WO2013187916A1

WO2013187916A1 - Static mixer for high pressure or supercritical fluid chromatography systems

Info

Publication number: WO2013187916A1
Application number: PCT/US2012/042828
Authority: WO
Inventors: Edwin E. Wikfors; Kimber Fogelman; Terry A. Berger; Samuel O. Colgate
Original assignee: Agilent Technologies, Inc.
Priority date: 2012-06-15
Filing date: 2012-06-15
Publication date: 2013-12-19
Also published as: GB201500530D0; GB2519686A

Abstract

An apparatus and process for hydrodynamic mixing of fluids at or near common liquid density values. The implementations relate to mixing fluids in high performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UHPLC), and/or supercritical fluid chromatography (SFC) and other high pressure applications where phases of dramatically different density, viscosity, and volumetric flow require mixing.

Description

STATIC MIXER FOR HIGH PRESSURE OR SUPERCRITICAL FLUID CHROMATOGRAPHY SYSTEMS

FIELD OF THE DISCLOSURE

[0001] The present invention relates to methods and systems for the hydrodynamic mixing of fluids at or near common liquid density values. More specifically, the invention and its embodiments relate to mixing fluids in high performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UHPLC) and/or supercritical fluid chromatography (SFC) and other high pressure applications where phases of dramatically different density, viscosity, and volumetric flow require mixing.

BACKGROUND

[0002] An example of an HPLC, UPLC or SFC system 10 is illustrated in Figure 1 . The system 10 comprises two pumps 14 and 20 each pumping from a reservoir 12 and 18 which contain different types of solvent. For example, in an SFC system the pumps are two HPLC-type reciprocating pumps. A first pump 14 draws a compressible fluid such as carbon dioxide from reservoir 12 and outputs the compressible fluid, to flow line 16. Similarly pump 20 draws an organic liquid such as methanol and outputs the fluid to flowline 22. The carbon dioxide and modifier are combined at junction 24, creating a mixture of modifier dissolved into the near critical or supercritical fluid C02.

[0003] The combined supercritical fluid is pumped at a controlled mass- flow rate from the mixing column 26 through transfer tubing at a fixed-loop injector 28 where the sample of interest is injected into the flow system. The sample combines with the compressed modifier fluid inside the injection valve 28 and discharges into at least one packed chromatography column 30. After fractionation of the sample occurs in the column 30, the elution mixture passes from the column outlet into a detector 32. After detection, a fraction may be directed by valve 34 into a collection system 36 or sent to a waste collector 38. [0004] Reciprocating dual-piston pumps are the preferred equipment for high pressure fluid delivery in modern HPLC and commercial offerings. The pumps have the advantage of being able to generate near continuous streams of fluids at very high differential pressures. However, such pumps tend to suffer from periodic lapses of flow immediately after each piston has completed its filling operation and begins fluid delivery to the chromatographic system. For a brief period in each pump cycle one piston stops after delivery of a unit of fluid and a second piston begins its delivery. No flow is observed during this brief period in the output of the pump. This effect can be caused by a number of factors including mechanical play, fluidic compression, or slow response of check valves in the system.

[0005] As described in relation to Figure 1 , many high-pressure

chromatography systems use two or more reciprocating pumps to generate varying composition of the fluid flowstream in an automatic manner. This process is known as high pressure mixing. When the individual output fluid streams are combined, the periodic lapses of each pump are additive. Figure 2 displays such a case for a binary pumping system. In the figure, flow trace A shows flow at the output of first pump A, while flow trace B shows flow output of a second pump B. Flow trace C shows the system total flow which additively combines traces A and B. Conversely, pump lags tend to have a reverse effect on relative composition of two components. A lag in flow trace A results in a composition rise in pumped component B. This behavior is illustrated in Figure 3 which charts the changes in %B composition as a result of the pumping behavior of Traces A and B.

