The estimation of relative water solubility for prodrugs that are unstable in water

Abstract

The pH 4.0 buffer solubilities ( S H 2O ) of three series of N-acyl-5-fluorouracil (5-FU) prodrugs have been estimated from their solubilities in isopropyl myristate (IPM) and their very rapidly determined partition coefficient values between IPM and pH 4.0 buffer ( K). These estimated values have been compared (1) with directly determined values for the two more hydrolytically stable series (1-alkyloxycarbonyl- and 1-alkylaminocarbonyl-5-FU), (2) with literature values and (3) with values calculated from (log water solubility) = −(log partition coefficient)−0.01(melting point) + 1.05. There is good agreement between the absolute and relative values of the estimated and directly measured buffer solubilities for the two more hydrolytically stable series. There is also excellent agreement between the estimated values for the two more hydrolytically stable series and the literature values except for the 1-ethyloxycarbonyl-5-FU derivative where the literature value appears to be almost an order of magnitude too low. The calculated water solubilities give values that are one to three orders of magnitude too high and do not accurately reflect trends in the series. The partition coefficient and estimated buffer solubility values for the hydrolytically unstable series (1-alkylcarbonyl-5-FU) are reproducible and consistent with those of the two more stable series. Thus, the estimated buffer solubilities for the hydrolytically unstable series are reliable values that are accurate relative to other series of N-acyl prodrugs.