Mixer for liquid chromatography

Abstract

This disclosure describes a mixer 50 for a liquid chromatography system. The mixer includes a flow distributor 52, a mixing disk 54, and a flow collector 56. The mixer includes an inlet face, an outlet face, and a plurality of channels, each channel having an inlet end at the inlet face and an outlet end at the outlet face. The channels have anisotropic flow direction between the inlet and outlet faces. The component solvent flow received at the flow distributor 52 is distributed on the inlet face of the mixing disk 54, and the flow collector 56 collects the distributed solvent composition flow after passing through the mixing disk 54. The mixing disk 54 can include a dispersive medium having a random porous structure. The residence time distribution of the mixer can depend on the structure of the channels between the inlet and outlet faces of the mixing disk.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of an earlier filing date of U.S. Provisional Patent Application Serial No. 63 / 048,684, entitled “Mixer for Liquid Chromatography,” filed on July 7, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates generally to liquid chromatography systems. More specifically, this invention relates to a mixer for mixing solvent composition streams in a liquid chromatography system. Background Technology

[0004] Chromatographic systems and methods can be used to separate mixtures. In liquid chromatography, a sample containing multiple components to be separated is injected into a system stream and directed to a column. The column separates the mixture into its individual components through differential retention. Typically, the components elute from the column as different bands separated over time.

[0005] A typical liquid chromatography (LC) system includes one or more pumps for delivering a fluid (“mobile phase”) at a controlled flow rate and composition, an injector to introduce a sample solution into the flowing mobile phase, a column containing packing material or adsorbent (“stationary phase”), and a detector to detect the presence and amount of sample components leaving the column in the mobile phase. Some LC systems may require sample dilution before injecting the sample into the mobile phase flowing into the column. As the mobile phase passes through the stationary phase, each component in the sample typically elutes from the column at different times because different components in the sample often have different affinities for the packing material. The presence of a specific component leaving the column in the mobile phase can be detected by measuring changes in the physical or chemical properties of the eluent. By plotting the detector signal as a function of time, “peaks” corresponding to the presence and amount of sample components can be observed.

[0006] In gradient elution chromatography, when mixing is performed at low pressure, the mobile phase is typically generated by pumping and then mixing two or more independently controlled solvent pack volumes. The volume of the solvent pack is typically a fraction of the pump stroke volume of a reciprocating pump. These solvent packs are connected in series to form a series of solvent plugs with different compositions at low pressure (e.g., atmospheric pressure) before reaching the pump system. Alternatively, the solvent packs are combined at high pressure in a tee fitting downstream of the pump system. Mixers are typically used to ensure that the time-programmed composition of the mobile phase at the column inlet is accurate and that there is a low compositional noise level throughout the duration of the chromatographic separation to maximize detection sensitivity.

[0007] Two types of mixers are typically used to achieve the desired mixing of solvent packages. The first type is a column packed with large (e.g., 200 μm nominal diameter) non-porous beads. Depending on the type of liquid chromatography system used, the void mixer volume can range from tens of microliters to over hundreds of microliters. The second type is a microfluidic device, in which the received solvent composition flow is split into multiple flow paths of varying lengths, which are then merged to provide a single outlet flow. Regardless of the type of mixer, the goal is to eliminate the periodic composition noise generated by the reciprocating pump in the pump system.

[0008] The first type of mixer suffers from poor mixer-to-mixer reproducibility due to the random nature of the non-porous bead-packed column. Furthermore, this type of mixer has limited mixing capacity and compositional noise reduction, as packed column beds are typically used for fractional separation, unlike mixing. These problems persist even for larger bead sizes. The second type of mixer is more difficult to manufacture due to its structural complexity and is not designed to eliminate periodic noise. The second type generates a wide residence time distribution (RTD) with pulsed input. Moreover, the second type of mixer exhibits an asymmetric residence time distribution, which limits its ability to rapidly achieve time-programmed composition of the mobile phase. Summary of the Invention

[0009] In one aspect of this disclosure, a mixer for liquid chromatography includes a flow distributor, a mixing disk, and a flow collector. The basic principle of the disk mixer design is that for a fixed mixer volume V filled with dispersive material of plate height H, mixer Volume-based dispersion or variance of RTD It is inversely proportional to its length L:

[0010]

[0011] The flow distributor has a distributor inlet port and a distributor outlet port. The distributor inlet port is configured to receive the flow rate of the constituent solvent flow, and the distributor outlet port has an outlet cross-section and is configured to provide the constituent solvent flow distributed across the outlet cross-section. The mixing disk has an inlet face, an outlet face, and multiple channels, each channel having an inlet end at the inlet face and an outlet end at the outlet face. The inlet face communicates with the distributor outlet port. The channels have flow direction anisotropy between the inlet and outlet faces. The flow collector has a collector inlet port and a collector outlet port. The collector inlet port has an inlet cross-section and communicates with the outlet face of the mixing disk to receive the flow rate of the constituent solvent flow after passing through the mixing disk.