[0006] Inline and tee type static mixers are common in the implementation of HPLC systems. Use of such mixers improves the local uniformity of mobile phase composition by elimination of local concentration gradients resulting from fluidic joining of two or more flow streams containing different compositions. Failure to fully mix the flow streams can result from differences in viscosity, flow turbulence, density, miscibility, and geometry of the mixing region and uniformity of the volumetric flow of each stream.

[0007] Local composition gradients are inconvenient in chromatography system using optical detectors since such gradients can introduce refractive index variations which appear as baseline noise at the detector. Generally, the more uniform the fluidic composition, the lower the baseline noise and the greater optical dynamic range available to the detector. As a goal, systems require high dynamic range to be able to observe both major peaks, on the range of 1000 to 2000 mAU peak height on the same chart as minor impurity peaks with peak heights less than 1 mAU in order to properly quantify impurities at the 0.05% to 0.1 % level. To achieve valid quantitation at 1 mAU, the noise levels must average less than 0.1 mAU at the baseline. This provides a generally accepted minimum ratio of signal-to-noise of 10:1 .

[0008] Standard inline mixers typically provide a combination of tortuous mixing paths and sufficient open diffusional volume to allow good local concentration equilibration for multiple streams of constant flow volume.

Unfortunately, HPLC systems typically employ reciprocating piston pumps which virtually guarantee periodic lapses of flow for each stream. Since the streams are typically at different and often variable rates, such flow lapses are considered asynchronous relative to each other. The result of such flow lapses is an instantaneous enrichment of the concentration of the other flow stream composition. Conventional mixers have a more difficult time dealing with such spatially distant concentration gradients since it would require large delay volumes to allow the various regions to diffuse together. Essentially, flow segments of high concentration must diffuse forward and backward relative to the flow stream across fairly long paths to mix fully. Such longitudinal mixing occurs to a degree under laminar flow conditions where the center of a flow tube travels approximately twice as fast as the wall flow. However, in mobile phases which pass through the transfer tubing under turbulent conditions local velocity differences are minimized in the tubing cross-section. Entering a broad mixing tube, which inherently slows the linear velocity of the bulk fluid, favors longitudinal mixing. However, unless the mixer is extremely large, this will not be sufficient to recombine mixing sections that are well spaced. In fact, most mixers fail at this task of longitudinal mixing because of inadequate residence time in the mixer. What is desired is a device and method to cause as much longitudinal spreading of a particular flow segment as possible in as low a volume as possible in order to realize composition changes quickly within the chromatographic flow stream.

SUMMARY

[0009] The various embodiments described as devices, systems, and methods of the present invention provide designs and techniques that solve many of the problems of existing flowstream mixing technology. The invention described herein has the desirable effect of promoting mixing of both local and spatially distant flow elements entering at one end of the mixing device and exiting at the other. While mixing of proximate flow elements is rather well accomplished in the prior art, the ability to bring two flow elements that are significantly spatially separated along the axis of a flow conduit is not well established. The basis of the current invention is to combine two or more conventional mixing zones which mix proximate flow elements, wherein the connecting conduit between each pair of mixing zones provides a near infinite number of paths into and out of the respective mixing zones. The

embodiments provide for proximate flow elements entering the first mixing chamber to first mix to homogeneity and then become significantly spatially separated while distant flow elements can become proximate and

subsequently mixed to homogeneity by the end of travel through the final mixing zone in the invention. When combined with the local mixing efficiencies of the conventional mixing chambers, this leads to improved homogeneity even over significant time and spatial variations of composition.

[0010] Other embodiments of the invention are designed to optimize longitudinal mixing of two flow streams under isocratic or gradient elution chromatographic conditions, while maintaining good local mixing at low internal volume relative to the standard flowrates of the system. This goal is accomplished by providing discrete regions within an embodiment that sequentially allow local diffusional mixing, eddy mixing, radial mixing, selective adsorption isotherms and a multitude of different paths of very different flow distances between the inlet and outlet ports of the mixer. It is the individual and coupled effects of the last two mixing features of the mixer that can dramatically impart superior longitudinal mixing that can allow dramatic broadening of various flow elements within the low total volume of the mixer body and thereby cause mixing of elements initially separated in either time or space from one another.

