Multi-layer Raman chemical mapping to investigate the effect of API particle size and blending shear rate on API domain sizes in pharmaceutical tablets

[Display omitted] •Effect of blending shear rate and API particle size on micro-mixing.•Multi-layer and multi-tablet Raman chemical mapping for API domain size distribution.•Multi-layered analysis enables a deeper understanding of the blending process.•Chemical mapping results correlated well with tablets content uniformity using NIR.•Results showcase the utility of Raman chemical mapping as an off-line PAT tool. While macromixing (gross uniformity) has received a lot of attention in pharmaceutical powder blending, micromixing (particularly, particle-level aggregation) has been significantly less studied. This study investigated the impact of active pharmaceutical ingredient (API) particle size (D50: 11, 28, and 70 µm) and blending shear rate (low and high) that was caused by tumbling blending (specifically, a V-blender) on micro-mixing. The effect on micro-mixing (API domain sizes) was assessed in direct compression tablets using high-resolution Raman chemical mapping. Analyses of multiple layers within tablets enabled a more reliable understanding of the variability in API domain sizes with respect to the independent variables. The relationship between API domain sizes and the manufactured tablets' content uniformity (CU) was also investigated using near-infrared transmission spectroscopy. Generally, at low shear, as the API particle size decreased, the frequency and size of API agglomerates increased, resulting in poor CU. However, in all cases, API domain sizes drastically reduced at high shear, resulting in an acceptable CU. The results of this work clearly demonstrated the utility of a multi-layer, multi-tablet, and high-resolution Raman chemical mapping as an off-line process analytical technology (PAT) system, to enable quality-by-design driven formulation and process development.