Development of Fast-Dissolving Amorphous Solid Dispersion of Itraconazole by Melt Extrusion of its Mixture with Weak Organic Carboxylic Acid and Polymer

Abstract

Purpose: The purpose of this study was to explore the feasibility of developing amorphous solid dispersion (ASD) by inducing acid-base interaction at an elevated temperature using hot melt extrusion.

Methods: Itraconazole and glutaric acid, which do not form salt with each other, were selected as, respectively, model basic drug and weak organic acid. A 1:4:1w/w mixture of itraconazole, glutaric acid and a polymer, Kollidon®VA64, was melt extruded at 95°C. The ground extrudate was characterized by DSC and PXRD and then tested for dissolution at pH 1.2, followed by a change in pH to 5.5.

Results: Despite the high melting point of 168°C, itraconazole dissolved in glutaric acid at around the melting temperature of acid (~98°C), and physically stable ASD was produced when the formulation was extruded at 95°C. Capsules containing 100-mg equivalent of itraconazole dissolved rapidly at pH 1.2 producing highly supersaturated solution. When the pH was changed from 1.2 to 5.5, very fine suspensions, facilitated by the presence of Kollidon®VA64, was formed.

Conclusions: Physically stable ASD of itraconazole with high drug load was prepared by interaction with glutaric acid in a hot melt extruder. This may be used as a platform technology for the development ASD of most poorly water-soluble basic drugs.

Keywords: amorphous solid dispersion; dissolution enhancement; itraconazole; melt extrusion; weak organic acid.