(553b) Deagglomeration of Cohesive Materials Using Intensifier Bar Blending

Pharmaceutical companies reduce drug substance particle size to improve in vivo exposure and to ensure unit dose uniformity of low dose drug products.  One consequence of particle size reduction is the formation of cohesive drug substances that tend to agglomerate.  These agglomerates can cause significant dose uniformity issues for low dose drug products.  Tumble bin blenders are often times ineffective at breaking up and dispersing these agglomerates during blending.  Tumble bins with intensifier bars have been used successfully to break up and disperse drug substance agglomerates.  Unfortunately, ensuring that all drug substance agglomerates have been removed is a challenge.  Development studies have demonstrated the utility of using red iron oxide as a surrogate for agglomerated drug substance.  Red iron oxide bulk contains fine particles that readily form large (>200 microns) agglomerates.  These agglomerates can be visualized using x-ray imaging techniques.  Formulations containing red iron oxide were blended with tumble bins and tumble bins with intensifier bars.  The intensifier bar blender was observed to break and disperse the red iron oxide agglomerates through mechanical agitation. The extent of blending was characterized by the fraction of intact red iron oxide agglomerates remaining in the blend over time. Studies have shown that the deagglomeration rate can be characterized by an ideal mixing model.  This model was used to determine the blending endpoint of a low dose formulation.