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Pharmaceutical Research

, Volume 20, Issue 1, pp 135–138 | Cite as

Identification of Phase Separation in Solid Dispersions of Itraconazole and Eudragit® E100 Using Microthermal Analysis

  • Karel Six
  • John Murphy
  • Ilse Weuts
  • Duncan Q. M. Craig
  • Geert Verreck
  • Jef Peeters
  • Marcus Brewster
  • Guy Van den Mooter
Article

Abstract

Purpose. To evaluate the phase separation in itraconazole/Eudragit® E100 solid dispersions prepared by hot-stage extrusion.

Methods. Extrudates were prepared using a corotating twin-screw extruder at 180°C. Micro-TA was used to evaluate the phase separation, where the AFM mode is used to visualize the different phases and local thermal analysis (LTA) to characterize the different phases

Results. Itraconazole formed a homogeneous mixture with Eudragit® E100 with drug concentrations up to approximately 20%. Above this concentration, phase separation was observed. MTDSC revealed two Tgs and the mesophase of free glassy itraconazole. Performing micro-TA on the surface of these dispersions indicated an increase in sample roughness in the z-axis piezo signal, which could be an indication of free glassy itraconazole. However, thermal conductivity did not reveal differences between separate phases. Performing LTA, where only a small area (20 × 20 μm) is heated, showed two separate and mixed phases of itraconazole and Eudragit® E100. Tip penetration in itraconazole and Eudragit® E100 occurred at 332K and 383K respectively. The difference in tip penetration was explained in terms of the difference in fragility.

Conclusion. Micro-TA makes it possible to characterize separate phases of itraconazole and Eudragit® E100, thereby confirming the MTDSC results on phase separation.

itraconazole solid dispersion phase separation microthermal analysis 

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REFERENCES

  1. 1.
    G. L. Amidon, H. Lennernäs, V. P. Shah, and J. R. Crison. Theoretical basis for a biopharmaceutical drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12:413-420 (1995).Google Scholar
  2. 2.
    S. M. Grant and S. P. Clissold. Itraconazole: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs 37:310-344 (1989).Google Scholar
  3. 3.
    A. Forster, J. Hempenstall, and T. Rades. Characterization of glass solutions of poorly water-soluble drugs produced by melt extrusion with hydrophilic amorphous polymers. J. Pharm. Pharmacol. 53:303-315 (2001).Google Scholar
  4. 4.
    K. Six, C. Leuner, J. Dressman, G. Verreck, J. Peeters, N. Blaton, P. Augustijns, R. Kinget, and G. Van den Mooter. Thermochemical properties of hot-stage extrudates of itraconazole and Eudragit® E100: Phase separation and polymorphism. J. Therm. Anal. Cal. 68:591-601 (2002).Google Scholar
  5. 5.
    D. Q. M. Craig. The mechanism of drug release from solid dispersions in water-soluble polymers. Int. J. Pharm. 231:131-144 (2002).Google Scholar
  6. 6.
    I. Moon, R. Androsch, W. Chen, and B. Wunderlich. The principles of micro-thermal analysis and its application to the study of macromolecules. J. Thermal Anal. Calor. 59:187-203 (2000).Google Scholar
  7. 7.
    D. M. Price, M. Reading, A. Hammiche, H. M. Pollock, and M. G. Branch. Localised thermal analysis of a packaging film. Thermochim. Acta 332:143-149 (1999).Google Scholar
  8. 8.
    D. Q. M. Craig, V. L. Kett, C. S. Andrews, and P. G. Royall. Pharmaceutical applications of micro-thermal analysis. J. Pharm. Sci. 91:1201-1213 (2002).Google Scholar
  9. 9.
    K. Six, G. Verreck, J. Peeters, K. Binnemans, H. Berghmans, P. Augustijns, R. Kinget, and G. Van den Mooter. Investigation of thermal properties of glassy itraconazole: Identification of a monotropic mesophase. Thermochim. Acta 376:175-181 (2001).Google Scholar
  10. 10.
    P. G. Royal, V. Kett, C. Andrews, and D. Q. M. Craig. Identification of crystalline and amorphous regions in low molecular weight materials using microthermal analysis. J. Phys. Chem. B. 105:7021-7026 (2001).Google Scholar
  11. 11.
    K. J. Crowley. and G. Zografi The use of thermal methods for predicting glass-former fragility. Thermochim. Acta 380:79-93 (2001).Google Scholar
  12. 12.
    J. M. Barton. Dependence of polymer glass transition temperatures on heating rate. Polymer. 10:151-154 (1969).Google Scholar
  13. 13.
    B. Hancock, C. Dalton, M. Pikal, and S. Shamblin. A pragmatic test of a simple calorimetric method for determining the fragility of some amorphous pharmaceutical materials. Pharm. Res. 15:762-767 (1998).Google Scholar
  14. 14.
    P. G. Royall, D. Q. M. Craig, D. M. Price, M. Reading, and T. Lever. An investigation into the use of micro-thermal analysis for the solid state characterisation of an HPMC tablet formulation. Int. J. Pharm. 190:97-103 (1999).Google Scholar

Copyright information

© Plenum Publishing Corporation 2003

Authors and Affiliations

  • Karel Six
    • 1
  • John Murphy
    • 2
  • Ilse Weuts
    • 1
  • Duncan Q. M. Craig
    • 2
  • Geert Verreck
    • 3
  • Jef Peeters
    • 3
  • Marcus Brewster
    • 3
  • Guy Van den Mooter
    • 1
  1. 1.Laboratorium voor Farmacotechnologie en Biofarmacie, K. U. LeuvenLeuvenBelgium
  2. 2.School of PharmacyThe Queen's University BelfastBelfastUnited Kingdom
  3. 3.Johnson & Johnson Pharmaceutical Research and DevelopmentBeerseBelgium

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