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Electronic (e)-cigarettes have been marketed for more than a decade as an alternative to conventional cigarettes. Their popularity and use among adolescents have grown significantly during recent years. While e-cigarettes do not release carcinogenic aromatic hydrocarbons, they can generate reactive carbonyls and radicals during the heating process in vitro. Emphasis has been placed in recent studies to introduce more rigorous and physiologically relevant in vitro models to characterise the toxicological profile of e-cigarettes. However, significant challenges are present due to difficulties for the developed systems to fully represent the in vivo inhalation settings. Furthermore, research protocols that fail to simulate the characteristics of e-cigarettes can affect the findings of in vitro studies. This review will illustrate the status quo of e-cigarette assays in vitro, discussing the various cellular assays used for evaluating the safety profile of e-cigarettes. Future directions will also be provided to better assist the scientific community in interpreting the health risks of e-cigarettes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The management of respiratory diseases relies on the daily administration of multiple active pharmaceutical ingredients (APIs), leading to a lack of patient compliance and impaired quality of life. The frequency and dosage of the APIs result in increased side effects that further worsens the overall patient condition. Here, the manufacture of polymer-polymer core-shell microparticles for the sequential delivery of multiple APIs by inhalation delivery is reported. The microparticles, composed of biodegradable polymers silk fibroin (shell) and poly(L-lactic acid) (core), incorporating ciprofloxacin in the silk layer and ibuprofen (PLLA core) as the antibiotic and anti-inflammatory model APIs, respectively. The polymer-polymer core-shell structure and the spatial distribution of the APIs have been characterized using cutting-edge synchrotron macro ATR-FTIR technique, which was correlated with the respective API sequential release profiles. The APIs microparticles had a suitable size and aerosol properties for inhalation therapies (≤4.94 ± 0.21μm), with low cytotoxicity and immunogenicity in healthy lung epithelial cells. The APIs compartmentalization obtained by the microparticles not only could inhibit potential actives interactions but can provide modulation of the APIs release profiles via an inhalable single administration., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Simvastatin (SV) is widely used as a lipid-lowering medication that has also been found to have beneficial immunomodulatory effects for treatment of chronic lung diseases. Although its anti-inflammatory activity has been investigated, its underlying mechanisms have not yet been clearly elucidated. In this study, the anti-inflammatory and antioxidant effects and mechanism of simvastatin nanoparticles (SV-NPs) on lipopolysaccharide-stimulated alveolar macrophages (AMs) NR8383 cells were investigated. Quantitative cellular uptake of SV-NPs, the production of inflammatory mediators (interleukin-6, tumor necrosis factor, and monocyte chemoattractant protein-1), and oxidative stress (nitric oxide) were tested. Furthermore, the involvement of the nuclear factor κB (NF-κB) signaling pathway in activation of inflammation in AMs and the efficacy of SV were visualized using immunofluorescence. Results indicated that SV-NPs exhibit a potent inhibitory effect on nitric oxide production and secretion of inflammatory cytokine in inflamed AM, without affecting cell viability. The enhanced anti-inflammatory activity of SV-NPs is likely due to SV-improved chemical-physical stability and higher cellular uptake into AM. The study also indicates that SV targets the inflammatory and oxidative response of AM, through inactivation of the NF-κB signaling pathway, supporting the pharmacological basis of SV for treatment of chronic inflammatory lung diseases., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The use of computational fluid dynamics (CFD) to model and predict surgical outcomes in the nasal cavity is becoming increasingly popular. Despite a number of well-known nasal segmentation methods being available, there is currently a lack of an automated, CFD targeted segmentation framework to reliably compute accurate patient-specific nasal models. This paper demonstrates the potential of a robust nasal cavity segmentation framework to automatically segment and produce nasal models for CFD. The framework was evaluated on a clinical dataset of 30 head Computer Tomography (CT) scans, and the outputs of the segmented nasal models were further compared with ground truth models in CFD simulations on pressure drop and particle deposition efficiency. The developed framework achieved a segmentation accuracy of 90.9 DSC, and an average distance error of 0.3 mm. Preliminary CFD simulations revealed similar outcomes between using ground truth and segmented models. Additional analysis still needs to be conducted to verify the accuracy of using segmented models for CFD purposes., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

