The current study analyzes the cause of the extreme change in dermal permeation resulting from a minute structural transformation within a temperature-sensitive direct hexagonal mesophase by a multiple-method approach. The evaluated mesophase is composed of Tween 80, propylene glycol, isopropyl myristate, benzyl alcohol, and water. 1 wt% ketoconazole (KCZ) was loaded in the concentrate as a model lipophilic drug. Evaluation of the mesophase at 25 °C indicated that the hexagonal mesophase region (33.0–42.5 wt% water along water dilution line N91) consists of two distinct structures. At water content below 39.0 wt%, the mesophase is structured as a bidiscontinuous hexagonal mesophase (BHM) consisting of occluded hydration centers and hexagonally oriented direct micelles. Above 39.5 wt% water, dilution of the BHM obstructs the hydration centers, transforming the mesophase to a water continuous hexagonal mesophase (CHM). FTIR evaluation indicated that the both the added water upon dilution and the water molecules released from the hydration centers bind to the surfactant's non-hydrated ethoxylates. Evaluation of the structural transition by PGSE-NMR and DSC indicated that the binding of water to the surfactant's heads immobilizes the inner core of the solubilized lipids. The reduction of the lipid core’s mobility prevents its crystallization at cryogenic temperatures. SAXS and rheological evaluations pointed out that both BHM and CHM are temperature-sensitive mesophases, which lose their range order and storage modulus at 32 °C. Obstruction of the hexagonal mesophase enhances KCZ's diffusion from both mesophases’ via cellulose acetate at 35 °C. Despite the similarity of both mesophases at elevated temperatures (35 °C), the lipidic inner core’s rotational correlation time for deformed CHM micelles remains substantially lower than from the deformed BHM. Franz cell evaluation indicated that the lipidic core mobility substantially influences KCZ's distribution upon dermal application, whereas from CHM KCZ's transdermal flux via a dermatome bovine graft at 35 °C, was 1.60 ± 0.28 µg/cm2 h, no flux was detected from BHM. On the other hand, KCZ's dermal accumulation from BHM, at 35 °C, was found to be more than double than that from CHM, indicating that the decrease in the lipidic inner core’s mobility of direct micelles prevents the accumulation of lipophilic compounds in the dermis, thereby enhancing their transdermal flux.
