Fluid Modulator

Abstract

To provide an efficient fluid modulator applicable to comprehensive two-dimensional gas chromatography.SOLUTION: A fluid modulator includes a 5-port manifold 10' constructed from: three union T-joints, i.e., a fluid primary T-joint 30', an exhaust T-joint 20' and a secondary T-joint 40'; and two tubes, i.e., a loop conduit 50' and a joining tube 60'. The primary T-joint is connected to the exhaust T-joint by means of the loop conduit 50'. The exit of a primary column 70' is connected to the primary t-joint, and the entrance of a secondary column 80' is connected to the secondary T-joint.SELECTED DRAWING: Figure 8

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 926,742, filed October 28, 2019, the disclosure of which is incorporated herein by reference in its entirety. [Technical Field]

[0002] FIELD OF THE DISCLOSURE The present disclosure relates generally to fluid modulators, including fluid modulators that may be used in connection with chromatography. [Background technology]

[0003] This background discussion is provided below for background purposes only, and therefore no aspect of this background discussion is admitted, explicitly or implicitly, as prior art to the present disclosure unless it otherwise qualifies as prior art.

[0004] Some fluid regulator designs do not provide sufficient performance, are inefficient, and / or are particularly complex.

[0005] Solutions / options that minimize or eliminate one or more of the problems or drawbacks of fluid regulators are desirable. The foregoing discussion is intended to be illustrative of the present invention and is not intended to deny its scope. Summary of the Invention

[0006] For illustrative purposes of the present disclosure, a fluid modulator may include a fluid manifold including a primary T-piece, a discharge T-piece, a secondary T-piece, a loop conduit, and / or a connecting tube; a fluid valve including a common port, a normally open output port connected to the secondary T-piece, and / or a normally closed output port connected to the primary T-piece; and / or a flow controller configured to supply an auxiliary fluid to the common port of the fluid valve. The primary T-piece, discharge T-piece, and secondary T-piece may be arranged in a line, for example, such that the primary T-piece and the secondary T-piece are located at opposite ends of the fluid manifold and the discharge T-piece is disposed therebetween. The primary T-piece may be connected to the discharge T-piece by a loop conduit. The discharge T-piece may be connected to the secondary T-piece by a connecting tube. The loop conduit may be longer than, or may be significantly longer than, the connecting tube. The primary T-piece may be configured to connect to a primary column. The secondary T-piece may be configured to connect to a secondary column.

[0007] The foregoing and other potential aspects, features, details, utilities, and / or advantages of examples / embodiments of the present disclosure will become apparent from reading the following description and reviewing the accompanying drawings. [Brief explanation of the drawings]

[0008] Although the claims are not limited to the specific drawings, an understanding of various aspects can be gained through the description of various embodiments. The drawings are not necessarily to scale, and certain features may be exaggerated or obscured to better illustrate and explain the innovative aspects of the embodiments. Furthermore, the exemplary illustrations described herein are not intended to be exhaustive or otherwise limiting, and are not limited to the precise forms and configurations shown in the drawings or disclosed in the following detailed description. The exemplary illustrations are described in detail below with reference to the drawings.

[0009] [Figure 1]FIG. 1 is an illustration showing three exemplary mechanisms that can be used to convert component peaks eluting from a primary column into a series of pulses separated by segments of carrier gas. [Figure 2] FIG. 1 is a schematic diagram of one embodiment of an RFF (reverse fill / flash) modulator according to a reference example of the present disclosure. [Figure 3] FIG. 1 is a schematic diagram of the flow pattern relative to the filling state of an embodiment of an RFF modulator according to the present disclosure. [Figure 4] FIG. 1 is a schematic diagram of flow patterns associated with injection conditions according to one embodiment of an RFF modulator of the present disclosure. [Figure 5] FIG. 1 is a schematic diagram of the flow pattern of an embodiment of an RFF modulator according to the present disclosure in a filled state, with the secondary flow split into two directions. [Figure 6] FIG. 1 is a schematic diagram of a flow pattern according to one embodiment of an RFF modulator of the present disclosure, generally showing the flow conditions immediately after transitioning to an injection state. [Figure 7] FIG. 1 is a schematic diagram of the flow pattern of one embodiment of an RFF modulator according to the present disclosure, generally showing the modulator at a point where all of the collected primary effluent fluid has just been transferred to the secondary column. [Figure 8] 1 is a schematic diagram of one embodiment of a modulator according to aspects and teachings of the present disclosure, including a five-port manifold. [Figure 9] FIG. 1 is a schematic diagram of the flow pattern of one embodiment of a modulator in a filled state in accordance with aspects and teachings of the present disclosure. [Figure 10] FIG. 1 is a schematic diagram of the flow pattern of one embodiment of a modulator in an injected state in accordance with aspects and teachings of the present disclosure. [Figure 11] FIG. 1 illustrates a schematic embodiment of a modulator configured for dynamic modulation according to aspects and teachings of the present disclosure, showing a starting point. [Figure 12]FIG. 1 illustrates a schematic embodiment of a modulator configured for dynamic modulation in accordance with aspects and teachings of the present disclosure, generally shown immediately after entering an injection state. [Figure 13] FIG. 1 illustrates a schematic embodiment of a modulator configured for dynamic modulation according to aspects and teachings of the present disclosure, generally illustrating an example of the final moments of an injection state. [Figure 14] FIG. 1 illustrates a schematic embodiment of a modulator configured for dynamic modulation in accordance with aspects and teachings of the present disclosure, generally showing an example of a state immediately after returning to a filled state. [Figure 15] FIG. 1 is a schematic diagram of one embodiment of a modulator according to aspects and teachings of the present disclosure. [Figure 16A] FIG. 1 is a close-up view of an exemplary flow pattern that may occur in the region of the discharge tee near the tip of the secondary column, generally illustrating the exemplary flow pattern during a packed condition. [Figure 16B] FIG. 1 is a close-up view of an exemplary flow pattern that may occur in the region of the discharge tee near the tip of the secondary column, generally illustrating the exemplary flow pattern during injection conditions. [Figure 17] FIG. 1 is a schematic diagram of one embodiment of a test apparatus that may be used in connection with aspects and teachings of the present disclosure. [Figure 18] FIG. 1 shows generally an example of a portion of a resulting signal constellation. [Figure 19] FIG. 10 generally illustrates an example of pulse overwriting. [Figure 20] FIG. 10 includes example plots of pulse height, width, and area as a function of injection time. [Figure 21] 1 is an example of a plot of a pulse signal as a function of time. [Figure 22] 1 is an example plot of pulse statistics (height, width, and area) as a function of injection time. [Figure 23] 10 is another example of a pulse signal plot as a function of time. [Figure 24] 10 is another example of a pulse signal plot as a function of time. [Figure 25] 10 is another example of a pulse signal plot as a function of time. [Figure 26] 1 is an example of a pulse signal plot as a function of time according to one embodiment of an RFF modulator. [Figure 27] This is an example of a GCxGC chromatogram of gasoline. [Figure 28] 1 is an example of a signal sequence as a function of time. [Figure 29] FIG. 1 is a schematic diagram of one embodiment of an underfilled / overdrained modulator according to aspects and teachings of the present disclosure, generally showing a starting point in a filled state. [Figure 30] FIG. 1 is a schematic diagram of one embodiment of an underfilled / overdrained modulator according to aspects and teachings of the present disclosure, generally illustrating the flow situation immediately after entering the infusion state. [Figure 31] 1 is a schematic diagram of one embodiment of an underfilled / overdrained modulator according to aspects and teachings of the present disclosure, generally illustrating the flow situation during the final moments of the injection state. [Figure 32] FIG. 1 is a schematic diagram of one embodiment of an underfilled / overdrained modulator according to aspects and teachings of the present disclosure, generally illustrating the flow situation immediately after returning to a filled state. [Figure 33] FIG. 1 is a schematic diagram of one embodiment of an underfilled / overdrained modulator according to aspects and teachings of the present disclosure, generally illustrating the flow conditions after being held in a filled state for approximately half the fill time. [Figure 34] FIG. 1 is a schematic diagram of one embodiment of a modulator according to aspects and teachings of the present disclosure, generally illustrating a staggered cross union joint. [Figure 35] FIG. 1 is a schematic diagram of one embodiment of a modulator according to aspects and teachings of the present disclosure, generally illustrating over-insertion of a secondary column into a standard cross-union fitting. [Figure 36] 10A-10C are schematic diagrams of the flow patterns of the cross union fitting during filling and injection. [Figure 37] FIG. 1 is a schematic diagram of one embodiment of a single five-port manifold according to aspects and teachings of the present disclosure. [Figure 38] FIG. 1 is a schematic diagram of an embodiment of a modulator operable in a back-fill-drain mode. DETAILED DESCRIPTION OF THE INVENTION

