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

Abstract

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.

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Materials

Two low-dose model formulations containing either metformin hydrochloride (Sohan Healthcare, Pune, India) or celecoxib (Zhejiang Chemsyn Pharm Co., Zhejiang, China) as API were used in this study. In both formulations, the drug load was 1%w/w. Metformin.HCl was selected as a highly water-soluble and wettable compound, whereas celecoxib was chosen due to its poor aqueous solubility and wettability. Both formulations contained lactose monohydrate (Pharmatose 200 M, DFE Pharma, Goch, Germany).

Louis Bouckaert, Mathieu Ombecq, Giorgia Adamo, Christoph Portier, Valérie Vanhoorne, Chris Vervaet, Continuous twin screw wet granulation of low-dose formulations: Impact of process variables and API/binder addition methods on granule quality attributes, International Journal of Pharmaceutics, 2026, 126684, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.126684.