Selection of Silica Type and Amount for Flowability Enhancements via Dry Coating: Contact Mechanics Based Predictive Approach.

PURPOSE: To investigate the effect of dry coating the amount and type of silica on powder flowability enhancement using a comprehensive set of 19 pharmaceutical powders having different sizes, surface roughness, morphology, and aspect ratios, as well as assess flow predictability via Bond number estimated using a mechanistic multi-asperity particle contact model. METHOD: Particle size, shape, density, surface energy and area, SEM-based morphology, and FFC were assessed for all powders. Hydrophobic (R972P) or hydrophilic (A200) nano-silica were dry coated for each powder at 25%, 50%, and 100% surface area coverage (SAC). Flow predictability was assessed via particle size and Bond number. RESULTS: Nearly maximal flow enhancement, one or more flow category, was observed for all powders at 50% SAC of either type of silica, equivalent to 1 wt% or less for both the hydrophobic R972P or hydrophilic A200, while R972P generally performed slightly better. Silica amount as SAC better helped understand the relative performance. The power-law relation between FFC and Bond number was observed. CONCLUSION: Significant flow enhancements were achieved at 50% SAC, validating previous models. Most uncoated very cohesive powders improved by two flow categories, attaining easy flow. Flowability could not be predicted for both the uncoated and dry coated powders via particle size alone. Prediction was significantly better using Bond number computed via the mechanistic multi-asperity particle contact model accounting for the particle size, surface energy, roughness, and the amount and type of silica. The widely accepted 200 nm surface roughness was not valid for most pharmaceutical powders.

Impact of Silica Dry Coprocessing with API and Blend Mixing Time on Blend Flowability and Drug Content Uniformity.

This paper considers two fine-sized (d50 ∼10 µm) model drugs, acetaminophen (mAPAP) and ibuprofen (Ibu), to examine the effect of API dry coprocessing on their multi-component medium DL (30 wt%) blends with fine excipients. The impact of blend mixing time on the bulk properties such as flowability, bulk density, and agglomeration was studied. The hypothesis tested is that blends with fine APIs at medium DL require good blend flowability to have good blend uniformity (BU). Moreover, the good flowability could be achieved through dry coating with hydrophobic (R972P) silica, which reduces agglomeration of not only fine API, but also of its blends while using fine excipients. For uncoated APIs, the blend flowability was poor, i.e. cohesive regime at all mixing times, and the blends failed to achieve acceptable BU. In contrast, for dry coated APIs, their blend flowability improved to easy-flow regime or better, improving with mixing time, and as hypothesized, all blends consequently achieved desired BU. All dry coated API blends exhibited improved bulk density and reduced agglomeration, attributed to mixing induced synergistic property enhancements, likely due to silica transfer. Despite coating with hydrophobic silica, tablet dissolution was improved, attributed to the reduced agglomeration of fine API.

Enhanced blend uniformity and flowability of low drug loaded fine API blends via dry coating: The effect of mixing time and excipient size.

Although previous research demonstrated improved flowability, packing, fluidization, etc. of individual powders via nanoparticle dry coating, none considered its impact on very low drug loaded blends. Here, fine ibuprofen at 1, 3, and 5 wt% drug loadings (DL) was used in multi-component blends to examine the impact of the excipients size, dry coating with hydrophilic or hydrophobic silica, and mixing times on the blend uniformity, flowability and drug release rates. For uncoated active pharmaceutical ingredients (API), the blend uniformity (BU) was poor for all blends regardless of the excipient size and mixing time. In contrast, for dry coated API having low agglomerate ratio (AR), BU was dramatically improved, more so for the fine excipient blends, at lesser mixing times. For dry coated API, the fine excipient blends mixed for 30 min had enhanced flowability and lower AR; better for the lowest DL having lesser silica, likely due to mixing induced synergy of silica redistribution. For the fine excipient tablets, dry coating led to fast API release rates even with hydrophobic silica coating. Remarkably, the low AR of the dry coated API even at very low DL and amounts of silica in the blend led to the enhanced blend uniformity, flow, and API release rate.

Reduced Fine API Agglomeration After Dry Coating for Enhanced Blend Uniformity and Processability of Low Drug Loaded Blends.

PURPOSE: The impact of dry coating on reduced API agglomeration remains underexplored. Therefore, this work quantified fine cohesive API agglomeration reduction through dry coating and its impact on enhanced blend uniformity and processability, i.e., flowability and bulk density of multi-component blends API loading as low as 1 wt%. METHODS: The impact of dry coating with two different types and amounts of silica was assessed on cohesion, agglomeration, flowability, bulk density, wettability, and surface energy of fine milled ibuprofen (~ 10 µm). API agglomeration, measured using Gradis/QicPic employing gentler gravity-based dispersion, resulted in excellent size resolution. Multi-component blends with fine-sized excipients, selected for reduced segregation potential, were tested for bulk density, cohesion, flowability, and blend content uniformity. Tablets formed using these blends were tested for tensile strength and dissolution. RESULT: All dry coated ibuprofen powders exhibited dramatic agglomeration reduction, corroborated by corresponding decreased cohesion, unconfined yield strength, and improved flowability, regardless of the type and amount of silica coating. Their blends exhibited profound enhancement in flowability and bulk density even at low API loadings, as well as the content uniformity for the lowest drug loading. Moreover, hydrophobic silica coating improved drug dissolution rate without appreciably reducing tablet tensile strength. CONCLUSION: The dry coating based reduced agglomeration of fine APIs for all three low drug loadings improved overall blend properties (uniformity, flowability, API release rate) due to the synergistic impact of a minute amount of silica (0.007 wt %), potentially enabling direct compression tableting and aiding manufacturing of other forms of solid dosing.