Eliminating Operator Dependence from Gelling Agent Addition – Improving the Robustness and Processing Time of Semi-Solid Dosage Forms Without Impacting the Viscosity or Aesthetics
Ruth Yu, Jason Carbol
Dow Development Laboratories, LLC
PURPOSE
Aqueous gelling agents for semi-solid dosage forms are typically fine powders that take technique and experience to add consistently and reproducibly to a drug product. Due to this technique dependence the manufactured drug product could result in operator dependent viscosity outcomes and even result in appearance differences such as “fish-eyes” due to incomplete gelling agent hydration. Typical addition instructions look like: “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 added1”. The need for such specific instructions are typical for most aqueous gelling agents. Similarly, Lubrizol supplies a 5-page technical data sheet on “Dispersion Techniques for Carbopol Polymers”2 similarly suggesting the need for very specific instruction for proper gelling agent addition. These challenges are only magnified as drug products are scaled up. Consider “…slow enough for the particles to separate without lump formation, but not so slow that the solution thickens appreciably…” when up to 20 kg of gelling agent could need to be added at commercial scale. Having to work through these challenges, easier methods for gelling agent addition have been identified. Specifically, gelling agents with specific co-solvents have been identified for each gelling type to pre-mix into to facilitate better drug product manufacturing. When the right co-solvent is chosen for the right gelling agent the technique dependence of the processing is no longer critical. This newly defined method allows for all the gelling agent to be immediately added “dumped” into a vessel, and the appropriately identified co-solvent is immediately added on top, and all that is needed is gentle mixing to make a solvent/gelling agent slurry that then can be immediately added to the aqueous system that will facilitate the gelling process, and result in the same viscosity outcomes. Using specific co-solvents/gelling agent systems proved easier, more robust, outcomes that are no longer operator nor technique dependent. Our goal was to investigate the co-solvent gelling agent addition method using 5 typically employed powdered gelling agents against 9 co-solvents to identify possible co-solvent/gelling agent combinations to improve gelling agent robustness and utilization. Our goal was to investigate the co-solvent gelling agent addition method using 5 typically employed powdered gelling agents against 9 co-solvents to identify possible co-solvent/gelling agent combinations to improve gelling agent robustness and utilization.
RESULTS
The experiments resulted in each of the 5 gelling agents being paired up successfully with a co-solvent that made (1) a pourable slurry side phase that (2) allowed for an immediate manufacturing addition step (vs. historically slow powder addition steps) that (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 9 different co-solvents, and proper gelling agent/co-solvent combinations need to be used (Image 1). For example, Hydroxyethylcellulose best paired up with Diethylene Glycol Monoethyl Ether, while Hydroxypropylcellulose best paired up with Glycerin. Similarly, the best co-solvent for Carbopol 980 was Cyclomethicone, however, to make the system work correctly an additional 0.5% of polysorbate 80 needed to be added to the water phase. Ultimately, every gelling agent had a conjugate co-solvent that improved the processability and overall drug product robustness.
METHODS
5 traditional powdered gelling agents were selected for investigation: Hydroxyethylcellulose 250HHX Pharm (1.5% w/w), Hydroxypropylcellulose 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 placed individually into one of nine selected co-solvents to evaluate the appropriateness. To evaluate appropriateness, a pre described amount of gelling agent was placed into a beaker and a 10% equivalent of each co-solvent was poured on top of the gelling agent and each was mixed. The desirable outcome was a “flowable slurry phase”. The co-solvent could not gel up nor form “fish-eyes”. The resulting phase had to be freely pourable to be considered successful. Next, the resulting pourable slurry had to be immediately added to the remaining drug product (~88% water) with normal mixing and the resulting product was tested for gelling time as well as final viscosity. The gelling time and final viscosity was measured against a control sample that was an equivalent product of the same ingredients, except the gelling agent was added as described in literature “…slow enough for the particles to separate without lump formation, but not so slow that the solution thickens appreciably…”. Successful systems were identified as ones where the processing time (including time for full drug product gelling) was equivalent or improved while at the same time there was no change in the resulting viscosity when comparing the new verses traditional gelling agent addition method.
CONCLUSION
If a drug product under development is currently using a powdered gelling agent and could incorporate a co-solvent, it should be seriously considered for improved drug product robustness. The addition of powdered gelling agents at scale is a recurring issue that can be easily solved with this co-solvent approach. The approach improves operator safety, de-risks the drug product manufacturing parameters, and results in an overall simpler process.
REFERENCE
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