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.
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