Continuous twin screw wet granulation of low-dose formulations: Impact of process variables and API/binder addition methods on granule quality attributes.

Continuous manufacturing technologies such as twin-screw wet granulation (TSWG) offer advantages over batch processing but face challenges when producing low-dose formulations. This study evaluated the impact of API/binder addition methods and granulator settings on critical granule quality attributes. Two low-dose model formulations were investigated, containing either a highly water-soluble (metformin.HCl) or a practically water-insoluble (celecoxib) Active Pharmaceutical Ingredient (API). A full factorial screening design was conducted by varying the liquid-to-solid (L/S) ratio, screw speed, screw design, and API/binder addition method. L/S ratio and screw speed exhibited the strongest effect on granule size, with higher settings reducing fines and narrowing the size distribution. Across all evaluated conditions, an inhomogeneous API distribution over granule size fractions was observed, with fines consistently underdosed and larger granules overdosed. Compartmental analysis revealed that the inhomogeneity originated in the wetting zone, while the first kneading zone most significantly improved uniformity. API wettability impacted nucleation behavior, with metformin.HCl incorporated in over-wetted nuclei and celecoxib forming surface layers around excipient cores. To quantify API uniformity, the weighted mean absolute deviation (WMAD), a novel metric, was introduced. The lowest WMAD values were obtained at high L/S ratio and screw speed, while API/binder addition method had a minimal impact.