Systematic investigation of the impact of screw elements in continuous wet granulation

Twin-screw wet granulation (TSG) is a continuous manufacturing technique either for granules as final dosage form or as an intermediate before tableting or capsule filling. A comprehensive process understanding is required to implement TSG, considering various parameters influencing granule and tablet quality. This study investigates the impact of screw configuration on granule properties followed by tableting, using a systematic approach for lactose-microcrystalline cellulose (lactose-MCC) and ibuprofen-mannitol (IBU) formulations.

Highlights

• Screw configuration analysis via DoEs for two formulations revealed L/S ratio as the most influential parameter during TSG.
• TMEs caused more oversized granules in the IBU formulation due to longer residence time and increased granule growth.
• At least one kneading zone, independent of type, is required to produce granules and tablets with sufficient strength.

The most affecting factor, as observed by other researchers, was the L/S ratio impacting the granule size, strength and tabletability. Introducing tooth-mixing-elements at the end of the screw, as for the IBU formulation, resulted in a high proportion of oversized granules, with values between 36% and 78%. Increasing the thickness of kneading elements (KEs) produced denser, less friable granules with reduced tablet tensile strength. Granulation with more KEs, larger thickness or stagger angle increased torque values and residence time from 30 to 65 s.

Generally, IBU granules exhibited high tabletability, requiring low compression pressure for sufficient tensile strength. At a compression pressure of 50 MPa, IBU tablets where at least one kneading zone was included resulted in approximately 2.5 MPa compared to lactose–MCC with 0.5 MPa. In conclusion, the TSG process demonstrated robustness by varying the screw design with minimal impact on subsequent tableting processes.

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Materials

Two formulations were utilized to investigate the screw configuration in wet granulation. The first formulation comprised 80.0% (w/w) alpha-lactose monohydrate (GranuLac® 200, MEGGLE; Wasserburg am Inn, Germany), 17.0% (w/w) microcrystalline cellulose (MCC, VIVAPUR® 101, JRS PHARMA, Rosenberg, Germany) and 3.0% (w/w) Polyvinylpyrrolidone K 30 (PVP, Kollidon® 30, BASF SE, Ludwigshafen, Germany) as a binder. This resulted in a formulation with good solubility, including MCC as a high water absorption excipient, allowing for the use of broader L/S ratios. The second formulation contained 48.5% (w/w) ibuprofen (IBU, Ibuprofen 50, BASF SE, Ludwigshafen, Germany) as active pharmaceutical ingredient (API), 48.5% (w/w) mannitol (Pearlitol® 200 SD, Roquette, Lestrem, France) and 3.0% (w/w) PVP K 30. The second formulation contains 48.5% of a hydrophobic API, which belongs to Class II of the Biopharmaceutical Classification System (BCS) due to its low solubility (Han et al., 2023). Therefore, this formulation is expected to present more challenges in achieving sufficient liquid distribution to improve granule and tablet quality and to be more sensitive in changes of L/S ratio. Demineralized water was used as granulation liquid. Iron (III) oxide (Carl Roth, Karlsruhe, Germany) was used as a tracer for residence time distribution measurements. For tableting, 1.0% (w/w) magnesium stearate (MgSt, Parteck® LUB MST, Merck, Darmstadt, Germany) was applied as a lubricant.

Katharina Kiricenko, Robin Meier, Peter Kleinebudde, Systematic investigation of the impact of screw elements in continuous wet granulation, International Journal of Pharmaceutics: X, Volume 8, 2024, 100273, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2024.100273.

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