A new cocrystal and salts of itraconazole: comparison of solid-state properties, stability and dissolution behavior

Abstract

Cocrystallization and salt formation have been shown to entail substantial promise in tailoring the physicochemical properties of drug compounds, in particular, their dissolution and hygroscopicity. In this work, we report on the preparation and comparative evaluation of a new cocrystal of itraconazole and malonic acid and two new hydrochloric salts (dihydrochloride and trihydrochloride) of itraconazole. The intrinsic dissolution rate, hygroscopicity, and thermodynamic stability were determined for the obtained solid-state forms and compared to itraconazole-succinic acid (2:1) cocrystal. The results show that the solid-state forms with higher intrinsic dissolution rate are less stable. Both itraconazole salts exhibited the highest dissolution rate, but also demonstrated high hygroscopicity at relative humidity above 70%. The new cocrystal, in contrast, were found to increase the dissolution rate of the parent drug by about 5-fold without compromising the hygroscopicity and the stability. This study demonstrates that, for dissolution rate enhancement of poorly water-soluble weak bases, cocrystallization is a more suitable approach than hydrochloric salt formation.