Deposition of a polydisperse aerosol (MR/ID = 4.8 mu m, GSD = 1.65) in a replica of a human mouth-throat is measured experimentally and compared to predicted results using computational fluid dynamics (CFD). The mouth-throat geometry represents an idealized, average mouth-throat. Experimental values of the fraction eta of aerosol depositing in this mouth-throat are obtained using a radiolabelled, nebulized aerosol generated with a Pari LC+ nebulizer. Gamma scintigraphy is used to measure amounts of aerosol depositing at laminar (21 min(-1)) and turbulent (28.31 min(-1)) flow rates. Deposition is predicted computationally using a commercial CFD code (TASCflow) for these two flow rates. For the turbulent case, the standard k-epsilon turbulence model was used with the most common eddy lifetime model for turbulent particle dispersion [Gosman and Ioannides (1983) J. Energy 7, 482-490].Good agreement between experiment and simulation is found for laminar flow (experiment: eta = 15.7 +/- 0.3%, simulation eta = 16%), but not for turbulent flow (experiment: eta = 25.6 +/- 0.7%, simulation eta = 65%). Measured and predicted pressure drops agree well for laminar flow (experiment: 0.26 +/- 0.02 Pa, simulation: 0.25 Pa), but differ less dramatically for the turbulent case than does deposition (experiment: 25.2 +/- 0.5 Pa, simulation: 22.3 Pa), indicating that accurate prediction of particle deposition in this geometry requires more accurate prediction of the fluid dynamics than can be obtained with the present turbulence model (C) 2000 Elsevier Science Ltd. All rights reserved.

The use of Anderson cascade impaction to measure droplet sizes from a vented nebulizer connected directly to the impactor was examined by performing two sets of impactor measurements. In the first set, the impactor was operated in room temperature air. In the second set, the impactor was immersed in a cooled water bath at the same temperature as the aerosol exiting the nebulizer (10°C). Normal saline was nebulized in five Pari LC Jet+nebulizers driven by a single Pulmo-Aide compressor, operating under ambient conditions of 36% RH and 22°C. Impaction was done once steady temperatures were reached. When the impactor was operated in room temperature air, the air travelling through the impactor warmed from 10°C at the entrance to the impactor to room temperature at the exit of the impactor. This heating resulted in significant droplet shrinkage due to humidification by evaporation from the droplets, since the impactor immersed in the cooled water bath gave an MMAD that was on average 70% larger than was obtained when the impactor was operated in room air (3.4μm vs 2.1μm). These results emphasize the need for caution when using impactors to measure nebulized hygroscopic aerosols, since even if these aerosols enter the impactor in vapor pressure equilibrium with their surrounding air, significant size changes can occur during transit through the impactor if the temperature of the aerosol differs significantly from that surrounding the impactor.

