Highly supersaturated solutions from dissolution of amorphous itraconazole microparticles at pH 6.8

Dry powders from aqueous dispersions, formed by antisolvent precipitation, dissolved to form solutions with supersaturation values up to 12 in 10 min at pH 6.8 with sodium dodecyl sulfate micelles. Itraconazole/hydroxypropylmethylcellulose (HPMC) aqueous particle dispersions were salt flocculated and filtered to produce medium surface area (2-5 m2/g) particles or lyophilized to produce high surface area (13-36 m2/g). Over 4 h, the decay in supersaturation was much slower for the medium surface area versus high surface area particles, since the smaller excess surface area of undissolved particles led to slower nucleation and growth from solution. A slow decay in supersaturation was also achieved by initially dissolving part of the drug at pH 1.2, and then shifting the pH to 6.8 thereby reducing the excess surface area of undissolved particles in the pH 6.8 media. This pH shift mimics the transition from stomach to intestines. The ability to generate and sustain high supersaturation at pH 6.8 by minimizing undissolved excess surface area may be expected to be beneficial for raising bioavailability by gastrointestinal delivery.