[0012] The mixing disk may include a dispersive medium with a random porous structure. The channels may have a tortuosity of at least five and no more than ten. The mixing disk may be formed of a material including glass, polymer, or metal. The mixing disk may have a void volume larger than that of a flow distributor and larger than that of a flow collector. The mixing disk may include at least one mesh layer.

[0013] The mixer may have a residence time distribution that depends on the structure of the channel between the inlet and outlet faces of the mixing disk. The individual streams of the component solvent streams distributed on the outlet cross-section of the flow distributor may have diameters between approximately 100 μm and approximately 200 μm.

[0014] The cross-sectional area of ​​the outlet of the flow distributor can be equal to the cross-sectional area of ​​the inlet surface of the mixing disc. The cross-sectional area of ​​the inlet of the flow collector can be equal to the cross-sectional area of ​​the outlet surface of the mixing disc.

[0015] Flow distributors may include angular dispersion plates and / or radial dispersion plates. Flow distributors may be fractal flow distributors. Flow collectors may include angular dispersion plates and / or radial dispersion plates. Flow collectors may be fractal flow collectors.

[0016] A flow distributor may include multiple openings at a distributor outlet port and multiple internal flow paths defined between a distributor inlet port and a distributor outlet port to guide the component solvent flow to the distributor outlet port. The openings may be arranged along multiple concentric circles defined on the distributor outlet port. A flow collector may include multiple openings at a collector inlet port and multiple internal flow paths defined between a collector inlet port and a collector outlet port to guide the component flow from a mixing disk to a collector outlet port. The openings at the distributor outlet port may be arranged in the same manner as the openings at the collector inlet port. The number of openings at the distributor outlet port may differ from the number of openings at the collector inlet port.

[0017] The flow collector may include multiple openings at the collector inlet port and multiple internal flow paths defined between the collector inlet port and the collector outlet port to guide the component flow from the mixing disk to the collector outlet port. The openings may be arranged along multiple concentric circles defined on the collector inlet port. Attached Figure Description

[0018] The above and other advantages of the present invention can be better understood by referring to the following description in conjunction with the accompanying drawings, in which the same reference numerals indicate the same elements and features in each drawing. For clarity, not every element is labeled in every drawing. The drawings are not necessarily drawn to scale, but are intended to illustrate the principles of the technology.

[0019] Figure 1This is a block diagram of a liquid chromatography system that may include embodiments of the mixer described herein.

[0020] Figure 2 It is a graphical depiction of the gradual change in the composition of the mobile phase of different liquid chromatography systems, each with a conventional mixer.

[0021] Figure 3 It is a graphical representation of the presence of solvent in the mobile phase of a liquid chromatography system over time for two systems with different reciprocating pumps.

[0022] Figure 4 This is a schematic diagram of a mixer with a flow distributor, a mixing disk, and a flow collector, which can be used to mix component solvent streams in a liquid chromatography system.

[0023] Figure 5A and Figure 5B Perspective view and cross-sectional schematic diagram of an embodiment of a mixer for a liquid chromatography system are shown respectively.

[0024] Figure 6A , Figure 6B and Figure 6C The figures show graphical representations of the output responses of a 200μm filled bed mixer, a multipath channel mixer, and a mixer utilizing a mixing disk, respectively.

[0025] Figure 7 It is a graphical representation of the mixing performance of nine different mixers as a function of solvent flow rate.

[0026] Figure 8 yes Figure 7 The peak skewness of the mixer in the image is graphically represented as a function of the solvent flow rate.

[0027] Figure 9 This is a graphical representation of the noise measured for four different implementations of a disc mixer.

[0028] Figure 10A , Figure 10B and Figure 10C These are, respectively, a side view, an end view, and a cross-sectional side view of an example of a mixer that can be used to mix component solvent streams in a liquid chromatography system.

[0029] Figure 11 yes Figure 10C The exploded view of the annular ring shown illustrates the components held within it.

[0030] Figure 12 This is an example of a fractal flow distributor.

[0031] Figure 13 This is another example of a fractal flow distributor.

[0032] Figure 14 A portion of an implementation of the hybrid disk is shown.

[0033] Figures 15A to 15D A photomask that can be used in a 3D manufacturing process is shown, which involves the sequential UV curing of a polymer material to build a hybrid disk.

[0034] Figure 16A and Figure 16B The surface of a flow distributor for an embodiment of a mixer is shown.

[0035] Figure 17 The spatial relationship between the openings in the downstream surface of the flow distributor and the openings in the upstream surface of the flow collector in one embodiment of the disc mixer is depicted.

[0036] Figure 18A and Figure 18B The surface of a flow distributor for another embodiment of a mixer is shown.

[0037] Figure 19 The spatial relationship between the opening in the downstream surface of the flow distributor and the opening in the upstream surface of the flow collector in another embodiment of the mixer is depicted. Detailed Implementation

[0038] In this specification, references to “example,” “implementation,” or “specific implementation” mean that a particular feature, structure, or characteristic described in connection with that example, implementation, or specific implementation is included in at least one implementation of this teaching. References to specific examples, implementations, or specific implementations within this specification do not necessarily refer to the same implementation.

