Increase In Fine Particle Fraction Research Articles

Optimization of methionine in inhalable High-dose Spray-dried amorphous composite particles using response surface Method, infrared and low frequency Raman spectroscopy

The influence of amino acids, other than leucine, in improving aerosolization of inhalable powders has not been widely explored. This detailed study focused on the use of methionine, another promising endogenous amino acid, in high dose spray-dried co-amorphous powders by investigating the influence of methionine proportion (0 – 20% w/w), and feed concentration (0.2 – 0.8% w/v) on aerosolization of kanamycin, a model drug, using a design of experiment approach. Low frequency Raman spectroscopy was used to assess the stability of the powders stored at 25 °C/53% relative humidity over 28 days. An increase in concentration of methionine was associated with an increase in fine particle fraction (FPF), with the highest FPF of 84% being achieved at 20% w/w and 0.2% w/v feed concentration. With an increase in feed concentration, both yield and particle size increased for all formulations; the FPF did not change except for kanamycin only formulation in which it decreased. During storage at high humidity, similar aerosolization stabilities were offered by different proportions of methionine although methionine crystallized out in all formulations. Furthermore, the crystallization was accompanied by surface enrichment of methionine on the particles. This study suggests that there is a direct relationship between methionine content and aerosolization for kanamycin-methionine amorphous matrices but feed concentration has little effect. In addition, methionine proportion has no effect on physical stability of such matrices at high humidity.

Inhalable, Spray-Dried Terbinafine Microparticles for Management of Pulmonary Fungal Infections: Optimization of the Excipient Composition and Selection of an Inhalation Device.

Terbinafine is a broad-spectrum antifungal agent with therapeutic potential against pulmonary aspergillosis. The main aim of the current study was to investigate the potential of l-leucine, alone and in combination with mannitol, to improve the performance of spray-dried terbinafine microparticles for inhalation. The study also aimed to investigate the potential of the low resistance Cyclohaler® and the high resistance Handihaler® as inhalation devices for spray-dried microparticles. To this end, eight powder inhalation formulations of terbinafine were prepared by nano spray drying via a factorial experimental design. The formulations were evaluated in vitro for their potential to deliver the antifungal drug to the lungs using the Cyclohaler® and the Handihaler®. Leucine was superior as an excipient to mannitol and to mixtures of leucine and mannitol. Using leucine as an excipient resulted in formulations with fine particle fractions of up to 60.84 ± 0.67% w/w and particle mass median aerodynamic diameters of down to 1.90 ± 0.20 μm, whereas using mannitol as an excipient resulted in formulations with fine particle fractions of up to 18.75 ± 3.46% w/w and particle mass median aerodynamic diameters of down to 6.79 ± 0.82 μm. When leucine was used as an excipient, using 50% w/w rather than 25% w/w ethanol in water as a spray solvent enhanced the dispersibility of the particles, with a mean absolute increase in the formulation fine particle fraction of 9.57% w/w (95% confidence interval = 6.40–12.73% w/w). This was potentially underlain by enrichment of the particle surfaces with leucine. The Cyclohaler® outperformed the Handihaler® as an inhalation device for the developed formulations, with a mean absolute increase in the fine particle fraction of 9.17% w/w (95% confidence interval = 8.17–10.16% w/w).

Controlled Pulmonary Delivery of Carrier-Free Budesonide Dry Powder by Atomic Layer Deposition.

Ideal controlled pulmonary drug delivery systems provide sustained release by retarding lung clearance mechanisms and efficient lung deposition to maintain therapeutic concentrations over prolonged time. Here, we use atomic layer deposition (ALD) to simultaneously tailor the release and aerosolization properties of inhaled drug particles without the need for lactose carrier. In particular, we deposit uniform nanoscale oxide ceramic films, such as Al2O3, TiO2, and SiO2, on micronized budesonide particles, a common active pharmaceutical ingredient for the treatment of respiratory diseases. In vitro dissolution and ex vivo isolated perfused rat lung tests demonstrate dramatically slowed release with increasing nanofilm thickness, regardless of the nature of the material. Ex situ transmission electron microscopy at various stages during dissolution unravels mostly intact nanofilms, suggesting that the release mechanism mainly involves the transport of dissolution media through the ALD films. Furthermore, in vitro aerosolization testing by fast screening impactor shows a ∼2-fold increase in fine particle fraction (FPF) for each ALD-coated budesonide formulation after 10 ALD process cycles, also applying very low patient inspiratory pressures. The higher FPFs after the ALD process are attributed to the reduction in the interparticle force arising from the ceramic surfaces, as evidenced by atomic force microscopy measurements. Finally, cell viability, cytokine release, and tissue morphology analyses verify a safe and efficacious use of ALD-coated budesonide particles at the cellular level. Therefore, surface nanoengineering by ALD is highly promising in providing the next generation of inhaled formulations with tailored characteristics of drug release and lung deposition, thereby enhancing controlled pulmonary delivery opportunities.

