Modification of phenytoin crystals. III. Influence of 3-butanoyloxymethyl-5,5-diphenylhydantoin on solution-phase crystallization and related crystal properties

Abstract

The modification of the physical properties of phenytoin (5,5-diphenylhydantoin; DPH) by recrystallization from methanol has been investigated as a function of the concentration of 3-butanoyloxymethyl-5,5-diphenylhydantoin (BMDPH; a potential ester prodrug of DPH) added to the crystallization medium. With increasing concentration of BMDPH in the crystallization solutions (0.5–12 g 1 −1), there exhibited a curvilinear increase in the sorption of BMDPH (0.01-0.5 mol'Y) and the specific surface area of the DPH crystals: a drastic reduction in crystallization yield and a progressive change of crystal habit from needles to elongated plates. Powder X-ray diffraction studies on the samples indicated essentially the same diffraction patterns and lattice spacings for both the pure and the BMDPH doped DPH crystals, suggesting that the doped crystals did not undergo gross structural modification. However, the enthalpy of fusion, ΔH f, and the entropy of fusion, ΔS f, as determined by differential scanning calorimetry, reduced by as much as 17° for the samples doped at 7 g 1 −1 BMDPH (equivalent to a sorption of 0.39 mol°), reflecting a significant upsurge in both the enthalpy and entropy of the DPH crystals. The disruption index of BMDPH, as quantitatively defined by the slope of the linear regression of ΔS f on the ideal molar entropy of mixing, ΔS ideal m, was 73 ± 11 suggesting that the additive is capable of inducing substantial lattice disorder and disruption (about 73 times that due to simple random mixing alone) in the DPH crystals. Vigorous repeated washing of the samples with 5'Y. methanol in water removed ∼ 25 ± 1.3°, w/w of sorbed BMDPH and a negligibly small amount of DPH (1.2 ± 0.1° w/w), suggesting the BMDPH resides mostly (∼ 75°) within the crystals. The initial dissolution rate (IR) at 25 and 37°C of the various samples increased sigmoidally, reaching a maximal increment of 4-5-fold for the samples prepared at BMDPH concentrations above 5 g 1 −1 whereas the intrinsic dissolution rate, IDR (i.e. IR divided by the initial surface area), at both temperatures attained a plateauing maximum ( ∼ 2-fold increase) for the crystals grown at and above 1 g l −1 BMDPH. The observed improvement of IDR is likely due to an increase in the concentration of crystal defects (both within and on the surface of the crystals) and/or to a change of crystal habit.