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 readily precipitates when formed from fosphenytoin due to its limited aqueous solubility. The objective of this study was to develop stable formulations 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 degreesC revealed that phenytoin could be effectively solubilized by (SBE)7m-beta-CD both in the presence and absence of 80.6 mg/mL fosphenytoin (as its dihydrate). The binding constants for the phenytoin/cyclodextrin complex were found to be 1073 and 792 M-1 at pH 7.4 and pH 8.0, respectively. 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 than in the absence of fosphenytoin, even though the binding constants for the fosphenytoin/cyclodextrin complex were relatively small (41-45 M-1). Initial rates were used to follow the production of phenytoin from fosphenytoin. Zero-order kinetics were observed under all conditions investigated. Phenytoin production rates were followed at 25, 37, and 50 degreesC 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 information that fosphenytoin shelf lives as high as nine years at 25 degreesC and pH 7.4 in the presence of 60 mM of (SBE)7m-beta-CD might be possible while longer shelf lives might be possible at pH 8.
Department of Pharmaceutical Chemistry and Higuchi Biosciences Center for Drug Delivery Research, The University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047, USA.
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Narisawa
V J
VJ
Stella
D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000737:chemistry*; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013696:Temperature; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D011355:Prodrugs; D047392:beta-Cyclodextrins; D010672:Phenytoin; C043114:fosphenytoin; C031215:betadex