One step preparation of spherical drug particles by contamination-free dry milling technique with corn starch beads
The novel dry milling technique has been developed by using a mechanical powder processor for improving the dissolution properties of poorly water-soluble drugs. It was found that the drug crystals were well pulverized by co-processing with fine particles of corn starch (CS). The morphological observation and particle size evaluation revealed that the processed products formed the composite particles with ordered-mixed structure, having double-layered particles with a core of CS and a coating layer of phenytoin (Phe), as a model drug. This result suggested that the drug crystals were selectively micronized and the resultant miniaturized Phe particles were adhered/fixed on the surface of un-milled CS particles. The mechanical characteristics detected by the indentation test assumed that the brittle Phe crystals sandwiched between elastic CS particles would be successfully crushed down by high shearing stress in the processor. The newly-established dispersion-sedimentation test indicated that the fine Phe particles were immediately detached from the composite particles in aqueous phase, constructing the suspension. The dissolution behavior from the processed particles was found to be improved and strongly dependent on the size and amount of detached Phe particles. Such milling and ordered-mixturization have been also successfully done by using recrystallized larger Phe particles than 100 μm. These results would propose the contamination-free dry milling technique without using hard milling balls or beads. The mechanism of the current milling and ordered-mixing phenomena is also provided in this report.