Physico-chemical determinants of dermal drug delivery: effects of the number and substitution pattern of polar groups

Abstract The aim of this study was to investigate the effect of number and substitution pattern of –OH groups of a set of phenols on the in vitro permeation of heat-separated human epidermis. The diffusion was calculated from Log( D / x )=log  k p −0.59 log  K oct +0.024 ( D , diffusion coefficient; x , pathlength; k p , permeability coefficient (cm/h); and K oct , octanol–water partition coefficient). The main factors reducing D were the dipolar and hydrogen bonding capabilities of the permeants quantified as their Hansen partial solubility parameters δ p and δ h . These parameters are significantly reduced by the degree of symmetry of the molecule, so that phloroglucinol (1,3,5-benzenetriol), with three –OH groups, diffuses more rapidly that phenol. When symmetry is absent, as in 1,2,4-benzenetriol, the number of –OH groups results in very slow diffusion. D / x (cm/h) was related to the combined solubility parameter δ a defined as √( δ p 2 + δ h 2 ) by: ( D / x )=0.0024−0.000065 δ a ( n =7, R 2 =0.70, P =0.012).