Modification of phenytoin crystals: influence of 3-acetoxymethyl-5,5-diphenylhydantoin on solution-phase crystallization and related crystal properties

Abstract

Phenytoin (5,5-diphenylhydantoin; DPH) crystals were grown under defined conditions from glass-distilled methanol containing various concentrations of the additive, 3-acetoxymethyl-5,5-diphenylhydantoin (AMDPH; a proposed prodrug of DPH), and their physical properties characterized. The addition of 0.5–12 g l −1 AMDPH to the crystallization solutions at 30° C led to an apparently sigmoidal increase in AMDPH sorption (0.034–0.5 mol%) by the crystals, a change of crystal habit from acicular prisms to long thin plates with rough surfaces, a reduction of crystallization yield, a wider density distribution, a decrease in particle size, and an increase in specific surface area. Vigorous repeated washing of the doped crystals with 5% methanol in water dislodged 51 ± 8% w/w of AMDPH and a negligible amount of DPH (1.0 ± 0.1% w/w), indicating that a substantial portion of the sorbed AMDPH is present at or near the crystal surface. Powder X-ray diffraction detected no significant changes in both the diffraction pattern and d-spacing values (< 0.5%), suggesting an absence of major structural changes. Thermal analysis of the doped crystals, however, revealed relatively marked decreases in the enthalpy of fusion, ΔH f, and entropy of fusion, ΔS f (by as much as 11%), suggesting that the sorption of AMDPH augments both the enthalpy and entropy of the crystals. The decreases in ΔS f are 27 ± 4 times the calculated ΔS m ideal values, reflecting a substantial rise in lattice disorder and disruption due to the presence of AMDPH. The initial dissolution rate (IR) at both 25 and 37 ° C increased by more than 3.5-fold for the samples prepared at 9 g l −1 AMDPH while the intrinsic dissolution rate, IDR (i.e. IR divided by initial surface area), at both temperatures increased by maximally 2–3-fold for the crystals grown at 5 g l −1 AMDPH. The enhancement of IDR is possibly associated with an increase in the density of crystal defects (on the surface and within the bulk) arising from both growth and the sorption of AMDPH, and with a positive contribution from crystal anisotropy.