The pathogenesis and progression of several lung disorders is propagated by inflammatory and oxidative processes, which can be controlled by adjunctive inhaled therapies. The present study aimed to develop an inhalable dry powder formulation consisting of co-spray-dried urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate (SD HA-CL-SAP), a novel combination which was recently shown to possess anti-inflammatory, antioxidant, and wound healing properties. Native HA and SAP were co-spray dried (SD HA-SAP) and evaluated as control formulation. Yield (Y%) and encapsulation efficiency (EE%) were 67.0 ± 4.8% and 75.5 ± 7.2% for SD HA-SAP, 70.0 ± 1.5% and 66.5 ± 5.7% for SD HA-CL-SAP, respectively. Both formulations were shown to be suitable for lung delivery in terms of morphology, particle size (median volumetric diameter ∼ 3.4 μm), physical and thermal stability, in vitro aerosol performance - respirable fraction: 30.5 ± 0.7% for SD HA-SAP and 35.3 ± 0.3% for SD HA-CL-SAP. SAP release was investigated using Franz cells and air-interface Calu-3 cell model (>90% of SAP transported within 4 h). The innovative SD HA-CL-SAP formulation holds potential as inhalable dry powder for the treatment of inflammatory lung disorders., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is partly characterized as epithelial-mesenchymal transition (EMT)-related airflow limitation. Extracellular vesicles (EVs) play crucial roles in the crosstalk between cells, affecting many diseases including COPD. Up to now, the roles of EVs in COPD are still debated. As we found in this investigation, COPD patients have higher miR-21 level in total serum EVs. EMT occurs in lungs of COPD mice. Furthermore, bronchial epithelial cells (BEAS-2B) could generate EVs with less miR-21 when treated with cigarette smoke extract (CSE), impacting less on the M2-directed macrophage polarization than the control-EVs (PBS-treated) according to EVs miR-21 level. Furthermore, the EMT processes in BEAS-2B cells were enhanced with the M2 macrophages proportion when co-cultured. Collectively, these results demonstrate that CSE-treated BEAS-2B cells could alleviate M2 macrophages polarization by modulated EVs, and eventually relieve the EMT process of BEAS-2B cells themselves under COPD pathogenesis, revealing a novel compensatory role of them in COPD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study investigated how varying the dosing cup size of a novel reservoir dry powder inhaler (DPI) affects the detachment of a micronized active pharmaceutical ingredient from larger carrier particles, and the aerosol performance of a DPI carrier formulation. Three different-sized dosing cups were designed: 3D printed with cup volumes of 16.26 mm 3 , 55.99 mm 3 , and 133.04 mm 3 , and tested with five different carrier type formulations with beclomethasone dipropionate (BDP) concentrations between 1% and 30% (w/w). The morphology of the BDP attached to the carrier was investigated using scanning electron microscopy and the aerosol performance using the Next Generation Impactor. Increasing the volume of the dosing cup led to a reduction of BDP deposition in the Next Generation Impactor preseparator, and an increase in BDP detachment from the carrier was observed, leading to increased aerosol performance. The decreased amount of BDP attached to carrier after aerosolization was attributed to the increased dosing cup void volume. This may enable greater particle-particle and particle-wall collisions, with greater BDP detachment from the carrier and deagglomeration of smaller agglomerates. The dosing cup volume was observed to have significant influence on particle dispersion and the overall aerosol performance of a DPI., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The current study presents a new approach to tackle high-dose lung delivery using a prototype multibreath Orbital® dry powder inhaler (DPI). One of the key device components is the "puck" (aerosol sample chamber) with precision-engineered outlet orifice(s) that control the dosing rate. The influence of puck orifice geometry and number of orifices on the performance of mannitol aerosols were studied. Pucks with different orifice configurations were filled with 400 mg of spray-dried mannitol and tested in the Orbital® DPI prototype. The emitted dose and overall aerodynamic performance across a number of "breaths" were studied using a multistage liquid impinger. The aerosol performances of the individual actuations were investigated using in-line laser diffraction. The emptying rate of all pucks was linear between 20% and 80% cumulative drug released (R(2) > 0.98), and the amount of formulation released per breath could be controlled such that the device was empty after 2 to 11 breath maneuvers. The puck-emptying rate linearly related to the orifice hole length (R(2) > 0.95). Mass median aerodynamic diameters of the emitted aerosol ranged from 4.03 to 4.62 μm and fine particle fraction (≤6.4 μm) were 50%-66%. Laser diffraction suggested that the aerosol performance and emptying rates were not dependent on breath number, showing consistent size distribution profiles., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Recent murine studies found that rifapentine, dosed daily, at least halved tuberculosis treatment times compared with standard rifampicin and isoniazid-containing regimens. However, in humans, an inhalable form of rifapentine may be necessary to considerably shorten treatment duration because of the physiological barriers associated with oral therapy. The current study compares two inhalable rifapentine dry powders-a novel pure crystalline form and an amorphous form-by a series of in vitro tests. The crystalline and amorphous powders had a mass median aerodynamic size of 1.68 ± 0.03 and 1.92 ± 0.01 μm, respectively, associated with a fine particle fraction of 83.2 ± 1.2% and 68.8 ± 2.1%, respectively. A quinone degradation product was identified in the amorphous powder stored for 1 month, whereas the crystalline form remained chemically stable after storage at both 0% and 60% relative humidity, 25°C, for at least 3 months. Solubilized rifapentine was well tolerated by pulmonary tissue and macrophage cells up to approximately 50 μM. The accumulation of rifapentine within alveolar macrophage cells was significantly higher than for rifampicin, indicating enhanced delivery to infected macrophages. The novel inhalable crystalline form of rifapentine is suitable for targeted treatment of tuberculosis infection and may radically shorten treatment duration., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

