Estimation of Maximum Transdermal Flux of Nonionized Xenobiotics from Basic Physicochemical Determinants

Abstract

An ability to estimate the maximum flux of a xenobiotic across skin is desirable both from the perspective of drug delivery and toxicology. While there is an abundance of mathematical models describing the estimation of drug permeability coefficients, there are relatively few that focus on the maximum flux. This article reports and evaluates a simple and easy-to-use predictive model for the estimation of maximum transdermal flux of xenobiotics based on three common molecular descriptors: logarithm of octanol-water partition coefficient, molecular weight and melting point. The use of all three can be justified on the theoretical basis of their influence on the solute aqueous solubility and the partitioning into the stratum corneum lipid domain. The model explains 81% of the variability in the permeation dataset comprised of 208 entries and can be used to obtain a quick estimate of maximum transdermal flux when experimental data is not readily available.

Transdermal patches: history, development and pharmacology

“…[The dashed black lines are calculated from the expression: log maximum delivery rate (μg·cm −2 ·h −1 ) = 1.6 + log MW − 0.0086 MW − 0.01 ( MP − 25) − 0.219 log P and is based on a regression of maximum transdermal flux (in nmol, equation 7) versus MP , MW and log P for the combined data set of M agnusson et al . () ( M ilewski and S tinchcomb, ). The level region in this plot recognises that 25°C is an approximate lower skin surface temperature for patches applied to human skin in vivo and at which all drugs with MP < 25°C will be liquid.]…”

“…As shown in Figure , most, but not all, of the marketed drugs used in patches are above the lower Berner–Cooper boundary of MW = 500, log P = 5 and MP < 250°C. All currently marketed drugs in the patch data fall within boundaries derived using a single pathway model similar to that used by Wiedersberg and Guy () and a larger data set (Magnusson et al ., ; Milewski and Stinchcomb, ) (Figure ). It is evident from Table that a candidate drug for transdermal patches should normally be moderately lipophilic (log P range from 1 to 5), have a low molecular weight (MW < 500 Da) and a low melting point (MP < 250°C).…”

“…Also shown, as dashed black lines, are the estimated upper and lower boundary lines for marketed drug delivery rate from patches as defined by the rates for small (MW = 100), polar (log P = 1) and large (MW = 500), lipophilic (log P = 5) solutes respectively. [The dashed black lines are calculated from the expression: log maximum delivery rate (μg·cm −2 ·h −1 ) = 1.6 + log MW − 0.0086 MW − 0.01 (MP − 25) − 0.219 log P and is based on a regression of maximum transdermal flux (in nmol, equation 7) versus MP, MW and log P for the combined data set of Magnusson et al (2004) (Milewski and Stinchcomb, 2012). The level region in this plot recognises that 25°C is an approximate lower skin surface temperature for patches applied to human skin in vivo and at which all drugs with MP < 25°C will be liquid.…”

Targeted skin delivery of topically applied drugs by optimised formulation design

“…Earlier studies (88,89) found that solubility, lipid-water partition coefficient, melting point and molecular weight are significant determinants of the permeability of drugs across the skin.…”

“…For example, Twist and Zatz (139) found that methyl paraben had the same flux from a range of saturated solutions in different vehicles applied to inert polydimethylsiloxane membranes that were not affected by the vehicles (139). Physicochemical properties including molecular size, melting point, lipophilicity, solubility and hydrogen bonding acceptor ability have been considered to be important in determining permeation flux (89,140). affecting the partitioning between the stratum corneum lipids and other stratum corneum components; (c) increasing its solubility in the stratum corneum lipids (141).…”