High-throughput fine-droplet nebulizer

Abstract

In various embodiments, the disclosed subject-matter is a nebulizer device having a gas-inlet port coupling to receive a compressed gas; a liquid-inlet port to receive a liquid containing a source to produce aerosol particles; a first-stage nebulizer, pneumatically coupled downstream of the gas-inlet port, the first-stage nebulizer having a first-stage orifice, the first-stage orifice located upstream from the liquid-inlet port; a second-stage nebulizer, pneumatically coupled downstream of the first-stage nebulizer and the liquid-inlet port, the second-stage nebulizer having a second-stage orifice; an aerosol-outlet port, pneumatically coupled downstream of the second-stage nebulizer; and an excess-liquid outlet, pneumatically coupled downstream of the second-stage nebulizer and the aerosol-outlet port. Other devices and systems are disclosed.

Description

HIGH-THROUGHPUT FINE-DROPLET NEBULIZERPRIORITY CLAIM

[0000] This patent application claims the benefit of priority of U.S. Provisional Patent Application Serial Number 63 / 691,543, entitled “HIGH-THROUGHPUT FINE- DROPLET NEBULIZER,” filed on 6 September 2024, which is hereby incorporated by reference herein in its entirety.TECHNICAL FIELD

[0001] The subject matter disclosed herein relates generally, but not by way of limitation, to a nebulizer device having a high-nebulization efficiency.BACKGROUND

[0002] Nebulizers are commonly used to disintegrate a liquid into airborne droplets. Pneumatic nebulizers are a type of nebulizer that utilize energy from compressed gas (frequently air or nitrogen) to break up a liquid stream introduced into the nebulizer. One advantage of pneumatic nebulizers is that they typically produce small droplets and can be used to aerosolize many types of liquids, including high-viscosity liquids. Two widely used pneumatic nebulizers are a Collison-type nebulizer and a DeVilbiss® type nebulizer. These types of nebulizers generally produce droplet sizes from a few micrometers to 10 pm with geometric standard deviations spanning from 1.5 to 2.5. There are numerous variations of these nebulizers commonly used in aerosol research, pharmaceutical, and nano-material generation applications. One such Collison-type nebulizer is the TSI Model 3076 Constant Output Atomizer (available from TSI Incorporated, Shoreview, Minnesota, USA).

[0003] Ganan-Calvo proposed a flow-blurring technique to enhance liquid nebulization efficiency. The technique utilizes back-flow perturbations to mix the compressed gas turbulently with the incoming liquid before compressed gas reaches the nebulizer orifice. The small turbulence scales and pre-mixing mechanism dramatically change the spray plume from a conventional flow-focusing pattern to a plume consisting of unsteady, chaotic-liquid ligaments. Ganan-Calvo referred to this flow pattern as a flowblurring pattern. The technique demonstrates a tenfold-efficiency increase over available plain-jet flow-focusing nebulizers. However, one drawback of this technique is that the unsteady, chaotic, and highly turbulent flow pattern leads to unpredictable andAttorney Docket 4270.035W01 1uncontrollable gas flow-fields and parti cl e / droplet trajectories. These characteristics are undesirable from the perspectives of instrument repeatability, reliability, and manufacturability. Therefore, a high-efficiency nebulizer useful for instrument repeatability, reliability, and manufacturability is desirable.

[0004] The information described in this section is provided to offer a person of ordinary skill in the art a context for the following disclosed subject-matter and should not be considered as admitted prior art.SUMMARY

[0005] In one exemplary embodiment, the disclosed subject-matter describes a nebulizer device having a gas-inlet port coupling to receive a compressed gas; a liquidinlet port to receive a liquid containing a source to produce aerosol particles; a first-stage nebulizer, pneumatically coupled downstream of the gas-inlet port, the first-stage nebulizer having a first-stage orifice, the first-stage orifice located upstream from the liquid-inlet port; a second-stage nebulizer, pneumatically coupled downstream of the first-stage nebulizer and the liquid-inlet port, the second-stage nebulizer having a second- stage orifice; an aerosol-outlet port, pneumatically coupled downstream of the second- stage nebulizer; and an excess-liquid outlet, pneumatically coupled downstream of the second-stage nebulizer and the aerosol-outlet port.

[0006] In one exemplary embodiment, the disclosed subject-matter describes a nebulizer device having a gas-inlet port coupling to receive a compressed gas; a liquidinlet port to receive a particle-producing liquid containing a source to produce aerosol particles; a first-stage nebulizer, pneumatically coupled downstream of the gas-inlet port coupling, the first-stage nebulizer having a first-stage orifice, the first-stage orifice being located upstream from the liquid-inlet port, the first-stage nebulizer being configured to create a high-velocity jet of the compressed gas downstream of the first-stage orifice sufficient to produce a low-pressure volume to draw the particle-producing liquid through the liquid-inlet port and to produce a filament of liquid downstream of the first-stage orifice; a second-stage nebulizer, pneumatically coupled downstream of the first-stage nebulizer and the liquid-inlet port, the second-stage nebulizer having a second-stage orifice; an aerosol-outlet port, pneumatically coupled downstream of the second-stage nebulizer; a virtual impactor created downstream of the second-stage orifice, the virtualAttorney Docket 4270.035W01 2impactor being configured to split droplets of the particle-producing liquid into two groups of the droplets according to a predetermined virtual impactor cut-off point; and an excess-liquid outlet, pneumatically coupled downstream of the second-stage nebulizer and the aerosol-outlet port, and configured to receive droplets larger than the predetermined virtual impactor cut-off point.

