Characterization and control of the aggregation behavior of cyclodextrins

  • István Puskás
  • Mária Schrott
  • Milo Malanga
  • Lajos Szente
Original Article


Photon correlation spectroscopy has been employed for the purpose of characterizing the aggregation behavior of cyclodextrin molecules in aqueous solutions. This optical method is generally intended to study particle size distribution of colloidal particles, associates and macromolecules. Herein we report on some general methodological issues of photon correlation spectroscopy aiming to illustrate aggregated and non-aggregated state of parent cyclodextrins and cyclodextrin derivatives, such as (2-hydroxy)propyl-β-cyclodextrin and tetraamino rhodaminyl (2-hydroxypropyl)-β-cyclodextrin in different aqueous media. Based on particle size analysis data we have demonstrated that the tendency of cyclodextrin molecules to form aggregates may be controlled by temperature and by various additives, e.g. urea, citric acid and polyvinylpyrrolidone. In the case of (2-hydroxypropyl)-β-cyclodextrin the effect of degree of substitution was also studied.


Photon correlation spectroscopy Non-complex forming additives Self-association Optical properties 


  1. 1.
    Loftsson, T., Vogensen, S.B., Brewster, M.E., Konraosdottir, F.: Effects of cyclodextrins on drug delivery through biological membranes. J. Pharm. Sci. 96(10), 2532–2546 (2007)CrossRefGoogle Scholar
  2. 2.
    Mishra, S., Webster, P., Davis, M.E.: PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. Eur. J. Cell Biol. 83(3), 97–111 (2004)CrossRefGoogle Scholar
  3. 3.
    Szente, L., Szejtli, J., Kis, G.L.: Spontaneous opalescence of aqueous gamma-cyclodextrin solutions: complex formation or self-aggregation. J. Pharm. Sci. 87(6), 778–781 (1998)CrossRefGoogle Scholar
  4. 4.
    Coleman, A.W., Nicolis, I., Keller, N., Dalbiez, J.P.: Aggregation of cyclodextrins: an explanation of the abnormal solubility of beta-cyclodextrin. J. Inclusion Phenom. Mol. Recognit. Chem. 13, 139–143 (1992)CrossRefGoogle Scholar
  5. 5.
    González-Gaitano, G., Rodríguez, P., Isasi, J.R., Fuentes, M., Tardajos, G., Sánchez, M.: The aggregation of cyclodextrins as studied by photon correlation spectroscopy. J. Inclusion Phenom. Macrocycl. Chem. 44(1–4), 101–105 (2002)CrossRefGoogle Scholar
  6. 6.
    Loftsson, T., Másson, M., Brewster, M.E.: Self-association of cyclodextrins and cyclodextrin complexes. J. Pharm. Sci. 93, 1091–1099 (2004)CrossRefGoogle Scholar
  7. 7.
    Sigurdsson, H.H., Magnusdottir, A., Másson, M., Loftsson, T.: The effects of cyclodextrins on hydrocortisone permeability through semi-permeable membranes. J. Inclusion Phenom. Macrocycl. Chem. 44(1–4), 163–167 (2002)CrossRefGoogle Scholar
  8. 8.
    Loftsson, T., Magnúsdóttir, A., Másson, M., Sigurjónsdóttir, J.F.: Self-association and cyclodextrin solubilization of drugs. J. Pharm. Sci. 91, 2307–2316 (2002)CrossRefGoogle Scholar
  9. 9.
    Messner, M., Kurkov, S.V., Jansook, P., Loftsson, T.: Self-assembled cyclodextrin aggregates and nanoparticles. Int. J. Pharm. 387(1–2), 199–208 (2010)CrossRefGoogle Scholar
  10. 10.
    Bikádi, Z., Kurdi, R., Balogh, S., Szemán, J., Hazai, E.: Aggregation of cyclodextrins as an important factor to determine their complexation behavior. Chem. Biodivers. 3(11), 1266–1278 (2006)CrossRefGoogle Scholar
  11. 11.
    Bonini, M., Rossi, S., Karlsson, G., Almgren, M., Lo Nostro, P., Baglioni, P.: Self-assembly of β-cyclodextrin in water. Part 1: Cryo-TEM and dynamic and static light scattering. Langmuir 22, 1478–1484 (2006)CrossRefGoogle Scholar
  12. 12.
    Rossi, S., Bonini, M., Lo Nostro, P., Baglioni, P.: Self-assembly of β-Cyclodextrin in water. 2. Electron spin resonance. Langmuir 23, 10959–10967 (2007)CrossRefGoogle Scholar
