Crystallization of Itraconazole Polymorphs from Melt

The impacts of the nucleation site and temperature on the melt crystallization of itraconazole (ITZ) were investigated. ITZ recrystallized from melt into three distinct spherulite zones between two glass coverslips, as observed under a polarized light microscope. The first two corresponded to Forms I and II which are monotropically related, as determined by solubility and thermal analyses. The third zone differed from the other two in the X-ray powder diffraction pattern, thermal properties, Fourier transform infrared spectrum, and dissolution rate, indicative of a new form (III) which has not been reported previously. Form III readily converted to the more stable Form II with the evolution of heat upon heating above 100 °C or Form I upon dissolution in aqueous ethanol. At 70–150 °C, Form II exhibited the fastest bulk crystal growth, followed successively by Form I and Form III. Analysis of the crystal growth data using the two-dimensional nucleation model afforded good data fitting with the model and revealed an inverse relationship between the bulk crystal growth rates and activation energies of individual polymorphs, reflecting the suitability of this model for describing the ITZ crystallization from melt. The polymorph selectivity of recrystallized ITZ appeared to be dictated by both the nucleation and crystal growth rates of individual polymorphs.