BRIEF DESCRIPTION OF THE FIGURES

[0011] The accompanying figures where like reference numerals refer to identical or functionally similar elements throughout the separate views and which together with the detailed description below are incorporated in and form part of the specification, serve to further illustrate various embodiments and to explain various principles and advantages:

FIG. 1 illustrates a prior art HPLC, UPLC or SFC chromatography system;

FIG. 2 includes charts that demonstrate the combined effect of flow perturbations by individual pumps with regard to total flow;

FIG. 3 includes charts that demonstrate the combined effect of flow perturbations by individual pumps with regard to flow composition;

FIG. 4 illustrates a preferred embodiment of a mixer apparatus of the present invention;

FIG. 5 illustrates a cross sectional view of the mixer apparatus of Figure 4 that includes dual mixing chambers within a cylinder;

FIG. 6 illustrates a cross sectional view of the mixer apparatus of Figure 4 demonstrating a fluidic path of an exemplary flowstream passing through the mixer;

FIG. 7 illustrates a cross sectional view of an alternative embodiment of the mixer apparatus of Figure 4 that includes three mixing chambers within a cylinder;

FIG. 8 illustrates a cross sectional view of an additional alternative embodiment of the mixer apparatus of Figure 4.

FIG. 9 is a flowchart describing an exemplary mixing process. DETAILED DESCRIPTION

[0012] In the following description of preferred and alternative embodiments, reference is made to the accompanying drawings which form a part hereof, and in which it is shown by way of illustration specific embodiments in which the invention may be practiced. It is to be understood that other embodiments may be utilized and structural or process changes may be made without departing from the scope of the invention and its preferred and alternative embodiments.

[0013] Referring to Figure 4, mixer apparatus ("mixer" or "mixing column") 100 of the preferred and alternative embodiments replaces prior mixing devices in chromatography systems such as mixer 26 shown and described in the system of Figure 1 . Conduit 180 provides an inlet flowpath into mixer 100 of a combined mobile phase flowstream fluid that is pumped or pressurized under isocratic or gradient elution chromatographic conditions S400.

Conversely, conduit 190 provides an outlet path from mixer 100 of the mobile phase fluid.

[0014] In Figure 5 and the process flowchart of Figure 9, an embodiment for mixer 100 is comprised of a hollow porous element such as cylinder 1 10 housed within close fitting, leak proof housing 120. The center channel of cylinder 1 10 is blocked by nonporous or highly flow resistant barrier 130 creating a first cylindrical mixing cavity 140 and a second cylindrical mixing cavity 150 within the interior of porous cylinder 1 10. A third annular cavity 160 is created between the outer wall of cylinder 1 10 and the inner wall of housing 120. Sealing end caps 170 are fixed to cylinder 1 10 at each end and prevent any flow into or out of annular cavity 160 except through the porous wall of cylinder 1 10. The end caps 170 are constructed to allow entry of fluid flow from a first conduit 180 of the housing 120 in communication with first mixing cavity 140 and allow exit of fluid flow out of a second conduit 190 of the second mixing cavity 150. Any or all of the cavities 140, 150, 160 may be enhanced to provide local turbulence or eddy current formation to enhance local mixing of proximate flow segments. Such enhancements may include, but are not limited to, spherical packings, helical flow diverters, tortuous baffles, glass or steel wool and others. The porous cylinder may be constructed of sintered metal or polymer, screens or woven or hot spin fibers as well as a variety of other materials. Two preferred aspects of the porous cylinder are high surface area and wettability to at least one of the

components of mobile phase.