  13. 13.
    Kurkov, S.V., Messner, M., Lucassen, M., van den Dobbelsteen, D.J., den Engelsman, J., Loftsson, T.: Evaluation of sugammadex self-association. Int. J. Pharm. 413(1–2), 134–139 (2011)CrossRefGoogle Scholar
  14. 14.
    He, Y., Fu, P., Shen, X., Gao, H.: Cyclodextrin-based aggregates and characterization by microscopy. Micron 39, 495–516 (2008)CrossRefGoogle Scholar
  15. 15.
    Messner, M., Kurkov, S.V., Maraver Palazón, M., Álvarez Fernández, B., Brewster, M.E., Loftsson, T.: Self-assembly of cyclodextrin complexes: effect of temperature, agitation and media composition on aggregation. Int. J. Pharm. 419(1–2), 322–328 (2011)CrossRefGoogle Scholar
  16. 16.
    Jansook, P., Moya-Ortega, M.D., Loftsson, T.: Effect of self-aggregation of γ-cyclodextrin on drug solubilization. J. Inclusion Phenom. Macrocycl. Chem. 68(1–2), 229–236 (2010)CrossRefGoogle Scholar
  17. 17.
    Messner, M., Kurkov, S.V., Flavià-Piera, R., Brewster, M.E., Loftsson, T.: Self-assembly of cyclodextrins: the effect of the guest molecule. Int. J. Pharm. 408(1–2), 235–247 (2011)CrossRefGoogle Scholar
  18. 18.
    Messner, M., Kurkov, S.V., Brewster, M.E., Jansook, P., Loftsson, T.: Self-assembly of cyclodextrin complexes: aggregation of hydrocortisone/cyclodextrin complexes. Int. J. Pharm. 407(1–2), 174–183 (2011)CrossRefGoogle Scholar
  19. 19.
    Brocos, P., Díaz-Vergara, N., Banquy, X., Pérez-Casas, S., Costas, M., Piñeiro, Á.: Similarities and differences between cyclodextrin–sodium dodecyl sulfate host–guest complexes of different stoichiometries: molecular dynamics simulations at several temperatures. J. Phys. Chem. B 114(39), 12455–12467 (2010)CrossRefGoogle Scholar
  20. 20.
    Brocos, P., Banquy, X., Díaz-Vergara, N., Pérez-Casas, S., Piñeiro, Á., Costas, M.: A Critical approach to the thermodynamic characterization of inclusion complexes: multiple-temperature isothermal titration calorimetric studies of native cyclodextrins with sodium dodecyl sulfate. J. Phys. Chem. B 115(49), 14381–14396 (2011)CrossRefGoogle Scholar
  21. 21.
    Malvern Instruments Ltd. (2009) Zetasizer nano series user manual. Malvern: Malvern Instruments LtdGoogle Scholar
  22. 22.
    Mie, G.: Beiträge zur Optik trüber Medien, speziell kolloidaler Metallösungen. Ann. Phys. 330, 377–445 (1908)CrossRefGoogle Scholar
  23. 23.
    Wu, A., Shen, X., He, Y.: Investigation of γ-cyclodextrin nanotube induced by N, N’-diphenylbenzidine molecule. J. Colloid Interface Sci. 297, 525–533 (2006)CrossRefGoogle Scholar
  24. 24.
    Szejtli, J.: Cyclodextrin Technology. Kluwer Academic Publisher, Dordrecht (1988)Google Scholar
  25. 25.
    Rao, C.T., Lindberg, B., Lindberg, J., Pitha, J.: Substitution in beta-cyclodextrin directed by basicity: preparation of 2-O- and 6-O-[(R)- and (S)-2-hydroxypropyl] derivatives. J. Org. Chem. 56(3), 1327–1329 (1991)CrossRefGoogle Scholar
  26. 26.
    Malanga, M., Jicsinszky, L., Kandoth, N., Sortino, S., Agostoni, V., Gref, R., Kirejev V., Ericson, M., Éva Fenyvesi: Fluorescent cyclodextrin—aid in the Development of Novel Anticancer Therapy. II. European Conference on Cyclodextrins, 2–4 October 2011, Asti Abstract book III-P19Google Scholar
  27. 27.
    Pharr, D.Y., Fu, Z.S., Smith, T.K., Hinze, W.L.: Solubilization of cyclodextrins for analytical applications. Anal. Chem. 61, 275–279 (1989)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • István Puskás
    • 1
  • Mária Schrott
    • 1
    • 2
  • Milo Malanga
    • 1
  • Lajos Szente
    • 1
  1. 1.CycloLab Research and Development Laboratory LtdBudapestHungary
  2. 2.Budapest University of Technology and EconomicsBudapestHungary

Personalised recommendations