Impact Of Stage Research Articles

Numerical Study of the RespiCon Sampler Performance in the Calm Air

Results of a numerical study of the RespiCon sampler performance in the calm air are presented. The air flow is described by the Navier–Stokes equations of axisymmetric stationary viscous flow of incompressible fluid that are numerically integrated by the computational fluid dynamics (CFD) software FLUENT. The collection efficiencies of RespiCon impactor stages agree quite well with experimental data and curves of the European standards for the thoracic and respirable dust fractions. The aspiration efficiencies derived from the numerical model overestimate the experimental data in the range of particle sizes of 10 μm < dp < 40 μm; however, they correctly predict the value of maximal size of aspirated particles. A new design of the RespiCon sampler with a higher volume flow rate was developed. Copyright 2014 American Association for Aerosol Research

Abstracts from The Aerosol Society Drug Delivery to the Lungs 22Edinburgh International Conference CentreEdinburgh, Scotland, UKDecember 7–9, 2011

Summary Background: In bronchial challenge testing lung deposition of the stimulus may be poorly controlled due to incorrect use of nebulisers. Furthermore, the need for freshly prepared solutions burdens personnel and budget. In this study we aim to develop a dry powder alternative with higher reproducibility, better stability and lower costs than the current nebulisation test. Methods: Different pharmacological stimuli in the solid state were characterised on physico-chemical properties to determine the optimal conditions for processing and storage and were tested on their potential for dry powder inhalation. Adenosine and methacholine were micronised and dispersed with the Twincer ™ dry powder inhaler (DPI). Laser diffraction technique was applied to measure particle size distributions in the aerosol clouds. Results: Adenosine allows processing under ambient conditions. It was mixed with a lactose carrier in various mass ratios to produce adhesive mixtures and nucleus agglomerates. With three formulations, almost the entire dose range could be delivered with the Twincer ™ DPI. However, the process of preparing nucleus agglomerates might not be suitable for upscaling. Currently, spherical pellets are investigated as a more robust alternative. Methacholine is very hygroscopic and should therefore not be exposed to a high relative humidity. The methacholine particles leaving the Twincer ™ had an appropriate particle size distribution for inhalation. However, inhaler retention was high and should be reduced by controlling processing and storage conditions. Conclusions: Dry powder adenosine and methacholine seem promising alternatives for nebulisation. Methacholine must be handled under dry conditions. The highest doses of adenosine require further fine tuning.

Cascade Epiphaniometer: An instrument for aerosol “Fuchs” surface area size distribution measurements

The measurement of aerosol particle surface area is of high importance to environmental and health studies. Up to now, real-time measurements of the total “Fuchs” surface area of aerosol particles have been achieved among other instruments by the Epiphaniometer. This work demonstrates how a new calibration and set-up employing a Göttingen on-line α-impactor combined with a 227Ac radioactive source was performed, so that the impactor can be operated as a “Cascade Epiphaniometer (CEPI)” for real-time “Fuchs” surface area size distribution measurements. The CEPI consists of six-stages with Passivated-Implanted-Planar-Silicon (PIPS) detectors attached to each impactor stage and the back-up filter, with the cut-off sizes ranging from 53nm (lower stage) to 2μm (upper stage). The system was thoroughly tested and evaluated in the laboratory using monodisperse and polydisperse aerosols (PSL, DEHS, NaCl, (NH4)2SO4) of known properties. Parallel measurements by means of a Scanning Mobility Particle Sizing system (SMPS) provided a reference “Fuchs” surface area size distribution, for spherical aerosol particles. Results allowed the introduction of a size independent calibration factor for the CEPI signal to be expressed as a surface area concentration. An inversion technique is employed in order to reconstruct the continuous size distribution from the CEPI signal. The direct measurement of “Fuchs” surface area size distribution provided by CEPI compared well with that calculated by the SMPS within a mean uncertainty of 12%. The performance of CEPI in measuring the ambient aerosol “Fuchs” surface area size distribution was also investigated. During parallel ambient measurements, general agreement was observed between the CEPI “Fuchs” surface area and the calculated surface distribution from SMPS data. CEPI can be considered as an alternative method to the Electrical Low Pressure Impactor (ELPI) for the measurement of the “Fuchs” surface area size distribution, especially in cases of low aerosol concentration.

