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.

The effects of processing intensity, time and particle surface energy on mixing of binary cohesive blends (size ratio 1:2, fine concentration at 10 %) in high intensity vibration system were investigated via DEM simulations. Results show that both increasing processing intensity from 50 to 100 Gs and reducing surface energy from 50 to 0.5 J/m2 lead to a faster mixing rate. Mixing Bond number (〖Bo〗_m) was introduced to capture the effective mixing rate, Rm; higher 〖Bo〗_m corresponding to lower mixing rate. The coefficient of variation, Cv, formed the basis for the mixing quality and Rm, while the mixing action is quantified by the product of Rm and mixing time (Pr,t). Simulation results show that Cv values drop initially, and then rise with Pr,t. Hence, low Pr,t indicates inadequate mixing intensity, while high Pr,t most likely indicates mixture segregation, and therefore too high or too low Pr,t values should be avoided.

This paper presents a review of our key advances in model-guided dry coating-based enhancements of poor flow and packing of fine cohesive powders. The existing van der Waals force-based particle -contact models are reviewed to elucidate the main mechanism of flow enhancement through silica dry coating. Our multi-asperity model explains the effect of the amount of silica, insufficient flowability enhancements through conventional blending, and the predominant effect of particle surface roughness on cohesion reduction. Models are presented for the determination of the amount and type of guest par-ticles, and estimation of the granular Bond number, used for cohesion nondimensionalization, based on particle size, particle density, asperity size, surface area coverage, and dispersive surface energy. Selection of the processing conditions for LabRAM, a benchmarking device, is presented followed by key examples of enhancements of flow, packing, agglomeration, and dissolution through the dry coating. Powder agglomeration is shown as a screening indicator of powder flowability. The mixing synergy is identified as a cause for enhanced blend flowability with a minor dry coated constituent at silica < 0.01%. The anal-ysis and outcomes presented in this paper are intended to demonstrate the importance of dry coating as an essential tool for industry practitioners.(c) 2022 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.

Objective Intervertebral disk degeneration is a prevalent postoperative complication after discectomy, underscoring the need to develop preventative and bioactive treatment strategies that decelerate degeneration and seal annulus fibrosus (AF) defects. Human mesenchymal stem cell–derived exosomes (MSC-Exos) hold promise for cell-free bioactive repair; however, their ability to promote AF repair is poorly understood. The objective of this study was to evaluate the ability of MSC-Exos to promote endogenous AF repair processes and integrate MSC-Exos within a biomaterial delivery system. Design We characterize biophysical and biochemical properties of normoxic (Nx) and hypoxic (Hx) preconditioned MSC-Exos from young, healthy donors and examine their effects on AF cell proliferation, migration, and gene expression. We then integrate a poly(lactic- co-glycolic acid) microsphere (PLGA µSphere) delivery platform within an interpenetrating network hydrogel to facilitate sustained MSC-Exo delivery. Results Hx MSC-Exos led to a more robust response in AF cell proliferation and migration than Nx MSC-Exos and was selected for a downstream protection experiment. Hx MSC-Exos maintained a healthy AF cell phenotype under a TNFα challenge in vitro and attenuated catabolic responses. In all functional assays, AF cell responses were more sensitive to Hx MSC-Exos than Nx MSC-Exos. PLGA µSpheres released MSC-Exos over a clinically relevant timescale without affecting hydrogel modulus or pH upon initial embedment and µSphere degradation. Conclusions This MSC-Exo treatment strategy may offer benefits of stem cell therapy without the need for exogenous stem cell transplantation by stimulating cell proliferation, promoting cell migration, and protecting cells from the degenerative proinflammatory microenvironment.

Objective Intervertebral disk degeneration is a prevalent postoperative complication after discectomy, underscoring the need to develop preventative and bioactive treatment strategies that decelerate degeneration and seal annulus fibrosus (AF) defects. Human mesenchymal stem cell–derived exosomes (MSC-Exos) hold promise for cell-free bioactive repair; however, their ability to promote AF repair is poorly understood. The objective of this study was to evaluate the ability of MSC-Exos to promote endogenous AF repair processes and integrate MSC-Exos within a biomaterial delivery system. Design We characterize biophysical and biochemical properties of normoxic (Nx) and hypoxic (Hx) preconditioned MSC-Exos from young, healthy donors and examine their effects on AF cell proliferation, migration, and gene expression. We then integrate a poly(lactic- co -glycolic acid) microsphere (PLGA µSphere) delivery platform within an interpenetrating network hydrogel to facilitate sustained MSC-Exo delivery. Results Hx MSC-Exos led to a more robust response in AF cell proliferation and migration than Nx MSC-Exos and was selected for a downstream protection experiment. Hx MSC-Exos maintained a healthy AF cell phenotype under a TNFα challenge in vitro and attenuated catabolic responses. In all functional assays, AF cell responses were more sensitive to Hx MSC-Exos than Nx MSC-Exos. PLGA µSpheres released MSC-Exos over a clinically relevant timescale without affecting hydrogel modulus or pH upon initial embedment and µSphere degradation. Conclusions This MSC-Exo treatment strategy may offer benefits of stem cell therapy without the need for exogenous stem cell transplantation by stimulating cell proliferation, promoting cell migration, and protecting cells from the degenerative proinflammatory microenvironment. Keywords intervertebral disk , hydrogels , extracellular vesicles , exosomes , drug delivery

