The effect of sinusoidal vibration on the uniformity of packing of powder beds

Sinusoidal vibration, at a number of defined sets of conditions, has been applied to packings of certain particle size fractions of lactose. The distribution of local porosity within these vibrated packings was determined using a gamma-ray attenuation technique, and could be compared with porosity data for samples not subjected to vibration. It was found that the application of vibration in a vertical mode markedly increased the uniformity of packing; horizontal vibration was less effective in this respect. The relationship between local porosity and position with a packing, observed in most non-vibrated samples, was generally absent from vibrated packings.     

Determination of porosity variations in powder beds

A gamma-ray attenuation technique for detecting local porosity variations in packings of pharmaceutical powders has been developed and assessed. It proved necessary to employ an empirical expression describing the attenuation coefficient of the model material, lactose, as a function of porosity. The precision of measurement of local porosity can be pre-selected due to the statistical basis of the method, and local porosity measurements with 95% confidence intervals of +/- 0.005 can readily be carried out. A method of producing grey-scale images of porosity distributions has been employed to enable the degree of inhomogeneity of a powder bed to be seen.     

Equivalence testing and equivalence limits of metered-dose inhalers and dry powder inhalers measured by in vitro impaction.

In this study, criteria for the acceptability of comparative in vitro equivalence testing are proposed. Furthermore, the following equivalence limits for in vitro impaction methods are postulated: the 90% confidence interval (CI) of the in vitro deposition ratio of the test product and the reference product should lie within 0.80-1.20. The aim of this study was to challenge these limits by applying them to in vitro impaction results of several groups of pressurized metered-dose inhalers and dry powder inhalers containing salbutamol and beclomethasone dipropionate. The deposition results were obtained with the Twin Impinger. All products had a marketing authorization in The Netherlands and were considered therapeutically equivalent within each group. The postulated equivalence limits/group were challenged by fictitiously assigning a preparation as a test product or reference product and calculating the 90% CI of the deposition ratio of the test and reference products. All possible combinations of products within a group were tested. The products were considered equivalent if the 90% CI of the quotient lay within 0.80-1.20. In most cases, the quotient of the test product and reference product remains within 0.80-1.20, but due to a high variability in the deposition results of several products, the 90% CI of the quotient sometimes falls outside the proposed equivalence limits. It is concluded that the equivalence limits postulated are rather conservative, with respect to accepting equivalence. The limits can therefore serve as a prudent predictor of equivalence within the acceptability criteria proposed, but have to be further validated.     

Nasal deposition and clearance in man: comparison of a bidirectional powder device and a traditional liquid spray pump

Abstract Background: Delivery of powder formulations to the nose is an attractive alternative for many drugs and vaccines. This study compared the regional nasal deposition and clearance patterns of lactose powder delivered by the OptiNose powder device (Opt-Powder; OptiNose US Inc., Yardley, PA, USA) to that of liquid aerosol administered via a traditional hand-actuated liquid spray pump (Rexam SP270, Rexam Pharma, France). Methods: The study was an open-label, crossover design in seven healthy subjects (five females, two males). The regional nasal deposition and clearance patterns of the Opt-Powder device were compared to a traditional liquid spray pump by dynamic gamma camera imaging after administration of either (99m)Tc-labeled lactose powder or liquid (99m)Tc- diethelyne triamine pentaacetic acid-aerosol. The gamma camera images were scaled and aligned with sagittal magnetic resonance images to identify nasal regions. Possible deposition of radiolabeled material in the lungs following both methods of delivery was also evaluated. Results: Both powder and spray were distributed to all of the nasal regions. The Opt-Powder device, however, achieved significantly larger initial deposition in the upper and middle posterior regions of the nose than spray (upper posterior region; Opt-Powder 18.3%±11.5 vs. Spray 2.4%±1.8, p<0.02; sum of upper and middle posterior regions; Opt-Powder 53.5%±18.5 vs. Spray 15.7%±13.8, p<0.02). The summed initial deposition to the lower anterior and posterior regions for spray was three times higher compared to Opt-Powder (Opt-Powder 17.4%±24.5 vs. Spray 59.4%±18.2, p<0.04). OptiNose powder delivery resulted in more rapid overall nasal clearance. No lung deposition was observed. Conclusions: The initial deposition following powder delivery was significantly larger in the ciliated mucosa of the upper and posterior nasal regions, whereas less was deposited in the lower regions. Overall nasal clearance of powder was slower initially, but due to retention in anterior nonciliated regions the overall nasal clearance after spray was slower.     