A study of water-soluble inorganic ions in size-segregated aerosols in atmospheric pollution episode

Particulate matter, the main pollutant in the atmospheric environment of the Santiago city in winter, was analyzed by means of the major water-soluble ionic species obtained under critical episodes of pollution in 2003. The particulate matter samples were collected using the Micro-Orifice uniform deposit impactors, with eight impactor stages connected in series, and the ionic species in particulate matter samples at each stage was analyzed by ion chromatography. While sulfate ion and nitrate ion showed bi-modal distributions, peaking in the fine and coarse mode, ammonium ion displayed a bi-modal size distribution, peaking in the fine and ultra fine mode. The equivalent concentration ratio of ammonium to sulfate was 2.03 ± 0.09, indicating the complete neutralization of sulfuric acid by ammonia. The excess ammonium ion was associated to nitrate ion. The study of the size distribution of water-soluble inorganic ions in particulate matter sup- ports the notion that secondary aerosols play a significant role in the urban atmosphere.

The Effect of Nonideal Cascade Impactor Stage Collection Efficiency Curves on the Interpretation of the Size of Inhaler-Generated Aerosols

Cascade impactors, operating on the principle of inertial size separation in (ideally) laminar flow, are used to determine aerodynamic particle size distributions (APSDs) of orally inhaled product (OIP) aerosols because aerodynamic diameter can be related to respiratory tract deposition. Each stage is assumed typically to be an ideal size fractionator. Thus, all particles larger than a certain size are considered collected and all finer particles are treated as penetrating to the next stage (a step function stage efficiency curve). In reality, the collection efficiency of a stage smoothly increases with particle size as an "S-shaped" curve, from approximately 0% to 100%. Consequently, in some cases substantial overlap occurs between neighboring stages. The potential for bias associated with the step-function assumption has been explored, taking full resolution and two-stage abbreviated forms of the Andersen eight-stage nonviable impactor (ACI) and the next-generation pharmaceutical impactor (NGI) as example apparatuses. The behavior of unimodal, log-normal APSDs typical of OIP-generated aerosols has been investigated, comparing known input values to calculated values of central tendency (mass median aerodynamic diameter) and spread (geometric standard deviation, GSD). These calculations show that the error introduced by the step change assumption is larger for the ACI than for the NGI. However, the error is sufficiently small to be inconsequential unless the APSD in nearly monodisperse (GSD ≤1.2), a condition that is unlikely to occur with realistic OIPs. Account may need to be taken of this source of bias only for the most accurate work with abbreviated ACI systems.

Assessment of the Contribution of Electron Microscopy to Nanoparticle Characterization Sampled with Two Cascade Impactors

This study assessed the contribution of electron microscopy to the characterization of nanoparticles and compared the degree of variability in sizes observed within each stage when sampled by two cascade impactors: an Electrical Low Pressure Impactor (ELPI) and a Micro-Orifice Uniform Deposit Impactor (MOUDI). A TiO2 nanoparticle (5 nm) suspension was aerosolized in an inhalation chamber. Nanoparticles sampled by the impactors were collected on aluminum substrates or TEM carbon-coated copper grids using templates, specifically designed in our laboratories, for scanning and transmission electron microscopy (SEM, TEM) analysis, respectively. Nanoparticles were characterized using both SEM and TEM. Three different types of diameters (inner, outer, and circular) were measured by image analysis based on count and volume, for each impactor stage. Electron microscopy, especially TEM, is well suited for the characterization of nanoparticles. The MOUDI, probably because of the rotation of its collection stages, which can minimize the resuspension of particles, gave more stable results and smaller geometric standard deviations per stage. Our data suggest that the best approach to estimate particle size by electron microscopy would rely on geometric means of measured circular diameters. Overall, the most reliable data were provided by the MOUDI and the TEM sampling technique on carbon-coated copper grids for this specific experiment. This study indicates interesting findings related to the assessment of impactors combined with electron microscopy for nanoparticle characterization. For future research, since cascade impactors are extensively used to characterize nano-aerosol exposure scenarios, high-performance field emission scanning electron microscopy (FESEM) should also be considered.

