SOLUBILITY AND STABILITY CHARACTERISTICS OF A SERIES OF METHOTREXATE DIALKYL ESTERS

A series of methotrexate (MTX) dialkyl esters were examined for their solubility in an aqueous and a co-solvent medium (20%) (Co-solvent solubility-stability relationship; Dimethylformamide/water co-solvent (DMF)-aqueous buffer) as a function of pH. The pH-solubility relationship showed an unusual increase at pH values above the pK8 of these weak bases. The stability of this series of compounds was also studied in the same 20% DMF medium. The rate constant for diester loss decreased as the series was ascended and additional stability resulted from the branching of the diisopropyl ester. Also, the stability of the MTX methyl ester was studied as a function of pH, with the resulting pH-stability profile showing a typical V-shaped pattern. The maximum aqueous stability of dimethyl ester was shown to be between pH 4 and 5. © 1990.