The aim of the present study was to develop controlled release inhalable lipid microparticles (LMs) loaded with the antioxidant flavonoid, quercetin and to investigate the interaction of these microparticles with A549 pulmonary alveolar epithelial cells. The LMs were produced using different lipidic materials and surfactants, by melt emulsification followed by a sonication step. The most efficient modulation of the in vitro release of quercetin was achieved by the LMs prepared with tristearin and hydrogenated phosphatidylcholine, which were used for subsequent studies. These LMs exhibited a quercetin loading of 11.8±0.3%, and a volume median diameter, determined by laser diffraction, of 4.1±0.2μm. Moreover, their mass median aerodynamic diameter (4.82±0.15μm) and fine particle fraction (27.2±3.9%), as measured by multi-stage liquid impinger, were suitable for pulmonary delivery. Quercetin was found to be highly unstable (complete decomposition within 6-h incubation) in Ham's F-12 medium used for A549 cell culture. Degradation was markedly reduced (16.4% of the initial quercetin content still present after 24-h incubation) after encapsulation in the lipid particle system. Viability studies performed by lactate dehydrogenase assay, demonstrated that quercetin LMs showed no significant cytotoxicity on the A549 cells, over the concentration 0.1-5μM. The uptake of quercetin by the A549 lung alveolar cells was also investigated. After 4-h incubation, the accumulation of quercetin in the A549 cells was significantly higher (2.3-fold increase) for the microparticle entrapped flavonoid when compare to non-encapsulated quercetin. The enhanced intracellular delivery of quercetin achieved by the LMs is likely due to the flavonoid stabilization after encapsulation., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Two combination dry powder inhalation formulations were engineered via spray drying and co-spray drying salbutamol base (SB) and beclomethasone dipropionate (BDP). The aerosol performances of the individual drugs, a physical mix and the co-spray-dried particle systems were investigated after blending with conventional lactose carrier, under realistic dose regimes. Furthermore, each system was evaluated in terms of the physicochemical properties and via high-throughput Raman microscopy (to study co-association and deposition patterns after in vitro aerosolisation studies). In general, analysis of the aerosol performance (measured using a next-generation impactor) of the single drug and physical mix formulations suggested that SB and BDP have significantly different stage-deposition profiles. Such observations were further substantiated by scanning electron microscopy, where SB-BDP agglomeration could be observed in the physical mix. Stage deposition from the SB-BDP co-spray-dried powders were different than that for the physical mix, wherein the amount of SB and BDP on each stage was equivalent; suggesting that the two drugs could be targeted and deposited at the same location on the lung epithelia. Raman microscopy of the physical mix and co-spray-dried formulations also confirmed the differences in stage deposition between formulations and co-localised deposition for the co-spray-dried formulation., (Copyright © 2012 Wiley Periodicals, Inc.)

