Patent Description:
The invention relates generally to chromatography. More particularly, the invention relates to a mixer arrangement for use in chromatography systems for minimizing noise generated by an upstream pump.

Chromatography is a set of techniques for separating a mixture into its constituents. Well-established separation technologies for fluid chromatography systems include HPLC (High Performance Liquid Chromatography), UPLC (Ultra Performance Liquid Chromatography) and SFC (Supercritical Fluid Chromatography). HPLC systems use high pressure, ranging traditionally between <NUM>,<NUM> x <NUM><NUM> Pa (<NUM> psi) to approximately <NUM>,<NUM> x <NUM><NUM> Pa (<NUM> psi), to generate the flow required for liquid chromatography (LC) in packed columns. Compared to HPLC, UPLC systems use columns with smaller particulate matter and higher pressures approaching <NUM>,<NUM> x <NUM> <NUM> Pa (<NUM><NUM> psi) to deliver the mobile phase. SFC systems use highly compressible mobile phases, which typically employ carbon dioxide (CO<NUM>) as a principle component.

In many of these fluid chromatography applications, it is desirable to mix fluids that are flowing continuously. For example, in liquid chromatography, a pump is used to deliver precise compositions of solvents to a chromatographic column for the purpose of separating liquid mixtures. The flow composition delivered by the pump can vary in time, and it is desirable to blend or mix the stream as it flows for the purpose of smoothing out compositional discontinuities that can cause interference with sample detection. In most cases, liquid chromatography systems operate in a laminar flow regime, where turbulence is not available to aid in mixing, and mixers require creative designs to promote controlled dispersion. Various mixers exist which seek to achieve a desirable mixing of fluids in liquid chromatography systems. For example, large volume mixers exist that mix effectively, but do so with an increase in volume which must be flown-through by a fluid or solvent, thereby drastically increasing testing time and diminishing throughput. In contrast, packed-bead LC mixers are inefficient relative to their delay volume, are difficult to manufacture, and are prone to contamination and clogging.

Testing has shown that one of the dominant sources of compositional noise is due to the pump stroke. Since liquid chromatography pumps tend to be piston or syringe style positive displacement pumps, flow is delivered into the system in discrete strokes. Withing a given stroke, the volume of solvent is often fairly well-mixed, but there tends to be a discontinuity in composition between strokes, and under certain chromatographic conditions this results in noise introduced at the stroke frequency of the pump. This noise can decrease the precision of sample quantification and render some samples undetectable.

Thus, a mixer that eliminates or reduces the above described deficiencies would be well received in the art.

A prior art arrangement is known from <CIT> which relates to a fluid mixer. A second prior art arrangement is known from <CIT> which relates to a mixer.

The present invention provides a mixer arrangement, chromatography system and method of mixing fluid in a fluid chromatography system in accordance with the claims.

A mixer arrangement for use in a chromatography system comprises: a first frequency targeting mixer including a first flow channel coupled between an inlet and an outlet and a second flow channel coupled between the inlet and the outlet, the second flow channel including a volume offset region configured to delay fluid propagation through the second flow channel, wherein the volume offset region is configured to reduce or eliminate fluidic compositional oscillations in a compositional solvent stream that depart from a desired composition at a first target frequency; and a residual noise targeting mixer fluidically connected in series to the frequency targeting mixer, the residual noise targeting mixer configured to dampen aperiodic baseline noise in the compositional solvent stream, wherein the residual noise targeting mixer includes a mixing disk having an inlet face and an outlet face located between the plurality of flow channels, wherein the mixing disk includes a dispersive medium having a random porous structure.

Additionally or alternatively, the mixer arrangement further includes a second frequency targeting mixer including a first flow channel coupled between an inlet and an outlet and a second flow channel coupled between the inlet and the outlet, the second flow channel including a volume offset region configured to delay fluid propagation through the second flow channel, wherein the volume offset region is configured to reduce or eliminate fluidic compositional oscillations in the compositional solvent stream that depart from a desired composition at a second target frequency that is different than the first target frequency, and wherein the second frequency targeting mixer is fluidically connected in series to the first frequency targeting mixer.

Additionally or alternatively, the residual noise targeting mixer includes a dispersion structure having a plurality of flow channels creating flow direction anisotropy.

Additionally or alternatively, the residual noise targeting mixer is located in a downstream arrangement relative to the first frequency targeting mixer.

Additionally or alternatively, the first flow channel of the first frequency targeting mixer includes a first flow restrictor region having a hydraulic resistance substantially representing the hydraulic resistance of the first flow channel, and wherein the second flow channel includes a second flow restrictor region fluidically connected in series with the volume offset region, the second flow restrictor region having a hydraulic resistance substantially representing the hydraulic resistance of the second flow channel.

Additionally or alternatively, the volume of the residual noise targeting mixer is between <NUM> and <NUM> times the noise volume of the aperiodic baseline noise in the compositional solvent stream.

In another exemplary embodiment, a fluid chromatography system comprises: at least one solvent reservoir; at least one pump connected to the at least one solvent reservoir configured to pump a compositional solvent stream from the at least one solvent reservoir downstream; a mixer arrangement located downstream from the at least one pump, the mixer arrangement including: a first frequency targeting mixer including a first flow channel coupled between an inlet and an outlet and a second flow channel coupled between the inlet and the outlet, the second flow channel including a volume offset region configured to delay fluid propagation through the second flow channel, wherein the volume offset region is configured to reduce or eliminate fluidic compositional oscillations in a compositional solvent stream that depart from a desired composition at a first target frequency; and a residual noise targeting mixer fluidically connected in series to the frequency targeting mixer, the residual noise targeting mixer configured to dampen aperiodic baseline noise in the compositional solvent stream, wherein, the residual noise targeting mixer includes a mixing disk having an inlet face and an outlet face located between the plurality of flow channels, wherein the mixing disk includes a dispersive medium having a random porous structure; a sample injector downstream from the mixer arrangement configured to inject a sample into the outlet flow of the solvent; a chromatography column downstream from the sample injector configured to perform separation of the sample; and a detector downstream from the chromatography column.

Additionally or alternatively, the first target frequency is a high frequency noise related to a full stroke volume of the at least one pump.

Additionally or alternatively, the volume offset region of the first frequency targeting mixer is approximately one quarter of the full stroke volume of the at least one pump.

Additionally or alternatively, the mixer arrangement further comprises: a second frequency targeting mixer including a first flow channel coupled between an inlet and an outlet and a second flow channel coupled between the inlet and the outlet, the second flow channel including a volume offset region configured to delay fluid propagation through the second flow channel, wherein the volume offset region is configured to reduce or eliminate fluidic compositional oscillations in the compositional solvent stream that depart from a desired composition at a second target frequency that is different than the first target frequency, and wherein the second frequency targeting mixer is fluidically connected in series to the first frequency targeting mixer.

Additionally or alternatively, the second frequency targeting mixer is fluidically connected downstream from the first frequency targeting mixer and upstream from the residual noise targeting mixer, and wherein the second target frequency is a low frequency residual noise that remains after the first frequency targeting mixer reduces or eliminates fluidic compositional oscillations.

Additionally or alternatively, the residual noise targeting mixer is configured to dampen aperiodic baseline noise in the compositional solvent stream by at least one of: smoothing residual noise related to the high frequency noise corresponding to the full stroke volume of the at least one pump; and further dampening the amplitude of the low frequency residual noise.

Additionally or alternatively, the residual noise targeting mixer is located downstream from the first frequency targeting mixer.

Additionally or alternatively, the volume of the residual noise targeting mixer is between <NUM> and <NUM> times the full stroke volume of the at least one pump.