Controlling the performance of adhesive mixtures for inhalation using mixing energy

A concept of mixing energy, ME, has been developed and applied to blending of adhesive mixtures for inhalation in a high shear blender. Six different systems were investigated, four of which included a coating agent. For blends containing a coating agent, it is shown that the applied ME is key to the control of two important functional mechanisms: i) coating of the carrier by the coating agent, and ii) the dispersibility of the active pharmaceutical ingredient (API). The mass of the carrier was identified to be the mass which is relevant to the forces acting during mixing. The dispersibility in terms of the fine particle fraction (FPF) can be expressed as the product of two exponentials which both are functions of ME. The first factor accounts for the initial increase in FPF, while the second accounts for the decrease observed at extensive mixing. For adhesive mixtures without a coating agent, a similar decrease in FPF is observed when high forces are applied during mixing. Mechanistic interpretation of the behavior is provided.

Occupational Exposure to Dust Produced when Milling Thermally Modified Wood.

During production, thermally modified wood is processed using the same machining operations as unmodified wood. Machining wood is always accompanied with the creation of dust particles. The smaller they become, the more hazardous they are. Employees are exposed to a greater health hazard when machining thermally modified wood because a considerable amount of fine dust is produced under the same processing conditions than in the case of unmodified wood. The International Agency for Research on Cancer (IARC) states that wood dust causes cancer of the nasal cavity and paranasal sinuses and of the nasopharynx. Wood dust is also associated with toxic effects, irritation of the eyes, nose and throat, dermatitis, and respiratory system effects which include decreased lung capacity, chronic obstructive pulmonary disease, asthma and allergic reactions. In our research, granular composition of particles resulting from the process of longitudinal milling of heat-treated oak and spruce wood under variable conditions (i.e., the temperature of modification of 160, 180, 200 and 220 °C and feed rate of 6, 10 and 15 m.min−1) are presented in the paper. Sieve analysis was used to determine the granular composition of particles. An increase in fine particle fraction when the temperature of modification rises was confirmed by the research. This can be due to the lower strength of thermally modified wood. Moreover, a different effect of the temperature modification on granularity due to the tree species was observed. In the case of oak wood, changes occurred at a temperature of 160 °C and in the case of spruce wood, changes occurred at the temperatures of 200 and 220 °C. At the temperatures of modification of 200 and 220 °C, the dust fraction (i.e., that occurred in the mesh sieves, particles with the size ≤ 0.08 mm) ranged from 2.99% (oak wood, feed rate of 10 m.min−1) to 8.07% (spruce wood, feed rate of 6 m.min−1). Such particles might have a harmful effect on employee health in wood-processing facilities.

Delivery of pDNA Polyplexes to Bronchial and Alveolar Epithelial Cells Using a Mesh Nebulizer.

In this study, a cell penetrating peptide was used as an uptake enhancer for pDNA delivery to the lungs. Polyplexes were prepared between pDNA and CPP. Intracellular delivery of pDNA was assessed in both alveolar (A549) and bronchial (Calu-3) epithelial cells. Aerosol delivery was investigated using a mesh nebulizer. Efficient intracellular delivery of pDNA occurs in both A549 and Calu-3 cells when delivered as polyplexes. Protection against nucleases and endosomal escape mechanism occurs when pDNA is formulated within the polyplexes. For aerosol delivery, 1% (w/v) mannitol was able to protect naked DNA structure during nebulization with a significant increase in fine particle fraction (particles <5μm). The structure of polyplexes when delivered via a mesh nebulizer using 1% (w/v) mannitol could partially withstand the shear forces involved in aerosolization. Although some loss in functionality occurred after nebulization, membrane-associated fluorescence was observed in A549 cells. In Calu-3 cells mucus entrapment was a limiting factor for polyplex delivery. The presence of CPP is essential for efficient intracellular delivery of pDNA. The polyplexes can be delivered to lung epithelial cells using mesh nebulizer. The use of different excipients is essential for further optimization of these delivery systems.

