Effect of manufacturing procedures on the dissolution and human bioavailability of diphenylhydantoin.

Abstract

The dissolution characteristics of commercial diphenylhydantoin (DPH) crystals, freeze-dried DPH, 20% simple blend DPH powder, and 20% solvent deposition DPH powder were determined by the use of a USP dissolution test apparatus in pH 1.2 and pH 7.5 test media. The solvent deposition method was found to give DPH with the fastest dissolution rate probably due to improvement in the wettability of the crystals as well as decrease in the particle size. Content uniformity was assessed and accelerated testing of the preparations was also performed to explore optimum formulations. No conversion of the crystal form of DPH or freeze-dried DPH was detected through powder X-ray diffractometry and IR spectrometry under the accelerated storage conditions. Based on the results of the above in vitro studies, 20% DPH solvent deposition powder and the DPH crystals (as a reference) were selected for a bioavailability study in humans. A cross over study in 6 healthy male volunteers revealed the existence of a critical particle size for satisfactory bioavailability. Other factors, such as the use of diluents, also substantially affect the bioavailability of a DPH preparation, even though the crystals used to prepare the finished product were all from the same batch. These results have important implications for manufacturing procedures for DPH preparations.