Discriminating the molecular identity and function of discrete supramolecular structures in topical pharmaceutical formulations

There is a need to understand how solvent structuring influences drug presentation in pharmaceutical preparations, and the aim of this study was to characterize the properties of propylene glycol (PG)/water supramolecular structures such that their functional consequences on drug delivery could be assessed. Shifts to higher wavenumbers in the C–H and C–O infrared stretching vibrations of PG (up to 8.6 and 11 cm^–1, respectively) implied that water supramolecular structures were being formed as a consequence of hydrophobic hydration. However, unlike analogous binary solvent systems, water structuring was not enhanced by the presence of the cosolvent. Two discrete populations of supramolecular structures were evident from the infrared spectroscopy: water-rich structures, predominant below a PG volume fraction (f_PG) of 0.4 (unmoving water bending vibration at 1211 cm^–1) and PG-rich structures, predominant above 0.4 f_PG (both C–H and water peaks moved to lower wavenumbers). The un-ionized diclofenac log–linear solubility and transmembrane transport altered dramatically when f_PG > 0.55 (a 10-fold increase in transport from 0.28 ± 0.06 μg·cm–2·h–1 at 0.2 fPG to 2.81 ± 0.16 μg·cm^–2·h^–1 at 0.9 f_PG), and this demonstrated the ability of the PG rich supramolecular structures, formed in the PG/water solvent, to specifically modify the behavior of un-ionized diclofenac.