Validation of Radiolabeling of Drug Formulations for Aerosol Deposition Assessment of Orally Inhaled Products

Radiolabeling of inhaler formulations for imaging studies is an indirect method of determining lung deposition and regional distribution of drug in human subjects. Hence, ensuring that the radiotracer and drug exhibit similar aerodynamic characteristics when aerosolized, and that addition of the radiotracer has not significantly altered the characteristics of the formulation, are critical steps in the development of a radiolabeling method. The validation phase should occur during development of the radiolabeling method, prior to commencement of in vivo studies. The validation process involves characterization of the aerodynamic particle size distribution (APSD) of drug in the reference formulation, and of both drug and radiotracer in the radiolabeled formulation, using multistage cascade impaction. We propose the adoption of acceptance criteria similar to those recommended by the EMA and ISAM/IPAC-RS for determination of therapeutic equivalence of orally inhaled products: (a) if only total lung deposition is being quantified, the fine particle fraction ratio of both radiolabeled drug and radiotracer to that of the reference drug should fall between 0.85 and 1.18, and (b) if regional lung deposition (e.g., outer and inner lung regions) is to be quantified, the ratio of both radiolabeled drug and radiotracer to reference drug on each impactor stage or group of stages should fall between 0.85 and 1.18. If impactor stages are grouped together, at least four separate groups should be provided. In addition, while conducting in vivo studies, measurement of the APSD of the inhaler used on each study day is recommended to check its suitability for use in man.

COMPARATIVE ANALYSIS OF THE IN VITRO EQUIVALENCE OF METERED AEROSOL INHALERS CONDUCTED BY THE NEW GENERATION IMPACTOR

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Development of Budesonide Nanocluster Dry Powder Aerosols: Formulation and Stability

The physical and chemical stability of dry powder aerosol formulations is an essential component in the development of an inhaled therapeutic. The pharmaceutical processing methods and storage conditions are primary determinants of the stability of a dry powder inhaler (DPI) formulation. Wet milling was used to produce budesonide NanoClusters (NCs), which are agglomerates of drug nanoparticles (≈ 300 nm) with a mean aerodynamic diameter between 1 and 3 µm, capable of deep lung penetration. In this study, the reproducibility of NC processing and performance was established. The physical stability of a selected budesonide NC formulation was investigated using industry standard dose content uniformity and cascade impaction techniques. The chemical stability of the lead formulation was also determined as a function of processing parameters and storage conditions. This study confirms the reproducibility and robust stability of NC powders as a novel means to turn drug particles into high-performance aerosols.

Measurement of Drug in Small Particles from Aqueous Nasal Sprays by Andersen Cascade Impactor

To determine if cascade impactor (CI) measurement of drug in small particles from aqueous nasal sprays, described in FDA's 2003 draft Nasal Bioavailability/Bioequivalence Guidance, can be optimized to reduce measurement variability. To examine the influence of flow rate configurations and number of impactor stages on CI deposition and explore the importance of inlet volume. A total of eight assemblies and manual vs. automatic actuation were tested for deposition on the sum of all stages of the CI, and for Group 2 total drug mass per the Guidance. Mean deposition and variance about the mean were determined for each assembly. The path length for a spherical 1 l inlet was too short to allow adequate aerosol formation. Data variance was reduced by a factor of two or more by using an automatic actuator relative to manual actuation. Impactor assembly modification did not improve variance over the standard assembly. Use of a spherical inlet (≥ 2 l volume) and automatic actuation are recommended for comparative measurements of drug in small particles arising from aqueous nasal sprays. The standard (8-stage) 28.3 lpm CI flow rate configuration is recommended when using the Andersen Cascade Impactor (ACI), as no other assembly showed a distinct advantage.

