(788e) Quantitative Investigation on Segregation Phenomenon Using Discrete Element Method in Large Scale Pharmaceutical Compression Process

Gao, Y., Takeda Pharmaceuticals International Co.
Segregation is a common issue in pharmaceutical manufacture of solid dose drug product. Especially during manufacture scale-up, pharmaceutical powder with segregation tendency has potential risk to fail specification of blend or content uniformity in large scale process. It may result in significant waste of drug substance or cause possible quality issues for the drug product. Moreover, experimental investigation on large scale segregation is usually inefficient to determine root cause or provide quantitative improvement plan while the consumption of drug substance was still significant. In this work, quantitative Discrete Element Method (DEM) simulation method was developed and applied on the prediction of segregation tendency of powder blend in large scale pharmaceutical unit operations.

In the large scale drug product manufacture of Project X, segregation was consistently observed in the last quarter of the tablet compression process. For the two major blend components in this project, material properties such as particle size distribution, true density, and flowability were measured and imported into simulation. The previous established correlation between shear flow of experiment and simulation was applied to guarantee that the flow behavior of simulated DEM particles was representative of real pharmaceutical powder [1]. Several slice geometries were developed to represent the dimensions of the current blender- hopper combination and alternative candidates for geometry improvement. The blender discharge and hopper feeding process in the bulk tablet compression of project X was then simulated using the commercial DEM software Star CCM+® v11.02 by CD-Adapco® and with processors of dual CPUs, Intel® Xeon® E52640 @ 2.50 GHz.

Based on the simulation results, difference on true density of the blending components was determined as the root cause of segregation in the compression process of Project X. Geometries show different segregation tendency with the maximum CU range 103% - 120% due to different powder flow and segregation mechanics in these geometries. It was observed that segregation mainly took place on the surface of inclined material bed during the discharging and feeding processes and was significantly influenced by the relative location of outlet. The method was then validated by performing feeding experiment of Project X final blends with 3D printed blender-hopper geometries, which match well with the segregation behavior of corresponding simulations. Suggestions were therefore made on the setting of hopper geometry for further manufacture activity. The case study shows robust applicability of the proposed simulation method on pharmaceutical powder flow and segregation. This method has potential benefit on significant saving of cost and drug substance, as well as risk reduction of batch failure especially in scale-up of solid dose manufacture.

1. Gao Y., Chalasani, S., Mittal, B., Investigation on Key Parameters of Common Pharmaceutical Blending Unit Operations Using Discrete Element Method, AIChE Annual Meeting, Salt Lake City UT, Nov 2015, paper 412e.