Influence of Fabrication Techniques on the Physicochemical, Textural, Release and Skin Delivery Performance of Polyvinyl Alcohol-Based Transdermal Films Containing Menthol: A Comparative Study

Background: Transdermal films are promising dosage forms for controlled delivery of active pharmaceutical ingredients through the skin. Polyvinyl alcohol (PVA)-based matrices are particularly attractive due to their biocompatibility, film-forming ability, and versatility. However, the development of films for volatile compounds such as menthol remains challenging due to high potential losses during processing and application. This study compares PVA-based transdermal films fabricated by 3D printing, solvent casting, and electrospinning, focusing on the effect of fabrication method on film properties, release behaviour, and skin delivery performance. Methods: A comprehensive characterization included morphology, structure, thickness, moisture content, mechanical properties, adhesion, menthol content, in vitro release, ex vivo permeation, and stability. Results: Fabrication method significantly influenced film microstructure, menthol entrapment, and stability. Menthol acted as a plasticiser, increasing thickness and moisture content while reducing mechanical strength via disruption of intermolecular interactions within the PVA matrix. The 3D-printed films exhibited the highest entrapment efficiency (14.40%, corresponding to 4.00% menthol content in the dried matrix) and superior menthol retention after 6 months (75.0%), compared to solvent-cast and electrospun films, due to their dense layered structure limiting volatile losses. All formulations showed biphasic release behaviour, strongly dependent on fabrication method. Electrospun films released menthol fastest (68.94% at 1 h), followed by solvent-cast films (63.48% at 1 h), whereas 3D-printed films exhibited a more sustained profile (46.14% at 2 h), reflecting differences in porosity and diffusion pathways. These structural differences also affected skin delivery, with 3D-printed systems demonstrating higher epidermal flux than the other formulations. Conclusions: Overall, fabrication method governed film microstructure and thereby controlled menthol entrapment, release, and transdermal performance. Extrusion-based 3D printing offers a promising strategy for designing transdermal systems for volatile compounds with improved structural control and delivery efficiency.