Physicochemical characterization of drug-cyclodextrin complexes prepared by supercritical carbon dioxide and by conventional techniques

  • Ali Al-Marzouqi
  • Baboucarr Jobe
  • Giovanna Corti
  • Marzia Cirri
  • Paola Mura
Original Article


The objective of this study was to investigate the effectiveness of supercritical carbon dioxide (SC CO2) technique for preparing solid complexes between β-cyclodextrin and three local anesthetic agents (benzocaine, bupivacaine, and mepivacaine) by comparing it to more traditional methods such as kneading, co-evaporation, co-grinding, and sealed-heating. Effects of variation of experimental conditions, i.e. temperature, pressure and exposure time, on the products prepared by SC CO2 method were also examined. The products obtained were characterized by powder X-ray diffractometry and Fourier transform infrared spectroscopy, and tested for dissolution properties. Results suggested the possibility of complex formation between β-cyclodextrin and the three anesthetic agents, and indicated that it was influenced by the preparation technique. The co-grinding method was the only one resulting in completely amorphous products for all three drugs. Almost amorphous products, with only limited residual crystallinity, were obtained by co-evaporation and kneading techniques, while SC CO2 and sealed-heating methods gave rise to more crystalline systems. As for the SC CO2 method, temperature (for benzocaine and bupivacaine) or exposure time (for mepivacaine) had significant effects on the solid-state properties of the final products. Dissolution studies indicated that all the examined methods were more effective than the simple physical mixing in improving drug dissolution properties, but the different rank orders observed for the different drugs suggested that there is no general rule for the selection of the most effective preparation method, which depends on the type of drug-Cyd system considered. Nevertheless, in all cases, products obtained by the SC CO2 method showed satisfactory dissolution properties.


Supercritical carbon dioxide mepivacaine Cyclodextrin Inclusion complex Benzocaine Bupivacaine Mepivacaine 


