Mixer for chromatography system

Abstract

The present disclosure describes a mixer (1) for a chromatography system. The mixer (1) comprises an inlet manifold channel (10), an outlet manifold channel (50) and a plurality of transfer channels (20A-20I). The inlet manifold channel (10) has an inlet (13) at a proximal end (11) of the inlet manifold channel (10) for receiving an inlet flow (13). The transfer passages (20A-20I) are fluidly connected between the inlet manifold passage (10) and the outlet manifold passage (50). A respective fluid connection is distributed along each of the inlet manifold channel and the outlet manifold channel. The transfer channels (20A-20I) have different volumes. The mixer may be formed from multiple layers, and the layers may be diffusely bonded to each other.

Description

[0001] Related Applications This application claims the benefit of the earlier filing date of U.S. Provisional Patent Application Serial No. 62 / 885,617, filed on August 12, 2019, and entitled “A Mixer,” the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention generally relates to a mixer. More particularly, the present invention relates to a mixer for calibration of a chromatography system and to a calibration device incorporating the mixer. Background Art

[0003] Chromatography is a group of techniques for separating a mixture into its components. Generally speaking, in liquid chromatography, a pump receives a composition of a liquid solvent and delivers it at high pressure to a sample manager, where the sample (i.e., the material being analyzed) awaits injection into the mixture. The resulting composition, consisting of a mixture of the liquid solvent and the injected sample, moves from the sample manager to a point of use, such as a chromatographic column filled with a stationary phase. By passing the composition through the column, the various components in the sample separate from each other at different rates and therefore elute from the column at different times. A detector receives the elution from the column and produces an output from which the type and amount of the analyte can be determined.

[0004] It is necessary to regularly qualify the components of the chromatographic equipment (and recalibrate and requalify the components as needed). A known qualification method is the System Qualification Technology (SystemsQT) provided by Waters Corporation (MA, USA), which allows the user to perform installation qualification (IQ), operational qualification (OQ), system performance testing and data management.

[0005] Known identification methods use chromatographic columns to measure the performance of chromatographic systems. This utilizes chromatographic data processing and regression analysis to substantially automate the collection and identification of test results. The key benefit of using chromatographic columns is predictable control over the shape of the peaks used for identification measurements. In addition, it is advantageous to use all of the same components that will be used during analysis to identify the instrument.

[0006] The problem with using a chromatographic column is that the user must wait for the column to equilibrate before being able to reliably perform an identification, to completely flush any fluid from a previous analysis and / or to reach thermal stability. Existing identification methods can take 3 hours to 24 hours, which is undesirable because the instrument will be unavailable during this time.

[0007] Furthermore, even when made to essentially the same specifications, no two chromatographic columns are likely to be identical. For example, there may be variations in the way the stationary phase is packed in the column, causing the chromatographic column to behave differently during analysis, which reduces the accuracy of the identification.

[0008] It has been proposed to replace the column with tubing during identification, which is connected to the detector. However, the use of tubing does not provide any control over the peak shape, and there is no separation. In addition, the tubing itself may not provide the appropriate back pressure to load the system.

[0009] It is necessary to ensure that the solvent and sample entering the column / tubing are of substantially homogeneous composition. The known use of tubing during characterization does not allow any mixing of the compositions.

[0010] U.S. Patent 8,511,889 discloses a mixer that attempts to output a substantially mixed composition. The mixer includes a plurality of flow channels. Each flow channel includes a first flow section that provides hydraulic resistance. A fluid distributor provides simultaneous arrival of fluid at all first flow sections, which are disclosed as having the same length and cross-section so that each first flow section has the same hydraulic resistance. There are second flow sections downstream of the first flow sections that are used to mix the composition transported in the corresponding second flow sections. The second flow sections have different volumes to delay fluid propagation to a corresponding degree. All second flow sections are combined at a single point (flow combiner).

[0011] The problem with the mixer of US Pat. No. 8,511,889 is that while it may promote mixing of the fluids conveyed within each flow channel, the operation of the individual flow distributors may not be sufficient to distribute the fluids into the first flow segments. Thus, while some smoothing of any compositional variations may be achieved to a local extent within each flow channel, any compositional variations in the fluid stream as a whole will still be present when the flow channels recombine.

