MODIFICATION OF PHENYTOIN CRYSTALS .3. INFLUENCE OF 3-BUTANOYLOXYMETHYL-5,5-DIPHENYLHYDANTOIN ON SOLUTION-PHASE CRYSTALLIZATION AND RELATEDCRYSTAL PROPERTIES

The modification of the physical properties of phenytoin (5,5-diphenyl hydantoin; DPH) by recrystallization from methanol has been investigat ed as a function of the concentration of 3-butanoyloxymethyl-5,5-diphe nylhydantoin (BMDPH; a potential ester prodrug of DPH) added to the cr ystallization medium. With increasing concentration of BMDPH in the cr ystallization solutions (0.5-12 g l(-1)), there exhibited a curvilinea r increase in the sorption of BMDPH (0.01-0.5 mol%) and the specific s urface area of the DPH crystals; a drastic reduction in crystallizatio n yield and a progressive change of crystal habit from needles to elon gated plates. Powder X-ray diffraction studies on the samples indicate d essentially the same diffraction patterns and lattice spacings for b oth the pure and the BMDPH-doped DPH crystals, suggesting that the dop ed crystals did not undergo gross structural modification. However, th e enthalpy of fusion, Delta H-f, and the entropy of fusion, Delta S-f, as determined by differential scanning calorimetry, reduced by as muc h as 17% for the samples doped at 7 g l(-1) BMDPH (equivalent to a sor ption of 0.39 mol%), reflecting a significant upsurge in both the enth alpy and entropy of the DPH crystals. The disruption index of BMDPH, a s quantitatively defined by the slope of the linear regression of Delt a S-f on the ideal molar entropy of mixing, Delta dS(ideal)(m) 73 +/- 11 suggesting that the additive is capable of inducing substantial lat tice disorder and disruption (about 73 times that due to simple random mixing alone) in the DPH crystals. Vigorous repeated washing of the s amples with 5% methanol in water removed similar to 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 (similar to 75%) within the cryst als. The initial dissolution rate (IR) at 25 and 37 degrees C of the v arious samples increased sigmoidally, reaching a maximal increment of 4-5-fold for the samples prepared at BMDPH concentrations above 5 gl(- 1) whereas the intrinsic dissolution rate, IDR (i.e. IR divided by the initial surface area), at both temperatures attained a plateauing max imum (similar to 2-fold increase) for the crystals grown at and above 1 gl(-1) BMDPH. The observed improvement of IDR is likely due to an in crease in the concentration of crystal defects (both within and on the surface of the crystals) and/or to a change of crystal habit.