[0007] In one exemplary embodiment, the disclosed subject-matter describes a two- stage nebulizer device having a gas-inlet port coupling to receive a compressed gas; a liquid-inlet port to receive a particle-producing liquid containing a source to produce aerosol particles; a first portion, pneumatically coupled downstream of the gas-inlet port coupling, the first portion having a first-stage orifice, the first-stage orifice being located upstream from the liquid-inlet port, the first portion being configured to create a high- velocity jet of the compressed gas downstream of the first-stage orifice sufficient to produce a low-pressure volume to draw the particle-producing liquid through the liquidinlet port and to produce a filament of liquid downstream of the first-stage orifice; a second portion, pneumatically coupled downstream of the first portion and the liquid-inlet port, the second portion having a second-stage orifice; and an aerosol-outlet port, pneumatically coupled downstream of the second portionAttorney Docket 4270.035W01 3BRIEF DESCRIPTION OF FIGURES

[0008] Various ones of the appended drawings merely illustrate examples of various implementations of the disclosed subject-matter and should not be considered as limiting its scope.

[0009] FIG. 1 shows a cross-sectional view of a single-stage nebulizer;

[0010] FIG. 2A shows an exemplary embodiment of a high-efficiency nebulizer, in accordance with various embodiments of the disclosed subject-matter;

[0011] FIG. 2B shows another view of the high-efficiency nebulizer of FIG. 2A, in accordance with various embodiments of the disclosed subject-matter; and

[0012] FIG. 3 show an exemplary embodiment of an efficiency -testing system for the high-efficiency nebulizer of FIG. 2 A, in accordance with various embodiments of the disclosed subject-matter.DETAILED DESCRIPTION

[0013] The following description includes a discussion of figures having illustrations given by way of examples of implementations of the disclosed subject-matter. The drawings should be understood by way of example, and not by way of limitation. As used herein, references to one or more “embodiments” are understood to be describing a particular feature, structure, or characteristic included in at least one implementation of the disclosed subject-matter. Thus, phrases such as “in one embodiment,” “in an exemplary embodiment,” or “in an alternative embodiment” appearing herein describe various embodiments and implementations of the disclosed subject-matter, and do not necessarily all refer to the same embodiment. However, the embodiments are also not necessarily mutually exclusive from one another. To identify easily the discussion of any particular element or act, the most significant digit or digits in a reference number (e.g., element number) refer to the figure (“FIG.”) number in which that element or act is first introduced.

[0014] In various embodiments described herein, the disclosed subject-matter is a nebulizer having a high-nebulization efficiency. The various embodiments of the disclosed subject-matter enable stability and matching among systems that incorporateAttorney Docket 4270.035W01 4this nebulizer design due, at least, to the combination of increased throughput, use of a virtual impactor design, and the control afforded by the use of specific control mechanisms including the compressed gas pressure and flow rate, the liquid pressure and flow rate, the make-up gas flow rate and the nebulizer heater temperature. Each of the non-limiting embodiments described herein can stand on its own, or can be combined in various permutations or combinations with one or more of the other embodiments.

[0015] The disclosed subject-matter will now be described in detail with reference to a few general and specific embodiments as illustrated in various ones of the accompanying drawings. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the disclosed subject-matter. It will be apparent, however, to a person of ordinary skill in the art upon reading and understanding the disclosed subject-matter, that the disclosed subject-matter may be practiced without some or all of these specific details. In other instances, well-known process steps, construction techniques, or structures have not been described in detail so as not to obscure the disclosed subject-matter.

[0016] Pneumatic nebulizers are versatile devices capable of producing both liquid and solid aerosol particles. Liquid-aerosol particles can be generated by directly nebulizing low-volatility liquids such as, for example, di (2-ethylhexyl) phthalate (DOP), mineral oils, and other liquids, while solid-aerosol particles can be produced by nebulizing diluted colloidal solutions, such as, for example, polystyrene latex spheres, gold particles, silica particles, and other types of solids. Another widely used method for producing small liquid particles and solid particles involves dissolving substances into a liquid or solvent, nebulizing the solution, and then evaporating the solvent from the droplets. Once the solvent is evaporated, aerosol particles of the original substance are obtained. As noted, water is commonly used as a solvent for solid particles, while isopropyl alcohol is frequently used for oil-type particles. In general, a liquid containing a source to produce aerosol particles describes an input source for generation of both liquid particles and solid particles.

[0017] A final particle-size of the generated aerosol with the nebulization and evaporation method may be determined by the volume fraction of solid / liquid materialAttorney Docket 4270.035W01 5(salute concentration), Fv, and the initial droplet diameter, ddropiet, as shown in equation (1), below.

[0018] Equation (1) illustrates that, for a given initial droplet size from a specific nebulizer design, various final sizes of aerosol particles can be produced by manipulating the salute concentration. Small particles such as, for example, sodium chloride, ammonia sulfate, and low-volatility oils, spanning from 20 nm to 1000 nm, are commonly generated using this method.

[0019] The initial droplet size is one key metric for assessing the quality of a nebulizer. Generally, smaller droplet sizes indicate a better-quality droplet. The droplet size is useful when nebulizing colloidal solutions. Colloidal solutions consist of dispersed insoluble particles (such as polystyrene latex spheres) suspended in a liquid. The initial droplet sizes should be small enough to reduce or minimize an impact of unwanted residue particles on measurements. One reason is that large number of droplets generated by the nebulizing process contain no colloidal particles. When these empty droplets evaporate, residue particles form from the dissolved impurities in the liquid (the Fv term in Equation (1)).

[0020] Primary sources of impurities include dissolved contents in the solvents used to dilute and prepare the colloidal solutions (or low-volatility liquids), stabilizing surfactants in the colloidal solutions, and contaminants from the sample preparation and nebulization equipment. The unwanted residue particles formed from these impurities are usually several orders of magnitude higher in number than the colloidal particles, limiting the use of aerosolized particles to applications insensitive to these residue particles. For example, applications such as calibration of airborne optical particle counters may still be feasible due to the significant differences in optical characteristics of residue and colloidal particles. Overall, the overwhelming residue particle counts relative to colloidal particles have restricted the use of nebulization method on colloidal solutions to a few applications.

