Interplay between semi-continuous blending and continuous twin-screw wet granulation: impact of blend uniformity on...

Achieving a uniform powder mixture in low-dose and complex formulations is inherently challenging and can undermine downstream process performance and product quality. This study aimed to assess the extent to which twin-screw wet granulation (TSWG) can mitigate upstream blend variability caused by short and less intensive mixing conditions. Two low-dose formulations, containing either a highly water-soluble (metformin.HCl) or a sparingly water-soluble (caffeine anhydrous powder) Active Pharmaceutical Ingredient (API), were studied. Granulator parameters, including liquid-to-solid (L/S) ratio and screw speed, were evaluated using a two-factor screening design to identify conditions yielding the most uniform API concentration across different granule sizes. To assess the impact of semi-continuous blender parameters on blend uniformity, impeller speed, blending time, and fill level were systematically varied using a central composite orthogonal (CCO) design. Subsequently, blends exhibiting progressively increasing relative standard deviation (RSD) values were granulated to evaluate how upstream blend uniformity affects downstream API distribution. High L/S ratios and screw speeds narrowed the granule size distribution and improved API distribution across granule size fractions. Blend uniformity improved with increasing blending time and impeller speed, whereas higher fill levels reduced mixing performance. For the investigated formulations, no statistically significant changes in API concentration across different granule sizes were observed at blend RSD levels up to 9.2% for the metformin.HCl formulation and 3.0% for the caffeine formulation. These findings demonstrate that TSWG can compensate for moderate up-stream variability, highlighting its potential to enable robust continuous manufacturing of low-dose formulations at high throughput.