Journal of Aerosol MedicineVol. 11, No. s1 International Society for Aerosols in Medicine Focus Symposium TOWARDS MEANINGFUL LABORATORY TESTS FOR EVALUATION OF PHARMACEUTICAL AEROSOLS Puerto Rico, January 29–31,1997Errors in Characterizing Nebulized Particle Size Distributions with Cascade ImpactorsK.W. STAPLETON and W.H. FINLAYK.W. STAPLETONSearch for more papers by this author and W.H. FINLAYSearch for more papers by this authorPublished Online:25 Mar 2010https://doi.org/10.1089/jam.1998.11.Suppl_1.S-80AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byHow Cold Is Cold Enough? Refrigeration of the Next-Generation Impactor to Prevent Aerosol Undersizing Uwe Schuschnig, Benjamin Heine, and Martin Knoch14 February 2022 | Journal of Aerosol Medicine and Pulmonary Drug Delivery, Vol. 35, No. 1Humidified and Heated Cascade Impactor for Aerosol Sizing13 November 2020 | Frontiers in Bioengineering and Biotechnology, Vol. 8Electrostatic Charge Characteristics of Jet Nebulized Aerosols Philip Chi Lip Kwok, Sebastiaan J. Trietsch, Michiko Kumon, and Hak-Kim Chan18 June 2010 | Journal of Aerosol Medicine and Pulmonary Drug Delivery, Vol. 23, No. 3Assessment methods of inhaled aerosols: technical aspects and applications29 July 2009 | Expert Opinion on Drug Delivery, Vol. 6, No. 9Influence of Impactor Operating Flow Rate on Particle Size Distribution of Four Jet Nebulizers7 October 2008 | Pharmaceutical Development and Technology, Vol. 12, No. 4Laser Diffractometry as a Technique for the Rapid Assessment of Aerosol Particle Size from Inhalers Jolyon P. Mitchell, Mark W. Nagel, Steve Nichols, and Ola Nerbrink29 December 2006 | Journal of Aerosol Medicine, Vol. 19, No. 4Improved Efficiency of Budesonide Nebulization Using Surface-Active Agents10 October 2008 | Drug Delivery, Vol. 13, No. 5Effect of Tubing Deposition, Breathing Pattern, and Temperature on Aerosol Mass Distribution Measured by Cascade Impactor Burak K. Gurses and Gerald C. Smaldone7 July 2004 | Journal of Aerosol Medicine, Vol. 16, No. 4Effect of Humidity on Constant Output and Breath Enhanced Nebulizer Designs When Tested in the EN 13544-1 EC StandardAerosol Science and Technology, Vol. 37, No. 3Evaluation of Four Breath-Enhanced Nebulizers for Home Use Sharon L. Ho, W.T. Jenny Kwong, Lisa O'Drowsky, and Allan L. Coates7 July 2004 | Journal of Aerosol Medicine, Vol. 14, No. 4New Nebulizer Technology23 August 2013Aerosols and Anti-Infectious Agents P. Diot, P.F. Dequin, B. Rivoire, F. Gagnadoux, F. Faurisson, E. Diot, E. Boissinot, A. Le Pape, L. Palmer, and E. Lemarié7 July 2004 | Journal of Aerosol Medicine, Vol. 14, No. 1 Volume 11Issue s1Jun 1998 To cite this article:K.W. STAPLETON and W.H. FINLAY.Errors in Characterizing Nebulized Particle Size Distributions with Cascade Impactors.Journal of Aerosol Medicine.Jun 1998.S-80-S-83.http://doi.org/10.1089/jam.1998.11.Suppl_1.S-80Published in Volume: 11 Issue s1: March 25, 2010PDF download

Regional lung dosages are estimated for 19 different nebulizer types, and variations in these dosages within each nebulizer type are given. Experimental methods are used to characterize the aerosols inhaled in vitro (inhalation flow rate = 300 mL/s, tidal volume = 750 mL) from nebulizers filled with 2.5 mL of Ventolin (1 mg/mL of salbutamol sulphate in normal saline) under ambient conditions of 50% +/- 3% relative humidity (RH), 22 degrees C +/- 1 degrees C. These data are input into a hygroscopic, mathematical lung deposition model to estimate regional lung dosages for a scaled Weibel A lung. The deposition model is a two-way coupled model (i.e., it includes the effects of droplet heat and mass transfer on the surrounding environment and vice versa). As a percentage of normal dose placed in the nebulizer, regional dosages differed significantly between the different nebulizer types (P < 0.01) and varied from 3.1% to 23.4%, 1.6% to 10.6%, 1.6% to 12.8%, and 1.8% to 9.5% for lung, tracheobronchial, alveolar, and extrathoracic deposition, respectively. Variations in regional dosages between nebulizers of each type had standard deviations that mere, on average, less than 2% of the nominal dose. Of the three nebulizer classes tested (ultrasonic, conventional, and vented), no class consistently gave higher regional dosages than the other two classes. Good agreement with published in vivo scintigraphic data mas found (P > 0.01) in lung dosages.

