Processing factors in development of solid solution formulation of itraconazole for enhancement of drug dissolution and bioavailability

This study investigated solid solutions of itraconazole, a water insoluble antifungal, for improved dissolution and improved bioavailability, Influenc e of processing factors on drug and carrier properties in solid solution an d subsequently on drug dissolution behavior was also studied. An optimized solid solution formulation was compared with marketed product in healthy hu man subjects under fasted and fed conditions for bioequivalency. Polyethyle ne glycol (PEG) and drug were made into a solid solution at 120 degreesC. T he cooled, solid solution was then ground into granules of different sizes. Solid solutions of lower drug concentration dissolved at a faster rate, an d drug dissolution improved considerably with increasing molecular weight o f PEG. Initial treatment of itraconazole with the wetting agent/cosolvent g lycerol prior to making itraconazole into a solid solution improved drug di ssolution, and also reduced the PEG amount required to dissolve drug to for m solid solution. Addition of a polymer such as HPMC to the solid solution eliminated precipitation of drug following dissolution. As the granule size of the solid solution was reduced, precipitation of drug during dissolutio n became prominent. Equivalence of two formulations could not be shown for pharmacokinetic parameters C-max and AUC, under both fasting and fed condit ions. (C) 2001 Published by Elsevier Science B.V.