[0015] Combined mobile phase fluid from two or more flow streams is directed under pressure into entry conduit 180 of the housing S400. The fluid enters first cylindrical mixing cavity 140 where it is allowed to mix by laminar, diffusional and eddy current phenomena created by flow into the cavity S410. In mixing cavity 140 adequate mixing occurs in proximate flow elements such that their compositions become nearly indistinguishable. The fluid is then forced through the wall of porous cylinder 1 10 to outer annular cavity 160 (S420). This path provides radial mixing of the fluid column since the flow must be directed orthogonally and radially from its entry flow direction. More importantly, fluid elements are directed to enter annular cavity 160 at very different locations along the longitudinal axis of the mixer 100. Adjacent flow elements entering the original cavity are randomly dispersed both radially and longitudinally into annular cavity 160. The result is a high degree of spatial separation between formerly proximate flow elements and opportunity for recombination with other flow elements from either earlier or later entry into the entry cavity 140. Flow continues along the annular cavity bypassing flow barrier 130 within cylinder 1 10 (S430) and through the porous cylinder wall into a second cylindrical cavity 150, where again flow elements are longitudinally dispersed with regard to their entry point through wall of porous cylinder 1 10 (S440). Second cylindrical cavity 150 again provides diffusional, radial and eddy mixing prior to exiting the mixer via conduit 190.

[0016] Referring to Figure 6, line 230 traces the path of two pumped fluids on an averaged path through mixer 100. Fluid streams 200 and 210 initially mix at tee 220 which can be mechanically incorporated into mixer housing 120 as a single assembly as desired. The outlet flow of tee 220 forms the imperfectly mixed flow stream subject to pumping lulls and concentration and flow variations. Flow path 230 traces the average path of a flow element through the inlet conduit, first mixing cavity, the annular cavity and second mixing cavity and outlet conduit described in Figure 5. Flow path 230 is only an average path for flow elements and may vary among the multitude of flow paths available. For example, portions of the fluid flow stream may enter at the extremes of the annular channel and some follow the shortest path around flow barrier 130. This concept can then be extended all around the circular cross section of the annular cavity of mixer 100 to provide an unlimited number of possible flow paths for individual flow elements between the two mixing cavities based on varying distances alone. For example, baffles in the annular cavity that induced spiral flow could

dramatically extend the physical distance traveled by individual flow elements.

[0017] A general assumption of the design of mixer 100 is that flow elements permeate the wall of porous cylinder 1 10 at a fairly uniform rate over the available surface of a given cavity. This is based on the rapid equilibration of pressure within each cavity as the result of flow. Some minor flow will travel longitudinally through the porous wall 1 10 but this is likely to be a minor fraction of the total flow. Regardless, longitudinal flow through the wall of porous cylinder 1 10 acts simply as another variable length path for flow elements through the mixer. Since the radial delivery of flow into and out of annular cavity 160 is relatively uniform, the profile of velocity in the

longitudinal direction is not. The average linear velocity of flow in a cross section of annular cavity 160 is known as its flux. The flux for annular cavity 160 is lowest at the extreme ends of the cavity where fluid is just starting to enter or completing exiting cavity 160. Flux increases continuously as more flow is added to cavity 160 up to flow barrier 130 where no additional permeation from cavity 140 is allowed. In the region of annular cavity 160 adjacent to flow barrier 130, the flux is approximately constant at its highest point since no flow is added or removed from the cavity 160. Just past this point, flow begins to be lost from annular gap 160 and the flux decreases. The result of this velocity profile is that a flow element entering at the beginning of annular cavity 160 and leaving at the farthest distance experiences both a longer path and a lower average velocity. Conversely, a flow element leaving mixing cavity 140 at flow barrier 130 and entering mixing cavity 150 just after barrier 130 experiences both the shortest travel distance and the fastest average velocity between the two mixers 140 and 150. This behavior is precisely what is desired to provide the highest redistribution of flow elements between the two cavities in the minimum possible volume.

