Skip to main content
SpringerLink
Log in

Influence of Preparation Methods on Solid State Supersaturation of Amorphous Solid Dispersions: A Case Study with Itraconazole and Eudragit E100

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

The present study aims to determine the drug / polymer miscibility level as a function of the preparation method for an amorphous solid dispersion model system containing itraconazole and eudragit E100. This value was compared to the theoretical crystalline drug solubility in the amorphous polymer and the miscibility of the amorphous drug in the amorphous polymer.

Methods

The amorphous solid dispersions were prepared via spray drying and film casting in order to evaluate the influence of the solvent drying rate. The experimental miscibility level was estimated using XRPD, MDSC, FT-IR, HPLC and TGA. The solubility and miscibility were estimated using the Flory-Huggins mixing theory and experimental drug in monomer solubility data.

Results

The experimental miscibility level was found to be 27.5% w/w for spray-dried and 15% for film-casted solid dispersions. FT-IR measurements confirmed the absence of saturable interactions like hydrogen bonds, and analysis of the mixed glass transition temperatures suggested low adhesion forces in the amorphous mixture. The solubility analysis rendered a positive FH interaction parameter, a crystalline solubility of approximately 0.012% w/w and an amorphous drug-polymer miscibility of approximately 7.07% w/w.

Conclusion

The solid dispersions are significantly supersaturated with respect to both crystalline solubility and amorphous miscibility demonstrating the influence of manufacturing methodology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50:47–60.

    Article  CAS  PubMed  Google Scholar 

  2. Vasconcelos T, Sarmento B, Costa P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Disc Today. 2007;12:1068–75.

    Article  CAS  Google Scholar 

  3. Serajuddin ATM. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 1999;88:1058–66.

    Article  CAS  PubMed  Google Scholar 

  4. Brouwers J, Brewster ME. P. augustijns. Supersaturating drug delivery systems: The answer to solubility limited oral bioavailability? J Pharm Sci. 2009;98:2549–72.

    Article  CAS  PubMed  Google Scholar 

  5. Bhugra C, Pikal MJ. Role of thermodynamic, molecular, and kinetic factors in crystallization from the amorphous state. J Pharm Sci. 2007;97:1329–49.

    Article  CAS  Google Scholar 

  6. Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev. 2001;48:27–42.

    Article  CAS  PubMed  Google Scholar 

  7. Bhattacharya S, Suryanarayanan R. Local mobility in amorphous pharmaceuticals—characterization and implications on stability. J Pharm Sci. 2009;98:2935–53.

    Article  CAS  PubMed  Google Scholar 

  8. Savolainen M, Heinz A, Strachan C, Gordon KC, Yliruusi J, Rades T, et al. Screening for differences in the amorphous state of indomethacin using multivariate visualization. Eur J Pharm Sci. 2007;30:113–23.

    Article  CAS  PubMed  Google Scholar 

  9. Surana R, Pyne A, Suryanarayanan R. Effect of preparation method on physical properties of amorphous trehalose. Pharm Res. 2004;21:1167–76.

    Article  CAS  PubMed  Google Scholar 

  10. Willart JF, Descamps M. Solid state amorphization of pharmaceuticals. Mol Pharm. 2008;5:905–20.

    Article  CAS  PubMed  Google Scholar 

  11. Peeters J, Neeskens P, Tollenaere JP, Van Remoortere P, Brewster ME. Characterization of the interaction of 2-hydroxypropyl-beta-cyclodextrin with itraconazole at pH 2, 4 and 7. J Pharm Sci. 2002;91:1414–22.

    Article  CAS  PubMed  Google Scholar 

  12. Marsac PJ, Shamblin SL, Taylor LS. Theoretical and practical approaches for prediction of drug-polymer miscibility and solubility. Pharm Res. 2006;23:2417–26.

    Article  CAS  PubMed  Google Scholar 

  13. Marsac PJ, Li T, Taylor LS. Estimation of drug-polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm Res. 2009;26:139–51.

    Article  CAS  PubMed  Google Scholar 

  14. Six K, Leuner C, Dressman J, Verreck G, Peeters J, Blaton N, et al. Thermal properties of hot-stage extrudates of itraconazole and Eudragit E100: phase separation and polymorphism. J Therm Anal Calor. 2002;68:591–601.

