Category: Manufacturing and Bioprocessing
Purpose: Wet granulation using twin screw extrusion process is a promising manufacturing approach for continuous processing of pharmaceutical materials. Compared to conventional batch wet granulation processes, such as high shear and fluidized bed wet granulation, twin screw wet granulation has a number of distinctive advantages, such as suitability for continuous production, short processing time, and material residence time, process design modularity/flexibility, and ease of scale up. One of the notable challenges of wet granulation process is processing of hydrophobic APIs due to difficulties with wetting the powder bed and non-uniform distribution of liquid binder, which result in compromised critical quality attributes of the granules.
This study aimed at systematically investigating the role of distributive comb mixing element (GLC) and neutral dispersive mixing kneading block element (K90) at various liquid to solid (L/S) ratios on the structure and physical properties of granules containing high-doses (50-80% drug loading) of a poorly water-soluble drug, Albendazole, in a twin-screw wet granulation process.
Methods: Twin screw wet granulation was performed on a Leistritz Micro 18 twin screw extruder with L/D ratio of 25:1 at a feeding rate of 0.7 kg/hr and screw speed of 100 rpm. Formulations contained 50-80% Albendazole and a 50-20% of a 70/30: Lactose/MCC mixture and 3% HPC aqueous solution as a binder. Granules were dried overnight at 35 ⁰C and sieved using a sonic sifter for 3 minutes to obtain different size fractions. Particle size distribution was studied using a Camsizer XT. Particle morphology and internal porous structure were studied using SEM and X-ray computed tomographic (CT) imaging, respectively. Liquid binder distribution was investigated by measuring the concentration of a sulforhodamine b dye (in liquid binder solution) at different size fractions. Compaction and flow properties of granules were studied using a compaction simulator (simulating a Korsch XL400 tablet press at 10 ms dwell time) and a ring shear cell (RST-XS), respectively.
Results: Several screw configurations different in the number and position of each mixing element were studied. In comparison to GLC element, K90 kneading element resulted in larger granules especially at higher L/S ratios. Placing a second GLC element before the extrudate discharge resulted in smaller granule with an approximately 8% and 57% reduction in the D50 for 0.2 and 0.3 L/S ratios. Thus, granule size is more sensitive to screw profile at a higher L/S ratio. Scanning electron microscopy images of the granules showed that the use of a kneading element resulted in the formation of compact elongated granules, while GLC element formed more porous irregularly-shaped granular particles, likely due to greater extent of granule break-up and aggregation within GLC shear fields (Fig 1(a) and (b)).
At the L/S=0.3, granule porosity estimated using X-ray CT scan was about 32% and 3.5% for granules prepared using a single GLC or K90 element along the screw, respectively. Clearly, the use of a GLC element is significantly less effective in consolidating granules. This was further elaborated using the tablet compaction experiments. Analysis of a sample (with L/S=0.4) prepared using two GLC elements as opposed to a sample prepared by a combination of K90 and GLC element showed an improvement of tablet tensile strength (compacted with 300 MPa compaction pressure) from 2.7 to 4 MPa; approximately 50% increase in the tablet’s tensile strength.
The use of a larger number of GLC element in the screw profile led to more uniform distribution of binder solution in the granule for all size fractions. In the case of a single K90 or all conveying elements screw profiles, binder was more concentrated in larger granules (Fig 1(c)). The higher mixing efficiency of GLC elements is also demonstrated by the longer mean residence time and broader residence time distribution (RTD) indicative of higher extent of axial back-mixing in the extrusion process (Fig 1(d)). All granules demonstrated good compactibility and compacts of 3 MPa tensile strength were readily achieved.
Conclusion: The results of this study demonstrate that twin-screw wet granulation with GLC elements are more efficient in terms of achieving granules with smaller particles sizes, higher porosity, and compactibility, more uniform binder distribution and a broader residence time distribution that was strongly dependent on the L/S ratio.