Modification of phenytoin crystals : influence of 3-propanoyloxymenthyl-5,5-diphenylhydantoin on solution-phase crystallization and related crystal properties
Creators: name: Gordon, John David
Publisher: name: University of British Columbia
Year: 2010

description: Recent studies in our laboratory have demonstrated that doping of phenytoin (5,5-diphenylhydantoin; DPH) crystals with traces of 3-acetoxymethyl-5,5-diphenylhydantoin, AMDPH, during growth from methanol consistently modifies their physical properties e.g., habit, energy, surface area, dissolution rate (Chow and Hsia, 1991). AMDPH is a suggested ester prodrug of DPH (Varia et al., 1984). In addition to being structurally akin to DPH, AMDPH is not appreciably greater in molecular size than DPH, which makes possible, from the thermodynamic standpoint, the incorporation of AMDPH into the crystal lattice of DPH. To investigate how the molecular sizes of the ester homologues of DPH influence their incorporation into DPH crystals and the resulting crystal properties, studies similar to those described above have been applied to another additive higher in the ester homologous series, viz. 3-propanoyloxymethyl-5,5-diphenylhydantoin (PMDPH) (Gordon and Chow, 1991). PMDPH , also cited as a prodrug candidate of DPH, differs from AMDPH in possessing an additional methylene group in its ester side chain (Varia et al., 1984). The effects of recrystallizing DPH from methanol under defined conditions in the presence of various concentrations of PMDPH were investigated. An increase in the concentrations of PMDPH (from 0.5 to 11 gL⁻¹) in the crystallization solutions at 30 °C brought about a linear increase in PMDPH sorption (0.03-0.57 mole %) by the DPH crystals, a morphological change of the crystal 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 ~ 70 ± 2 %w/w of PMDPH and a negligible amount of DPH (1.0 ± 0.1 %w/w), indicating that the additive was predominantly adsorbed on 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, ΔHf, and entropy of fusion, ΔSf, of the crystals, as determined by differential scanning calorimetry, were lowered with increasing sorption of PMDPH (by as much as 8 % at 0.57 mole % of PMDPH), indicating that the sorption of PMDPH raised both the enthalpy and entropy of the crystals. The disruption index of PMDPH, as estimated from the negative slope of the linear regression of ΔSf on the ideal entropy of mixing, ΔSideal, was 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 dissolution rate of the various samples at 25 ° and 37 °C afforded an upward trend in initial dissolution rate (IR) as a function of the PMDPH sorption, with the largest increase at 0.36 mole % of PMDPH (-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 mole % of sorbed PMDPH (corresponding to ~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.