[0010] Reference will now be made in detail to the embodiments of the present disclosure, examples of which are described herein and illustrated in the accompanying drawings. While the present disclosure will be described in conjunction with the embodiments and / or examples, it will be understood that they are not intended to limit the disclosure to these embodiments and / or examples. Rather, the present disclosure is directed to alternatives, modifications, and equivalents thereof.

[0011] In embodiments, a fluid system may include a device configured to combine two fluid streams to generate a new stream containing alternating segments of the incoming streams. Intermixing between the segments may be reduced and / or minimized. The size of the fluid segments may be controlled by the magnitude of the incoming streams and / or the timing of the switching process. The device may be optimized as a flow modulator that can be used in conjunction with comprehensive two-dimensional gas chromatography (GC×GC) separations. The device may combine gas exiting a gas chromatograph column (primary column) with a secondary stream of carrier gas to generate a stream having segments of the primary exit fluid separated by larger segments of carrier gas. This new stream may be introduced into a secondary column for further separation. While the device is described in conjunction with a GC×GC modulator, it is not limited to this application and may be used in a wide variety of applications, including, but not limited to, conventional gas chromatography injectors, liquid chromatography modulators, and / or sample inlets for flow injection analysis.

[0012] GCxGC analysis extends conventional gas chromatography (GC) by adding a high-speed secondary separation at the end of the GC separation. GCxGC separations can be generated using a standard gas chromatograph with nearly all original components, except for the addition of one device unique to GCxGC: a modulator. The modulator samples the effluent flowing out of the primary column and transfers the sampled effluent to the front of the secondary column in a narrow pulse (typically less than 100 milliseconds).

[0013] A fluid mixture of interest can first be injected into a standard GC column, which functions as the primary column. A carrier gas flow can transport each component of the mixture into the primary column at a velocity characteristic of that component. A modulator can be positioned in the fluid path between the end of the primary column and the beginning of the secondary column. Components eluting from the primary column can be sampled by the modulator at regular intervals (e.g., "modulation periods"). The modulation period can be kept slightly smaller than the width of the component peaks emerging from the primary column. In some cases, the modulation period can range, for example, from about 1 second to about 3 seconds. At the end of each modulation period, the components sampled during that particular interval can be transferred to the secondary column. Because the stationary phase of the secondary column can have a different selectivity than the primary column, components co-eluted by the primary column can also be separated by the secondary column. The secondary column can also perform high-speed GC separation of each fraction transported by the modulator. In this way, a sample analysis of a mixture can involve one separation by the primary column and hundreds of sub-separations by the secondary columns. Experimental conditions can be adjusted to restrict the range of retention times on the secondary column to values ​​less than the modulation period. Sample components can be detected upon exiting the secondary column. The detector signal array can be divided into individual segments with widths approximately equal to the modulation period. These signal segments represent each sub-separation and can be plotted side-by-side to obtain a two-dimensional chromatogram.

[0014] A GCxGC modulator can be configured to convert component peaks eluting from the primary column into a series of pulses separated by segments of carrier gas. Three example mechanisms that can be used to create this effect are generally illustrated in Figure 1. The first mechanism may be configured to concentrate analyte molecules. This involves temporarily immobilizing eluting analyte molecules and allowing carrier gas molecules to pass through the modulator. At the end of each modulation cycle, the collected analyte molecules can be rapidly remobilized into the carrier stream as concentrated pulses. By repeating this process, a gas stream with zones of high concentration separated by pure carrier gas can be created. Immobilization and remobilization of analyte molecules in this manner can be achieved by introducing large temperature changes. This type of modulation process is sometimes referred to as temperature modulation.

[0015] An example of a second modulation mechanism is replacing a segment of the primary exhaust fluid with an equal-sized segment of carrier gas (e.g., pure carrier gas). This may involve supplying a secondary column with a secondary stream of pure carrier gas and briefly introducing a portion of the primary exhaust fluid at the beginning of each modulation period. This may result in a stream of small primary exhaust fluid segments separated by carrier segments. Unlike temperature modulation, the analyte is not concentrated in the primary exhaust fluid segment, so this method may result in a loss of a large proportion of analyte molecules, resulting in reduced sensitivity. However, this method is relatively simple to implement. For example, and without limitation, such a method may involve only a valve and a few fittings. This mechanism may also be a low-duty-cycle modulation mechanism and may be referred to herein as split-flow modulation.

[0016] A third example modulation mechanism can include inserting large segments of auxiliary carrier gas between segments of primary exhaust fluid. Unlike split flow modulation, analyte molecules from the primary exhaust fluid may not be discarded, but they may also not be concentrated. Adding auxiliary carrier gas without discarding the primary exhaust fluid can result in a modulated flow with a significantly higher flow rate than the original flow in the primary column, which can result in a significantly higher flow rate in the secondary column. This can result in a high velocity flow of segments of non-concentrated primary exhaust fluid separated by large segments of pure carrier gas. This mechanism may be configured as a high duty cycle modulation mechanism and may be referred to herein as differential flow modulation.

[0017] For example, differential flow modulation may be fairly easy to implement using valves and some fittings, but finding the conditions that produce the optimal pulse shape may be difficult. Mass spectrometer detection may also be limited by differential flow modulation. Benchtop mass spectrometers may be designed with a maximum inlet flow rate similar to that of traditional single-column GC separations. The increased flow rate associated with differential flow modulation can lead to a significant portion of the secondary effluent being diverted before entering the benchtop mass spectrometer. This can significantly reduce the flux advantage of differential flow modulation over diverted flow modulation for flow-limited detectors or detectors that respond only to analyte concentration. Some GC×GC separations are sometimes performed using flame ionization detectors (FIDs). An FID is an example of a single-channel detector, but it is not limited to this. FIDs can be configured to easily handle increased carrier flow levels and exhibit increased signal strength with differential flow modulation.

