Macro- and micro-mixing of a cohesive pharmaceutical powder during scale up

•The mixing mechanism using blender-comil-blender changes upon scale up.•The mixing in the first bin blender is macro-mixing only regardless of scale.•Micro-mixing from comil has different effectiveness between scales.•Micro-mixing in the second bin blender is enabled by the comilling step.•Micro-mixing in the second bin blender becomes apparent upon scale up.

Efficient powder mixing involves a macro- and micro-mixing mechanism, achieved by a combination of various types of mixers. Selection of the mixer is based on the understanding of the cohesiveness of the components in the mixture. In the current study, a cohesive active pharmaceutical ingredient (API), X, was used as the model compound to study the effectiveness of convective mixing in a bin blender and intensive shear mixing with a comil (conical mill). Convective mixing in the bin blender only delivered limited macro-mixing for API X and the resulting blend was heterogeneous at both micro- and macro-scales. After blending in the bin blender, the comilling process added micro-level mixing by introducing locally intensive mechanical shear. The resulting blend showed improved homogeneity at the micro-scale, but was still heterogeneous at the macro-scale. An additional mixing step in the bin blender after comilling was required to ensure the uniformity of the mixture at both micro-and macro-scales. The significance of the second convective mixing to micro-mixing was underscored at commercial-scale manufacture as compared to the development scale. Despite the scale dependency on the comilling step, the extensive shear exerted during the comilling step facilitated further micro-mixing by the convective mixing in the second bin mixing step. The investigation demonstrates that a rational selection of mixing steps with various types of mixers is crucial to achieve both macro- and micro-mixing of cohesive materials from development to commercial scales.

Graphical abstractImpact of scale up on the blend uniformity of pharmaceutical powder using a blender-comil-blender process.Figure optionsDownload full-size imageDownload as PowerPoint slide