AU767486B2 - Method for producing an aerosol - Google Patents

Method for producing an aerosol Download PDF

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Publication number
AU767486B2
AU767486B2 AU53318/00A AU5331800A AU767486B2 AU 767486 B2 AU767486 B2 AU 767486B2 AU 53318/00 A AU53318/00 A AU 53318/00A AU 5331800 A AU5331800 A AU 5331800A AU 767486 B2 AU767486 B2 AU 767486B2
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Prior art keywords
liquid
gas
supply means
exit opening
exit
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AU5331800A (en
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Alfonso Ganan Calvo
Joan Rosell
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Universidad de Sevilla
Aradigm Corp
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Universidad de Sevilla
Aradigm Corp
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Priority to US60/138698 priority
Application filed by Universidad de Sevilla, Aradigm Corp filed Critical Universidad de Sevilla
Priority to PCT/US2000/015931 priority patent/WO2000076673A1/en
Publication of AU5331800A publication Critical patent/AU5331800A/en
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    • BPERFORMING OPERATIONS; TRANSPORTING
    • B05SPRAYING OR ATOMISING IN GENERAL; APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05BSPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/02Spray pistols; Apparatus for discharge
    • B05B7/04Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge
    • B05B7/0416Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid
    • B05B7/0441Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid with one inner conduit of liquid surrounded by an external conduit of gas upstream the mixing chamber
    • B05B7/0475Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid with one inner conduit of liquid surrounded by an external conduit of gas upstream the mixing chamber with means for deflecting the peripheral gas flow towards the central liquid flow
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B05SPRAYING OR ATOMISING IN GENERAL; APPLYING LIQUIDS OR OTHER FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05BSPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B7/00Spraying apparatus for discharge of liquids or other fluent materials from two or more sources, e.g. of liquid and air, of powder and gas
    • B05B7/02Spray pistols; Apparatus for discharge
    • B05B7/04Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge
    • B05B7/0416Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid
    • B05B7/0483Spray pistols; Apparatus for discharge with arrangements for mixing liquids or other fluent materials before discharge with arrangements for mixing one gas and one liquid with gas and liquid jets intersecting in the mixing chamber

Description

Method for Producing an Aerosol FIELD OF THE INVENTION This application generally relates to the creation of an aerosol created by the directed flow of fluids.

BACKGROUND OF THE INVENTION Devices for creating finely directed streams of fluids and/or creating aerosolized particles of a desired size are used in a widerange of different applications, such as, for example, finely directed streams of ink for ink jet printers, or directed streams of solutions containing biological molecules for the preparation of microarrays. The production of finely dispersed aerosols is also important for aerosolized delivery of drugs to obtain deep even flow of the aerosolized particles into the lungs of patients; aerosolizing fuel for delivery in internal combustion engines to obtain rapid, even dispersion of any type of fuel in the combustion chamber; or the formation of uniform sized particles which themselves have a wide range of uses including making chocolate, which requires fine particles of a given size to obtain the desired texture or "mouth feel" in the resulting product, making pharmaceutical products for timed release of drugs or to mask flavours; and making small inert particles which are used as standards in tests or as a substrate onto which compounds to be tested, reacted or assayed are coated.

Any discussion of documents, acts, materials, devices, articles or the like which 25 has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

SUMMARY OF THE INVENTION In a first aspect, the present invention is a method, comprising the steps of: S .forcing a liquid out of an exit opening of a liquid supply means; forcing a fluid into a pressure chamber which surrounds the exit opening of the liquid supply means, the fluid being provided in a manner such that the fluid: 35 focuses liquid exiting the exit opening to a stream having dimensions smaller than that of the exit opening; provides momentum to and interacts with the liquid exiting the liquid supply means; creates a violent interaction between the liquid and the fluid which destabilizes the liquid so as to form particles of the liquid wherein the mean dimensions of particles formed is less than the dimensions of the focused liquid stream; and carries the liquid stream out of the pressure chamber.

In a second aspect, the present invention is a method of creating an aerosol, the method comprising the steps of: forcing a liquid through a feeding tube and out of an exit opening of the feeding tube wherein the exit opening of the feeding tube is positioned such that the liquid flowing out of the tube flows toward and out of an exit orifice of a chamber surrounding the exit opening of the feeding tube; forcing a gas into the chamber and out of the exit orifice of the chamber creating a violent interaction between the liquid and the gas; wherein the exit opening of the feeding tube has a diameter in the range of about 5 to about 10,000 microns and the exit opening of the tube is positioned at a distance in a range of from about 5 to about 10,000 microns from an entrance point of the exit orifice.

In another aspect, the present invention is a method of creating an aerosol, comprising the steps of: forcing a liquid out of an exit opening of a liquid supply means to form a liquid stream; and forcing a gas into a chamber and out of an exit orifice aligned with a flow path of liquid having the exit opening whereby the liquid stream is focused by the gas to dimensions smaller than dimensions of the exit opening; wherein the exit' opening and exit orifice are positioned to create a violent interaction between the liquid and the gas such that particles formed outside the exit orifice have a size determined by the relationship between the particle surface tension and the amplitude of turbulent pressure fluctuation outside the chamber and further *30 wherein that relationship is such that the particles have dimensions smaller than dimensions of the focused liquid stream.

S•In a further aspect, the present invention is a method, comprising the steps of: forcing a liquid out of an exit opening of a liquid supply means; forcing a gas into a pressure chamber and out of an exit orifice of the chamber; 35 and causing the gas to converge against the liquid exiting the liquid supply means thereby; causing the liquid to assume dimensions smaller than dimensions of the exit opening of the liquid supply means; creating a violent interaction between the liquid and the gas; carrying the liquid away from the exit orifice of the pressure chamber; and resulting in the liquid forming particles which are smaller in size than expected based on spontaneous capillary breakup of the assumed smaller dimensions of the liquid.

A method of creating small particles and aerosols by a technology referred to here as "violent focusing" of a liquid to break up and disperse a liquid is disclosed, along with devices for generating such violent flow focusing. In general, a "violent focusing" method comprises the steps of forcing a first liquid through a feeding tube and out of an exit opening of the feeding tube is positioned inside a pressure chamber which is continually filled with a second fluid which may be a second liquid immiscible in the first liquid or a gas. The exit opening of the feeding tube is positioned such that the liquid flowing out of the tube flows toward and out of an exit or discharge orifice of the chamber surrounding the exit opening of the feeding tube.

