(M1330-09-49) Eliminating Operator Dependence from Gelling Agent Addition - Improving the Robustness and Processing Time of Semi-Solid Dosage Forms Without Impacting the Viscosity or Aesthetics

Purpose: Aqueous gelling agents for semi-solid dosage forms are typically fine powders that require technique and experience to add consistently and reproducibly to a product. Typical instructions for gelling agent addition read: "Natrosol™ 250 Pharm HEC is sifted slowly into the vortex of vigorously agitated water. The rate of addition should be slow enough for the particles to separate without lump formation, but not so slow that the solution thickens appreciably before all the solids are added".¹ The need for specific instructions is common for most aqueous gelling agents. Similarly, Lubrizol supplies a 5-page technical data sheet "Dispersion Techniques for Carbopol Polymers" suggesting the need for specific instructions for gelling agent addition.² Due to variability between operators, drug products manufactured with the same formula can result in different viscosity measurements and even appearance due to incomplete gelling agent hydration, commonly referred to as fisheyes. These challenges are magnified as drug products are scaled up from benchtop. The large scale scenario where the addition of up to 20 kg of powder is instructed "to add to a vortex, must be slow enough to prevent lumps from forming, but fast enough that the powder is added before the solution gets too thick". To address this, a technique where gelling agents coupled with specific cosolvents have been identified to facilitate easier and more consistent gelling agent addition during product manufacturing. When the right cosolvent is chosen for the right gelling agent the technique dependance of the processing is no longer critical. This new method allows for a gelling agent to be weighed into a container, followed by immediately adding of the appropriately identified cosolvent on top. A gentle mixing process is then employed to create a solvent/gelling agent slurry, that can be immediately added to the aqueous system to facilitate the gelling process while resulting in the same viscosity outcomes as traditional addition methods. Using specific cosolvent/gelling agent systems proved easier, with more robust results that are no longer dependent on operator or addition technique. Our goal was to investigate the cosolvent gelling agent addition method using five typically employed powdered gelling agents against nine cosolvents to identify optimal cosolvent/gelling agent combinations to improve gelling agent utility while preserving product robustness.

Methods: Five powdered gelling agents were selected for investigation: Hydroxyethyl Cellulose 250HHX Pharm (1.5% w/w), Hydroxypropyl Cellulose HF Pharm (2% w/w), Hydroxypropyl Methylcellulose (2% w/w), Carbopol 980 (0.75% w/w), and Xanthan Gum (2% w/w). Each gelling agent was individually combined with one of nine selected cosolvents to evaluate the feasibility of each blend. The gelling agent powder was placed into a beaker and 10% w/w of each cosolvent was poured on top of the gelling agent and mixed until a uniform slurry phase was obtained (Image 1). The target outcome was a flowable slurry phase without the formation of a gel or fisheyes. The resulting phase had to be freely pourable to be considered successful. Next, the resulting pourable slurry was immediately added ~88% w/w water in a separate vessel with propeller mixing. The resulting product was assessed based on gelling time as well as final viscosity. The gelling time and final viscosity was measured against identical control samples that was an equivalent product of the same ingredients, except the gelling agent was added as described in traditional literature. Successful systems were identified as ones where the processing time was equivalent or improved while simultaneously resulting in no viscosity change when comparing the new method versus the traditional gelling agent addition method.

Results: The experiments resulted in each of the five gelling agents being paired up successfully with a cosolvent that made (1) a pourable slurry side phase that (2) allowed for an immediate manufacturing addition step and (3) decreased total gelling agent hydration time, all while (4) seeing the same viscosity results as when the traditional operator dependent process was used. Each gelling agent responded differently to the nine different cosolvents and select cosolvent/gelling agent combinations need to be used (Image 2). For example, Hydroxyethyl Cellulose best paired up with Diethylene Glycol Monoethyl Ether, while Hydroxypropyl Cellulose best paired up with Glycerin. Similarly, the best cosolvent for Carbopol 980 was Cyclomethicone, however, to make the system work correctly 0.5% w/w Polysorbate 80 was added to the water phase. Ultimately, every gelling agent had a conjugate cosolvent that improved the process ability and overall drug product robustness.

Conclusion: If a semi-solid product under development is currently using a powdered gelling agent and could incorporate a cosolvent, it should be seriously considered for improved processing times while maintaining product reproducibility. The challenges caused by adding powdered gelling agents at scale is a recurring issue that can be easily solved by utilizing this cosolvent approach. This method improves operator safety, de-risks the drug product manufacturing parameters, and results in an overall simpler process.

References: 1 Ashland. "Formulating elegant liquid and semisolid drug products with Natrosol™ 250 HEC." Ashland. Accessed July 10, 2024. https://www.ashland.com/file_source/Ashland/links/PHA18-101_Natrosol_250_HEC_Formulating_elegant_liquid_and_semisolid_%20drug_products.pdf
2 Lubrizol. "Dispersion Techniques for Carbopol Polymers." Technical Data Sheet TDS-103. Lubrizol. Accessed July 10, 2024. https://www.lubrizol.com/-/media/Lubrizol/Health/TDS/TDS-103_Dispersion_Techniques_Carbopol_Polymers.pdf

Image 1. Slurry Phase Preparation (Steps Pictured from Left to Right)

Image 2. Data Table Summary for Gelling Agents and Cosolvent Results