Cascade Impactor Measurements Research Articles

Nebulization and In Vitro Upper Airway Deposition of Liposomal Carrier Systems.

Liposomal carrier systems have emerged as a promising technology for pulmonary drug delivery. This study focuses on two selected liposomal systems, namely, dipalmitoylphosphatidylcholine stabilized by phosphatidic acid and cholesterol (DPPC-PA-Chol) and dipalmitoylphosphatidylcholine stabilized by polyethylene glycol and cholesterol (DPPC-PEG-Chol). First, the research investigates the stability of these liposomal systems during the atomization process using different kinds of nebulizers (air-jet, vibrating mesh, and ultrasonic). The study further explores the aerodynamic particle size distribution of the aerosol generated by the nebulizers. The nebulizer that demonstrated optimal stability and particle size was selected for more detailed investigation, including Andersen cascade impactor measurements, an assessment of the influence of flow rate and breathing profiles on aerosol particle size, and an in vitro deposition study on a realistic replica of the upper airways. The most suitable combination of a nebulizer and liposomal system was DPPC-PA-Chol nebulized by a Pari LC Sprint Star in terms of stability and particle size. The influence of the inspiration flow rate on the particle size was not very strong but was not negligible either (decrease of Dv50 by 1.34 μm with the flow rate increase from 8 to 60 L/min). A similar effect was observed for realistic transient inhalation. According to the in vitro deposition measurement, approximately 90% and 70% of the aerosol penetrated downstream of the trachea using the stationary flow rate and the realistic breathing profile, respectively. These data provide an image of the potential applicability of liposomal carrier systems for nebulizer therapy. Regional lung drug deposition is patient-specific; therefore, deposition results might vary for different airway geometries. However, deposition measurement with realistic boundary conditions (airway geometry, breathing profile) brings a more realistic image of the drug delivery by the selected technology. Our results show how much data from cascade impactor testing or estimates from the fine fraction concept differ from those of a more realistic case.

A matrix-free fixed-point iteration for inverting cascade impactor measurements with instrument's sensitivity kernels and hardware

This study focuses on advancing the inversion of aerosol data measured by a cascade impactor. We aim to find and validate a comprehensive and robust mathematical model for reconstructing a particle mass distribution. In this paper, we propose a fixed-point iteration as a method for inverting cascade impactor measurements with relatively simple measurement hardware, which is not optimized for handling advanced linear algebraic operations such as large matrices. We validate this iteration numerically against an iterative L1 norm regularized iterative alternating sequential inversion algorithm. In the numerical experiments, we investigate and compare a point-wise (matrix-free) and integrated kernel-based approach in inverting five different aerosol mass concentration distributions based on simulated measurements and sensitivity kernel functions.

Using Filters to Estimate Regional Lung Deposition with Dry Powder Inhalers

To develop an in vitro method to rapidly evaluate regional lung doses delivered by pharmaceutical inhalers. Currently, cascade impactor measurements are used, but these are resource intensive and require significant post processing of in vitro data to arrive at regional deposition estimates. We present a specialized filter apparatus that mimics tracheobronchial (TB) deposition of pharmaceutical aerosols emitted by commercially available dry powder inhalers (DPIs). The filter housing includes an electrostatic neutralizer to eliminate artificial electrostatic filtration effects. Regional deposition (tracheobronchial and alveolar) for four DPIs (Onbrez Breezhaler, Flovent Diskus, Pulmicort Turbuhaler, and Asmanex Twisthaler) was estimated using cascade impactor measurements and an in silico regional deposition model. These estimates were compared to direct measurements of regional deposition as provided by the TB filter mimic and an absolute filter placed downstream of the TB filter housing, representing the alveolar dose. The two methods were shown to provide similar estimates of extrathoracic, tracheobronchial, and alveolar deposition, as well as total recovery of active pharmaceutical ingredients. Because of its design, the TB filter apparatus makes it possible to estimate regional deposition with inhalers directly using variable inhalation profiles without any additional equipment or changes to the experimental configuration. This method may be useful to expedite development of both innovative and generic drug products as it provides regional respiratory tract deposition estimates using fewer resources than exisiting methods.

