Improving blend content uniformity via dry particle coating of micronized drug powders

Abstract

Content uniformity of low dose blends with fine active pharmaceutical ingredients (API) is adversely impacted due to API agglomeration caused by high powder cohesion. Dry coating using high-intensity vibratory mixing is employed to reduce API cohesion and granular Bond number as well as agglomeration as predicted by contact models, hence improve blend content uniformity (CU). Micronized acetaminophen (mAPAP) (~10μm), a model API, was dry coated with nano-silica R972P (20nm), and mixed with Avicel 102. The amount of silica was varied from 0 to 2.74wt%, corresponding to theoretical surface area coverage (SAC) from 0 to 100% respectively. Bulk density, unconfined yield strength, and dispersive surface energy results indicated dry coating with 0.27 to 1.0wt% silica was adequate for API property enhancement; further corroborated by improved CU for 5wt% API blends. Excellent CU was achieved for 3, 5 and 10wt% API loaded blends, where 30min of mixing was found to be acceptable for all three. 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. Sieving of mAPAP illustrated the reduction in mAPAP agglomeration, necessary for improved CU after dry coating, corroborating model based predictions. Compared to theoretical predictions, actual CU was higher unless API agglomerate size distribution obtained via sieving was taken into account. Overall, cohesion reduction by dry coating is shown as a promising approach for improving content uniformity of cohesive API blends.

Manufacturability and Properties of Granules and Tablets Using the Eco-Friendly Granulation Method Green Fluidized Bed Granulation Compared to Direct Compression

“…[32][33][34] Though a large amount of excipients could be added to improve flowability and compaction properties, blending with fine API may lead to segregation problems. 35,36) Therefore, changing the formulation to improve powder properties is not always the preferred method. For this reason, GFBG was considered a useful granulation method because it allowed the preparation of the final mixture with a processing time comparable to DC and is applicable to high drug load formulations.…”

Discrete element method simulation of binary blend mixing of cohesive particles in a high‐intensity vibration system

“…The mixing of powders is a common but important step in chemical, mining, pharmaceutical, food, and other industries 1–6 . The aim of mixing is to produce a mixture with adequate homogeneity, despite potential variations in powder properties such as particle size, particle‐size distribution, density, flowability, surface characteristics.…”

“…The aim of mixing is to produce a mixture with adequate homogeneity, despite potential variations in powder properties such as particle size, particle‐size distribution, density, flowability, surface characteristics. Processing conditions, such as the equipment, and operating conditions, as well as the upstream and downstream processing steps, can also vary 4,6–11 . For example, in a continuous direct compression tableting process, blend and drug content uniformity after feeding and mixing are critical factors for meeting tablet product uniformity requirements 12–14 .…”

“…For example, in a continuous direct compression tableting process, blend and drug content uniformity after feeding and mixing are critical factors for meeting tablet product uniformity requirements 12–14 . In addition to particle size disparities between the constituents, the flowability of the powders is expected to have a critical impact on degree of mixing or segregation 4,14–16 . Existing literature provides the phenomenological explanations as well as some model‐based understanding of particle mixing behavior 1,3,17–19 .…”

“…There are a variety of mixers available, and several different ones have been used for dry mixing of powders 4,24–29 . Most industrial mixing devices exert relatively low intensity in comparison to those used in creating interactive mixtures 4,14,23 .…”