Kenneth B. Sloan

The Potts and Guy equation that has been used to predict permeability coefficients for molecules being delivered from aqueous vehicles has been transformed to accommodate lipid vehicles that are less polar than skin, and polar vehicles that are less polar than water. Solubilities in pH 4.0 aqueous buffer (SAQ), solubilities in isopropyl myristate (SIPM), and molecular weights (MW) of prodrugs of 5-fluorouracil (5-FU), theophylline (Th), and 6-mercaptopurine (6-MP) have been regressed against their fluxes from suspensions in IPM (JM). Seven series (n = 39) of alkylcarbonyloxymethyl (ACOM), alkyloxycarbonyl (AOC), alkylcarbonyl (AC), and alkylaminocarbonyl (AAC) prodrugs were used to determine the best fit to the transformed Potts and Guy equation (eq 6): log JM = x + y log SIPM + (1 - y)log SAQ - z MW. The estimated values for x, y, and z were -0. 193, +0.525, and +0.00364, respectively, with r 2 = 0.945 for n = 39. Inclusion of a miscellaneous series comprised of the parent drugs and a branched alkyl chain prodrug gave an equally good fit only if 6-MP was excluded from the analysis. The best performer (largest JM) in each series was usually correctly identified. The values for x, y, and z were consistent with values obtained by Potts and Guy, but the inclusion of the (l - y)log SAQ term in eq 6 and the value for y, shows that water solubility is almost as important as lipid solubility in predicting flux. There were no significant changes in predicted log JM or xi for each series if their log JM or xi were calculated using y and z coefficients obtained for solutions to eq 6 from which the data for the series had been excluded. This suggests that the data from all the series is homogeneous. Data from Kasting, Smith, and Cooper for SIPM, SPG, and MW of unrelated molecules were regressed against their fluxes from propylene glycol (PG) using eq 7: log JM = x + y log SIPM + (1 - y) log SPG - z MW. The estimated values for x, y, and z were -1.673, +0.599, and +0.00595, respectively, with r 2 = 0.852 for n = 28. These values for x, y, and z are also consistent with those previously reported by Potts and Guy, and, together with the results for fluxes from IPM, show the general utility of the transformed Potts and Guy equation in predicting flux from vehicles other than water and in showing the importance of solubility in a polar solvent as well as a nonpolar solvent in predicting flux.

Four homologous 1,3-bisalkylcarbonyl and the corresponding 3-alkylcarbonyl derivatives of 5-fluorouracil (1, 5-FU) have been synthesized and characterized by 1H nuclear magnetic resonance, and infrared and ultraviolet spectroscopy. The 1,3-bisacetyl derivative hydrolyzed rapidly in pH 7.1 buffer at 32°C (t1/2 =0.8 min) to give the 3-acetyl derivative. The hydrolyses of 3-acetyl-, 6, and 3-propionyl-5-FU, 7, were much slower (t1/2 = 200 and 300 min, respectively) and they were biexponential. Both the 1,3- and the 3-derivatives hydrolyzed in the presence of formaldehyde to give significant, and approximately equal amounts of 1- and 3-alkylcarbonyloxymethyl-5-FU derivatives, in addition to 5-FU, which suggested that for both types of derivatives the hydrolyses of the 3-alkylcarbonyl group went through a symmetrical O2-alkylcarbonyl intermediate. The 1,3-derivatives were thermally unstable above about 110°C, giving up to about 20% of the corresponding 1-alkylcarbonyl derivatives at 140°C. On the other hand, the 3-derivatives were thermally unstable even at 95°C, where complete decomposition to 1- and 1,3-derivatives as well as 5-FU was observed.

Six homologous 1 -alkylcarbonyl derivatives of 5-fluorouracil (5-FU) have been synthesized and characterized by 1H NMR, infrared and UV spectroscopy. The derivatives were found to hydrolyze rapidly in pH 7.1 buffer at 32°C (t1/2 = 3-5 min). Although the hydrolysis was found to be catalyzed by hydrated formaldehyde, only 5-FU was observed as a product of the hydrolysis: no 1- or 3-alkylcarbonyloxymethyl products were observed. The 1 -alkylcarbonyl derivatives were recovered intact upon heating at 145°C for 1 h, but, upon heating at 205°C for 1 h, 25% of the sample decomposed to 5-FU with the assumed loss of ketene. The 1-alkylcarbonyl derivatives were stable when stored in a desiccator but decomposed to carboxylic acid and 5-FU upon exposure to atmospheric moisture.