A method of mixing fluid in a fluid chromatography system comprises: providing a compositional solvent stream, by at least one fluidic pump, to a mixer arrangement comprising: a first frequency targeting mixer including a first flow channel coupled between an inlet and an outlet and a second flow channel coupled between the inlet and the outlet, the second flow channel including a volume offset region configured to delay fluid propagation through the second flow channel, wherein the volume offset region is configured to reduce or eliminate fluidic compositional oscillations in a compositional solvent stream that depart from a desired composition at a first target frequency; and a residual noise targeting mixer fluidically connected in series to the frequency targeting mixer, the residual noise targeting mixer configured to dampen aperiodic baseline noise in the compositional solvent stream, wherein the residual noise targeting mixer includes a mixing disk having an inlet face and an outlet face located between the plurality of flow channels, wherein the mixing disk includes a dispersive medium having a random porous structure; receiving, by the first frequency targeting mixer, the compositional solvent stream; reducing or eliminating, by the first frequency targeting mixer, fluidic compositional oscillations in a compositional solvent stream that depart from a desired composition at a first target frequency; receiving the fluid by the residual noise targeting mixer fluidically connected in series to the frequency targeting mixer; and dampening, by the residual noise targeting mixer, aperiodic residual baseline noise in the compositional solvent stream.

Additionally or alternatively, the mixer arrangement further includes a second frequency targeting mixer fluidically connected in series to the first frequency targeting mixer, and the method further comprises: receiving, by the second frequency targeting mixer, the compositional solvent stream; and reducing or eliminating, by the second frequency targeting mixer, fluidic compositional oscillations in the compositional solvent stream that depart from a desired composition at a second target frequency that is different than the first target frequency.

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

In brief overview, the invention relates to a mixer arrangement for use in chromatography systems that minimizes noise generated upstream. The mixer arrangement includes at least two separate components - one or more frequency targeting mixers coupled in series with one or more passive residual noise targeting mixers.

The mixer arrangements consistent with the present invention may further be configured to cancel and/or otherwise reduce fluidic oscillations in composition that depart from a desired composition by one or more frequencies. For example, in cases described herein, one or more pumps (e.g. a single quaternary pump or two binary pumps) located upstream from the mixer arrangements embodied by the present invention may be configured to pump fluid downstream to the mixer. However, prior to mixing by the mixer arrangements embodied by the present invention, the composition expelled by the pump is not sufficiently mixed. Depending on the pump, the composition downstream from the pump oscillate from a desired composition, referred to in the art as "compositional ripple. " Such unwanted compositional variance may occur at frequencies dependent on the upstream pump system being used, and may become known to a chromatography system designer such that the mixer arrangements embodied by the present invention may be particularly configured to cancel or reduce one or more the frequencies in composition ripple or variance in accordance with embodiments described herein below.

Mixers described herein may be configured to reduce or cancel this unwanted compositional ripple whether the pump is set to pump a constant amount of solvent, or alternatively set to deliver a gradient. In either situation, there is a desired composition at a given point in time. Any departure from that desired composition, in the form of a compositional oscillation at a given frequency, is unwanted and may be prevented by the mixers described herein.

The mixer arrangements embodied by the present invention are also configured to reduce low frequency noise generated by a quaternary pump and/or two binary pumps in a liquid chromatography system. This problem may be particularly detrimental in reverse phase HPLC gradient with acetonitrile / water mobile phase mixtures containing <NUM>% trifluoroacetic acid. Such a mobile phase causes a significant loss in signal-to-noise ratio, decrease in number of peaks detected, and incomplete identification of compounds present in complex sample mixtures identification. Thus, the mixer arrangements embodied by the present invention are configured to prevent these problems by reducing loss in signal-to-noise ratio, increase the number of peaks detected, and increase identification of compounds present in complex sample mixtures identification.

Thus, embodiments of the present invention are configured to reduce the overall amplitude of quasi-periodic, low frequency, baseline signal noise by coupling in series one or more split-flow mixers for interference destruction of the periodic noise with a residual noise reducing mixer, such as a disk shaped mixer, for dampening noise amplitude after the destructive interference.

<FIG> depicts a block diagram of an embodiment of a liquid chromatography system <NUM> having a mixer arrangement <NUM>, in accordance with one embodiment. The liquid chromatography system <NUM> can be an HPLC, UPLC, or the like. The liquid chromatography system <NUM> includes a solvent delivery system that includes a plurality of solvent reservoirs 18A, 18B, 18C, 18D. The solvent reservoirs are connected to a gradient proportioning valve <NUM> which provides the combined solvents to a quaternary pump <NUM>. The quaternary pump <NUM> draw solvents through a fluidic conduit, which may be a fluidic conduit, line, tube or channel.

While not shown, other embodiments of the liquid chromatography system <NUM> contemplated may be a binary pump system having two binary pumps (i.e. using a binary solvent manager BSM system). Thus, the present invention may be included in a BSM system including two high pressure mixing pumps in which frequencies due to the pump cycle cause flow perturbations. In such instances, the frequencies of unwanted compositional fluctuations may be fixed in these BSM systems. Hereinafter, while the quaternary pump <NUM> is shown, it should be understood that the mixers described herein, and concepts described herein, are applicable to BSM systems as well as quaternary solvent manager (QSM) systems.

The quaternary pump <NUM> may have a single pair of pump heads and alter the composition via a switching valve upstream of the pump <NUM>. The quaternary pump <NUM> may be configured to deliver up to four different solvents (as shown, solvents from reservoirs 18A, 18B, 18C, 18D) with the switching valve. Compositional ripple as described herein occurs because only one solvent is delivered at a time to the quaternary pump <NUM> by the gradient proportioning valve <NUM>. The valve <NUM> alternates between the solvents rapidly to achieve the commanded composition. However, the solvents may not fully blend in the pump heads. Additionally, during a gradient where the set composition is changing over time, each pump stroke has a different composition. Thus, the quaternary pump <NUM> in this case creates an undesirable staircase-shaped delivered composition curve that needs additional mixing for proper detection downstream.

Downstream from the quaternary pump <NUM> is the mixer arrangement <NUM>. The mixer arrangement <NUM> may be configured to passively mix the pumped fluid in accordance to the embodiments described herein. While the specific features of mixer arrangement <NUM> is shown in <FIG> and described herein below, the liquid chromatography system <NUM> can include any mixer consistent with the mixer arrangement embodiments described herein.

Downstream from the mixer arrangement <NUM> is shown an injector <NUM>. The injector <NUM> may be included as a feature of a sample manager or other assembly or sub-system configured to inject a sample into the flow of fluid coming from the mixer arrangement <NUM>. The injector <NUM> may include an injector valve with a sample loop. The sample manager may control the injection of the sample and may operate in one of two states: a load state and an injection state. In the load state, the position of the injector valve of the injector <NUM> is such that the solvent manager loads the sample into the sample loop; in the injection state, the position of the injector valve of the injector <NUM> changes so that solvent manager introduces the sample in the sample loop into the continuously flowing mobile phase arriving from the mixer arrangement <NUM>.

With the injector valve of the injector <NUM> in the injection state, the mobile phase carries the sample into a column <NUM>. The chromatography column <NUM> is in fluidic communication with the injector <NUM> through, for example, a fluidic tube. The chromatography column <NUM> may be configured to perform sample separation according to techniques known in the art. Another fluidic tube couples the output port of the column <NUM> to a detector <NUM>, for example, a mass spectrometer, a UV detector, or any other detector. Through the fluidic tube, the detector <NUM> may be configured to receive the separated components of the sample from the column <NUM> and produce an output from which the identity and quantity of analytes of the sample may be determined. Noise in the absorbance of the separated components over time may be reduced by the mixers described herein.

