INCREASED SHELF-LIFE OF FOSPHENYTOIN - SOLUBILIZATION OF A DEGRADANT,PHENYTOIN, THROUGH COMPLEXATION WITH (SBE)(7M)-BETA-CD

Fosphenytoin, a water-soluble prodrug of phenytoin, degrades primarily to phenytoin at pH values <8 during long term storage; phenytoin read ily precipitates when formed from fosphenytoin due to its limited aque ous solubility. The objective of this study was to develop stable form ulations of fosphenytoin in the pH range of 7.4-8.0 by inhibiting the phenytoin precipitation through complexation with a parenterally safe cyclodextrin, (SBE)(7m)-beta-CD. Phase solubility studies at 25 degree s C revealed that phenytoin could be effectively solubilized by (SBE)( 7m)-beta-CD both in the presence and absence of 80.6 mg/mL fosphenytoi n (as its dihydrate). The binding constants for the phenytoin/cyclodex trin complex were found to be 1073 and 792 M-1 at pH 7.4 and pH 8.0, r espectively. Because of the competitive inclusion between fosphenytoin and phenytoin with (SBE)(7m)-beta-CD, the extent of solubilization of phenytoin was lower, as expected, in the presence of fosphenytoin tha n in the absence of fosphenytoin, even though the binding constants fo r the fosphenytoin/cyclodextrin complex were relatively small (41-45 M -1). Initial rates were used to follow the production of phenytoin fro m fosphenytoin. Zero-order kinetics were observed under all conditions investigated. Phenytoin production rates were followed at 25, 37, and 50 degrees C in the presence of 0.03 or 0.06 M (SBE)(7m)-beta-CD. It was projected from the solubility of phenytoin and the kinetic informa tion that fosphenytoin shelf lives as high as nine years at 25 degrees C and pH 7.4 in the presence of 60 mM of (SBE)(7m)-beta-CD might be p ossible while longer shelf lives might be possible at pH 8.