[0012] The present invention seeks to address at least some of the foregoing problems. Summary of the invention

[0013] In one aspect, the mixer includes an inlet manifold channel, an outlet manifold channel, and a plurality of transfer channels. The inlet manifold channel has an inlet at the proximal end of the inlet manifold channel for receiving an inlet flow. The plurality of transfer channels are fluidly connected between the inlet manifold channel and the outlet manifold channel. The corresponding fluid connections are distributed along each of the inlet manifold channel and the outlet manifold channel, and the transfer channels have different volumes.

[0014] The corresponding fluid connections may be substantially equally distributed along the length of the inlet manifold and the outlet manifold.

[0015] The plurality of transfer channels may extend from the inlet manifold channel and the outlet manifold channel at each fluid connection substantially in the same plane. The transfer channels may be arranged in substantially the same plane. The plurality of transfer channels may include a flow restrictor.

[0016] The outlet manifold channel may have an outlet at a distal end of the outlet manifold channel for delivering the outlet flow, and the proximal end of the outlet manifold channel may be disposed adjacent to the distal end of the inlet manifold channel.

[0017] The first of the delivery channels may have a fluid connection with the inlet manifold channel adjacent to a proximal end of the inlet manifold channel, and the first of the delivery channels may have a fluid connection with the outlet manifold channel adjacent to a distal end of the outlet manifold channel. The last of the delivery channels may have a fluid connection with the inlet manifold channel adjacent to a distal end of the inlet manifold channel, and the last of the delivery channels may have a fluid connection with the outlet manifold channel adjacent to a proximal end of the outlet manifold channel.

[0018] The flow restrictor may be fluidly connected to the mixer. The flow restrictor may be located downstream of the outlet manifold. The mixer may be formed of a plurality of layers. The layers may be diffusion bonded to each other and may be formed of titanium. The mixer may be provided in, by, or adjacent to one of the layers, and the flow restrictor may be provided in, by, or adjacent to another of the layers. The mixer may be fluidly connected to the flow restrictor via a through hole in at least one of the layers.

[0019] In another aspect, the mixer includes an intermediate manifold channel, a plurality of primary transfer channels, and a plurality of secondary transfer channels. The plurality of primary transfer channels and the plurality of secondary transfer channels are fluidly connected to the intermediate manifold channel. The fluid connection of the primary transfer channel to the intermediate manifold channel is arranged to be substantially opposite to the fluid connection of the corresponding secondary transfer channel.

[0020] The mixer may be configured such that fluid flows may be received from the plurality of primary transfer channels in the intermediate manifold channel and may be delivered from the intermediate manifold channel to the plurality of secondary transfer channels.

[0021] The primary delivery channels may have different volumes. The secondary delivery channels may have different volumes. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The above advantages and other advantages of the present invention may be better understood by referring to the following description in conjunction with the accompanying drawings, in which similar reference numerals refer to similar elements and features in the various drawings. Letters may be appended to the reference numerals to distinguish them from the reference numerals of similar features and to indicate the corresponding relationship with other features in the drawings. For clarity, not every element is labeled in every drawing. The drawings are not necessarily drawn to scale, and emphasis is placed on illustrating the principles of the present invention.

[0023] Figure 1 A mixer embodying the invention is shown schematically.

[0024] Figure 2 Another mixer embodying the invention is shown schematically.

[0025] Figure 3 Another mixer embodying the invention is shown schematically.

[0026] Figure 4 Another mixer embodying the invention is shown schematically.

[0027] Figure 5 A calibration device embodying the invention is shown schematically.

[0028] Figure 6 A cross-section of a microfluidic device embodying the invention is schematically shown.

[0029] Figure 7 A microfluidic device embodying the invention is schematically shown.

[0030] Figure 8 A flow restrictor of a microfluidic device embodying the present invention is schematically shown. DETAILED DESCRIPTION

[0031] Generally speaking, the present disclosure provides a device that simulates the advantages of using a chromatographic column while avoiding or reducing related disadvantages. Some embodiments of the device disclosed herein control dispersion and back pressure to better simulate a chromatographic column. The device can be repeatable and predictable in nature, and also provides a back pressure load (which may be required so that the valve works effectively).

[0032] Generally speaking, one aspect of the present invention provides a mixer. The mixer includes an inlet manifold channel, an outlet manifold channel, and a plurality of transfer channels fluidly connected between the inlet manifold channel and the outlet manifold channel. In other embodiments of the present invention, one or more intermediate manifold channels may be provided between the inlet manifold channel and the outlet manifold channel, as will be described below.