Ability to predict the porosity, and its reduction after nano-silica dry coating, based on the Bond number and cohesion force estimated via multi-asperity contact model was examined for twenty different pharmaceutical powders. A new model for first order estimates of bulk density improvements after dry coating was found to be reasonably predictive despite variations in size (10-225 mu m), particle size distribution, aspect ratios (1-3.5), material density, and dispersive surface energy. For the porosity prediction model based on Bond numbers, Microcrystalline Cellulose (MCC) excipients were outliers, regardless of size (20-200 mu m). Analysis of their shape, surface morphology and specific surface areas (SSA), indicated that compared to other powders, MCCs had the highest SSA compared to equivalent spheres and high macro-roughness, while having high aspect ratios. This unique characteristic made them effectively more cohesive leading to their poor packing independent of their size, which is in line with previous simulations. (C) 2020 Elsevier B.V. All rights reserved.

The effects of material stiffness, host and guest particle sizes, and mixing intensity on dry coating quality were investigated using a high-intensity vibrational mixer, using KCl, cornstarch, aluminum silicate and nano-sized silica. The coating quality deteriorated with larger guest particle size at high process intensity, and high material stiffness. Coarse guest particles detached from host particles above certain mixing intensity, indicating higher intensity is not recommended; e.g., the best coating quality for cornstarch was for medium-sized hosts below 30 Gs intensity. However, for nano-silica guests, higher processing intensity did not lead to their detachment, but decreased their agglomeration. Such behavior was explained using the energy-based stick/bounce model and two indices. The coating quality index (Kc), the ratio of total detachment energy to relative kinetic energy, assessed the guest particle attachment tendency. The deagglomeration index (Kd), the ratio of deagglomeration energy to relative kinetic energy, assessed the guest particle agglomeration tendency.

Recent work showed that contrary to conventional wisdom, fine surface engineered excipients outperform their larger counterparts in blends of highly loaded blends of cohesive drug powders in terms of their packing, flowability and tablet tensile strength. Here, two continuous devices, fluid-energy mill (FEM) and conical mill (Comil), are compared with LabRAM, a batch device used in previous work, for nano-silica dry coating of microcrystalline cellulose (MCC) excipients, 20 and 30 μm. Coated MCCs from all three devices had higher bulk densities and flow function coefficients (FFCs) compared with Avicel PH-102. Silica coating quality was best with LabRAM, but also good with FEM and Comil, although Comil was less effective for the finer MCC. However, the better coating quality of LabRAM had a downside of having poorer compaction properties. The most surprising outcome was that multi-component blends of 17 wt% coated MCC with 60 wt % Ibuprofen 50 had higher bulk density, higher or similar flowability, higher tablet tensile strength, and comparable Ibuprofen dissolution from tablets, compared to those with Prosolv 50, a silicified excipient. The FEM dry coated MCC blends, having only 0.17 wt% silica, performed the best, having desirable bulk density, FFC, and tensile strength that could facilitate high-speed direct compression tableting. In summary, considering that achieving best coating quality need not be the primary objective, FEM may be the best option for producing desired sized dry coated fine excipients.

