Pharmaceutical Research

, Volume 27, Issue 7, pp 1377–1389 | Cite as

Investigation of the Milling-Induced Thermal Behavior of Crystalline and Amorphous Griseofulvin

  • Niraj S. Trasi
  • Stephan X. M. Boerrigter
  • Stephen Robert Byrn
Research Paper



To gain a better understanding of the physical state and the unusual thermal behavior of milled griseofulvin.


Griseofulvin crystals and amorphous melt quench samples were milled in a vibrating ball mill for different times and then analyzed using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Modulated DSC (mDSC) and annealing studies were done for the milled amorphous samples to further probe the effects of milling.


Milling of griseofulvin crystals results in decrease in crystallinity and amorphization of the compound. A double peak is seen for crystallization in the DSC, which is also seen for the milled melt quench sample. Both enthalpy and temperature of crystallization decrease for the milled melt quenched sample. Tg is visible under the first peak with the mDSC, and annealing shows that increasing milling time results in faster crystallization upon storage.


Milling of griseofulvin results in the formation of an amorphous form and not a mesophase. It increases the amount of surface created and the overall energy of the amorphous griseofulvin, which leads to a decreased temperature of crystallization. The two exotherms in the DSC are due to some particles having nuclei on the surface.


amorphous crystallization griseofulvin milling 



The authors would like to acknowledge financial support from the McKeehan Graduate Assistantship. We would also like to thank Dr. Katsuhiro Kobayashi for help with cryomilling of griseofulvin.


