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Interaction of native CDs and their hydroxypropyl derivatives with parabens in aqueous solutions. Part 2: evaluation of paraben/cyclodextrin complex aggregation

  • André Rodrigues Sá Couto
  • Sara Aguiar
  • Alexey Ryzhakov
  • Kim Lambertsen Larsen
  • Thorsteinn LoftssonEmail author
Original Article
  • 13 Downloads

Abstract

Cyclodextrins (CDs) and their inclusion complexes are known to self-assemble in aqueous solutions to form aggregates and the physicochemical characteristics of guest molecules have been linked to the aggregate formation. A series of parabens was selected as model compounds due to their small size (aromatic ring fits in the cavity) and different side chain length. In Part 1 it was demonstrated that CDs and parabens form a range of soluble and insoluble complexes dependent on the type of CD (native or hydroxypropylated αCD, βCD or γCD) and the length of the alkyl residue of the parabens. Furthermore, phase-solubility studies suggested that higher order complexes (e.g., aggregates) were formed. Here we apply osmometry and permeation studies to evaluate if and how the alkyl chain length of the parabens influences the process of aggregate formation. Furthermore, the possible effect of CD aggregates on permeation profile of parabens is also elucidated. Changes in osmometry correlate with the type pf phase-solubility profile. For AL-types total osmolality remained unchanged throughout experiment, while for B-types the osmolality of systems displayed significant changes mainly due to precipitation of poorly-soluble complexes. The permeation method is an effective and useful method to detect and evaluate self-assembly of CDs and to detect aggregate formation in aqueous γCD and HPβCD solutions containing parabens. Generally, all parabens modified the natural aggregation behavior of HPβCD and γCD as the apparent critical aggregation concentration (cac) values for paraben/CD systems decreased compared to those of pure aqueous CD solutions. The longer the alkyl side chain, the greater was the promotion of aggregates formation (methyl < ethyl < propyl < butyl) and, consequently, more and larger aggregates are formed. These superstructures are responsible for the observed changes in apparent cac and flux values, as well as, for the observed slopes greater than unity for the phase-solubility diagrams.

Keywords

Cyclodextrin Osmolality Aggregation Permeation Drug delivery system 

Notes

Acknowledgements

The financial support received from the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT) (Grant No. 135040) is gratefully acknowledged.

