Understanding the Role of Solvents in Hypromellose-Based Film-Forming Solutions for Topical Administration of Ketoprofen Through a Design of Experiments Approach

Background/Objectives: Topical ketoprofen gels are limited by the need for frequent reapplication, short skin residence time, and the risk of sunlight-induced photoallergic dermatitis. Film-forming solutions (FFSs) allow for extended retention; however, the solvents used may affect the polymer film’s characteristics. The present study aimed to elucidate the effect of macrogol 400 and isopropanol and develop a hypromellose-based ketoprofen FFS using a design of experiments (DoE) approach. Methods: A 3² full factorial design was applied to investigate the effects of macrogol 400 (0–5%, w/w) (X₁) and isopropanol (25–50%, w/w) concentrations (X₂) on film mechanical properties (tensile strength (Y₁), elongation at break (Y₂), and Young’s modulus (Y₃)). The DoE-based placebo and ketoprofen-loaded FFSs were characterized for their physicochemical, rheological, and textural properties, while the corresponding films were evaluated for appearance, weight, stickiness, and mechanical properties. In vitro ketoprofen release from the drug-loaded FFS was also evaluated. Results: Macrogol 400 concentration was identified as a significant factor influencing film mechanical properties. As a film plasticizer, macrogol 400 improved film mechanical properties up to the optimal concentration (2.75%), whereas the water/isopropanol ratio mainly affected the applicative (rheological and textural) properties of the FFSs. Ketoprofen incorporation significantly reduced the film tensile strength and elongation at break. In vitro release testing demonstrated 58.52% ketoprofen release after 6 h, with the Weibull model showing the best fit to the release profile. Conclusions: Macrogol 400 and isopropanol have a complex, mutually conditioned influence on the application characteristics of hypromellose-based FFS and the mechanical characteristics of the films. Incorporation of ketoprofen into the selected placebo formulation significantly reduced film deformability but yielded a thin, transparent film with favorable in vitro drug-release characteristics. The developed FFS represents a promising topical dosage form for non-steroidal anti-inflammatory drugs and warrants further investigation, particularly in terms of skin retention and in vivo performance.