(189g) Experimental Analysis of Influence Screw Configuration in View of Understanding Granulation Mechanism in Pharmaceutical Twin-Screw Melt Granulation

For 15 years, there has been increasing interest in continuous manufacturing in pharmaceutical industry. In order to improve process efficiency and reduce costs innovative continuous manufacturing processes, e.g. twin-screw melt granulation, are gaining interest. Twin-screw melt granulation is a particle enlargement process where a meltable solid binder is used to achieve agglomeration of pharmaceutical powder particles. This process has an extensive list of advantages e.g. the exclusion of a drying step in the production process compared to twin-screw wet granulation and the ability to formulate high-dosed formulations with up to 95% of API.

The aim of this study was to gain process understanding of the granulation mechanisms in continuous twin-screw melt granulation by evaluating the influence of different screw elements and process parameters for a miscible and an immiscible formulation on the granule properties.

METHODS

Soluplus was used as a thermoplastic binder in the 2 formulations selected for this study. Metoprolol tartrate (MPT) and Caffeine anhydrous (CAF) were chosen as model drugs due to their different miscibility¹. The former is miscible, while the latter is immiscible with Soluplus. Physical mixtures (85% API/binder w/w) were processed using a twin-screw extruder (Prism Eurolab 16, Thermo Fisher Scientific) with a screw configuration containing 2 kneading zones of each five kneading elements and a screw mixing element at the end of the screws. A D-optimal screening design was performed with screw speed (150-500 rpm), material throughput (0.4kg/h-0.8kg/h), barrel temperature (60°-80°C for MPT and 90°-110°C for CAF), stagger angle (30°, 60° and 90°) and direction of the kneading zone (forward and reversed) as factors. Several granule and process properties were evaluated as responses like friability, granule size, shape, torque and porosity.

RESULTS

The stagger angle, direction of the kneading zone and the interaction of these two factors determine the formation of granules and their quality attributes most significantly. In addition, the formulation also has an influence on granule formation. Granule formation for MPT and SLP can already be observed with screw configurations with lower shear compared to CAF and SLP due to the difference in drug-polymer miscibility. The largest, strongest and more needle-shaped granules are obtained with a small stagger angle of kneading elements in reversed direction due to back-mixing and therefore more material build-up occurs at the kneading zones. Due to this material build-up, more densification and more melting of the binder takes place and thus stronger, more dense and larger granules can be obtained. For the reversed configuration, the material build-up occurs due to the little amount of space for the material to pass the kneading zone, which results in the material passing along the gap between the wall of the barrel and the edges of the kneading elements which results in shear elongation. How smaller the stagger angle in reversed configuration, how more shear elongation that takes place and how more needle-shaped granules are obtained. The needle-shaped granules become more spherical by adding a screw mixing element at the end of the screws which can break up the needle-shaped granules. For this screw configuration, shear elongation followed by breakage and layering can be proposed as the granulation mechanism for both formulations. In contrast, forward direction does not cause back-mixing and shear elongation. Therefore, breakage and layering occurs as granulation mechanism with this screw configuration.

CONCLUSION

This study demonstrates that screw configuration is the most influencing factor that determines granule and process properties. Depending on raw material properties, desired granule properties can be obtained by optimizing the screw configuration. The reversed configuration with the smallest stagger angle is the most robust configuration to obtain granules with the best properties for downstream processing.

REFERENCES

1. Monteyne, T. et al. The use of rheology to elucidate the granulation mechanisms of a miscible and immiscible system during continuous twin-screw melt granulation. Int. J. Pharm. 510, 271–284 (2016).