Influence of excipients on physical and aerosolization stability of spray dried high-dose powder formulations for inhalation

The aim of this study is to investigate the influence of excipients on physical and aerosolization stability of spray dried Ciprofloxacin dry powder inhaler formulations. The model drug, Ciprofloxacin hydrochloride, was co-spray dried with excipients such as disaccharides (sucrose, lactose, trehalose), mannitol and l-leucine. The spray dried samples were stored at two different relative humidity (RH) conditions of: (1) 20% and (2) 55% RH at 20 °C. Ciprofloxacin co-spray dried with disaccharides and l-leucine in the mass ratio of 1:1 demonstrated an increase in fine particle fraction (FPF) as compared with the spray dried Ciprofloxacin alone when stored at 20% RH. However, deterioration in FPF of Ciprofloxacin co-spray dried with disaccharide and mannitol was observed upon storage at 55% RH as compared to the corresponding formulations stored at 20% RH due to particle agglomeration. Whereas, 10% and 50% w/w l-leucine in the formulation showed no change in aerosol performance (FPF of 71.1 ± 3.5% and 79.5 ± 3.1%, respectively) when stored at 55% RH for 10 days as compared to 20% RH (FPF of 68.1 ± 0.3% and 73.6 ± 7.1%, respectively). l-Leucine demonstrated aerosolization stability by alleviating crystallization of Ciprofloxacin to some extent and preventing significant change in particle morphology. l-Leucine is well-recognized as aerosolization enhancer; our study has shown l-leucine is also a physical and aerosolization stabilizer for spray dried Ciprofloxacin DPI formulations. Such stability enhancing activities were attributed to the enrichment of l-leucine on the particle surface as confirmed by XPS data, and intermolecular interactions between l-leucine and Ciprofloxacin as measured by FT-IR.

Influence of Added of Fines to the Decanted Carrier Surfaces Used in Dry Powder Formulations

Investigation of the effect of adding carrier fines to the wet decanted carriers and the subsequent effects on the in vitro deposition of salbutamol sulphate. Methods: The wet decantation process used to remove the surface carrier fines carried out nine time for lactose and mannitol carriers. Addition lactose fines up to 8% to decanted lactose. Additionally, mannitol fines up to 16% were added to decanted mannitol. In vitro deposition carried out for those treated carriers after mixing with salbutamol sulphate using the NGI. Results: There were significant increase in fine particle fraction (FPFs). This probably by reducing drug-carrier adhesion and allowing easy detachment of the drugs from the carrier surface. Although this addition of fines could not revert the FPFS to the original value of the untreated carriers. Conclusions: Addition of micronized carriers to decanted carriers found to increase significantly the dispersion of the drug and the in vitro deposition.

Surface Modification of Pollen-Shape Carriers for Dry Powder Inhalation through Surface Etching

Surface modification of pollen-shape hydroxyapatite (HA) carriers is achieved using surface etching technique. Characterization of HA carriers before and after etching are performed by scanning electron microscopy (SEM), Carr’s compressibility index (CI), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). Four surface etching temperatures are tested but only the particles etched at 40 and 50 °C are found satisfactory. Proper surface etching allows a reduction of the petal-like structure on the particle surface and improves the crystallinity of the particles. While the reduction of petal-like structure decreases the emitted dose (ED) of the drug particles, an increase in fine particle fraction (FPF) can be attained owing to the improvement in drug liberation. An increase in the air flow rate, however, decreases the significance of particle surface morphology and the difference in FPF among the use of different carrier particles diminishes. Surface etching technique is found to have good potenti...

Influence of the polydispersity of the added fine lactose on the dispersion of salmeterol xinafoate from mixtures for inhalation

The purpose of this study was to determine and understand the effect of the polydispersity of fine lactose (FL) on the dispersion of salmeterol xinafoate (SX) from SX-coarse lactose mixtures for inhalation. SX mixtures were prepared using validated laboratory mixing. The in vitro deposition of SX was measured using a twin-stage impinger and SX analysed using high performance liquid chromatography. The distributions of FL included both cohesive to non-cohesive fractions. Reduction in the span of the FL distributions with a volume median diameters (VMD) about 7μm showed no significant difference in the fine particle fraction (FPF) of SX (P>0.05), while reduced FPF of SX was observed with the reduction in the span of FL with VMD about 19 and 32μm, respectively. When the FPF of SX was correlated with the concentration of FL in specific fractions, there was a marked, linear increase in FPF for increasing concentrations of FL in the 5–10μm fraction; however, all other fractions showed no significant increase in FPF. The study reflects the importance of lactose polydispersity in drug dispersion. Specific size fractions of cohesive FL enhance dispersion, while non-cohesive fractions of FL act as secondary carriers and decrease dispersion performance.