[0021] One solution to the residue particle count issue is to ensure that the physical sizes of unwanted residue particles are much smaller than that of the desired colloidal particles, thereby rendering the residue particles undetectable by a particle-measurementAttorney Docket 4270.035W01 6device. This particle size difference means that only the colloidal particles, being larger, will be detected and counted by the measurement device, while the residue particles remain too small to be counted. Ideally, residue particles would be completely excluded from the measurements. In practice, it is generally acceptable if a small fraction of these residue particles are measured, provided their counts have a negligible effect on the overall measurement.

[0022] From Equation (1), above, one way to obtain smaller residue particles is to nebulize liquids with lower levels of impurities. Lower impurity levels can be achieved by, for example, using cleaner liquids and / or colloidal solutions without surfactants. However, cleaner liquids, such as higher-grade ultrapure water (UPW), require significant equipment and maintenance costs, making this approach potentially unviable from a cost perspective. While surfactant-free colloidal solutions are commercially available, they are much more expensive and limited in sel ecti on, further restricting the use of the nebulization method for colloidal solutions.

[0023] Another approach to reducing residue particles is to produce smaller initial droplets. Smaller initial droplets contain fewer liquid impurities, resulting in smaller residue particles after the liquid / solvent evaporates. Colloidal particles, being insoluble, are not affected by the initial droplet sizes as long as the droplets are reasonably larger than the colloidal particles. One method to achieve smaller initial droplets is to use a higher pressure of the nebulizing gas. Additionally, a small cutoff impactor, known in the art, can be used to remove large droplets immediately after nebulization.

[0024] However, both higher gas pressures and a small cutoff impactors increase a probability of droplets striking the nebulizer walls due to the increased gas velocity, leading to higher transport losses. As a result, the increase in small droplet generation can be offset by transport losses. Conventional nebulizers that produce smaller initial droplet sizes may do so at the expense of extremely low nebulization efficiencies or liquid-to- aerosol conversion efficiencies. Fine droplet nebulizer efficiencies are typically less than about 0.1%, meaning about 99.9% of the nebulized liquids are removed from the gas stream and wasted. This high level of waste is usually unacceptable for many applications. Additionally, such low conversion efficiency results in low counting statistics for the nebulized colloidal-particles.Attorney Docket 4270.035W01 7

[0025] With reference now to FIG. 1, a cross-sectional view of a single-stage nebulizer 100 is shown. One such nebulizer is the Collison-type TSI Model 3076 Constant Output Atomizer (available from TSI Incorporated, Shoreview, Minnesota, USA). The single-stage nebulizer 100 is shown to include a gas-inlet port 103, an orifice disk 111 on a support plate 113 held in place by, for example, an O-ring, a liquid-inlet port 105, a produced-aerosol outlet 101, and an excess-liquid outlet port 107.

[0026] In one embodiment, the orifice disk may be a thin disk, formed from, for example, a metallic or dielectric material, and having a small hole formed therethrough. The disk may be about 9.5 mm in diameter (approximately 0.375 inches) with a hole diameter of about 0.34 mm (approximately 0.0125 inches) in diameter. A compressed gas (e.g., clean-dry air, nitrogen, or other inert gas) is transported into the gas-inlet port 103 and through the orifice disk 111. The compressed gas, traveling at a high velocity through the orifice disk 111, then expands downstream of the orifice disk 111, thereby creating a low-pressure volume and creating a Bernoulli effect. The Bernoulli affect draws in liquid through the liquid-inlet port 105. The drawn-in liquid can comprise a source of, for example, colloidally-suspended particles, such as polystyrene-latex (PSL) spheres suspended in water (a colloidal solution). The high velocity of the compressed gas then produces (atomizes) solid-phase particles and liquid components of the colloidal solution into droplets 109. The solid-phase particles from the droplets 109 will be transported by the compressed gas out through the produced-aerosol outlet 101, while the liquid component is transported from the single-stage nebulizer 100 through the excess-liquid outlet port 107 to, for example, a closed excess-liquid reservoir. However, as noted above, the single-stage nebulizer 100 may have a liquid-to-aerosol conversion efficiency of about 0.1% when used to produce, for example, sub-300 nm droplets.

[0027] FIG. 2A shows an exemplary embodiment of a front view 200 of a high- efficiency nebulizer 210, in accordance with various embodiments of the disclosed subject-matter.

[0028] The high-efficiency nebulizer 210 is a two-stage nebulizer device, having a first-stage nebulizer and a second-stage nebulizer with the second-stage nebulizer pneumatically coupled downstream of the first-stage nebulizer. The high-efficiency nebulizer 210 uses the two nebulization stages to obtain fine droplets, as described inAttorney Docket 4270.035W01 8more detail below. In this embodiment, the high-efficiency nebulizer 210 of FIG. 2A is shown to include a gas-inlet port coupling 211, and a first-stage orifice 217 mechanically coupled to the gas-inlet port coupling 211 by an O-ring 219. The high-efficiency nebulizer 210 is further shown to include a first portion 205, a second portion 207, and a third portion 209, each described in detail below.

[0029] A gas-inlet flow-stream 201, comprising, for example, compressed air, nitrogen, or another inert gas, is introduced into the gas-inlet port coupling 211. The gasinlet port coupling 211 is mechanically coupled to the first portion 205 by an O-ring 221. The first portion 205 generally comprises the first stage of the two-stage nebulizer. A liquid-inlet port 213 is configured to introduce a liquid flow-stream 203. The liquid can comprise a source of, for example, colloidally-suspended particles, such as polystyrene- latex (PSL) spheres suspended in water (a colloidal solution). In a specific exemplary embodiment, the liquid is drawn into the liquid-inlet port 213 at a rate of, for example, about 10 mL / hour.

[0030] The second portion 207 generally comprises the second stage of the two-stage nebulizer and is shown to include an adapter portion 215 that has a second-stage orifice 223 on a downstream side of the adapter portion 215. As described in more detail below, the adapter portion 215 receives and transports aerosol produced by the first-stage orifice 217.