Journal of Aerosol MedicineVol. 11, No. s1 International Society for Aerosols in Medicine Focus Symposium TOWARDS MEANINGFUL LABORATORY TESTS FOR EVALUATION OF PHARMACEUTICAL AEROSOLS Puerto Rico, January 29–31,1997Comparisons between Inhaled Fine Particle Fractions and Lung Dose for Nebulized AerosolsW.H. FLNLAY, K.W. STAPLETON, and P. ZUBERBUHLERW.H. FLNLAYSearch for more papers by this author, K.W. STAPLETONSearch for more papers by this author, and P. ZUBERBUHLERSearch for more papers by this authorPublished Online:25 Mar 2010https://doi.org/10.1089/jam.1998.11.Suppl_1.S-65AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetails Volume 11Issue s1Jun 1998 To cite this article:W.H. FLNLAY, K.W. STAPLETON, and P. ZUBERBUHLER.Comparisons between Inhaled Fine Particle Fractions and Lung Dose for Nebulized Aerosols.Journal of Aerosol Medicine.Jun 1998.S-65-S-72.http://doi.org/10.1089/jam.1998.11.Suppl_1.S-65Published in Volume: 11 Issue s1: March 25, 2010PDF download

The amount of aerosol inhaled in different fine particle definitions is compared to the amount of aerosol depositing in the lung and alveolar regions for nearly isotonic nebulized aerosols. These comparisons are made using a two-way coupled hygroscopic deposition model with experimental data obtained for over 200 different nebulizers from 19 different nebulizer models nebulizing salbumatol sulphate (1 mg ml−1 in isotonic saline). Mass depositing in the lungs and mass inhaled in particles with diameters 1–6 μm are statistically different (p < 0.05). Results are also presented for log-normally distributed aerosols as a function of mass median aerodynamic diameter (MMAD) ranging from 1.0 to 9.0 μm and geometric standard deviations (GSDs) from 1.0–2.5. Fine particle fraction definitions of 0–5, 1–5, 0–6, 1–7 and 1–10 μm are considered. For the polydisperse aerosols considered, each inhaled fine particle mass is equal to mass depositing in the lungs at a unique critical MMAD. However, all of the inhaled fine particle definitions give results much different from mass depositing in the lungs at MMADs away from their critical MMADs, overestimating mass depositing in the lungs by as much as 3.7 times and underestimating it by as much as 6.3 times. Although mass depositing in the lungs and the different fine particle definitions are correlated over certain particle size ranges, no correlation is valid over the entire particle size range considered. For reasonably polydisperse aerosols, inhaled fine particle mass strongly overemphasizes the benefits of MMADs in the 2–4 μm range, since lung deposition is much less weakly dependent on MMAD than predicted by fine particle dose.

A method for estimating the regional lung dosages of a nebulized suspension is presented and applied to Pulmicort(R) (budesonide) suspension (4 ml, 0.5 mg/ml) nebulized with three Pari LC+ nebulizers driven by a Pulmo-Aide compressor. The methodology combines experimental measurements of the nebulized aerosol with a mathematical lung deposition model. By adding methylene blue as a tracer for the water, cascade impaction with UV spectrophotometry is used to characterize the distribution of both budesonide and water in the inhaled droplets. Tidal breathing is simulated experimentally using a breath simulator to estimate the amount of inhaled drug. A valve system allows cascade impaction to occur at a constant flow rate of 28.3 l/min. while inhalation at 18 l/min. occurs through the nebulizer. Lung dosages (as % of inhaled dose) obtained with the methodology are in good agreement with values observed in vivo by previous researchers using pharmacokinetic methods with the LC+ nebulizer and the present budesonide formulation. Budesonide is found to be preferentially contained in the larger droplets, and calculated regional lung dosages show that an assumption of homogeneous distribution of the budesonide in the inhaled droplets is incorrect.