Application and Mechanism of Inhalation Profile Improvement of DPI Formulations by Mechanofusion with Magnesium Stearate

In our previous paper, we reported the inhalation properties of dry powder inhaler (DPI) formulations containing Compound A and mechanofusion-processed lactose carriers. The mechanofusion process with magnesium stearate (Mg-St) on the lactose carrier enhanced the fine particle fraction (FPF) value of the Andersen cascade impactor (ACI) study. The increase of FPF seemed to be associated with the increase of the dispersibility of drug particles. The objectives of this study were (1) to evaluate the applicability of lactose carrier mechanofusion-processed with Mg-St and (2) to examine the mechanism of FPF alteration by the mechanofusion process applied on the lactose carrier with or without additive. The inhalation profiles of DPI formulations containing four different pharmaceutical compounds were evaluated with an ACI. The dispersibility of the formulations was observed by particle size distribution measurement in the air stream and the adhesive force was measured bydirect separation method. It was found that higher FPF was obtained with lactose mechanofusion-processed with Mg-St as compared to control lactose carriers for all four compounds. This suggested that mechanofusion process with Mg-St is widely applicable in DPI formulations. The homogenization of surface adhesiveness was attributed to the increased FPF of the DPI including lactose mechanofusion-processed with Mg-St, as suggested by the combination of several physicochemical characteristics. Combination of different characterization methods would be of help to clarify the whole mechanism which defines the inhalation properties of DPI formulations.

The influence of fluid physicochemical properties on vibrating-mesh nebulization

In this study, the effect of fluid physicochemical properties and the vibrating-mesh mechanism on the aerosols generated from vibrating-mesh nebulizers have been evaluated using fluids having a range of viscosity, surface tension and ion concentration. Two nebulizers were investigated: the Omron MicroAir NE-U22 (passively vibrating) and the Aeroneb Pro (actively vibrating) mesh nebulizers. For both devices, the total aerosol output was generally unaffected by fluid properties. Increased viscosity or ion concentration resulted in a decrease in droplet volume median diameter (VMD) and an increase in fine particle fraction (FPF). Moreover, increased viscosity resulted in prolonged nebulization and reduced output rate, particularly for the Omron nebulizer. Both nebulizers were unsuitable for delivery of viscous fluids since nebulization was intermittent or completely ceased at >1.92 cP. The presence of ions reduced variability particularly for the Aeroneb Pro nebulizer. No clear effect of surface tension was observed on the performance of nebulizers employing a vibrating-mesh technology. However, when viscosity was low, reduced surface tension seemed advantageous in shortening the nebulization time and increasing the output rate, but for the Omron nebulizer this also increased the droplet VMD and decreased the FPF. This study has shown that vibrating-mesh nebulization was highly dependent on fluid characteristics and nebulizer mechanism of operation.

Physicochemical and in vitro deposition properties of salbutamol sulphate/ipratropium bromide and salbutamol sulphate/excipient spray dried mixtures for use in dry powder inhalers

The physicochemical and aerodynamic properties of spray dried powders of the drug/drug mixture salbutamol sulphate/ipratropium bromide were investigated. The in vitro deposition properties of spray dried salbutamol sulphate and the spray dried drug/excipient mixtures salbutamol sulphate/lactose and salbutamol sulphate/PEG were also determined. Spray drying ipratropium bromide monohydrate resulted in a crystalline material from both aqueous and ethanolic solution. The product spray dried from aqueous solution consisted mainly of ipratropium bromide anhydrous. There was evidence of the presence of another polymorphic form of ipratropium bromide. When spray dried from ethanolic solution the physicochemical characterisation suggested the presence of an ipratropium bromide solvate with some anhydrous ipratropium bromide. Co-spray drying salbutamol sulphate with ipratropium bromide resulted in amorphous composites, regardless of solvent used. Particles were spherical and of a size suitable for inhalation. Twin impinger studies showed an increase in the fine particle fraction (FPF) of spray dried salbutamol sulphate compared to micronised salbutamol sulphate. Co-spray dried salbutamol sulphate:ipratropium bromide 10:1 and 5:1 systems also showed an increase in FPF compared to micronised salbutamol sulphate. Most co-spray dried salbutamol sulphate/excipient systems investigated demonstrated FPFs greater than that of micronised drug alone. The exceptions to this were systems containing PEG 4000 20% or PEG 20,000 40% both of which had FPFs not significantly different from micronised salbutamol sulphate. These two systems were crystalline unlike most of the other spray dried composites examined which were amorphous in nature.

