Solubility and ionization characteristics of phenytoin

J Pharm Sci. 1977 Jul;66(7):994-7. doi: 10.1002/jps.2600660724.


The solubility of phenytoin was determined in pH 7.4 and 5.4 phosphate buffers at five temperatures; in hydroalcoholic solutions, 0--4% methanol; and in pH 4.8--8.4 buffer solutions. From the temperature data, the enthalpy and entropy of solution of this nonideal system were calculated and were similar at both pH values. The data obtained from the buffer solutions were used to calculate the apparent dissociation constant, pKa', of phenytoin as 8.06. A GLC method with on-column methylation was used to quantitate phenytoin with 5-(p-methyl-phenyl)-5-phenylhydantoin as an internal standard. The assay uses chloroform of extraction of the drug from aqueous solutions. The ratio of peak heights was adjusted for weights of aqueous and organic layers, and results were calculated in micrograms per gram of sample and mole fraction of phenytoin. Although hydroalcoholic solutions enhanced drug solubility, there is a potentially significant disadvantage in using alcohol for clinical studies.

MeSH terms

  • Chemical Phenomena
  • Chemistry, Physical
  • Hydrogen-Ion Concentration
  • Methanol
  • Phenytoin* / analysis
  • Solubility
  • Temperature
  • Thermodynamics


  • Phenytoin
  • Methanol