[0039] As used herein, a mobile phase is a solvent or mixture of solvents used to carry the sample through the stationary phase of a liquid chromatography system. The mobile phase can be a gradient mobile phase, in which the composition of the mobile phase changes over time. The mobile phase may also be referred to herein as a system flow, which typically flows from the source of the mobile phase to at least the detector of the liquid chromatography system.

[0040] The brief overview describes a passive mixer with a disc-shaped mixing element. This mixer improves the accuracy and precision of the time-programmed composition of the mobile phase delivered by a reciprocating pump in a liquid chromatography system. The mixer includes a flow distributor, a mixing disc, and a flow collector. The mixing disc has an inlet face, an outlet face, and multiple channels, each channel having an inlet end at the inlet face and an outlet end at the outlet face. The channels exhibit flow direction anisotropy between the inlet and outlet faces. The constituent solvent flow is distributed by the flow distributor at the inlet face of the mixing disc and collected after passing through the mixing disc and exiting at the outlet face, such that the mixer output is a mixed constituent solvent flow.

[0041] The present disclosure will now be described in more detail with reference to embodiments illustrated in the accompanying drawings. While the teachings have been described in conjunction with various embodiments and examples, they are not intended to be limited to such embodiments. In contrast, the present disclosure covers various alternatives, modifications, and equivalents, as will be understood by those skilled in the art. Those of ordinary skill who have access to the teachings herein will recognize additional implementations, modifications, and embodiments, as well as other areas of use, within the scope of this disclosure.

[0042] Figure 1 is a block diagram of a liquid chromatography system 10 that may include an embodiment of the mixer described below. System 10 includes a system processor 12 (e.g., a microprocessor and controller) in communication with a user interface device 14, which receives input parameters and displays system information to an operator. System processor 12 communicates with a solvent manager 16 that provides one or more solvents for the mobile phase. For example, solvent manager 16 may include a mixer to mix two or more solvents and may provide a gradient mobile phase. A sample provided by sample manager 20 is injected into the mobile phase upstream of column 22 at injection valve 24. Sample manager 20 may include one or more sample sources, such as sample reservoirs, vials, or other containers containing a volume of sample. In some embodiments, sample manager 20 is a flow-through needle sample manager that includes a sample needle and a sample syringe for aspirating the sample from the sample source. In some cases, sample manager 20 provides a diluted sample comprising the sample and a diluent. Column 22 is coupled to a detector 26 that provides a signal to system processor 12. This signal is in response to various components detected in the eluent from column 22. After passing through detector 26, the system flow exits to the waste port; however, when used for fraction collection, a diversion valve may be included to temporarily redirect the system flow to one or more collection reservoirs.

[0043] Figure 2 This is a graphical representation of the presence of solvent B in the mobile phase as a function of time for different liquid chromatography systems, each equipped with a conventional mixer. The horizontal axis represents time, and the vertical axis represents the absorption units based on the system detector. The graph shows how different systems respond to a programmed gradual decrease in solvent B (acetone) in the aqueous mobile phase composition from 100% to 10% (vertical dashed line 34 at time t). A sharp transition can be achieved in the absence of a mixer; however, large compositional noise may be present.

[0044] Figure 3This is a graphical representation of the presence of solvent in the mobile phase of a liquid chromatography system over time. The vertical axis represents the absorption units and corresponds to the presence of a specific solvent component (e.g., acetonitrile in an aqueous solvent composition). The upper curve 36 is for a reciprocating pump with a pump stroke volume of 20 μL, while the lower curve 38 is for a reciprocating pump with a pump stroke volume of 100 μL. The noticeable high-frequency noise in curves 36 and 38 is due to the operation of the plunger in the reciprocating pump.

[0045] Figure 4 This is a height schematic diagram of a mixer 50 used to mix component solvent streams in a liquid chromatography system. The mixer 50 includes a flow distributor 52, a mixing disk 54, and a flow collector 56.

[0046] The flow distributor has a distributor inlet port 58 and a distributor outlet port 60 with an outlet cross-section. The flow distributor 52 distributes the combined solvent flow received at the distributor inlet port 58 substantially uniformly across the outlet cross-section at the distributor outlet port 60.

