(W1130-08-51) Impact of Microcrystalline Cellulose Particle Size Grade on Loss-in-Weight Continuous Feeding

Purpose: Continuous manufacturing (CM) of pharmaceutical products can potentially improve drug product quality and reduce manufacturing footprint and costs. Continuous feeding of materials with high accuracy and low variability is a critical step in manufacturing drug products using CM technologies. Excipients and excipient selection may impact the robustness of CM operations, like feeding. This study investigated the impact of excipient selection, specifically microcrystalline cellulose (MCC) particle size grade, and feed rate on the feeding rate variability of a loss-in-weight twins screw continuous feeder.

Methods: Three grades of Avicel® PH MCC (2 different lots per grade) were supplied from IFF Pharma Solutions and used as received. Nominal average particle sizes for each grade were 50 µm for Avicel® PH-101, 100 µm for Avicel® PH-102 and 200 µm for PH-200. A Coperion K-Tron loss-in-weight twin screw feeder (K3-PH-ML-D4-QT20, 20 mm auger coarse screws) was set to one of 3 different target feeding rates: 3.75 kg/h, 10 kg/h and 25 kg/h. The actual mass delivered was recorded and plotted in 5 second intervals such that 3.75 kg/h equals 5.2 g/5 second, and 10 kg/h equals 13.9 g/5 seconds. The standard deviation of the readings is reported in a percentage basis to better compare variability across different feeding rates.

Results: For robust continuous manufacturing of pharmaceutical solid dosages, such as tablets, accurate feeding of excipients and actives is critical to maintain consistent content uniformity. The feed rate had the largest impact on the variability (% standard deviation) of the feed rate across all MCC particle size grades. In all cases, feed rates had an inverse relationship with variability (higher feed rate resulted in lower variability). For example, the variability of the 100 µm MCC grade was highest at the 3.75 kg/h target feed rate (~6.2%). The variability was reduced by half (to 2.25-3%) with a 3x increase in target feed rate. Increasing the feed rate to 25 kg/h further decreased the variability (~1-1.5%). Similar trends were seen for the 50 and 200 µm MCC grades. For each feed rate, the variability showed a similar trend across grades. The 200 µm particle size material had similar variability to the 50 µm particle size material and both were lower than the variability of the 100 µm particle size material. The difference in grades became less pronounced as the target feed rate increased. For example, at 3.75 kg/h, the 200 µm MCC grade had a variability of ~4.7% and the 100 µm MCC grade had a variability of ~6.2%; however, at 25 kg/h, both grades had an average variability of ~1%. The trend at low feed rates among particle size grades was surprising because it doesn’t necessarily follow typical flow properties of these MCC grades. Typically, flowability increases with increasing particle size of MCC, and cohesive properties of the 50 µm and 100 µm grades tend to be similar. However, given MCC is usually a major component of an oral solid formulation, the likelihood is low of feeding MCC at low feed rates.

Conclusion: The variability of feeding MCC in a continuous twin screw feeder increases with increasing feed rate. At low feed rates, moving to a different particle size grade can reduce the variability of the feed; however, this difference diminishes as the feed rate increases from 3.75 to 25 kg/hr. Although not presented here, the addition of feeding assistance, like ActiFlow™ technology, could aid in reducing variability, especially at the 3.75 kg/h target feed rate.

Coperion K-Tron K3-PH twin screw feeder (a) set up and (b) close-up of outlet.

Example output weight for one lot each of (a, d) 50 µm, (b, e) 100 µm, and (c, f) 200 µm MCC materials being feed at target rates of (a, b, c) 3.75 kg/h and (d, e, f) 10 kg/hr.

The percent variability of the three different particle size grades of MCC (both lots per grade). Each feed rate is individually colored: blue x for 3.75, orange • for 10 and grey ∆ for 25 kg/hr.