(T0930-01-06) Comparison of High Shear Granulation and Twin-Screw Granulation for Achieving High Drug Loading in Extrusion-Spheronization of a Highly Soluble API (Active Pharmaceutical Ingredient)

Purpose: Extrusion-spheronization is one of the most common processes to produce multiparticulate. The drug loading in the multiparticulate is influenced by the initial granulation process used to prepare the wet mass for extrusion. Therefore, establishing the optimal granulation endpoint is critical in achieving a good yield of beads with the desired particle size distribution after the extrusion-spheronization. This study aimed to determine the optimum processing window of high shear granulation (HSG) and twin-screw granulation (TSG) of the initial wet mass for extrusion by evaluating their effect on drug loading and particle size distribution of the extruded-spheroid beads of a highly soluble API.

Methods: Theophylline anhydrous (THa) was used as a model drug. Four different drug loading (50%, 60%, 70%, 80%) were evaluated for HSG, and two different drug loading (50% and 80%) were evaluated for TSG. Table 1 describes the compositions of dry mix utilized to prepare wet mass using HSG and TSG processes. All high shear granulations were performed in a KG-5 (Key International) high-shear granulator. Dry powder blends with 50%, 60%, 70% & 80% drug loading (DL) containing a highly water-soluble drug Theophylline anhydrous (THa), diluent, and binder were prepared. The impeller and chopper were operated without water addition for the first 2 min. Of each trial to mix the dry powder. A dry mass of 0.56 kg was used for each trial; this mass was within the optimum range of operation for this granulator. Table 2 summarizes the process parameters utilized for High Shear granulation experiments. The twin screw wet granulation experiments were conducted on a co-rotating twin screw granulator (Thermo Pharma11 TSG, 40:1 L:D, Thermo Fisher Scientific, Karlsruhe, Germany). In twin screw granulation, the dry powder is fed in the barrel through the feeding zone while the granulating liquid is added using a nozzle. The granule formation occurs through a combination of capillary and viscous forces facilitating particle binding in the wet stage. Subsequently, the wet material is distributed, compacted, and elongated in the kneading elements (mixing zone), transforming the particle morphology from small (microstructure) to large (macrostructure) irregular and porous granules. Other sub-processes, such as aggregation and breakage, can also occur during granulation. Once the wet masses were produced, they were extruded using an LCI Basket extruder through a 1.2 mm screen at 20 rpm. Next, the extrudates were transferred to a Caleva spheronizer (Model 120) fitted with a 120 mm crosshatch pattern plate and spheronized at up to 2000 rpm for 30 seconds. After tray drying at 40°C, the particle size of the beads was characterized by sieving.

Results: Plastic mass was not obtained with the HSG process for trials having drug loading >50%. The water was observed to stay on the surface of granules during HSG. Therefore, it did not penetrate deep inside the granules, and the granules grew bigger due to the snow-balling effect. This made the granules unextrudable. On the contrary, plastic mass was obtained with the TSG process even up to 80% drug loading. Long extrudates were obtained with the wet mass, and extrudates were successfully spheronized. THa responds to stress through facile plastic deformation. It deforms through a slip mechanism. The theophylline molecules in THa form V-shaped hydrogen-bonded rigid columns, which stack to form flat layers. Columns can slide more easily when subject to stress than plastic crystals' classical stacking flat sheet’s structure. The amount of stress generated during TSG is more as compared to HSG. Besides this, water can penetrate deep inside the granules and give a better plasticization effect in granules prepared using TSG. These factors made the granules prepared using TSG more plastic and extrudable, even at an extremely high drug loading of 80%. Figure 1 is the comparison of PSD data of 50% DL beads obtained after extrusion-spheronization of wet mass prepared using HSG & TSG. The amount of water used for both granulation processes is similar (~75%). The fines generated are ~10% higher for the HSG process than the TSG process

Conclusion: Wet mass-produced using TSG was more plastic than the HSG process. The higher loading of theophylline anhydrous (Up to 80%) was achieved when the TSG process was used to prepare wet mass for the extrusion-spheronization process. Beads obtained after the TSG process had tighter particle size distribution than the HSG process. At similar water levels, the fines generated were 10% lower for TSG than HSG.