[0033] Figure 1A mixer 1 according to one embodiment of the present invention is shown. The mixer 1 comprises an inlet manifold channel 10 having a proximal end 11 and a distal end 12. An inlet 13 is provided at or adjacent the proximal end 11 for receiving an inlet flow. The inlet flow may be a fluid that is mixed by the mixer 1. Figure 1 The inlet manifold channel 10 shown is generally slot-shaped and may have a substantially semicircular cross-section. This is not required. The cross-section of the inlet manifold channel 10 may take different forms, such as square, U-shaped or V-shaped. The cross-section of the inlet manifold channel 10 may have the same shape and size between the proximal end 11 and the distal end 12. Alternatively, the cross-section and / or size may be different between the proximal end 11 and the distal end 12. For example, the cross-sectional area of ​​the inlet manifold channel 10 may decrease from the proximal end 11 toward the distal end 12.

[0034] The mixer 1 also includes an outlet manifold channel 50. The outlet manifold channel 50 may be substantially similar to the inlet manifold channel 10. The outlet manifold channel 50 has a proximal end 51 and a distal end 52. The cross-sectional shape and / or size of the outlet manifold channel 50 may be substantially the same as the cross-sectional shape and / or size of the inlet manifold channel 10. In at least one embodiment, the cross-sectional area and / or size of the inlet manifold channel 10 may be different from the cross-sectional area and / or size of the outlet manifold channel 50. The outlet manifold channel 50 may include an outlet 54 at the distal end 52 for delivering the outlet flow. Preferably, the composition of the fluid discharged from the outlet 54 can be significantly more uniform (or less heterogeneous) than the flow of the inlet flow 13 at the proximal end 11 entering the inlet manifold channel 10.

[0035] The mixer 1 also includes a plurality of transfer channels 20 fluidly connected between the inlet manifold channel 10 and the outlet manifold channel 50. Figure 1 In the embodiment of the mixer 1 shown, there are nine delivery channels 20, referenced 20A to 201. More or fewer channels 20 may be present.

[0036] from Figure 1 It can be seen that the respective fluid connections between the plurality of transfer channels 20A- 20I may be distributed along the length of each of the inlet manifold channel 10 and the outlet manifold channel 50 .

[0037] In at least one embodiment, the respective fluid connections of the plurality of transfer channels 20A- 20I are substantially equally distributed along the length of the inlet manifold channel 10 and the outlet manifold channel 50 .

[0038] The plurality of transfer channels 20A-20I may extend substantially perpendicularly from the inlet manifold channel 10 and the outlet manifold channel 50 at each fluid connection. That is, at the point of each fluid connection between the transfer channels 20A-20I and the inlet manifold channel 10 and the outlet manifold channel 50, the longitudinal axis of each transfer channel 20A-20I is perpendicular (90°) to the longitudinal axis of the inlet manifold channel 10 and the outlet manifold channel 50 at that point.

[0039] The inlet manifold channels 10 and outlet manifold channels 50 may be substantially elongate and linear. This is not required and they may take other forms, including curved.

[0040] In at least one embodiment, the plurality of transfer channels 20A to 20I may extend at a non-perpendicular angle to the inlet manifold channel 10 and the outlet manifold channel 50 at each fluid connection. This may facilitate the transfer of fluid within the inlet manifold channel 10 into the plurality of transfer channels 20A to 20I. In another embodiment, the angle between the fluid connection of the inlet manifold channel 10 to each of the plurality of transfer channels 20A to 20I may be different. For example, the fluid connection of the first transfer channel 20A may be substantially perpendicular to the axis of the inlet manifold channel 10, whereas the angle between the ninth transfer channel 20I and the inlet manifold channel 10 may be non-perpendicular (e.g., 45°).

[0041] In at least one embodiment, the plurality of transfer channels 20A to 20I extend substantially in the same plane from the inlet manifold channel 10 and the outlet manifold channel 50 at each fluid connection. That is, the longitudinal axes of the transfer channels 20A to 20I at the fluid connection points are all in the same plane as one another. In at least one embodiment, the entire length of the plurality of transfer channels 20A to 20I are arranged in the same plane.

