(642d) Continuous Mixing Technology: Design Space Exploration with Discrete Element Simulations

Continuous Mixing Technology: Design
Space Exploration with Discrete Element Simulations

Peter Toson¹, Pankaj Doshi², Eva
Siegmann¹, Johannes Khinast^1,3, Daniel Blackwood²,
Ashwinkumar Jain², Alexandre Bonnassieux², Dalibor
Jajcevic¹

¹ Research Center Pharmaceutical
Engineering, Inffeldgasse 13, 8010 Graz, Austria

² Worldwide Research and Development,
Pfizer Inc. Groton CT 06340

³ Graz University of Technology,
Institute of Process and Particle Engineering, Inffeldgasse 13, 8010 Graz, Austria

Keywords:
Pharmaceutical Manufacturing; Continuous Mixing Technology; Process Design
& Development

Continuous
manufacturing has many advantages over batch processing, including smaller
footprints, faster turnaround times, and better control of process parameters
and product quality. A minimal setup for a continuous tableting line consists
only of three unit operations (direct compression): feeding of the individual
components, mixing and tableting. Many critical quality attributes (CQAs) of
the final tablet depend on the mixing step: the mixing quality directly
influences the content uniformity of the tablet, the extent of lubrication
influences the tensile strength of the final tablet.

The aim of this
work is an in-depth analysis of a vertical continuous mixing device termed
Continuous Mixing Technology (CMT, see Fig. 1). The vertical design allows to
control the impeller speed (and thus the shear rates) independently from the
hold-up mass (and thus mean residence time). The same number of blade passes
can be generated with different impeller speed and hold-up mass combinations.
Thus, the vertical design of the CMT opens up more degrees of freedoms when it
comes to process design compared to the traditional horizontal mixing devices,
where the screw speed directly influences both shear rate and mean residence
time.

Discrete Element
Method (DEM) simulations have been performed using the commercial software
package XPS (Extended Particle System). The simulations model production-scale
processes with a hold-up mass of up to 1000g and mass throughputs ranging from
30kg/h to 40kg/h with 5.7million particles. The model has been validated with
tracer experiments in a previous study [1].

A wide range operating conditions have been examined
with DEM simulations. Simulation results elucidate the powder mixing dynamics
as captured by residence time distribution throughout the operating space. It
helps in identifying most optimal operating space. Thus virtual design space
exploration with DEM simulations has been proving to be a valuable tool in
process development.

References:

[1] Toson et
al., Int. J. Pharm. 552, 1–2 (2018), 288–300.
doi:10.1016/j.ijpharm.2018.09.032.

Figure 1. (a) CMT
overview. (b) A cut through the CMT to reveal the powder bed shape in the
mixing zone at 350 rpm. (c) Tracer particles (red) used to determine the
residence time distribution. Snapshot taken 2s after insertion of the tracer
impulse.