Regional lung deposition predictions from a stable particle model and a conventional, one-way hygroscopic model (Stapleton, K.W., Finlay, W.H. and Zuberbuhler, P., An in vitro method for determining regional dosages delivered by jet nebulizers. J. Aerosol Med., 7 (1994) 325–344) are compared with results from a more general, fully two-way coupled hygroscopic model (Finlay, W.H. and Stapleton, K.W., The effect on deposition of coupled heat and mass transfer between hygroscopic droplets and their surrounding phase. J. Aerosol Sci. 26, (1995) 137–145) for actual nebulized aerosols characterized experimentally. Data is obtained for Ventolin® (2.5 ml nebule, 1 mg/ml salbutamol sulphate in normal saline) with ambient conditions of 50% RH and six nebulizer brands, and for 15% RH and 90% RH for three nebulizer brands, all at room temperature. This data is entered into a deposition model with the three hygroscopic models for an inhalation flow rate of 300 ml/s and tidal volume of 750 ml. The results indicate that errors in regional dosages of less than 14% of the two-way coupled value occur when using either a stable particle model or a one-way coupled hygrosopic model at 90% RH. Similarly small errors occur at all humidities tested with the stable particle model for the nebulizer brands having high number density; however, for the other nebulizer brands, errors up to 19% in extrathoracic deposition and 35% in alveolar deposition occur at 15% RH and 50% RH. The one-way coupled model gives significant errors (up to 48%) in alveolar and extrathoracic deposition at these two lower humidities for most nebulizer brands tested.

Computational fluid dynamics (CFD) can produce erroneous results if not used with adequate thought to several issues, some of which are discussed in the present article. Some of these issues are associated with modeling the physics, particularly the turbulence that occurs in the upper airways. For determining the location of deposition of inhaled aerosols, physical models of particle motion must also be specified and various issues associated with such models should be considered. Numerical modeling issues, including grid resolution and numerical boundary condition effects, can also profoundly affect a numerical simulation. The purpose of the present article is to highlight the importance of some of these issues in the context of modeling the fluid dynamics and particle motion in the human respiratory tract, especially for those researchers whose background is not in a discipline normally associated with CFD.

The regional deposition patterns of inhaled hygroscopic aerosols obtained in vivo in the studies of Phipps et al. (P. R. Phipps, I. Gonda, D. L. Bailey, P. Borham, G. Bautovich, and S. D. Anderson. Am. Rev. Respir. Dis. 139: 1516, 1989; and P. R. Phipps, I. Gonda, S. D. Anderson, D. L. Bailey, and G. Bautovich. Eur. Respir. J. 7: 1474-1482, 1994) and Chan et al. (H.-K. Chan, P. R. Phipps, I. Gonda, P. Cook, R. Fulton, I. Young, and G. Bautovich. Eur. Respir. J. 7: 1483-1489, 1994) by using single-photon-emission computerized tomography (SPECT) are compared with the regional deposition predicted by the hygroscopic lung deposition model of Finlay and Stapleton (W. H. Finlay and K. W. Stapleton. J. Aerosol Sci. 26: 655-670, 1995). Three pairs of saline aerosols are considered: isotonic with small [2.6-microns mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD) 1.4] vs. large (5.5-microns MMAD, GSD 1.7) droplets; hypotonic (0.3% NaCl) vs. hypertonic (4.5% NaCl) with 3.7- to 3.8-microns MMAD (GSD 1.4), and hypotonic vs. hypertonic (3.7- to 3.8-microns MMAD, GSD 1.5-1.8) with reduced number of droplets per cubic centimeter. For each of the three pairs of aerosols, no significant difference (P > 0.05) was found between the in vivo and computational results for either the mean value or the variance of the difference in peripheral to central deposition. Thus it appears that theoretical calculations can be used to predict the pattern of lung deposition of hygroscopic aerosols in populations of normal subjects.

In this study, the output of DeVilbiss Pulmo-Neb(R) disposable jet nebulizers driven by a DeVilbiss Pulmo-Aide(R) compressor to nebulize 2.5 ml nebules of 1 mg/ml Ventolin(R) was measured at five ambient relative humidities ranging from 3% to 95%. It was found that as the humidity was increased from 3% to 95%, the mass median diameter of the aerosol increased by 14% while the concentration of the nebulizer solution at the end of the nebulization period decreased by 19%. Calculations using the procedure of Stapleton, Finlay, and Zuberbuhler (J. Aerosol Med., 7:325-344, 1994) predict that as the ambient relative humidity is increased from 3% to 95%, there is a 100% increase in extrathoracic dosage, a 9% increase in bronchial dosage, and a 63% decrease in pulmonary dosage. The major source of this effect is the hygroscopic shrinkage of the particles as they are inhaled with low humidity ambient air, although there is a minor effect due to changes in initial particle size distribution at different humidities. The significant effect of ambient relative humidity can be an important consideration for clinical settings and for in vivo measurements of lung deposition.

