Dissolution rate enhancement by in situ micronization of poorly water-soluble drugs

The purpose of this study was to evaluate a novel in situ micronization method avoiding any milling techniques to produce nano- or microsized drug particles by controlled crystallization to enhance the dissolution rate of poorly water-soluble drugs.

Ibuprofen, itraconazole, and ketoconazole microcrystals were prepared by the association of the previously molecularly dispersed drug using a rapid solvent change process. The drug was precipitated in the presence of stabilizing agents, such as hydrocolloids. The obtained dispersion was spray-dried. Particle size, morphology, dissolution rate, specific surface area, and wettability were analyzed. Physicochemical properties were characterized using differential scanning calorimetry and X-ray diffractometry.

The obtained dispersions showed a homogeneous particle size distribution. Drugs are obtained in a mean particle size of approximately 2 microm and below. A high specific surface area was created and in situ stabilized. Different stabilizers showed differences in protecting the precipitated drug from crystal growth. The surface was hydrophilized because of the adsorbed stabilizer. Thus, a drug powder with markedly enhanced dissolution rate was obtained.

In situ micronization is a suitable method for the production of micro-sized drugs. This technique can be performed continuously or discontinuously and uses only common technical equipment. Compared to milled products drug properties are optimized as all particle surfaces are naturally grown, the particle size is more uniformly distributed and the powder is less cohesive.