(W1130-06-35) Effect of Kneading Disk Geometry on Twin-Screw Continuous Melt Granulation

Purpose: Twin-screw melt granulation (TSMG) relies on heat and mixing (distributive and dispersive) at the kneading zone for granulation to occur. The design features of the elements in this zone affecting mixing are kneading disc width, staggering angle, and overflight clearance. The current kneading elements sold with these machines are engineered for plastics compounding and hot melt extrusion of amorphous solid dispersions. The rationale behind the design is to balance applied shear and elongational stresses for mixing together with the need to transport materials forward for less heat due to viscous dissipation in the polymer melt. . However, the contributing stresses of current kneading elements to mixing might be excessive for melt granulation. In-process physicochemical changes such as drug degradation, polymorph changes, particle size reduction etc. have been observed with these elements. The primary objective of this study is to evaluate new kneading elements (reduced disc width and increased overflight clearance) in melt granulation of mannitol (model compound) using hydroxypropyl cellulose as the thermal binder. Narrower discs are commercially available for some polymer mixing applications, but processors would never consider increasing the overflight clearance with liquids. However, to achieve exceptional results with extrusion technology in the application of particle processing, some radical design changes should be contemplated for its elements.

Methods: Crystalline mannitol was used as the model compound for the study with hydroxypropylcellulose (HPC) as the binder. Mannitol-HPC granules were processed on a Leistritz ZSE-18 twin-screw co-rotating extruder with a 25 L/D barrel configuration. Feed rate and binder level (10%) were fixed for the study while kneading disc width (2-4 mm), overflight clearance (0.2-0.4 mm), screw configuration, barrel temperature (90-155 °C), and screw speed were chosen as processing variables. The obtained granules from the process were sieved to obtain different particle size fractions. 250-600 µm granules were chosen for further characterization. Sieved granules were compressed on a single station hydraulic tablet press at 215 MPa and tensile strength of tablets was measured along with particle size distribution (through a Camsizer) and percent weight fraction of fines.

Results: Higher barrel temperatures were required for granulation with these new kneading elements as compared to the conventional kneading element, which was taken as a positive change pointing to reduced viscous dissipation. Most notably, no granulation was observed at barrel temperatures below 150 °C with any of the new kneading elements when configured with a staggering angle of 30°. Barrel temperature had a significant effect on the weight fraction of fines produced (p < 0.05) (Table 1). The tabletability of mannitol was found to be generally acceptable with these new kneading elements, using 2 MPa as the target threshold and in comparison, to direct compression of the physical mixture which had a tensile strength of 0.4 MPa (Figure 1). The new kneading elements resulted in granules with lower tabletability when compared to the control (current kneading elements 5 mm disc width and 0.1 mm overflight clearance) at a staggering angle of 30°. Increasing the staggering angle from 30° to 60 or 90° significantly improved the tensile strength of the tablets ( >5 MPa) while producing less fines ( < 6%). In this case the excipients spent more time in the kneading zone, which seems necessary in the presence of the lower shear stresses created by the thinner disc. Barrel temperature could also be reduced significantly by increasing the stacking angle to 60, 90° while attaining good tensile strength of the tablets.

Conclusion: Reducing the kneading disc width and increasing the overflight clearance was found to lower undesirable viscous dissipation which can otherwise damage drug products. The reduced mixing due to lower peak shear and dispersive mixing was compensated by increasing the staggering angle to achieve good granule tabletability. Increased staggering angle not only resulted in significantly stronger granules but also lower barrel temperature for granulation. Studies are being conducted to investigate the effect of the new kneading elements on drug stabilities.


Fig 1. Tensile strength (MPa) vs compression pressure (MPa) for granules processed at different conditions (DW-Disc width, OC- Overflight clearance, Angle- Staggering angle) compressed on a single station hydraulic press at 215 MPa compression pressure. 5 mm DW, 0.1 mm OC is the current kneading element design.


Table 1. Statistical analysis of percent weight fraction of fines produced across different processing variables (p < 0.05 for statistical significance). Fines were defined as < 150µm.