Particle size dependency of dissolution rate and human bioavailability of phenytoin in powders and phenytoin-polyethylene glycol solid dispersions.

Abstract

Commercially available phenytoin crystals were fractionated by passing them through 44-350 μm sieves, then blended with diluents to prepare phenytoin-diluent physical mixture or made into solid dispersions with polyethylene glycol 4000 (PEG 4000). Dissolution studies of phenytoin in artificial gastric juice suggested that less than 1 to 10 ratio of phenytoin to PEG 4000 was required to disperse amorphous phenytoin completely in the carrier. A comparative dissolution study of various sizes of phenytoin crystals revealed the existence of a critical particle size between 74-149 μm, but phenytoin in solid dispersions showed far faster dissolution and higher solubility than any of the particle fractions. A three-way cross-over study was carried out for phenytoin crystals of particle size 44-53 μm, phenytoin-diluent physical mixture and the phenytoin solid dispersion in five healthy human volunteers. The solid dispersion gave the highest bioavailability of phenytoin, followed by the physical mixture. Thus, phenytoin solid dispersion in PEG 4000 appears to have the clinical advantages of quick release and excellent bioavailability. It also appears that there is a critical particle size for dissolution of phenytoin from powders in vitro. The phenytoin solid dispersion gave a larger bioavailability than crystals below the critical size in vivo.