Although there have been published electrostatic characterisation studies of drug-only Turbuhaler® and lactose carrier-drug formulations, there has not been an investigation into spheronised agglomerates containing micronised lactose and eformoterol, such as in Oxis® Turbuhaler®. Ten doses of Oxis® (12 µ g eformoterol) were dispersed into an electrical next generation impactor (eNGI) in a single run, and runs were conducted in triplicate to determine the aerosol performance and aerosol charge distribution at flow rates of 30, 60 and 90 L/min. Eformoterol fine particle fraction (FPF) reached a maximum of 50%-60% at 60 and 90 L/min, whereas lactose FPF increased from 31% to 42% when flow rate was increased from 30 to 90 L/min. Specific net charge (C/µ g) within the eNGI stages increased from 30 to 60 L/min, but then decreased at 90 L/min. These results were attributed to the shift in balance between surface charging after interparticle and particle-surface collision (dominant at 30 and 60 L/min) and charge separation after impact fragmentation of agglomerates (dominant at 90 L/min). However, the aerosol charge profiles do not suggest that electrostatic forces play a major role in the deposition of Oxis® Turbuhaler® dry powder formulation., (Copyright © 2011 Wiley-Liss, Inc.)

This study aimed to investigate the influence of grid structures on the break-up and aerosol performance of a model inhalation formulation through the use of standardised entrainment tubes in combination with computational fluid dynamics (CFD). A series of entrainment tubes with grid structures of different aperture size and wire diameters were designed in silico and constructed using three-dimensional printing. The flow characteristics were simulated using CFD, and the deposition and aerosol performance of a model agglomerate system (496.3-789.2 µm agglomerates containing 3.91 µm median diameter mannitol particles) were evaluated by chemical analysis and laser diffraction, respectively. Analysis of the mannitol recovery from the assembly indicated that mass deposition was primarily on the grid structure with little before or after the grid. Mass deposition was minimal down to 532 µm; however, for smaller grid apertures, significant blockage was observed at all airflow rates (60-140 L · min(-1)). Analysis of the particle size distribution exiting the impactor assembly suggested that mannitol aerosolisation was dependent on the void percentage of the grid structure. It is proposed that initial particle-grid impaction results in a shearing force causing agglomerate fragmentation followed by immediate re-entrainment into the turbulent airstream within the grid apertures which causes further dispersion of the fine particles. Such observations have significant implications in the design of dry powder inhaler devices., (Copyright © 2011 Wiley-Liss, Inc.)

Mucociliary clearance is compromised by airway surface liquid dehydration in respiratory disease states such as cystic fibrosis. Rehydration by hyperosmolar agents such as nebulised hypertonic saline and dry powder mannitol has demonstrated in vivo safety and efficacy for restoring mucociliary function. Mannitol, delivered as a nebulised formulation for this purpose, has not been investigated as yet. The current study examines the feasibility of delivering such a formulation using recent vibrating mesh technology. Nebulisation was conducted using an Aeroneb Go(TM) vibrating mesh nebuliser, and aerosol size was assessed by laser diffraction. Cascade impaction coupled with mass assay by high-performance liquid chromatography was used to confirm fluid uniformity and correlation with laser diffraction sizing. The following nebuliser formulations were prepared and aerosolised: deionised water, mannitol (150 mg/mL) aqueous solution, sodium chloride aqueous solution [0.2%, 1%, 3%, 5%, 7% (w/v)] and mannitol (150 mg/mL) in sodium chloride solution [0.2%, 1%, 3%, 7% (w/v)]. Mannitol aqueous solution was poorly nebulised, resulting in lengthy treatment times and large median droplet size. Addition of sodium chloride drastically improved nebuliser performance and aerosol characteristics. In vivo studies are necessary to confirm efficacy of nebulised mannitol. If substantiated, it could provide a pleasant-tasting alternative mucoactive agent with prolonged therapeutic action., (Copyright © 2011 Wiley-Liss, Inc. and the American Pharmacists Association)

