An investigation into the crystallization tendency/kinetics of amorphous active pharmaceutical ingredients: A case study with dipyridamole and cinnarizine

Eur J Pharm Biopharm. 2016 Jul:104:59-71. doi: 10.1016/j.ejpb.2016.04.017. Epub 2016 Apr 21.


Amorphous drug formulations have great potential to enhance solubility and thus bioavailability of BCS class II drugs. However, the higher free energy and molecular mobility of the amorphous form drive them towards the crystalline state which makes them unstable. Accurate determination of the crystallization tendency/kinetics is the key to the successful design and development of such systems. In this study, dipyridamole (DPM) and cinnarizine (CNZ) have been selected as model compounds. Thermodynamic fragility (mT) was measured from the heat capacity change at the glass transition temperature (Tg) whereas dynamic fragility (mD) was evaluated using methods based on extrapolation of configurational entropy to zero [Formula: see text] , and heating rate dependence of Tg [Formula: see text] . The mean relaxation time of amorphous drugs was calculated from the Vogel-Tammann-Fulcher (VTF) equation. Furthermore, the correlation between fragility and glass forming ability (GFA) of the model drugs has been established and the relevance of these parameters to crystallization of amorphous drugs is also assessed. Moreover, the crystallization kinetics of model drugs under isothermal conditions has been studied using Johnson-Mehl-Avrami (JMA) approach to determine the Avrami constant 'n' which provides an insight into the mechanism of crystallization. To further probe into the crystallization mechanism, the non-isothermal crystallization kinetics of model systems were also analysed by statistically fitting the crystallization data to 15 different kinetic models and the relevance of model-free kinetic approach has been established. The crystallization mechanism for DPM and CNZ at each extent of transformation has been predicted. The calculated fragility, glass forming ability (GFA) and crystallization kinetics are found to be in good correlation with the stability prediction of amorphous solid dispersions. Thus, this research work involves a multidisciplinary approach to establish fragility, GFA and crystallization kinetics as stability predictors for amorphous drug formulations.

Keywords: Amorphous; Crystallization kinetics; Fragility; Glass forming ability; Mean relaxation time; Molecular mobility; Stability.

MeSH terms

  • Chromatography, High Pressure Liquid
  • Cinnarizine / chemistry*
  • Crystallization
  • Dipyridamole / chemistry*
  • Kinetics
  • Pharmaceutical Preparations*
  • Powder Diffraction


  • Pharmaceutical Preparations
  • Cinnarizine
  • Dipyridamole