[0031] Downstream of the second-stage orifice 223, a minor-flow receiving tube 225 generally transports excess liquids into the third portion 209. The third portion 209 serves as an excess-liquid outlet and includes a drain orifice (or opening) 227 and an excessliquid outlet flow-stream 229. The drain orifice 227 may be sized such that a particle flow-stream, described with reference to FIG. 2B, below, along with a makeup flowstream, may be output from the high-efficiency nebulizer 210 such that particle generation is enhanced while preventing excess liquid from being output through a particle outlet port.

[0032] In a specific exemplary embodiment, the first-stage orifice 217 is about 0.32 mm (approximately 0.0135 inches) in diameter, the second-stage orifice 223 is about 0.35 mm (approximately 0.0142 inches) in diameter, and the drain orifice 227 is about 0.35Attorney Docket 4270.035W01 9mm (approximately 0.0142 inches) in diameter. However, the actual sizes of these orifices, and the ratios of the diameters (one-to-another), may change depending on a number of factors. The factors may include, for example, an actual flow-rate of fluids (e.g., compressed gases) and particle-laden gases flowing through the high-efficiency nebulizer 210, a pressure of the fluids introduced into the high-efficiency nebulizer 210, a viscosity of the liquid used as the carrier liquid for the colloidal suspension, and other factors. Also, the orifices are generally sized so as to avoid a choked-flow condition (a limiting condition where the mass flow cannot increase with a further decrease in the downstream pressure). A choked-flow condition may lead to decreased performance of the high-efficiency nebulizer 210. Upon reading and understanding the disclosed subjectmatter, a person of ordinary skill in the art will recognize how to determine the actual sizes of these orifices, and the ratios of the diameters, depending upon a given application.

[0033] In a specific exemplary embodiment, the adapter portion 215 has a length of about 19 mm (approximately 0.752 inches) and an internal diameter of about 4.9 mm (approximately 0.191 inches). However, upon reading and understanding the disclosed subject-matter, a person of ordinary skill in the art will recognize that other lengths and diameters may be used. In certain applications, if the length of the adapter portion 215 is increased, depending at least partially on a flow regime and a desired particle size to be generated, evaporation may occur within the adapter portion 215. Conversely, if the length is decreased, an overall efficiency may be reduced.

[0034] FIG. 2B shows a side view 230 of the high-efficiency nebulizer 210 of FIG. 2A, in accordance with various embodiments of the disclosed subject-matter. The side view 230 is shown to include make-up flow inlet port 233 and an aerosol-outlet port 237. A make-up flow-stream 231, comprising, for example, the same or similar gas as the gasinlet flow-stream 201, may be introduced into the high-efficiency nebulizer 210. A combination major and make-up flow-stream 235 exiting the aerosol-outlet port 237 is comprised of at least a portion of the make-up flow-stream 231, and the gas-inlet flowstream 201.

[0035] However, in certain operations, the make-up flow-stream 231 may be considered optional and is not used. A decision may be made as to whether the make-upAttorney Docket 4270.035W01 10flow-stream 231 is used depending on factors such as, for example, a volumetric or mass flow-rate of a desired flow-rate of the combination major and make-up flow-stream 235 exiting the high-efficiency nebulizer 210.

[0036] The following description illustrates more fully how the high-efficiency nebulizer 210 may be used in operation in a specific exemplary embodiment. With concurrent reference to FIG. 2A and FIG. 2B, compressed gas (e.g., clean-dry air or nitrogen) at about 290 kPa (approximately 42 psig) is introduced through the gas-inlet port coupling 211, creating a high-velocity jet downstream of the first-stage orifice 217. Because of the expansion of the compressed gas downstream of the first-stage orifice 217, the low-pressure volume created by the Bernoulli effect draws the liquid (e.g., a particleladen liquid or a particle-producing liquid) through the liquid-inlet port 213 into the first- stage nebulization region. A thin filament of liquid exiting a small opening downstream of the first-stage orifice 217 is then accelerated in the gas flow-stream and eventually breaks up and disperses into droplets.

[0037] Since the nebulization process and operating parameters are similar to Collison-type nebulizers, the droplet size distributions from the first stage nebulization of this nebulizer are expected to be comparable to those of Collison nebulizers (e.g., see FIG. 1), which typically produce droplets of a few micrometers in size. Conventional nebulizers generally remove most of the droplets generated by impacting them onto an internal wall or impactor to obtain small droplets. In contrast, the two stage-nebulizer disclosed herein retains substantially all the first-stage nebulized droplets. The dropletladen gas jet from the first-stage nebulization region then enters the adapter portion 215 in which the gas expands and slows down, and the velocity profile of the gas becomes more uniform before the flow reaches the second-stage orifice 223.

[0038] To further fine-tune the sizes of the droplets subsequently exiting the high- efficiency nebulizer 210, a virtual impactor created downstream of the second-stage orifice 223 splits the droplets into two groups according to a predetermined virtual impactor cut-off point. A virtual impactor is a device used to separate particles by size into two airstreams, comprising airstream flows in the minor-flow receiving tube 225 and the combination major and make-up flow-stream 235. The virtual impactor is therefore similar to a conventional impactor, but an impaction surface is replaced with a virtualAttorney Docket 4270.035W01 11space of stagnant or slow-moving air, comprising minor and major flow-streams. By controlling a size of the second-stage orifice 223, the gas flow-rate, and the parameters of the virtual impactor as noted above, the cut-off point can be adjusted, thereby determining the sizes of droplets that go into the minor-flow receiving tube 225 and the combination major and make-up flow-stream 235 (the minor and major flows). Using the specific exemplary sizes of orifices noted above, the cut-off point is set to 250 nm. However, upon reading and understanding the disclosed subject-matter, a person of ordinary skill in the art will recognize how to adjust the virtual-impactor cut-off point based at least partially on a selection of the three orifice sizes as discussed herein). Large droplets follow the minor-flow receiving tube 225 and exit the high-efficiency nebulizer 210 via the excessliquid outlet flow-stream 229, while droplets smaller than the virtual impactor cut-off point exit through the combination major and make-up flow-stream 235.