References

  1. 1.
    Bonnet, P., Jaime, C., Morin-Allory, L.: Structure and thermodynamics of alpha-, beta-, and gamma-cyclodextrin dimers. Molecular dynamics studies of the solvent effect and free binding energies. J. Org. Chem. 67(24), 8602–8609 (2002)CrossRefGoogle Scholar
  2. 2.
    Kurkov, S.V., Loftsson, T.: Cyclodextrins. Int. J. Pharm. 453(1), 167–180 (2013).  https://doi.org/10.1016/j.ijpharm.2012.06.055 CrossRefGoogle Scholar
  3. 3.
    Mixcoha, E., Campos-Terán, J., Piñeiro, Á: Surface adsorption and bulk aggregation of cyclodextrins by computational molecular dynamics simulations as a function of temperature: α-CD vs β-CD. J. Phys. Chem. B. 118(25), 6999–7011 (2014).  https://doi.org/10.1021/jp412533b CrossRefGoogle Scholar
  4. 4.
    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(4), 1478–1484 (2006).  https://doi.org/10.1021/la052878f CrossRefGoogle Scholar
  5. 5.
    Bai, Y., Xu, G.-Y., Sun, H.-Y., Yang, X.-D., Hao, A.-Y., Pang, J.-Y., Gong, H.-J., Ao, M.-Q.: The surface property and aggregation behavior of a hydrophobically modified cyclodextrin. Colloid Polym. Sci. 288(4), 415–421 (2010).  https://doi.org/10.1007/s00396-009-2136-7 CrossRefGoogle Scholar
  6. 6.
    Paduano, L., Sartorio, R., Vitagliano, V., Costantino, L.: Diffusion properties of cyclodextrins in aqueous solution at 25 °C. J. Solut. Chem. 19(1), 31–39 (1990).  https://doi.org/10.1007/bf00650642 CrossRefGoogle Scholar
  7. 7.
    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), 235–247 (2011).  https://doi.org/10.1016/j.ijpharm.2011.02.008 CrossRefGoogle Scholar
  8. 8.
    Motoyama, K., Nagatomo, K., Abd Elazim, S.O., Hirayama, F., Uekama, K., Arima, H.: Potential use of 2-hydroxypropyl-beta-cyclodextrin for preparation of orally disintegrating tablets containing dl-alpha-tocopheryl acetate, an oily drug. Chem. Pharm. Bull. 57(11), 1206–1212 (2009)CrossRefGoogle Scholar
  9. 9.
    Marques, H.M.C.: A review on cyclodextrin encapsulation of essential oils and volatiles. Flavour Fragr. J. 25(5), 313–326 (2010).  https://doi.org/10.1002/ffj.2019 CrossRefGoogle Scholar
  10. 10.
    Jude Jenita, M., Thulasidhasan, J., Rajendiran, N.: Encapsulation of alkylparabens with natural and modified α- and β-cyclodextrins. J. Incl. Phenom. Macrocycl. Chem. 79(3), 365–381 (2014).  https://doi.org/10.1007/s10847-013-0360-8 CrossRefGoogle Scholar
  11. 11.
    Caira, M.R., de Vries, E.J.C., Nassimbeni, L.R.: Cyclodextrin inclusion of p-hydroxybenzoic acid esters. ‎J. Therm. Anal. Calorim. 73(2), 647–651 (2003).  https://doi.org/10.1023/a:1025446617121 CrossRefGoogle Scholar
  12. 12.
    Saokham, P., Do, T.T., Van den Mooter, G., Loftsson, T.: Inclusion complexes of p-hydroxybenzoic acid esters and γ-cyclodextrin. J. Incl. Phenom. Macrocycl. Chem. 90(1), 111–122 (2017).  https://doi.org/10.1007/s10847-017-0776-7 Google Scholar
  13. 13.
    Stappaerts, J., Do Thi, T., Dominguez-Vega, E., Somsen, G.W., Van den Mooter, G., Augustijns, P.: The impact of guest compounds on cyclodextrin aggregation behavior: a series of structurally related parabens. Int. J. Pharm. 529(1), 442–450 (2017).  https://doi.org/10.1016/j.ijpharm.2017.07.026 CrossRefGoogle Scholar
  14. 14.
    Cohen, J., Lach, J.L.: Interaction of pharmaceuticals with schardinger dextrins. I. Interaction with hydroxybenzoic acids and p-hydroxybenzoates. J. Pharm. Sci. 52, 132–136 (1963)CrossRefGoogle Scholar
  15. 15.
    Lach, J.L., Cohen, J.: Interaction of pharmaceuticals with schardinger dextrins II: interaction with selected compounds. J. Pharm. Sci. 52(2), 137–142 (1963).  https://doi.org/10.1002/jps.2600520207 CrossRefGoogle Scholar
  16. 16.
    de Vries, E.J.C., Caira, M.R., Bogdan, M., Farcas, S.I., Bogdan, D.: Inclusion of parabens in β-cyclodextrin: a solution NMR and X-ray structural investigation. Supramol. Sci. 21(5), 358–366 (2009).  https://doi.org/10.1080/10610270801956202 CrossRefGoogle Scholar
  17. 17.
    Chan, L.W., Kurup, T.R.R., Muthaiah, A., Thenmozhiyal, J.C.: Interaction of p-hydroxybenzoic esters with beta-cyclodextrin. Int. J. Pharm. 195(1), 71–79 (2000).  https://doi.org/10.1016/S0378-5173(99)00393-2 CrossRefGoogle Scholar