The first liquid exiting the tube is focused to a substantially reduced diameter and subjected to a violent action created by the second liquid or gas, breaking up the flow into particles substantially smaller than if the reduced diameter flow underwent spontaneous capillary breakup. The exit opening of the feeding tube preferably has a diameter in the range of about 5 to about 10,000 microns and the exit opening of the tube is positioned at a distance in a range of from about 5 to about 10,000 microns, more preferably about 15 to about 200 microns from an entrance point of the exit orifice.

A stream of the first liquid flows out of the tube and is focused by the flow of the second liquid or gas in the surrounding pressure chamber. The focused stream then exits out of the discharge orifice of the pressure chamber, destabilizing and forming small particles. The size of the particles of the first liquid is governed by the balance between the surface tension forces of the first liquid particle formed, and the amplitude S•of the turbulent pressure fluctuations at, and outside of the exit orifice of the pressure chamber. When the particles are sufficiently small that their surface tension forces substantially match the amplitude of the pressure fluctuation then the particles are 35 stabilized and will not break up into still smaller particles.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic cross-sectional plan view of a nozzle of the invention; Figure 2 is another embodiment of the nozzle of Figure 1 showing and labelling various angles and areas of the nozzle; Figure 3 is the same embodiment as shown in Figure 1 with various angles and areas labelled; Figure 4 is another embodiment of the nozzle of Figure 1 with certain areas and angles labelled; Figure 5 is an embodiment of the nozzle of Figure 1 with various parameters labelled.

Oo WO 00/76673 PCT/USOO/15931 Figure 6 is a graph of the volume median diameter (VMD) vs the liquid supply flow rate for four different liquids; Figure 7 is a graph of the dimensionless volume median diameter (VMD) versus dimensionless liquid flow rate with a line through the data points showing the best power-fit; Figure 8 is a graph of the data with the line shown in Figure 7 compared to a theoretical line for the Rayleigh breakup prediction of a flow-focused jet; and Figure 9 is a graph of data obtained with the different liquids listed of the geometric standard deviation (GSD) vs. dimensionless liquid flow rates.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Before the present aerosol device and method are described, it is to be understood that this invention is not limited to the particular components and steps described, as such may, of course, vary. It is arso to.be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

It must be noted that as used herein and in the appended claims, the singular forms "and," and "the" include plural referents unless the context clearly dictates otherwise.

Thus, for example, reference to "a particle" includes a plurality of particles and reference to "a fluid includes reference to a mixture of fluids, and equivalents thereof known to those skilled in the art, and so forth.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety to disclose and describe the methods and/or materials in connection with which the publications are cited.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior

I

WO 00/76673 PCTUSOO/15931 invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

GENERAL METHODS The method is carried out by forcing a liquid from a liquid supply means, e.g. a tube. The liquid exits the supply means into a pressure chamber filled with a second fluid which is preferably a gas. The chamber has an exit port preferably positioned directly in front of and preferably downstream of the flow of liquid exiting the supply means. The exit port may be positioned slightly upstream of the liquid supply means exit. The liquid is focused by the gas to substantially smaller dimensions as it exits the supply means e.g. a tubular stream of liquid one unit in diameter is focused to a stream 1/2 1/400 of a unit in diameter or smaller depending on operating conditions. In this proposed example, a focused cylindrical stream of one unit in.diameter would be expected to undergo Rayleigh breakup and form particles which are about 1.89 times the diameter of the focused stream. However, by correctly adjusting parameters (such as positioning the exit of the liquid supply means relative to the chamber exit port) the liquid stream is first focused by the gas flowing out of the chamber thereby forming a stream with a much smaller diameter. That stream leaves the chamber and forms particles which are smaller in diameter than the focused stream.

Based on the above it will be understood that the nozzles and methods of the present invention are capable of producing extremely small particles. As an example, consider producing particles using a cylindrical liquid supply means having a diameter of 1000 units. The stream from such a supply means would be expected to undergo normal Rayleigh breakup of the 1000 unit diameter stream to form spherical particles having a diameter of about 1.89 x 1000 or 1890 units in diameter. If the stream having a diameter of 1000 units is focused to a stream or jet of smaller dimension by a surrounding gas the jet might have a diameter of one tenth that size or 100 units. That 100 unit diameter focused jet would be expected to undergo normal Rayleigh breakup to form particles having a diameter of 1.89 x 100 or 189 units.

Focusing the diameter of the stream to a narrow focused jet or "stable microjet"jet has been referred to as flow focusing technology. When using the flow focusing technology -4- W oond6673 PCT/US00/15931 the focused jet has a diameter d at a given point A in the stream characterized by the formula: d 8p I2AP wherein dj is the diameter of the stable microjet, indicates approximately equally to where an acceptable margin of error is 10%, p, is the density of the liquid and AP, is change in gas pressure of gas surrounding the stream at the point A. The diameter of the jet can be any reduced dimension smaller than that of liquid stream exiting the supply means, e.g. can have a cross-sectional diameter of from about one half to about 1/100 the area of the stream exiting the liquid supply means.

In accordance witA the violent flow focusing of the present invention the liquid flow exiting the supply nreans with a diameter of 1000 units is focused as it leaves the supply means so that the end of the exiting drop exiting the liquid supply tube is focused by the surrounding gas to a reduced dimension to 1/100 the cross-sectional diameter of the liquid supply means). For purposes of example we will say the 1000 unit stream is reduced to a diameter of about 100 units. That 100 unit end of the drop is subjected to turbulent action by the gas exiting the pressure chamber thereby forming particles which are 10 units in diameter. Thus, the above proposed examples can be summarized as follows: Supply Means Diameter Particle Diameter Rayleigh 1000 1890 Flow Focusing 1000 189 Violent Flow Focusing 1000 1 Based on the above it will be appreciated that the method of the invention can produce particles which are substantially smaller than /2 to 1/100) the size of particles produced using flow focusing technology. Further, flow focusing technology can produce particles which are substantially smaller than V 2 to 1/100) the size of particles produced by normal capillary breakup of a stream.