This study utilised a combination of computational fluid dynamics (CFD) and standardised entrainment tubes to investigate the influence of impaction on the break-up and aerosol performance of a model inhalation formulation. A series of entrainment tubes, with different impaction plate angles were designed in silico and the flow characteristics, and particle tracks, were simulated using CFD. The apparatuses were constructed using three-dimensional printing. The deposition and aerosol performance of a model agglomerate system (496.3-789.2 μm agglomerates containing 3.91 μm median diameter mannitol particles) were evaluated by chemical analysis and laser diffraction, respectively. Analysis of the mannitol recovery from the assembly and CFD simulations indicated that mass deposition on the plate was dependent on the impactor angle (45°-90°) but independent of the airflow rate (60-140 L·min(-1)). In comparison, wall losses, perpendicular to the impactor plate were dependent on both the impactor angle and flow rate. Analysis of the particle size distribution exiting the impactor assembly suggested mannitol aerosolisation to be independent of impactor angle but dependent on the air velocity directly above the impactor plate. It is proposed that particle-wall impaction results in initial agglomerate fragmentation followed by reentrainment in the airstream above the impaction plate. Such observations have significant implications in the design of dry powder inhaler devices., (Copyright © 2011 Wiley-Liss, Inc. and the American Pharmacists Association)

To study if electrostatic charge initially present in mannitol powder plays a role in the generation of aerosols, mannitol was unipolarly charged to varying magnitudes by tumbling the powder inside containers of different materials. The resulting charge in the powder was consistent with predictions from the triboelectric charging theories, based on the work function values from literature and electron transfer tendencies from measurement of contact angle. The latter generated a parameter, gamma(-)/gamma+, which is a measure of the electron-donating capacity relative to the electron-accepting tendency of material. Lowering the work function value or increasing the gamma(-)/gamma+ ratio of the container material resulted in mannitol being more negatively charged, and vice versa. After charging, the powder was dispersed from an Aerolizer(R), at 30 and 60 L/min, to study the aerosol performance. Irrespective of the charge level, the powder showed similar fine particle fraction, emitted dose and device retention at a given flow rate, indicating that charge induced by different containers during tumbling does not play a significant role in mannitol powder aerosolisation.

A series of microparticle formulations, designed for controlled release pulmonary therapy, were evaluated in terms of their physical properties, aerosol performance, lung epithelial cell toxicity, and controlled release profile. A protein, bovine serum albumin (BSA) was chosen as a model macromolecule active ingredient which was coprocessed, using spray drying, with varying concentrations of the release modifier, polyvinyl alcohol (PVA). The spray dried microparticles were tested for their physico-chemical characteristics (e.g., size distribution, morphology and density), in vitro aerosolisation performance using a 5-stage Marple Miller Impactor (MMI) and in vitro release profiles by a custom-built diffusion cell (in 100 mL phosphate buffer pH 7.4). The toxicity of PVA on lung epithelial cells was investigated using a human alveolar basal epithelium A549 cell line. Analysis of the particle size data indicated that all the spray dried BSA/PVA samples had similar size distributions with a median particle diameter (d(0.5)) across all samples of 2.79 +/- 0.11 microm. All formulations had relatively good aerosolisation performance when compared to conventional dry powder inhalation (DPI) formulations although increasing PVA percentage had a negative effect on the aerosol performance in vitro. Analysis of the difference and similarity factors for the release profiles indicated significant differences with respect to PVA concentration. Furthermore, cell toxicity analysis indicated PVA to have limited effect on cell viability after 24 h exposure. A series of protein-based inhalation formulations have been developed and tested, and shown to be suitable for controlled release in the respiratory tract., (Copyright 2009 Wiley-Liss, Inc.)