Direct compaction tableting, a desired manufacturing option, is infeasible for blends containing fine cohesive poorly-compactable APIs at higher drug loadings. In this study, the feasibility of using fine, dry coated excipients is investigated instead of dry coating of the APIs, as was done previously. Avicel PH-105 (20.1 µm) dry coated with 1 wt% hydrophilic silica A200 as an engineered excipient was blended with fine (11.3 µm) or semi-fine (30.2 µm) Acetaminophen, or Ibuprofen 50 (55.4 µm) in binary blends at low, medium and high drug loadings (10%, 30%, 60%). The blend uniformity, bulk density, flowability, as well as tablet properties such as friability, weight variation and strength demonstrate overall better performance compared to blends with Avicel PH-105, Prosolv 50 or Prosolv 90 as the excipient. These results along with processability maps of bulk density vs. FFC and tablet tensile strength vs. FFC indicate dry coated Avicel PH-105 could enable direct compaction for IBU50 and cAPAP at all drug loadings, and up to 30% drug loading for mAPAP. In contrast, Prosolv 90 failed for IBU50 at 60% drug loading, and for mAPAP at all drug loadings. Prosolv 50 could only enable direct compaction for IBU50 at all drug loadings. These unexpected outcomes suggest that for direct compaction of very fine, cohesive APIs at higher drug loadings, surface modified fine excipients perform better. A surprising outcome is the improvement in tablet strength for blends with dry coated Avicel PH-105 compared to uncoated Avicel PH-105 at higher drug loading, especially considering parts I and II showed that silica dry coating decreases the placebo tablet tensile strength.

The effect of particle size on the dissolution behavior of the particles of amorphous solid dispersions (ASDs) of griseofulvin (GF), with 0%-50% Kollidon® VA 64 as a crystallization inhibitor is investigated. Both the final dissolved GF concentration and the dissolution rate of GF ASDs were found to be inversely proportional to the particle size. The solution concentrations for the smallest (45-75 μm) size group with different polymer loadings were significantly higher than those for the largest (250-355 μm) group regardless of the initial GF amount. Specifically, the dissolution rate of GF ASDs with 50% polymer loading for the finest group was 2.7 times higher than for the largest group under supersaturating conditions. The rates of dissolution and recrystallization were assessed through surface concentration (Cs) and Avrami recrystallization rate kinetics, where the solid-state recrystallization was confirmed using Raman spectroscopy. Outcomes indicated that particle size reduction enhanced ASD drug loading by reducing the amount of polymer necessary as finest size ASDs initially dissolve faster, negating their higher recrystallization rate. Kollidon® VA 64 at 30% loading was sufficient to inhibit the GF recrystallization. Overall, the combination of particle size reduction and recrystallization inhibition is effective for improved dissolution behavior of GF ASDs.

A solventless process for simultaneously milling and dry coating microcrystalline cellulose (MCC) was investigated for producing fine excipients in five different sizes (∼20, 25, 30, 35, 40 µm) having high bulk density (BD), good flow function coefficient (FFC), and excellent compaction. Avicel PH-102, used as the starting material, was milled and coated with two grades of silicas, hydrophobic and hydrophilic (R972P and A200), using a fluid energy mill (FEM). Through judicious selection of the FEM feed rate, feeding pressure, and grinding pressure, five desired milled sizes were produced. The bulk density of all the milled-coated (1 wt% A200) excipients was significantly better than uncoated-milled MCC, Avicel PH-102, and Prosolv 50 and 90. Whereas the FFC values were greater than uncoated-milled MCC, Avicel PH-102, and Prosolv 50 (latter for ∼30, 35, and 40 µm sizes). The tablet compaction testing was used to evaluate compactibility (tensile strength vs tablet porosity), compressibility (tablet porosity vs compaction pressure), and tabletibility (tensile strength vs compaction pressure). The results indicate that all finer grade milled and A200 coated MCC had lower porosity and higher tablet strengths than Prosolv 50 and 90 at all compaction pressures. Surprisingly, the BD and FFC were better for A200 than for R972P coated-milled MCCs; explained through analyzing inter-particle contact models. Finally, milling did not increase the moisture content but coating with silica led to a slight increase; A200 higher than R972P. It is hoped that these engineered excipients would help formulators with a multitude of options for finer excipients without loss of flow and bulk density.

Dispersion of ultrafine powders is difficult due to their high cohesion and consequent agglomeration. Dry coating with additives such as nano-silica, magnesium stearate (MgSt), or Leucine (Leu), an amino acid, may help mitigate this problem. Unfortunately, when the powders to be coated are very fine, the additives such as MgSt or Leu need to be of even finer size, requiring a separate milling process. Here, a two-step co-milling process is investigated to produce well dispersible inhalable size range (<5 mu m) particles. The main advantage is that the powder to be coated and additives have starting size of several hundred microns and do not require separate pre-milling. In the first step, Potassium Chloride (KCl), used as a surrogate API, and Leu are pre-milled in a ball mill to achieve KCl coated with Leu of similar to 10 mu m. In the second step, simultaneous co-milling via jet-milling of pre-coated KCl down to inhalable size KCl, coated with Leu is done. The dispersibility of coated KCl was assessed through laser diffraction of dry powder at low dispersion pressure (Sympatec Rodos-Helos), corroborated via scanning electron microscopy (SEM), and FT4 powder tester measuring flow function coefficient (FFC), conditioned bulk density, and aerated energy. This assessment revealed that about 2 wt% Leu was adequate to provide best overall dispersibility. The dispersibility of milled KCl after coating with Leu was found to be better compared with uncoated and MgSt or nano-silica coated KCl. Overall, this two-step co-milling of KCl with 2 wt% Leu yielded well-dispersible, <5 mu m particles from starting particles of two orders of magnitude larger sizes. (C) 2018 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.