[0039] Before exiting the high-efficiency nebulizer 210, the small droplet-laden major flow merges with the makeup flow near an inlet side of the minor-flow receiving tube 225 (the major flow goes past a small gap at near the inlet side of the minor-flow receiving tube 225 (the conical area shown between an incoming flow at the make-up flow-stream 231 and an outlet flow at the combination major and make-up flow-stream 235) and then merges with the makeup flow; the small gap serves as a choked point so that the split of the virtual impactor major and minor flows is not affected substantially by the makeup flow). Consequently, the makeup flow can be varied without affecting the major and minor flows. The makeup flow rapidly dries and reduces the droplets to smaller sizes, reducing or minimizing transport losses and condensation of liquids on interior walls of the nebulizer. To further facilitate the evaporation process, a diffusion dryer, heater, or other type of drying aid (e.g., such as a polymer tubing with occasional side chains of another fluorocarbon) can be used downstream of the high-efficiency nebulizer 210 if desired. The final version of dried particles that have exited the high-efficiency nebulizer 210 through the aerosol-outlet port 237 may comprise a mixture of colloidal particles and unwanted residue particles (depending upon a cleanliness level of the original liquid containing a source to produce the particles), but the physical sizes of the colloidal particles and unwanted residue particles are substantially different from each other. Due to the small initial-droplet size (e.g., due to the 250 nm virtual -impactor cut-point in this example), residue particles are much smaller than the colloidal particles. By adjusting aAttorney Docket 4270.035W01 12detection-threshold limit of an instrument under test, the majority of the residue particles can be excluded from the measurement. Further, if desired, the sizes of the residue particles can be further reduced by using a smaller virtual-impactor cut-point.

[0040] The large droplets carried out through the minor-flow receiving tube 225 are typically not used and can be filtered out or drained to a sink, vessel, or other type of reservoir. However, if desired, droplets in the minor flow can also be collected and analyzed. For example, one possible use of minor flow samples is that larger droplets in the minor flow contain more liquid impurities so they could be collected and analyzed to help identify sources of these impurities.

[0041] Due to gas adiabatic expansion and droplet evaporation, the temperature in the vicinities of the first-stage nebulization region and the second-stage nebulization region is typically a few degrees lower than ambient temperature. The cooler temperature on the adapter walls may cause liquid vapor to condense on inside walls of the high-efficiency nebulizer 210. The condensed liquids may eventually drip down, reach the second-stage orifice 223, and become nebulized. The nebulized droplets from these condensed liquids may have substantially different characteristics and could create unwanted spontaneous spikes in the data. Additionally, the cooler nebulizer may cause water condensation on the outside walls of the high-efficiency nebulizer 210 if operated in high temperature and humidity environments, potentially leading to long-term maintenance issues. To reduce or minimize vapor / liquid condensation on the inside and outside walls of the nebulizer, a small heater may be used to elevate the wall temperature to a few degrees above an anticipated dew-point.

[0042] Further, although the high-efficiency nebulizer 210 is shown in a vertical orientation, any orientation may be considered based on a particular application. However, upon reading and understanding the disclosed subject-matter, a person of ordinary skill in the art will recognize that, depending upon a flow-rate and a desired particle size to be generated, certain orientations of the high-efficiency nebulizer 210 may increase particle losses on internal sidewalls of the nebulizer.

[0043] With reference now to FIG. 3, an exemplary embodiment of an efficiencytesting system 300 for the high-efficiency nebulizer 210 of FIG. 2A is shown, inAttorney Docket 4270.035W01 13accordance with various embodiments of the disclosed subject-matter. The efficiencytesting system 300 is shown to include a syringe 301, containing either a colloidal solution of particles, low-volatility liquids in solution, or a liquid without particles contained therein, a syringe pump 303, to inject the liquid from a syringe 301 as a desired flow-rate, and a liquid-volume measurement device 305 to measure a volume of liquid 307 output from the excess-liquid outlet flow-stream 229. Excess air 309 exits the liquidvolume measurement device 305.

[0044] Overall, one of the metrics of nebulization is the nebulization efficiency or liquid-to-aerosol conversion efficiency, which measures the percentage of nebulized liquid that becomes usable droplets. Conventional fine droplet nebulizers, as described above with reference to FIG. 1, typically have nebulization efficiencies of less than 0.1%. To determine two-stage nebulizer liquid-to-aerosol conversion efficiency, in a specific exemplary embodiment, three prototypes of a two-stage nebulizer were tested using the efficiency-testing system 300 of FIG. 3. The syringe pump 303 was used to precisely deliver 8 mL / hour, 10 mL / hour, or 15 mL / hour liquid feed to the nebulizer under test (in the example of FIG. 3, the high-efficiency nebulizer 210). Since all of the nebulized droplets were either carried out by the minor or major flow, a determination of the efficiency value could be determined by measuring the amount of liquid in either flow. In this example, the minor flow was a more convenient choice as the droplets in the flow were larger so they could be more easily removed from the gas stream and collected. A cyclone-type device (known in the art) was used to facilitate the droplet and gas separation process. The collected liquid was then quantified to determine the liquid-to- aerosol conversion efficiency. It was found that the efficiency values from all three units were around 81% and the values were relatively constant for the liquid feed ranging from 8 mL / hour to 15 mL / hour. This determination indicates that 81% of the feed liquid was converted into usable fine droplets carried by the major flow, while the remaining 19% of the liquid was drained via the minor flow. This efficiency represents an improvement of well over two-orders of magnitude compared to conventional fine droplet nebulizers.

[0045] One of the aspects of the flow-blurring technique of the prior art and discussed above involves utilizing turbulent back-flow patterns and pre-mixing of gas and liquid to break the liquid stream into chaotic large liquid-ligaments and droplets before reaching the nebulizer orifice, thereby achieving a higher nebulization efficiency. These largeAttorney Docket 4270.035W01 14liquid-ligaments and droplets further break into smaller droplets as they pass through the orifice.