A procedure for coupling the heat and mass transfer between inhaled aerosol droplets and the continuous phase that carries the droplets is described and incorporated into a hygroscopic human lung deposition model. Heat and mass transfer coefficients at the airway walls are used to account for the effect of the coupling on wall heat and mass transfer. At 50% ambient RH, 20°C, and typical inhalation and nebulizer flow rates, by far the largest effect of coupling is on extrathoracic dosages, which are up to 137% and 50% greater than that predicted without coupling for initially isotonic 2.5 μ MMAD (GSD l.7) and 6.0 pm MMAD (GSD l.7) aerosols respectively, with 106 droplets cm−3. Coupling affects dosages by < 10% for all reg ions only if < 25,000 droplets cm−3 are present in the inhaled stream, indicating that coupling between the aerosol droplets and the continuous phase is an important consideration for modelling deposition of most hygroscopic medical aerosols.

This study describes an in vitro technique for calculating the dosages of drug delivered to the different regions of the human lung by an ultrasonic nebulizer. The technique uses phase Doppler anemometry to measure particle sizes. Tidal breathing is simulated with a reciprocating pump. Inhalation is divided into an interval in which the sizes of the particles are nearly independent of the relative humidity (RH) of the inlet ambient air and a second interval in which the particles have evaporated. The numerical hygroscopic lung deposition model of Stapleton, Finlay, and Zuberbuhler (J. Aerosol Med. 7, 325, 1994) is used to calculate the regional dosages. The methodology is applied to the DeVilbiss Aerosonic® ultrasonic nebulizer for 2.5 ml nebules of 1 mg ml−1 Ventolin®. The dosage of drug delivered to the extrathoracic, bronchial, and pulmonary regions is 0.42, 0.10, and 0.22 mg, respectively, at an inlet RH of 95% and 20°C. The corresponding values for RH = 3% are 0.39, 0.097, and 0.22 mg.

The concentration of the solution within aerosol droplets exiting a jet nebbulizer is determined by applying a control volume analysis to the air, and solute transport through the nebulizer. Measurements and calculations are made for the DeVilbiss Pulmo-Neb® disposable nebulizer delivering two unit dose nebules of Ventolin® (2.5 ml, 1 mgl−1 salbutamol sulphate, 0.9% saline), and it is shown that the droplet solution concentration is closely approximated by the concentration of the solution remaining in the nebulizer's reservoir. By increasing the time the aerosol droplets have before contacting the ambient environment, it is shown that the droplets are in equilibrium as they exit the nebulizer, and therefore the concentration of the solution in the droplets is independent of the droplet size.

A methodology for determining the regional dosages delivered to the respiratory tract by a jet nebulizer is presented and applied to the DeVilbiss PulmoNeb disposable nebulizer delivering a 2.5 ml nebule of Ventolin (1 mg/ml salbutamol sulphate). Results are obtained both with tapping of the nebulizer, which enhances nebulizer performance, and without tapping. The nebulizer output is characterised by measuring the total mass and the mass of solids leaving the nebulizer per minute, and performing a control volume analysis of the nebulizer. Particle size distributions are determined by phased Doppler anemometry. Deposition probabilities are calculated using a semi-empirical model for the deposition of hygroscopic aerosol particles in healthy adult Caucasian males. Deposition probabilities are then converted to regional dosages using the measured nebulizer output characteristics. The regional dosages (% of initial dose in nebulizer) of Ventolin delivered to the extrathoracic, bronchial, and alveolar regions of the respiratory tract are 0.248 +/- 0.005 mg (9.9%), 0.034 +/- 0.001 mg (1.4%), and 0.071 +/- 0.002 mg (2.8%) respectively when the nebulizer was tapped during operation, and 0.184 +/- 0.005 mg (7.4%), 0.025 +/- 0.001 mg (1.0%), and 0.052 +/- 0.002 mg (2.1%) when tapping was not used. This methodology provides a well controlled and rapid means of comparing the effectiveness of different nebulizers for use in aerosol therapy.