Characterization of highly concentrated organic aerosols by optical extinction in the mid infrared regime: Application to e-cigarettes

Highly concentrated submicron condensation aerosols are formed in electronic cigarettes. They consist primarily of the carrier substances glycerol, propylene glycol and water. The purpose of this paper is to introduce a three wavelength light extinction method in the near and mid-infrared wavelength regime enabling transient measurements of the mass concentration and the mean particle size of the mainstream, undiluted aerosol. The measuring device uses the strong absorption bands at wavelengths of 3.4 and 2.9µm caused by the excitation of CH- and OH-vibrations of the dominating aerosol components. The absorption allows for a direct measurement of the mass concentration. Two further light attenuation signals at non-absorbing (or negligibly absorbing) wavelengths of 1.65 and 2.01µm reveal information on the mean particle size. The data evaluation scheme is based on a set of correlations between light attenuation and size distribution parameters derived from Mie calculations using a lognormal approximation of the mass size distribution. The development of a simple sensor is facilitated due to the availability of light emitting diodes in the mid infrared wavelength range. Extinction path lengths of the order of 0.5cm are sufficient to measure concentrations larger than several milligrams per liter, typical for the mainstream aerosol of e-cigarettes. The aerosol quantities were measured for a wide range of operating parameters of the e-cigarette. Time integrated signals were compared with results of filter (mass generation) and impactor samples (mean particle size and standard deviation). The sensor’s concentration signal is directly proportional to the concentration measured gravimetrically, independent of the relative composition of the condensate in view of glycerol, propylene glycol and water. The mass median droplet diameters determined by the extinction method agree fairly well with cascade impactor measurements. The method, presented here, does not deliver information on the geometric standard deviation of the aerosol mass distribution as it is insensitive to this distribution parameter for values in the range between 1.3 and 2.0, typical for condensation aerosols.

Investigation of dry powder inhaler (DPI) resistance and aerosol dispersion timing on emitted aerosol aerodynamic particle sizing by multistage cascade impactor when sampled volume is reduced from compendial value of 4 L.

Compendial methods determining dry powder inhaler (DPI)-emitted aerosol aerodynamic particle size distribution (APSD) collect a 4-L air sample containing the aerosol bolus, where the flow, which propagates through the cascade impactor (CI) measurement system from the vacuum source, is used to actuate the inhaler. A previous article described outcomes with two CIs (Andersen eight-stage cascade impactor (ACI) and Next-Generation Pharmaceutical Impactor (NGI)) when the air sample volume was ≤4L with moderate-resistance DPIs. This article extends that work, examining the hypothesis that DPI flow resistance may be a factor in determining outcomes. APSD measurements were made using the same CI systems with inhalers representing low and high flow resistance extremes (Cyclohaler® and HandiHaler® DPIs, respectively). The ratio of sample volume to internal dead space (normalized volume (V*)) was varied from 0.25 to 1.98 (NGI) and from 0.43 to 3.46 (ACI). Inhaler resistance was a contributing factor to the rate of bolus transfer; the higher resistance DPI completing bolus relocation to the NGI pre-separator via the inlet when V* was as small as 0.25, whereas only ca. 50% of the bolus mass was collected at this condition with the Cyclohaler® DPI. Size fractionation of the bolus from either DPI was completed within the ACI at smaller values of V* than within the NGI. Bolus transfer from the Cyclohaler® capsule and from the HandiHaler® to the ACI system were unaffected by the different flow rise time observed in the two different flow controller systems, and the effects the ACI-based on APSD measurements were marginal.

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.

A model for predicting size distributions delivered from pMDIs with suspended drug

A new model has been developed for predicting size distributions delivered from pressurized metered dose inhalers (pMDIs) that contain suspended drug particles. This model enables the residual particle size distribution to be predicted for a broad range of formulations. It expands on previous models by allowing for polydisperse micronized input drug, multiple suspended drugs, dissolved drug, and dissolved or suspended excipient to be included in the formulation. The model indicates that for most pMDI configurations, the majority of droplets contain no drug or a single drug particle and the residual particle size distribution delivered from the pMDI is essentially equivalent to the size distribution of the micronized drug used in the formulation. However, for pMDIs with a high drug concentration or that use small micronized drug particles, there can be a substantial fraction of the droplets that contain multiple drug particles. The residual particle size distribution obtained from these pMDIs can be substantially larger than the size distribution of the micronized drug. Excellent agreement was observed between size distributions predicted using this model and those obtained from experimental cascade impactor measurements ( r 2 = 0.97), thus demonstrating the ability of the model to accurately predict the size distributions obtained from suspension pMDIs.

