(509d) Continuous Mixing Technology: Design Optimization with Discrete Element Simulations

Continuous Mixing Technology: Design
Optimization with Discrete Element Simulations

Peter
Toson¹, Pankaj Doshi²,
Eva Siegmann¹, Johannes Khinast^1,3,
Daniel Blackwood², Ashwinkumar Jain²,
Alexandre Bonnassieux², Kai
Lee⁴, David Wilsdon⁴ and James Kimber⁴,
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

⁴ Pfizer Ltd. Discovery Park House IPC009,
Sandwich, Kent. CT13 9ND

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

Mixing is a crucial processing step in a
continuous pharmaceutical processing line. It is one of the three unit
operations in a direct compression process (feeding, mixing, tablet pressing)
and is responsible for content uniformity, lubrication of the powder and thus
the tensile strength of the final tablet.

The operating space of a vertical continuous
mixing device termed CMT (continuous mixing technology) has been analyzed with
discrete element simulations. The advantage of the vertical design is that hold-up
mass (and thus mean residence time MRT) and impeller speed (and thus the shear
rate and stress) can be controlled independently from each other. In a previous
study [1], process maps in terms of mixing quality, travel distance and extent
of lubrication, and particle velocities have been created with DEM simulations
and validated with tracer experiments. The process maps were created for
operation at 10kg/h.

One challenge that remains is the scale up of
the process to higher throughputs. The available operating space shrinks:
Higher throughput means lower mean residence times. Higher impeller speeds and
hold-up masses are required to offset the lower MRT, but both of these
parameters have physical limits. In addition, higher impeller speeds come with
higher centrifugal forces exerted on the powder bed, restricting the outlet
flow and adding challenges to process control.

Instead of finding the optimal process
conditions in the restricted operating space, the aim of this work is the
design optimization of the CMT. Various impeller, screen, and baffle designs
have been studied with DEM simulations. The DEM simulations revealed how the
modifications to the geometry changed the particle dynamics inside CMT. This
opened up the operating space, making high-throughput operation not only
feasible, but also easy control. The best-performing virtual impeller prototype
has been 3D printed and it was possible to confirm the predictions
experimentally.

References:

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