[0046] In contrast to the disclosed subject-matter, the flow-blurring method discussed above utilizes unsteady and a chaotic flow-pattern. The two-stage nebulizer disclosed herein retains conventional flow-focusing and predictable and controllable flow-fields of a nebulizer. In addition, the droplet-size distributions from the first-stage nebulization are narrower and more controllable compared to those from the flow-blurring technique. This controllable droplet-size distribution results in more uniform droplet sizes after the second-stage nebulization. These attributes described herein with reference to the high- efficiency nebulizer 210 significantly enhance instrument performance in terms of repeatability, reliability, and manufacturability.

[0047] In the context of the disclosed subject-matter contained herein, various embodiments of a high-efficiency nebulizer have been shown and described. Further, the description provided herein includes references to the accompanying drawings, which form a part of the detailed description. The drawings show, by way of illustration, specific embodiments in which the disclosed subject-matter can be practiced. These embodiments are also referred to herein as “examples.” Such examples can include elements in addition to those shown or described. However, the present inventors also contemplate examples in which only those elements shown or described are provided. Moreover, the present inventors also contemplate examples using any combination or permutation of those elements shown or described (or one or more aspects thereof), either with respect to a particular example (or one or more aspects thereof), or with respect to other examples (or one or more aspects thereof) shown or described herein.

[0048] In the event of inconsistent usages between this document and any documents so incorporated by reference, the usage in this document controls. Moreover, in this document, the terms “a” or “an” are used, as is common in patent documents, to include one or more than one, independent of any other instances or usages of “at least one” or “one or more.” In this document, the term “or” is used to refer to a nonexclusive or, such that “A or B” includes “A but not B,” “B but not A,” and “A and B,” unless otherwise indicated. In this document, the terms “including” and “in which” are used as the plain- English equivalents of the respective terms “comprising” and “wherein.” Also, in theAttorney Docket 4270.035W01 15following claims, the terms “including” and “comprising” are open-ended, that is, a system, device, article, composition, formulation, or process that includes elements in addition to those listed after such a term in a claim are still deemed to fall within the scope of that claim. Moreover, in the following claims, the terms “first,” “second,” and “third,” etc. are used merely as labels, and are not intended to impose numerical requirements on their objects.

[0049] Geometric terms, such as “parallel,” “perpendicular,” “round,” “tubular,” or “square,” are not intended to require absolute mathematical precision, unless the context indicates otherwise. Instead, such geometric terms allow for variations due to manufacturing or equivalent functions. For example, if an element is described as “round” or “generally round,” a component that is not precisely circular (e.g., one that is slightly oblong or is a many-sided polygon) is still encompassed by this description.

[0050] As used herein, the term “or” may be construed in an inclusive or exclusive sense. Further, other embodiments will be understood by a person of ordinary skill in the art upon reading and understanding the disclosure provided. Further, upon reading and understanding the disclosure provided herein, the person of ordinary skill in the art will readily understand that various combinations of the techniques and examples provided herein may all be applied in various configurations.

[0051] Although various embodiments are discussed separately, these separate embodiments are not intended to be considered as independent techniques or designs. As indicated above, each of the various portions may be inter-related and each may be used separately or in combination with other embodiments discussed herein. For example, although various embodiments of methods, operations, and processes have been described, these methods, operations, and processes may be used either separately or in various combinations.

[0052] Consequently, many modifications and variations can be made, as will be apparent to a person of ordinary skill in the art upon reading and understanding the disclosure provided herein. Further, functionally equivalent methods and devices within the scope of the disclosure, in addition to those enumerated herein, will be apparent to the skilled artisan from the foregoing descriptions. Portions and features of someAttorney Docket 4270.035W01 16embodiments, materials, and construction techniques may be included in, or substituted for, those of others. Such modifications and variations are intended to fall within a scope of the appended claims. Therefore, the present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0053] The Abstract of the Disclosure is provided to allow the reader to quickly ascertain the nature of the technical disclosure. The abstract is submitted with the understanding that it will not be used to interpret or limit the claims. In addition, in the foregoing Detailed Description, it may be seen that various features may be grouped together in a single embodiment for the purpose of streamlining the disclosure. This method of disclosure is not to be interpreted as limiting the claims. Thus, the following claims are hereby incorporated into the Detailed Description, with each claim standing on its own as a separate embodiment. As used herein, the terms “about,” “approximately,” and “substantially” may refer to values that are, for example, within +10% of a given value or range of values. Also, the term “exemplary” is used herein to indicate an example of an embodiment or concept, and not necessarily the best or sole means of achieving or practicing the embodiment or concept.THE FOLLOWING NUMBERED EXAMPLES ARE SPECIFIC EMBODIMENTS OF THE DISCLOSED SUBJECT-MATTER

[0054] Example 1. In an embodiment, the disclosed subject-matter describes a nebulizer device having a gas-inlet port coupling to receive a compressed gas; a liquidinlet port to receive a liquid containing a source to produce aerosol particles; a first-stage nebulizer, pneumatically coupled downstream of the gas-inlet port, the first-stage nebulizer having a first-stage orifice, the first-stage orifice located upstream from the liquid-inlet port; a second-stage nebulizer, pneumatically coupled downstream of the first-stage nebulizer and the liquid-inlet port, the second-stage nebulizer having a second- stage orifice; an aerosol-outlet port, pneumatically coupled downstream of the second- stage nebulizer; and an excess-liquid outlet, pneumatically coupled downstream of the second-stage nebulizer and the aerosol-outlet port.Attorney Docket 4270.035W01 17

[0055] Example 2. The nebulizer device of Example 1, further comprising a make-up flow inlet port.

[0056] Example 3. The nebulizer device of any one of the preceding Examples, further comprising a drain orifice or opening formed within the excess-liquid outlet and pneumatically coupled downstream of the second-stage nebulizer and the aerosol-outlet port.

[0057] Example 4. The nebulizer device of Example 3, wherein a combination of the first-stage orifice, the second-stage orifice, and the drain orifice (or opening) combines to form a virtual impactor within the nebulizer device.