-i V I WO 00/76673 PCT/USOO/15931 GENERAL DEVICE The basic device or nozzle of the invention can have a plurality of different configurations. However, each configuration or embodiment will comprise a means for supplying a liquid or first fluid and a means for supplying a second fluid (preferably a gas) in a pressure chamber which surrounds at least an exit of the means for supplying a liquid. The liquid supply means and pressure chamber are positioned such that turbulent action takes place between the liquid exiting the liquid supply means and the second fluid, a liquid or a gas, exiting the supply chamber. Preferably, the exit opening of the pressure chamber is downstream of and more preferably it is directly aligned with the flow path of the means for supplying the liquid. To simplify the description of the invention, the means for supplying a liquid is often referred to as a cylindrical tube (tube shape could be varied, e.g. oval, square, rectangular). The first fluid or liquid can be any liquid depending on the overall device which the invention is used withln. For example, the liquid could be a liquid formulation of a pharmaceutically active drug used to create dry particles or liquid particles for an aerosol for inhalation or, alternatively, it could be a hydrocarbon fuel used in connection with a fuel injector for use on an internal combustion engine or heater or other device which bums hydrocarbon fuel. Further, for purposes of simplicity, the second fluid is generally described herein as being a gas and that gas is generally air or an inert gas. However, the first fluid is a liquid and the second fluid may be a gas or a liquid provided the first and second fluids are sufficiently different from each other immiscible). It is possible to have situations wherein the liquid exits either the liquid supply means or the pressure chamber vaporizes to a gas on exit. Such is not the general situation. Notwithstanding these different combinations of liquid-gas, and liquid-liquid, the invention is generally described with a liquid formulation being expelled from the supply means and interacting with surrounding gas flowing out of an exit of the pressure chamber. Further, the exit of the pressure chamber is generally described-as circular in cross-section and widening in a funnel shape (Fig. 1), but could be any configuration.

Referring to the figures a cross-sectional schematic view of the nozzle 1 is shown in Figure 1. The nozzle 1 is comprised of two basic components which include the pressure chamber 2 and the liquid supply means 3. The pressure chamber 2 is pressurized by fluid WO 00/76673 PCTIUSODJIS93l flowing into the chamber by the entrance port 4. The liquid supply means 3 includes an inner tube 5 where liquid flows. The inner tube 5 of the Liquid supply means 3 is preferably supplied with a continuous stream of a fluid which fluid is preferably in'the form of a liquid.

The pressure chamber 2 is continuously supplied with a pressurized fluid which may be a liquid or a gas. When the fluid is a liquid the liquid is preferably insoluble and incompatible with the liquid being provided from the inner tube 5 oil and water which do not readily mix and form a distinct interface). The inner tube 5 of the liquid supply means 3 includes an exit point 6. The pressurized chamber 2 includes an exit point 7. The exit point 7 of the pressure chamber is preferably positioned directly downstream of the flow of liquid exiting the exit point 6. The liquid supply means exit and the exit of the pressure chamber are configured and positioned so as to obtain two effects the dimensions of the stream exiting the liquid supply means are reduced by the fluid exiting the pressure chamber; and the liquid exiting the liquid supply means and the fluid exiting the pressure chamber undergo a violent interaction to fomiA much smaller particles than would form if the stream of liquid in reduced dimensions underwent normal capillary instability, e.g. formed spherical particles 1.89 times the diameter of the cylindrical stream.

Preferably, the exit port of the chamber 2 is directly aligned with the flow of liquid exiting the liquid supply means 3. An important aspect of the invention is to obtain small particles 8 from the liquid 9 flowing out of the exit port 6 of the inner tube 5. Obtaining the desired formation of par-ticles 8 is obtained by correctly positioning and proportioning the various components of the liquid supply means 3 and the chamber 2 as well as the properties of the fluids including the speed of these fluids which flow out of both the liquid supply means 3 and the chamber 2. Specifically, there are some important geometnic parameters that define the nozzie I of the present invention. Those skilled in the art will adjust those parameters using the information provided here in order to obtain the most preferred results depending on a particular situation.

Preferably, the liquid 9 is held within the inner tube 5 which is cylindrical in shape- However, the inner tube 5 holding the liquid 9 may be asymmetric, oval, square, rectangular or in other configurations including a configuration which would present a substantially planar flow of liquid 9 out of the exit port 6- Thus, the nozzle of the invention -7- I. WO 00/76673 PCTIUSOO/15931 applies to all kinds of round axi-syminetric) and planar symmetric twodimensional) configurations that have a convergent passage for the outer fluid. 'For example, a round but not axi-symm&ric geometry would be one in whic -h the surfaces of the orifice plate are faceted at different azimuthal angles. Accordingly, the figures including Figure 1 are used only to define the variabl.es but are not intended to imply any restrictions on the type of geometry or the specific details of the design of the nozzle I of the present invention.

There are infinite degrees of freedom of design. For example, corners which are shown as sharp could be rounded or finished in different ways.

Formation of the microjet and its acceleration and ultimate particle formation are based on the abrupt pressure drop associated with the steep acceleration experienced by the liquid on passing through an exit orifice of the pressure chamber which holds the second fluid the gas).

Without being limite$ to any one theory, the creation of the violently focused aerosol (in an axisynimethc configuration) may occur as follows. The strong radial fluid flow (10) that exists in the very narrow gap between the points 6 and 7 becomes circulatory as it passes through and out of the orifice of the exit 7 of the pressure chamber 2. At the same time, the liquid meniscus is sucked in towards the center of the exit point 7 of the chamber 2. As the gas 10 exits the hole at point 7, its strong circulatory motion induces the fluid dynamic effect referred to as a vortex breakdown. This is an instability in which fluid particles gain so much centrifuigal inertia that they spin off away from the axis. As a result, a bubble of gas is created along the axis downstream from this point, in which the outer fluid (preferably a gas) flow reverses, flowing upstream back towards the nozzle. Consequently, the droplets are accelerated radially outwards resulting in enhanced dispersion.

Referring now to Figure 2 in order to describe the relationships between some of the components shown in Figure 1. First, a dashed line C C' is shown running through the center of the inner tube-5 in which the liquid 9 flows as well as the exit of the chamber 2. In symmetric atomizers the line C-C'represents the plane of symmetry intersection of the plane of view. The line represents the bisector of the convergent passage near the center of the nozzle. The area refer-red to as the "convergent passage" is the region which is the open area between the terminal face I I of the liquid supply means 3 and the front face 12 WO 00/76673 PCT/USOO/1 5931 of the chamber 2. To obtain desired results with the nozzle of the present invention the following characteristics must be present: a strong convergence of the outer fluid (liquid of gas) in the chamber 2 towards and around the inner fluid 9 coming out of the inner tube sufficient momentum for the fluid 10 in the chamber 2 before it interacts with the fluid 9; a focusing or compression of the stream of liquid 9 by the surrounding fluid The above characteristics combine with each and with other characteristics in order to result in the desired vortex breakdown of the stream of fluid 9 exiting the inner tube 5. For example, other characteristics will include sonic speeds and shock waves when the outer fluid 10 is a gas.

