Control oriented modeling of twin-screw granulation in the ConsiGma-25 production plant

ConsiGma^TM-25 is a continuous production plant integrating a twin-screw granulation, fluid bed drying, granule conditioning, and a tableting unit. The particle size distribution (PSD), active pharmaceutical ingredient (API) content, and liquid content of wet granules after twin-screw granulation affect the quality of intermediate and final products. This paper proposes methods for real-time monitoring of these quantities and control-oriented modeling of the granulator.

The PSD of wet granules is monitored via an in-line process analytical technology (PAT) probe based on the spatial velocimetry principle. The algorithm for signal processing and evaluation of PSD characteristics is developed and applied to the acquired PSD data. A dynamic process model predicting PSD characteristics from granulation parameters is trained via the local linear model tree (LoLiMoT) approach. The experimental data required for the model training are collected via systematically designed excitation runs. Finally, the performance of the identified model is examined and verified by means of a new set of validation runs.

Furthermore, an in-line PAT probe based on Raman spectroscopy is developed and integrated after the granulator. The API- and liquid content of produced wet granules are evaluated from the spectral data by means of chemometric modeling, and chemometric models are validated on a separate set of experimental data. The solutions proposed in this research can be used as a reliable (and necessary) basis for the development of advanced quality-by-design control concepts (e.g., PSD process control). Such concepts would ultimately improve the ConsiGma^TM-25 process performance in terms of robustness against disturbances and quality of intermediate and final products.

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Materials

Wet granules were produced from a powder pre-blend and deionized water. The pre-blend material consisted of Methyl 4-hydroxybenzoate (Sigma Aldrich, USA), also known as Methylparaben, as the API surrogate material, and three excipients, i.e., VIVAPHARM HPMC (Demacsa, Mexico), Avicel PH101 (DuPont, Ireland), and Granulac 200 (Meggle, Germany). Table 1 shows the nominal pre-blend composition.

Selma Celikovic, Johannes Poms, Johannes Khinast, Martin Horn, Jakob Rehrl, Control oriented modeling of twin-screw granulation in the ConsiGmaTM-25 production plant, International Journal of Pharmaceutics, 2023, 123038, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2023.123038.

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