[0018] Some temperature modulators use a liquid nitrogen cooled gas jet to immobilize the analyte and a heated gas jet for re-immobilization. Operation of a temperature modulator can involve the consumption of large amounts of cryogenic fluid, which can significantly increase operating costs when compared to conventional gas chromatography.

[0019] Some flow modulators may employ high-speed multiport valves to generate the primary component pulses. Multiport valves with internal diaphragms (as opposed to rotating elements) may be fast enough to generate narrow pulses, but these valves may have temperature constraints that can limit the upper temperature limit of a GC×GC separation. A second drawback of multiport valves is that actuation of the valve during modulation can cause brief but large flow rate changes in the secondary column. This can lead to peak distortion in the resulting chromatogram.

[0020] An example fluidic modulator may employ a three-way valve and a union fitting and tubing assembly (or equivalent integrated tubing and union fitting). An auxiliary stream of carrier gas may be introduced into a common port of the three-way valve (e.g., an input port for flow from a fluid / pressure controller). The two output ports of the valve may be connected to the union fitting assembly. The outlet of the primary column and the inlet of the secondary column may also be connected to the union fitting assembly. The exact arrangement of the tubing and union fitting may be modulator-specific.

[0021] The fluidic modulator can use a valve to switch the inlet position of the auxiliary gas within the union fitting assembly. This results in a change in the direction / magnitude of flow within the union fitting assembly, generating a desired mixture of the primary exhaust fluid and the auxiliary carrier gas. The fluidic modulator can have several advantages: (1) the only moving part of the device may be a three-way valve, and / or (2) the sample components may not pass through the three-way valve. Thus, the valve may be located outside the chromatography oven, may not be constructed from inert materials, and may not be overly miniaturized. The union fittings and tubing within the sample path may be stationary devices that are more easily fabricated from inert materials and miniaturized. The fluidic modulator may not impose additional temperature limitations on the chromatographic separation.

[0022] An example of a fluidic device is the proprietary Capillary Flow Technology (CFT) modulator offered by Agilent Technologies. CFT modulators may be configured to provide 100% transfer of the primary effluent to the secondary column, but may produce pulses with "tails" that can obscure adjacent low intensity peaks. Another example of a fluidic device is the Reverse Fill / Flush (RFF) modulator.

[0023] Some modulators, such as those offered by Agilent Technologies and Sepsolve, may require high flow rates on the secondary column, making them difficult to couple to a mass spectrometry detector without some form of flow splitting. Differential flow modulation GC×GC-MS instruments are complex and can be difficult to implement properly.

[0024] If the flow rate of the secondary column is comparable to that of the primary column (as in a GC x GC-MS separation), a differential flow modulator may not offer a significant advantage. The simplicity and flexibility of a split flow modulator may make it a more effective option. However, if the detector operates at a higher flow rate and has a response proportional to the analyte flux (like an FID), a differential flow modulator can provide greater sensitivity.

[0025] The chromatographic efficiency of a GC column of a given length tends to decrease with increasing flow rate, for example, above approximately 2 mL / min. This may suggest that high-resolution second-order separations are not possible at the high flow rates associated with differential flow modulation. However, the chromatographic resolution achieved at high flow rates may be much greater than previously thought. Separation can be improved by increasing the column length while increasing the flow rate, using a thinner stationary membrane, and / or operating with a smaller retention factor. For example, a 5-m-long capillary column can produce separations with narrow peaks (peak widths < approximately 50 ms) at a flow rate of 10 mL / min.

[0026] Injecting pulses wider than approximately 50 ms into the secondary column can be counterproductive. Traditionally, increasing modulation transmission has been shown to increase sensitivity. However, this is incorrect if increasing transmission results in wider peaks without increasing their height. For example, a separation in which an RFF modulator transfers 100% of the primary effluent to the secondary column can produce peaks with widths approaching 200 ms. Injecting a narrow pulse into the secondary column can produce peaks of the same height but one-quarter the width. Therefore, injecting narrow pulses may provide higher resolution without sacrificing sensitivity.

[0027] The pulse width generated by a full-transfer differential flow modulator may be proportional to the ratio of the primary column flow to the secondary column flow. Therefore, decreasing the primary flow and / or increasing the secondary flow may allow the pulse width to be decreased while maintaining 100% transfer. However, this approach may result in changes beyond simply decreasing the pulse width (e.g., slower primary separation, faster secondary separation, reduced chromatographic efficiency of both the primary and secondary columns, etc.).

[0028] A schematic diagram of one embodiment of an RFF modulator 10 is generally shown in Figure 2. Some RFF modulators may integrate some of the unions and conduits into a single piece of hardware. The design shown in Figure 2 includes separate unions and tubing, but may employ the same principles and flow patterns as an integrated design.

[0029] The center of the assembly may include a five-port manifold 10 composed of three T-junctions and two tubings. The T-junctions may be designated as a discharge T-junction 20, a primary T-junction 30, and a secondary T-junction 40. The unions may be arranged, for example, in a linear (e.g., coaxial) configuration, with the discharge T-junction 20 and the secondary T-junction 40 located at opposite ends of the manifold and the primary T-junction 30 positioned therebetween. The discharge T-junction 20 may be connected to the primary T-junction using a length of tubing, also referred to as a loop (or loop conduit) 50. The primary T-junction 30 may be connected to the secondary T-junction 40 using a length of tubing, also referred to as a connecting tube 60. The loop conduit 50 may be longer than the connecting tube 60, or even significantly longer. The outlet of the primary column 70 may be connected to the primary T-junction 30, and the inlet of the secondary column 80 may be connected to the secondary T-junction 40.

[0030] Also shown in the embodiment of FIG. 2 are a primary column 70, a secondary column 80, a flow regulator 90, a valve (e.g., a solenoid valve) 100, and an auxiliary carrier 110 (from a flow controller). An auxiliary flow of carrier gas can be introduced into the manifold 10 by one or more additional components. A flow controller (which may be configured as a pressure / flow controller) may supply the auxiliary gas to a common port of a fluid valve 100, such as a three-port, two-way solenoid valve. The normally open output port of the valve 100 may be connected to a secondary tee 40 by a short length of tubing (e.g., 120). The normally closed output port of the valve 100 may be connected to an exhaust tee 20 by a similar short length of tubing (e.g., 130). Two streams may enter the modulator: (i) the primary column exhaust fluid, and (ii) the auxiliary carrier fluid. Fluid is exhausted from the device by entering the secondary column 80 and / or by entering the flow regulator 90. In embodiments, the flow regulator 90 may be connected to the exhaust tee 20 and may be a static device such as a carefully selected length of capillary tubing, or an adjustable device such as a back pressure regulator, or a combination of a static and adjustable flow regulator.