In order to more fully inderstand the invention each of the characteristics referred to above are described in further detail below.

Strong convergence of outer fluid: The primary characteristic of the present invention is the facilitation of a strongly convergent (imploding) flow of outer fluid 10 towards and around the inner liquid 9. The fluid 10 in the pressure chamber, should preferably not merely flow parallel to the liquid 9 exiting the liquid supply means, i.e. should preferably not intersect at a 0 degree angle.

Further, the fluid 10 in the pressure chamber should preferably not flow directly perpendicular to the liquid stream 9 exiting the liquid supply means, i.e. should preferably not interact at a 90 degree angle or more. Thus, convergence of the two fluids is preferably at an angle of more than 0 degrees and less than 90 degrees. However, the fluid 10 of the pressure chamber could, in. some situations be directed at the liquid 9 from the liquid supply means at an angle of 90 degrees or more, at an angle such that the fluid 10 is flowing back toward the liquid 9 and is converging on the liquid 9 at an angle of up to 150 degrees.

Flow convergence improves the transfers of momentum and kinetic energy from the outer fluid 10 to the inner liquid 9 required to breakup the inner fluid 9 into particles 8.

Improving the efficiency of such transfer results in energy savings for a given amount of -9- WO 00176673 PCTUSOOI1 5931 inner liquid 9 atomized and a given droplet size requirement. A greater efficiency of atomnization is achieved by transferring a greater fraction of pressure energy originally in the outer fluid 10 per unit mass of the outer fluid to the inner liquid 9.

In order to generate significant convergence in the outer fluid 10 towards the inner liquid 9, *the outer fluid 10 must be admitted into a path that gives it a sufficiently high converging speed. Specifically, the following design constraints shown in Figure 3 are preferred.

a convergent passage convergence angle a smaller than 90 degrees, ct 90 degrees, the exterior surface I I of the feeding passage exit should form an angle 13with center line CC' greater than 45 degrees but smaller than 15 0 degrees, 150 degrees P3 45 degrees, and the lengthlof the convergent passage (shown in Figure 3) should be chosen such that an optimum is fbund that encourages a significant bending of the streamlines towards the inner fluid 9. In general, D, is required to be at least equal to 1.2 times D, 1.2 DI.

Incident momentum in outer fluid: To ensure sufficient momentum in the outer fluid at the point where it meets the inner liquid 9, the convergent passage separation between R and P (see Figure 2) must be chosen appropriately. This distance can be defined as the distance between points R and P in Figure 2. For given conditions of pressure and temperature in the outer fluid chamber and outside region, this variable regulates the relative average velocity between the inner liquid 9 and the outer fluid 10 at the point of encounter (inner rim of tube exit indicated by point P in Figures 2 and For example, a very narrow convergent passage is one in which fictional losses dissipate the outer fluid momentum significantly. Widening such a passage will encourage coupling between outer fluid 10 and inner liquid 9. On the other hand, if the separation between R and P is made too wide, then the effect of efficient atomization is lost, because the fastest speed is encountered then in the discharge orifice, not at the end of te convergent passage.

WO 00/76673 PCT/US00/15931 In general, thus, one desires to have as high a momentum as possible in the outer fluid 10 for a certain amount of outer fluid mass flow (and pressure and temperature conditions). The ratio between momentum and mass fluxes is similar to its average speed (in fact, is very nearly such value when variations in local speed are negligibly small across the convergent passage). The fastest speed is generally obtained in the narrowest part of the outer fluid flow path. Again, if the distance between R and P is too large, then the narrowest part will be at the discharge orifice. Thus, if the distance of R to P is H the largest value of H compatible with this requirement typically is: Hmax p D For axi-symmetric configurations, P equals 0.25; while for planar-two dimensional configurations, 0 equals On the other hand! H must be large enough to preclude excessive friction between the outer fluid and the convergent passage walls that can slow down the flow and waste pressure energy (stagnation enthalpy) into heat (internal energy). An approximate guiding principle is that H should be greater than Hmin, defined as a few times the thickness of the viscous boundary layer 5, that develops inside the outer fluid 10 in its acceleration through the convergent passage: Hmin X 8L I to The thickness of the boundary layer at point P' (Figure 2) for the case when the outer fluid is near the speed of sound is approximately given by the following expression: 6 L (L Ap 2 /(p 2 P2) 0 0 Here V, is the dynamic viscosity coefficient of the outer fluid 10, p, is its density, and Po, is the pressure of the outer fluid 10 in the upstream chamber. X is a numerical factor, which generally is between I and 10. L is the length of the convergent passage (Figure 3) L 0.5 -11- ~a WO 00/76673 PCT/US00/15931 These expressions neglect the presence of liquid in the discharge orifice, or the possibility of swirling in the flow. Therefore, the equations provided above should be considered as approximate guides, e.g. ±30% error factors.

Flow-focusing of the inner liquid: In the presence of airflow, the inner liquid 9 coming out of the inner tube 5 gets funnel-shaped into ajet that gets thinner as it flows downstream: Thejet can have a variety of different configurations, e.g. a circular cross-section, or a flat planar one. Any configuration can be used which provides flows through the center of the discharge orifice 7, and can become much thinner as it enters the discharge orifice 7 than at the exit 6 of the inner tube 5. This phenomenon has previously been termed "flow-focusing" (see WO 99/31019 published June 24, 1999). The forces responsible for the shaping of the inner liquid 9 are believed to arise from the pressure gradients that set within the outer fluid 10 as it flows through the discharge orifice 7. For example, in axi-symmetric configurations, a round inner liquid jet is expected to attain a diameter dj determined by the '2 power law with liquid flow rate Q (in volume per unit of time, e.g. cubic meter per second; Gafiin-Calvo A.

1998): d- (8pJ 2

Q

1 2 p, is the inner liquid density, t is pi, and AP, is the pressure drop in the outer fluid between the upstream value and the value at the point where dj is taken and means approximately equal to with about a 10% error margin. This equation will be herein referred to as the "flow-focusing" formula and only applies for a uniform velocity distribution along the inner liquid jet radius.