[0047] The mixing disc 54 has an inlet face 62, an outlet face 64, and channels having an inlet end at the inlet face 62 and an outlet end at the outlet face 64. In some embodiments, the mixing disc 54 is a circular disc; however, alternative embodiments may include discs with other shapes (such as rectangular edges or other non-circular outer edges). The inlet face 62 communicates with the distributor outlet port 60. The channels have anisotropic flow direction between the inlet face 62 and the outlet face 64. For example, the length of the flow path defined between the inlet and outlet ends of each channel can typically be different and vary within a range of flow path lengths, as described in more detail below. Each channel typically does not have a direct path between the inlet face 62 and the outlet face 64, but is defined by a change in direction such that the channel direction varies along its length. For example, each path may have one or more upward, downward, and / or lateral offsets (i.e., radial offsets), making the path substantially non-linear. In some embodiments, the channels may allow liquid to flow backward along a portion of the flow path, but in such embodiments, pressure resistance may be significant. The channel orientation includes a longitudinal component (defined along a "thickness axis" perpendicular to the disk surface) and a radial component (defined in a plane orthogonal to the thickness axis) along a portion of its length. Therefore, the width of each solvent component in the solvent pack widens in its channel through the mixing disk 54, as the pack is distributed into different channels with different flow path lengths through the disk material, and the stacked solvent packs generated by the gradient proportional valve can be effectively mixed within the mixing disk volume. The solvent components thus mix with adjacent solvent components, which also widen as they pass through the mixing disk 54. The mixing disk 54 can be fabricated using three-dimensional (3D) manufacturing processes (e.g., via stereolithography) to achieve mixer-to-mixer reproducibility of mixer properties.

[0048] The flow collector 56 has a collector inlet port 66 and a collector outlet port 68. The collector inlet port 66 has an inlet cross-section and communicates with the outlet face 64 of the mixing disk 54, thereby receiving the flow rate of the constituent solvent flow after passing through the mixing disk 54. The flow collector 56 collects the fluid from the channel end at the outlet face 64 of the mixing disk 54 substantially uniformly and combines it into a single flow at the collector outlet port 68.

[0049] In some implementations, the area of ​​the outlet cross-section of the flow distributor 52 is substantially equal to the cross-sectional area of ​​the inlet surface 62 of the mixing disk 54. Similarly, the area of ​​the inlet cross-section of the flow collector 56 may be substantially equal to the cross-sectional area of ​​the outlet surface 66 of the mixing disk 54. The flow distributor 52 may be a radial flow distributor, an angular flow distributor, a combination of radial and angular flow distributors, or a fractal flow distributor. Similarly, the flow collector 56 may be a radial flow collector, an angular flow collector, a combination of radial and angular flow collectors, or a fractal flow collector. These types of flow distributors 52 and flow collectors 56 allow a large portion of the volume of the mixing disk 54 to be used for mixing. Similarly, for a given mixer volume, the disk used for mixing produces maximum mixing.

[0050] In the absence of flow restriction, the limited divergence of the received solvent flow will not diffuse across the entire input surface 62 of the mixing disk 54. Furthermore, the performance of the mixer 50 is proportional to the square of the mixer volume. Therefore, the flow distributor 52 is used to uniformly distribute the constituent solvent flow received at the inlet port 58 into a large number (e.g., at least ten) of individual flows incident at the inlet surface 62 of the mixing disk 54. For example, the diameter of the solution flow at the inlet port 58 can be approximately 100 μm to 200 μm, and the diameter of each individual flow can similarly be approximately 100 μm to approximately 200 μm. Similarly, the flow collector 56 uniformly collects the individual flows exiting the outlet surface 64 of the mixing disk 54 into individual flows with a diameter of approximately 100 μm to 200 μm. This diameter range can induce significant molecular dispersion in the mixing disk 54 and provide a flow restriction greater than the flow restrictions of the flow distributor 52 and the flow collector 56.

[0051] As used herein, tortuosity refers to the normalized ratio of the flow path length between the ends of a channel to the straight-line distance between its ends. Therefore, tortuosity is a characterization of the swirling channels through which fluid disperses through the mixing medium. The tortuosity of the mixing disk 54 is given by the average flow path length of the channels relative to the thickness of the mixing disk 54. In some embodiments, the tortuosity of the channels is at least five, and in other embodiments, the tortuosity of the channels does not exceed ten. The mixer 50 can be characterized by its RTD, which is determined by the different flow path lengths through the mixing disk 54. The random channel structure through the mixing disk 54 aims to increase the RTD. The flow anisotropy and multi-channel tortuosity of the mixing disk 54 allow the skewness of the RTD to be reduced to near zero, and allow for more rapid programmed solvent composition of the solvent mixture at the collector outlet port 68.

[0052] In some embodiments, the flow path lengths are randomly defined based on the internal porous structure of the mixing disk 54. The mixing disk 54 may be formed of a dispersive material with a random porous structure. In this case, the flow path lengths of the channels are substantially independent of each other.

[0053] The void volume of the mixing disc 54 is preferably selected based on the pump stroke volume of the pump system. In some embodiments, the void volume value is between about two times the pump stroke volume and about three times the pump stroke volume. For example, a 400 μm mixer can be used with a pump system having a pump stroke volume of 132 μL based on three times the pump stroke volume.

[0054] In some embodiments, the mixing disk 54 is manufactured via machining or 3D printing. The mixing disk 54 may include a predetermined channel arrangement with a range of path flow path lengths or comprise a channel maze. The disk material is preferably a chemically inert material, such as glass, polymer, or metal. In a preferred embodiment, the mixing disk 54 is a clean, passivated stainless steel disordered structure that is inert relative to the solvent.