[0031] RFF modulators may be configured to produce intended results by precisely controlling the flow patterns within the device. The flow rates into and out of the modulator may be essentially constant and balanced. This condition leads to the flow balance equation F1 + Fs = F2 + Fx, where F1 is the primary column flow, Fs is the auxiliary carrier gas flow, F2 is the secondary column flow, and Fx is the exhaust flow. RFF modulators may be configured as two-state devices. The state of the device may be determined by the injection position of the auxiliary carrier gas, which may in turn be determined by the state of the solenoid valve. The two primary states of the device may be designated as a fill state and an inject state.

[0032] FIG. 3 generally illustrates an exemplary embodiment of a flow pattern during a packed condition. A packed condition may be created by directing an auxiliary gas stream into the secondary tee 40. The magnitude of the auxiliary stream may be carefully adjusted to be slightly larger than the secondary carrier stream. This allows the auxiliary stream to supply all of the gas required for the secondary column 80, while excess carrier gas may exit the secondary tee 40 through the junction tube 60 toward the primary tee 30 at a flow rate given by Fs - F2. This carrier gas flow may facilitate the modulation process and may be referred to as the curtain flow Fc = Fs - F2. The primary stream may simultaneously enter the RFF modulator at the primary tee 30, where it may mix with the curtain flow and then enter the loop 50. The combined primary exhaust fluid and curtain flow may pass through the loop 50 during a packed condition at a flow rate that may be referred to as the exhaust flow Fx. The flow balance equation Fx = F1 + Fs - F2 can be used to express the exhaust flow in terms of the other three external streams. This flow may ultimately exit the modulator through the discharge tee 20 and then enter the flow adjuster 90 .

[0033] FIG. 4 generally illustrates an exemplary flow pattern embodiment during the injection state. The injection state can be created by energizing a solenoid valve to send a secondary flow to the discharge tee. Under differential flow conditions that may be utilized by an RFF modulator, the secondary column flow may be greater than the primary column flow. Thus, the secondary flow splits upon entering the discharge tee 20, with a portion F2-F1, given by the difference between the secondary and primary flows, passing through loop 50 to primary tee 30, and the remaining portion Fs+F1-F2 (which is equal to Fx), exiting the modulator through flow regulator 90. The F2-F1 loop flow may combine with the incoming primary flow at the primary tee to generate a flow F2 that passes through combining tube 60, then secondary tee 40, and finally into secondary column 80.

[0034] The RFF modulator may be configured to generate a fluid stream containing segments of primary exhaust fluid separated by larger segments of carrier gas. Figures 5 through 7 generally illustrate an exemplary modulation process embodiment. The undiluted primary exhaust fluid is identified in the figures as a fill by hatching, and the carrier gas is shown as a white fill. The RFF modulator can generate pulses through adjustment and control of flow rate, loop size, and timing of switching between fill and inject states. For example, and without limitation, the following external flow rate values ​​may be involved: F1 = 1 mL / min, Fs = 10.3 mL / min, F2 = 10 mL / min, and Fx = 1.3 mL / min.

[0035] The beginning of a modulation cycle (see, e.g., FIG. 5) can be considered when the modulator has been in a filling state long enough for the primary outlet fluid to nearly fill (but not overfill) loop 50. Because the modulator is in a filling state, the secondary flow (e.g., 10.3 mL / min) may split into two directions, with a first portion (e.g., 10.0 mL / min) flowing to secondary column 80 and a second portion (e.g., 0.3 mL / min) acting as a curtain flow. This second portion (e.g., 0.3 mL / min) of flow may merge with the primary column flow (e.g., 1.0 mL / min) before entering loop 50, which may reduce the concentration of the analyte in the outlet fluid by up to, about, or more than 30%.

[0036] The solenoid valve may switch the RFF modulator to the inject state before the primary exhaust fluid reaches the exhaust tee 20. Figure 6 generally illustrates an example of the situation immediately after transitioning to the inject state. The auxiliary carrier allows a portion of the flow (e.g., 1.3 mL / min) to immediately exit through the flow regulator 90, while the remaining portion of the flow (9.0 mL / min) pushes the collected primary exhaust fluid toward the primary tee 30. Within the primary tee 30, the collected primary exhaust fluid combines with the new primary exhaust fluid and can then proceed to the coupling capillary (e.g., coupling tube 60), the secondary tee 40, and finally to the secondary column 80.

[0037] 7 generally illustrates the RFF modulator at a point where all of the collected primary exhaust fluid has just been transferred to secondary column 80. At this point, valve 100 may be de-energized and the RFF modulator may be allowed to return to a filling state where the injected pulse continues to travel through secondary column 80 and primary exhaust fluid begins to fill loop 50 again.

[0038] However, in some applications, RFF modulators may present one or more potential challenges. First, during the fill state, the RFF modulator may mix curtain gas with the incoming primary exhaust fluid. This can dilute / expand the primary exhaust fluid, reducing pulse strength and increasing pulse width. Therefore, it may be desirable to keep curtain flow to a minimum. However, curtain flow may also be used to prevent primary exhaust fluid from "bleeding" into the secondary column 80 during the fill state. Thus, a balance may be involved to achieve optimal peak shape without baseline smearing. Maintaining this balance may be difficult, as the magnitude and direction of curtain flow may be determined by the difference between two large numbers (Fs and F2). A second potential challenge is related to the first. Small curtain flows may make it difficult to operate the modulator at less than 100% duty cycle (e.g., less than full transport modulation). It may be possible to inject narrower pulses into secondary column 80 by returning the RFF modulator to a full state (e.g., clipping the trailing edge of the outgoing pulse) before flushing all of the collected primary exhaust fluid from loop 50. However, the small curtain flow involved in peak height optimization may make it difficult to quickly reverse the movement of the primary exhaust fluid still in coupling tube 60. Thus, using the RFF modulator in a less-than-full transfer mode may result in pulses with significant tailing. RFF modulators may be less effective when operated at low duty cycles, which may involve generating narrow pulses that can fully utilize the resolution of the secondary separation.

[0039] Embodiments of the flow modulator may be configured to avoid diluting the collected primary exhaust fluid (a challenge that can be associated with RFF modulators) and / or allow the user to directly control the width of the injection pulse. Embodiments of the flow modulator may be configured as a differential flow modulator, which may allow the user to maximize peak height while operating at an optimal peak width (e.g., a peak having a width in the range of about 30 ms to 60 ms).

[0040] FIG. 8 generally illustrates a schematic diagram of one embodiment of a modulator. The modulator may include, for example, a five-port manifold 10′ composed of three union tees and two tubings. The union tees may include a primary tee 30′, a discharge tee 20′, and a secondary tee 40′. The union tees may be arranged, for example, in a linear (or coaxial) configuration, with the primary tee 30′ and the secondary tee 40′ located at opposite ends of the manifold and the discharge tee 20′ disposed therebetween. The primary tee 30′ may be connected to the discharge tee 20′ using a length of fluid conduit (e.g., tubing) called a loop 50′. The discharge tee 20′ may be connected to the secondary tee 40′ by a length of fluid conduit called a coupling tube 60′. The loop conduit 50' may be longer than the coupling conduit 60', and may be significantly longer (notably, some of the illustrated modulator schematics show the coupling conduits at a larger scale than may actually be used in the application). The outlet of the primary column 70' may be connected to the primary Tee 30', and the inlet of the secondary column 80' may be connected to the secondary Tee 40'. While the inventive concept is not necessarily limited to linear configurations, it should be noted that configuring the modulator / system linearly (e.g., a coaxial arrangement among three Tee conduits) may allow adjustment of the effective length of the loop and coupling capillaries, such as by changing or adjusting the insertion depth of the primary and / or secondary columns, among other things. Such an advantage or effect may arise, for example, by making the loop coaxial with the primary column 70' and inserting the primary column 70' through the primary Tee 30', and making the secondary column 80' coaxial with the coupling capillary (e.g., the coupling conduit 60') and inserting the secondary column 80' through the secondary Tee 40'.