Product Lifecycle Approach to Cascade Impaction Measurements

Over the lifecycle of an orally inhaled product (OIP), multi-stage cascade impactor (CI) measurements are used for different purposes and to address different questions. Full-resolution CIs can provide important information during product development and are widely used but are time- and resource-intensive, highly variable, and suboptimal for OIP quality control (QC) testing. By contrast, Efficient Data Analysis (EDA) combined with Abbreviated Impactor Measurement (AIM) systems pertinent either for QC and-possibly-for adult Human Respiratory Tract (pHRT) has been introduced for OIP performance assessment during and post-development. This article summarizes available evidence and discusses a strategy for using either abbreviated or full-resolution CI systems depending on the purpose of the measurement, such that adequate, accurate, and efficient testing of aerodynamic particle size distribution (APSD) of OIPs can be achieved throughout the lifecycle of a product. Under these proposals, a comprehensive testing program should initially be conducted by full-resolution CI in OIP development to ascertain the product's APSD. Subsequently, correlations should be established from the selected AIM CIs to the corresponding full-resolution system, ideally developing specifications common to both techniques. In the commercial phase, it should be possible to release product using AIM/EDA, keeping the full-resolution CI for investigations, change control, and trouble-shooting, thus optimizing resources for APSD characterization throughout the product lifecycle. If an in vitro-in vivo relationship is established and clinically relevant sizes are known, an AIM-pHRT could serve as a quick indicator that clinically relevant fractions have not changed and also, in the management of post-approval changes.

Application of a Droplet Evaporation Model to Aerodynamic Size Measurement of Drug Aerosols Generated by a Vibrating Mesh Nebulizer

Droplet evaporation has been known to bias cascade impactor measurement of aerosols generated by jet nebulizers. Previous work suggests that vibrating mesh nebulizers behave differently from jet nebulizers. Unlike jet nebulizers, vibrating mesh nebulizers do not rely on compressed air to generate droplets. However, entrained air is still required to transport the generated droplets through the cascade impactor during measurement. The mixing of the droplet and entrained air streams, and heat and mass transfer occurring downstream determines the final aerosol size distribution actually measured by the cascade impactor. This study is aimed at quantifying the effect of these factors on droplet size measurements for the case of vibrating mesh nebulizers. A simple droplet evaporation model has been applied to investigate aerodynamic size measurement of drug aerosol droplets produced by a proprietary vibrating mesh nebulizer. The droplet size measurement system used in this study is the Next Generation Impactor (NGI) cascade impactor. Comparison of modeling results with experiment indicates that droplet evaporation remains a significant effect when sizing aerosol generated by a vibrating mesh nebulizer. Results from the droplet evaporation model shows that the mass median aerodynamic diameter (MMAD) measured by the NGI is strongly influenced not only by the initial droplet size, but also by factors such as the temperature and humidity of entrained air, the nebulizer output rate, and the entrained air flow rate. The modeling and experimental results indicate that the influence of these variables on size measurements may be reduced significantly by refrigerating the impactor down to 5°C prior to measurement. The same data also support the conclusion that for the case of nebulized drug solutions, laser diffraction spectrometry provides a meaningful droplet sizing approach, that is simpler and less susceptible to such droplet evaporation artifacts.

Temporal variation and impact of wood smoke pollution on a residential area in southern Germany

This paper is a continuation of our previous publication (Bari, M.A., Baumbach, G., Kuch, B., Scheffknecht, G., 2009. Wood smoke as a source of particle-phase organic compounds in residential areas. Atmospheric Environment 43, 4722–4732) and describes a detailed characterisation of different particle-phase wood smoke tracer compounds in order to find out the impact of wood-fired heating on ambient PM 10 pollution in a residential area near Stuttgart in southern Germany. The results from previous flue gas measurements help distinguishing different tracer compounds in ambient PM 10 samples. In the residential area, significant amounts of hardwood markers (syringaldehyde, acetosyringone, propionylsyringol, sinapylaldehyde) and low concentrations of softwood markers (vanillin, acetovanillone, coniferyldehyde, dehydroabietic acid, retene) were found in the ambient air. The general wood combustion markers Levoglucosan, mannosan and galactosan were detected in high concentrations in all particle-phase PM 10 samples. To find out the size distribution of ambient particles, cascade impactor measurements were carried out. It was found that more than 70% of particulate matter was in the particle diameter of less than 1 μm. Using emission ratio of levoglucosan to PM 10, it can be demonstrated that during winter months 59% of ambient PM 10 pollution could be attributed to residential wood-fired heating.

