Correlation between molecular mobility and physical stability of amorphous itraconazole

Sunny P. Bhardwaj, Kapildev K. Arora, Elizabeth Kwong, Allen Templeton, Sophie Dorothee Clas, Raj Suryanarayanan

Research output: Contribution to journalArticlepeer-review

91 Scopus citations


The goal was to investigate the correlation between molecular mobility and physical stability in amorphous itraconazole and identify the specific mobility mode responsible for its instability. The molecular mobility of amorphous itraconazole, in the glassy as well as the supercooled liquid state, was comprehensively characterized using dynamic dielectric spectroscopy. Isothermal frequency sweeps in the 5-40 C temperature range revealed a β-relaxation which exhibited Arrhenius temperature dependence. As the temperature approached Tg, β-relaxation became progressively less resolved due to interference from the high frequency tail of the α-relaxation and then transformed into an excess wing. Above Tg, nonlinear temperature dependence of the α-relaxation was described by the Vogel-Tammann-Fulcher (VTF) model. Itraconazole was found to be a fragile glass former with a VTF strength parameter of ∼4. Isothermal crystallization kinetics, at several temperatures over the range of 75 to 95 C, was best described by the 3-dimensional nucleation and growth model. Primary relaxation appeared to be the mobility responsible for the observed physical instability at temperatures above Tg as indicated by the linear correlation of α-relaxation with both crystallization onset and kinetics (represented by the inverse of the crystallization rate constant). A strong coupling between global mobility and crystallization onset was evident. However, for growth kinetics, the coupling was less pronounced, indicating the involvement of factors other than global mobility.

Original languageEnglish (US)
Pages (from-to)694-700
Number of pages7
JournalMolecular Pharmaceutics
Issue number2
StatePublished - Feb 4 2013


  • amorphous
  • crystallization kinetics
  • crystallization onset
  • dielectric spectroscopy
  • itraconazole
  • molecular mobility


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