[0042] from Figure 1 It can be seen that the plurality of delivery channels 20A to 20I can be substantially arcuate. In at least one embodiment, the plurality of delivery channels 20A to 20I are substantially semicircular. In at least one embodiment, the plurality of delivery channels 20A to 20I are substantially concentric with each other. In at least one embodiment, the plurality of delivery channels 20A to 20I are substantially parallel to each other.

[0043] The arrangement of the transfer channels 20A to 20I allows a compact arrangement of the transfer channels 20A to 20I on the mixer in order to save space.

[0044] In at least one embodiment, each of the plurality of delivery channels 20A to 20I has a different length. In at least one embodiment, there may not be two delivery channels 20A to 20I of the same length. The second delivery channel 20B may be longer than the first delivery channel 20A. The third delivery channel 20C may be longer than the second delivery channel 20B. The fourth delivery channel 20D may be longer than the third delivery channel 20C, and so on. The difference in length between two adjacent delivery channels 20A to 20I may be uniform, or it may be different. Reference Figure 1 , it should be noted that the radius of each of the arcuate delivery channels 20A to 20I increases substantially linearly. The length of each delivery channel 20A to 20I is equal to the radius multiplied by π (because they are semicircular). Therefore, the length of each of the corresponding delivery channels 20A to 20I can increase linearly. That is, the difference between the length of the first delivery channel 20A and the second delivery channel 20B can be the same as the difference between the length of the second delivery channel 20B and the third delivery channel 20C.

[0045] In other embodiments, the lengths of the delivery channels 20A-20I may increase non-linearly.

[0046] Figure 1 A cross-sectional view of a portion of a mixer 1 is shown. The inlet manifold channel 10, outlet manifold channel 50, and multiple transfer channels 20A to 20I appear "open" on the top. In at least one embodiment, the fluid passing through the mixer 1 is at high pressure. Therefore, the mixer 1 embodying the present invention can be hermetically sealed.

[0047] In at least one embodiment, as will be described later, the mixer 1 may include Figure 1 Another layer on top of the layer shown, which is used to close the top of the inlet manifold channel 10, the outlet manifold channel 50 and the plurality of transfer channels 20A to 20I. Figure 1 The underside of the top layer shown may be planar, or it may have corresponding inlet manifold channels, outlet manifold channels, and transfer channels. Thus, where the inlet manifold channels 10, outlet manifold channels 50, and multiple transfer channels 50 are substantially semicircular, when two corresponding layers are placed adjacent to each other, they may define substantially circular composite inlet manifold channels, outlet manifold channels, and multiple transfer channels.

[0048] In at least one embodiment, each of the delivery channels 20A-20I has a different volume. That is, the volume between the inlet fluid connection of a delivery channel 20A-20I and the outlet of the delivery channel 20A-20I is different from the corresponding volume of another delivery channel 20A-20I. In embodiments where all delivery channels 20A-20I have substantially the same cross-sectional shape and area, if the length of each of the delivery channels 20A-20I increases linearly between the respective delivery channels 20A-20I, then the corresponding volumes will also increase linearly.

[0049] In at least one embodiment, the plurality of delivery channels 20A to 20I have different cross-sectional areas and / or different cross-sectional shapes. It should be understood that for a particular length of a delivery channel, adjusting the cross-sectional shape and / or area along at least a portion of a delivery channel 20A to 20I will affect its overall volume.

[0050] In at least one embodiment, the plurality of delivery channels 20A-20I have at least one flow restrictor disposed within at least one of the delivery channels 20A-20I.

[0051] It should be understood that the longer the delivery channel 20A-20I is, the greater the dynamic fluid resistance it will provide to the fluid passing therethrough. Therefore, in at least one embodiment, one or more flow restrictors may be added to the path of the delivery channels 20A-20I in order to avoid or reduce the chance of the incoming fluid taking the easiest (least resistance, shortest) delivery channel 20. The resistance of the delivery channels 20A-20I may be altered by changing the cross-sectional dimensions and / or by adding physical flow restrictor features.

[0052] A beneficial effect of multiple delivery channels 20A-20I having different lengths, volumes, cross-sectional areas, cross-sectional shapes, and / or having at least one flow restrictor is that the time required for fluid to pass through a respective delivery channel 20A-20A is different than the time required for another delivery channel 20A-20I. Thus, after receiving the inlet flow at the inlet 13 at the proximal end 11 of the inlet manifold channel 10, the respective components of the inlet flow transferred into the delivery channels 20A-20I will emerge from the outlet of each delivery channel 20A-20I at different times. This arrangement serves to reduce / smooth out any component noise that may be present in the fluid flow.

