pharmaceutics Article Assessment of Vehicle Volatility and Deposition Layer Thickness in Skin Penetration Models Abdullah Hamadeh 1 , John Troutman 2 and Andrea N. Edginton 1, *   Citation: Hamadeh, A.; Troutman, J.; Edginton, A.N. Assessment of Vehicle Volatility and Deposition Layer Thickness in Skin Penetration Models. Pharmaceutics 2021, 13, 807. https://doi.org/10.3390/ pharmaceutics13060807 Academic Editors: Heather Benson and Maria Camilla Bergonzi Received: 8 April 2021 Accepted: 24 May 2021 Published: 28 May 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 School of Pharmacy, University of Waterloo, Kitchener, ON N2G 1C5, Canada; ahamadeh@uwaterloo.ca 2 The Procter & Gamble Company, Mason, OH 45040, USA; troutman.ja@pg.com * Correspondence: aedginto@uwaterloo.ca Abstract: Systemic disposition of dermally applied chemicals is often formulation-dependent. Rapid evaporation of the vehicle can result in crystallization of active compounds, limiting their degree of skin penetration. In addition, the choice of vehicle can affect the permeant’s degree of penetration into the stratum corneum. The aim of this study is to build a predictive, mechanistic, dermal absorption model that accounts for vehicle-specific effects on the kinetics of permeant trans- port into skin. An existing skin penetration model is extended to explicitly include the effect of vehicle volatility over time. Using in vitro measurements of skin penetration by chemicals applied in both a saline and an ethanol solvent, the model is optimized to learn two vehicle-specific quan- tities: the solvent evaporation rate and the extent of permeant deposition into the upper stratum corneum immediately following application. The dermal disposition estimates of the trained model are subsequently compared against those of the original model using further in vitro measurements. The trained model showed a 1.5-fold improvement and a 19-fold improvement in overall goodness of fit among compounds tested in saline and ethanol solvents, respectively. The proposed model structure can thus form a basis for in vitro to in vivo extrapolations of dermal disposition for skin formulations containing volatile components. Keywords: dermal; skin; permeation; in silico; models; vehicle; volatility 1. Introduction Establishing reliable estimates of the bioavailability of dermally applied chemicals is a requirement for efficacy and risk assessment studies and for subsequent regulatory approval. Bioavailability may be inferred by training an in silico model of dermal absorp- tion using in vitro skin permeation test data and then extrapolating the trained model to predict the disposition of actives in the in vivo setting [1]. The reliability of such model- based approaches, however, depends on a quantitative understanding of the processes that ultimately determine dermal absorption. Following application of a dose preparation to the skin surface, the formulation com- ponents begin to undergo a series of transport processes: (1) a fraction of the applied dose on the skin surface permeates into a ‘deposition layer’ occupying the upper stratum corneum (SC) through a process of convection [2], (2) the concentration difference between the vehicle and the top layers of the SC drives diffusion of the permeant [3], and, (3) de- pending on exposure and ambient conditions, volatile components of the formulation may evaporate. While evaporation of the solvent can concentrate active ingredients near the skin surface, accelerating absorption, the eventual precipitation of active ingredients on the skin surface can inhibit their diffusive flux into the SC [4–7]. The time scales over which these processes occur have significant bearing on the degree of cumulative skin penetration and, importantly, are often formulation-dependent [8]. In the earlier modeling work reported in Dancik et al. [9], the vehicle/stratum corneum boundary conditions of Kasting and Miller [2,10] were integrated with the skin layer partitioning, diffusion and clearance models reported in [11–14]. Among the assumptions Pharmaceutics 2021, 13, 807. https://doi.org/10.3390/pharmaceutics13060807 https://www.mdpi.com/journal/pharmaceutics