Visualization of the granule temperature using thermal imaging to improve understanding of the granulation mechanism in continuous twin-screw melt granulation.

The aim of this study is to increase process understanding of the granulation mechanism in twin-screw melt granulation by evaluating the influence of different screw configurations on granule formation and granule temperature via thermal imaging. The study used a Design of Experiments (DoE) to process a miscible and immiscible formulation (85% API/binder w/w) using a twin-screw extruder with varying screw configurations. The barrel temperature (°C), screw speed (rpm), throughput (kg/h), and kneading zone (direction and stagger angle) were varied. Granule and process properties were evaluated for samples collected at four different locations along the length of the granulation barrel to visualize the granule formation, and granule temperature was monitored by an infrared camera to measure heat transfer on the granules. The resulting temperature was linked to the granule properties and the granule formation along the length of the barrel. The most influencing factors on the granule temperature are the direction of the kneading zone and the set barrel temperature. It was observed that granule formation mainly occurred in the zones that apply more kneading on the granules. The highest temperature increase was observed when the smallest stagger angle in reverse configuration was used, and could be linked to better granule quality attributes.

Elucidation of granulation mechanisms along the length of the barrel in continuous twin-screw melt granulation.

In the pharmaceutical industry, innovative continuous manufacturing technologies such as twin-screw melt granulation (TSMG) are gaining more and more interest to process challenging formulations. To enable the implementation of TSMG, more elucidation of the process is required and this study provides a better understanding of the granule formation along the length of the barrel. By sampling at four different zones, the influence of screw configuration, process parameters and formulation is investigated for the granule properties next to the residence time distribution. It showed that conveying elements initiate the granulation by providing a limited heat transfer into the powder bed. In the kneading zones, the consolidation stage takes place, shear elongation combined with breakage and layering is occurring for the reversed configurations and densification with breakage and layering for the forward and neutral configurations. Due to the material build-up in the reversed configurations, these granules are larger, stronger, more elongated and less porous due to the higher degree of shear and densification. This configuration also shows a significantly longer residence time compared to the forward configuration. Hence, the higher level of shear and the longer period of time enables more melting of the binder resulting in successful granulation.

Identification of continuous twin-screw melt granulation mechanisms for different screw configurations, process settings and formulation.

Twin-screw melt granulation (TSMG) is a promising continuous manufacturing technology for the processing of high drug load formulations and to formulate heat- and moisture-sensitive active pharmaceutical ingredients (APIs). This study evaluates the influence of process parameters for TSMG, mainly focusing on the effect of the screw configuration combined with screw speed, throughput and barrel temperature, to elucidate the melt granulation mechanisms. For the kneading zone, the stagger angle was varied between 30°, 60° and 90°, and investigated for both the forward and the reversed direction. In addition to the process parameters, the influence of the formulation differing in their API-binder miscibility was evaluated. As responses, the granule (size, friability and porosity) and process properties such as torque were evaluated, indicating that the screw configuration is the most influential factor. Nucleation, consolidation and breakage are the granulation mechanisms for the forward and the neutral configuration, while consolidation and densification with shear elongation are identified for the reversed configuration. The formulations differ mainly in the forward and neutral configuration since the immiscible formulation shows a bimodal granule size distribution with a larger fraction of fines and weaker granules is obtained. For the reversed configuration, similar granulation mechanisms are seen for both formulations.