Minimizing variability of cascade impaction measurements in inhalers and nebulizers.

The purpose of this article is to catalogue in a systematic way the available information about factors that may influence the outcome and variability of cascade impactor (CI) measurements of pharmaceutical aerosols for inhalation, such as those obtained from metered dose inhalers (MDIs), dry powder inhalers (DPIs) or products for nebulization; and to suggest ways to minimize the influence of such factors. To accomplish this task, the authors constructed a cause-and-effect Ishikawa diagram for a CI measurement and considered the influence of each root cause based on industry experience and thorough literature review. The results illustrate the intricate network of underlying causes of CI variability, with the potential for several multi-way statistical interactions. It was also found that significantly more quantitative information exists about impactor-related causes than about operator-derived influences, the contribution of drug assay methodology and product-related causes, suggesting a need for further research in those areas. The understanding and awareness of all these factors should aid in the development of optimized CI methods and appropriate quality control measures for aerodynamic particle size distribution (APSD) of pharmaceutical aerosols, in line with the current regulatory initiatives involving quality-by-design (QbD).

Fine and Coarse Particulate Matter Chemical Characterization in a Heavily Industrialized City in Central Mexico during Winter 2003

This paper presents the results of the first reported study on fine particulate matter (PM) chemical composition at Salamanca, a highly industrialized urban area of Central Mexico. Samples were collected at six sites within the urban area during February and March 2003. Several trace elements, organic carbon (OC), elemental carbon (EC), and six ions were analyzed to characterize aerosols. Average concentrations of PM with aerodynamic diameter of less than 10 μm (PM10) and fine PM with aerodynamic diameter of less than 2.5 μm (PM2.5) ranged from 32.2 to 76.6 μg m-3 and 11.1 to 23.7 μg m-3, respectively. OC (34%), SO4 = (25.1%), EC (12.9%), and geological material (12.5%) were the major components of PM2.5. For PM10, geological material (57.9%), OC (17.3%), and SO4 = (9.7%) were the major components. Coarse fraction (PM10 –PM2.5), geological material (81.7%), and OC (8.6%) were the dominant species, which amounted to 90.4%. Correlation analysis showed that sulfate in PM2.5 was present as ammonium sulfate. Sulfate showed a significant spatial variation with higher concentrations to the north resulting from predominantly southwesterly winds above the surface layer and by major SO2 sources that include a power plant and refinery. At the urban site of Cruz Roja it was observed that PM2.5 mass concentrations were similar to the submicron fraction concentrations. Furthermore, the correlation between EC in PM2.5 and EC measured from an aethalometer was r2 = 0.710. Temporal variations of SO2 and nitrogen oxide were observed during a day when the maximum concentration of PM2.5 was measured, which was associated with emissions from the nearby refinery and power plant. From cascade impactor measurements, the three measured modes of airborne particles corresponded with diameters of 0.32, 1.8, and 5.6 μm.

Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols: Part 2—Evaluation of a method for determining equivalence

The purpose of this article is to present the thought process, methods, and interim results of a PQRI Working Group, which was charged with evaluating the chi-square ratio test as a potential method for determining in vitro equivalence of aerodynamic particle size distribution (APSD) profiles obtained from cascade impactor measurements. Because this test was designed with the intention of being used as a tool in regulatory review of drug applications, the capability of the test to detect differences in APSD profiles correctly and consistently was evaluated in a systematic way across a designed space of possible profiles. To establish a "base line," properties of the test in the simplest case of pairs of identical profiles were studied. Next, the test's performance was studied with pairs of profiles, where some difference was simulated in a systematic way on a single deposition site using realistic product profiles. The results obtained in these studies, which are presented in detail here, suggest that the chi-square ratio test in itself is not sufficient to determine equivalence of particle size distributions. This article, therefore, introduces the proposal to combine the chi-square ratio test with a test for impactor-sized mass based on Population Bioequivalence and describes methods for evaluating discrimination capabilities of the combined test. The approaches and results described in this article elucidate some of the capabilities and limitations of the original chi-square ratio test and provide rationale for development of additional tests capable of comparing APSD profiles of pharmaceutical aerosols.

