Ionisation effects on the permeation of pharmaceutical compounds through silicone membrane

Abstract

8Silicone membrane is frequently used as an in vitro skin mimic whereby experiments 9 incorporate a range of buffered media which may vary in pH. As a consequence of such 10 variability in pH there is a corresponding variability in the degree of ionisation which in turn, 11 could influence permeation through the mainly hydrophobic-rich membrane structure. This 12 study reports the effect of pH on the permeation of five model compounds (benzoic acid, 13 benzotriazole, ibuprofen, ketoprofen and lidocaine). For the five compounds analysed, each 14 at three distinct percentages of ionisation, it was found that the greater extent of permeation 15 was always for the more 'neutral', i.e. more greatly unionised, species rather than the anionic 16 or cationic species. These findings fit with the theory that the hydrophobic membrane 17 encourages permeation of 'lipid-like' structures, i.e. the more unionised form of compounds.

Permeation of pharmaceutical compounds through silicone membrane in the presence of surfactants

“…The formation of surfactant micelles creates a hydrophobic core which contains the hydrophobic regions of surfactant and it is known that the hydrophobic core of micelles can strongly interact with hydrophobic molecules and entrap them inside the core [26]. A similar mechanism can be observed in this study where ibuprofen, with a log P value of 3.6 [11], strongly interacted with the hydrophobic core of CHAPS micelles and became trapped inside them thus reducing the number of ibuprofen molecules available to cross through PDMS membrane. Consequently, there would be a reduction in ibuprofen permeation.…”

“…However, as PDMS is a very simplified model of skin it has the advantage of significantly increasing the level of reproducibility in data acquired yet has the disadvantage of potentially behaving differently to skin under certain conditions. Several factors have already been found to effect permeation including ionisation (as a result of pH) [11], membrane thickness [12] and solvent selection (i.e. donor and receptor solution composition) [13].…”

“…to 3.6 for ibuprofen[11]. The surfactants were chosen to include all four categories, namely SDS (anionic), CTAB (cationic), CHAPS(zwitterionic) and Brij 35 (non-ionic).As a control, the permeation of the model compounds through silicone membrane were assessed at 32 °C with no surfactant present in the donor solution over a period of 6 hours.…”

An equation for the prediction of human skin permeability of neutral molecules, ions and ionic species

“…It has been known for years that the permeability of ionizable compounds depends on the pH of the donor solution, attributed to the slower rate of permeation of ionic species compared to the corresponding neutral species (Roy and Flynn, 1990;Swarbrick et al, 1984;Waters and Bhuiyan, 2016). For instance, Waters and Bhuiyan (2016) recently reported that as an in vitro skin mimic, silicone membrane encouraged permeation of the more unionized forms of pharmaceutical compounds rather than the ionized forms. However, the above reviews completely ignore the possibility of ionization and associated factors such as the dependence of permeation on pH for ionizable compounds, and our previous study represents the only attempt to include ionized species in a model for skin permeation (Zhang et al, 2012).…”

“…Various kinds of empirical and mathematical models for the correlation and prediction of human skin permeability, as log Kp, have been reported (Baba et al, 2015;Mitragotri, 2003), and there have been a number of reviews of these models (Chen et al, 2013;Geinoz et al, 2004;Mitragotri et al, 2011;Moss et al, 2011;Neely et al, 2009). It has been known for years that the permeability of ionizable compounds depends on the pH of the donor solution, attributed to the slower rate of permeation of ionic species compared to the corresponding neutral species (Roy and Flynn, 1990;Swarbrick et al, 1984;Waters and Bhuiyan, 2016). For instance, Waters and Bhuiyan (2016) recently reported that as an in vitro skin mimic, silicone membrane encouraged permeation of the more unionized forms of pharmaceutical compounds rather than the ionized forms.…”