The liquid chromatography system <NUM> is shown for exemplary purposes, and the various features shown may be modified, changed or replaced with any features of any known liquid chromatography system without departing from the scope of the invention. For Furthermore, while the invention is shown by way of example with a liquid chromatography system, mixers described herein may be deployed with any fluidic system, including supercritical fluid chromatography (SFC) systems or even non-chromatography applications.

In one exemplary embodiment of the liquid chromatography system <NUM> shown above, two solvents are delivered from each of solvent reservoirs 18A and 18B. The other solvent reservoirs 18C and 18D may not be used in this embodiment. The solvent from reservoir 18A may be water with <NUM>% trifluoroacetic acid (TFA). The solvent from reservoir 18B may be acetonitrile (ACN) with <NUM>% TFA. In such an embodiment, more TFA sticks to the column when solvent from reservoir 18A passes through, less sticks when solvent from reservoir 18B passes through. In this manner, oscillations in the composition will cause the amount of TFA leaving the column to oscillate. The TFA in the compositions absorbs light at the wavelength the detector <NUM> is observing. Thus, the mixer arrangement <NUM> is configured to prevent noise waves seen in the baseline of the chromatogram that would otherwise be present if unwanted oscillations in the composition, or "compositional ripple" was present. Such oscillations would interfere with the quantification of the size of sample peaks and thereby are desirable to prevent by the mixer arrangement <NUM> in accordance with embodiments described herein.

<FIG> depicts a schematic diagram of an embodiment of the mixer arrangement <NUM> of the liquid chromatography system <NUM> of <FIG>, in accordance with one embodiment. <FIG> depicts a photograph of the embodiment of the mixer arrangement <NUM> of <FIG>, in accordance with one embodiment. Referring to both <FIG> and <FIG>, the mixer arrangement <NUM> includes a first frequency targeting mixer <NUM> and a second frequency targeting mixer <NUM> that is coupled in series to the first frequency targeting mixer <NUM>. A residual noise targeting mixer <NUM> is connected in series to the second frequency targeting mixer <NUM>. When incorporated into the liquid chromatography system <NUM>, the first frequency targeting mixer <NUM> is located at the upstream end closest to the pump <NUM>, while the residual noise targeting mixer <NUM> is located at the downstream end closest to the injector <NUM> and/or column <NUM>. However, the invention is not limited to an arrangement whereby the residual noise targeting mixer is located downstream from one or more frequency targeting mixers. In other embodiments, one or more noise targeting mixer may be located upstream from the frequency targeting mixers in the mixer arrangement. However, it has been found that placing the residual noise targeting mixer <NUM> downstream from the one or more frequency targeting mixers <NUM>, <NUM> provides for better mixing and less compositional variation than only placing the residual noise targeting mixer <NUM> upstream relative the one or more frequency targeting mixers <NUM>, <NUM>.

While the embodiment shown in <FIG> and <FIG> show two frequency targeting mixers and a single noise targeting mixer <NUM>, the invention is not limited in this respect. Embodiments contemplated may include any combination of one or more frequency targeting mixers coupled in series to one or more residual noise targeting mixers. For example, a single frequency targeting mixer may be coupled to a single residual noise targeting mixer. By way of another example, a second residual noise targeting mixer may be coupled in series downstream from the noise targeting mixer <NUM> in the embodiment shown. While other embodiments are contemplated, the embodiment shown in <FIG> has been found to particularly reduce most of the compositional noise generated by fluctuations caused by an upstream pump in liquid chromatography systems.

The first frequency targeting mixer <NUM> is shown including a first flow channel <NUM> coupled between an inlet <NUM> and an outlet <NUM>. The frequency targeting mixer <NUM> includes a second flow channel <NUM> that is also coupled between the inlet <NUM> and the outlet <NUM>. The first frequency targeting mixer <NUM> may thus be a split flow mixer whereby fluid introduced to the inlet is split into one or more parallel paths. In the embodiment shown, the frequency targeting mixer <NUM> is a split flow mixer having two parallel paths. Such a two-path split flow mixer has been found to target compositional noise oscillations of a specific frequency related to the volume offset between the two paths.

The first flow channel <NUM> is shown including a first flow restrictor region <NUM>, while the second flow channel <NUM> is shown including a volume offset region <NUM> located upstream from a second flow restrictor region <NUM>. The volume offset region <NUM> may be configured to delay fluid propagation through the second flow channel <NUM>. The volume offset region <NUM> may create a volume disparity between the first flow channel <NUM> and the second flow channel <NUM> which results in the reduction or elimination of fluidic compositional oscillations of a solvent stream that depart from a desired composition at a first target frequency. In the embodiment shown, the first target frequency may be a high frequency noise that corresponds to a full stroke volume of the pump <NUM>. For example, the pump <NUM> may include a stroke volume <NUM> uL. In such an embodiment, the volume offset region <NUM> may include a total volume of about <NUM> uL, which corresponds to ¼ of the full stroke volume of the pump <NUM>. This ratio has been determined to be particularly advantageous in creating the destructive interference with the two flow paths <NUM>, <NUM> to dampen noise occurring that oscillates according to the specific frequency associated with the <NUM> uL stroke volume of the pump <NUM>.

Specifically, the present invention defines "frequency targeting" as specifically dampening a compositional oscillation occurring at a specific frequency that corresponds to a specific volume of fluid moving through the system. One method of "frequency targeting" includes calculating the volume difference between the two flow paths in a split flow mixer and making that volume difference equate to ¼ of the oscillatory volume that the mixer is looking to dampen. For example, if the oscillations correspond to a roughly <NUM> uL stroke volume, frequency targeting may include creating a split flow mixer whereby the first path is approximately <NUM> uL (<NUM> uL divided by <NUM>) larger than the second path. Since the volume offset region may comprise the vast majority of a flow path, this amount of approximately <NUM> uL would be the approximate volume of the volume offset region to target such an oscillation. Other techniques may be found "frequency targeting" that may include other forms of split flow mixers or other types of mixers. However, whatever the embodiment, a "frequency targeting" mixer, as described herein, is configured to dampen compositional oscillation occurring at a specific frequency that corresponds to a specific volume of fluid moving through the mixer. While the embodiment above corresponds to a specific pump having a full stroke volume of <NUM> uL, for other pump volumes, other volume offset region volumes are contemplated.

The second frequency targeting mixer <NUM> may be similar to the first frequency targeting mixer <NUM>. However, the second frequency targeting mixer may include a different volume difference between the two parallel paths. As shown, the second frequency targeting mixer <NUM> includes a first flow channel <NUM> coupled between an inlet <NUM> and an outlet <NUM>. The frequency targeting mixer <NUM> includes a second flow channel <NUM> that is also coupled between the inlet <NUM> and the outlet <NUM>.

Like the first frequency targeting mixer <NUM>, the first flow channel <NUM> of the second frequency targeting mixer <NUM> is shown including a first flow restrictor region <NUM>, while the second flow channel <NUM> is shown including a volume offset region <NUM> located upstream from a second flow restrictor region <NUM>. The volume offset region <NUM> may be configured to delay fluid propagation through the second flow channel <NUM> with a different volume than the volume offset region <NUM> of the first frequency targeting mixer <NUM>. The volume offset region <NUM> may create a volume disparity between the first flow channel <NUM> and the second flow channel <NUM> which results in the reduction or elimination of fluidic compositional oscillations of a solvent stream that depart from a desired composition at a second target frequency that is different than the first target frequency of the first frequency targeting mixer <NUM>.

