Assessing processability of milled HME extrudates: Consolidating the effect of extrusion temperature, drug loading, and particle size via Non-dimensional cohesion.

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.

Impact of dry coating lactose as a brittle excipient on multi-component blend processability.

Previous work demonstrated the benefits of dry coating fine-grade microcrystalline cellulose (MCC) for enabling direct compression (DC), a favored tablet manufacturing method, due to enhanced flowability while retaining good compactability of placebo and binary blends of cohesive APIs. Here, fine brittle excipients, Pharmatose 450 (P450, 19 μm) and Pharmatose 350 (P350, 29 μm), having both poor flowability and compactability are dry coated with silica A200 or R972P to assess DC capability of multi-component cohesive API (coarse acetaminophen, 22 μm, and ibuprofen50, 47 μm) blends. Dry coated P450 and P350 not only attained excellent flowability and high bulk density but also heightened tensile strength hence processability, which contrasts with reported reduction for dry coated ductile MCC.

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).

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

This paper considers two fine-sized (d ∼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).

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.

Preparation of Free-Flowing Spray-Dried Amorphous Composites Using Neusilin.

A highly porous additive, Neusilin, with high adsorption capability is investigated to improve bulk properties, hence processability of spray-dried amorphous solid dispersions (ASDs). Griseofulvin (GF) is applied as a model BCS class 2 drug in ASDs. Two grades of Neusilin, US2 (coarser) and UFL2 (finer), were used as additives to produce spray-dried amorphous composite (AC) powders, and their performance was compared with the resulting ASDs without added Neusilin.

Dose Titration of Solid Dosage Forms via FDM 3D-Printed Mini-Tablets.

The robustness of 3D-printed mini-tablets as a platform to administer milligram dosages, intended for age-specific therapy, without the need of tablet splitting while maintaining similar release profiles, was investigated. Griseofulvin, as a model poorly water-soluble drug, and hydroxypropyl cellulose along with Kollicoat Protect as polymers were used to prepare filaments at 1-20% drug concentrations via hot-melt extrusion (HME). Higher drug concentrations served for testing the feasibility of a reduced number of mini-tablets to be administered.

Hydrogel-Embedded Poly(Lactic--Glycolic Acid) Microspheres for the Delivery of hMSC-Derived Exosomes to Promote Bioactive Annulus Fibrosus Repair.

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.

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.

Decoding Fine API Agglomeration as a Key Indicator of Powder Flowability and Dissolution: Impact of Particle Engineering.

Purpose: Fine API agglomeration and its mitigation via particle engineering, i.e., dry coating, remains underexplored.

Enhanced Supersaturation via Fusion-Assisted Amorphization during FDM 3D Printing of Crystalline Poorly Soluble Drug Loaded Filaments.

Filaments loaded with griseofulvin (GF), a model poorly water-soluble drug, were prepared and used for 3D printing via fused deposition modeling (FDM). GF was selected due to its high melting temperature, enabling lower temperature hot-melt extrusion (HME) keeping GF largely crystalline in the filaments, which could help mitigate the disadvantages of high HME processing temperatures such as filament quality, important for printability and the adverse effects of GF recrystallization on tablet properties. Novel aspects include single-step fusion-assisted ASDs generation during FDM 3D printing and examining the impact of tablet surface areas (SA) through printing multi-mini and square-pattern perforated tablets to further enhance drug supersaturation during dissolution.

Impact of altered hydrophobicity and reduced agglomeration on dissolution of micronized poorly water-soluble drug powders after dry coating.

The impact of dry coating with hydrophobic or hydrophilic nano-silica at 25-100% surface area coverage on dissolution of micronized poorly water-soluble drugs was investigated by examining their agglomeration and surface hydrophobicity. Ibuprofen (20 µm and 10 µm) and griseofulvin (10 µm) were selected having differing solubility, hydrophobicity, and surface morphology. Characterization involved particle agglomeration via two dry dispersion methods, drug dissolution using the USP IV method, cohesion reduction through shear testing, and powder wettability via the modified Washburn method.

Impact of Mixing on Content Uniformity of Thin Polymer Films Containing Drug Micro-Doses.