[0055] The volumes of the flow distributor 52 and the flow collector 56 are preferably smaller than the void volume of the mixing disc 54, thereby limiting the total pressure drop across the mixer 50. In one example, for water at room temperature, at a flow rate of 5 mL / min, the pressure drop across the mixer 50 does not exceed 20 MPa (3000 psi).

[0056] Figure 5A and Figure 5B Perspective and cross-sectional schematic views of an example mixer 70 for a liquid chromatography system are shown, respectively. The mixer 70 is formed of stacked metal mesh layers, wherein certain combinations of mesh layers substantially correspond to… Figure 4 The mixer 50 includes a flow collector 52, a mixing disk 54, and a flow collector 56, which enable the evaluation of mixing performance.

[0057] The mixer 70 includes a housing 72, an inlet 74 for receiving a flow of solvent composition along a flow axis 76, and an outlet 78 for providing a mixed flow of solvent composition. The inlet 74 is configured to receive a fitting connected to a conduit (e.g., a stainless steel pipe) that guides the flow of the solvent composition. Similarly, the outlet 78 is configured to receive a fitting connected to a conduit to guide the flow of the mixed solvent composition from the mixer 70. Due to the symmetrical structure of the sieve mixer 70, the functions of the inlet 74 and outlet 78 can be reversed.

[0058] Mixer 70 includes a first pair of mesh layers 80A and 80B, a second pair of mesh layers 82A and 82B, and a set of three mesh layers 84A, 84B, and 84C. In one embodiment, the two pairs of mesh layers 80 and 82 serve as alternatives to flow distributors and flow collectors. Each layer 80 or 82 is a 75μm thick stainless steel mesh with a 5μm mesh gap. Each pair of layers 80 and 82 serves as a flow limiter to approximate ideal flow distribution or ideal flow collection. Each of the three layers 84 in the middle of the layer stack is a 400μm thick stainless steel mesh with a 40μm mesh gap. The layer set 84 forms a porous dispersive structure that serves as a mixing disk. It should be noted that in improved implementations, disordered or random materials are used instead of the layer set 84 which has preferential diffusion in the radial direction, thereby increasing tortuosity and enabling an improvement in the reduction of RTD skewness.

[0059] Figure 6A , Figure 6B and Figure 6C The output responses of a 200 μm packed bed mixer, a multipath channel mixer, and a mixer utilizing a mixing disk are shown respectively. Each graph in the figure represents the mixer's response to pulses of composition in the solvent stream received at the mixer inlet at different flow rates. The position of each graph relative to the x-axis is not based on when the response was observed, but can be shifted to allow for easier observation of the individual graphs; however, the shape and width of each graph do represent the shape and duration of each response. The graph shown on the right is at a slower flow rate and exhibits the greatest diffusion over time. The flow rate range is from 0.005 mL / min to 2.0 mL / min.

[0060] Figure 7 It is a graphical representation of the mixing performance (normalized dispersion) of nine different mixers as a function of solvent flow rate, and Figure 8 yes Figure 7 The symmetry of the mixer (represented by peak skewness) is graphically represented as a function of solvent flow rate. Mixing performance is represented by σ. 2 / V 2 , where σ 2 σ is the variance, V is the mixing volume of the mixer, and σ is the mixing volume of the mixer.2 / V 2 The ideal value is one. The skewness value is limited to μ³ / σ. 1.5 , where μ3 is the volume-based third central moment of the concentration distribution. When evaluating the performance characteristics of a mixer, it should be recognized that there is a trade-off between dispersive performance and symmetry.

[0061] Although packed bed mixers have one to two orders of magnitude worse mixing performance, their symmetry is the best because they have near-zero skewness values ​​at all flow rates. In contrast, two multi-path mixers have better mixing performance. However, their peak skewness is worse at higher flow rates.

[0062] Disc mixers exhibit good mixing performance, similar to multi-flow-path mixers, and show even better symmetry. While 5μm and 14μm sieve mixers mix well, they exhibit "tailing" and therefore poor symmetry. Figure 8 As shown in the figure. Based on good mixing and better skewness, the 40μm, 95μm, and 180μm mesh mixers have the best overall performance, disregarding the two packed bed mixers with poor mixing. Although multi-flow-path mixers have better skewness at low flow rates, their symmetry deteriorates rapidly as the flow rate increases. The mesh mixers are significantly more independent of flow rate, especially the 40μm, 95μm, and 180μm mesh mixers. There is no mixer that is optimal in both mixing and symmetry. This trade-off is based on selecting a mixer with good mixing ( Figure 7 Then, based on the skewness at all relevant flow rates, one or more mixers are identified from that group. Figure 8 In some cases, this identification is based on an acceptable skewness value, which is also largely independent of flow rate.