In the embodiment shown, the second target frequency may be a frequency that corresponds to a low frequency noise of the pump <NUM>. Using the above example of the pump <NUM> that includes a stroke volume <NUM> uL, a resulting low frequency noise may also be included in the flow stream after the first stage of frequency targeting. Specifically, such a noise may correspond to an oscillatory frequency that corresponds to a larger volume of approximately <NUM> uL. In such an embodiment, the volume offset region <NUM> may include a total volume of about <NUM> uL, which corresponds to ¼ of this low frequency noise volume of approximately <NUM> uL.

The residual noise targeting mixer <NUM> is shown having an inlet port <NUM>, a mixing disk <NUM>, and an outlet port <NUM>. The residual noise targeting mixer <NUM> may be configured to dampen aperiodic baseline noise in the compositional solvent stream. For example, the residual noise targeting mixer <NUM> may be configured to smooth residual noise from the high frequency noise related to the full stroke volume of the pump <NUM> that may remain even downstream from the first frequency targeting mixer <NUM>. Additionally or alternatively, the residual noise targeting mixer <NUM> may be configured to further dampen the amplitude of the low frequency noise residual that may remain even downstream from the second frequency targeting mixer <NUM>. The frequency targeting mixer may be a disk mixer that includes a mixing disk having an inlet face and an outlet face locat4ed between a plurality of flow channels. The mixing disk may include, for example, a dispersive medium having a random porous structure. The total volume of the residual noise targeting mixer <NUM> may be between <NUM> and <NUM> times the noise volume of the baseline noise in the compositional solvent stream prior to the mixing arrangement <NUM> (i.e. the full stroke volume of the pump). For example, in one embodiment, the residual noise targeting mixer <NUM> may include a volume of <NUM> uL, which is less than <NUM> times the stroke volume of <NUM> uL.

<FIG> depicts a picture of the embodiment of the mixer arrangement <NUM> of <FIG>, in accordance with one embodiment. As shown, the inlets <NUM>, <NUM> and outlets <NUM>, <NUM> of the two split flow mixers <NUM>, <NUM> are tee union connectors or fittings configured to split the flow into two paths at the inlet, and return the flow to one path at the outlet. The flow restrictor capillaries may be, for example, <NUM> - <NUM> inner diameter channels of <NUM> in length. The volume offset regions <NUM>, <NUM> include long tubular columns having the specified volumes described above. Further, included in this figure along the second flow channels <NUM>, <NUM> of each of the first and second frequency targeting mixers <NUM>, <NUM> includes respective short columns <NUM>, <NUM>. The short columns <NUM>, <NUM> may each be <NUM> inner diameter columns, and may be <NUM> in length. The short columns <NUM>, <NUM> may each be packed with inert non-porous particle beads of <NUM> in size.

<FIG> depicts a schematic diagram of an embodiment of the first frequency targeting mixer <NUM> of the mixer arrangement of the liquid chromatography system of <FIG>, in accordance with one embodiment having a mobile phase entering at a first phase and frequency 25a. The mobile phase is shown after the flow restrictor <NUM> as having flow of mobile phase with a second phase and frequency 26a, which has the same frequency in a different phase as the phase and frequency 25a. The mobile phase is shown after emerging from the volume offset region <NUM> and the flow restrictor <NUM> of the second flow channel <NUM> with a third phase and frequency 27a. The third phase and frequency 27a includes a phase shift that causes destructive interference when the mobile phase from the second flow channel <NUM>. A mobile phase with reduced compositional and noise emerges having an emerging phase and frequency 28a. The <FIG> depicts a graphical representation of compositional noise over time having a first regular frequency at the <NUM> uL stroke volume of the pump <NUM>, in accordance with one embodiment. While not shown, it should be understood that this graph plots absorptive units over time of the mobile phase after emerging from the pump <NUM> but prior to entering the first frequency targeting mixer <NUM> at the first stage of the mixer arrangement <NUM>. <FIG> depicts a graphical representation of compositional noise over time after the mobile phase flows through the first frequency targeting mixer <NUM>, again plotted as absorptive units over time, in accordance with one embodiment. As shown, the compositional noise of the graphical representation of <FIG> shows far less noise. Further, the noise corresponding to the <NUM> uL volume level frequency has been eliminated. A <NUM> uL low frequency volume level noise remains.

<FIG> depicts a schematic diagram of an embodiment of the second frequency targeting mixer <NUM> of the mixer arrangement of the liquid chromatography system of <FIG>, in accordance with one embodiment having a mobile phase entering at a first phase and frequency 25b. The mobile phase is shown after the flow restrictor <NUM> as having flow of mobile phase with a second phase and frequency 26b, which has the same frequency in a different phase as the phase and frequency 25b. The mobile phase is shown after emerging from the volume offset region <NUM> and the flow restrictor <NUM> of the second flow channel <NUM> with a third phase and frequency 27b. The third phase and frequency 27b includes a phase shift that causes destructive interference when the mobile phase from the second flow channel <NUM>. A mobile phase with reduced compositional and noise emerges having an emerging phase and frequency 28b. The <FIG> depicts a graphical representation of compositional noise over time having a low frequency noise occurring at approximately <NUM> uL of volume of the mobile phase. While not shown, it should be understood that this graph plots absorptive units over time of the mobile phase after emerging from the first frequency targeting mixer <NUM> but prior to entering the second frequency targeting mixer <NUM> at the second stage of the mixer arrangement <NUM>. <FIG> depicts a graphical representation of compositional noise over time after the mobile phase flows through the second frequency targeting mixer <NUM>, again plotted as absorptive units over time, in accordance with one embodiment. As shown, the second frequency targeting mixer <NUM> reduces the compositional noise significantly so that only an aperiodic residual noise.

<FIG> depicts a schematic diagram of the residual noise targeting mixer <NUM> of the mixer arrangement of the liquid chromatography system of <FIG>. As shown the residual noise targeting mixer <NUM> receives the mobile phase from the first and second frequency targeting mixers <NUM>, <NUM> whereby the mobile phase includes aperiodic noise 25c. The aperiodic noise is minimized with the emerging flow of mobile phase 28c. <FIG> depicts the graphical representation of compositional noise over time after the composition flows through the first and second frequency targeting mixers <NUM>, <NUM> but prior to the residual noise targeting mixer <NUM>. <FIG> depicts a graphical representation of compositional noise over time after the composition flows through the residual noise targeting mixer <NUM>. As shown, the residual noise targeting mixer <NUM> is configured to significantly dampen, reduce and/or eliminate the aperiodic noise that remains after the two frequency targeting stages in the mixer arrangement <NUM>.

<FIG> depicts a schematic diagram of a frequency targeting mixer <NUM>, in accordance with one embodiment. The frequency targeting mixer <NUM> may be representative of either the first frequency targeting mixer <NUM> or the second frequency targeting mixer <NUM> described herein above. The frequency targeting mixer <NUM> is shown as a split flow mixer that that splits the flow of fluid in order to provide for mixing. Embodiments described herein of the frequency targeting mixer <NUM> include one or more of the following desirable traits of a liquid chromatography mixer: ability to operate passively; ease of manufacture, consistent performance, and efficient mixing of a continuous flow stream with respect to pressure drop and delay volume. The frequency targeting mixer <NUM> described herein is configured to mix longitudinally, i.e. along the flow direction, and may provide for a smaller decay volume than an equivalent packed-bead mixer.

Moreover, the frequency targeting mixer <NUM> may be configured for any setting where a continuous flow of fluid needs to be mixed. Particular embodiments described herein are geared toward fluid chromatography applications, and more particularly to liquid chromatography systems (i.e. HPLC and/or UPLC). However, embodiments may also be applicable to supercritical fluid systems (SFC). Any system in which fluid mixing is required may be applicable to the mixer embodiments described herein.

