(T1030-03-13) The Selection of Microcrystalline Cellulose Based Excipient in Extrusion Spheronization

Purpose: Extrusion spheronization (ES) is a multi-stage process, involving granulation, extrusion, spheronization, and drying steps, to make the final uniformly sized pellets with high level of active pharmaceutical ingredient. The Critical Quality Attributes (CQAs) of the pellets that are produced from an ES process include narrow size distribution, sphericity, smooth surfaces, and low friability, etc. The pellet CQAs can be impacted by the Critical Process Parameters (CPPs) of the ES process, such as equipment type, amount of moisture, granulation mixing time and speed, extrusion screen size, spheronizer plate design, time, batch size, and speed, etc. In addition, the pellet CQAs are also greatly influenced by the Critical Material Attributes (CMAs) of the ES formulation components. Microcrystalline cellulose (MCC) based excipient, such as MCC or co-processed MCC, are critical functional excipients often used in the ES formulations, it impacts and determines pellet robustness and process feasibility. During an ES process, MCC absorbs and retains a large quantity of water, which plasticizes and binds the granulated wet mass, enabling the subsequent extrusion and spheronization steps. The CMAs of MCC or co-processed MCC, such as material composition, fiber type, water binding capacity, particle size distribution, and morphology, directly impact the ES process and final pellet quality, especially where the amount of water and other process parameters are fixed. The objective of this study was to investigate one of the CPPs, the amount of moisture introduced during the ES process, as well as the selection of different MCC-based material in a model formulation on the ES processibility and pellet quality.

Methods: Avicel® PH-101 and Avicel® PH-301 were selected to represent MCC and Avicel® RC-591 was chosen to represent co-processed MCC. As shown in Table 1, three paracetamol model formulations were prepared that contained different MCC. Formulations F1 and F2 contain different grades of MCC, Avicel® PH-101 and Avicel® PH-301, respectively. Formulation F3 contains co-processed MCC Avicel® RC-591. The three formulations were prepared via wet granulation, extrusion, and spheronization as follows. Components were combined in a benchtop planetary mixer and dry mixed for the prescribed amount of time. Water was then added slowly into the benchtop planetary mixer until a homogenous wet mass was formed that was able to hold its shape under low pressure and also deemed to have sufficient gliding properties suitable for extrusion. Each wet granulation was then manually metered into the Multi Granulator MG-55 extruder forming elongated and cylindrical extrudates. Wet extrudates were then charged into the Marumerizer QJ-230T spheronizer equipped with a 2 mm friction plate where they were converted into well-rounded spheres. These spheres were subsequently dried in a fluid bed dryer.

Results: One of the CPPs is the amount of moisture introduced during the ES process. Figure 1 shows the amount of moisture required to generate spherical pellets from the three formulations using different Avicel® grades. The amount of moisture required to produce quality pellets is different for each formulation, F1 with Avicel® PH-101 requires the most amount of moisture (30-38%), followed by F3 with Avicel® RC-591 (30-34%) and F2 with Avicel® PH-301 (25-30%). During the moisture optimization process, trial batches with different pellet size were generated. Figure 2 displays the pellet size distribution curves of various ES trial batches from the three formulations. The results indicate that at each formulation’s optimal moisture level, the mean pellet sizes are different. The optimal moisture level for F1 with Avicel® PH-101 was 38%, which led to d50 of 1600µm, the optimal moisture level for F3 with Avicel® RC-591 was 32%, which led to d50 of 1500µm, and finally the optimal moisture level for F2 with Avicel® PH-301 was 27%, which led to d50 of 1100µm.

Conclusion: MCC based excipients are effective processing aids for ES process. The selection of the proper Avicel® grade is very important to achieve the desired pellet size and distribution. In addition, to ensure the quality of the pellets, it is essential to optimize the ES process and the amount of moisture introduced during the ES process.

References: 1. The Criticality of MCC in Extrusion Spheronization, AAPS poster 2013
2. Ghebre-Sellassie, I., Martin, C., Pharmaceutical Extrusion Technology (Vol. 133), 2003, CRC Press


Table 1. Formulation details


Figure 1. ES process optimization through moisture adjustment


Figure 2. Pellet size and distribution curves