[0018] A second aspect of the design of mixer 100 also contributes to longitudinal dispersion of at least one component of the flow stream. This occurs within porous cylinder 1 10 itself and its effect is dependent on the wettability and total surface area contacted by the fluid stream. When a fluid contacts a wettable surface, it tends to spread out on the surface to form as much contact as possible area. This can be a very strong force as seen when a narrow capillary tube draws a liquid to a significant height against gravity to achieve this wetting action. Generally a balance will be struck between the surface tension of the fluid, gravity forces and this capillary force to end the travel upward. This effect is true in mixtures as well and can affect one component of the mixture much more than another. It is well known, for example, that many mono layers of methanol tend to adsorb on the surface of polar stationary phases in SFC. These layers are called adsorption isotherm layers and are similar to those described by Lanngmuir for gas adsorption. Higher concentrations of the wetting components tend to build higher number of layers until an equilibrium limit is reached. The adsorbed layers remain in rapid equilibrium with the bulk fluid of the flow stream. If the concentration of the wettable component decreases suddenly the equilibrium of the adsorption isotherm will shift to decrease of the number of adsorbed layers.

[0019] Porous sintered metal is described earlier as a preferred component for the porous cylinder 1 10 and is wettable by polar solvents such as water and alcohols. When this material is exposed to flow containing such solvents it tends to form a film of the polar solvent on its surface to some degree based on the concentration of the polar solvent concentration. This film then acts as a reservoir the can adsorb additional solvent when local concentrations increase and desorb solvent when local concentrations decrease. The beneficial result of this behavior is to resist small changes in the local concentration of the flowing fluid as might result from the pumping lulls described earlier and disperse the change over a larger volume of flow. The greater the surface area of exposure, the greater the effect. Obviously, too much of a good thing causes problems. In gradient elution

chromatographic systems, this behavior can lead to sluggish response in gradient changes and prevent very rapid gradient analysis. The effect can also be eliminated by suitable choice of porous material. For example, sintered polyetheretherketone, PEEK, or Teflon materials show little adsorption behavior.

[0020] An alternative embodiment of the invention is illustrated in Figure 7. This embodiment demonstrates the extensibility of adding additional mixing cavities to the design. The displayed number of mixing stages is exemplary and can be extended as needed for an application. Mixer 300 in Figure 3 displays a mixer with three flow barriers 310, 320 and 360 forming three mixing cavities 330, 340 and 350. At least one flow barrier 360 is formed within annular cavity 160 thereby creating a first annular cavities space 370 that receives flowstream fluid from first mixing cavity 330 and delivers flow to intermediate mixing cavity 340 and a second annular cavity space 380 that conducts randomized accelerated transport of flow elements between mixing cavities 340 and 350. Flow behavior between any two adjacent mixing cavities remains as described earlier. Mixing cavity 340 is shown to be packed with metal spheres 390 as a means of limiting volume and

encouraging local mixing. This is not intended to be limiting to the design and it will be recognized by those trained in the art that the same effect can be achieved by a variety of other means.

[0021] A third preferred embodiment is shown in Figure 8 as mixer 400. In this embodiment, a first individual porous element 410 and a second individual porous element 420 are fabricated as cup-shaped sintered frits arranged in housing 430 with their open ends facing outward. Mixing cavities 440,450 are created by the hollow cavities of the cup design. Barrier 460 is fabricated from a nonporous sheet of metal or polymer and positioned between porous elements 410 and 420. Perforations 470 are included in barrier 460 to allow flow along annular cavity 480.

[0022] As a general design rule, the selection specific internal mixing features and volume are largely based on the mixing application, but the same general design can be anticipated for flow in the microliter to kiloliter per minute range and beyond. Reduction in internal volume of the annular cavities will tend to shorten the range of longitudinal dispersion while reduction of the internal volume of the mixing chambers will lead to poorer local mixing. Fluid viscosity and flow rate will limit pore size and total porosity of the porous cylinder. Finally, the mixer does degrade the minimum response time to changes of flow composition and consideration must be made to accommodate the fastest changes required by the flow system.