[0058] Example 5. The nebulizer device of Example 4, wherein the virtual impactor is configured to split droplets of the liquid into two groups of the split droplets according to a predetermined virtual impactor cut-off point.

[0059] Example 6. The nebulizer device of Example 5, wherein the excess-liquid outlet is configured to receive droplets larger than the predetermined virtual impactor cutoff point.

[0060] Example 7. The nebulizer device of Example 6, wherein the aerosol outlet is configured to receive droplets smaller than the predetermined virtual impactor cut-off point.

[0061] Example 8. The nebulizer device of any one of the preceding Examples, wherein the first-stage nebulizer is configured to create a high-velocity jet of the compressed gas downstream of the first-stage orifice sufficient to produce a low-pressure volume to draw the liquid through the liquid-inlet port and to produce a filament of liquid downstream of the first-stage orifice.

[0062] Example 9. In an embodiment, the disclosed subject-matter describes a nebulizer device having a gas-inlet port coupling to receive a compressed gas; a liquidinlet port to receive a particle-producing liquid containing a source to produce aerosol particles; a first-stage nebulizer, pneumatically coupled downstream of the gas-inlet port coupling, the first-stage nebulizer having a first-stage orifice, the first-stage orifice being located upstream from the liquid-inlet port, the first-stage nebulizer being configured toAttorney Docket 4270.035W01 18create a high-velocity jet of the compressed gas downstream of the first-stage orifice sufficient to produce a low-pressure volume to draw the particle-producing liquid through the liquid-inlet port and to produce a filament of liquid downstream of the first-stage orifice; a second-stage nebulizer, pneumatically coupled downstream of the first-stage nebulizer and the liquid-inlet port, the second-stage nebulizer having a second-stage orifice; an aerosol-outlet port, pneumatically coupled downstream of the second-stage nebulizer; a virtual impactor created downstream of the second-stage orifice, the virtual impactor being configured to split droplets of the particle-producing liquid into two groups of the droplets according to a predetermined virtual impactor cut-off point; and an excess-liquid outlet, pneumatically coupled downstream of the second-stage nebulizer and the aerosol-outlet port, and configured to receive droplets larger than the predetermined virtual impactor cut-off point.

[0063] Example 10. The nebulizer device of Example 9, wherein the aerosol-outlet port is configured to receive droplets smaller than the predetermined virtual impactor cutoff point.

[0064] Example 11. The nebulizer device of either of the Example 9 or Example 10, wherein the aerosol-outlet port is located downstream of an aerosol outlet.

[0065] Example 12. The nebulizer device of any one of the preceding Example 9 through Example 11, further comprising a drain opening located upstream from the excess-liquid outlet.

[0066] Example 13. The nebulizer device of any one of the preceding Example 9 through Example 12, further comprising a make-up flow inlet port pneumatically coupled downstream from the second-stage orifice to transport a make-up flow-stream.

[0067] Example 14. The nebulizer device of Example 13, wherein the make-up flowstream comprises the compressed gas.

[0068] Example 15. The nebulizer device of Example 13, wherein the make-up flowstream is configured to dry and reduce a size of the droplets to reduce transport losses on interior walls of the nebulizer device.Attorney Docket 4270.035W01 19

[0069] Example 16. The nebulizer device of any one of the preceding Example 9 through Example 15, further comprising a heater mechanically coupled to the nebulizer device to increase a temperature of the nebulizer device above an anticipated dew-point to reduce condensation on inside and outside walls to the nebulizer device.

[0070] Example 17. The nebulizer device of any one of the preceding Example 9 through Example 16, wherein the first-stage orifice and the second-stage orifice are each sized to avoid a choked-flow condition.

[0071] Example 18. In an embodiment, the disclosed subject-matter describes a two- stage nebulizer device having a gas-inlet port coupling to receive a compressed gas; a liquid-inlet port to receive a particle-producing liquid containing a source to produce aerosol particles; a first portion, pneumatically coupled downstream of the gas-inlet port coupling, the first portion having a first-stage orifice, the first-stage orifice being located upstream from the liquid-inlet port, the first portion being configured to create a high- velocity jet of the compressed gas downstream of the first-stage orifice sufficient to produce a low-pressure volume to draw the particle-producing liquid through the liquidinlet port and to produce a filament of liquid downstream of the first-stage orifice; a second portion, pneumatically coupled downstream of the first portion and the liquid-inlet port, the second portion having a second-stage orifice; and an aerosol-outlet port, pneumatically coupled downstream of the second portion.

[0072] Example 19. The two-stage nebulizer device of Example 18, further comprising a virtual impactor formed downstream of the second-stage orifice, the virtual impactor being configured to split droplets of the particle-producing liquid into two groups of the droplets according to a predetermined virtual impactor cut-off point; and an excess-liquid outlet, pneumatically coupled downstream of the second-stage orifice and the aerosol-outlet port, and configured to receive droplets larger than the predetermined virtual impactor cut-off point.

[0073] Example 20. The two-stage nebulizer device of Example 19, further comprising a drain opening located upstream from the excess-liquid outlet.

[0074] Example 21. The two-stage nebulizer device of any one of the preceding Example 18 through Example 20, further comprising a make-up flow inlet portAttorney Docket 4270.035W01 20pneumatically coupled downstream from the second-stage orifice to transport a make-up flow-stream.

[0075] Example 22. The two-stage nebulizer device of any one of the preceding Example 18 through Example 21, wherein the make-up flow-stream comprises the compressed gas.

[0076] Example 23. The two-stage nebulizer device of Example 22, wherein the make-up flow-stream is configured to dry and reduce a size of produced droplets to reduce transport losses on interior walls of the two-stage nebulizer device.Attorney Docket 4270.035W01 21

Claims

CLAIMSWhat is claimed is:

1. A nebulizer device comprising: a gas-inlet port coupling to receive a compressed gas; a liquid-inlet port to receive a liquid containing a source to produce aerosol particles; a first-stage nebulizer, pneumatically coupled downstream of the gas-inlet port coupling, the first-stage nebulizer having a first-stage orifice, the first-stage orifice located upstream from the liquid-inlet port; a second-stage nebulizer, pneumatically coupled downstream of the first-stage nebulizer and the liquid-inlet port, the second-stage nebulizer having a second-stage orifice; an aerosol-outlet port, pneumatically coupled downstream of the second-stage nebulizer; and an excess-liquid outlet, pneumatically coupled downstream of the second-stage nebulizer and the aerosol-outlet port.