[0063] The performance of the disc mixer was evaluated based on disc mixers made of 40μm and 100μm dielectric grade stainless steel. Figure 9A graphical representation of the measurement data is shown. Each data point is plotted as a function of mixer volume in microliters along the x-axis and noise in microabsorption units along the y-axis. The noise value for each data point was determined as the average of the maximum interpeak noise over sixty measurement windows, each window lasting ten seconds. Four graphs correspond to a disc mixer with a 40 μm mixer disk medium, a disc mixer with a 40 μm disc mixer medium combined with an additional shunt mixer, a disc mixer with a 100 μm disc mixer medium, and a disc mixer with a 100 μm disc mixer medium combined with an additional shunt mixer. The disc mixer medium was purchased from Mott Corporation, Farmington, CT. The measurements show that even at lower mixer volumes, periodic pump noise is no longer observable; only random interpeak noise contributes to the measured noise values ​​within the measurement windows. At higher mixer volumes, the plotted noise values ​​are not significantly greater than the background noise of the ultraviolet (UV) detector.

[0064] Figure 10A , Figure 10B and Figure 10C These are side views, end views, and cross-sectional side views of an example of a mixer 100 used to mix component solvent streams in a liquid chromatography system. The mixer includes a first housing component 102, a second housing component 104, an annular ring 106, a flow distributor 108, a mixing disk 110, and a flow collector 112. The flow distributor 108, mixing disk 110, and flow collector 112 are held within the annular ring 106. The first housing component 102 includes threads on its outer surface that engage threads on the inner bore surface of the second housing component 104. The first housing component 102 is inserted into the second housing component 104 until both components are in contact with opposite sides of the annular ring 106. A pair of gaskets 114A and 114B form fluid seals between the annular ring 106 and the first housing component 102, and between the annular ring 106 and the second housing component 104, respectively. Liquid entering the mixer 100 at mixer port 116A exits at mixer port 116B. The mixer 100 can also be used with liquids flowing in the opposite direction (i.e., by entering at mixer port 116B and exiting at mixer port 116A).

[0065] Figure 11 This is an exploded view of the annular ring 106 and the components held within it. The flow distributor 108 includes an inlet radial dispersion plate 118 and an inlet radial dispersion plate 120. The mixing disc 110 includes a disc 122 with a random porous structure disposed between two fine-mesh discs 124A and 124B (e.g., two metal sieves each with a 5 μm spacing). The flow collector 112 includes an outlet radial dispersion plate 126 and an outlet radial dispersion plate 128.

[0066] The inlet radial dispersion plate 118 and the outlet radial dispersion plate 128 each include a central opening 130 and 131, respectively, from which a groove 132 extends radially. The groove 132 is wedge-shaped, meaning its width increases with distance from the center. The inlet radial dispersion plate 120 and the outlet radial dispersion plate 126 each include an arrangement of concentric arcuate grooves 134 at one of three different radii from the center of the plate. The width of the grooves increases with distance from the center. The combination of the radial dispersion plates and the radial dispersion plates is used to effectively distribute or collect the independent flows flowing into or out of the mixing disk 110. It should be understood that the materials and dimensions of the plates 118 and 128, as well as the arrangement (including the number and size) of the grooves 132 and 134 within the plates, may differ in other embodiments.

[0067] Figure 12 This is an example of a fractal flow distributor 140 that can be manufactured, for example, using 3D printing stereolithography. The distributor 140 includes a central through-hole divided into two branch channels, each branch channel further divided into two branch channels, each branch channel further divided into another two branch channels, and so on. The splitting of the channels occurs across the thickness of the distributor plate or disk to generate a fractal distribution of flow on the surface. Figure 13 This is another example of a fractal flow distributor 150 that can be manufactured using a similar manufacturing process. In this example, the distributor 150 includes a structure divided into three branch channels, each branch channel being split and leading to the other three branch channels.

[0068] Figure 14 This is an example of a hybrid disk 160, which can be made of polymer materials using 3D manufacturing processes such as stereolithography. For example, Figure 15A and Figure 15D The photomask shown can be used alternately for sequential UV curing of polymer materials to construct a 50 μm square feature on one side. First, using... Figure 15A The light mask shown forms a straight channel, and then uses... Figure 15D The photomask shown forms a square cross-sectional channel. The thickness of the resulting slice depends on the intensity of the UV light source, the concentration of the photoinitiator compound in the polymer material, the monomer concentration, and the UV exposure time. The curing process can be repeated multiple times, removing unpolymerized material between curing cycles. In this way, many layers can be stacked to be translated and / or rotated relative to other slices (e.g., see...). Figure 15B and Figure 15C Each slice (using a photomask) is used to fabricate various 3D structures. This process is merely one example of a manufacturing technique used to form hybrid disks, and it should be understood that other manufacturing techniques can also be used.

[0069] In the various embodiments described above, the flow distributor and the flow collector are constructed similarly. For example, the structure of the flow distributor from the distributor inlet to the distributor outlet can be the same as the structure of the flow collector from the collector outlet to the collector inlet.

