Thermal Properties of Hot-Stage Extrudates of Itraconazole and Eudragit E100: Phase separation and polymorphism

Abstract

Solid dispersions of itraconazole and eudragit E100 were prepared by hot-stage extrusion. Analysis of the physical structure revealed the existence of different phases, depending on the manufacturing condition. Extrudates prepared at 453 K existed as a molecular dispersion of itraconazole in eudragit E100 when the drug concentration did not exceed ca. 13% mass/mass. At higher concentrations, a second phase consisting of pure glassy itraconazole emerged. In other dispersions prepared at 413 K, the second phase consisted of pure crystalline itraconazole. The difference can be attributed to the relation of the process-temperature to the melting point. Heating of both dispersions induced cold crystallization. Extrudates prepared at 453 K showed comparable behavior before and after milling, with the exception that unmilled dispersions with a drug load of ≥60% mass/mass recrystallized upon heating into a polymorphic modification of itraconazole (Tm=431 K). Upon further heating the polymorph recrystallized to the stable crystalline form (Tm=441 K).