Models of deposition,pharmacokinetics, and intersubject variability in respiratory drug delivery

ABSTRACT

Introduction: Aerosol drug delivery to the lungs via inhalation is widely used in the treatment of respiratory diseases. The deposition pattern of inhaled particles within the airways of the respiratory tract is key in determining the initial delivered dose. Thereafter, dose-dependent processes including drug release or dissolution, clearance, and absorption influence local and systemic exposure to inhaled drugs over time.

Areas covered: Empirical correlations, numerical simulation, and in vitro airway geometries that permit improved prediction of extrathoracic and lung deposition fractions in a variety of age groups and breathing conditions are described. Efforts to link deposition models with pharmacokinetic models predicting lung and systemic exposure to inhaled drugs over time are then reviewed. Finally, new methods to predict intersubject variability in extrathoracic deposition, capturing variability in both size and shape of the upper airways, are highlighted.

Expert opinion: Recent work has been done to expand in vitro deposition experiments to a wide range of age groups and breathing conditions, to link regional lung deposition models with pharmacokinetic models, and to improve prediction of intersubject variability. These efforts are improving predictive understanding of respiratory drug delivery, and will aid the development of new inhaled drugs and delivery devices.     

The vibratory consolidation of particle size fractions of powders

The use of controlled sinusoidal vibration as a means of consolidating packings of lactose within small containers has been examined. Vertical vibration was found significantly more effective and reproducible than horizontal vibration in terms of the degree of consolidation achieved. An optimum frequency range was identified within which the densification was greatest, and this range was largely independent of particle size for particle size fractions of mean volume diameters ranging from 15.6 to 155 μm. The consolidation increased with increasing vibration acceleration up to a level beyond which no further decrease in porosity resulted. Typical effective vibration conditions were characterized by amplitudes of an order of magnitude similar to the particle sizes studied. For particle size fractions of mean diameters 17·8, 37·5 and 80·8 μm, there is evidence that an optimum particle size range exists, within which energy requirements for consolidation are at a minimum.     

Influence of Mouthpiece Geometry on the Aerosol Delivery Performance of a Dry Powder Inhaler

Purpose

To investigate the influence of mouthpiece geometry on the amount of throat deposition and device retention produced using a dry powder inhaler (Aerolizer^®), along with the subsequent effect on the overall inhaler performance.

Materials and Methods

Computational Fluid Dynamics analysis of the flowfield generated in the Aerolizer^® with various modified mouthpiece geometries (including cylindrical, conical and oval designs) was used in conjunction with experimental dispersions of mannitol powder using a multi-stage liquid impinger to determine how the overall inhaler performance varied as the mouthpiece geometry was modified.

Results

Geometry of the inhaler mouthpiece had no effect on device retention or the inhaler dispersion performance. In contrast, the mouthpiece geometry strongly affected the amount of throat deposition by controlling the axial component of the exit air flow velocity. The radial motion of the emitted aerosol jet was found to have little effect on throat deposition in representative mouth–throat models. Despite the reduced throat deposition, there was no difference in the overall inhaler performance.

Conclusions

For cases where low throat deposition is a key design parameter, this study demonstrates that the amount of throat deposition can be reduced by making minor modifications to the inhaler mouthpiece design.

     

Optimum support properties for protein separations by high-performance size exclusion chromatography

Optimum chromatographic properties of high performance size exclusion chromatography (HPSEC) of proteins, such as resolution, molecular weight accuracy and recovery, are obtained on packings and columns with tailor-made physical and chemical structures, employed at properly adjusted eluent compositions and operation conditions. SEC-theory suggests that a broad molecular weight fractionation range and high linearity of the log-linear calibration plot can be achieved by the use of two packings (10- and 80-nm pore size, characterized by a pore-size distribution (psd) equal to or less than 1 decade and by equal internal column porosity (p)), rather than a single 30- to 50-nm pore-size packing with a wide psd. Favourably high-phase ratios of (p)/(o)/ 1.0 for HPSEC columns were accomplished with a minimum interstitial column porosity (o) and a high value for the internal column porosity (p) (the specific pore volume, nu(p), multiplied by the packing density, varrho(p).) Ligands such as diol, N-acetoxyamino and oligomeric ether with a propyl- or propoxy-spacer bonded to the silica at the highest density appear to provide high mass recovery and bioactivity as well as chemical stability. Such packings, available in 3-5 mum particle size ranges of narrow distribution, packed into columns 6 mm i.d. and 500 mm in length, offer the best compromise with respect to resolution, speed and pressure drop. More careful studies are required to explain the effects of protein conformational changes and interconversions during elution on HPSEC columns.     

