Correlation of aqueous and lipid solubilities with flux for prodrugs of 5‐fluorouracil, theophylline, and 6‐mercaptopurine: A potts–Guy approach

Abstract

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.

Prodrugs of Theophylline Incorporating Ethyleneoxy Groups in the Promoiety: Synthesis, Characterization, and Transdermal Delivery

“…1) where n=42 (6). The coefficients to the IPM and aqueous solubility parameters were approximately equal, which supported the previous observations (4,5) that a balance of improved lipid and aqueous solubilities was important to optimize flux from a lipid vehicle.…”

“…The synthesis of alkyloxycarbonyl-Th derivatives (4)(5)(6) involves the acylation of Th-H with alkyoxycarbonyl chlorides in presence of mild base, TEA, and DCM as the solvent (Scheme 2). The synthesis of alkyloxycarbonyl chlorides from commercially available alcohols, i.e., MEA, MDEA, or MPA involves the conversion of the alcohol to a chloroformate by reaction with triphosgene and pyridine in DCM as the solvent as reported by us before (14).…”

“…(1) is much more versatile. It can be used if the vehicle is water (9) or if the vehicle is a lipid such as IPM (6). In fact, when the largest collected database consisting in solubilities in the lipid octanol, S OCT , and water, S AQ , molecular weights, MW, and the maximum fluxes of n=184, different permeants through human skin in vitro from water (J MHAQ ) was fitted to the RS equation, the same results were obtained as when data for J MMIPM for a different set of permeants was fitted to RS: The coefficients to the lipid (OCT or IPM, respectively) and aqueous solubility parameters were about the same (10).…”

Application of the transformed Potts–Guy equation to in vivo human skin data

“…9 The MO solubilties (S MO ) have been converted to units of mM. Although the partition coef®cients (K MO:AQ ) for the distribution of unionized NSAIDS between MO and acidic water (we will use AQ instead of W*) were measured, their values were not reported.…”

“…1 Sloan and co-workers 2±8 have published numerous articles on the delivery of theophylline, 5-¯uorouracil, and 6-mercaptopurine from suspensions of their prodrugs in isopropyl myristate (IPM) through hairless mouse skin under essentially identical conditions. For this data set, Roberts and Sloan 9 have shown that the transformed Potts±Guy equation, which speci®cally makes it possible to predict¯ux from lipid vehicles, shows a large positive dependence of ux on the aqueous solubilities (S AQ ) as well as the solubilities in IPM (S IPM ) of the prodrugs that comprise the data set. This result is not consistent with previous results that suggested that the solubility properties of the skin barrier are most accurately modeled by octanol alone.…”