[0023] One skilled in the relevant art will recognize that many possible modifications and combinations of the disclosed embodiments can be used, while still employing the same basic underlying mechanisms and

methodologies. The descriptions herein, for purposes of explanation, have been written with references to specific embodiments. However, the illustrative discussions within the present application are not intended to be exhaustive or to limit the disclosure to the precise forms disclosed.

[0024] Many modifications and variations can be possible in view of the above teachings. The embodiments were chosen and described to explain the principles of the disclosure and their practical applications, and to enable others skilled in the art to best utilize the disclosure and various embodiments with various modifications as suited to the particular use contemplated.

[0025] While this specification contains many specifics, these should not be construed as limitations on the scope of what is being claimed or of what may be claimed, but rather as descriptions of features specific to particular embodiments. Certain features that are described in this specification in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable subcombination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a subcombination or variation of a subcombination.

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Claims

CLAIMS What is claimed is:

1 . An apparatus, comprising:

a fluidically porous element comprising a hollow internal channel that is blocked by at least one highly restricting flow barrier creating at least a first mixing cavity and at least a second mixing cavity;

a housing, surrounding said porous element, that is sealed to create an external cavity around said porous element,

wherein the element and housing are arranged to allow communication of a flowstream between the first mixing cavity and the second mixing cavity primarily via the external cavity by directing the flowstream through the porous element wall adjacent to each mixing cavity

2. The apparatus of claim 1 , wherein the porous element and housing are formed cylindri cally creating an annular mixing cavity around said porous element, and said housing comprises a first sealing end cap that allows the flowstream into the first mixing cavity and a second end cap that allows the flowstream out of the second mixing cavity, and said first and second end caps prevent flow into or out of the annular cavity except through the porous element.

3. The apparatus of claim 1 , further comprising:

enhancements formed within at least one of the mixing cavities or annular cavity which provide local turbulence or eddy current formations.

4. The apparatus of claim 1 , wherein the porous element is constructed with one of a sintered metal, polymer, screen, woven fiber, or hot spin fiber.

5. The apparatus of claim 1 , further comprising:

at least one flow barrier formed within said annular cavity creating at least a first annular cavity space and a second annular cavity area,

1 wherein the porous element further comprises a plurality of the flow barriers within the channel forming a plurality of mixing cavities, and

the flowstream is directed into or out of said plurality of mixing cavities and said annular cavity spaces depending upon the location of the flow barriers.

6. The apparatus of claim 1 , comprised of

at least one flow barrier extending beyond the porous element wall and dividing the porous element into a plurality of separate porous elements

7. The apparatus in claim 6 wherein at least one porous element is cup shaped.

8. The apparatus in claim 6 wherein the flow barrier extends into the cavity created by the housing and allows flow via perforations in the barrier in this region.

9. A process, comprising:

directing a pressurized mobile phase fluid comprising a plurality of flow streams into a first mixing cavity within a porous element;

surrounding the porous element with an outer mixing cavity created between the porous element outer wall and an outer housing that surrounds the porous barrier;

directing the fluid out of the porous element into the outer mixing cavity; directing the fluid past a restrictive flow barrier within the porous element that divides the first mixing cavity from a second mixing cavity;

directing the fluid out of the outer mixing cavity and into the second mixing cavity through the porous barrier.

10. The process of claim 9, wherein the step of surrounding the porous element with the housing further comprises sealing a first end of said housing except to allow the flowstream into the first mixing cavity and sealing a second end of said housing except to allow the flow stream to exit the second mixing cavity.

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11 . The process of claim 9, further comprising enhancing at least one of the mixing cavities with local turbulence or eddy current formations.

12. The process of claim 9, further comprising directing said flowstream through the first mixing cavity into a first outer housing cavity, directing said flowstream around a barrier in the first outer housing cavity and into an intermediate mixing cavity within said porous element; and directing said flowstream out of said intermediate mixing cavity into a second outer housing cavity.

13. The process of claim 12, further comprising, alternating the direction of said flowstream through said porous element between a plurality of mixing cavities each separated by a flow barrier and a plurality of outer housing cavities that are each separated by impermeable flow barrier.

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