  1. 1.
    Covino, B., Vassallo, H.: Local Anesthetics. Grune and Stratton, New York (1976)Google Scholar
  2. 2.
    Benumof, J.: Clinical Procedures in Anesthesia and Intensive Care. JB Lippincott, Philadelphia (1992)Google Scholar
  3. 3.
    Szejtli, J.: Cyclodextrins in Pharmacy, Dordrecht. Kluwer, The Netherlands (1994)Google Scholar
  4. 4.
    Duchene, D., Wouessidjewe, D.: Pharmaceutical uses of cyclodextrins and derivatives. Drug Dev. Ind. Pharm. 16, 2487–2499 (1990)Google Scholar
  5. 5.
    Lee, B., Lee, J.: Enhancement of solubility and dissolution rate of poorly water-soluble naproxen by complexation with 2-hydroxypropyl-β-cyclodextrin. Arch. Pharm. Res. 18, 22–26 (1995)CrossRefGoogle Scholar
  6. 6.
    Dhanaraju, M., Kumaran, K., Baskaran, T., Moorthy, M.: Enhancement of bioavailability of griseofulvin by its complexation with beta-cyclodextrin. Drug Dev. Ind. Pharm. 24(6), 583–587 (1998)CrossRefGoogle Scholar
  7. 7.
    Dollo, G., Thompson, D., Le Corre, P., Chevanne, F., Le Verge, R.: Inclusion complexation of amide-typed local anesthetics with β-cyclodextrin and its derivatives. III. Biopharmaceutics of bupivacaine-SBE7-βCD complex following percutaneous sciatic nerve administration in rabbits. Int. J. Pharm. 164(1–2), 11–19 (1998)CrossRefGoogle Scholar
  8. 8.
    Greczy, J., Bruhwyler, J., Scuvee-Moreau, J., Seutin, V., Masset, H., Van Heugen J., Dresse, A., Lejeune, C., Decamp, E., Szente, L., Szejtli, J., Liegeois, J.: The inclusion of fluoxetine into gamma-cyclodextrin increases its bioavailability: behavioural, electrophysiological and pharmacokinetic studies. Psychopharmacology 151(4), 328–334 (2000)CrossRefGoogle Scholar
  9. 9.
    Nagarsenker, M., Meshram, R., Ramprakash, G.: Solid dispersion of hydroxypropyl beta-cyclodextrin and ketorolac: Enhancement of in-vitro dissolution rates, improvement in anti-inflammatory activity and reduction in ulcerogenicity in rats. J. Pharm. Pharmacol. 52, 949–956 (2000)CrossRefGoogle Scholar
  10. 10.
    Kang, J., Kumar, V., Yang, D., Chowdhury, P., Hohl, R.: Cyclodextrin complexation: influence on solubility, stability and cytotoxicity of camptothecin, an antineoplastic agent. Eur. J. Pharm. Sci. 15, 163–170 (2002)CrossRefGoogle Scholar
  11. 11.
    Stanley, T.: New routes of administration and new delivery systems of anesthetics. Anaesthesiolog 38, 665–668 (1988)Google Scholar
  12. 12.
    Szejtli, J.: Cyclodextrins and their Inclusion Complexes. Akademiai Kiado, Budapest (1982)Google Scholar
  13. 13.
    Jones, S. Grant, D., Hadgraft, J., Parr, G.: Cyclodextrins in the pharmaceutical sciences. Part I: Preparation, structure and properties of cyclodextrins and cyclodextrin inclusion compounds. Acta Pharm. Technol. 30, 213–223 (1984)Google Scholar
  14. 14.
    Irie, T., Uekama K.: Protection against the photosensitized skin irritancy of chlorpromazine by cyclodextrin complexation. J. Pharmacobiol. Dyn. 8(9), 788–791 (1985)Google Scholar
  15. 15.
    Mura, P., Faucci, M., Bettinetti, G.: The influence of polyvinylpyrrolidone on naproxen complexation with hydroxypropyl-β-cyclodextrin. Eur. J. Pharm. Sci. 13, 187–194 (2001)CrossRefGoogle Scholar
  16. 16.
    Cirri, M., Rangoni, C., Maestrelli, F., Corti, G., Mura, P.: Development of fast-dissolving tablets of flurbiprofen-cyclodextrin complexes. Drug Dev. Ind. Pharm. 31(7), 697–707 (2005)CrossRefGoogle Scholar
  17. 17.
    Mura, P., Furlanetto, S., Cirri, M., Maestrelli, F., Corti, G., pinzauti, S.: Interaction of naproxen with ionic cyclodextrins in aqueous solution and in the solid state. J. Pharm. Biomed. Anal. 37, 987–994 (2005)CrossRefGoogle Scholar
  18. 18.
    Veiga, M., Merino, M., Cirri, M., Maestrelli, F., Mura, P.: Comparative study on triclosan interactions in solution and in the solid state with natural and chemically modified cyclodextrins. J. Incl. Phenom. 53(1), 77–83 (2005)CrossRefGoogle Scholar
  19. 19.
    Hirayama, F., Uekama, K.: Cyclodextrins and their Industrial Uses. Editions de Santé, Paris (1987) pp. 133Google Scholar
  20. 20.
    Blanco, J., Vila-Jato, J.L., Otero, F., Anguiano, S.: Influence of the method of preparation on inclusion complexes of naproxen with different cyclodextrins. Drug Dev. Ind. Pharm. 17, 943–957 (1991)Google Scholar