[0053] Fluid conveyed by transfer channels 20A-20I is delivered to outlet manifold channels 50. In general, it should be noted that delivering fluid from transfer channels 20A-20I to outlet manifold channels 50 is actually the reverse of the arrangement in which fluid in inlet manifold channels 10 is transferred to transfer channels 20A-20I.

[0054] The outlet manifold channel 50 can be used to combine and further mix the fluids delivered to the outlet manifold channel 50 through each of the transfer channels 20A to 20I. The fluid is then delivered out of the mixer 1 through the outlet 54 at the distal end 52 of the outlet manifold channel 50. In another embodiment, the outlet 54 can be disposed at the proximal end 51 of the outlet manifold channel 50. Alternatively, the outlet 54 can be disposed at a point between the proximal end 51 and the distal end 52 of the outlet manifold channel 50. The same arrangement can be implemented for the inlet 13 of the inlet manifold channel 10.

[0055] The outlet manifold channel 50 may be provided with physical features on the surface of the outlet manifold channel 50 that may promote further mixing. For example, such features may include fins, protrusions, baffles, or recesses that help create turbulence within the outlet manifold channel 50. Similar features may be provided within the inlet manifold channel 10.

[0056] use Figure 1 In the arrangement shown, the proximal end 51 of the outlet manifold channel 50 is arranged substantially adjacent to the distal end 12 of the inlet manifold channel 10. In at least one embodiment, the inlet manifold channel 10 is arranged substantially co-linearly with the outlet manifold channel 50. That is, the longitudinal axis of the inlet manifold channel 10 is substantially coaxial with the longitudinal axis of the outlet manifold channel 50. This is not required, and is more a result of the fact that the transfer channels 20A to 20I in the embodiment shown are semi-circular.

[0057] from Figure 1 It should be noted that the fluid connection of the first transfer channel 20A to the inlet manifold channel 10 is adjacent to the proximal end 11 of the inlet manifold channel 10. The fluid connection of the first transfer channel 20A to the outlet manifold channel 50 is adjacent to the distal end 52 of the outlet manifold channel 50. Therefore, the fluid connection of the last transfer channel 20I to the inlet manifold channel 10 is adjacent to the distal end 12 of the inlet manifold channel 10. In addition, the fluid connection of the last transfer channel 20I to the outlet manifold channel 50 is adjacent to the proximal end 51 of the outlet manifold channel 50.

[0058] Now refer to Figure 2 Another embodiment of the present invention is described. It should be understood from the following description that Figure 2 The mixer 2 shown uses many reference Figure 1 The same features as the mixer 1 shown and described. Figure 2The mixer 2 is shown to include an intermediate manifold channel 30. The mixer 2 also includes a plurality of primary transfer channels 20A to 20I fluidly connected to the intermediate manifold channel 30. The mixer 2 also includes a plurality of secondary transfer channels 21A to 21I fluidly connected to the intermediate manifold channel 30. The fluid connections of the primary transfer channels 20A to 20I to the intermediate manifold channel 30 may be arranged to be substantially opposite to the fluid connections of the corresponding fluid connections of the secondary transfer channels 21A to 21I.

[0059] The fluid is delivered to the intermediate manifold passage 30 through the plurality of primary transfer passages 20A to 20I, and then the fluid is transferred from the intermediate manifold passage 30 into the plurality of secondary transfer passages 21A to 21I.

[0060] In at least one embodiment, the respective fluid connections of the plurality of primary delivery channels 20A to 20I and the secondary delivery channels 21A to 21I are substantially equally distributed along the length of the intermediate manifold channel 30. In at least one embodiment, the respective fluid connections are equally distributed between the proximal end 31 and the distal end 32 of the intermediate manifold channel 30. The spacing of the fluid connections may be as large as Figure 1 The fluid connections of the mixers shown are of the same or similar spacing.

[0061] As will be understood from the following description, the mixer 2 can be used with Figure 1 The mixer 1 shown shares similar physical characteristics. For example, the plurality of primary transfer channels 20A to 20I and the secondary transfer channels 21A to 21I extend substantially vertically from the intermediate manifold channel 30 at each fluid connection. In at least one embodiment, the plurality of primary transfer channels 20A to 20I extend substantially in the same plane from the intermediate manifold channel 30 at each fluid connection. In at least one embodiment, the plurality of primary transfer channels 20A to 20I and the plurality of secondary transfer channels 21A to 21I are all arranged in substantially the same plane, such as Figure 2 shown.