A notable consequence of flow-focusing is that the inner liquid is stabilized towards the center of the discharge orifice. For example, in one of the preferred device embodiments (Figure the exit of both the inner tube 5 and the chamber 2 at point 7 were of equal diameter. However, in all the tests done the inner liquid 9 was observed to flow through the center of the discharge orifice without impacting or wetting its side walls. (Due to the random nature of the drop trajectories under conditions of very high inner liquid flow 12- WO 00/76673 PCT/USOO/15931 rates used for violent focusing, a small degree of wetting has indeed been detected, but is associated with an insignificant fraction of the inner liquid.) Vortex breakdown: A theoretical model based on the existence of a vortex cell near the region of breakup is proposed to explain the effectiveness of atomization obtained by the present invention in the case of axi-symmetric geometries. In such cases, it is hypothesized that the strong radial forces provided by the outer fluid flow between the orifice body and the liquid dispenser (a cylindrical tube in its simplest form) result in a violent swirl in the outer fluid (Shtern and Hussain 1999). The swirling motion results in a vortex which breaks down near the region of breakup. Such breakdown is the centrifugal explosion of the fluid streamlines due to their rapid spinning motion. The entrained particles and filaments of the inner liquid are spun away and dispersed before they get a chance to coalesce (two or more particles forming one). The benefts of vortex breakdown in promoting liquid breakup and drop dispersion have previously been reported (Hopfinger and Lasheras 1996; Lasheras et al.

1998). In the new invention any swirling of the outer fluid is not created upstream by means of swirling vanes or other shapes of the atomizer body. Instead, the swirling is induced locally by the strong converging motions forced by the very simple-geometry of the atomizer.

Gas sonic speeds and shock waves: Sonic speeds and shock waves take place when the outer fluid is a gas. In all tests to date using that configuration, the pressure drop across the atomizer was such that the gas attained sonic and supersonic speeds. Under these conditions shock waves are also expected to be present.

Characteristics of supersonic flow such as shock waves may improve atomization.

However, such are not believed to be required.

Unique characteristics of the present invention include: High frequency of droplet generation, Low requirements on liquid pressure, Low sensitivity of drop size -13- WO 00/76673 PCT/US00/15931 to inner liquid flow rate, Little apparent effect of atomizer size on droplet size. These characteristics are described further below.

High frequency of droplet generation: When the outer fluid is a gas and the inner fluid a liquid, the data demonstrate that the droplets are much smaller than predicted from the spontaneous capillary breakup, such as Rayleigh breakup in axi-symmetric configurations; (Rayleigh 1882) of an inner liquid column of size dj equal to that predicted by the flow-focusing formula discussed earlier. Or, what is the same, for given values of the liquid properties and operational variables, the final size of the droplets is many times smaller than the flow-focusing diameter dj discussed earlier. As a result, the frequency of droplet production is much higher than predicted by spontaneous capillary breakup of the flow focused jet. Accordingly, particles formed via the method described here are substantially smaller 1/2 the size or less or 1/20 the size or less) than would be obtained due to spontaneous capillary break-up of the stream exiting the tube 5 and chamber 2. (See Figure 7) Low requirements on liquid pressure: The inner liquid 9 does not have to be pushed out of its inler tube 5 with a sufficiently high pressure capable of maintaining a stable liquid jet in the absence of outer fluid flow and solid surfaces in its way. It is not necessary for the inner liquid to form a stable microjet structure. Further, pre-existent inner liquid jet structure coming directly out of the exit opening 6 is not required because, a explained in the liquid meniscus is focused by the action of the outer fluid pressure forces.

Low sensitivity of drop size to inner liquid flow rate: In the cases tested thus far, a low sensitivity of droplet size on flow rate has been observed. The dependence is close to a power law with exponent 1/5 of the liquid flow rate.

-14- WO 00/76673 PCT/USOO/15931 Small apparent effect of atomizer size: Based on the experimental data available thus far (reported later herein), the drop size dependence with inner liquid flow rate, outer fluid pressure and inner liquid physical properties does not seem to involve any variables characterizing the size of the atomizer.

(See the EXAMPLES.) However, under certain conditions of operation, for example at high flow rates that lead to a large fraction of the discharge orifice occupied by the liquid, one would expect certain dependence.

EXAMPLES

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have,been made to ensure accuracy with respect to numbers used (e.g.

amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade.

Figures 6-9 show results for aerosols produced by methodg of the present invention using dry air and dry nitrogen as outer fluids 10, and a range of liquids as inner fluids 9: distilled water, 2-propanol, 20 by volume of ethanol in water and 0.1% weight in volume Polysorbate-20 in distilled de-ionized water ("0.1%Tween"). Tests were performed in four separate experiments with different atomizers. The atomizers were of an axi-symmetric type and had dimensions as specified below in Table A.

The droplet size was determined by phase Doppler anemometry (Lefebvre 1989; Bayvel and Orzechowski 1993) along the axis of the aerosol plume a few centimeters downstream from the exit of the atomizer. This measurement technique led to notoriously low rates of validated counts, i.e. low rates of detected light pulses ("bursts"). This problem appears to result from a combination of high droplet concentrations and high velocities.

Validation count rates lower than 50% have been excluded from the sets of data presented WO 00/76673 PCT/US00/15931 here. As a consequence, all of the droplet size measurements in experiments 3 and 4 with were excluded from the graphs. Nevertheless, atomizer dimensions have been included in table A to indicate that stable aerosols were obtained in a third and fourth experiment with an atomizer of similar characteristics as in experiment 2, but otherwise of a very different design.

TABLE A Atomizer geometric dimensions (in micron unless indicated) used in the experiments (refer to figure for key); typical tolerance (a=O degrees; 90 degrees) Experiment Do Dt D1 H T cp degrees 0, degrees 1 62 50 90 19 50 13 2 200 200 400 35 75 0 0 3 200 200 400 50 75 0 0 4 200 200 400 50-80 75 0 0 Figure 6 is a graph of the volume median diameter (VMD) vs the liquid supply flow rate for four different liquids.

In Figure 7 the volume median diameter and liquid flow rates have been non-dimensionalized using similar variables to those identified in the flow-focusing literature (Gafiin-Calvo 1998), d o and Qo: do o/AP, and Qo AP'3 where a is the interfacial tension of the liquid-gas interface (newton/meter). However, the definition of the pressure drop AP, used here is based not on the upstream (stagnation) and downstream (ambient) values of the pressure, but on the upstream value P, and the value P' at the sonic point. The sonic pressure was computed using the well-known isentropic expression: P P k 16nr WO 00/76673 PCT/US00/15931 where k is the heat capacity ratio of the gas (equal to 1.4 for dry air and dry nitrogen; White 1994). Therefore AP, P -P P, (1 k k-1 Thus, for both dry air and nitrogen, APg= 0.4717 Po In these experiments Po was varied between 200 kPa and 700 kPa.