[0041] In the example of a modulator, an auxiliary flow of carrier gas may be introduced into the manifold via one or more additional components. A flow controller (or pressure / flow controller) may deliver the auxiliary gas to a common port of a valve 100′ (e.g., a three-port, two-way solenoid valve). The normally open output port of the valve 100′ may be connected to a secondary tee 40′ via a short length of tubing 120′. The normally closed output port of the valve 100′ may be connected to a primary tee 30′ via a similar short length of tubing 130′.

[0042] Gas can enter the modulator at two locations: (i) the primary exhaust fluid can enter through primary column 70', and (ii) the carrier gas can enter through valve 100'. Gas can exit the modulator at two locations: (i) the gas can enter secondary column 80', and (ii) the gas can enter flow regulator 90'. Flow regulator 90' can be configured as a static device, such as a length of capillary tubing, or an adjustable device, such as a backpressure regulator, or a combination of a static and an adjustable flow regulator.

[0043] An example modulator can generate pulses of primary exhaust fluid, such as by precisely controlling the flow pattern within the device. The flow rate into the modulator can be essentially constant and / or balanced with the flow rate out of the modulator. This condition can lead to a flow balance equation: F1 + Fs = F2 + Fx, where F1 corresponds to the primary column flow, Fs corresponds to the auxiliary carrier gas flow, F2 corresponds to the secondary column flow, and Fx corresponds to the exhaust flow (see, e.g., Figure 9). The modulator may be configured as a two-state device. The state of the device may be determined by the injection position of the auxiliary carrier gas, which may in turn be determined by the state of the valve. The two states of the device may be designated as a fill state and an inject state.

[0044] FIG. 9 generally illustrates an exemplary flow pattern during a packed state. The packed state may be created by directing an auxiliary gas flow to the secondary tee 40′. The magnitude of the auxiliary flow may be set to be greater than the secondary carrier flow. This allows the auxiliary flow to supply all of the carrier gas for the secondary column 80′, with excess carrier gas flowing out of the secondary tee 40′, through the connecting tube 60′, and into the exhaust tee 20′. This flow may be referred to as a curtain flow and may have a magnitude represented by Fc = Fs - F2. The curtain flow may be configured to limit and / or prevent the primary exhaust fluid from entering the secondary column 80′ during the packed state. While the auxiliary flow supplies carrier gas to the secondary column 80′, the primary column exhaust fluid may enter the modulator through the primary tee 30′ and flow through the loop 50′ toward the exhaust tee 20′ at a flow rate of F1. Unlike an RFF modulator, the primary exhaust fluid may not be diluted by the curtain gas during the packed state. This ensures that the analyte concentration is not reduced by the modulation process. The primary exhaust fluid may continue through loop 50' until it eventually reaches exhaust tee 20', where it may combine with the curtain flow. The combined flow may pass through flow regulator 90' and exit the modulator at a flow rate of Fx, which is related to the other external flows by Fx=F1+Fs-F2.

[0045] FIG. 10 generally illustrates an exemplary flow pattern during an injection state. The injection state may be generated by energizing a valve 100′, which may direct a secondary flow to a primary tee 30′. The secondary flow and the primary flow may combine within the primary tee 30′ and travel (e.g., rapidly) through a loop 50′, such as at a velocity of F1 + Fs. When the flow reaches the discharge tee 20′, it may split into two flow portions. The first portion, having a flow rate of F2, may pass through a combining tube 60′ to a secondary tee 40′ and ultimately enter a secondary column 80′. The second portion may exit the discharge tee 20′ at a flow rate of Fx = F1 + Fs - F2 and pass through a flow regulator 90′.

[0046] Modulator embodiments may be configured to create a fluid stream containing short, undiluted segments of primary exhaust fluid separated by larger segments of carrier gas. The modulator can achieve this, at least in part, by controlling the magnitude of the inflow and outflow and / or the timing of switching between the fill and injection states. An example of dynamic modulation is generally shown in Figures 11 through 14. The undiluted primary exhaust fluid is identified in the figures as the fill by hatching, and the carrier gas is shown as the white fill. By way of example and not limitation, the external flows are given by F1 = 1.0 mL / min, F2 = 10.0 mL / min, Fs = 15.0 mL / min, and Fx = 6.0 mL / min (approximately). The internal flows can be inferred from the magnitude of the external flows and the state of the device. Both external and internal flows are generally included in Figures 11 through 14.

[0047] The beginning of a modulation cycle can be considered to be the point at which the modulator has been held in a filled state long enough that the primary exhaust fluid has filled the entire loop 50' and a small portion of the exhaust fluid has overfilled the loop 50' and begun to flow out of the modulator through the flow regulator 90'. Such a starting point is generally shown in FIG.

[0048] After the loop 50' is filled, the valve 100' may be switched to place the device in the infusion state. Figure 12 generally illustrates an exemplary situation immediately after entering the infusion state. The auxiliary carrier enters the primary tee 30' and combines with the incoming primary exhaust fluid, creating a high flow rate, e.g., 16 mL / min, that can rapidly push a plug of undiluted primary exhaust fluid through the exhaust tee 20' and branch between the connecting tube 60' and the flow regulator 90'.

[0049] Figure 13 generally illustrates an example of the final moments of the inject state. The auxiliary stream may have pushed most, but not all, of the undiluted primary exhaust fluid out of the loop. Most of the primary exhaust fluid that entered the combining tube 60' may have moved to the secondary column 80'. Once the modulator has moved the desired segment of the primary exhaust fluid to the secondary, the modulator may be returned to the fill state.

[0050] FIG. 14 generally illustrates an exemplary situation immediately after returning to the fill state. In the example, a secondary flow (e.g., 15.0 mL / min) may enter the secondary tee, allowing a portion (e.g., 10.0 mL / min) to continue pushing the undiluted exhaust fluid segment downstream of the secondary column 80′. The remaining portion (e.g., 5.0 mL / min) of the secondary flow may act as a curtain flow to prevent the ingress of additional primary exhaust fluid and / or purge the fill of the connecting tube 60′ out of the modulator through the flow regulator 90′. Meanwhile, the undiluted primary exhaust fluid may begin to refill the loop 50′. The device may remain in the fill state until the loop 50′ is completely filled (see FIG. 11), and the cycle may be repeated.

[0051] For example, in contrast to RFF modulators, the curtain gas in modulator embodiments may not dilute the collected primary exhaust fluid. Thus, modulator embodiments may operate without penalty with larger curtain gas flows. Larger curtain flows may allow the device to switch more quickly and more completely between fill and inject states. This may enable the modulator to generate narrow pulses (e.g., ultra-narrow pulses) with sharp leading and trailing edges.