Mass size distribution of carbon in atmospheric humic-like substances and water soluble organic carbon for an urban environment

Aerosol samples were collected with a micro-orifice uniform deposit impactor in an aerodynamic diameter (AD) range of 0.5–10μm in central Budapest, Hungary for 12 days. Aqueous aerosol extracts and atmospheric humic-like substances (HULIS) were obtained from the combined aerosol samples for each impactor stage. Water-soluble organic carbon (WSOC) and carbon in HULIS (HULIS-C) were measured in the samples with a total organic carbon analyzer. The analytical data were inverted into semi-smooth mass size distributions, and modal parameters were derived. The size distributions for both WSOC and HULIS-C consisted of three peaks: a coarse mode and two accumulation submodes. The geometric mean AD for the coarse mode was 6.4μm for both WSOC and HULIS-C. Contribution of the coarse mode to the total concentration of WSOC and HULIS-C were substantial and similar for both components, i.e., approximately 20%. The splitting of the accumulation mode into condensation and droplet submodes was explained by water processing of aerosol particles in the air. The geometric mean ADs of the condensation submode for the WSOC and HULIS-C were 0.37 and 0.31μm, respectively, and the droplet submode appeared at 1.72 and 1.22μm, respectively. The condensation submode was larger than the droplet submode by similar ratios of 1.7–1.8 for both WSOC and HULIS-C. The relative concentrations of the two submodes were likely influenced by local meteorology, in particular by relative humidity, pollutant gases, and water uptake properties and aging of fine particles.

The influence of nozzle throat length on the resolution of a low pressure impactor—An experimental and numerical study

This study investigates the effect of the nozzle throat length on the resolution of the low pressure impactor (LPI). Two basic nozzle geometries, rectangular slit and round nozzle with 25nm cutpoint were investigated both experimentally and by numerical simulation. A new impactor stage with variable nozzle throat length and jet-to-plate distance was designed, built and tested. The impactor was calibrated at four different configurations with monodisperse dioctyl sebacate (DOS) aerosol. A very good agreement between the simulated and the experimental resolutions and cutpoints were found. The main conclusions are that (a) the length of the nozzle is a crucial parameter affecting the resolution and (b) it is possible to achieve a better resolution with a rectangular slit type impactor than with a round nozzle type LPI. The best observed resolution was achieved with the slit type LPI with a nozzle throat length to width ratio of only 0.33. Compared to similar cutpoint impactor stages of commercially available LPIs, the resolution of the new stage is by far the highest.

Size-segregated characterization of PM10 at the EMEP site Melpitz (Germany) using a five-stage impactor: a six year study

Size-segregated particle samples were collected using a Berner 5-stage impactor (stages 1–5: 0.05–0.14–0.42–1.2–3.5–10 μm aerodynamic diameter). The means for all 169 days and for different categories of days were used for a characterization. The sorting criteria were (a) the distinction between winter (Wi, November to April) and summer (Su, May to October), (b) the distinction between air mass inflow from a sector West (W, 210 °–320 °) and from a sector East (E, 35 °–140 °). For the assignment of the air mass origin 96-h backward trajectories were used and four categories (WiW, WiE, SuW and SuE) with 48, 18, 42 and 29 days were established. The lowest mean particle mass concentrations were found for SuW and the highest for WiE with relative mass concentration distributions of 5.9, 28.2, 36.5, 18.0, and 11.4 % and 3.5, 22.7, 52.6, 16.7, and 4.5 % for stages 1–5, respectively. The mass closure for water soluble ions, water, organic material (OM) and elemental carbon (EC) accounts for 81–99 % of the gravimetric mass in Wi and for 60–81 % for Su, depending on the stage. The fractions of nitrate were relatively high for WiW while sulphate fractions are high for WiE. The estimated concentrations of secondary organic carbon (SOA) on stage 3 for WiW, WiE, SuW and SuE were 0.32, 1.25, 0.27 and 0.58 μgm−³, respectively. The highest amount of SOA is found for WiE, representing 59 % of organic carbon (OC). The highest difference in the percentages of SOA in OC was found between winter (WiW 55 %, WiE 59 %) and summer (SuW and SuE 74 %) indicating photochemical processes during long-range transport. The mean Carbon Preference Indices (CPI) are highest for SuE (stage 4: 7.57 and stage 5: 9.82) resulting mainly from plant wax abrasion in the surrounding forests. For WiE the mean PAH concentration on stage 3 (9.7 ngm−3) is about five times higher than for WiW, indicating long range transport following domestic heating and other combustion processes.