Novel Temperature Controlled Surface Dissolution of Excipient Particles for Carrier Based Dry Powder Inhaler Formulations

ABSTRACTThe surface of lactose monohydrate was modified by solution phase variable temperature dissolution. Lactose monohydrate crystals were added to a known volume of a saturated solution of lactose monohydrate at 25°C. The temperature of the mixture was then ramped to either 30, 35, 40, or 50°C to produce lactose monohydrate batches with reduced levels of fines and lower surface roughness. A dramatic decrease in surface roughness with increasing dissolution temperature was visually observed using scanning electron microscopy. Particle size analysis suggested that the level of lactose fines was reduced after treatment at the lowest dissolution temperature, 30°C. Evaluation of the samples' drug aerosolization using a twin stage impinger, after blending with salbutamol sulphate, suggested that even though there were dramatic changes in roughness and particle size distribution after surface dissolution at 30°C, there was no significant difference in aerosolization as measured by fine particle fraction. However, after surface dissolution at 35°C, there was an increase in fine particle fraction. Surface dissolution at even higher temperatures did not result in any further increase in fine particle fraction. These observations suggest that surface roughness and fines play an important role in the aerosolization of salbutamol sulphate, but the inter-relationships are not straightforward.

Predicting the aerosol performance of dry powder inhalation formulations by interparticulate interaction analysis using inverse gas chromatography

Previous studies have demonstrated the utility of inverse gas chromatography (IGC) in discriminating the differences in surface energy between salmeterol xinafoate (SX) powders prepared by conventional sequential batch crystallization and micronization and by supercritical fluid crystallization. In the present study, solubility parameters derived from IGC analysis at infinite dilution (zero coverage) were further utilized to evaluate the influence of solid-solid interactions on the in vitro aerosol performance of these SX samples, with or without the inclusion of a lactose carrier. To this end, the strength of cohesive SX-SX interactions and that of adhesive SX-lactose interactions were computed for the samples from the corresponding solubility parameters, and their fine particle fractions determined using a multi-stage liquid impinger. It was found that the aerosol performance of SX could be substantially improved by the addition of lactose carrier only if the adhesive SX-lactose interactions were stronger than the cohesive SX-SX interactions. The difference in strength between these two forms of interactions also displayed a significant correlation with the increase in fine particle fraction after the addition of lactose carrier. These results suggest that IGC-based interparticulate interaction measurements may serve as a useful means for predicting the aerosol performance of dry powder inhalation formulations.

Use of a lognormal distribution model for estimating soil water retention curves from particle-size distribution data

Particle-size distribution (PSD) of soils has been widely used to estimate water retention curves (WRCs). Lognormal distribution model, which estimates the WRC directly from the PSD data by applying a lognormal distribution law to both PSD and void-size distribution (VSD), has been recently developed and successfully applied to sandy soils. The objective of this study was to investigate in detail the applicability of the lognormal distribution model for a broader range of soil textures. Performance of the model was evaluated on five aggregated USDA texture classes (coarse-, moderately coarse-, medium-, moderately fine-, and fine-texture soils) using 229 ‘undisturbed’ soils (159 soils for model calibration and 70 soils for validation). The model performed worst for moderately fine-textured soils, since the PSDs and VSDs of soils included in this texture did not strongly follow the lognormal distribution. In general, performance of the model decreased with increase in fine particle fraction, possibly because of the surface sorption behavior of clay particles.

Aerosolisation behaviour of micronised and supercritically-processed powders

Comparative analysis of salmeterol xinafoate (SX) powders was carried out to define the aerodynamic properties and mechanism of particle dispersion relevant to the use of these materials in dry powder inhalation drug delivery. Particle sizing methodology was evaluated using laser diffraction, time-of-flight and Andersen cascade impactor measurements combined with electron microscopy and surface area determination. Particle interactions, assessed on the basis of powder bulk density and inverse gas chromatography surface energy measurements, were compared with the aerodynamic forces generated by a dry-powder dispersion device. The supercritically produced material showed by a factor of seven reduced tensile strength of the aggregates and indicated a two-fold increase of fine particle fraction deposited in a cascade impactor when blended with lactose. This effect was explained by the reduced particle aggregation at low differential air pressures and flow rates. A relatively small value of aerodynamic stress required to disperse supercritically produced particles in comparison to micronized material comes from: (a) lower bulk density (loose aggregate structure), (b) larger volume mean diameter, (c) larger aerodynamic shape factor and (d) smaller specific free energy of S-SX particles, in this order of priority. It is shown that aggregation between primary drug particles is important for SX/lactose formulations because such aggregates survive the pre-separation impactor stage.