Particle Size Analysis in Pharmaceutics: Principles, Methods and Applications

Physicochemical and biopharmaceutical properties of drug substances and dosage forms can be highly affected by the particle size, a critical process parameter in pharmaceutical production. The fundamental issue with particle size analysis is the variety of equivalent particle diameters generated by different methods, which is largely ascribable to the particle shape and particle dispersion mechanism involved. Thus, to enable selection of the most appropriate or optimal sizing technique, cross-correlation between different techniques may be required. This review offers an in-depth discussion on particle size analysis pertaining to specific pharmaceutical applications and regulatory aspects, fundamental principles and terminology, instrumentation types, data presentation and interpretation, in-line and process analytical technology. For illustration purposes, special consideration is given to the analysis of aerosols using time-of-flight and cascade impactor measurements, which is supported by a computational analysis conducted for this review.

EFFECTIVE DOSE SCALING FACTORS FOR USE WITH CASCADE IMPACTOR SAMPLING DATA IN TENORM INHALATION EXPOSURES

When assessing the effective dose to workers following radio-aerosol inhalation exposures, significant reductions in dose uncertainty can be achieved through direct measurement of the particle-size distribution. The University of Washington Mark III cascade impactor is one such air sampling device that permits the user to determine aerosol mass and radioactivity concentrations as a function of particle size within eight different size intervals (each corresponding to a different impactor stage or end filter). Traditionally, dose assessments made using the LUDEP code or other internal dosimetry software utilize this air sampling information by assigning the radioactivity measured at each stage as concentrated at a single representative size central to the size interval. In this study, we explore more realistic assumptions that the measured radioactivity distributes uniformly, linearly increases, or linearly decreases across the particle size interval for each impactor stage. The concept of an effective dose scaling factor, SF(E), is thus introduced whereby (1) the former approach can be used (which requires less computational effort using the LUDEP code), and (2) the resulting values of effective dose per stage can then be rescaled to values appropriate to a linear radioactivity distribution per stage. For a majority of (238)U-series radionuclides, particle size ranges, and absorption classes, differences in these two approaches are less than 10%, and thus no corrections in effective dose per particle stage are needed. Significant corrections, however, were noted in select cases. For uniform or linearly decreasing radioactivity distributions, end-filter particles (0.03 to 0.35 microm) of type F, M, or S radionuclides were assigned values of SF(E) ranging from 1.15 to 1.44, while 3(rd) stage particles (4.5 to 12 microm) of type M and S radionuclides were assigned values of SF(E) ranging from 1.11 to 1.53. When the cascade impactor measurements indicate a linear increase of activity across a given impactor-stage size range, values of SF(E) range from a high of 1.11 (6(th) stage particles of type F radionuclides) to lows of 0.85 to 0.91 (4(th) stage and end-filter particles of type M and S radionuclides). In these cases, the inhalation dose coefficient varies non-linearly across the particle size range, and the assumption of a mono-size distribution per impactor stage either underestimates (SF(E) > 1) or overestimates (SF(E) < 1) that stage's contribution to the worker effective dose.

Modeling particulate matter in the San Joaquin Valley with a source-oriented externally mixed three-dimensional photochemical grid model

Air pollution in California's San Joaquin Valley (SJV) rivals that of the Los Angeles area and ranks among the worst in the United States for particulate matter (PM) and ozone. The application and validation of an atmospheric chemical transport model to the SJV will aid in the design of emissions control programs to improve air quality. The extensive data required for meaningful Eulerian modeling of airborne PM in the SJV region were collected as a part of the 1995 Integrated Monitoring Study (IMS95). In the current study, the CIT-UCD source-oriented air quality model is applied to the IMS95 data set to verify model performance in the SJV. This article represents the first published application of a full-scale photochemical grid model with diagnostic meteorological data to simulate PM concentrations in the SJV and is the first study outside of the Los Angeles area to include complete PM model performance statistics. The CIT-UCD model results show excellent agreement with most measurements collected during the IMS95 4–6 January 1996 modeling episode. The fractional bias (FBIAS) for SJV ozone and PM 10 are approximately 0.16 and −0.19, respectively, for all SJV stations excluding Bakersfield. Most modeled criteria gases, PM precursor gases, and chemically speciated PM concentrations show strong agreement with their corresponding measurements at the Chowchilla, Fresno, Kern Wildlife Refuge, and Bakersfield sampling stations. Furthermore, the modeled PM size distribution of nitrate, ammonium ion, and sulfate agree well with cascade impactor measurements made at Bakersfield on 5 January 1996. Given the robust model agreement with both gas and condensed phase measurements, it appears that the CIT-UCD model adequately captures the fundamental transport and chemical reactivity of air pollutants in the IMS95 domain during a typical severe pollution episode. These results suggest that the CIT-UCD model can be used to explore control scenarios designed to improve air quality in the SJV.