The frequency targeting mixer <NUM> is configured to receive a fluid flow that enters an inlet and is split into two or more fluidic paths. One of those paths may include a volume offset region configured to delay fluid propagation through the second flow channel relative to the first flow channel. Connected in series downstream from such a volume offset region may be a flow restrictor region having a hydraulic resistance substantially representing a hydraulic resistance of the second flow channel. One or more other paths may include only a flow restrictor region. This split flow may produce the desired mixing and noise reduction / cancellation in compositional ripple.

As shown in <FIG>, a plurality of these split-flow arrangements (i.e. stages) may be combined in series. A plurality of such stages has been found to sufficiently cancel (i.e. significantly reduce) specific frequencies of fluidic oscillation. Depending on the specific design of the volume offset regions and flow restriction regions, each series-connected stage of contemplated multi-stage mixers described herein may be particularly designed to reduce or cancel these unwanted oscillations in composition at a specific frequency. In combination, a plurality of these series-connected stages may be configured to significantly cancel most or all of the unwanted compositional ripple or oscillation in the composition of fluid coming from the pump.

Referring still to <FIG>, the frequency targeting mixer <NUM> may be a passive mixer, in that it does not require any power or controlling. Putting the frequency targeting mixer <NUM> in line within a chromatography system such as the chromatography system <NUM> allows the frequency targeting mixer <NUM> to function as intended to mix a continuous flow stream entering the frequency targeting mixer <NUM> efficiently with respect to both pressure drop and delay volume.

As shown, the frequency targeting mixer <NUM> includes an inlet tube <NUM>, which may be located downstream from a pump system, such as the pump <NUM>. The inlet tube <NUM> may or may not be considered a component of the frequency targeting mixer <NUM> and may alternatively or additionally be considered a component of the liquid chromatography system <NUM>. The inlet tube <NUM> is connected to an inlet <NUM> configured to receive an inlet flow of fluid from the inlet tube <NUM>. The inlet <NUM> is configured to split the flow through the inlet tube <NUM> into multiple paths and then recombine the flow upstream at an outlet <NUM>. Each path includes either one section, such as a flow restrictor region, or two sections, such as an upstream volume offset region and a downstream flow restrictor region.

As shown, the inlet <NUM> is configured to distribute the inlet flow of fluid to each of a first flow channel <NUM> and a second flow channel <NUM>. The first and second flow channels <NUM>, <NUM> may be considered channels connected in parallel between the inlet <NUM> and an outlet <NUM>. The outlet <NUM> is configured to provide outlet flow of fluid to an outlet tube <NUM>. Like the inlet tube <NUM>, the outlet tube <NUM> may or may not be considered a component of the frequency targeting mixer <NUM> and may alternatively or additionally be considered a component of a liquid chromatography system <NUM>.

The first flow channel <NUM> may comprise a flow restrictor region having a hydraulic resistance substantially representing a hydraulic resistance of the first flow channel <NUM>. In one embodiment, the first flow channel <NUM> only includes a flow restrictor component extending between the inlet <NUM> and the outlet <NUM>. The flow restrictor region of the first flow channel <NUM> may include a relatively small volume and a relatively high hydraulic resistance compared to a volume offset region <NUM> of the second flow channel <NUM>. In addition to a low volume flow restrictor tube, the flow restrictor first channel <NUM> and the flow restrictor region <NUM> of the second channel <NUM> may include or alternatively be a check valve, a spring loaded check valve, a back pressure regulator, a spring loaded back pressure regulator, a venturi type capillary, or any other fluidic mechanism for giving a fixed pressure drop across the flow path.

The second flow channel <NUM> may comprise a volume offset region <NUM> located upstream and connected in series to a flow restrictor region <NUM>. The volume offset region <NUM> makes up or otherwise contributes a majority of the volume of the second flow channel <NUM> path. The volume offset region <NUM> is configured to contribute relatively little hydraulic resistance to the second flow channel <NUM>. In contrast, the flow restrictor region <NUM> contributes a majority of the hydraulic resistance to the second flow channel <NUM> but has a relatively small volume compared to the volume offset region <NUM>.

The high volume of the volume offset region <NUM> may be configured to delay fluid propagation through the second flow channel <NUM> relative to the first flow channel <NUM>. The high hydraulic resistance section of each of the first and second flow channels <NUM> is configured to control the flow rate through the paths. By controlling the flow rate and the delay volume on each of the paths (i.e. the first and second flow channels <NUM>, <NUM>), the incoming flow to the inlet <NUM> through the inlet tube <NUM> can be split and recombined with a volumetric offset that cancels out oscillations in composition at a specific oscillation frequency or frequencies.

Rather than being a simple greater-volume tube, the volume offset region <NUM> may alternatively be a diffusion bonded block having an internal chamber, or the like. Further, the volume offset region <NUM> may apply principles of a split mixer, a chamber mixer, a bead mixer, or a cross flow mixer (i.e. a mixer in which half the flow goes perpendicular left, and the other half goes through a three-quarter turn through a circular passage). The volume offset region <NUM> may take any form that contributes a delay in fluid propagation through the channel relative another channel.

In the embodiment shown, the hydraulic resistance of the flow restrictor first path <NUM> may be the same as the hydraulic resistance of the flow resistor region <NUM> of the second flow channel <NUM>. In other words, the first and second flow channels <NUM>, <NUM> may each include substantially the same flow restriction (i.e. restriction balance) in order to ensure that the flow is split evenly at the inlet <NUM>. In such an embodiment, the flow configured to split the flow equally between each of the first and second flow channels <NUM>, <NUM> at the inlet <NUM>. The invention is not limited in this respect, and one or more of the principles described herein may be applicable to split flow mixers where the flow distribution across the various channels is unequally split via varying the flow restriction across each of a plurality of channels in a purposefully uneven or unequal manner to change the flow through each channel in any desired manner. Thus, the restrictions through the flow channels may be un-equal in order to distribute flow unevenly.

In some embodiments, both paths may include a volume offset region located upstream and connected in series to a flow restrictor region. While the embodiment shown includes two paths, other embodiments may include three or more paths where some or all of the paths include a volume offset region located upstream and connected in series to a flow restrictor region. In embodiments having three or more paths, the volume offset regions may each be configured to cancel out oscillations from a desired composition at a different specific oscillation frequency.

In one embodiment, the volume offset region <NUM> is a <NUM> uL (microliter) volume offset and may be configured specifically to cancel oscillations in composition occurring at a frequency of about <NUM> uL (i.e. four times the volume of the volume offset region <NUM>). Any amount of volume offset is contemplated, however. In the case of using a volume offset tube as shown, the volume offset can be increased by lengthening the length of tube used, or by using a larger inner diameter tube. Other examples of appropriate volume offset volumes may be <NUM> uL, <NUM> uL, <NUM> uL, <NUM> uL. In the embodiment shown in <FIG>, the volume offset region of the first frequency targeting mixer <NUM> may be <NUM> uL and the volume offset region of the second frequency targeting mixer <NUM> may be <NUM> uL. The amount of volume offset may be determined by the oscillation frequency relative to a desired composition that is naturally output by a pump system (e.g. a BSM or QSM system) used upstream from the mixer <NUM>. The volume offset region <NUM> may be connected to the flow restrictor region <NUM> in series via a two-way fitting or fluidic connector.

Both the first and second flow channels <NUM>, <NUM> may be connected to the outlet <NUM>, which may be a block having two inlet fittings and an outlet. Thus, the first and second flow channels <NUM>, <NUM> may be connected in parallel to each other between the inlet <NUM> and the outlet <NUM>. An inlet block having more than two outlet fittings, and an outlet block having more than two inlet fittings is contemplated in the case that more flow channels are desired in the mixer.