The aim of this study was to assess the potential of delivering a combination antibiotic therapy, containing doxycycline and ciprofloxacin (both hydrochloride) as a dry powder (DPI) formulation for inhalation. Single and combination antibiotics were produced by spray drying. Particle size distributions were characterized by laser diffraction and imaging conducted by scanning electron microscopy. Solid-state characterisation of the antibiotics was carried out using differential scanning calorimetry, dynamic vapour sorption, X-ray powder diffraction, and differential scanning calorimetry. Using the Aerolizer device, the aerosol performance was measured using multistage liquid impinger and analysed using high performance liquid chromatography (R(2) = 1.0, CV = 0.4-1.0%). Furthermore, a disk diffusion test was performed for the assessment of the in vitro antimicrobial activity of the raw and spray dried antibiotics against bacteria. Results showed that cospray drying of the ciprofloxacin and doxycycline produced an antibiotic formulation (in a 1:1 ratio) suitable for inhalation that showed to be physically more stable then the analogous single spray dried antibiotic. The cospray dried powder has improved dispersion over the less stable single spray dried ciprofloxacin. The spray dried antibiotics were observed to have similar antimicrobial activity to the original antibiotics for Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyrogenes, suggesting the spray drying process does not affect the anti-bacterial activity of the drug. Cospray dried antibiotics from a DPI is thus feasible and can potentially be an attractive delivery alternative to the more conventional systemic delivery route.

The purpose of this study was to characterise the role of agglomeration on salmeterol xinafoate (SX) dispersion from mixtures for inhalation by varying the SX concentration and the proportion of fine lactose (FL). SX concentrations and SX:FL ratios ranged from 1.0% to 5.0% (w/w) and from 1:0 to 1:8, respectively. The in vitro deposition of SX was measured using a twin stage impinger (TSI). The aerosol was characterized by particulate capture in the TSI stages and subsequent imaging by scanning electron microscopy and by real-time particle sizing. The presence of coarse lactose reduced SX dispersion compared with SX alone, and the dispersion was independent of SX concentration. SX dispersion in binary mixtures of SX and FL was independent of SX:FL ratio and was similar to that of carrier-based mixtures with high particulate loads. Increased concentrations of SX and proportions of FL in carrier-based mixtures resulted in increased SX dispersion. Agglomerate formation coincided with increased dispersion. The study demonstrated that agglomeration is one of the important factors in SX dispersion from carrier-based mixtures at high particulate loads.

The physicochemical properties of two forms of spray dried bovine serum albumin (BSA) have been investigated using particle sizing, surface energy measurement, atomic force microscopy (AFM) and colloid probe microscopy. The BSA powder had similar particle size distributions and surface energy but significantly different morphologies and roughness, classified as smooth and corrugated BSA. Adhesion forces between the corrugated BSA and alpha-lactose monohydrate indicated median adhesion forces were significantly less than for smooth/carrier interaction forces. These observations correlated well with aerosolisation from BSA/carrier blends, where the corrugated BSA particles gave a higher fine particle fraction than the smooth BSA, suggesting reduced BSA/carrier adhesion and increased drug liberation. The use of corrugated drug particle morphology in drug carrier DPI systems may lead to improved aerosol performance through reduced drug carrier contact area.

The influence of processing on the performance of carrier material used in dry powder inhalers was investigated. alpha-Lactose monohydrate crystals were processed by ball milling for cumulative time durations and their properties evaluated. As expected, milling reduced the median particle diameter while increasing fine particulate (<10 microm) and amorphous levels. Recrystallization of these partially amorphous samples resulted in a reduction in fines, elimination of amorphous material with little change in median diameter. To study the effects of processing on aerosolization performance, blends of lactose monohydrate with a model drug (nedocromil sodium trihydrate), were evaluated using an in vitro multistage liquid impinger (MSLI) model. In general, milling and storage of the carriers at high humidity (prior to blending) had a significant (ANOVA, p < 0.05) effect on the fine particle fractions (FPF; <6.8 microm). These effects were attributed predominantly to the fines content, showing a strong correlation between increased fines and FPF (R(2) = 0.974 and 0.982 for milled and recrystallized samples, respectively). However, this relationship only existed up to 15% fines concentration, after which agglomerate-carrier segregation was observed and FPF decreased significantly. These results suggest that, after processing, high-dose drug formulation performance is dominated by the presence of fines., ((c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association.)