(W1030-07-40) Using Gravitational Force to Determine the Minimum Concentration of Various Gelling Agents Needed to Maintain Homogeneity of Micronized API in Suspension

Purpose: Gelling agents create network structures which adsorb onto the surface of suspended particles, sterically stabilizing them by creating a physical barrier around the particles to prevent them from settling.¹ Stokes’ Law indicates that if the force of gravity overcomes the strength of the gel network in a suspension, the API particles will settle.² Centrifugation is a common technique used to challenge the physical stability of suspensions by means of high gravitational forces providing a predictor of whether a suspended API is likely to remain homogeneous in a drug product over a longer period of storage. Our study aims to determine the minimum concentration of various gelling agents needed to maintain an API in suspension when subjected to increasing gravitational forces through centrifugation. The benefit of determining this concentration is that it acts as a starting point when using these FDA IID-listed gelling agents for suspended drug products, lending flexibility to adjust a formula for other needs, such as aesthetic elegance to enhance patient compliance. Minimizing the gelling agent concentration has the added benefit of reducing material costs, process times, and labor.

Methods: Gelling agents Carbopol 980, Sepineo P 600, hydroxyethylcellulose (HEC; Natrosol 250 HHX Pharm), and xanthan gum (XG) were evaluated for this study. Simple formulas were made using 0.05% w/w clobetasol propionate as the micronized API. (Clobetasol propionate was chosen as a model API for this study since it is in the market at this clinical concentration as a suspension.) Batches were filled into centrifuge tubes (30 g each) and centrifuged for 20 minutes with increasing gravitational force: 100 g, 500 g, 1000 g, 2000 g, 3000 g, and 4000 g. Samples were taken from the top of the bulk before centrifugation (control) and the top of the centrifuged samples for clobetasol assay (% of expected concentration) and viscosity (cP) measurements. A decrease in assay of clobetasol in the top samples following centrifugation indicates a loss of homogeneity in the formulation. As it relates to Stokes’ Law, variations in viscosity trends with increasing gravitational force may be attributed to density differences between the API and vehicle gel in the suspension system.

Results: The minimum concentration for each gelling agent is as follows: 0.10% w/w Carbopol, 1.1% w/w Sepineo, 0.90% w/w XG, and 1.4% w/w HEC. The assays of these top samples from the different gravitational forces were similar to the controls (Figure 1). Lower gelling agent concentrations had decreasing assays, demonstrating that these concentrations represent the minimum thresholds for which the API can remain suspended under increasing gravitational forces. The Carbopol suspensions showed that a decrease in assay correlated with a decrease in viscosity. The 0.09% w/w Carbopol suspension was slightly thicker than the 0.1% w/w Carbopol suspension due to differences in their end pH (5.58 and 5.47, respectively; Figure 2). Despite this, the 0.09% w/w suspension showed a decreasing assay, while the 0.1% w/w suspension assay remained ~96% of expected API concentration at all gravitational forces. The viscosities of the Sepineo suspensions correlated inversely to Carbopol— as the assays decreased, the viscosities slightly increased. The control assay of 1% w/w Sepineo (94.3% of expected API concentration) was less than the other assays (~98% of expected API concentration), possibly due to inhomogeneity of the batch. Thus, the 1.1% w/w suspension was deemed the minimum concentration. The XG and HEC suspensions had minimal change in viscosity despite decreasing assays. Depending on the concentration of HEC, these formulas showed sedimentation (≤1.1% w/w), uniformity (1.2–1.75% w/w) or creaming (≥2% w/w) at 4000 g (Figure 3). Interestingly, specific gravities measured from the top and bottom of a high concentration HEC sample were equivalent. The assay for the 2% w/w HEC suspension at 4000 g was like the control, which may be attributed to the API concentrating directly above the clear layer instead of at the top of the centrifuge tube where assay sampling took place.

Conclusion: Each gelling agent presents different advantages and challenges when suspending micronized API. Carbopol requires the lowest concentration to suspend the API. While this can help reduce costs, care must be taken with the process to minimize API agglomeration before neutralization. XG’s advantage is that the gel is still thin at the concentration needed to suspend the API, which is ideal for products requiring thinner formulations such as ophthalmic suspensions packaged into dropper bottles. Like Carbopol, however, there is an issue with API agglomeration due to delayed thickening times. Sonication or other methods of dispersing the API are recommended when using these two gelling agents. Sepineo is the easiest thickener to process, but it is a proprietary blend of excipients, so there is less flexibility in sourcing. HEC’s capacity to build viscosity quickly following initial hydration is adequate to prevent agglomeration of the API, however the optimal concentration must be determined to simultaneously keep the API suspended and prevent creaming.

References: 1. Physical Stability of Disperse Systems; Lubrizol; Cleveland, OH, USA; 1620 datasheet; Oct 2019
2. Dennis Laba; How Do I Thicken My Cosmetic Formula?; Cosmetic and Toiletries Magazine, 2001, 116(11): 35–44

Figure 1. % of expected clobetasol propionate concentrations of suspensions sampled from the top with increasing gravitational force. The minimum gelling agent concentrations are highlighted in the x-axis with asterisks.

Figure 2. Viscosities of suspensions sampled from the top with increasing gravitational force. The minimum gelling agent concentrations are highlighted in the legend with asterisks.

Figure 3. The optimal concentration of HEC must be determined to prevent sedimentation and creaming of API suspensions.