[0052] FIG. 15 generally illustrates a schematic diagram of one embodiment of a modulator 10″. The modulator may include three union tees. In some embodiments, the peripheral union tees (e.g., primary tee 30″ and secondary tee 40″) may have an internal bore (e.g., a 0.5 mm internal bore), and the internal union tee (e.g., exhaust tee 20″) may have a different sized internal bore (e.g., a 0.25 mm internal bore). The loop 50″ and coupling tube 60″ may comprise, for example, but not limited to, a length of metal capillary tubing having a passivated inner surface and an internal diameter of 0.53 mm. The loop 50″ may be disposed between the primary tee 30″ and the exhaust tee 20″. The loop 50″ may have a length of, for example, but not limited to, about 5.0 cm or about 12.5 cm. The connecting tube 60" may have a length of, for example, about 2.5 cm and / or may be located between the discharge tee 20" and the secondary tee 40". The valve 100" may comprise, for example, a high-speed, miniature, three-port solenoid valve and / or may be connected to the primary and secondary tee 30", 40" by a length (e.g., 12 cm) of transfer line (e.g., MXT transfer line). The remaining port of the discharge tee 20" may be connected, for example, to a back-pressure regulator.

[0053] In an embodiment, hydrogen may be used as the carrier gas. The auxiliary carrier gas flow Fs may be controlled using a mass flow meter. The output of the mass flow meter may be provided to a common port of a valve (e.g., a solenoid valve). The state of the valve may determine the state of the modulator. The fill state of the modulator may be generated when the valve directs the auxiliary gas flow to a secondary tee (e.g., as generally shown in FIG. 15). The fill state may be generated by actuating the solenoid valve so that the auxiliary flow is instead directed to the primary tee.

[0054] In embodiments, the primary column may be inserted into the upstream end of the loop through a primary T-joint. The coaxial arrangement of the primary column and the loop may allow for the effective loop length to be varied by adjusting the depth of insertion of the primary column. The effective loop length may correspond to the distance from the tip of the primary column to the downstream end of the loop (e.g., the inlet of the discharge T-joint).

[0055] In an embodiment, the secondary column may be inserted into the connecting tube through the secondary T-joint. The secondary column may be pushed through the entire length of the connecting capillary until it contacts the outlet T-joint. The secondary column may then be withdrawn slightly (e.g., about 1 mm). This arrangement allows the effective connecting tube length to be extremely short, about 1 mm.

[0056] By coaxially positioning the primary column with the loop and the secondary column with the coupling tube, the effective lengths of the loop and coupling tube can be adjusted. This allows for proper tuning of the modulator, which can be particularly useful in the early stages of modulator development for a new or given application. The effective length of the loop can be shortened to ensure that the loop is overfilled during the filling phase, or lengthened (if necessary) to prevent the loop from being completely washed out during the injection phase. Overfilling and under-evacuating the loop can be considered desirable because the switching action of the modulator can cause sharp edges in the outgoing pulse.

[0057] The coaxial arrangement of the secondary column and the connecting tube may also allow for adjustment of the effective length of the connecting tube. Adjusting the effective length of the connecting tube may be desirable to minimize the length of the connecting tube to prevent the primary discharge fluid from diffusively seeping into the secondary column during the packed state. Figures 16A and 16B generally illustrate close-up views of exemplary flow patterns that may occur in the discharge Tee region near the tip of the secondary column. Figure 16A generally illustrates an exemplary flow pattern during the packed state. A supplementary carrier flow Fs may enter the secondary Tee and then flow through the connecting tube in an annular region that may occur in the space between the inner wall of the connecting tube and the outer surface of the secondary column. A portion of the auxiliary flow (e.g., F2) may enter the secondary column, pass through the tip of the secondary column, and the remainder may further flow into the discharge Tee and finally exit through the flow regulator. This remaining flow may be a curtain flow Fc = Fs - F2, which may prevent the primary flow F1 from entering the secondary column during the packed state. However, if the secondary column is inserted too far toward the discharge T-joint, the curtain flow may not be able to travel a sufficient distance to prevent the primary discharge fluid from diffusing against the curtain flow and reaching the secondary column. The ideal effective coupling length can be established by first fully inserting the secondary column into the discharge T-joint (e.g., an effective coupling length of 0) and then withdrawing the secondary column until no oozing is observed. The benefit of operating with the minimum effective coupling length (maximum insertion depth) can be confirmed by examining the flow pattern present during the injection state (e.g., see Figure 16B). When the modulator enters the injection state, an auxiliary carrier is introduced into the primary T-joint, and the primary discharge fluid accumulated in the loop may flow into the discharge T-joint at a flow rate of Fs + F1. Operating with the minimum effective coupling length may allow the primary discharge fluid to reach the inlet of the secondary column almost immediately after switching to the filling state. Thus, embodiments can be used to precisely control the width of extremely narrow pulses with little time delay introduced by the modulator.

[0058] FIG. 17 generally illustrates a schematic of one embodiment of the test apparatus. The left half of the system can be used to generate a flow of, for example, dilute pentane in hydrogen. A mass flow controller can be used to introduce a 3 mL / min flow of hydrogen carrier gas into a three-port, two-way solenoid valve, for example, and without limitation. The output port of the solenoid valve can be connected to a switch (e.g., a Deans switch) having a cross / T-shaped configuration. The cross port (exhaust port) of the Deans switch can be connected to a backpressure regulator. The downstream T-shaped port can be connected to, for example, but not limited to, a 1 m x 0.1 mm piece of deactivated fused silica capillary. By way of example, and not limitation, in some embodiments, the backpressure regulator can be adjusted so that, for example, 2 mL / min of H flows out the exhaust port and 1 mL / min of H passes through the fused silica column. In some embodiments, liquid pentane can be pumped (e.g., by a syringe pump) into the switch (e.g., a Deans switch) at a flow rate of, for example, 0.4 μL / hr. The state of the switch may be determined by the state of the solenoid valve. Directing the carrier gas through the T-joint junction may force all of the injected pentane out the outlet port, preventing it from entering the fused silica column. Directing the carrier gas through the cross-joint junction may allow one-third of the injected pentane to enter the fused silica column. In this way, the left half of the system can accurately simulate the primary exhaust flow from a GC×GC separation. For example, but not limited to, a steady 1.0 mL / min flow of H2 can be generated and passed through the capillary column, turning the added pentane on and off.

[0059] The right side of Figure 17 shows the modulator portion of an example device. The primary column may be inserted into the primary Tee of the modulator. The value of the auxiliary flow may be controlled by a mass flow controller and may range, for example, but not limited to, from 10 mL / min to 20 mL / min. A length of deactivated fused silica (e.g., 1 m x 0.25 mm) may serve as the secondary column. A backpressure regulator may be connected to the outlet port of the outlet Tee and adjusted to generate a flow of, for example, 10 mL / min to the secondary column. The modulated pentane pulse may be detected by a fast flame ionization detector (FID), which may be housed within a gas chromatograph (e.g., Perkin-Elmer AutosystemXL). The timing of the switch and modulator actuation may be controlled by one or more controllers, such as two independent microprocessor circuits. For example, and without limitation, the system or device may be operated with an auxiliary flow of Fs = 14.4 mL / min. This value, when combined with F1=1 mL / min and F2=10 mL / min, can lead to a curtain flow of Fc=4.4 mL / min and an ejection flow of Fx=5.4 mL / min.