The best power law fit to the available data (Figure 7) is: ,VMD do 5.60 (Q/Qo) 0 20 8 Figure 8 graphs the new fit characteristic of the new method together with the one which would correspond to the Rayleigh breakup of a flow focused jet at the same conditions of liquid properties, flow rate, and gas pressure (thus equal do, Q, and Qo). The results shown in Figure 8 are based on the theoretical assumption that Rayleigh break-up of a flow-focused jet would result in droplets of uniform diameter (VMD) equal to 1.89 times the jet diameter (Brodkey 1995). Applying the equation for the jet diameter given earlier leads to: VMD 1.89 (8p/ (7AP 4 Q'2 This expression can be cast into dimensionless form using the definitions of do and Qo: VMD d o 1.89 2 In Figure 8 the "Rayleigh breakup" line has been represented between the limits believed to occur in reality. If this expression could be extrapolated to higher Q/Qo values, it would predict larger drop sizes at equal conditions of Q/Qo and do. But, more importantly, -17- I WO 00/76673 PCT/US00/15931 because the dependence with Q/Qo is much less pronounced than for flow-focused jets, the range of liquid flow rates over which a certain band of desired drop sizes can be generated is much wider than from Rayleigh breakup of flow-focusedjets. These conclusions should apply as well when a comparison is being made to non-Rayleigh breakup of flow-focused jets, provided the droplet diameters become similar to the jet diameter.

Another notable result is that data from dissimilar atomizers seems to follow the same scaling law. In other words, based on currently available data, the scaling law appears to be relatively insensitive to the scale of the atomizer.

The proposed atomization system obviously requires delivery of the liquid to be atomized and the gas to be used in the resulting spray. Both should be fed at a rate ensuring that the system lies within.the desired parameter window. Multiplexing is effective when the flow-rates needed exceed those obtained for an individual cell. More specifically, a plurality of feeding sources 3 or holes therein forming tubes 3 may be used to increase the rate at which aerosols are created. The flow-rates used should also ensure the mass ratio between the flows is compatible with the specifications of each application.

The gas and liquid can be dispensed by any type of continuous delivery system a compressor or a pressurized tank the former and a volumetric pump or a pressurized bottle the latter). If multiplexing is needed, the liquid flow-rate should be as uniform as possible among cells; this may entail propulsion through several capillary needles, porous media or any other medium capable of distributing a uniform flow among different feeding points.

Although a single liquid supply means 3 is shown in Figures 1-5 it, of course, is possible to produce a device with a plurality of feeding members where each feeding member feeds fluid to an array of outlet orifices in a single surrounding pressure chamber.

In addition, the liquid supply means may be planar with grooves therein, but need not be strictly planar, and may be a curved feeding device comprised of two surfaces that maintain approximately the same spatial distance between the two pieces of the liquid supply means.

Such curved devices may have any level of curvature, e.g. circular, semicircular, elliptical, hemi-elliptical, etc.

18- WO 00/76673 PCT/US00/ 5931 DRUG DELIVERY DEVICE A device of the invention may be used to provide particles for drug delivery, e.g.

the pulmonary delivery of aerosolized pharmaceutical compositions. The device would produce aerosolized particles of a pharmaceutically active drug for delivery to a patient by inhalation. The device is comprised of a liquid feeding source such as a channel to which formulation is added at one end and expelled through an exit opening. The feeding channel is surrounded by a pressurized chamber into which gas is fed and out of which gas is expelled from an opening. The opening from which the gas is expelled is positioned directly in front of the flow path of liquid expelled from the feeding channel. Various parameters are adjusted so that pressurized gas surrounds liquid flowing out of the feeding channel in a manner so as to reduce the .dimension of the flow which is then broken up on leaving the chamber. The aerosolized particles are inhaled into a patient's lungs and thereafter reach the patient's circulatory system., PRODUCTION OF DRY PARTICLES The method of the invention is also applicable in the mass production of dry particles. Such particles are useful in providing highly dispersible dry pharmaceutical particles containing a drug suitable for a drug delivery system, e.g. implants, injectables or pulmonary delivery. The particles formed of pharmaceutical are particularly useful in a dry powder inhaler due to the small size of the particles 1-5 microns in aerodynamic diameter) and conformity of size 3 to 30% difference in diameter) from particle to particle. Such particles should improve dosage by providing accurate and precise amounts of dispersible particles to a patient in need of treatment. Dry particles are also useful because theymay serve as a particle size standard in numerous applications.

For the formation of dry particles, the first fluid is preferably a liquid, and the second fluid is preferably a'gas, although two liquids may also be used provided they are generally immiscible. Atomized particles are produced within a desired size range 1 micron to about 5 microns). The first fluid liquid is preferably a solution containing a high concentration of solute. Alternatively, the first fluid liquid is a suspension containing a uniform concentration of suspended matter. In either case, the liquid quickly evaporates -19r WO 00/76673 PCT/US00/15931 upon atomization (due to the small size of the particles formed) to leave very small dry particles.

FUEL INJECTION APPARATUS The device of the invention is useful to introduce fuel into internal combustion engines by functioning as a fuel injection nozzle, which introduces a fine spray of aerosolized fuel into the combustion chamber of the engine. The fuel injection nozzle has a unique fuel delivery system with a pressure chamber and a fuel source. Atomized fuel particles within a desired size range 5 micron to about 500 microns, and preferably between 10 and 100 microns) are produced from a liquid fuel fonrmulation provided via a fuel supply opening. Different size particles of fuel may be required for different engines. The fuel may be provided in any desired manner, forced through a channel of a feeding needle and expelled out of an exit opening of the needle. Simultaneously, a second fluid, e.g. air, contained in a prissure chamber which surrounds at least the area where the formulation is provided surrounds the exit opening of the needle) is forced out of an opening positioned in front of the flow path of the provided fuel in front of the fuel expelled from the feeding needle). Various parameters are adjusted to obtain a fuel-fluid interface and an aerosol of the fuel, which allow formation of atomized fuel particles on exiting the opening of the pressurized chamber.