  21. 21.
    Mura, P., Adragna E., Rabasco, A., Moyano, J., Perez-Martinez, J., Arias, M., Gines, J.: Effects of the host cavity size and the preparation method on the physicochemical properties of ibuproxam-cyclodextrin systems. Drug Dev. Ind. Pharm. 25, 279–287 (1999a)CrossRefGoogle Scholar
  22. 22.
    Mura, P., Faucci M.T., Manderioli A., Bramanti G.: Influence of the preparation method on the physicochemical properties of binary systems of econazole with cyclodextrins. Int. J. Pharm. 193, 85–95 (1999b)CrossRefGoogle Scholar
  23. 23.
    Mura, P., Faucci, M.T., Parrini, P.L., Furlanetto, S., Pinzauti, S.: Influence of the preparation method on the physicochemical properties of ketoprofen-cyclodextrin binary systems. Int. J. Pharm. 179, 117–128 (1999c)CrossRefGoogle Scholar
  24. 24.
    Kiran, E., Brennecke J.: Supercritical Fluid Engineering Science, ACS Symposium Series 514, American Chemical Society, Washington DC (1993)Google Scholar
  25. 25.
    Van Hees, T., Piel, G., Evrard, B., Otte, X., Thunus, L., Delattre, L.: Application of supercritical carbon dioxide for the preparation of a piroxicam-β-cyclodextrin inclusion compound. Pharm. Res. 16, 1864–1870 (1999)CrossRefGoogle Scholar
  26. 26.
    Junco, S. Casimiro T., Ribeiro, N., da Ponte, M.N., Cabral Marques, H.: A comparative study of naproxen-beta cyclodextrin complexes prepared by conventional methods and using supercritical carbon dioxide. J. Incl. Phenom. 44(1–4), 117–121 (2002)Google Scholar
  27. 27.
    Charoenchaitrakool, M., Dehghani, F., Foster, R.F.: Utilization of supercritical carbon dioxide for complex formation of ibuprofen and methyl-β-cyclodextrin. Int. J. Pharm. 239(1–2), 103–112 (2002)CrossRefGoogle Scholar
  28. 28.
    Lai, S., Locci E., Piras, A., Porcedda, S., Lai, A., Marongiu B.: Imazalil-cyclomaltoheptaose (β-cyclodextrin) inclusion complex: Preparation by supercritical carbon dioxide and 13C CPMAS and 1H NMR characterization. Carbohydr. Res. 338(21), 2227–2232 (2003)CrossRefGoogle Scholar
  29. 29.
    Al-Marzouqi A., Shehatta, I., Jobe, B., Dowaidar, A.: Phase solubility and inclusion complex of itraconazole with β-cyclodextrin using supercritical carbon dioxide. J. Pharm. Sci. 95, 292–304 (2006)CrossRefGoogle Scholar
  30. 30.
    Shehatta, I., Al-Marzouqi, A., Jobe, B., Dowaidar, A.: Enhancement of aqueous solubility of itraconazole by complexation with cyclodextrins using supercritical carbon dioxide. Can. J. Chem. 83(10), 1833–1838 (2005)CrossRefGoogle Scholar
  31. 31.
    de Jong, R.H.: Local Anestethics. Springfield, Illinois (1994)Google Scholar
  32. 32.
    Strichartz, G.R., Sanchez, V., Arthue, R., Chafetz, R., Martin, D.: Fundamental properties of local anesthetics. II. Measured octanol:buffer partition coefficients and pK(a) values of clinically used drugs. Anest. Analg. 71(2), 158–170 (1990)CrossRefGoogle Scholar
  33. 33.
    Dollo, G., LeCorre, P., Chevanne, Le Verge, R.: Inclusion complexation of amide-typed local anaesthetics with ß-cyclodextrin and its derivatives. I. Physicochemical characterization. Int. J. Pharm. 131(2), 219–228 (1996)CrossRefGoogle Scholar
  34. 34.
    Pinto, L., Fraceto L., Santana, M., Pertinhez, T., Oyama Junior, S., de Paula, E.: Physico-chemical characterization of benzocaine-β-cyclodextrin inclusion complexes. J. Pharmaceut. Biomed. 39(5), 956–963 (2005)CrossRefGoogle Scholar
  35. 35.
    Hassan, A., Tang, Y., Ayres, J.: Itraconazole formation using supercritical carbon dioxide. Drug Dev. Ind. Pharm. 30(10), 1029–1035 (2004)CrossRefGoogle Scholar
  36. 36.
    Khan, K.A.: The concept of dissolution efficiency. J. Pharm. Pharmacol. 27(1), 48–49 (1975)Google Scholar

Copyright information

© Springer Science+Business Media, Inc. 2007

Authors and Affiliations

  • Ali Al-Marzouqi
    • 1
  • Baboucarr Jobe
    • 1
  • Giovanna Corti
    • 2
  • Marzia Cirri
    • 2
  • Paola Mura
    • 2
  1. 1.Department of Chemical & Petroleum EngineeringU.A.E. UniversityAl-AinUAE
  2. 2.Dipartimento di Scienze FarmaceuticheUniversita di Firenze, Polo Scientifico di Sesto Fiorentino Sesto FiorentinoItaly

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