(T1530-01-04) Evaluation of Process Parameters for Continuous Manufacturing of Quetiapine Fumarate Immediate Release Tablets Using Twin Screw Wet Granulation

Purpose: Granulation is one of the important unit operations in the manufacturing of solid dosage forms like tablets and capsules that regulate the quality of end products. It is a process of particle enlargement by agglomeration technique, which improves flow properties, compressibility, reduction of dust formation, drug content uniformity, dissolution rates, and overall product stability. Traditionally, it has been a batch process due to a better understanding of the process. However, there has been a shift towards continuous manufacturing using a twin screw granulator, which is more robust, scalable, and versatile for a wide range of applications. Therefore, understanding the impact of twin screw granulation (TSG) process parameters is vital to achieve optimum granulation. This work specifically focuses on the impact of various binders and process parameters including screw configuration, liquid feed rate, and solid feed rate on twin screw wet granulation (TSWG) in the development of Quetiapine fumarate (QTF) immediate release tablets.

Methods: As described in Table 1, five batches underwent granulation using a Process 11 Twin-Screw Extruder (Thermo Fisher™, Waltham, MA). Water was added via a peristaltic pump through a liquid injection port. Different L/S ratios were tested for each batch, ranging from 0.16 to 0.95, to determine the optimal ratios. Batches F1, F2, and F3 were processed using a single mixing zone in Zone 2 with 5% Klucel EXF, 3%, and 5% Kollidon K30 as binders respectively. In contrast, the F4 and F5 batches were processed using two and three mixing zones (zones 2, 4, and 6), respectively using F3 composition. The screw RPM was set to 50, and temperatures for all zones were set at 18°C for all the formulations. All obtained granules were dried at 40°C until the moisture content reached 2-5%. The dried granules were then evaluated for particle size distribution (PSD) and flow properties. The granules of F5, processed at an L/S ratio of 0.52, were compressed into tablets with a unit dose of QTF for each tablet set at 400 mg. The compressed tablets were further evaluated for friability, disintegration, assay, and dissolution (500 mL of 0.1N HCl).

Results: The L/S ratio has an impact on the size and uniformity of granules. A lower L/S ratio leads to an under-granulated mass, while an increased L/S ratio results in good granulation. However, the optimal L/S ratio varies depending on the specific binder used and the number of mixing zones incorporated. Formulations with Kollidon K30 (low viscosity and high wettability) as a binder produce more uniform-sized granules compared to Klucel EXF (high viscosity and low wettability). The PSDs of formulations F1 to F5 followed a trend based on the L/S ratios (Figure 1). As the L/S ratio increased, the percentage of uniform-sized granules also increased (sieve #20 pass and #60 retain). However, higher L/S ratios showed an increase in oversized granules (sieve #20 retain) and a decrease in fines (sieve #60 pass). The screw configuration, which exerts high shear with increasing number of mixing zones, affects the percentage of uniform-sized granules produced. Specifically, 75% of the granules were uniform in size when the configuration was F5 (three mixing zones) at an L/S ratio of 0.42. Formulations that comprise Kollidon K30 have better flow properties than Klucel EXF. Additionally, flow properties improved as the number of mixing zones increased from 1 to 3 in batches F3 to F5, respectively (Figure 2). The compressed tablets of F5 passed friability (0.7%) and resulted in an assay of 96.5%w/w, disintegrated within 5 minutes, and released 95%w/w of QTF within 5 minutes, categorizing them as immediate release.

Conclusion: This study aimed to evaluate how each process parameter affects granule quality and the development of QTF immediate-release tablets. We established a clear relationship between various parameters. The optimum L/S ratio varied with the material properties (binder used) as well as the screw configuration used. Overall, an increase in L/S showed an improvement in flow properties, as well as the production of more uniform-sized granules with a lower percentage of fines. Increasing the number of mixing zones inside the barrel creates higher shear, resulting in optimal granulation while using less liquid. This potentially reduces the drying time of granules. The tablets that were compressed with granules processed with three mixing zones and 0.52 L/S ratio surprisingly disintegrated and released ~95% of QTF rapidly within 5 minutes, attributing to the drug’s higher solubility in 0.1N HCl and the possible presence of porosity of granules. Overall, these results emphasize the potential of continuous twin screw wet granulation as an alternative approach to enhance pharmaceutical manufacturing processes.


Table 1. Formulation composition


Figure 1. PSDs of granules processed at different L/S ratios (F1 – F5).


Figure 2. The Hausner ratio for formulations processed at different L/S ratios.