Category: Formulation and Quality
Purpose: Colloidal microcrystalline cellulose (MCC) like Avicel® RC-591 is well established as an effective suspending agent for pharmaceutical dosage forms. It provides excellent suspension performance as a structured vehicle former with outstanding stability over a wide range of pH and temperatures.
In addition to the benefits listed above, some pharmaceutical suspension applications require high viscosity. For such pharmaceutical suspension applications, a thickening agent is often added.
The objective of this study was to evaluate commonly used pharmaceutical grade polymers, such as Kollidon®30 PVP, METHOCELTM E3 Premium LV HPMC, METHOCELTM K3 Premium LV HPMC, METHOCELTM F5 Premium LV HPMC, METHOCELTM VLV HPMC, and WALOCEL™ CRT 30 PA NaCMC, in colloidal Avicel® RC-591 suspensions as thickening agents. Specifically, with the unique temperature dependent sol-gel transition of METHOCEL™ and anionic property of WALOCEL™, synergetic effect could exist between these polymeric materials and colloidal Avicel® RC-591.
Methods: Stock suspensions of 2.4 wt% Avicel® RC-591 were prepared by activating Avicel® RC-591 dispersions under high shear (Silverson mixer, 8000 rpm for 5 min). Six polymer solutions at 6% concentration were prepared from Kollidon®30, METHOCELTM E3 Premium LV, METHOCELTM K3 Premium LV, METHOCELTM F5 Premium LV, METHOCELTM VLV, and WALOCEL™ CRT 30 PA, respectively. For each polymer, equal parts of the concentrated Avicel® RC-591 and polymer solutions were mixed together with an overhead mixer for 5 minutes to fully blend and make the final solutions of 1.2 wt% Avicel® RC-591 with 3 wt% polymer (6 mixtures in total). Equal parts Avicel® RC-591 and water were mixed together with an overhead mixer for 5 min to make the final 1.2 wt% Avicel® RC-591 suspensions. Likewise, equal parts polymer solution and water were mixed together with an overhead mixer for 5 min to make the 3 wt% polymer solutions.
Microscope analysis was performed on Avicel® RC-591 suspensions using Nikon Eclipse Ci Microscope to ensure Avicel® RC-591 was fully dispersed. Viscosity was tested using RVT Brookfield viscometer on (A) 1.2% Avicel® RC-591 suspension; (B) 3% polymer solution; (C) 1.2% Avicel® RC-591 suspension contains 3% polymer as thickening agent. The initial viscosity was measured directly after the suspension was mixed to its final concentration. The “set-up” viscosity was measured on the solutions after 24 hour of rest at room temperature. Finally, rheology analysis was performed with TA-Instruments DHR3 rheometer using a 50 mm parallel geometry with a 1.8 mm gap size at 20°C on the above (A), (B), and (C) formulations.
Results: As expected, the 1.2% Avicel® RC-591 suspension with 3.0% polymer solution had increased initial viscosity. The 1.2% Avicel® RC-591 suspensions had viscosities of 39 +/- 4 cP and the 3% polymer solutions ranged from 5-60 cP. The addition of the polymer to the Avicel® increased the initial viscosities to 50-500 cP, with Kollidon®30 PVP having the lowest change in viscosity and METHOCEL™ F5LV having the highest change. Unlike the initial viscosities, the set-up viscosities for the combination suspensions were not all higher than the Avicel® RC-591 alone. The set-up Avicel® RC-591 only suspensions had viscosities of 550 +/- 77 cP. Only the METHOCEL™ HPMC polymers increased the set-up viscosity of the suspension (increase of 100-500 cP). Both the Kollidon®30 PVP and the WALOCEL™ NaCMC decreased the set-up viscosity relative to Avicel® RC-591 (decrease of 150 and 400 cP, respectively).
All 1.2% Avicel® RC-591 only suspensions exhibited gel network with shear-thinning and thixotropy properties. All polymer solutions by themselves did not show any gel network. Povidone PVP had “Newtonian-like” behavior, while all METHOCEL™ HPMC and WALOCEL™ NaCMC polymer solutions showed some extent of shear-thinning behavior at low shear. All combination suspensions, with the exception of WALOCEL™ CRT 30 PA, displayed gel networks. The addition of WALOCEL™ CRT 30 PA appeared to break the gel network of the colloidal Avicel® RC-591.
Conclusion: The choice of polymer is not only important to the viscosity and thickening of the final suspension, but also contributes to the final suspension structure. There is synergetic effect between METHOCEL™ HPMC and Avicel® RC-591, which significantly increase the initial and set-up viscosities. The addition of Kollidon®30 PVP and WALOCEL™ NaCMC increased the initial viscosity of the suspension, but reduced the viscosity of the set-up suspension which could be from the de-stabilization of the suspension.