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The downstream processability of Hot Melt Extrusion (HME) Amorphous Solid Dispersions (ASD), an underexplored topic of importance, was assessed through a multi-faceted particle engineering approach. Extrudates, comprised of griseofulvin (GF), a model poorly water-soluble drug, and hydroxypropyl cellulose (HPC), were prepared at four drug concentrations and three HME temperature profiles to yield cases with and without residual crystallinity and subsequently milled to five sieve cuts ranging from < 45 μm to 355 – 500 μm. Solid state characterization was performed with XRPD, FT-IR, and TGA. Particle scale properties of the milled extrudates were evaluated including particle size, density, surface energy, and morphologies imaged via SEM. It was observed that regardless of sieve cut size, drug concentration and HME conditions impacted the flowability trends, quantified via Flow Function Coefficient (FFC) and bulk density. As a novelty, the effects of various process parameters and drug loadings were consolidated into a dimensionless interparticle cohesion measure, granular Bond Number (Bog), to better correlate them with bulk powder properties. The significant contrast in particle morphologies, particle size, and densities among selected cases demonstrated that particle size alone should not be the sole consideration when correlating particle scale to bulk powder scale properties of milled extrudates. Instead, the HME temperature profile and ASD drug loading may be more suitable parameters affecting the bulk powder properties of the milled extrudates. 

The possibility of attaining direct compression (DC) tableting using silica coated fine particle sized excipients was examined for high drug loaded (DL) binary blends of APIs. Three APIs, very-cohesive micronized acetaminophen (mAPAP, 7 μm), cohesive acetaminophen (cAPAP, 23 μm), and easy-flowing ibuprofen (IBU, 53 μm), were selected. High DL (60 wt%) binary blends were prepared with different fine-milled MCC-based excipients (ranging 20- 37 μm) with or without A200 silica coating during milling. The blend flowability (flow function coefficient −FFC) and bulk density (BD) of the blends for all three APIs were significantly improved by 1 wt% A200 dry coated MCCs; reaching FFC of 4.28 from 2.14, 7.82 from 2.96, and > 10 from 5.57, for mAPAP, cAPAP, and IBU blends, respectively, compared to the uncoated MCC blends. No negative impact was observed on the tablet tensile strength (TS) by using dry coated MCCs despite lower surface energy of silica. Instead, the desired tablet TS levels were reached or exceeded, even above that for the blends with uncoated milled MCCs. The novelty here is that milled and silica coated fine MCCs could promote DC tableting for cAPAP and IBU blends at 60 wt% DL through adequate flowability and tensile strength, without having to dry coat the APIs. The effect of the silica amount was investigated, indicating lesser had a positive impact on TS, whereas the higher amount had a positive impact on flowability. Thus, the finer excipient size and silica amounts may be adjusted to potentially attain blend DC processability for high DL blends of fine APIs. 

Predictive selection of silica size, type (hydrophobic/hydrophilic), and amount is addressed for achieving significant property enhancements of fine active pharmaceutical ingredients (APIs). Four models, Chen’s multiasperity particle-adhesion, total surface energy-based guest-host compatibility, dispersive surface energy-based tablet tensile strength, and stick-bounce-based silica aggregation on coated particles, are invoked. The impact on the bulk properties of four APIs cohesive API powders (~10 μm) and 40 wt% (wt%) blends of one API, drycoated at 50% and 100% surface area coverage (SAC) of four nano-silicas (7–20 nm), hydrophobic (R972P), hydrophilic (M5P, A200, A300) is assessed. Significant enhancements in flowability, bulk density, compactability, agglomeration reduction, and dissolution for API or blend are achieved with all silicas. The experimental and model-based outcomes demonstrate that silica performance is impacted by multiple factors, silica size and coating effectiveness being most critical. In conclusion, R972P and A200 at lower 50% SAC present two excellent choices. 

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.