecin, an antineoplastic agent. Eur. J. Pharm. Sci. 15, 163–170 (2002)

    Article  CAS  Google Scholar 

  16. Alkhamis, K.A., Obaidat, A.A., Nuseriat, A.F.: Solid state characterization of fluconazole. Pharm. Dev. Tech. 7, 491–503 (2002)

    Article  CAS  Google Scholar 

  17. Desai, S.R., Shaikh, M.M., Dharwadkar, S.R.: Thermoanalytical study of polymorphic transformation in fluconazole drug. Thermochim. Acta 399, 81–89 (2003)

    Article  CAS  Google Scholar 

  18. Nacsa, A., Àmbrus, R., Berkesi, O., Szabó-Révész, P., Aigner, Z.: Water-soluble loratadine inclusion complex: Analytical control of the preparation by microwave irradition. J. Pharmaceut. Biomed. 48, 1020–1023 (2008)

    Article  CAS  Google Scholar 

  19. Yazan, Y., Sumnu, M.: Improvement in the dissolution properties of theophylline with β-cyclodextrin. S.T.P. Pharm. Sci. 4(2), 128–132 (1994)

    CAS  Google Scholar 

  20. Fernandes, C.M., Vieira, M.T., Veiga, F.J.B.: Physicochemical characterization and in vitro dissolution behavior of nicardipin cyclodextrins inclusion compounds. Eur. J. Pharm. Sci. 15, 79–88 (2002)

    Article  CAS  Google Scholar 

  21. Denadai, A.M.I., Santoro, M.M., Lopes, M.T.P., Chenna, A., De Sousa, F.B., Avelar, G.M., Gomes, M.R.T., Guzman, F., Salas, C.E., Sinisterra, R.D.: A supramolecular complex between proteinases and beta-cyclodextrin that preserves enzymatic activity. Biodrugs 20, 283–291 (2006)

    Article  CAS  Google Scholar 

  22. Legendre, J.Y., Rault, I., Petit, A., Luijten, W., Demuynck, I., Horvath, S., Ginot, Y.M., Cuine, A.: Effects of β-cyclodextrins on skin: implications for the transdermal delivery of piribedil and a novel cognition enhancing-drug, S-9977. Eur. J. Pharm. Sci. 3, 311–322 (1995)

    Article  CAS  Google Scholar 

  23. Rasheed, A., Kumar, A.C.K., Sravanthi, V.V.N.S.S.: Cyclodextrins as drug carrier molecule: a review. Sci. Pharm. 76, 567–598 (2008)

    Article  CAS  Google Scholar 

  24. Gandhi, R.B., Karara, A.H.: Characterization, dissolution and diffusion properties of tolbutamide-β-cyclodextrin complex system. Drug Dev. Ind. Pharm. 14, 657–682 (1988)

    Article  CAS  Google Scholar 

  25. Lin, S.-H., Kao, Y.-H.: Solid particles of drug-β-cyclodextrin inclusion complexes directly prepared by a spray-drying technique. Int. J. Pharm. 56, 249–259 (1989)

    Article  CAS  Google Scholar 

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Acknowledgments

The authors thank to Dr. Özgür Alver for helping on NMR and IR analysis.

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Correspondence to Müzeyyen Demirel.

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Yurtdaş, G., Demirel, M. & Genç, L. Inclusion complexes of fluconazole with β-cyclodextrin: physicochemical characterization and in vitro evaluation of its formulation. J Incl Phenom Macrocycl Chem 70, 429–435 (2011). https://doi.org/10.1007/s10847-010-9908-z

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  • DOI: https://doi.org/10.1007/s10847-010-9908-z

Keywords

  • Fluconazole
  • β-cyclodextrin
  • Phase solubility
  • Inclusion complex
  • Hard cellulose capsules