Pharmaceutical Research

, Volume 23, Issue 2, pp 429–437

Dense Gas Processing of Micron-Sized Drug Formulations Incorporating Hydroxypropylated and Methylated Beta-Cyclodextrin

  • Raffaella Mammucari
  • Fariba Dehghani
  • Neil R. Foster
Research Paper


Because of their importance in pharmaceutical applications, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin have been selected to study the formation of micronized complexes incorporating active pharmaceutical ingredients (APIs) and cyclodextrins (CDs) by dense gas (DG) processing.


A single-step DG technique was used as an alternative to conventional methods for the manufacturing of API/CD complexes. The DG technology is highly attractive in the pharmaceutical industry because of its potential to generate micronized particles with controlled particle size distributions at moderate operating conditions. The effect of the aerosol solvent extraction system (ASES) processing on the dissolution performance of naproxen (NPX) was examined.


The CDs were produced as microspheres smaller than 3 μm. The coprecipitation of each CD with NPX resulted in the production of microparticles with enhanced dissolution rates.


The ASES was operated under mild conditions and generated micron-sized spherical particles that could be of particular interest in formulations for pulmonary delivery.

Particular advantages of the technique are that (1) nontoxic solvents are used, and (2) it is suitable for the processing of thermally labile compounds. The proposed process can create opportunities to improve current administration routes and exploit novel delivery systems for drug formulations incorporating CDs.

Key Words

carbon dioxide cyclodextrin dense gases pulmonary drug delivery supercritical fluids 



