Four model compounds, nifedipine, indomethacin, felodipine, and ketoconazole, all with nearly identical glass transition temperatures, were chosen to study the effects of thermodynamics and molecular mobility on their crystallization propensities. The time and temperature dependence of the crystallization induction time of each compound was determined by differential scanning calorimetry (DSC) and enabled the generation of their time-temperature-transformation (TTT) diagrams. The relaxation times (τα) were measured by dielectric spectroscopy, and the Gibbs free energy (ΔG) and entropy (ΔS) difference between the crystalline and amorphous states were obtained by DSC. The temperature dependence of the crystallization induction time (τ0(T)) is a function of the thermodynamic activation barrier and the frequency of "attempted jumps" (1/τα(T)) to overcome the barrier. Even though the four model compounds exhibited very similar molecular mobility (relaxation time) over a wide range of temperatures, their crystallization propensities were very different. The observed difference in crystallization propensity was explained in terms of the difference in the thermodynamic barrier, and it is correlated to the empirical relation (TΔS3)/ΔG2.
Keywords: activation barrier; amorphous pharmaceuticals; crystallization; molecular mobility; time−temperature-transformation.