Process Modeling and Simulation of Tableting—An Agent-Based Simulation Methodology for Direct Compression

In pharmaceutical manufacturing, the utmost aim is reliably producing high quality products. Simulation approaches allow virtual experiments of processes in the planning phase and the implementation of digital twins in operation. The industrial processing of active pharmaceutical ingredients (APIs) into tablets requires the combination of discrete and continuous sub-processes with complex interdependencies regarding the material structures and characteristics.

The API and excipients are mixed, granulated if required, and subsequently tableted. Thereby, the structure as well as the properties of the intermediate and final product are influenced by the raw materials, the parametrized processes and environmental conditions, which are subject to certain fluctuations.

In this study, for the first time, an agent-based simulation model is presented, which enables the prediction, tracking, and tracing of resulting structures and properties of the intermediates of an industrial tableting process. Therefore, the methodology for the identification and development of product and process agents in an agent-based simulation is shown. Implemented physical models describe the impact of process parameters on material structures. The tablet production with a pilot scale rotary press is experimentally characterized to provide calibration and validation data. Finally, the simulation results, predicting the final structures, are compared to the experimental data.

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Materials

Anhydrous dicalcium phosphate (DCPA) in two grades (DI-CAFOS^® A60, DI-CAFOS^® A150, Chemische Fabrik Budenheim KG, Budenheim, Germany) were used as model materials. The characteristic particle sizes of DCPA A60 and DCPA A150, determined by laser diffraction (Mastersizer 3000, Malvern Panalytical, Kassel, Germany), differ over the whole distribution. To enable their processability, DCPAs were mixed with 1 wt% magnesium stearate (MgSt, Magnesia GmbH, Lüneburg, Germany) in a cube blender (ERWEKA GmbH, Langen, Germany) for five minutes at 30 rpm. The bulk ρ_b and tapped density ρ_t were determined according to the Ph. Eur. 9.3 2.9.34 using a 100 mL cylinder and a volumetric analyzer (Erich Tschacher Laboratoriumsbedarf, Bielefeld, Germany). As the two grades consist of the same chemical material, the solid density ρ_s, measured in triplicate with the helium pycnometer Ultrapyc 1200e (Quantachrome Instruments, Boynton Beach, FL, USA), are practically identical

Martin, N.L.; Schomberg, A.K.; Finke, J.H.; Abraham, T.G.-m.; Kwade, A.; Herrmann, C. Process Modeling and Simulation of Tableting—An Agent-Based Simulation Methodology for Direct Compression. Pharmaceutics 2021, 13, 996. https://doi.org/10.3390/pharmaceutics13070996

excipients formulation