active pharmaceutical ingredient


aerosol solvent extraction system




depressurization of an expanded liquid organic solution








particles from gas-saturated solutions


supercritical assisted atomization


  1. 1.
    Szejtli, J. 1988Cyclodextrin TechnologyKluwer Academic PublishersDordrecht, The NetherlandsGoogle Scholar
  2. 2.
    Loftsson, T. 2002Cyclodextrins and the biopharmaceutics classification system of drugsJ. Incl. Phenom. Macrocycl. Chem.446367CrossRefGoogle Scholar
  3. 3.
    Thompson, D. O. 1997Cyclodextrins-enabling excipients: their present and future use in pharmaceuticalsCrit. Rev. Ther. Drug Carr. Syst.141104Google Scholar
  4. 4.
    Szejtli, J. 1994Medicinal applications of cyclodextrinsMed. Res. Rev.14353386PubMedGoogle Scholar
  5. 5.
    Stella, V. J., Rajewski, R. A. 1997Cyclodextrins: their future in drug formulation and deliveryPharm. Res.14556567CrossRefPubMedGoogle Scholar
  6. 6.
    Szente, L., Szejtli, J. 1999Highly soluble cyclodextrin derivatives: chemistry, properties, and trends in developmentAdv. Drug Deliv. Rev.361728CrossRefPubMedGoogle Scholar
  7. 7.
    Szejtli, J., Osa, T. 1996CyclodextrinsElsevier Science Ltd.New YorkGoogle Scholar
  8. 8.
    Rajewski, R. A., Stella, V. J. 1996Pharmaceutical applications of cyclodextrins. 2. In vivo drug deliveryJ. Pharmacol. Sci.8511431169Google Scholar
  9. 9.
    Merkus, F. W. H. M., Verhoef, J. C., Marttin, E., Romeijn, S. G., Kuy, P. H. M., Hermens, W. A. J. J., Schipper, N. G. M. 1999Cyclodextrins in nasal drug deliveryAdv. Drug Deliv. Rev.364157CrossRefPubMedGoogle Scholar
  10. 10.
    Pinto, J. M. C. L., Marques, H. M. C. 1999Beclomethasone/cyclodextrin inclusion complex for dry powder inhalationSTP Pharma Sci.9253256Google Scholar
  11. 11.
    A. Clark, M. C. Kuo, and C. Lalor. Phospholipids, cyclodextrins, starch, and cellulose as hygroscopic growth inhibitors in dry powders for pulmonary drug delivery, Inhale Therapeutic Systems, Inc., USA, WO, 2000, pp. 46.Google Scholar
  12. 12.
    Cappello, B., Maio, C., Iervolino, M. 2002Investigation on the interaction of bendazac with β-, hydroxypropyl-β-, and γ-cyclodextrinsJ. Incl. Phenom. Macrocycl. Chem.43251257CrossRefGoogle Scholar
  13. 13.
    Y. H. Chou and D. L. Tomasko. Gas crystallization of polymer–pharmaceutical composite particles. The 4th International Symposium on Supercritical Fluids, Vol. A, ISSF, Sendai, Japan, 1997, pp. 55–57.Google Scholar
  14. 14.
    Bettinetti, G., Gazzaniga, A., Mura, P., Giordano, F., Setti, M. 1992Thermal behavior and dissolution properties of naproxen in combinations with chemically modified β-cyclodextrinsDrug Dev. Ind. Pharm.183953Google Scholar
  15. 15.
    Mura, P., Bettinetti, G., Melani, F., Manderioli, A. 1995Interaction between naproxen and chemically modified β-cyclodextrins in the liquid and solid stateEur. J. Pharm. Sci.3347355CrossRefGoogle Scholar
  16. 16.
    Charoenchaitrackool, M., Dehgani, F., Foster, N. R. 2002Utilization of supercritical carbon dioxide for complex formation of ibuprofen and methyl-β-cyclodextrinInt. J. Pharm.239103112Google Scholar
  17. 17.
    Thiering, R., Dehghani, F., Dillow, A., Foster, N. R. 2000Solvent effects on the controlled dense gas precipitation of model proteinsJ. Chem. Technol. Biotechnol.754253Google Scholar
  18. 18.
    Thiering, R., Dehghani, F., Dillow, A., Foster, N. R. 2000The influence of operating conditions on the dense gas precipitation of model proteinsJ. Chem. Technol. Biotechnol.752941Google Scholar
  19. 19.
    G. S. Gurdial. Solubility behaviour of organic compounds in supercritical carbon dioxide, PhD dissertation, School of Chemical Engineering and Industrial Chemistry, University of New South Wales, Sydney, Australia, 1991.Google Scholar
  20. 20.
    Reverchon, E. 1999Supercritical antisolvent precipitation of micro- and nano-particlesJ. Supercrit. Fluids15121CrossRefGoogle Scholar
  21. 21.
    Ventosa, N., Sala, S., Veciana, J., Torres, J., Llibre, J. 2001Depressurization of an expanded liquid organic solution (DELOS): a new procedure for obtaining submicron- or micron-sized crystalline particlesCryst. Growth Des.1299303CrossRefGoogle Scholar
  22. 22.
    Reverchon, E., Porta, G., Spada, A., Antonacci, A. 2004Griseofulvin micronization and dissolution rate improvement by supercritical assisted atomizationJ. Pharm. Pharmacol.5613791387CrossRefPubMedGoogle Scholar
  23. 23.
    Reverchon, E., Porta, G. 2003Micronization of antibiotics by supercritical assisted atomizationJ. Supercrit. Fluids26243252Google Scholar
  24. 24.
    Fages, J., Lochard, H., Letourneau, J.-J., Sauceau, M., Rodier, E. 2004Particle generation for pharmaceutical applications using supercritical fluid technologyPowder Technol.141219226Google Scholar
  25. 25.
    X. Han, A. R. Baxter, K. W. Koelling, D. L. Tomasko, and L. J. Lee. Influences of solubility and viscosity in the polystyrene/CO2 microcellular foaming extrusion, 60th Annual Technical Conference—Society of Plastics Engineers, San Francisco, CA, 2002, pp. 1910–1914.Google Scholar
  26. 26.
    A. J. Busby, K. S. Morley, C. J. Roberts, M. S. Watson, P. B. Webb, B. Wong, J. Zhang, G. Kokturk, and S. M. Howdle. Polymers, biomaterials and supercritical fluids, Proceedings of the 8th Meeting on Supercritical Fluids, Vol. 1, Bordeaux, 2002, pp. 115–120.Google Scholar
  27. 27.
    Trotta, F., Zanetti, M., Camino, G. 2000Thermal degradation of cyclodextrinsPolym. Degrad. Stab.69373379Google Scholar
  28. 28.
    J. Sztatisz, S. Gal, J. Komives, A. Stadler-Szoke, and J. Szejtli. Thermoanalytical investigations on cyclodextrin inclusion compounds, 1st International Symposium on Cyclodextrins, Budapest, 1981.Google Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Raffaella Mammucari
    • 1
  • Fariba Dehghani
    • 1
  • Neil R. Foster
    • 1
  1. 1.School of Chemical Engineering and Industrial ChemistryThe University of New South WalesSydneyAustralia

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