(492g) Visualization of Granule Temperature Along the Length of the Barrel Using Thermal Imaging to Improve Process Understanding of Pharmaceutical Twin-Screw Melt Granulation

INTRODUCTION

The pharmaceutical industry has been showing an increasing interest in continuous manufacturing for the past 15 years. In order to improve process efficiency, reduce costs and decrease the environmental footprint, innovative continuous manufacturing processes are gaining more interest. Twin-screw melt granulation (TSMG) is an interesting technique to perform agglomeration due to its multiple advantages. For instance, the use of a solid meltable binder to achieve agglomeration instead of using a solvent like in wet granulation enables the use of moisture-sensitive drugs and the exclusion of a drying step. Additionally, the high-dosed formulations with up to 95% of API and the ability to modulate release kinetics can be added to the extensive list of advantages.

In batch melt processes, the heat transfer on powder particles is not uniformly distributed and is uncontrolled. In combination with a long residence time, batch melt processes are not desirable to be used in pharmaceutical industry to obtain uniform quality attributes of granules. On the contrary, in continuous TSMG heat transfer is uniformly distributed and therefore also granule growth can be controlled because every powder particle is exposed to an equal amount of heat and mechanical stress. Furthermore, the residence time in continuous melt granulation is much lower than in batch 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, granule temperature and the relation between this.

MATERIALS AND 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 miscibility with Soluplus [1]. 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.

Granule and process properties were evaluated as responses like friability, granule size, shape, density, porosity and torque. These properties were evaluated for samples collected at 4 different locations along the length of the granulation barrel to visualize and understand the granule formation along the length of the barrel [2]. Samples were collected after only conveying elements, after the first kneading zone, after the second kneading zone and after the screw mixing element at the end of the barrel.

Furthermore, the granule temperature and barrel temperature were monitored at these 4 locations. Therefore, a FLIR A655sc Infrared Camera (FLIR systems, Frankfurt am Main, Germany) was used. Heat can be transferred onto the granules from the heated barrel wall, but heat can also be generated due to the shear created by the friction forces of the kneading elements. The temperature of the barrel wall was monitored with the data logging system of the granulator, but this does not represent the actual temperature of the granules. The maximum and the mean granule temperature was calculated and the difference between the programmed barrel temperature and the measured granule temperature was calculated for the different runs of the DoE to evaluate the influence of the different factors on the granule temperature. Granule formation, granule temperature and resulting granule properties are closely related. Therefore, the link between granule and process properties and granule temperature was also investigated in this study.

RESULTS AND DISCUSSION

The most influencing factors of the DoE on the granule temperature increase is the reversed configuration with a small stagger angle and as to be expected the programmed barrel temperature. The higher granule temperature for this screw configuration can be linked with an increased torque value and therefore a higher amount of shear. Because of this, the binder can be melted sufficiently to attain granule formation. Granules that are obtained with this kneading zone configuration also have the best quality attributes, e.g. the granules produced are the largest and strongest and have a monomodal granule size distribution.

It can be observed that granule formation occurs in the zones along the barrel that create higher shear and subsequently higher temperature which ensures enough melting of the binder. Therefore, no granule formation is occurring in the conveying zones or in the kneading zones with forward configuration. The torque value for the forward configuration is not increasing sufficiently and hence not enough shear is created to form granules with good quality attributes. This can be countered by changing the screw configuration or by elevating the barrel fill level. For these two options there will be an increase of the torque value to ensure enough shear at the kneading zones to obtain granules with good quality attributes.

CONCLUSION

Heat transfer in continuous melt granulation occurs in a more controllable and uniform way compared to batch melt granulation, resulting in granules with more uniform quality attributes. By applying different amounts of shear and barrel temperature, different granule properties can be obtained. The smallest stagger angle in reversed configuration creates the highest shear and the largest granule temperature increase and therefore, more melting of the binder and densification occurs and better quality attributes of granules are obtained. Because the solid state of various active pharmaceutical ingredients are not resistant for all levels of shear and temperature, the screw configuration can be optimized for every formulation so that optimal quality attributes can be obtained.

REFERENCES

[1] T. Monteyne 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., vol. 510, no. 1, pp. 271–284, 2016.

[2] M. Verstraeten et al., “In-depth experimental analysis of pharmaceutical twin-screw wet granulation in view of detailed process understanding,” Int. J. Pharm., vol. 529, no. 1–2, pp. 678–693, 2017.