[0062] In at least one embodiment, the plurality of primary transfer channels 20A-20I and secondary transfer channels 21A-21I are substantially arcuate.

[0063] In at least one embodiment, the plurality of primary transfer channels 20A-20I and secondary transfer channels 21A-21I are substantially semicircular.

[0064] In at least one embodiment, the plurality of primary transfer channels 20A-20I and secondary transfer channels 21A-21I are substantially concentric with one another.

[0065] The plurality of primary transfer passages 20A to 20I and secondary transfer passages 21A to 21I are substantially parallel to each other.

[0066] With reference Figure 1 As with the embodiment described with reference to the mixer 1 in FIG. 1 , the plurality of primary transfer channels 20A to 20I and the secondary transfer channels 21A to 21I may have different lengths, different volumes, different cross-sectional areas and / or different cross-sections.

[0067] In at least one embodiment, at least one of the plurality of primary transfer channels 20A to 20I and the secondary transfer channels 21A to 21I comprises the Figure 1 The mixer 1 shown has at least one flow restrictor of the type described.

[0068] The outlets of the primary transfer channels 20A-20I may be substantially opposite and coaxial with the inlets of the corresponding secondary transfer channels 21A-21I. Thus, when fluid is transferred from the primary transfer channels 20A-20I into the intermediate manifold channel 30, it may generally be directed toward the inlets of the secondary transfer channels 21A-21I.

[0069] In at least one embodiment, the outlets of the primary transfer channels 20A to 20I may be offset from the inlets of the secondary transfer channels 21A to 21I. The beneficial effect of such an arrangement may be to promote further mixing of the fluid within the intermediate manifold channel 30. The fluid exiting a given primary transfer channel 20A to 20I may not then necessarily be delivered to the corresponding (e.g., opposite) inlet of the secondary transfer channel 21A to 21I. In at least one embodiment, while a particular portion of the fluid exiting the primary transfer channel 20A to 20I may be directed into the inlet of the corresponding opposite secondary transfer channel 21A to 21I, other portions of the fluid may be distributed through the intermediate manifold channel 30 and delivered to the inlets of other secondary transfer channels 21A to 21I.

[0070] In at least one embodiment, the volume of the intermediate manifold channel 30 can be configured to act as a dwell volume wherein fluids received from the primary transfer channels 20A-20I are mixed and then transferred into the secondary transfer channels 21A-21I.

[0071] In at least one embodiment, the fluid connections of some or all of the primary transfer passages 20A- 20I may not be perpendicular to the longitudinal axis of the intermediate manifold passage 30 .

[0072] Figure 3 A further mixer 3 according to another embodiment of the invention is shown.

[0073] The mixer 3 comprises an inlet manifold channel 10 , at least one intermediate manifold channel 30 and an outlet manifold channel 50 . Figure 3 Only one intermediate manifold channel 30 is shown.

[0074] The mixer 3 includes a plurality of primary transfer passages 20A to 20I fluidly connected between the inlet manifold passage 10 and the intermediate manifold passage 30. Furthermore, the mixer 3 includes a plurality of secondary transfer passages 21A to 21I fluidly connected between the intermediate manifold passage 30 and the outlet manifold passage 50.

[0075] and Figure 1 As with the mixer 1 shown, the inlet manifold channel 10 has a proximal end 11 and a distal end 12. The inlet 13 is provided at the proximal end 11. Similar features are indicated by similar reference numerals. Figure 1 As with the mixer 1 shown, the outlet manifold channel 50 has a proximal end 51 and a distal end 52 , wherein the outlet 54 is disposed at the distal end 52 .

[0076] The arrangement of the intermediate manifold passage 30 can be Figure 2 The arrangement of the mixer 2 shown is essentially the same. Figure 2 All features and embodiments described and illustrated for the mixer 2 shown can also be applied to Figure 3 The intermediate manifold passage 30 of the mixer 3 is shown. In broad terms, Figure 3 The mixer 3 shown is Figure 1 and Figure 2 The combination of features and functions of the mixers 1 , 2 is shown.