The role of fine particle lactose on the dispersion and deaggregation of salbutamol sulphate in an air stream in vitro

Sieved (63–90 μm) lactose (L) particles supported on a 63- μm sieve was subjected to a compressed airstream with a flow rate of 160 l/min in order to remove existing fine particles. Fractions of the air-treated L were then blended separately with either 1.5%, w/w micronised L (5.0 μm) or magnesium stearate (7.6 μm, MS) and the blends were further sieved gently using a 45- μm sieve to remove any freely dispersed fine L. Other fractions of the air-treated L were also blended with different quantities of intermediate sized lactose (15.9 μm, IML) to obtain final concentrations of IML between 1.5 and 9% w/w. The various batches of L were then mixed separately with salbutamol sulphate (SS, 5.8 μm) in a ratio of 67.5:1 (w/w). The particle size and shape of L were characterised by laser diffraction, a time-of-flight technique and scanning electron microscopy. The in vitro deposition of SS was measured using a twin impinger after aerosolisation at 60 l/min via a Rotahaler®. Air treatment of the coarse L was found to reduce significantly (ANOVA, p<0.01) the fine particle fraction (FPF) and fine particle dose (FPD) of SS but such an effect was reversible by adding fine L back to the powder formulations. Gentle sieving of coarse-fine L mixtures on a 45- μm sieve removed the majority of freely dispersed fine L thereby reducing significantly ( p<0.05) the FPF and FPD of the drug. MS exhibited a similar effect on the dispersion of SS to that of the fine L. The more IML that was added the higher the FPF or FPD of the drug. However, the greatest stepped-increase in the drug FPF occurred when 1.5% w/w of IML was added, which resulted in >60% increase in FPF of SS whilst increasing the concentration of the added IML from 1.5 to 9% produced an approximate 50% further increase in the drug FPF.

AEROSOL DELIVERY FROM AN ACTIVE EMISSION MULTI-SINGLE DOSE DRY POWDER INHALER

ABSTRACT All commercially available dry powder inhalers depend solely on the patient's inspired airflow to aerosolize the drug formulation. The dose delivered is therefore subject to inter-patient variability that may be overcome by devices actively imparting energy to the powder bed to disperse particles. The current studies were performed to evaluate powder filling and dose delivery from a prototype active emission multi-single dose dry powder dispersion device. The device contained interchangeable cartridges (12 doses/cartridge, three cartridges with dosing chamber diameters of 0.5, 1.0, and 1.5 mm, each 6mm in length) which were vacuum filled with the powder formulation. Individual doses were emitted by compressed gas propulsion following actuator depression. Studies were performed using bulk lactose powders (˜25-100 and ˜ 40-200μm); and sieved lactose (45-75 and 75-125μm), alone and in 2% albuterol sulfate blends. Vacuum fill flow rates of 7, 14, 21, and 28 L/min were used. Filled cartridges were inserted into the device and emitted masses determined gravimetrically. Aerodynamic particle size measurements and fine particle fractions were determined by inertial impaction (8-stage Andersen impactor, 60L/min). Powders filled at a flow rate of 28L/min exhibited a high packing density and were delivered as a pellet. Consequently, lower flow rates of 7, 14, and 21 L/min were used to evaluate filling conditions required for optimal aerodynamic performance and dose delivery. As anticipated, the total mass output and emitted dose delivered decreased as the dosing chamber diameter decreased. For a fixed dosing chamber diameter, the total mass output, of drug and excipient, decreased slightly as the fill flow rate was increased. However, the fine particle fraction and fine particle mass, of drug alone, followed an opposite trend, by increasing with an increase in fill flow rate. A decrease in dosing chamber diameter resulted in an increase in air velocity (higher Re) and a subsequent increase in packing density of the filled powders at a fixed flow rate. As the dosing chamber diameters decreased (at a given fill flow rate) the total mass output and fine particle mass decreased, however, an increase in fine particle fraction was observed. Dose reproducibility as indicated by standard deviations within f 10%, and a mean dose recovery of 95%+4%, indicated acceptable performance of the device. Future work will evaluate the relationship between particle size, powder flow, fill flow rate, fill density, and dose emission to optimize aerodynamic performance and dose delivery.