    Article  CAS  Google Scholar 

  15. Van den Mooter G, Wuyts M, Blaton N, Busson R, Grobet P, Augustijns P, et al. Physical stabilization of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. Eur J Pharm Sci. 2001;12:261–9.

    Article  PubMed  Google Scholar 

  16. Six K, Verreck G, Peeters J, Binnemans K, Berghmans H, Augustijns P, et al. Investigation of thermal properties of glassy itraconazole: identification of a monotropic mesophase. Thermochim Acta. 2001;376:175–81.

    Article  CAS  Google Scholar 

  17. Gordon S, Taylor JS. Ideal copolymers and the second-order transitions of synthetic rubbers I. Non-crystalline copolymers. J Appl Chem. 1952;2:493–500.

    Article  CAS  Google Scholar 

  18. Kelley FN, Bueche F. Viscosity and glass temperature relations for polymer-diluent systems. J Pol Sci. 1961;50:549–56.

    Article  CAS  Google Scholar 

  19. Simha R, Boyer RF. General relation involving the glass transition temperature and coefficient of expansion of polymers. J Chem Phys. 1962;37:1003–7.

    Article  CAS  Google Scholar 

  20. Hancock BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci. 1997;86:1–12.

    Article  CAS  PubMed  Google Scholar 

  21. Pinal R. Entropy of mixing and the glass transition of amorphous mixtures. Entropy. 2008;10:207–23.

    Article  CAS  Google Scholar 

  22. Couchman PR, Karasz FE. A classical thermodynamic discussion of the effect of composition on glass transition temperatures. Macromolecules. 1978;11:117–9.

    Article  CAS  Google Scholar 

  23. Wertheim MS. Fluids with highly directional attractive forces. I. Statistical thermodynamics. J Stat Physics. 1984;35:19–34.

    Article  Google Scholar 

  24. Wertheim MS. Fluids with highly directional attractive forces. II. Thermodynamic perturbation theory and integral equations. J Stat Physics. 1984;35:35–47.

    Article  Google Scholar 

  25. Monograph on basic butylated methacrylate copolymer. In European Pharmacopoeia, sixth edition. Strassbourg, France, 2008, pp. 1254.

  26. Sandler SI. Chemical & engineering thermodynamics. New York: Whiley; 1999.

    Google Scholar 

  27. Yalkowsky SH. Solubility and solubilization in aqueous media. New York: Oxford University Press; 1999. p. 49–80.

    Google Scholar 

  28. Flory PJ. Principles of polymer chemistry. Ithaca: Cornell university press; 1953.

    Google Scholar 

  29. Luder K, Lindfors L, Westergren J, Nordholm S, Kjellander R. In silico prediction of drug solubility. 3. Free energy of solvation in pure amorphous matter. J Phys Chem. 2007;111:7303–11.

    Google Scholar 

  30. Wulsten E, Kiekens F, Van Dycke F, Voorspoels J, Lee G. Levitated single-droplet drying: Case study with itraconazole dried in binary organic solvent mixtures. Int J Pharm. 2009;378:116–21.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The laboratory for pharmaceutical analysis (K.U.Leuven) is acknowledged for the FT-IR measurements, and S.J. acknowledges B.O.F., bijzonder onderzoeksfonds K.U.Leuven, for financial support (PDM grant). This study was supported by a grant from Onderzoeksraad K.U.Leuven (IOF/KP/06/021)

Author information

Authors and Affiliations

  1. Laboratorium voor Farmacotechnologie en Biofarmacie, K.U.Leuven, Herestraat 49, bus 921, 3000, Leuven, Belgium

    Sandrien Janssens, Ann De Zeure, Amrit Paudel, Patrick Rombaut & Guy Van den Mooter

  2. Department MTM, K.U.Leuven, Leuven, Belgium

    Jan Van Humbeeck

Authors
  1. Sandrien Janssens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ann De Zeure
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amrit Paudel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan Van Humbeeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patrick Rombaut
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guy Van den Mooter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guy Van den Mooter.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Janssens, S., De Zeure, A., Paudel, A. et al. Influence of Preparation Methods on Solid State Supersaturation of Amorphous Solid Dispersions: A Case Study with Itraconazole and Eudragit E100. Pharm Res 27, 775–785 (2010). https://doi.org/10.1007/s11095-010-0069-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-010-0069-y

Key Words

Search

Navigation