Fuel injectors of the invention have two significant advantages over prior injectors. First, fuel generally does not contact the periphery of the exit orifice from which it is emitted because the fuel stream is surrounded by a gas air) which flows into the exit orifice. Thus, clogging of the orifice is eliminated or substantially reduced. In addition, formation of carbon deposits around the orifice exit is also substantially reduced or eliminated. Second, the fuel exits the orifice and forms very small particles which may be substantially uniform in size, thereby allowing faster and more controlled combustion of the fuel.

WO 00/76673 PCT/USOO/15931

MICROFABRICATION

Molecular assembly presents a 'bottom-up' approach to the fabrication of objects specified with incredible precision. Molecular assembly includes construction of objects using tiny assembly components, which can be arranged using techniques such as microscopy, e.g. scanning electron microspray. Molecular self-assembly is a related strategy in chemical synthesis, with the potential of generating nonbiological structures with dimensions as small as 1 to 100 nanometers, and having molecular weights of 104 to 1010 daltons. Microelectro-deposition and microetching can also be used in microfabrication of objects having distinct, patterned surfaces.

Atomized particles within a desired size range 0.001 micron to about microns) can be produced to serve as assembly components to serve as building blocks for the microfabrication of objects, or may serve as templates for the self-assembly of monolayers for microassem5ly of.objects. In addition, the method of the invention can employ an atomizate to etch configurations and/or patterns onto the surface of an object by removing a selected portion of the surface.

The instant invention is shown and described herein in a manner which is considered to be the most practical and preferred embodiments. It isf ecognized, however, that departures may be made therefrom which are within the scope of the invention and that obvious modifications will occur to one skilled in the art upon reading this disclosure.

-21-

Claims (11)