2. The nebulizer device of claim 1, further comprising a make-up flow inlet port.

3. The nebulizer device of claim 1, further comprising a drain opening formed within the excess-liquid outlet and pneumatically coupled downstream of the second-stage nebulizer and the aerosol-outlet port.

4. The nebulizer device of claim 3, wherein a combination of the first-stage orifice, the second-stage orifice, and the drain opening combines to form a virtual impactor within the nebulizer device.

5. The nebulizer device of claim 4, wherein the virtual impactor is configured to split droplets of the liquid into two groups of the split droplets according to a predetermined virtual impactor cut-off point.

6. The nebulizer device of claim 5, wherein the excess-liquid outlet is configured to receive droplets larger than the predetermined virtual impactor cut-off point.Attorney Docket 4270.035W01 227. The nebulizer device of claim 6, wherein the aerosol outlet is configured to receive droplets smaller than the predetermined virtual impactor cut-off point.

8. The nebulizer device of claim 1, wherein the first-stage nebulizer is configured to create a high-velocity jet of the compressed gas downstream of the first-stage orifice sufficient to produce a low-pressure volume to draw the liquid through the liquid-inlet port and to produce a filament of liquid downstream of the first-stage orifice.

9. A nebulizer device comprising: a gas-inlet port coupling to receive a compressed gas; a liquid-inlet port to receive a particle-producing liquid containing a source to produce aerosol particles; a first-stage nebulizer, pneumatically coupled downstream of the gas-inlet port coupling, the first-stage nebulizer having a first-stage orifice, the first-stage orifice being located upstream from the liquid-inlet port, the first-stage nebulizer being configured to create a high-velocity jet of the compressed gas downstream of the first-stage orifice sufficient to produce a low-pressure volume to draw the particleproducing liquid through the liquid-inlet port and to produce a filament of liquid downstream of the first-stage orifice; a second-stage nebulizer, pneumatically coupled downstream of the first-stage nebulizer and the liquid-inlet port, the second-stage nebulizer having a second-stage orifice; an aerosol-outlet port, pneumatically coupled downstream of the second-stage nebulizer; a virtual impactor created downstream of the second-stage orifice, the virtual impactor being configured to split droplets of the particle-producing liquid into two groups of the droplets according to a predetermined virtual impactor cut-off point; and an excess-liquid outlet, pneumatically coupled downstream of the second-stage nebulizer and the aerosol-outlet port, and configured to receive droplets larger than the predetermined virtual impactor cut-off point.

10. The nebulizer device of claim 9, wherein the aerosol-outlet port is configured to receive droplets smaller than the predetermined virtual impactor cut-off point.Attorney Docket 4270.035W01 2311. The nebulizer device of claim 9, wherein the aerosol-outlet port is located downstream of an aerosol outlet.

12. The nebulizer device of claim 9, further comprising a drain opening located upstream from the excess-liquid outlet.

13. The nebulizer device of claim 9, further comprising a make-up flow inlet port pneumatically coupled downstream from the second-stage orifice to transport a make-up flow-stream.

14. The nebulizer device of claim 13, wherein the make-up flow-stream comprises the compressed gas.

15. The nebulizer device of claim 13, wherein the make-up flow-stream is configured to dry and reduce a size of the droplets to reduce transport losses on interior walls of the nebulizer device.

16. The nebulizer device of claim 9, further comprising a heater mechanically coupled to the nebulizer device to increase a temperature of the nebulizer device above an anticipated dew-point to reduce condensation on inside and outside walls to the nebulizer device.

17. The nebulizer device of claim 9, wherein the first-stage orifice and the second-stage orifice are each sized to avoid a choked-flow condition.Attorney Docket 4270.035W01 2418. A two-stage nebulizer device, comprising: a gas-inlet port coupling to receive a compressed gas; a liquid-inlet port to receive a particle-producing liquid containing a source to produce aerosol particles; a first portion, pneumatically coupled downstream of the gas-inlet port coupling, the first portion having a first-stage orifice, the first-stage orifice being located upstream from the liquid-inlet port, the first portion being configured to create a high- velocity jet of the compressed gas downstream of the first-stage orifice sufficient to produce a low-pressure volume to draw the particle-producing liquid through the liquid-inlet port and to produce a filament of liquid downstream of the first- stage orifice; a second portion, pneumatically coupled downstream of the first portion and the liquidinlet port, the second portion having a second-stage orifice; and an aerosol-outlet port, pneumatically coupled downstream of the second portion.

19. The two-stage nebulizer device of claim 18, further comprising: a virtual impactor formed downstream of the second-stage orifice, the virtual impactor being configured to split droplets of the particle-producing liquid into two groups of the droplets according to a predetermined virtual impactor cut-off point; and an excess-liquid outlet, pneumatically coupled downstream of the second-stage orifice and the aerosol-outlet port, and configured to receive droplets larger than the predetermined virtual impactor cut-off point.

20. The two-stage nebulizer device of claim 19, further comprising a drain opening located upstream from the excess-liquid outlet.

21. The two-stage nebulizer device of claim 18, further comprising a make-up flow inlet port pneumatically coupled downstream from the second-stage orifice to transport a make-up flow-stream.

22. The two-stage nebulizer device of claim 21, wherein the make-up flow-stream comprises the compressed gas.Attorney Docket 4270.035W01 2523. The two-stage nebulizer device of claim 21, wherein the make-up flow-stream is configured to dry and reduce a size of produced droplets to reduce transport losses on interior walls of the two-stage nebulizer device.Attorney Docket 4270.035W01 26

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