(W0930-09-50) Determining the Most Suitable Gelling Agent for Topical Semi-Solid Formulation Development- An Investigation into the Physical Robustness of Various Gelling Agents

Purpose: Development of topical semi-solid formulations can prove challenging in a variety of conditions. An optimal formula couples long term stability with favorable aesthetic properties to increase patient compliance without sacrificing physical robustness. Polymeric gelling agents are frequently used to increase the viscosity of the aqueous phase in both one and two phase systems.¹ Four gelling agents, which are commonly used in the pharmaceutical industry, were evaluated: Xanthan Gum (XG), Hydroxyethyl Cellulose (HEC), Carbopol, and Sepineo. This selection will compare nonionic (HEC) with anionic (XG, Carbopol, and Sepineo) gelling agents.  Our investigation seeks to determine the most suitable gelling agents for three challenging formulation conditions: variable pH systems, high conductivity systems, and two phase systems with high solvent concentrations. Understanding the interplay of these relationships will facilitate gelling agent selection with the highest confidence in the overall stability of the final formulation.

Methods: Current literature dictates that XG and HEC are minimally impacted by changes in pH conditions. HEC has good tolerance for dissolved electrolytes, while the XG macromolecule can more compactly conform in aqueous phases with increased ion concentrations, thereby causing an increase in the viscosity of the final formulation.^2,3 Conversely, acrylic acid based gelling agents, like Carbopol and Sepineo, are highly sensitive to changes in pH and ion concentration, with a loss in product viscosity as these values increase.^4,5,6 To compare the viscosity characteristics of these gelling agents directly, three pH targets (pH 5, 7, and 9) and three ion concentrations (10 mM, 50 mM, and 100 mM) of either buffer or NaCl solution, as appropriate, were selected. Simple gel formulations containing either 1% w/w XG, 1.5% w/w HEC, 0.75% w/w Carbopol 980, or 2% w/w Sepineo P600 were manufactured using each combination of the listed pH targets and ion concentrations. Control batches of each product were made with water. The viscosity of each gel was taken using a Brookfield DV2T viscometer. Appropriate viscosity methods were developed to encompass both the highest and lowest viscosity product for each gelling agent. The pH and conductivity of each gel was measured using a Mettler-Toledo Model Seven Compact S220 pH Meter and a Control Company Model 89094-958 Expanded-Range Conductivity Meter, respectively. To evaluate the effectiveness of each gelling agent in a two-phase system, a control cream formulation was developed using high concentrations of solvents that are historically difficult to formulate. Batches were manufactured using the control cream formula with the addition of either 0.75% w/w XG, 0.54% w/w HEC, 0.14% w/w Carbopol 974P, or 0.60% w/w Sepineo P600. Samples of each batch were dispensed into glass vials for storage at 50 °C and evaluated visually for the appearance of syneresis.

Results: The resulting conductivity and viscosity measurements were plotted based on the type of gelling agent and evaluated for potential trends. For XG and HEC, products manufactured at the three pH ranges were mostly indistinguishable. Interestingly, while the HEC batches remained unchanged regardless of the conductivity, the batches made with XG saw a slight positive correlation between increasing conductivity and viscosity, most notably at lower conductivities (Figure 1). Products made with HEC resulted in less variability over the same conductivity range as XG. For Carbopol and Sepineo, the viscosity steadily decreased when either the pH or conductivity increased. Compared to the batches made with Sepineo P600, those made with Carbopol 980 have better ion tolerance, as these batches maintained some viscosity at higher pH values (Figure 2). While the Hydrophilic-Lipophilic Balance in the control cream formula was appropriate, the cream showed noted signs of syneresis following T=1 Week at CRT and T=1 Day at 50 °C. By comparison, when visual evaluations were performed on the cream samples, observable syneresis was noted at T=1 Week at 50 °C in all samples except those prepared with XG and Sepineo P600, which showed superior stability (Figure 3).

Conclusion: XG and HEC have proven more robust in formulations with greater ion concentrations. In particular, HEC has lower relative viscosity variability with respect to pH and conductivity fluctuations compared to XG. However, as XG and HEC have unfavorable aesthetic qualities due to their high break points, Carbopol can offer a suitable balance for retaining both ion tolerance and superior aesthetic properties in formulations with suitably low ion concentrations. Conversely, when optimizing a two-phase system with high solvent concentrations, formulations made with XG and Sepineo provide greater stability. It should be noted that while XG has better ion tolerance, Sepineo can offer preferrable aesthetic properties in systems with low ion concentrations. Gelling agent selection should be performed based on the desired physical and chemical characteristics of the product, including appearance, aesthetic properties, target pH, electrolyte concentration, viscosity, and solvent concentration.

References: 1. Milutinov J, Krstonošić V, Ćirin D, Pavlović N. Emulgels: Promising Carrier Systems for Food Ingredients and Drugs. Polymers (Basel). 2023 May 13;15(10):2302. doi: 10.3390/polym15102302. PMID: 37242878; PMCID: PMC10223308.
2. Nsengiyumva EM, Heitz MP, Alexandridis P. Salt and Temperature Effects on Xanthan Gum Polysaccharide in Aqueous Solutions. Int J Mol Sci. 2023 Dec 29;25(1):490. doi: 10.3390/ijms25010490. PMID: 38203659; PMCID: PMC10778890.
3. Formulating Elegant Liquid and Semisolid Drug Products- Natrosol™ 250 Hydroxyethylcellulose (HEC); CAS Number 9004-62-0; Ashland Global; Covington, KY, USA; 2018
4. Carbopol® Polymers for Thickening, Suspending & Stabilizing; Lubrizol; Cleveland, OH, USA; September 2000
5. Pharmaceutical Bulletin 6- Thickening Properties; Lubrizol; Cleveland, OH, USA; May 2011
6. Bonacucina G, Cespi M, Palmieri GF. Characterization and stability of emulsion gels based on acrylamide/sodium acryloyldimethyl taurate copolymer. AAPS PharmSciTech. 2009;10(2):368-75. doi: 10.1208/s12249-009-9218-1. Epub 2009 Apr 2. PMID: 19340587; PMCID: PMC2690781.

Figure 1. Graph illustrating the changes in viscosity with increasing conductivity at three different pH values for aqueous gels made with XG and HEC.

Figure 2. Graph illustrating the changes in viscosity with increasing conductivity at three different pH values for aqueous gels made with Carbopol 980 and Sepineo P600.

Figure 3. Image taken of cream samples made with the addition of small amounts of gelling agent, along with a sample of control cream for comparison, following T=1 Week at 50 °C storage.