[0060] In an embodiment, testing may be performed using, for example and without limitation, a 12.5 cm loop (e.g., instead of the usual 5.0 cm loop). The modulator may be held in the fill state for a period of time (e.g., about 4 seconds), and the time spent in the fill state (e.g., injection time) may be varied, for example, from 10 ms to 140 ms in 10 ms increments. This may produce a series of pulses of increasing width separated by a fixed period of time (e.g., about 4 seconds). FIG. 18 generally illustrates a portion of the resulting signal sequence. FIG. 19 generally illustrates the pulse overlay. As generally illustrated in the figure, the pulses may initially increase in both height and width as the injection time increases (e.g., from 10 ms to 40 ms). As the injection time increases to larger values ​​(e.g., greater than 40 ms), the width may continue to increase, but the pulse height may not increase. This effect can be generally observed in FIG. 20, which plots pulse height, width, and area as a function of injection time. Figure 20 confirms what can be seen from visual inspection of the pulses: the pulse height plateaus (e.g., for injection times greater than 40 ms) but the width continues to increase in direct proportion to the injection time. The width of the peak can correspond to the injection time within 5%. Thus, the pulse does not show significant broadening on a short secondary column, and the primary exhaust fluid can pass through the gap almost instantly during the packed state. Figure 20 also demonstrates that the pulse area can be directly proportional to the injection time. This is expected if the injection time is not sufficient to completely flush the primary exhaust fluid from the loop. For example, injection times greater than 40 ms may result in broader peaks, but not taller peaks (at least when using a 1 m × 0.25 mm uncoated secondary column). A modulator capable of injecting narrow pulses is desirable for many applications.

[0061] When modulating around a 40 ms injection time, the loop (e.g., a 12.5 cm loop) may be too large. A smaller loop (e.g., a 5.0 cm loop) could be used instead. Because it may take less time to fill the loop, the modulator may be held in the fill state for a fixed time (e.g., 1.5 seconds), and the injection time may be varied in fixed increments (e.g., from 10 ms to 140 ms in 10 ms increments). Figure 21 generally illustrates pulse overlay. In the configuration described above, the pulse height may essentially plateau as the injection time increases (e.g., above 40 ms). In this configuration, the pulse width may plateau as the injection time increases (e.g., above 60 ms). A longer injection time may not increase the pulse width, but may increase the trailing shoulder of the pulse. This may be a result of the time required to wash out the loop (e.g., a 5 cm loop) (e.g., approximately 60 ms). After a certain time (e.g., 60 ms) in the inject state, the source of pentane may no longer be the primary exhaust fluid collected during the preceding fill state, but instead the primary exhaust fluid entering the current inject state. Because the pentane entering the loop during the inject state may be diluted by the auxiliary carrier gas, the signal intensity of the trailing shoulder may be lower (see, e.g., Figure 21). Pulse statistics are plotted as a function of inject time in Figure 22. The peak height may plateau after a certain time (e.g., 40 ms). The width may plateau at a value (e.g., about 58 ms) for inject times greater than 60 ms. The pulse area may increase in direct proportion to the inject time until the loop is completely washed out (e.g., 60 ms). After that point, the area may increase more slowly, due to factors such as the extension of the low-intensity trailing shoulder of the pulse. For example, but not by way of limitation, when using a loop approximately 5 cm long (under the current flow conditions), a sharp, symmetrical pulse can be obtained if the inject time is approximately 60 ms or less.

[0062] For example, the modulator can be designed to produce the best (or optimal) pulse shape when the loop is overfilled during the fill state. A test setup can be used to investigate the effect of the extent to which the loop is filled during the fill state. For example, but not by way of limitation, the test setup can include a 5.0 cm long loop, with the injection time held at 150 ms and the fill time varied from 500 ms to 2500 ms in 250 ms increments. Figure 23 shows an example of pulse overlay. As the fill time increases, the leading edge of the pulse may shift to the left (e.g., have a shorter arrival time), possibly due to increased loop filling. The leading edge of the pulse may assume a consistent shape at certain fill times (e.g., 1.25 s or greater), indicating that it takes a certain time (e.g., approximately 1.25 s) to begin overfilling the loop under the current conditions. As the fill time increases, the trailing edge may shift to the right. This may be due, at least in part, to the primary exhaust fluid diffusing into the unswept region of the primary T-joint during the fill state. Increasing the fill time can cause the primary drainage fluid to diffuse further from the loop inlet. This can be avoided by using an injection time shorter than the pulse width so that the trailing edge is clipped, which can be an advantage to under-draining the loop.

[0063] In embodiments, the modulator (e.g., under current flow conditions using a 5 cm loop) can generate ideal and / or consistent pulse shapes for injection times that under-drain the loop (e.g., 60 ms or less) and for fill times that over-fill the loop (e.g., 1.25 s or more). By way of example, and not limitation, pulses generated with a 40 ms injection time can be compared with fill times ranging from 1.5 s to 3.0 s in 0.5 s increments. An example of the resulting pulse overlay is shown in FIG. 24. All seven pulses overlap almost perfectly, demonstrating the reproducibility generated when operating under over-drained / under-drained conditions. Over-drained / under-drained conditions can provide the additional benefit that the sharpness of the pulse edges can be determined by the environment immediately adjacent to the inlet of the secondary column. Therefore, the unswept volume of the primary or exhaust tee may have little effect on the pulse shape.

[0064] In embodiments, the auxiliary carrier gas can serve at least two functions in the fluid modulator: (i) to provide carrier gas to the secondary column, and (ii) to create a curtain flow that can prevent the primary exhaust fluid from entering the secondary column during a packing condition.

[0065] Potential advantages of modulator embodiments include ensuring that the curtain gas does not dilute the primary exhaust fluid collected in the loop. Pulses may be generated with an auxiliary carrier gas flow, for example, in the range of 10.5 mL / min to 17.0 mL / min. For a secondary column flow of, for example, 10.0 mL / min, this can correspond to a curtain flow in the range of 0.5 mL / min to 7.0 mL / min. While the magnitude of the input flow rate can be accurately measured, accurately measuring the curtain flow may be more difficult. Curtain flow may increase with increasing auxiliary carrier flow, and / or the actual value of curtain flow may only be an estimate. For example, but not by way of limitation, the injection time may be set to 40 ms and the fill time may be 1460 ms. An example of pulse overlay is shown in FIG. 25. Pulses with the lowest curtain flow may have the highest amount of tailing. This is likely due to the small amount of curtain flow pushing the primary exhaust fluid back out the inlet of the secondary column immediately after the modulator switches from injection to fill. The amount of tailing may decrease as the curtain flow increases. Once the curtain flow reaches a certain flow rate, e.g., 3.1 mL / min, further increases in curtain flow (e.g., for a 4.4 mL / min curtain flow) may not result in a noticeable change in pulse shape. Because increasing the curtain flow rate does not change peak intensity, users may be able to adjust the auxiliary carrier gas flow rate significantly higher than the secondary column flow rate (e.g., from 4 mL / min to 8 mL / min higher) and still obtain satisfactory peak shape and maximum signal intensity.

