(W0930-07-47) The Importance of Microcrystalline Cellulose Selection for Fluid Bed Wet Granulation

Purpose: Wet granulation is essential for developing certain pharmaceutical dosage forms, as it enhances the flowability and uniformity of powder formulations, ensuring consistent and high-quality products. Among the various methods, fluid bed wet granulation is particularly notable for its efficiency, production of uniform granules, and the combination of granulation and drying in a single step, making it ideal for temperature-sensitive materials. Microcrystalline Cellulose (MCC) plays a crucial role in the wet granulation process as a processing aid. It directly influences granule size and distribution, uniformity, flowability, and ultimately the performance of the final granules. Understanding MCC's characteristics and carefully selecting the appropriate grade are important for achieving consistent and high-quality granulation results. This study aimed to demonstrate the impact of MCC's material properties on granule outcomes using a fluid bed granulation process. By examining different grades of MCC, the study highlighted how excipient selection can influence the properties of the final granules.

Methods: Two 50:50 MCC/lactose powder blends were prepared using two different grades of MCC, Avicel® PH-101 and Avicel® PH-301. Table 1 lists the Critical Material Attributes (CMAs) of Avicel® PH-101 and Avicel® PH-301 that are important for granule outcomes. Data indicated that loose bulk density (LBD) and water binding capacity (WBC) were the main differences between these two MCC grades. These two powder blends were then wet granulated and dried using a Hüttlin Fluid Bed Granulator. Deionized water was used as the wet granulation fluid. The same fluid bed process parameters were used for both granulation processes, involving fluidizing the MCC/lactose powder mixture with air, spraying it with deionized water to form granules, and allowing the particles to agglomerate as they collided and formed granules. The granules were dried in the fluid bed chamber, then cooled and discharged, resulting in the final granules. In this study, only slight granulation was targeted. The granules were analyzed for their particle size and distribution, loose and tapped densities, flowability, and compactibility, and these characteristics were compared to those of the original powder blend.

Results: As anticipated and shown in Figure 1, the flowability of the Avicel® PH/lactose powder blends improved following fluid bed wet granulation. The Carr’s index decreased from 21 to 18 for the Avicel® PH-101/lactose blend to granule, and from 20 to 16 for the Avicel® PH-301/lactose blend to granule. The slightly superior flowability of the Avicel® PH-301/lactose granule compared to the Avicel® PH-101/lactose granule was due to differences in granule particle size and density. Both Avicel® PH-101/lactose and Avicel® PH-301/lactose granules showed single modal particle size distribution curves (data not shown here), with the Avicel® PH-301/lactose granule having a slightly larger particle size (D50=83µm) than the Avicel® PH-101/lactose granule (D50=75µm). This difference in granule size was attributed to the WBC difference between Avicel® PH-301 and Avicel® PH-101, with lower WBC leading to larger granule size. Additionally, Avicel® PH-301 is a higher density grade MCC, resulting in a higher density Avicel® PH-301/lactose granule (LBD=0.49g/ml) compared to the Avicel® PH-101/lactose granule (LBD=0.44g/ml). Figure 2 shows the compactibility of Avicel® PH/lactose blends versus granules. The wet granulation process generally reduced the compactibility of the powder blends. For instance, the compactibility slope decreased from 0.28 to 0.17 for the Avicel® PH-101/lactose blend to granule, and from 0.25 to 0.17 for the Avicel® PH-301/lactose blend to granule. It is known that Avicel® PH-101 has higher compactibility than Avicel® PH-301, which was confirmed in the compactibility of powder blends. However, the fluid bed wet granulation process eliminated the compactibility difference between the different Avicel® PH grades, resulting in granules with similar compactibility.

Conclusion: Results indicated that, with the same formulation and fluid bed process parameters, the choice of different Avicel® PH grades affected the final granules' particle size and distribution, density, and flowability. This suggests that product yield could vary depending on the specified granule characteristics. However, the difference in powder blends' compactibility was minimized through the wet granulation process, resulting in granules with reduced but similar compactibility.

References: 1. Gregory Thoorens, 2014, Microcrystalline cellulose, a direct compression binder in a quality by design environment—A review, International Journal of Pharmaceutics, 473, 64-72.


Table 1. CMAs of Avicel® that impact granule outcome


Figure 1. Flowability of Avicel® PH/Lactose blends vs. granules


Figure 2. Compactibility of Avicel® PH/Lactose blends vs. granules