[0070] In one embodiment, the flow distributor is made of a single disc plate 160 having a first (upstream) surface 160A and a second (downstream) surface 160B, respectively as shown in the figure. Figure 16A and Figure 16B As shown, the first surface 160A illustrates a fractal distribution path structure. A series of fluid paths begin from an open, circular central region 162 that receives flow from the distributor inlet. A first flow path 164A extends radially from the central region 162 at one end to the opposite end at the midpoint of a second flow path 164B perpendicular to the first flow path 164A. Each end of the second flow path 164B is near or located at the midpoint of a third flow path 164C. As shown, there are 12 first flow paths 164A, 12 second flow paths 164B, and 24 third flow paths 164C. At each end of each of the third flow paths 164C is an opening 166 at the downstream surface 160B.

[0071] The fluid path and other features of the flow distributor can be formed in a variety of ways. For example, known micromachining techniques can be used. Alternatively, etching processes can be used to form the desired structure.

[0072] Each opening 166 is defined along one of two concentric circles with radii R1 or R2, each circle being concentric with the mixer flow axis. Thus, the flow received at the distributor inlet port is internally divided into 12 flows, each of which is further divided into four flows, resulting in 48 flows exiting the second surface 160B. The diameters of the openings 166 are preferably equal. In a non-limiting numerical example, the total area defined by all 48 openings is approximately five percent of the total surface area of ​​the second surface 160B.

[0073] In one embodiment (Embodiment A), the flow distributor and the flow collector have the same construction, i.e., the mixer exhibits axial mirror symmetry about the mixing disc. In other words, the first surface 160A of the flow distributor is the same as the second surface of the flow collector, and the second surface 160B of the flow distributor is the same as the first surface of the flow collector. Therefore, the mixer is configured such that the features of the flow collector are arranged in the opposite axial flow direction to the features of the flow distributor, but are otherwise identical. Figure 17The relationship between an opening 166 in the second (downstream) plate 160B of the flow distributor and an opening 176 in the first (upstream) surface 170A of the flow collector in a mixer constructed in this manner is illustrated. Each opening 166 and 176 lies on one of two concentric circles with radii R1 and R2. The opening at the distributor outlet port is arranged in the same manner as the opening at the collector inlet port. Therefore, there is a one-to-one correspondence between each opening 166 in the second surface 160B of the flow distributor and the corresponding opening 176 in the first surface 170A of the flow collector. However, in other embodiments, the flow distributor and flow collector are not limited to a symmetrical arrangement around the mixing disk, as further described below.

[0074] Figure 18A and Figure 18B The upstream surface 180A and downstream surface 180B used in different implementations of the flow distributor are depicted. The first surface 180A shows a series of fluid paths beginning at an open, circular central region 182 that receives flow from the distributor inlet. A first flow path 184A extends radially from one end of the central region 182 to its opposite end at the midpoint of a short second flow path 184B arranged perpendicular to the first flow path 184A. Each end of each second flow path 184B is connected to one end of each of three third flow paths 184C. As shown, there are 12 first flow paths 184A, 12 second flow paths 184B, and 36 third flow paths 184C. At each end of each of the third flow paths 184C is an opening 186 at the downstream surface 180B.

[0075] Each opening 186 is defined by one of four concentric circles with radii R1', R2', R3', and R4', all concentric circles being concentric with the mixer flow axis. The flow received at the distributor inlet port is split into 12 flows, each of which is split into two flows, and each of which is further split into three flows, such that the number of flows exiting the second surface 180B is 72. Therefore, the number of individual flows incident on the upstream surface of the mixing disk is greater than Figure 16A and Figure 16B The number of each flow in the implementation scheme shown.

[0076] In one embodiment of the mixer (Implementation B), the flow distributor and the flow collector are both formed as identical components, each having 72 openings and arranged symmetrically around the mixing disk.

[0077] In another implementation scheme (Implementation Scheme C), the following is used: Figure 16A and Figure 16B The flow distributor shown and such Figure 18Aand Figure 18B The flow collector shown is used to construct the mixer. Thus, the flow distributor includes 48 openings 166 adjacent to the upstream side of the mixing disk, while the flow collector includes 72 openings 186 on the downstream side of the mixing disk. Figure 19 The relationship between the opening 166 in the second surface 160B of the flow distributor and the opening 176 in the first (upstream) surface 180A of the flow collector in the mixer constructed in this manner is shown. It can be seen that the concentric circles defining the opening 166 with radii R1 and R2 are different from the concentric circles defining the opening 176 with radii R1', R2', R3' and R4'.

[0078] In yet another implementation scheme (Implementation Scheme D), the following is used: Figure 18A and Figure 18B The flow distributor shown and according to Figure 16A and Figure 16B The structure shown forms a flow collector to construct the mixer. In this arrangement, the flow distributor includes 72 openings 186 adjacent to the upstream side of the mixing disk, and the flow collector includes 48 openings 166 on the downstream side of the mixing disk. As in embodiment C, the concentric circles of openings 166 and 176 are different.

