Development and Physicochemical Characterization of Trans-Resveratrol Liposomes: Influence of Phospholipid Composition and Ultrasound-Assisted Processing

Background/Objectives: Trans-resveratrol is a bioactive polyphenol with limited pharmaceutical applicability due to poor aqueous solubility, chemical instability, and low bioavailability. This study aimed to develop trans-resveratrol-containing liposomal formulations and evaluate the influence of phospholipid composition and ultrasound-assisted processing (UAP) using a conventional ultrasonic bath on their physicochemical properties and storage behavior. Methods: Liposomes were prepared by the ethanol injection method using Lipoid® S75, Lipoid® P45, soybean lecithin, egg yolk lecithin, and selected binary phospholipid mixtures. Trans-resveratrol identity was verified by LC–MS. Particle size, polydispersity index (PDI), and zeta potential were determined before and after UAP, and physical stability was assessed after 30 days of refrigerated, light-protected storage. Results: Phospholipid composition markedly influenced liposome physicochemical characteristics. Lipoid® P45-based formulations exhibited favorable initial particle size, PDI, and zeta potential profiles. UAP generally reduced particle size and improved particle size distribution immediately after preparation, although the magnitude of the effect depended on formulation composition. During refrigerated storage, short-term physical storage behavior was strongly formulation-dependent. Selected trans-resveratrol-containing formulations, particularly Lr12, Lr13, and Lr15, exhibited marked particle growth and increased polydispersity, whereas Lr20–Lr22 exhibited the most favorable particle size and PDI profiles after 30 days. Conclusions: Phospholipid composition was a critical determinant of trans-resveratrol liposome performance. Conventional ultrasonic-bath processing provided a simple and accessible means of improving initial liposomal characteristics, but did not universally ensure short-term physical stability during 30 days of refrigerated storage. Selected binary phospholipid formulations, particularly Lr20–Lr22, showed favorable physicochemical profiles and may represent promising candidates for further formulation development.