Characterization of Submicron Exhaust Particles from Engines Operating Without Load on Diesel and JP-8 Fuels

Diluted exhaust from a selection of Air Force ground support vehicles was subjected to gravimetric, carbon, and size distribution analyses in September 1999. The vehicles operated on diesel and JP-8 fuels. In most cases, the engines involved were similar to civilian counterparts. The tests involved low and high idle settings but no external loads were imposed. Particle size distribution data, obtained over the 10 to 352 nanometer diameter range using an SMPS instrument, showed that the relative number count of accumulation mode particles increased with respect to nucleation mode particles as the engine rpm increased. The SMPS distributions often explained the main variations in the integrated PM 2.5 gravimetric mass data. Particulate mass derived from the SMPS data and from cascade impactor measurements were well correlated (regression slope 1.02). Empirically determined elemental carbon (EC) and organic carbon (OC) were the main constituents of the PM 2.5 gravimetric mass (regression slope 0.89)....

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.

An Evaluation of Mass-Weighted Size Distribution Measurements with the Model 3320 Aerodynamic Particle Sizer

The ability of the Model 3320 aerodynamic particle sizer (APS) to make accurate mass-weighted size distribution measurements was investigated. Significant errors were observed in APS size distribution measurements with measured mass median aerodynamic diameters (MMADs) as much as 17 times higher than from cascade impactor measurements. Analysis of APS correlated time-of-flight and light scattering data indicated that the MMAD distortions were due to a few anomalous large particle measurements (∼0.1% of the total measurements) with surprisingly low scattered light. Computational fluid dynamics modeling indicated that these anomalous measurements were due to particles that deviated from the intended aerosol pathway and recirculated through the APS measurement volume at low velocities leading to erroneous large particle measurements. A technique for removing erroneous measurements based on correlated aerodynamic diameter and light scattering values is presented. When this technique was used, APS and cascade impactor size distribution measurements agreed well.

Respiratory Deposition Patterns of Salbutamol pMDI with CFC and HFA-134a Formulations in a Human Airway Replica

This paper describes a technique that uses a well-defined human airway replica and gamma counting as a standard method for evaluating and comparing the performance of medical inhalers and spacers. High-fidelity replicas reproduced as needed from master casts made from human cadavers include the oropharyngeal cavity, larynx, trachea, and five to nine generations of bronchi. Deposition in the small airways and alveoli region of the cast is simulated by material that passes through the upstream airways and is collected on foam filters. Deposition patterns in the respiratory tract replica were obtained by using radiolabel in the medical inhaler and by gamma scintigraphy. This technique was used to determine respiratory deposition patterns of salbutamol in a pressurized metered dose inhaler (pMDI) with chlorofluorocarbon (CFC, in-house formulation) and HFA-134 formulations (Proventil hydrofluoroalkane [HFA]). At an inspiration flow of 30 L/min, patterns in the salbutamol/CFC formula showed a high deposition in the oropharyngeal airway (78%) and a 16% deposition in the lung, similar to in vivo measurements reported in the literature. However, the salbutamol/HFA formula showed lower oral deposition (56%) but higher lung deposition (24%). The difference in the oral deposition patterns may be attributed to lower initial spray velocity, initial droplet evaporation rate, and possibly initial droplet sizes of Proventil HFA. The small orifice diameter (0.25 mm) of the Proventil HFA actuator produced a softer plume with a smaller impact force, resulting in lower oropharyngeal deposition. Cascade impactor measurements showed similar aerodynamic particle size distribution of the CFC and HFA formulations. We also showed that using spacers in the Proventil HFA resulted in a lower oropharyngeal deposition and higher lung deposition, indicating beneficial effects. Comparison of oropharyngeal deposition and those predicted by artificial throats used in the impactor measurements showed that, in general, the artificial throat predicted a lower deposition.