Deposition of inhaled micrometer-sized particles in oropharyngeal airway replicas of children at constant flow rates

This study is aimed at quantifying the deposition of micrometer-sized aerosols in realistic oropharyngeal airway replicas of children 6–14 years old, as well as minimizing interindividual scatter in correlations that fit this data. To perform this study, computed tomography (CT) images of nine children were taken during inhalation at a constant flow rate delivered by an AKITA® inhalation system. After segmenting the oral airways from the CT scan images, rapid prototyping technology was employed to fabricate plastic replicas of the airways. Deposition was then measured by comparing the number concentration of jojoba oil particles, generated by a six-jet Collison atomizer, passing through the replica vs. a blank line with no replica attached. The number concentration and the size of particles in 6 size ranges in the aerodynamic size range of 0.5–5.3μm associated with the impactor stage cutpoints were measured using an electrical low pressure impactor (ELPI). Five medium to high constant breathing flow rates, ranging from 30 to 150L/min, were generated using two vacuum pumps in series. Prior to testing the children's replicas, our deposition measurements were validated using a well-characterized and commercially-available geometry, the Alberta Idealized Throat. The replicas were re-scanned with CT to ensure a high quality fabrication and to measure their dimensions. These dimensions were used to establish a non-dimensional correlation, consisting of Stokes and Reynolds numbers, to reduce the scatter in deposition. Our proposed correlation may be useful for the prediction of deposition of micrometer-sized particles in the oropharyngeal airways of children during inhalation at moderate to high constant flow rates, typical of that seen during the use of pharmaceutical aerosol inhalers.

Production and Characterization of Plutonium Dioxide Particles as a Quality Control Material for Safeguards Purposes

Plutonium (Pu) dioxide particles were produced from certified reference material (CRM) 136 solution (CRM 136-plutonium isotopic standard, New Brunswick Laboratory, Argonne, IL, U.S.A., 1987) using an atomizer system on December 3, 2009 after chemical separation of americium (Am) on October 27, 2009. The highest density of the size distribution of the particles obtained from 312 particles on a selected impactor stage was in the range of 0.7-0.8 μm. The flattening degree of 312 particles was also estimated. The isotopic composition of Pu and uranium (U) and the amount of Am were estimated by thermal ionization mass spectrometry (TIMS), inductively coupled plasma mass spectrometry (ICPMS), and α-spectrometry. Within uncertainties the isotopic composition of the produced particles is in agreement with the expected values, which were derived from the decay correction of the Pu isotopes in the CRM 136. The elemental ratio of Am to Pu in the produced particles was determined on the 317th and 674th day after Am separation, and the residual amount of Am in the solution was estimated. The analytical results of single particles by micro-Raman-scanning electron microscopy (SEM)-energy-dispersive X-ray spectrometry (EDX) indicate that the produced particles are Pu dioxide. Our initial attempts to measure the density of two single particles gave results with a spread value accompanied by a large uncertainty.

Accurate measurement of nanoparticle charge, number and size with the ELPI+™ instrument

Nanoparticle characterization is mainly carried out by microscopy techniques and measurements of size and concentration. However to be able to comprehensively understand the behavior of the aerosol, information on particle charge level is critical. Particle charge has a major effect on the coagulation, deposition and transport as well as on the health effects of the particles. While aged aerosols generally are mainly neutral in terms of charge, freshly generated or resuspended particles can have high charge levels that vary depending on the size, material and generation method of the particles. Charging processes for particles are problematic as they are usually both time dependent and material dependent with sudden changes in magnitude. This makes the charge of a particle nearly impossible to predict without detailed studies and direct measurements. ELPI+™ instrument is a completely new aerosol measurement instrument based on the widely used Electrical Low Pressure Impactor (ELPI) technique. ELPI+™ measures particle concentration and size in a wide size range from 6nm to 10μm in real-time. The operation is based on first charging the particles in a corona charger and then size segregating them in a cascade impactor where all impactor stages are electrically insulated. With the ELPI+™ instrument it is possible to measure not only the particle size and concentration in real-time, but also the charge distribution of the particles. As the particle size classification is made with an impactor, the measured particles can be subsequently analyzed if needed with a suitable technique.

