MODIFICATION OF PHENYTOIN CRYSTALS .2. INFLUENCE OF 3-PROPANOYLOXYMETHYL-5,5-DIPHENYLHYDANTOIN ON SOLUTION-PHASE CRYSTALLIZATION AND RELATED CRYSTAL PROPERTIES

The effects of crystallizing phenytoin (5,5-diphenylhydantoin; DPH) from methanol under defined conditions in the presence of various concentrations of the additive, 3-propanoyloxymethyl-5,5-diphenylhydantoin (PMDPH; a cited prodrug of DPH) were investigated. An increase in the concentrations of PMDPH (from 0.5 to 11 g l-1) in the crystallization solutions at 30-degrees-C brought about a linear increase in PMDPH sorption (0.03-0.57 mol%) by the DPH crystals, a morphological change of the crystals from needles to elongated plates, a drop in crystallization yield, a decrease in particle size and an increase in specific surface area of the crystals. Vigorous multiple washing of the doped crystals with methanol/water (5:95) detached approx. 70 +/- 2% w/w of PMDPH and a neglible amount of DPH (1.0 +/- 0.1% w/w), indicating that the sorbed dopant is predominantly located at or close to the crystal surface. While powder X-ray diffraction studies on the doped and pure crystals presented no significant differences in both their diffraction patterns and lattice spacings, the enthalpy of fusion, DELTA-H(f), and entropy of fusion, DELTA-S(f), of the crystals, as determined by differential scanning calorimetry, were lowered with increasing sorption of PMDPH (by as much as 8% at 0.57 mol% of sorbed PMDPH), suggesting that the sorption of PMDPH raises both the enthalpy and entropy of the crystals. The disruption index of PMDPH, as estimated from the negative slope of the linear regression of DELTA-S(f) on the ideal molar entropy of mixing, DELTA-S(ideal)m, is 19 + 2, implying an introduction of considerable disorder and disruption (about 19-times that expected from pure random mixing alone) in the crystal lattice of DPH by the presence of PMDPH. Determination of the aqueous dissolution rate of the various samples at 25 and 37-degrees-C afforded an upward trend in initial dissolution rate (IR) as a function of the PMDPH sorption, with the largest increase at 0.36 mol% of PMDPH (approximately 3.3-times those of the pure, undoped crystals). The intrinsic dissolution rate, IDR (i.e. IR divided by initial surface area), of the crystals at both temperatures also displayed a rise but peaked at 0.16 mol% of sorbed PMDPH (corresponding to approximately 1.7-fold increase). The observed increases in IDR are probably mediated through increases in the concentration of crystal defects arising from the sorption of PMDPH, and to a much lesser extent, through changes in crystal habit.