The influence of properties of packing materials upon the recovery of biological substances isolated from urine by solid-phase extraction

A series of packing materials with alkyl phase chemically bonded to silica gels of various porosity have been prepared. These packings have been used to isolate the test substances 5-hydroxyindole-3-acetic acid (5-HIAA) and serotonin (5-HT) from urine. The influence of the support porosity, structure of chemically bonded phase, length of alkyl chain, and coverage density of the recovery of isolated substances was studied.     

DR. MARY AMDUR MEMORIAL LECTURE

The laboratory rat has frequently been used as a human surrogate in inhalation toxicology to assess potential health effects of inhaled particulate matter. Differences in initial particle deposition patterns in the human and rat lungs may be attributed primarily to their differences in airway morphology, that is, a relatively symmetric division scheme in the human lung as compared to a distinct asymmetric branching pattern in the rat lung, and to their differences in breathing parameters. To account for the experimentally observed variability and asymmetry of airway bifurcations in both lungs, our present computations of particle deposition patterns are based on previously developed stochastic morphometric lung models. Regional (i.e., tracheobronchial and pulmonary) and local (i.e., airway-by-airway) deposition patterns were calculated for a wide range of unit density particle sizes (1 nm to 10 mum) and flow rates for nasal breathing conditions. Different human physical activities were characterized by specified breathing parameters, while corresponding ventilation intensities in rat inhalation experiments were simulated by different CO2 exposure levels. Since this study focuses on the relative distribution of deposited particles among bronchial and pulmonary airways, deposition patterns were normalized to the number of particles entering the trachea. While there are noticeable quantitative differences between the corresponding deposition patterns in both lungs, their dependence on particle size and flow rate is qualitatively similar. Due to the intrasubject variability in airway morphology and related flow rates, deposition fractions are highly variable within a given generation. As a result of this, regional and total deposition also exhibit intrasubject variations. In general, intrasubject variability in the pulmonary region is larger than that in the bronchial airways, while the dispersion of the frequency distribution is even further enlarged for total deposition. At the airway generation level, frequency distributions of deposition probabilities within bronchial airway generation 4 and bronchiolar airway generation 12 in the human lung can be approximated by lognormal distributions. In contrast, two distinct deposition maxima can be observed in upper bronchial airways of the rat lung, reflecting deposition in major and minor daughter airways. These two modes, however, disappear upon penetration deeper into the lung and are no longer discernible in airway generation 12.     

Particle engineering of materials for oral inhalation by dry powder inhalers. II-Sodium cromoglicate

Sodium cromoglicate is an antiasthmatic and antiallergenic drug used in inhalation therapy and commonly administered by a dry powder inhaler. In the present study we sought to examine the feasibility of producing nanoporous microparticles (NPMPs) of this hydrophilic material by adaptation of a spray drying process previously applied to hydrophobic drugs, and to examine the physicochemical and in vitro deposition properties of the spray dried particles in comparison to a commercial product. The storage stability of successfully prepared NPMPs was assessed under a number of conditions (4°C with dessicant, 25°C at 60% relative humidity and 25°C with dessicant). Spray dried sodium cromoglicate was amorphous in nature. NPMPs of sodium cromoglicate displayed superior aerodynamic properties resulting in improved in vitro drug deposition, as assessed by Andersen Cascade Impactor and twin impinger studies, in comparison to the commercial product, Intal. Deposition studies indicated that porosity and sphericity were important factors in improving deposition properties. The optimum solvent system for NPMP production was water:methanol:n-butyl acetate, as spherical NPMPs spray dried from this solvent system had a higher respirable fraction than non-spherical NPMPs of sodium cromoglicate (spray dried from methanol:n-butyl acetate), non-porous sodium cromoglicate (spray dried from water) and micronised sodium cromoglicate (Intal). While particle morphology was altered by storage at high humidity (60% RH) and in vitro deposition performance deteriorated, it was possible to maintain NPMP morphology and aerosolisation performance by storing the powder with dessicant.     