Use of a Berner Low-Pressure Impactor at Low Inlet Pressures. Application to the Study of Aerosols and Vapors at High Temperature

The behavior of a Berner-type low-pressure impactor operated at low inlet pressures (down to 0.04 bar) has been studied both theoretically and experimentally. The stage cut diameters have been found to decrease with inlet pressure, the general behavior of the impactor being similar to that of the atmospheric case down to ∼0.1 bar. At this inlet pressure, particles in the range 3–100 nm are classified along six different impactor stages, which offer the possibility of studying, e.g., freshly nucleated aerosols. The impactor so operated has been applied to the study of aerosol formation in biomass combustion, connected to the exit of a probe used in a previous work. The results presented in this article confirm and complement the conclusions of that work regarding submicron particle formation (i.e., nucleation of alkali sulfate occurs first and is followed by chloride condensation at lower temperatures) and also illustrate the possibilities of the impactor operated at low pressures. Finally, the relevance o...

Aerosol charge state characterisation using an ELPI

A new technique has been developed to measure the size distribution and charge state of highly charged aerosols using an Electrical Low Pressure Impactor (ELPI). The internal charger was switched alternately on and off and the time between stable charge states found to be ∼ 10 s. The size distribution of aerosols was found when the charger was on, from which the charge distribution can be estimated when the charger is off using the current at each impactor stage. This method was tested in background conditions, when a candle was burning and when a negative air ioniser was used. The ELPI electrometers were not sensitive enough to accurately measure the charge state on background and candle air, but gave a value for air charged by an ioniser. Comparing results from the ELPI with other techniques showed inaccuracies in this method that need to be addressed before further use of this technique.

Particulate emissions from large-scale medium-speed diesel engines: 1. Particle size distribution

This paper addresses particulate matter (PM) size distributions in large-scale diesel engine exhaust. The test engines were multivariable large-scale turbo-charged, after-cooled medium speed (~ 500 rpm, ~ 1 MW power per cylinder) direct injection diesel engines. Emissions measurements were carried out while burning heavy fuel (HFO) and light fuel (LFO) oils. Test modes for investigation were propulsion mode (marine) and generator mode (power plant), with load varying from 25 to 100%. PM was measured using a gravimetric impactor with four impactor stages plus a filter, classifying particles between 0.005 and 2.5 μm (aerodynamic diameter). The results show that HFO firing produces significantly higher PM emissions (more than factor of ~three on mass bases for high load operation) compared to LFO, especially for particles smaller than 0.5 μm. This is mainly due to higher ash-forming elements and sulphur content of HFO. For HFO, the fraction of the finest particles increases with load, more strongly for generator mode than for propulsion mode, with generator mode giving ~ 50% higher PM emissions than propulsion mode. With LFO firing, the largest amount of fine PM was emitted at the lowest load, for propulsion mode being lower and almost independent of load at higher loads, while for generator mode a steady decrease in emissions with increasing load is seen for all PM size classes measured.

Micro-homogeneity studies of boron carbide powders

We have studied the micro-homogeneity of boron carbide powders by inductively coupled plasma optical emission spectrometry (ICP-OES) and total reflec- tion X-ray fluorescence spectrometry (TXRF) using slurry sampling. To get information on the particle size distribu- tions of the powders, the stabilized slurries of boron carbide powders were nebulized, the aerosols were transported into a Batelle impactor and the droplets were collected on the impactor stages bearing TXRF sample holders. In a first series of measurements, parameters of the impaction like the duration of the impaction and the use of glutinous substance on the sample holders were optimized. The different mass size fractions for industrial boron carbide powders were determined by weight measurements of the fractions collected on the different stages. The established particle size distributions were in the range of 0.5 to >16 μm and found similar to those determined by laser diffraction reported elsewhere. Analyses of the mass fractions by slurry sampling TXRF showed that Ca, Ti, Cr, Mn, Fe, Ni and Cu within the measurements errors were homogeneously distributed over the mass fractions between 0.5 and 4 μm and that their concentrations agreed with the bulk composition, as determined with ICP-OES subsequent to digestion. However, light underestimates were found at the 5 (Mn) up to 150 μ gg �1 (Fe) level. Finally, boron carbide powders were washed out with nitric acid with different concentrations and leaching solutions and the residues were analyzed by ICP-OES and TXRF respective- ly. It is shown that up to 60% of the residual trace impurities in the powder studied can be removed by leaching with 34% (v/v) of nitric acid.