Although strip films are a promising platform for delivery of poorly water-soluble drug particles via slurry casting, the effect of critical material attributes, for example, superdisintegrants (SDIs) on critical quality attributes, including film disintegration time (DT), remains underexplored. A 2-level factorial design is considered to examine the impact of the SDI type (sodium starch glycolate and croscarmellose sodium), their amount, and film thickness. SDIs were used with hydroxypropyl methylcellulose (E15LV) and glycerin solutions along with viscosity matching. Fenofibrate, a model poorly water-soluble drug, was micronized and surface modified via fluid energy milling. Significant decreases in film DT, measured using 3 different methods, were observed due to the addition of SDIs. Percentage reduction in DT was a strong function of SDI amount, and thinner films disintegrated faster. Films with either higher SDI concentrations (>9%) or films under 80 μm, exhibited fast DT (<180 s, European Pharmacopeia). All thin films (50-60 μm) exhibited immediate release (>80% in 10 min). All films achieved good content uniformity, except for those with the lowest amount of SDI, attributed to insufficient viscosity and thickness nonuniformity due to the SDI. Finally, all films achieved adequate mechanical properties, notwithstanding minor negative impact of SDIs.

It has been shown that dry coating cohesive active pharmaceutical ingredients (APIs) with nano-silica can improve packing and flow of their blends, facilitating high speed direct compression tableting. This paper examines the broader scope and generality of previous work by examining three fine APIs; micronized Acetaminophen (mAPAP), coarse Acetaminophen (cAPAP) and micronized Ibuprofen (mIBU), and considers dry coating with both hydrophobic or hydrophilic nano-silica to examine the effect not only on packing density and flow of their blends, but also dissolution and tensile strength of their tablets. The impact of the excipient size on blend and tablet properties are also investigated, indicating blend flow is most improved when matching API particle size with excipient particle size. In all cases where the API is dry coated, the blend packing and flow improve, so as to suggest such high drug loaded blends could enable direct compression. Using dry coated API along with finer excipients in blends lead to improved hardness of the corresponding tablets. Interestingly, dissolution profiles show dry coated API tablets generally have faster dissolution rates, regardless of silica hydrophilicity, suggesting API powder deagglomeration via nano-silica coating plays a crucial role. The most significant conclusion is that, although there are differences in properties of blends that depend on the API, hydrophobic or hydrophilic nano-silica coating, as well as large or fine excipients, in all cases, dry coating of APIs significantly improves the possibility of using the specific blend at high drug loading in direct compression tableting.

Excipients with good flowability, bulk density as well as compaction properties are desired for use in tableting since they play important roles in formulation development and processing, including, handling, mixing, feeding and compaction. The objective of this paper is to examine the feasibility of using dry coating based surface modification of microcrystalline cellulose, Avicel PH-105, to produce an engineered fine grade (<30 μm) excipient that has all three desired properties. Using a material sparing high-intensity vibrational mixer, Avciel PH-105 is dry coated with 1 wt% Aerosil 200, selected due to its relatively higher dispersive surface energy and lower particle size amongst other silica choices. The results indicated that as expected, the bulk density and flowability are significantly improved, while there was an appreciable loss of compaction. To minimize the loss of compaction, attributed to decreased surface energy after coating, while maintaining improved bulk density and flowability, the effect of reduced silica amount was examined. Remarkably, at reduced levels (0.5 wt% to 0.7 wt%) of Aerosil 200, significant improvements in bulk density and flowability were attained with only 9%-12% compaction reduction. The properties of the surface-engineered excipients were compared with several other commercially available pharmaceutical excipients using two different processibility or regime maps; tablet tensile strength versus bulk density or flow function coefficient (FFC). The surface engineered excipients exhibited the best overall performance establishing a promising pathway to engineer excipients using dry processing instead of complex processes such as spray drying.

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.