<FIG> depicts a schematic diagram of an embodiment of another mixer <NUM> for use in a liquid chromatography system such as the liquid chromatography system <NUM>, in accordance with one embodiment. Rather than splitting the flow evenly between two paths, the mixer <NUM> is configured with six separate flow channels <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. The top flow channel <NUM> includes only a flow restrictor region without any volume offset region. However, each of the other flow channels <NUM>, <NUM>, <NUM>, <NUM>, <NUM> includes its own respective volume offset region <NUM>, <NUM>, <NUM>, <NUM>, <NUM>. The different volume offset regions <NUM>, <NUM>, <NUM>, <NUM>, <NUM> are shown having different volume offsets. In particular, the volume offset region <NUM> of the flow channel <NUM> includes the smallest volume offset. The volume offset region <NUM> of the flow channel <NUM> includes the second smallest volume offset. The volume offset region <NUM> of the flow channel <NUM> includes the third smallest volume offset. The volume offset region <NUM> of the flow channel <NUM> includes the second largest volume offset. The volume offset region <NUM> of the flow channel <NUM> includes the largest volume offset. Staggering the volume offsets in this manner may result in a single stage mixer configured to mix a composition in a manner that cancels unwanted compositional ripples. While the mixer <NUM> is shown with a flow channel having only a restrictor and no volume offset region, other embodiments contemplated include each flow channel having an upstream volume offset region followed by a downstream flow restrictor region. Further, while the mixer <NUM> displays that mixers having several parallel channels are contemplated, more or less channels than the embodiment shown may be desirable for various applications and are also contemplated. Moreover, the mixer <NUM> may include even flow restriction through each of the various flow channels <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> so that the flow remains evenly or equally distributed between the channels. In other embodiments, the mixer <NUM> may include different flow restrictions (i.e. unequal flow restrictions) through each of the various channels <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> in order to distribute flow in an uneven manner.

<FIG> depicts a schematic diagram of a residual noise targeting mixer <NUM> of the mixer arrangement <NUM> of the liquid chromatography system <NUM> of <FIG>. In brief overview, the residual noise targeting mixer may include a disk-shaped mixing element. The residual noise targeting mixer improves the accuracy and precision of a time-programmed composition of a mobile phase delivered by reciprocating pumps in a liquid chromatography system. The residual noise targeting mixer includes a flow distributor, a mixing disk and a flow collector. The mixing disk has an inlet face, an outlet face and a plurality of channels each having an inlet end at the inlet face and an outlet end at the outlet face. The channels have a flow direction anisotropy between the inlet and outlet faces. A compositional solvent stream is distributed across an inlet face of the mixing disk by the flow distributor and is collected after exiting at the outlet face after passing through the mixing disk such that the output of the mixer is a mixed compositional solvent stream.

The residual noise targeting mixer <NUM> includes a flow distributor <NUM>, a mixing disk <NUM> and a flow collector <NUM>. The flow distributor has a distributor inlet port <NUM> and a distributor outlet port <NUM> having an outlet cross-section. The flow distributor <NUM> distributes the composition solvent stream received at the distributor inlet port <NUM> substantially evenly across the outlet cross-section at the distributor outlet port <NUM>.

The mixing disk <NUM> has an inlet face <NUM>, an outlet face <NUM> and channels that have inlet ends at the inlet face <NUM> and outlet ends at the outlet face <NUM>. In some embodiments, the mixing disk <NUM> is a circular disk; however, alternative embodiments may include disks having other shapes such as a rectangular edge or other non-circular outer edge. The inlet face <NUM> is in communication with the distributor outlet port <NUM>. The channels have a flow direction anisotropy between the inlet face <NUM> and outlet face <NUM>. For example, the flow path length defined between the inlet and outlet ends of each channel may generally be different and vary across a range of flow path lengths as described in more detail below. Each channel generally does not have a direct path between the inlet face <NUM> and outlet face <NUM> but instead is defined by changes in direction such that channel direction varies along its length. For example, each path may have one or more upward, downward and/or sideways excursions (i.e., radial excursions) such that the path is substantially nonlinear. In some embodiments, channels may allow the liquid to flow backwards along portions of a flow path although in such embodiments the pressure resistance may be significant. The channel direction at a portion along its length includes a longitudinal component (defined along a "thickness axis" that is perpendicular to the disk faces) and a radial component (defined in a plane orthogonal to the thickness axis). Thus, the width of an individual solvent component of a solvent packet is broadened in its passage through the mixing disk <NUM> as the packet is distributed into different channels having different flow path lengths through the disk material and the stacked packets of solvents generated by the gradient proportional valve can be mixed effectively in the mixing disk volume. The solvent component is thereby mixed with adjacent solvent components that are also broadened by passage through the mixing disk <NUM>. The mixing disk <NUM> can be fabricated using a three-dimensional (3D) manufacturing process (e.g., by stereolithography) to achieve mixer-to-mixer reproducibility of the mixer properties.

The flow collector <NUM> has a collector inlet port <NUM> and a collector outlet port <NUM>. The collector inlet port <NUM> has an inlet cross-section and is in communication with the outlet face <NUM> of the mixing disk <NUM> to thereby receive the flow of the compositional solvent stream after passing through the mixing disk <NUM>. The flow collector <NUM> substantially evenly collects and combines the flows from the ends of the channels at the outlet face <NUM> of the mixing disk <NUM> into a single flow at the collector output port <NUM>.

In some embodiments, the area of the outlet cross section of the flow distributor <NUM> is substantially equal to a cross-sectional area of the inlet face <NUM> of the mixing disk <NUM>. Similarly, an area of the inlet cross-section of the flow collector <NUM> may be substantially equal to a cross-sectional area of the of the outlet face <NUM> of the mixing disk <NUM>. The flow distributor <NUM> 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 <NUM> may be a radial flow collector, an angular flow collector, a combination of a radial and angular flow collector, or a fractal flow collector. These types of flow distributors <NUM> and flow collectors <NUM> enable most of the volume of the mixing disk <NUM> to be used for mixing. Similarly, use of a disk for mixing yields maximum mixing for a given mixer volume.

In the absence of a flow restriction, the limited divergence of the received solvent stream would not spread across the full input face <NUM> of the mixing disk <NUM>. Moreover, the performance of the mixer <NUM> is proportional to the square of the mixer volume. Thus, the flow distributor <NUM> is used to even distribute the compositional solvent stream receive at the inlet port <NUM> into a large number (e.g., at least ten) of individual flows incident at the inlet face <NUM> of the mixing disk <NUM>. For example, the solvent flow at the inlet port <NUM> may be approximately <NUM> to <NUM> in diameter and each individual flow may similarly be approximately <NUM> to approximately <NUM> in diameter. The flow collector <NUM> similarly evenly collects the individual flows exiting from the outlet face <NUM> of the mixing disk <NUM> into a single flow of approximately <NUM> to <NUM> in diameter. This range of diameters can induce significant molecular dispersion in the mixing disk <NUM> and provide a flow restriction that is greater than the flow restrictions of the flow distributor <NUM> and flow collector <NUM>.

As used herein, tortuosity means a ratio of a flow path length of a channel between its ends normalized to the straight-line distance between its ends. Thus, tortuosity is a characterization of the convoluted channels for fluid dispersion through the mixing medium. The tortuosity of the mixing disk <NUM> is given by the average flow path length of the channels relative to the thickness of the mixing disk <NUM>. 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 <NUM> may be characterized by a retention time distribution (RTD) which is determined by the different flow path lengths through the mixing disk <NUM>. The objective of the random channel structure through the mixing disk <NUM> is to enlarge the RTD. The flow anisotropy and multi-channel tortuosity of the mixing disk <NUM> enables a skewness for the RTD to be reduced to a value close to zero and allows the solvent composition of the solvent mixture at the collector outlet port <NUM> to more quickly achieve the programmed solvent composition.

