Process robustness in twin-screw wet granulation: the role of formulation, screw configurations and liquid-to-solid...

This study aimed to examine the effects of formulation, screw configuration, and liquid-to-solid (L/S) ratio on granule and tablet characteristics. Milling was also examined using different screen sizes and types. Two formulations were tested, with filler combinations of mannitol-microcrystalline cellulose (MCC) or MCC-anhydrous dibasic calcium phosphate (DCPA) in a 70:30 ratio, along with 25 % allopurinol as the active pharmaceutical ingredient. Three different screw configurations and three L/S ratios were evaluated. A mixer torque rheometer (MTR) was used to determine suitable L/S ratios. The higher excipient solubility resulted in a lower predicted L/S ratio for the mannitol-MCC based formulation compared with the insoluble MCC-DCPA formulation. At the predicted L/S ratio, all granules demonstrated excellent flow properties (>10 g/s), and all tablets had high tensile strengths (>2 MPa). All tablets but the MCC-DCPA formulation at the 110 % L/S level had satisfactory dissolution. Formulation and screw configuration had only minor effects on tablet tensile strength (<0.1 MPa). Particle size distribution (PSD) differences were observed in unmilled granules, but these differences were largely evened out after milling. Both mill screen sizes and types impacted residence time but had only a moderate impact on the PSD. The results confirm that twin-screw wet granulation is a robust granulation method, where multiple screw configurations and formulations can yield high-quality drug products. Since twin-screw granules are larger than those from high-shear granulation, milling plays a key role in controlling PSD and optimizing final product quality.