[0079] Performance evaluation was performed by determining the residence time distribution of mixers according to embodiments A through D using pulsed input of the analyte. Measurements showed that, compared to embodiment A, embodiment B had a higher peak and a slightly narrower width in its residence time distribution. Embodiments C and D had nearly identical residence time distributions, with peak heights similar to those of embodiment B; however, embodiments C and D exhibited better symmetry in their residence time distributions.

[0080] It should be recognized that the number of internal flow paths and / or openings can differ from those described above. For example, any flow branch with a fractal order greater than two can be used. For example, two or more flow disk elements can be stacked. Similarly, the arrangement of internal flow paths and openings can differ. For example, openings can be arranged on different numbers of concentric circles. Other arrangements of openings can be considered.

[0081] Although the present technology has been shown and described with reference to specific embodiments, those skilled in the art will understand that various changes in form and detail may be made without departing from the scope of the claims.

Claims

1. A mixer for a liquid chromatography system, comprising: A flow distributor having a distributor inlet port and a distributor outlet port, the distributor inlet port being configured to receive a flow rate of a constituent solvent flow, and the distributor outlet port having a distributor outlet cross-section and being configured to provide the constituent solvent flow distributed across the distributor outlet cross-section; A mixing disc having an inlet face, an outlet face, and multiple channels, each channel having an inlet end at the inlet face and an outlet end at the outlet face, the inlet face communicating with the outlet port of the distributor, and the channels having anisotropic flow direction between the inlet face and the outlet face; and A flow collector having a collector inlet port and a collector outlet port, the collector inlet port having a collector inlet cross-section and communicating with the outlet surface of the mixing disk to receive the flow rate of the constituent solvent flow after passing through the mixing disk.

2. The mixer of claim 1, wherein the mixing disk comprises a dispersive medium having a random porous structure.

3. The mixer of claim 1, wherein the channel has a tortuosity of at least five and no more than ten.

4. The mixer of claim 1, wherein the residence time distribution of the mixer depends on the structure of the channel between the inlet face and the outlet face of the mixing disc.

5. The mixer according to claim 1, wherein each of the constituent solvent flows distributed on the distributor outlet cross-section of the flow distributor has a diameter between 100 μm and 200 μm.

6. The mixer of claim 1, wherein the area of ​​the distributor outlet cross-section of the flow distributor is equal to the cross-sectional area of ​​the inlet surface of the mixing disc.

7. The mixer of claim 1, wherein the area of ​​the inlet cross-section of the flow collector is equal to the cross-sectional area of ​​the outlet surface of the mixing disc.

8. The mixer of claim 1, wherein the mixing disc is formed of a material comprising one of glass, polymer and metal.

9. The mixer of claim 1, wherein the void volume of the mixing disk is greater than the volume of the flow distributor and greater than the volume of the flow collector.

10. The mixer of claim 1, wherein the mixing disc comprises at least one mesh layer.

11. The mixer of claim 1, wherein the flow distributor comprises a role distribution plate.

12. The mixer of claim 1, wherein the flow distributor comprises a radial dispersion plate.

13. The mixer of claim 1, wherein the flow collector comprises a role plate.

14. The mixer of claim 1, wherein the flow collector comprises a radial dispersion plate.

15. The mixer of claim 1, wherein the flow distributor is a fractal flow distributor.

16. The mixer of claim 1, wherein the flow collector is a fractal flow collector.

17. The mixer of claim 1, wherein the flow distributor includes a plurality of openings at the distributor outlet port and a plurality of internal flow paths defined between the distributor inlet port and the distributor outlet port to direct the component solvent flow to the distributor outlet port.

18. The mixer of claim 17, wherein the opening is arranged along a plurality of concentric circles defined on the distributor outlet port.

19. The mixer of claim 1, wherein the flow collector includes a plurality of openings at the collector inlet port and a plurality of internal flow paths defining the constituent solvent flow between the collector inlet port and the collector outlet port to guide the constituent solvent flow from the mixing disk to the collector outlet port.

20. The mixer of claim 19, wherein the opening is arranged along a plurality of concentric circles defined on the collector inlet port.

21. The mixer of claim 17, wherein the flow collector includes a plurality of openings at the collector inlet port and a plurality of internal flow paths defining the collector inlet port and the collector outlet port to guide the constituent solvent flow from the mixing disk to the collector outlet port.

22. The mixer of claim 21, wherein the opening at the distributor outlet port is arranged in the same manner as the opening at the collector inlet port.

23. The mixer of claim 21, wherein the number of openings at the distributor outlet port is different from the number of openings at the collector inlet port.

24. The mixer according to claim 1, wherein, The distributor inlet port has a distributor inlet cross-section, and wherein the distributor outlet cross-section is larger than the distributor inlet cross-section.

25. The mixer according to claim 24, wherein, The collector outlet port has a collector outlet cross-section that is smaller than the collector inlet cross-section.

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