Continuous mixing technology: Validation of a DEM model

Peter Toson, Pankaj Doshi*, Marko Matic, Eva Siegmann, Daniel Blackwood, Ashwinkumar Jain, Jenna Brandon, Kai Lee, David Wilsdon, James Kimber, Hugh Verrier, Johannes Khinast, Dalibor Jajcevic*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Continuous powder mixing is an important technology used in the development and manufacturing of solid oral dosage forms. Since critical quality attributes of the final product greatly depend on the performance of the mixing step, an analysis of such a process using the Discrete Element Method (DEM) is of crucial importance. On one hand, the number of expensive experimental runs can be reduced dramatically. On the other hand, numerical simulations can provide information that is very difficult to obtain experimentally. In order to apply such a simulation technology in product development and to replace experimental runs, an intensive model validation step is required. This paper presents a DEM model of the vertical continuous mixing device termed CMT (continuous mixing technology) and an extensive validation workflow. First, a cohesive contact model was calibrated in two small-scale characterization experiments: a compression test with spring-back and a shear cell test. An improved, quicker calibration procedure utilizing the previously calibrated contact models is presented. The calibration procedure is able to differentiate between the blend properties caused by different API particle sizes in the same formulation. Second, DEM simulations of the CMT were carried out to determine the residence time distribution (RTD) of the material inside the mixer. After that, the predicted RTDs were compared with the results of tracer spike experiments conducted with two blend material properties at two mass throughputs of 15 kg/h and 30 kg/h. Additionally, three hold-up masses (500, 730 and 850 g) and three impeller speeds (400, 440 and 650 rpms) were considered. Finally, both RTD datasets from DEM and tracer experiments were used to predict the damping behavior of incoming feeder fluctuations and the funnel of maximum duration and magnitude of incoming deviations that do not require a control action. The results for both tools in terms of enabling a control strategy (the fluctuation damping and the funnel plot) are in excellent agreement, indicating that DEM simulations are well suited to replace process-scale tracer spike experiments to determine the RTD.

Original languageEnglish
Article number121065
JournalInternational Journal of Pharmaceutics
Publication statusPublished - 25 Oct 2021


  • Continuous processing
  • Mixing
  • Physical characterization
  • Powder technology
  • Residence time
  • Simulation
  • Solid dosage form

ASJC Scopus subject areas

  • Pharmaceutical Science


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