Formulation and Characterization of Lipid-Coated Tobramycin Particles for Dry Powder Inhalation

Purpose This study was conducted to develop and evaluate the physicochemical and aerodynamic characteristics of lipid-coated dry powder formulations presenting particularly high lung deposition. Methods Lipid-coated particles were prepared by spray-drying suspensions with different concentrations of tobramycin and lipids. The solid-state properties of the formulations, including particle size and morphology, were assessed by scanning electron microscopy and laser diffraction. Aerosol performance was studied by dispersing the powders into a Multistage Liquid Impinger and determining drug deposition by high-performance liquid chromatography. Results Particle size distributions of the formulations were unimodal, narrow with more than 90% of the particles having a diameter of less than 2.8 μm. All powder formulations exhibited mass median diameters of less than 1.3 and 3.2 μm, as determined by two different laser diffraction methods, the Malvern's Mastersizer? and Spraytec?, respectively. The fine particle fraction varied within a range of 50.5 and 68.3%. Conclusions Lipid coating of tobramycin formulations resulted in a reduced agglomeration tendency and in high fine particle fraction values, thus improving drug deposition. The very low excipients content (about 5% m/m) of these formulations offers the benefit of delivering particularly huge concentrations of antibiotic directly to the site of infection, while minimizing systemic exposure, and may provide a valuable alternative treatment of cystic fibrosis.     

The formulation of powder inhalation systems containing a high mass of nedocromil sodium trihydrate

Nedocromil sodium trihydrate is not amenable to conventional methods of dry powder inhaler formulation, including the preparation of coarse carrier systems and aggregation of the pure drug powder. It is considered that the in vitro aerosol performance of such systems is governed by the cohesive drug-drug interactions. Therefore, alternative powder formulation strategies (novel to nedocromil sodium) were developed. By decreasing the particle size of the lactose carrier, the deaggregation and subsequent fine particle drug deposition were significantly improved. Further improvements were made by selecting and then optimizing high-shear mixing procedures. It was concluded, based on these findings and supportive microscopic studies (low-temperature and environmental scanning electron microscopy together with energy-dispersive X-ray analysis), that the FPL are producing their functional effects by intercalating within the drug self-agglomerates and physically disrupting the cohesive drug-drug interactions. The use of a smaller-sized lactose fraction in conjunction with a blending procedure capable of optimally disrupting the drug self-agglomerates allowed maximal intercalation of the excipient material within the drug self-agglomerates. The adhesive drug-FPL interactions are considered to be weak compared with the cohesive drug-drug particle interactions, cohesive interactions that would normally govern the aerosol performance of powder systems containing a high mass of nedocromil sodium trihydrate.     

Understanding penetration index measurements and regional lung targeting

Radiolabeling of pharmaceutical inhalation aerosols began in the late 1970s. Since then, well over 100 studies have been published. These studies have documented lung deposition for all inhalation dosage forms; pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs), soft mist inhalers (SMIs), and nebulizers. They have provided valuable insight into the factors that influence total and regional lung deposition. Taken globally, this collection of data has recently been used to elucidate the influence of intersubject variability in head geometry on total lung deposition, showing good correspondence between theory and experiment. The analysis reported here is an attempt to take this data set one step "deeper" into the airways and understand the relationship between P/C ratio, derived from 2D imaging, and a more anatomically relevant biological distribution within the lung, 24-h clearance. Intersubject variability in regional deposition is also analyzed, although due to the sparse nature of the reported individual data only tentative conclusions can be drawn. Many different techniques for derivation and analysis of scintigraphic data have been reported in the literature, and this leads to some difficulties when performing the "meta-analyses" reported below. In this regard it is recommended that standardization of scintigraphy techniques should be a future goal.     

Degree of throat deposition can explain the variability in lung deposition of inhaled drugs.