The flow path lengths are randomly defined according to the internal porous structure of the mixing disk <NUM>. The mixing disk <NUM> is formed from a dispersive material having a random porous structure. In this instance, the flow path lengths of the channels are substantially uncorrelated to each other.

The void volume of the mixing disk <NUM> is preferable selected based on the pump stroke volume for the pump system. In some embodiments, the value of the void volume is between about two time the pump stroke volume to about three times the pump stroke volume. For instance, based on three times the pump stroke volume, a <NUM> mixer may be used with a pump system having a <NUM>µL pump stroke volume.

In some embodiments, the mixing disk <NUM> is manufactured via a machining process or 3D printing. The mixing disk <NUM> may include a predefined arrangement of channels having a range of path flow path lengths or include a labyrinth of channels. The disk material preferably is a chemically inert material such as a glass, polymer or metal. In one preferred implementation, the mixing disk <NUM> is a cleaned passivated stainless steel disordered structure that is inert with respect to the solvents.

The volumes of the flow distributor <NUM> and flow collector <NUM> are preferably small compared to the void volume of the mixing disk <NUM> to thereby limit the total pressure drop across the residual noise targeting mixer <NUM>. In one example, the pressure drop across the residual noise targeting mixer <NUM> does not exceed <NUM> MPa (<NUM>,<NUM> psi) at a flow rate of <NUM>/min. for water at room temperature.

<FIG> and <FIG> show a perspective view and cutaway schematic view, respectively, of an example of a mixer <NUM> for a liquid chromatography system. The mixer <NUM> is formed from stacked layers of metal mesh in which combinations of certain mesh layers substantially correspond to the flow collector <NUM>, mixing disk <NUM> and flow collector <NUM> of the mixer <NUM> of <FIG> to enable evaluation of mixing performance.

The mixer <NUM> includes a housing <NUM>, an inlet <NUM> to receive a solvent composition flow along flow axis <NUM>, and and an outlet <NUM> to provide a mixed solvent composition flow. The inlet <NUM> is configured to receive a fitting to couple to a conduit (e.g., stainless steel tubing) that conducts the solvent composition stream. Similarly, the outlet <NUM> is configured to receive a fitting to couple to a conduit to conduct the mixed solvent composition stream from the mixer <NUM>. Due to the symmetrical construction of the mesh mixer <NUM>, the roles of the inlet <NUM> and outlet <NUM> may be reversed.

The mixer <NUM> includes a first pair of mesh layers 80A and 80B, a second pair of mesh layers 82A and 82B, and a group of three mesh layers 84A, 84B and 84C. In one embodiment, the two pairs of mesh layers <NUM> and <NUM> are used as substitutes for the flow distributor and flow collector. Each layer <NUM> or <NUM> is a <NUM> thick stainless steel mesh with a <NUM> mesh interstitial spacing. Each pair of layers <NUM> and <NUM> acts as a flow restrictor to approximate an ideal flow distribution or ideal flow collection. Each of the three layers <NUM> in the middle of the layer stack is a <NUM> thick stainless steel mesh with a <NUM> mesh interstitial spacing. The group of layers <NUM> forms a porous dispersive structure that acts as the mixing disk. It will be noted that in an improved implementation a disordered, or random, material would be used instead of the group of layers <NUM> with a preferential diffusion in the radial direction thereby increasing the tortuosity and enabling an improvement in the reduction of skewness of the RTD.

<FIG> are a side, end view and cutaway side view, respectively, of an example of a mixer <NUM> that can be used to mix a compositional solvent stream in a liquid chromatography system. The mixer includes a first housing part <NUM>, a second housing part <NUM>, an annular ring <NUM>, a flow distributor <NUM>, a mixing disk <NUM> and a flow collector <NUM>. The flow distributor <NUM>, mixing disk <NUM> and flow collector <NUM> are held within the annular ring <NUM>. The first housing part <NUM> includes threads on an outer surface which engage threads on an inner bore surface of the second housing part <NUM>. The first housing part <NUM> is inserted into the second housing part <NUM> until both components are in contact with opposite sides of the annular ring <NUM>. A pair of gaskets 114A and 114B create a fluidic seal between the annular ring <NUM> and the first housing part <NUM> and the annular ring <NUM> and the second housing part <NUM>, respectively. Liquid entering the mixer <NUM> at mixer port 116A exits at mixer port 116B. The mixer <NUM> may alternatively be used with liquid flowing in the reverse direction, that is, by entering at mixer port 116B and exiting at mixer port 116A.

<FIG> is an exploded view of the annular ring <NUM> and the components held within the ring <NUM>. The flow distributor <NUM> includes an inlet angular dispersion plate <NUM> and an inlet radial dispersion plate <NUM>. The mixing disk <NUM> includes a disk <NUM> having a random porous structure disposed between two fine mesh disks 124A and 124B (e.g., two metal mesh screens each having a <NUM> spacing). The flow collector <NUM> includes an outlet radial dispersion plate <NUM> and an outlet angular dispersion plate <NUM>.

The inlet and outlet angular dispersion plates <NUM> and <NUM>, respectively, include a central opening <NUM> and <NUM>, respectively, with slots <NUM> extending radially from the central opening <NUM> and <NUM>. The slots <NUM> are wedge-shaped, that is, increasing in width with increasing distance from the center. The inlet and outlet radial dispersion plates <NUM> and <NUM>, respectively, include an arrangement of concentric arc-shaped slots <NUM> arranged at one of three different radii from the center of the plate. The widths of the slots are greater for increased distance from the center. The combination of an angular dispersion plate and a radial dispersion plate act to efficiently distribute or collect independent flows into or out from the mixing disk <NUM>. It will be recognized that the materials and dimensions of the plates <NUM> and <NUM>, as well as the arrangement (including the number and dimensions) of the slots <NUM> and <NUM> in a plate may be different in other embodiments.

<FIG> is an example of a fractal flow distributor <NUM> that can be fabricated, for example, using a 3D-printing stereolithography process. The distributor <NUM> includes a central through hole that is split into two ramification channels each of which is again split into two ramification channels each of which is further split into another two ramification channels and so on. The splitting of channels occurs through the thickness of the distributor plate or disk to generate a fractal distribution of the flow over a surface. <FIG> is another example of a fractal flow distributor <NUM> that can be fabricated using a similar fabrication process. In this example, the distributor <NUM> includes a structure that splits into three ramification channels each of which is split and leads to three ramification channels each of which leads to another three ramification channels.

<FIG> is an example of a portion of a mixing disk <NUM> that can be made using a 3D fabrication process, such as stereolithography, with a polymer material. For example, use of the photomasks shown in <FIG> may be alternately used in a sequential ultraviolet (UV) cure of a polymer material to build square-like features of <NUM> on a side. First, straight channels are formed using the photomask shown in <FIG> then a square cross-section channel is formed using the photomask shown in <FIG>. The thickness of the resulting slice depends on the intensity of the UV light source, the concentration of a photo-initiator compound in the polymer material, monomer concentration and the UV exposure time. The curing process can be repeated multiple times with removal of unpolymerized material between cure cycles. In this way many layers can be stacked to fabricate various 3D structures by translating and/or rotating (e.g., see photomasks in <FIG>) each slice relative to the other slices. This process is just one example of a fabrication technique for forming a mixing disk and it will be recognized that other fabrication techniques can also be used.