1. A method, comprising the steps of: forcing a liquid out of an exit opening of a liquid supply means; forcing a fluid into a pressure chamber which surrounds the exit opening of the liquid supply means, the fluid being provided in a manner such that the fluid: focuses liquid exiting the exit opening to a stream having dimensions smaller than that of the exit opening; provides momentum to and interacts with the liquid exiting the liquid supply means; creates a violent interaction between the liquid and the fluid which destabilizes the liquid so as to form particles of the liquid wherein the mean dimensions of particles formed is less than the dimensions of the focused liquid stream; and carries the liquid stream out of the pressure chamber.
2. The method of claim 1, wherein the fluid forced into the pressure chamber is a gas and wherein the gas rapidly converges toward the liquid along streamlines that form an angle of 45' or greater with respect to the liquid.
3. The method of claim 1 or claim 2, wherein the fluid forced into the pressure chamber is a liquid which is immiscible in the liquid in the liquid supply means.
4. The method according to any one of the preceding claims, wherein the liquid exiting the liquid supply means is focused to dimensions which are /2 or less the dimensions of the liquid supply means.
5. The method of claim 2, wherein particles formed have 1/10 or less the mean ooooo volume of the particles expected to be formed by normal Rayleigh breakup and the gas converges on the liquid at an angle of from 450 to less than 900.
6. The method of claim 2, wherein the particles formed are sufficiently small that their surface tension forces substantially match the amplitude of pressure fluctuations created by the liquid and gas exiting the pressure chamber.
7. A method of creating an aerosol, the method comprising the steps of: forcing a liquid through a feeding tube and out of an exit opening of the feeding tube wherein the exit opening of the feeding tube is positioned such that the liquid flowing out of the tube flows toward and out of an exit orifice of a chamber surrounding the exit opening of the feeding tube; and forcing a gas into the chamber and out of the exit orifice of the chamber creating a violent interaction between the liquid and the gas; wherein the exit opening of the feeding tube has a diameter in the range of about 5 to about 10,000 microns and the exit opening of the tube is positioned at a distance in a range of from about 5 to about 10,000 microns from an entrance point of the exit orifice.
8. A method of creating an aerosol, comprising the steps of: forcing a liquid out of an exit opening of a liquid supply means to form a liquid stream; and forcing a gas into a chamber and out of an exit orifice aligned with a flow path of liquid having the exit opening whereby the liquid stream is focused by the gas to dimensions smaller than dimensions of the exit opening; wherein the exit opening and exit orifice are positioned to create a violent interaction between the liquid and the gas such that particles formed outside the exit orifice have a size determined by the relationship between the particle surface tension and the amplitude of turbulent pressure fluctuation outside the chamber and further wherein that relationship is such that the particles have dimensions smaller than dimensions of the focused liquid stream.
9. A method, comprising the steps of: forcing a liquid out of an exit opening of a liquid supply means; forcing a gas into a pressure chamber and out of an exit orifice of the chamber; and causing the gas to converge against the liquid exiting the liquid supply means thereby; causing the liquid to assume dimensions smaller than dimensions of the exit opening of the liquid supply means; creating-a violent interaction between the liquid and the gas; carrying the liquid away from the exit orifice of the pressure chamber; and 25 resulting in the liquid forming particles which are smaller in size than expected based on spontaneous capillary breakup of the assumed smaller dimensions of the liquid.
The method according to any one of claims 1 to 6, wherein the exit opening of the liquid supply means has an opening with a cross-sectional configuration selected from the group consisting of a circle, an oval, a square and an elongated rectangular ***slit. oO* o* .*o
11. A method of creating an aerosol substantially as herein described with reference to the accompanying figures and examples. Dated this fifteenth day of September 2003 Aradigm Corporation, Universidad De Sevilla Patent Attorneys for the Applicant: F B RICE CO 0 go 000. 0 .0
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Families Citing this family (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060169800A1 (en) * 1999-06-11 2006-08-03 Aradigm Corporation Aerosol created by directed flow of fluids and devices and methods for producing same
US20070122353A1 (en) 2001-05-24 2007-05-31 Hale Ron L Drug condensation aerosols and kits
US6759029B2 (en) 2001-05-24 2004-07-06 Alexza Molecular Delivery Corporation Delivery of rizatriptan and zolmitriptan through an inhalation route
CA2447519C (en) 2001-05-24 2008-09-16 Alexza Molecular Delivery Corporation Delivery of alprazolam, estazolam, midazolam or triazolam through an inhalation route
EP1392262A1 (en) 2001-05-24 2004-03-03 Alexza Molecular Delivery Corporation Delivery of drug esters through an inhalation route
US20030051728A1 (en) 2001-06-05 2003-03-20 Lloyd Peter M. Method and device for delivering a physiologically active compound
JP4834861B2 (en) * 2001-09-25 2011-12-14 株式会社イノアックコーポレーション Fluid mixing mechanism
EP1446104B2 (en) 2001-11-01 2011-08-03 Novartis AG Spray drying methods
WO2003041693A1 (en) 2001-11-09 2003-05-22 Alexza Molecular Delivery Corporation Delivery of diazepam through an inhalation route
US7078016B2 (en) 2001-11-21 2006-07-18 Alexza Pharmaceuticals, Inc. Delivery of caffeine through an inhalation route
US9339459B2 (en) 2003-04-24 2016-05-17 Nektar Therapeutics Particulate materials
JP2006507921A (en) * 2002-06-28 2006-03-09 プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ Method and apparatus for fluid distribution
US20050221339A1 (en) 2004-03-31 2005-10-06 Medical Research Council Harvard University Compartmentalised screening by microfluidic control
GB0307428D0 (en) 2003-03-31 2003-05-07 Medical Res Council Compartmentalised combinatorial chemistry
GB0307403D0 (en) 2003-03-31 2003-05-07 Medical Res Council Selection by compartmentalised screening
JP2006523142A (en) * 2003-04-10 2006-10-12 プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ Fluid species formation and control
EP1625333A1 (en) 2003-05-21 2006-02-15 Alexza Pharmaceuticals, Inc. Self-contained heating unit and drug-supply unit employing same
US20040235308A1 (en) 2003-05-22 2004-11-25 Dainippon Screen Mfg. Co., Ltd. Substrate treatment method and sustrate treatment apparatus
EP2662135A3 (en) 2003-08-27 2013-12-25 President and Fellows of Harvard College Method for mixing droplets in a microchannel
ES2264608B2 (en) * 2004-09-30 2007-08-16 Universidad De Sevilla Device and method for the pneumatic atomization of liquids by implosive gas flow.
US7968287B2 (en) 2004-10-08 2011-06-28 Medical Research Council Harvard University In vitro evolution in microfluidic systems
US20060078893A1 (en) 2004-10-12 2006-04-13 Medical Research Council Compartmentalised combinatorial chemistry by microfluidic control
EP2842635A1 (en) 2005-01-17 2015-03-04 Universidad de Sevilla Method and device for the micromixing of fluids using a reflux cell
EP1861194A2 (en) 2005-03-04 2007-12-05 The President and Fellows of Harvard College Method and apparatus for forming multiple emulsions
ES2265270B1 (en) * 2005-04-18 2008-01-01 Universidad De Sevilla Method and device for micro-fluid mixing by cell reflux.
EP2363205A3 (en) 2006-01-11 2014-06-04 Raindance Technologies, Inc. Microfluidic Devices And Methods Of Use In The Formation And Control Of Nanoreactors
US9562837B2 (en) 2006-05-11 2017-02-07 Raindance Technologies, Inc. Systems for handling microfludic droplets
US20080014589A1 (en) 2006-05-11 2008-01-17 Link Darren R Microfluidic devices and methods of use thereof
WO2008021123A1 (en) 2006-08-07 2008-02-21 President And Fellows Of Harvard College Fluorocarbon emulsion stabilizing surfactants
WO2008097559A2 (en) 2007-02-06 2008-08-14 Brandeis University Manipulation of fluids and reactions in microfluidic systems
WO2008121342A2 (en) 2007-03-28 2008-10-09 President And Fellows Of Harvard College Emulsions and techniques for formation
WO2008130623A1 (en) 2007-04-19 2008-10-30 Brandeis University Manipulation of fluids, fluid components and reactions in microfluidic systems
US9091434B2 (en) 2008-04-18 2015-07-28 The Board Of Trustees Of The University Of Alabama Meso-scaled combustion system
US20100176063A1 (en) * 2009-01-12 2010-07-15 Yuri Kokotov Method for coalescence induced liquid-liquid separations and apparatus thereof
US9366632B2 (en) 2010-02-12 2016-06-14 Raindance Technologies, Inc. Digital analyte analysis
EP3392349A1 (en) 2010-02-12 2018-10-24 Raindance Technologies, Inc. Digital analyte analysis
US9399797B2 (en) 2010-02-12 2016-07-26 Raindance Technologies, Inc. Digital analyte analysis
WO2011150368A1 (en) 2010-05-28 2011-12-01 Arizona Board Of Regents Acting For And On Behalf Of Arziona State University Apparatus and methods for a gas dynamic virtual nozzle
EP2622103B1 (en) 2010-09-30 2018-09-12 Raindance Technologies, Inc. Sandwich assays in droplets
US9364803B2 (en) 2011-02-11 2016-06-14 Raindance Technologies, Inc. Methods for forming mixed droplets
US9150852B2 (en) 2011-02-18 2015-10-06 Raindance Technologies, Inc. Compositions and methods for molecular labeling
KR20140034242A (en) 2011-05-23 2014-03-19 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 Control of emulsions, including multiple emulsions
US8841071B2 (en) 2011-06-02 2014-09-23 Raindance Technologies, Inc. Sample multiplexing
JP2014522718A (en) 2011-07-06 2014-09-08 プレジデント アンド フェローズ オブ ハーバード カレッジ Multi-phase emulsions and multiple emulsion formation method
EP2777818A1 (en) 2013-03-15 2014-09-17 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Method and device of producing an intermittent liquid jet
US9821325B2 (en) 2013-04-30 2017-11-21 Arizona Board Of Regents On Behalf Of Arizona State University Apparatus and methods for lipidic cubic phase (LCP) injection for membrane protein investigations
ES2663217B1 (en) * 2016-10-10 2019-02-07 Ingeniatrics Tecnologias S L Apparatus and method for mixing at least two liquids

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5868322A (en) * 1996-01-31 1999-02-09 Hewlett-Packard Company Apparatus for forming liquid droplets having a mechanically fixed inner microtube
US5884846A (en) * 1996-09-19 1999-03-23 Tan; Hsiaoming Sherman Pneumatic concentric nebulizer with adjustable and capillaries

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05138080A (en) * 1991-11-25 1993-06-01 Matsushita Electric Ind Co Ltd Atomization device
AU745904B2 (en) 1997-12-17 2002-04-11 Universidad De Sevilla Device and method for creating spherical particles of uniform size
ES2140998B1 (en) * 1996-05-13 2000-10-16 Univ Sevilla Liquid atomization process.

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5868322A (en) * 1996-01-31 1999-02-09 Hewlett-Packard Company Apparatus for forming liquid droplets having a mechanically fixed inner microtube
US5884846A (en) * 1996-09-19 1999-03-23 Tan; Hsiaoming Sherman Pneumatic concentric nebulizer with adjustable and capillaries

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