Dual-effect of size/polymorph to enhance itraconazole bioavailability by freeze-dissolving crystallization

Abstract

The enhancement of solubility or bioavailability can be achieved by stabilizing the metastable solid state or reducing the particle size, particularly for pharmaceutical candidates classified under the Biopharmaceutics Classification System (BCS) II. In this paper, the ultrafine powder of itraconazole (ITZ) in the amorphous state was prepared by a novel preparation method, the freeze-dissolving technology (FDT). The influence of additives, solvent systems, and process parameters on the particle size and solid state of the ITZ slurry suspension was comprehensively investigated. The experiments were conducted to investigate the solubility and dissolution rate, revealing a more than six-fold increase in accumulated dissolution of the amorphous phase with reduced size. The enhanced dissolution performance of the drug is attributed to its reduced particle size and amorphous state. Moreover, the final ultrafine powder of ITZ meets the size requirements for inhalable particles (usually the particles must be in the size range of 0.5 to 5 microns), making it a potential dry powder inhalant (DPI) preparation mechanism for treating pulmonary fungal infections.