[0077] Similarly, Figure 1 The features and functions of the inlet manifold channel 10 and the outlet manifold channel 50 of the mixer 1 shown may also be applied to Figure 3 The inlet manifold channel 10 and the outlet manifold channel 50 of the mixer 3 are shown. Figure 3 In the case of the mixer 3 shown, the intermediate manifold channel 30 is used to further mix the fluid passing between the inlet manifold channel 10 and the outlet manifold channel 50. This provides a significant advantage over the arrangement shown in the previously described US8511889, as it allows the fluid passing down one of the primary transfer channels 20A to 20I to be fully or at least partially transferred to a different secondary transfer channel 21A to 21I before reaching the outlet manifold channel 50. This serves to promote mixing of the fluid passing through the mixer 3. In effect, the inlet manifold channel 10, the intermediate manifold channel 30 and the outlet manifold channel 50 together serve to promote distribution and uniform mixing of the fluid.

[0078] It will therefore be appreciated that providing more than one intermediate manifold passage 30 will further promote mixing of the fluids.

[0079] Figure 4 Another embodiment of the mixer 4 is shown. Generally speaking, the mixer 4 corresponds to Figure 3The mixer 3 shown in FIG. 1 is different from the mixer 3 shown in FIG. 1 , but has two (first and second) intermediate manifold passages 30, 40. A plurality of primary transfer passages 20A to 20I are fluidly connected between the inlet manifold passage 10 and the first intermediate manifold passage 30. A plurality of secondary transfer passages 21A to 21I are fluidly connected between the second intermediate manifold passage 40 and the outlet manifold passage 50. The mixer 4 also includes a plurality of tertiary transfer passages 22A to 22I, which are fluidly connected between the first intermediate manifold passage 30 and the second intermediate manifold passage 40.

[0080] The first intermediate manifold passage 30 may be substantially identical to the second intermediate manifold passage 40 .

[0081] The skilled person will well appreciate that a mixer embodying the invention may include more than two intermediate manifold channels 30, 40. No further explanation is required as these would merely be a repetition and extension of the functions and features already described.

[0082] refer to Figure 4 It should be noted that the fluid passes through three sets of transfer channels 20 , 22 , 21 between the inlet manifold channel 10 and the outlet manifold channel 50 via the two intermediate manifold channels 30 , 40 .

[0083] The fluid conveyed through the first primary transfer channel 20A will be delivered to the first intermediate manifold channel 30 near the entrance of the first tertiary transfer channel 22A. The fluid conveyed through the first tertiary transfer channel 22A will be delivered to the second intermediate manifold channel 40 near the entrance of the first secondary transfer channel 21A. The first tertiary transfer channel 22A is shorter than the first primary transfer channel 20A. The first secondary transfer channel 21A is longer than the first primary transfer channel 20A. The first tertiary transfer channel 22A can be the same length as the first secondary transfer channel 21A. Therefore, it should be understood that when the fluid passes through the transfer channels 20, 22, 21, it generally results in alternation between longer sections and shorter sections. This helps to promote mixing.

[0084] Another embodiment of the present invention provides a calibration device. The calibration device can be a microfluidic device 100, which includes a mixer 1-4 and a restrictor 110. Figure 5 Schematically shown in FIG. The mixer 1-4 is fluidly connected to the flow restrictor 110. The mixer may include any of the mixers 1-4 described and shown herein.

[0085] In at least one embodiment, flow restrictor 110 is located downstream of mixers 1-4. Figure 8 As shown, the flow restrictor 110 may include an elongated channel 111 configured to provide appropriate hydraulic resistance to build a desired back pressure. The elongated channel 111 may be labyrinthine or tortuous so that it may be disposed within a relatively compact rectangular area.

[0086] The microfluidic device 100 includes an inlet port 120 and an outlet port 130. The inlet port 120 is fluidly connected to the inlet 13 of the input manifold channel 10. The outlet port 130 is fluidly connected to the outlet of the restrictor 110. The ports 120, 130 may be provided with standard fluid fittings.