Inhalation is a mainstay for treatment of asthma, and lung deposition can be seen as a surrogate marker for the ensuing clinical effects. Not only absolute lung deposition, but also its variability is of interest, as it indicates the range of expected lung deposition in an individual patient when prescribing the drug and the expected day-to-day variability when using it. A literature survey found 71 studies with relevant information on lung deposition and its variability. Further characteristics of the studies, such as if the subjects were healthy or asthmatics, adults or children, and what device that was used, were noted. In all, 187 data points were included. Variability in lung deposition was depicted as a function of mean lung deposition; for the entire data set and for subsets thereof. Independent of device type or subject category high lung deposition was associated with low relative variability and vice versa. Using a published throat deposition model, the observed correlation of lung deposition variability to mean lung deposition could be explained as being determined largely by the extent of and variability in throat deposition. We hypothesize that throat deposition is the major determinant for lung deposition of an inhaled aerosol, and its absolute variability will largely be determined by the absolute variability in throat deposition. The relative variability in lung deposition will therefore tend to be high for low lung deposition and low for high lung deposition. Consequently, low relative variability in lung deposition can only be attained if high lung deposition is achieved.     

Pulmonary delivery of influenza vaccine formulations in cotton rats: site of deposition plays a minor role in the protective efficacy against clinical isolate of H1N1pdm virus

Administration of influenza vaccines to the lungs could be an attractive alternative to conventional parenteral administration. In this study, we investigated the deposition site of pulmonary delivered liquid and powder influenza vaccine formulations and its relation to their immunogenicity and protective efficacy. In vivo deposition studies in cotton rats revealed that, the powder formulation was mainly deposited in the trachea (?～?65%) whereas the liquid was homogenously distributed throughout the lungs (?～?96%). In addition, only 60% of the antigen in the powder formulation was deposited in the respiratory tract with respect to the liquid formulation. Immunogenicity studies showed that pulmonary delivered liquid and powder influenza formulations induced robust systemic and mucosal immune responses (significantly higher by liquids than by powders). When challenged with a clinical isolate of homologous H1N1pdm virus, all animals pulmonary administered with placebo had detectable virus in their lungs one day post challenge. In contrast, none of the vaccinated animals had detectable lung virus titers, except for two out of eight animals from the powder immunized group. Also, pulmonary vaccinated animals showed no or little signs of infection like increase in breathing frequency or weight loss upon challenge as compared to animals from the negative control group. In conclusion, immune responses induced by liquid formulation were significantly higher than responses induced by powder formulation, but the overall protective efficacy of both formulations was comparable. Thus, pulmonary immunization is capable of inducing protective immunity and the site of antigen deposition seems to be of minor relevance in inducing protection.     

In vivo-in vitro correlations: predicting pulmonary drug deposition from pharmaceutical aerosols

In order to answer the question "what research remains to be done?" we review the current state of the art in pharmaceutical aerosol deposition modeling and explore possible in vivo- in vitro correlations (IVIVC) linking drug deposition in the human lung to predictions made using in vitro physical airway models and in silico computer models. The use of physical replicas of portions of the respiratory tract is considered, alongside the advantages and disadvantages of the different imaging methods used to obtain their dimensions. The use of airway replicas to determine drug deposition in vitro is discussed and compared with the predictions from different empirical curve fits to long-standing in vivo deposition data for monodisperse aerosols. The use of improved computational models and three-dimensional computational fluid dynamics (CFD) to predict aerosol deposition within the respiratory tract is examined. CFD's ability to predict both drug deposition from pharmaceutical aerosol sprays and powder behavior in dry powder inhalers is examined; both were highlighted as important areas for future research. Although the authors note the abilities of current in vitro and in silico methods to predict in vivo data, a number of limitations remain. These include our present inability to either image or replicate all but the most proximal airways in sufficient spatial and temporal detail to allow full capture of the fluid and aerosol mechanics in these regions. In addition, the highly complex microscale behavior of aerosols within inhalers and the respiratory tract places extreme computational demands on in silico methods. When the complexity of variations in respiratory tract geometry is associated with additional factors such as breathing pattern, age, disease state, postural position, and patient-device interaction are all considered, it is clear that further research is required before the prediction of all aspects of inhaled pharmaceutical aerosol deposition is possible.     

Determination of the Porosity of PLGA Microparticles by Tracking Their Sedimentation Velocity Using a Flow Imaging Microscope (FlowCAM)

Purpose

To investigate whether particle sedimentation velocity tracking using a flow imaging microscope (FlowCAM) can be used to determine microparticle porosity.

