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

Abstract

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.

Popular Abstract

A “Physical Examination” of the Microscopic World of Creams: How to Ensure a Perfect Tactile Sensa-tion for Every Tube?
Why do some creams feel smooth and hydrating upon application, while others resemble stiff butter? The secret lies hidden within a microscopic “sandwich” structure invisible to the na-ked eye. We have identified a technology akin to “fingerprint recognition.” This technology can accurately diagnose whether a cream has been structurally compromised during industrial production. Consequently, it ensures that every tube delivered to patients is flawless.
Topical drug delivery is an extremely common treatment method in our daily lives. However, an excellent semi-solid cream is far from a simple mixture of water and oil. Its core consists of an extremely complex lamellar gel network. You can imagine this network as countless microscopic “sandwiches” formed by alternating layers of lipids and water. This three-dimensional sandwich framework traps a large amount of water and provides the cream with its solid form. Furthermore, it directly dictates whether the cream can melt instantly and spread smoothly upon contact with the skin. It also determines whether the active pharmaceu-tical ingredients can effectively penetrate the human skin barrier.
However, stably manufacturing these microscopic “sandwiches” in large-scale industrial facil-ities presents a massive challenge. The manufacturing process involves complex pipeline transportation, intense agitation, and rapid cooling. During these stages, a slight loss of tem-perature control or an excessively high pump speed can cause severe damage. These fragile microscopic frameworks can be torn, deformed, or grown into coarse agglomerates. Once the internal structure collapses, the cream exhibits severe macroscopic defects. It becomes ex-tremely difficult to squeeze out and may undergo phase separation. This not only results a terrible user experience but also severely compromises the intended therapeutic efficacy.
To solve this industrial challenge, we successfully identified a method to conduct a “compre-hensive physical examination” on these creams. By studying a commercial cream with a com-plex liquid crystalline structure (Zalve®), we established a set of “physical fingerprints” based on its perfectly healthy state. We intentionally manufactured defective creams in the laborato-ry by removing cooling equipment or omitting key components. During these tests, we dis-covered that this examination method could highly sensitively capture the pathological chang-es in their internal structures. This implies that pharmaceutical companies can simply perform basic physical tests during future continuous production. Just like taking an X-ray, they can instantly diagnose which specific step on the production line damaged the microscopic struc-ture of the cream. They can precisely identify whether the cooling was too rapid or the me-chanical squeezing was too intense. This capability will greatly assist factories in trouble-shooting and reducing scrap rates.
During our research, we also discovered a fascinating detail. The cream is essentially alive! The internal structure of the cream is not permanently fixed immediately after filling on the production line. Over the following days, the product will slowly mature at room temperature. The microscopic crystals will spontaneously adjust their positions, becoming more densely packed and rigid. Just as wine requires time to settle, the cream typically undergoes physical aging to reach a more settled structural state.
To reach these conclusions, we primarily subjected the creams to precise “mechanical torture.” We did not utilize complex chemical reagents. Instead, we placed different batches of creams onto rheological instruments and applied precise compressive, tensile, and rotational shear forces. We observed their responses at the exact moment of initial flow and structural collapse. Furthermore, we combined these measurements with microscopes to capture vivid images of their internal crystals. Ultimately, these comprehensive data helped us decode the hidden rela-tionship between the manufacturing process and the final microstructure.

• author: Zhu, Ruiqian
• supervisor: Marie Wahlgren; Cathrine Albèr
• organization: Pharmaceutical Technology (master); Food Technology and Nutrition (M.Sc.)
• course: KLGM06 20261
• year: 2026
• type: H2 - Master's Degree (Two Years)
• subject: Medicine and Health Sciences; Chemistry
• keywords: lamellar gel network, rheology, semi-solid formulation, pharmaceutical formulation
• language: English
• id: 9239147
• date added to LUP: 2026-06-16 16:20:11
• date last changed: 2026-06-16 16:20:11