  1. 1.
    Patterson JE, James MB, Forster AH, Lancaster RW, Butler JM, Rades T. Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling. Int J Pharm. 2007;336(1):22–34.CrossRefPubMedGoogle Scholar
  2. 2.
    Sussich F, Cesaro A. Trehalose amorphization and recrystallization. Carbohydr Res. 2008;343(15):2667–74.CrossRefPubMedGoogle Scholar
  3. 3.
    Surana R, Pyne A, Suryanarayanan R. Effect of preparation method on physical properties of amorphous trehalose. Pharm Res. 2004;21(7):1167–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Chikhalia V, Forbes RT, Storey RA, Ticehurst M. The effect of crystal morphology and mill type on milling induced crystal disorder. Eur J Pharm Sci. 2006;27(1):19–26.CrossRefPubMedGoogle Scholar
  5. 5.
    Crowley KJ, Zografi G. Cryogenic grinding of indomethacin polymorphs and solvates: assessment of amorphous phase formation and amorphous phase physical stability. J Pharm Sci. 2002;91(2):492–507.CrossRefPubMedGoogle Scholar
  6. 6.
    Qiu ZH, Stowell JG, Cao WJ, Morris KR, Byrn SR, Carvajal MT. Effect of milling and compression on the solid-state Maillard reaction. J Pharm Sci. 2005;94(11):2568–80.CrossRefPubMedGoogle Scholar
  7. 7.
    Ward GH, Schultz RK. Process-induced crystallinity changes in albuterol sulfate and its effect on powder physical stability. Pharm Res. 1995;12(5):773–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Fecht HJ. Defect induced melting and solid-state amorphization. Nature 1992;356(6365):133–5.CrossRefGoogle Scholar
  9. 9.
    Willart JF, Descamps M. Solid state amorphization of pharmaceuticals. Mol Pharmacol. 2008;5(6):905–20.CrossRefGoogle Scholar
  10. 10.
    Descamps M, Willart JF, Dudognon E, Caron V. Transformation of pharmaceutical compounds upon milling and comilling: the role of T-g. J Pharm Sci. 2007;96(5):1398–407.CrossRefPubMedGoogle Scholar
  11. 11.
    Feng T, Pinal R, Carvajal MT. Process induced disorder in crystalline materials: differentiating defective crystals from the amorphous form of griseofulvin. J Pharm Sci. 2008;97(8):3207–21.CrossRefPubMedGoogle Scholar
  12. 12.
    Feng T, Bates S, Carvajal MT. Toward understanding the evolution of griseofulvin crystal structure to a mesophase after cryogenic milling. Int J Pharm. 2009;367(1–2):16–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Zili Z, Sfar S, Fessi H. Preparation and characterization of poly-[var epsilon]-caprolactone nanoparticles containing griseofulvin. Int J Pharm. 2005;294(1–2):261–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Yamamura S, Takahira R, Momose Y. Crystallization kinetics of amorphous griseofulvin by pattern fitting procedure using X-ray diffraction data. Pharm Res. 2007;24(5):880–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Chieng N, Rades T, Saville D. Formation and physical stability of the amorphous phase of ranitidine hydrochloride polymorphs prepared by cryo-milling. Eur J Pharm Biopharm. 2008;68(3):771–80.CrossRefPubMedGoogle Scholar
  16. 16.
    Sheth AR, Bates S, Muller FX, Grant DJW. Local structure in amorphous phases of piroxicam from powder X-ray diffractometry. Cryst Growth Des. 2005;5(2):571–8.CrossRefGoogle Scholar
  17. 17.
    Willart JF, De Gusseme A, Hemon S, Odou G, Danede F, Descamps M. Direct crystal to glass transformation of trehalose induced by ball milling. Solid State Commun. 2001;119(8–9):501–5.CrossRefGoogle Scholar
  18. 18.
    Hockerfelt MH, Nystrom C, Alderborn G. Dry mixing transformed micro-particles of a drug from a highly crystalline to a highly amorphous state. Pharm Dev Technol. 2009;14(3):233–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Mosharraf M, Nystrom C. The effect of dry mixing on the apparent solubility of hydrophobic, sparingly soluble drugs. Eur J Pharm Sci. 1999;9(2):145–56.CrossRefPubMedGoogle Scholar
  20. 20.
    Hancock BC, Shamblin SL, Zografi G. Molecular mobility of amorphous pharmaceutical solids below their glass-transition temperatures. Pharm Res. 1995;12(6):799–806.CrossRefPubMedGoogle Scholar
  21. 21.
    Zhu L, Wong L, Yu L. Surface-enhanced crystallization of amorphous nifedipine. Mol Pharm. 2008;5(6):921–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Rani M, Govindarajan R, Surana R, Suryanarayanan R. Structure in dehydrated trehalose dihydrate—Evaluation of the concept of partial crystallinity. Pharm Res. 2006;23(10):2356–67.CrossRefPubMedGoogle Scholar
  23. 23.
    Qi S, Weuts I, Cort SD, Stokbroekx S, Leemans R, Reading M et al. An investigation into the crystallisation behaviour of an amorphous cryomilled pharmaceutical material above and below the glass transition temperature. J Pharm Sci. 2010;99(1):196–208.CrossRefPubMedGoogle Scholar
  24. 24.
    Bhugra C, Shmeis R, Pikal MJ. Role of mechanical stress in crystallization and relaxation behavior of amorphous Indomethacin. J Pharm Sci. 2008;97(10):4446–58.CrossRefPubMedGoogle Scholar
  25. 25.
    Chamarthy SP, Pinal R. The nature of crystal disorder in milled pharmaceutical materials. Colloid Surface Physicochem Eng Aspect. 2008;331(1–2):68–75.CrossRefGoogle Scholar
  26. 26.
    Tsukushi I, Yamamuro O, Suga H. Heat-capacities and glass transitions of ground amorphous solid and liquid-quenched glass of tri-O-methyl-beta-cyclodextrin. J Non-Cryst Solids. 1994;175(2–3):187–94.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Niraj S. Trasi
    • 1
  • Stephan X. M. Boerrigter
    • 1
    • 2
  • Stephen Robert Byrn
    • 1
  1. 1.Department of Industrial and Physical PharmacyPurdue UniversityWest LafayetteUSA
  2. 2.SSCI, a division of AptuitWest LafayetteUSA

Personalised recommendations