Methods

Two different methods were explored. In the first method the sedimentation rate of microparticles was tracked in suspending media with different densities. The porosity was calculated from the average apparent density of the particles derived by inter- or extrapolation to the density of a suspending medium in which the sedimentation velocity was zero. In the second method, the microparticle size and sedimentation velocity in one suspending fluid were used to calculate the density and porosity of individual particles by using the Stokes’ law of sedimentation.

Results

Polystyrene beads of different sizes were used for the development, optimization and validation of the methods. For both methods we found porosity values that were in excellent agreement with the expected values. Both methods were applied to determine the porosity of three PLGA microparticle batches with different porosities (between about 4 and 52%). With both methods we obtained microparticle porosity values similar to those obtained by mercury intrusion porosimetry.

Conclusions

We developed two methods to determine average microparticle density and porosity by sedimentation velocity tracking, using only a few milligrams of powder.

     

Variability of fine particle dose and lung deposition of budesonide delivered through two multidose dry powder inhalers

OBJECTIVE: To assess the reliability of dosing through two budesonide multidose dry powder inhalers (DPI) as derived from the in-vitro variability of the fine particle dose (FPD) and the in-vivo variability of the lung deposition at different flow rates. METHODS: The same two DPIs [device N (Novolizer) and device T (Turbuhaler)] were compared in both studies. In the in-vitro study, the variability of the FPD, measured at flow rates of 30-100 L/min, was determined for equal flow rates and at comparable maximal inspiratory pressures (MIP). In the in-vivo study in healthy subjects (scintigraphic, randomised, crossover design) the variability of the lung deposition was determined at targeted flow rates of 45, 60 and 90 L/min for device N, and at 60 L/min for device T. RESULTS: The variability of the FPD was lower with device N than with device T by 34%-86%. The differences were statistically significant for flow rates of 60, 70, 90 and 100 L/min (not significant for 40, 50 and 80 L/min) in the in-vitro study. Results for comparable MIPs showed analogous differences (79%, p = 0.004, at the clinically relevant MIP of 4.5 kPa). The variability of the lung deposition was clearly lower with the device N than with the device T. The difference was statistically significant (p = 0.029) at a comparable targeted flow rate of 60 L/min. CONCLUSIONS: Thus, this study showed that device N is likely to improve the reliability of inhalation therapy by reducing both the variability of the delivered drug and that of the lung deposition. The reliability of inhalation therapy and consequently the quality of long-term control of asthma and the patient's compliance might improve when choosing the DPI with the better characteristics.     

Optimization of Particle Properties of Nanocrystalline Solid Dispersion Based Dry Powder for Inhalation of Voriconazole

A one-step spray drying based process was employed to generate ready-to-use nanocrystalline solid dispersion (NCSD) dry powder for inhalation (DPI) of voriconazole (VRC). The solid dispersion was prepared by spray drying VRC, MAN (mannitol) and soya lecithin (LEC) from mixture of methanol-water. Various formulation and process related parameters were screened, including LEC, inlet temperature, total solid content and feed flow rate to generate particles of geometric size ≤5 µm. Aerosil® 200 was explored as the quaternary excipient either during spray drying or by physically mixing with the optimized ternary NCSD. The powders were extensively characterized for solid form, primary particle size, assay, embedded nanocrystal size, morphology, porosity, density and moisture content. Aerodynamic properties were studied using next generation impactor (NGI), while surface elemental composition and topography were investigated using SEM-EDS (scanning electron microscopy- energy dispersive spectroscopy) and AFM (atomic force microscopy), respectively. At selected inlet temperature of 120 ?C, total solid content and feed flow rate significantly impacted the size of primary NCSD particles. Size of primary particles increased with increase in total solid content and feed flow rate of the solution. VRC nanocrystals were obtained in polymorphic Form B whereas the matrix of MAN consisted of mixture of polymorphic Forms α, β and δ. SEM-EDS analysis confirmed deposition of Aerosil® 200 on surface of spray dried particles. In addition to increased porosity and reduced density, increase in surface roughness of particles (evident from AFM topographic analysis) contributed to enhanced powder deposition at stages 3 and 4 in NGI. In comparison, physical blending of NCSD with Aerosil® 200 showed improvement in aerosolization due to flow enhancement property.