Particle – particle interactions in dry powder blending: Applying theoretical concepts to real-life particles

In pharmaceutical production, dry powder mixing is a common and critically important unit operation. It is required that active pharmaceutical ingredients (APIs) are uniformly distributed among other excipients (non-active ingredients) at the end of the mixing process. In today’s pharmaceutical drug discovery pipelines, about 90% of all APIs are reported to be poorly water soluble. Therefore, micronized APIs particles are normally used to obtain sufficient bioavailability. However, powders of micronized particles are normally cohesive. Such powders have the tendency to spontaneously form lumps or agglomerates. The presence of such lumps in the final powder blends is not tolerable. This could lead to non-uniformity and safety issue of the final product. Therefore, it is necessary to understand the properties and the behaviors of such lumps in a mixing process. The ultimate goal is to break and uniformly distribute the APIs in the final powder blend. In this thesis, we investigated the lumps from particle-particle interaction point of view. The cohesion forces between particles were measured by a centrifuge technique and atomic force microscopy (AFM). The structures of agglomerates were studied using X-ray microtomography. Numerical simulation using Discrete Element Method (DEM) was used to study agglomerate behavior in powder mixing processes. An abrasion model was used to describe the size reduction of such agglomerate in a powder mixing process. The validity of the abrasion model was confirmed by both simulation data and experimental data. The abrasion model supports guidance for the selection of ingredients and process-settings in pharmaceutical product development.