The impact of mixer type and critical process parameters (CPPs) on critical quality attributes (CQAs), including the drug content uniformity (CU) of slurry-cast polymer films loaded with micro-sized poorly water-soluble drugs were investigated. Previously untested hypothesis was that the best mixer at suitable CPPs promotes uniform drug dispersion within film precursors leading to acceptable dried-film CU at low, ~0.6 wt% drug concentrations.

Exploring tablet design options for tailoring drug release and dose via fused deposition modeling (FDM) 3D printing.

The aim of this paper was to explore tablet design options for FDM 3D printing for simultaneous tailoring of drug release and dose. The drug, griseofulvin (GF), the polymer, hydroxypropyl cellulose (HPC), and processing temperatures were selected to avoid confounding effects arising from drug-polymer interactions. Filaments containing 0-30 wt% GF were prepared using a twin-screw extruder.

Effect of solvents and cellulosic polymers on quality attributes of films loaded with a poorly water-soluble drug.

The combined effect of solvent, cellulosic polymer, and a poorly water-soluble drug, fenofibrate (FNB) on solution-cast pharmaceutical film quality attributes, e.g., morphology, drug recrystallization, content uniformity, mechanical properties, dissolution rate and supersaturation level, was investigated.

Fine grade engineered microcrystalline cellulose excipients for direct compaction: Assessing suitability of different dry coating processes.

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.

Fenofibrate Nanocrystal Composite Microparticles for Intestine-Specific Oral Drug Delivery System.

Hydrophobic drug nanocrystals (NCs) manufactured by particle engineering have been extensively investigated for enhanced oral bioavailability and therapeutic effectiveness. However, there are significant drawbacks, including fast dissolution of the nanocrystals in the gastric environment, leading to physicochemical instability. To solves this issue, we developed an innovative technique that involves the encapsulation of nanocrystals in composite spherical microparticles (NCSMs).

A predictive transport model for convective drying of polymer strip films loaded with a BCS Class II drug.

Drying is an important unit operation in the manufacturing of polymer strip films as it affects various film quality attributes. Optimal design and control of convective drying process require models that capture the impact of critical process parameters such as air temperature and velocity on the temporal evolution of film thickness and moisture. Here, a detailed transport model was presented to capture moisture diffusion, heat transfer and moving boundary in convective drying of polymer strip films loaded with griseofulvin (GF), a poorly water-soluble drug.

Convective Drying Kinetics of Polymer Strip Films Loaded with a BCS Class II Drug.

Polymer strip film is a promising dosage form for oral delivery of poorly water-soluble drugs. Drying is an important step in the production of polymer strip films with significant effects on critical quality attributes (CQAs). In this study, a custom-made batch drying setup was used to study convective drying kinetics of wet polymer strip films loaded with dry-coated micronized griseofulvin (GF) at various drying conditions.

Surface engineered excipients: III. Facilitating direct compaction tableting of binary blends containing fine cohesive poorly-compactable APIs.

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.

Effect of Particle Size and Polymer Loading on Dissolution Behavior of Amorphous Griseofulvin Powder.

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.

Bioavailability Enhancement of Poorly Water-Soluble Drugs via Nanocomposites: Formulation⁻Processing Aspects and Challenges.

Drug nanoparticles embedded in a dispersant matrix as a secondary phase, i.e., drug-laden nanocomposites, offer a versatile delivery platform for enhancing the dissolution rate and bioavailability of poorly water-soluble drugs.

Sustained Release of Poorly Water-Soluble Drug from Hydrophilic Polymeric Film Sandwiched Between Hydrophobic Layers.

This proof-of-concept study explores the feasibility of using a drug-loaded hydrophilic polymeric layer sandwiched between two hydrophobic layers for improving film drug load while achieving sustained release of poorly water-soluble drug. Such films having total thickness in range ~ 146-250 μm were prepared by slurry-based casting using hydrophilic hydroxypropyl methylcellulose (HPMC) as matrix layer containing fenofibrate (FNB) as the model drug, encased between two very thin rate-limiting layers of 10 μm each of hydrophobic poly-ɛ-caprolactone (PCL). Film precursor slurry consisted of HPMC with plasticizer and water along with micronized FNB powders, which were dry-coated with hydrophilic silica.

Surface engineered excipients: II. Simultaneous milling and dry coating for preparation of fine-grade microcrystalline cellulose with enhanced properties.

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.