Category: Formulation and Quality
Purpose: Cross-linked acrylic acid polymers such as carbomers are commonly used as thickeners, emulsifiers and stabilizers in the formulation of semi-solid and solid pharmaceutical products like emulsions and topical dosage forms. However, their unique features such as yield stress and viscosifying properties can be challenging during the manufacturing processes including blending and pumping. Moreover, an accurate estimation of their yield stress can be used to predict the shelf-life as well as their ease of application for the end use.
Rheological studies and mathematical modeling have been used for quality control, process design (blending, pumping, filling), scale-up, and optimization of process variables in the food industry. Accordingly, in the pharmaceutical industry, understanding the flow behavior of the excipients and formulations is critical in designing feasible dosage forms with controlled quality attributes and optimized process parameters. Furthermore, the mathematical models can be used to quantify the stress at which the formulation undergoes a permanent plastic flow (yield stress).
In this study, we investigated the rheological behavior of various crosslinked acrylic acid polymers at different concentrations using four more common rheological models (Bingham, Power-Law, Casson and Herschel-Bulkley). Three of the models have also been used to calculate the yield stress of the samples, which is a critical parameter determining the pourability and spreadability of the compositions containing such polymers. Moreover, we measured the gel strengths of the formulations and compared them with the rheological yield strengths to see whether it can alternatively be used in the rheological characterization at low shear rates.
Methods: Aqueous solutions of the acrylic polymers (carbomer homopolymer type A (Carbopol 981) and type B (Carbopol 974P), carbomer interpolymer type A (Carbopol ultrez 10NF), carbomer copolymer type B (Pemulenä TR-1) and polycarbophil (Noveon)) were prepared at different concentrations (0.1-1.0% w/w) and neutralized to the pH of 5.0-6.0 using NaOH. A cone & plate rheometer (spindles 2.4 cm or 1.2 cm, 0.5 mL sample, 25°C) was used to generate the shear stress/shear rate rheograms. The confidence of fit (COF) to the models was determined using Rheocalc V3.3 software, and the yield values were calculated according to the software method for each model. The gel strength of the samples was measured using a CT-3 texture analyzer (compression mode, stainless-steel sphere probe, crosshead speed of 5 mm/s).
Results: All acrylic polymers displayed a shear thinning behavior over the concentration range of 0.1-1.0% w/w. Based on the calculated COF (Table 1), Herschel-Bulkley (HB) model best fitted the flow behavior of all polymers over the concentration range studied. However, it failed to correctly or consistently estimate the yield value as either it predicted negative values or positive values with high variations (standard deviation of 0.27-4264.3). This could be due to the very high viscosity of such polymers at low shear rates as the HB model estimates the yield value using shear stress values at low shear rates. According to the yield stress values (Table 2), the HB model is more efficient for calculating the yield stress at low polymer concentrations (0.1-0.3%) of lightly and highly crosslinked homopolymers of acrylic acid where the gel strength is lower. For other grades or at higher concentrations of the homopolymers, the HB model cannot be used to estimate the yield stress. This could be due to a more solid behavior of poly(acrylic acid)s at higher concentrations or in the presence of other functional groups in the structure of copolymer, interpolymer, and polycarbophil. On the other hand, measuring the gel strength (Fig. 1) at high concentrations of all poly(acrylic acid)s or low concentrations of interpolymer, copolymer and polycarbophil where they acted more like a solid than a liquid could better predict the resistance to flow of these viscous gels under static conditions.
Conclusion: Among the four rheological models, the Herschel-Bulkley can better predict the flow behavior of the cross-linked poly(acrylic acid) excipients at higher shear rates, making it useful in process development. However, it fails to accurately estimate their behavior at lower shear rates. As such, the gel strength data from a texture analyzer can more accurately characterize the flow properties and quantify the spreadability and pourability of the compositions containing these excipients.