(673d) Improved Pharmaceutical Blend Content Uniformity Due to Reduced Agglomeration of Dry Coated Micronized Drug Powders

Content uniformity of low dose blends with fine active pharmaceutical ingredients (API) is adversely impacted due to API agglomeration caused by high powder cohesion. In this work, dry coating using high-intensity vibratory mixing is employed to reduce API cohesion. This leads to a dramatic decrease in granular Bond number resulting in reduced agglomeration as predicted by contact models, thus greatly improving blend content uniformity (CU). Micronized acetaminophen (mAPAP) (~10 µm), a model API, was dry coated with nano-silica R972P (20nm), and mixed with Avicel 102 as a model excipient. The amount of silica was varied from 0 to 2.74 wt %, corresponding to theoretical surface area coverages (SAC) from 0 to 100 % respectively. Bulk density, unconfined yield strength, and dispersive surface energy results indicated dry coating with 0.27 to 1 wt % silica was adequate for API property enhancement. Sieving of mAPAP illustrated the reduction in mAPAP agglomeration, necessary for improved CU after dry coating, corroborating model based predictions. The predictions were corroborated by excellent CU for 3, 5, 10 wt % API loaded blends. The CU with dry coated mAPAP was significantly lower and within the acceptable range as compared to control blends without silica, as well as those with silica added during blending. Compared to theoretical prediction, actual CU was higher unless API agglomerate size distribution obtained via sieving was taken into account. Further investigations are ongoing to properly quantify powder agglomeration before/after mixing. In return, this will allow for better understanding of the powder agglomeration/CU relationship with an eye toward proper prediction of blend CU. Overall, cohesion reduction by dry coating is shown as a promising approach for improving content uniformity of cohesive API blends.