In one embodiment, a flow distributor is made of two plates 160A and 160B as shown in <FIG>, respectively, in views of their downstream surfaces. The first plate 160A has a fractal distribution path structure. Internally, the first plate 160A includes a series of fluidic paths that start from an open circular central region <NUM> that receives the flow from the distributor inlet. First flow paths 164A extend at one end radially from the central region <NUM> to an opposite end at a midpoint of a second flow path 164B that is perpendicular to the first flow paths 164A. Each end of a second flow path 164B is near or at a midpoint of a third flow path 164C. As illustrated, there are <NUM> first flow paths 164A, <NUM> second flow paths 164B and <NUM> third flow paths 164C. At each end of each of the third flow paths 164C is an opening <NUM> at the downstream surface of the first plate 160A. The plates <NUM> are secured together such that openings <NUM> in the first plate 160A are aligned with corresponding openings <NUM> in the second plate 160B.

The fluidic paths and other features of the flow distributor may be formed in a variety of ways. For example, known micro-machining techniques may be utilized. Alternatively, an etching process may be utilized to form the desired structure.

Each opening <NUM> is defined along one of two concentric circles of radius R<NUM> or R<NUM> with each circle being concentric with the mixer flow axis. Thus, a flow received at the distributor inlet port is internally separated into <NUM> flows, each of which is separated into four flows so that the number of flows exiting the second plate 160B is <NUM>. The diameters of the openings <NUM> are preferably equal. In a non-limiting numerical example, the total area defined by all <NUM> openings is approximately five percent of the total downstream surface area of the second plate 160B.

In one embodiment (Embodiment A), the flow distributor and flow collector are of identical construction, i.e., the mixer exhibits axial mirror symmetry about the mixing disk. In other words, the first plate 160A of the flow distributor is identical to the second plate of the flow collector and the second plate 160B of the flow distributor is identical to the first plate of the flow collector. The mixer is therefore configured such that the features of the flow collector are arranged in an inverse axial flow direction to those of the flow distributor but are otherwise the same. <FIG> illustrates the relationship between the openings <NUM> in the second (downstream) plate 160B of a flow distributor with respect to the openings <NUM> in a first (upstream) plate 170A of a flow collector in a mixer constructed in this manner. Each opening <NUM> and <NUM> is located on one of the two concentric circles of radius R<NUM> and R<NUM>. The openings at the distributor outlet port are arranged identically to the openings at the collector inlet port. Thus, there is a one-to-one correspondence between each opening <NUM> in the second plate 160B of the flow distributor with a respective opening <NUM> in the first plate 170A of the flow collector. However, in other embodiments, the flow distributor and flow collector do not define a symmetrical arrangement about the mixing disk, as described further below.

<FIG> depict the downstream surfaces of two plates 180A and 180B, respectively, used in a different implementation of a flow distributor. Internally, the first plate 180A includes a series of fluidic paths that start from an open circular central region <NUM> that receives the flow from the distributor inlet. First flow paths 184A extend at one end radially from the central region <NUM> to an opposite end at a midpoint of a short second flow path 184B arranged perpendicular to the first flow paths 184A. Each end of each second flow path 184B is coupled to one end of each of three third flow paths 184C. As illustrated, there are <NUM> first flow paths 184A, <NUM> second flow paths 184B and <NUM> third flow paths 184C. At each end of each of the third flow paths 184C is an opening <NUM> at the downstream surface of the plate 180A. The plates 180A and 180B are secured together such that openings <NUM> in the first plate 180A are aligned with the openings <NUM> in the second plate 180B.

Each opening <NUM> is defined along one of four concentric circles of radius R<NUM>', R<NUM>', R<NUM>' and R<NUM>', all of which are concentric with the mixer flow axis. A flow received at the distributor inlet port is separated into <NUM> flows, each of which is separated into two flows which are each further separated into three flows such that the number of flows exiting the second plate 180B is <NUM>. Thus, the number of individual flows incident on the upstream surface of the mixing disk is greater than that for the embodiment illustrated in <FIG>.

In one embodiment (Embodiment B) of a mixer, both the flow distributor and flow collector are formed as identical components each having <NUM> openings and are symmetrically arranged about the mixing disk.

In another embodiment (Embodiment C), a mixer is constructed using a flow distributor as shown in <FIG> and a flow collector as shown in <FIG>. Thus, the flow distributor includes <NUM> openings <NUM> adjacent to the upstream side of the mixing disk while the flow collector includes <NUM> openings <NUM> at the downstream side of the mixing disk. <FIG> illustrates the relationship between the openings <NUM> in the second plate 160B of the flow distributor with respect to the openings <NUM> in the first (upstream) plate 180A of the flow collector in a mixer constructed in this manner. It can be seen that the concentric circles of radii R<NUM> and R<NUM> on which the openings <NUM> are defined are different from the concentric circles of radii R<NUM>', R<NUM>', R<NUM>' and R<NUM>' on which the openings <NUM> are defined.

In yet another embodiment (Embodiment D), a mixer is constructed using a flow distributor as shown in <FIG> and a flow collector formed according to the structure shown in <FIG>. In this arrangement, the flow distributor includes <NUM> openings <NUM> adjacent to the upstream side of the mixing disk and the flow collector includes <NUM> openings <NUM> at the downstream side of the mixing disk. As with Embodiment C, the concentric circles for the openings <NUM> and <NUM> are different.

An evaluation of performance was made using a pulse input of an analyte to determine the retention time distribution for mixers according to Embodiments A to D. Measurement results showed that Embodiment B has a higher peak and a marginally narrower width in its retention time distribution relative to that for Embodiment A. Embodiments C and D had nearly identical retention time distributions with peaks heights similar to that of Embodiment B; however, Embodiments C and D had retention time distributions with better symmetry.

It should be recognized that the number of internal flow paths and/or openings may be different from those described above. For instance, any flow splitting ramification having a number of fractal steps greater than two may be used. For example, two or more flow splitting disk elements may be stacked. Similarly, the arrangement of the internal flow paths and openings may be different. For example, the openings may be arranged on a different number of concentric circles. Other arrangements of openings are contemplated.

Methods are also contemplated of mixing fluid. Methods include providing a compositional solvent stream, by at least one fluidic pump such as the pump <NUM>, to a mixer arrangement, such as the mixer arrangement <NUM>, that includes a first frequency targeting mixer, such as the frequency targeting mixer <NUM>, and a residual noise targeting mixer, such as the residual noise targeting mixer <NUM>. Methods include receiving, by the first frequency targeting mixer, the compositional solvent stream and reducing or eliminating, by the first frequency targeting mixer, fluidic compositional oscillations in a compositional solvent stream that depart from a desired composition at a first target frequency, such as a frequency corresponding to a full stroke volume of the pump. Methods include receiving the fluid by the residual noise targeting mixer fluidically connected in series to the frequency targeting mixer, and dampening, by the residual noise targeting mixer, aperiodic residual baseline noise in the compositional solvent stream.

Claim 1:
A mixer arrangement (<NUM>) for use in a chromatography system (<NUM>) comprising:
a first frequency targeting mixer (<NUM>) including a first flow channel (<NUM>) coupled between an inlet (<NUM>) and an outlet (<NUM>) and a second flow channel (<NUM>) coupled between the inlet (<NUM>) and the outlet (<NUM>), the second flow channel (<NUM>) including a volume offset region (<NUM>) configured to delay fluid propagation through the second flow channel (<NUM>), wherein the volume offset region (<NUM>) is configured to reduce or eliminate fluidic compositional oscillations in a compositional solvent stream that depart from a desired composition at a first target frequency; and
a residual noise targeting mixer (<NUM>) fluidically connected in series to the first frequency targeting mixer (<NUM>), the residual noise targeting mixer (<NUM>) configured to dampen aperiodic baseline noise in the compositional solvent stream, wherein the residual noise targeting mixer (<NUM>) includes a mixing disk (<NUM>) having an inlet face (<NUM>) and an outlet face (<NUM>) located between the plurality of flow channels, wherein the mixing disk includes a dispersive medium having a random porous structure.