  18. 18.
    Matsuda, H., Ito, K., Sato, Y., Yoshizawa, D., Tanaka, M., Taki, A., Sumiyoshi, H., Utsuki, T., Hirayama, F., Uekama, K.: Inclusion complexation of p-hydroxybenzoic acid esters with 2-hydroxypropyl-beta-cyclodextrins. On changes in solubility and antimicrobial activity. Chem. Pharm. Bull. 41(8), 1448–1452 (1993)CrossRefGoogle Scholar
  19. 19.
    Lehner, S.J., Müller, B.W., Seydel, J.K.: Interactions between p-hydroxybenzoic acid esters and hydroxypropyl-β-cyclodextrin and their antimicrobial effect against Candida albicans. Int. J. Pharm. 93(1), 201–208 (1993).  https://doi.org/10.1016/0378-5173(93)90178-I CrossRefGoogle Scholar
  20. 20.
    Holm, R., Olesen, N.E., Alexandersen, S.D., Dahlgaard, B.N., Westh, P., Mu, H.: Thermodynamic investigation of the interaction between cyclodextrins and preservatives—application and verification in a mathematical model to determine the needed preservative surplus in aqueous cyclodextrin formulations. Eur. J. Pharm. Sci. 87, 22–29 (2016).  https://doi.org/10.1016/j.ejps.2015.09.011 CrossRefGoogle Scholar
  21. 21.
    Loftsson, T., Stefánsdóttir, Ó, Friôriksdóttir, H., Guômundsson, Ö: Interactions between preservatives and 2-hydroxypropyl-β-cyclodextrin. Drug Dev. Ind. Pharm. 18(13), 1477–1484 (1992).  https://doi.org/10.3109/03639049209040853 CrossRefGoogle Scholar
  22. 22.
    Malaekeh-Nikouei, B., Bazzaz, F., Soheili, B.S., Mohammadian, V.: K.: Problems in ophthalmic drug delivery: evaluation of the interaction between preservatives and cyclodextrins. Jundishapur J. Microbiol. 6(5), e6333 (2013).  https://doi.org/10.5812/jjm.6333 CrossRefGoogle Scholar
  23. 23.
    Loftsson, T., Duchene, D.: Cyclodextrins and their pharmaceutical applications. Int. J. Pharm. 329(1–2), 1–11 (2007).  https://doi.org/10.1016/j.ijpharm.2006.10.044 CrossRefGoogle Scholar
  24. 24.
    Ryzhakov, A., Do Thi, T., Stappaerts, J., Bertoletti, L., Kimpe, K., Sá Couto, A.R., Saokham, P., Van den Mooter, G., Augustijns, P., Somsen, G.W., Kurkov, S., Inghelbrecht, S., Arien, A., Jimidar, M.I., Schrijnemakers, K., Loftsson, T.: Self-assembly of cyclodextrins and their complexes in aqueous solutions. J. Pharm. Sci. 105(9), 2556–2569 (2016).  https://doi.org/10.1016/j.xphs.2016.01.019 CrossRefGoogle Scholar
  25. 25.
    Sá Couto, A.R., Aguiar, S., Ryzhakov, A., Larsen, K.L., Loftsson, T.: Interaction of native cyclodextrins and their hydroxypropylated derivatives with parabens in aqueous solution. Part 1: evaluation of inclusion complexes. J. Incl. Phenom. Macrocycl. Chem. (2019).  https://doi.org/10.1007/s10847-018-00876-5 Google Scholar
  26. 26.
    Martin, A.: Diffusion and dissolution. In: Martin, A. (ed.) Physical Pharmacy, pp. 324–361. Lea & Febiger, Philadelphia (1993)Google Scholar
  27. 27.
    Brodin, B., Steffansen, B., Nielsen, C.U.: Passive diffusion of drug substances: the concepts of flux and permeability. In: Steffansen, B., Brodin, B., Nielsen, C.U. (eds.) Molecular Biopharmaceutics: Aspects of Drug Characterisation, Drug Delivery and Dosage form Evaluation, pp. 135–151. PharmaPress Ltd., London (2010)Google Scholar
  28. 28.
    Sá Couto, A.R., Ryzhakov, A., Loftsson, T.: Self-assembly of alpha-cyclodextrin and beta-cyclodextrin: identification and development of analytical techniques. J. Pharm. Sci. (2018).  https://doi.org/10.1016/j.xphs.2018.03.028 Google Scholar
  29. 29.
    Sá Couto, A.R., Ryzhakov, A., Loftsson, T.: 2-Hydroxypropyl-β-cyclodextrin aggregates: identification and development of analytical techniques. Materials 11(10):1971 (2018).  https://doi.org/10.3390/ma11101971 CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • André Rodrigues Sá Couto
    • 1
  • Sara Aguiar
    • 1
  • Alexey Ryzhakov
    • 1
  • Kim Lambertsen Larsen
    • 2
  • Thorsteinn Loftsson
    • 1
    Email author
  1. 1.Faculty of Pharmaceutical SciencesUniversity of IcelandReykjavikIceland
  2. 2.Dept. of Chemistry and Bioscience, Frederik Bajers Vej 7HAalborg UniversityAalborgDenmark

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