Rheological Characterization of a Semi-solid Cream: Impact of Process Dynamics and Storage on Lamellar Gel Networks

Sammanfattning

The macroscopic physical stability and clinical application performance of topical semi-solid formulations are highly dependent on the complex lamellar gel network (LGN) formed within their continuous phase. However, this microscopic three-dimensional scaffold exists in a thermodynamically metastable state and is extremely sensitive to kinetic parameters during the manufacturing process, such as thermal history and shear forces. This study aims to sys-tematically evaluate the microstructural evolution and physical stability of a lipid-liquid crys-talline system under various processing pathways, industrial scale-up stages, and long-term storage conditions, utilizing rheological characterization techniques combined with polarized light microscopy (PLM). This research compares steady-state industrial batches with laborato-ry and industrial samples exhibiting various process deviations. By conducting comprehensive rheological tests, including amplitude and frequency sweeps, yield stress determination, steady-state flow, and the three-interval thixotropy test (3ITT), and tracking the aging trajec-tory for several days, this study reveals the profound relationships between process, structure, and performance. The results demonstrate that products reaching a thermodynamic steady state during continu-ous manufacturing exhibit a highly uniform birefringent microtexture, a moderate storage modulus (G’), and balanced thixotropic recovery. Early-stage process deviations and laborato-ry-scale extreme cases, such as missing key electrolytes or insufficient cooling and shear, pro-duce coarse, anisotropic crystals or collapsed networks, which manifest rheologically as either elevated modulus or near-complete loss of solid-like behaviour. Rheological tracking during storage also revealed three distinct aging trajectories across the studied samples: the commer-cial Zalve® baseline showed an increase in storage modulus and a decrease in thixotropic re-covery, qualitatively consistent with physical aging behaviour reported for related soft solid systems; whereas faulty production-line batches and freshly collected steady-state material followed different trajectories, with changes in yield stress and recovery rate that suggest structurally distinct relaxation pathways. The interpretation of these trajectories is tentative; absolute aging times differed between samples due to project-imposed timing constraints. This study supports the use of multi-parameter rheology as a sensitive structural fingerprint for complex semi-solid formulations, with potential applications in Q3 structural equivalence assessment, process troubleshooting, and shelf-life evaluation of topical drug products.