[0087] The microfluidic device 100 may include Figure 6 The multiple layers 101-104 shown, and in at least one embodiment, can be Figure 7 The device shown in the figure is provided in the form of a device shown in the figure. The mixer 1-4 can be provided in one of the layers 101-104, provided by one of the layers, or provided adjacent to one of the layers, and the flow restrictor 110 can be provided in another layer of the layers 101-104, provided by another layer of the layers, or provided adjacent to another layer of the layers. The interlayer 101-104 fluid connection can be formed by a through hole 105, which includes a through hole passing through the layers 101-104. The mixer 1-4 can be arranged in a plane that is roughly parallel to the plane in which the flow restrictor 110 is arranged. This can provide a microfluidic device 100 with a relatively compact and short form factor while providing a relatively longer fluid path internally. The length of the path taken by the fluid through the microfluidic device 100 can be an order of magnitude longer than the length of the microfluidic device 100.

[0088] In at least one embodiment, layers 101-104 are composed of titanium.Mixers 1-4, restrictors 110, and through-hole 105 features may be machined into the surfaces of layers 101-104. Microfluidic device 100 may be formed by diffusion bonding multiple layers 101-104.

[0089] The microfluidic device 100 is used to simulate the behavior of a chromatography column in use and can be used to characterize chromatography equipment.

[0090] When used in this specification and claims, the terms "comprises" and "comprising" and variations thereof mean that specified features, steps or integers are included. These terms should not be interpreted as excluding the presence of other features, steps or components.

[0091] The features disclosed in the foregoing description, the appended claims or the drawings are presented in their specific forms, or are embodied as devices for performing the functions of the present disclosure or, when appropriate, methods or processes for achieving the results of the present disclosure. These features may be independent or in any combination of these features, for realizing the present invention in various forms.

Claims

1. A mixer, comprising: intermediate manifold passage; a plurality of primary transfer passages fluidly connected to the intermediate manifold passage, each primary transfer passage configured to convey a fluid flow having a volume different than the volume of each other primary transfer passage; and a plurality of secondary transfer channels fluidly connected to the intermediate manifold channel, each secondary transfer channel having a volume different from a volume of each other secondary transfer channel, Wherein, the fluid connection of each primary transfer channel to the intermediate manifold channel is arranged opposite to the fluid connection of a corresponding one of each secondary transfer channel.

2. The mixer of claim 1, the mixer being configured such that fluid flow can be received from the plurality of primary transfer passages in the intermediate manifold passage and can be delivered from the intermediate manifold passage to the plurality of secondary transfer passages.

3. The mixer according to claim 1, wherein The respective fluid connections of the primary transfer passages are substantially equally distributed along the length of the intermediate manifold passage.

4. The mixer according to claim 1, wherein The respective fluid connections of the secondary transfer channels are substantially equally distributed along the length of the intermediate manifold channel.

5. The mixer according to claim 1, wherein The plurality of primary transfer channels are arranged in substantially the same plane.

6. The mixer according to claim 1, wherein The plurality of primary transfer channels and the plurality of secondary transfer channels are arranged in substantially the same plane.

7. The mixer according to claim 1, wherein The mixer is formed from a plurality of layers.

8. The mixer according to claim 7, wherein The layers are diffusion bonded.

9. The mixer according to claim 7, wherein: The layer comprises titanium.

10. The mixer of claim 1 further comprising an inlet manifold passage to receive an inlet flow, and wherein A primary transfer channel fluidly connects the inlet manifold channel with the intermediate manifold channel.

11. The mixer of claim 1 further comprising an outlet manifold channel, and wherein: A secondary transfer channel fluidly connects the intermediate manifold channel with the outlet manifold channel.

12. The mixer according to claim 11, wherein The outlet manifold channel includes an outlet, and the mixer further includes a flow restrictor fluidly coupled to the outlet of the outlet manifold channel.

13. A mixer comprising: inlet manifold passage; intermediate manifold passage; outlet manifold passage; a plurality of primary transfer passages, each primary transfer passage fluidly connected between the inlet manifold passage and the intermediate manifold passage, and each primary transfer passage having a volume different from a volume of each other primary transfer passage; and a plurality of secondary transfer channels, each secondary transfer channel being fluidly connected between the intermediate manifold channel and the outlet manifold channel, and each secondary transfer channel having a volume different from a volume of each other secondary transfer channel, Wherein, the fluid connection of each primary transfer channel to the intermediate manifold channel is arranged opposite to the fluid connection of a corresponding one of each secondary transfer channel to the intermediate manifold channel.

14. The mixer according to claim 13, wherein The plurality of primary transfer channels and the plurality of secondary transfer channels are arranged in the same plane.

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