[0066] Independence of peak intensity from curtain gas flow can be an advantage of modulator embodiments, such as those compared to backfill / backdrain modulators. For example, and without limitation, a modulator embodiment such as that shown in FIG. 15 can be converted to an RFF modulator embodiment by changing (e.g., swapping) the positions of primary column 70″ and flow regulator 90″. FIG. 26 shows a pulse overlay for such an RFF modulator embodiment. While increasing the curtain flow can reduce pulse tailing, the pulse intensity for an RFF modulator is small even at the lowest curtain flow, and increasing the curtain flow can significantly reduce pulse intensity. In some situations, the pulse intensity at a curtain flow of, for example, 7.0 mL / min, can be nearly 10 times lower than that which can be produced by modulator embodiments. The decrease in pulse intensity with increasing curtain flow observed with the RFF modulator is believed to be due to the RFF flow pattern causing curtain flow that dilutes the primary drain fluid collected in the loop. Notably, data (e.g., FIG. 26) indicate that modulation of RFF modes can be readily achieved with different embodiments, such as that illustrated in FIG. 15, by swapping the positions of the primary column and flow regulator. Such novel embodiments of RFF modulators may offer advantages over other RFF-type modulators, particularly due to the coaxiality / configuration of the secondary column with the coupling tube and the coaxiality / configuration of the flow regulator with the loop. In particular, such conduit coaxiality / configuration allows for tuning of the effective length of the coupling tube and / or loop simply by changing the insertion depth of the secondary column and / or flow regulator.

[0067] An embodiment of the modulator may be used to perform GC×GC separations of gasoline and the like. The modulator may be mounted on a gas chromatograph (e.g., Agilent 7890). For example, but not by way of limitation, a 15.0 m x 0.25 mm x 0.50 μm DB-1 column may serve as the primary column, and a 5.0 m x 0.25 mm x 0.25 μm Stabilwax column may serve as the secondary column. Hydrogen may be used as the carrier gas. By way of example and not by way of limitation, a 0.5 μL volume of gasoline may be injected through a split inlet (split ratio 100:1) maintained at 250°C. The split inlet may provide a primary column flow of 1.0 mL / min. A supplemental carrier gas flow of 15 mL / min may be supplied to the modulator by a pneumatic control module (PCM). A backpressure regulator associated with the PCM was connected to the modulator's outlet port and used to establish a secondary column flow of 10 mL / min, resulting in a curtain flow of 5.0 mL / min. The modulator was operated with an injection time of 30 ms and a fill time of 1470 ms, resulting in a modulation period of 1.5 s. The components of the mixture were detected with a flame ionization detector. The chromatograph oven was held at 40 °C for 1 min and then ramped to 200 °C at 17 °C / min.

[0068] Figure 27 shows an example GCxGC chromatogram of gasoline. This chromatogram displays the GCxGC separation of a petrochemical mixture using a non-polar x polar column set. Saturated hydrocarbons may produce a horizontal band near the bottom of the chromatogram. Aromatic hydrocarbons may produce a series of "roof tile"-shaped bands that run diagonally from medium to high secondary retention times. This example column set is capable of rapid separation of gasoline. For example, gasoline may be separated in approximately 12 minutes.

[0069] The performance of an embodiment of a modulator can be evaluated by examining the width of the peaks along the two-dimensional direction. To this end, a segment of the signal sequence used to construct the two-dimensional chromatogram may be examined. Figure 27 generally highlights the location of this segment with a vertical dotted line. Figure 28 shows an example signal sequence. The modulated peaks may be quite narrow, e.g., 35 ms for the saturated hydrocarbon peak and 45 ms for the moderately retained benzene peak. Both of these widths may be close to the 30 ms injection width. All peaks may have a symmetric Gaussian distribution.

[0070] The second-order resolution of chromatograms, such as GC×GC chromatograms of gasoline, produced using embodiments of the modulator may be much higher than the resolution obtained using a full transport flow modulator, without a loss of signal intensity.

[0071] Modulator embodiments may be able to generate extremely narrow pulses without compromising peak intensity. Modulator embodiments may be easier to optimize / tune than other differential flow modulators. Modulator embodiments may produce superior performance without increased mechanical complexity when compared to RFF modulators.

[0072] In some of the above-described embodiments, the modulator is disclosed in what is referred to as an "overfill / underdrain" mode. In the overfill / underdrain mode, the modulator may be held in a fill state long enough to overfill the loop with primary exhaust fluid, and then placed in an inject state long enough that the primary exhaust fluid does not completely drain the loop. In such a mode, an undiluted pulse of primary exhaust fluid may occur with a width slightly shorter than the inject time. In the overfill / underdrain mode, a pulse with very sharp leading and trailing edges may occur.

[0073] However, in other embodiments of the present disclosure, it has been found that there may be advantages to operating the modulator in essentially the opposite manner. In such an opposite mode, referred to as an "underfill / overdrain" mode, the loop volume may be increased (e.g., by only withdrawing the primary column a few centimeters into the loop) so that the primary exhaust fluid does not overfill the loop during the fill state, and the switch flow Fs may be increased so that all of the collected primary exhaust fluid is drained from the loop during the fill state.

[0074] An underfilled / overdrained modulator embodiment is generally shown in Figures 29 through 33. In these figures, the undiluted primary drain fluid is identified by hatching. The remaining charge in the system is generally made up of carrier gas. For illustrative purposes, the figures generally include some example values ​​for flows that may exist within the modulator. Example flow rates assume that the external flow rates are given by F1 (e.g., 1.0 mL / min), F2 (e.g., 10.0 mL / min), Fs (e.g., 30.0 mL / min), and Fx (e.g., 21.0 mL / min). Both the external and internal flow rates are shown in conjunction with Figures 29 through 33.

[0075] The starting point of a modulation cycle is considered to be the point at which modulator 10''' has been held in a filled state for a sufficient period of time such that primary exhaust fluid has nearly filled loop 50'''. Figure 29 generally illustrates an embodiment that illustrates such a starting point.

[0076] In such an embodiment, valve 100'" may be switched to the inject state prior to overfilling the loop with undiluted primary exhaust fluid. FIG. 30 generally illustrates an example of the start of the inject state. The auxiliary carrier then enters primary tee 30'", where it combines with the incoming primary exhaust fluid at a high flow rate (e.g., 31 mL / min), rapidly pushing a plug of undiluted primary exhaust fluid through exhaust tee 20'", where it is diverted between secondary column 80'" and flow regulator 90'". The ratio of the collected primary exhaust fluid entering secondary column 80'" (i.e., F2 / Fs) may be, for example, 10 / 31.

[0077] FIG. 31 generally illustrates the embodiment during the final moments of the fill state. In such a state, the auxiliary flow may have pushed all of the undiluted primary exhaust fluid out of loop 50′″. FIG. 32 generally illustrates such an embodiment immediately after returning to the fill state. By way of example, and not limitation, the auxiliary flow (e.g., 30.0 mL / min) may continue to push a segment of undiluted primary exhaust fluid downstream of secondary column 80′″, with a portion (e.g., 10.0 mL / min) continuing to enter secondary tee 40′″. The remaining portion (e.g., 20.0 mL / min) of such auxiliary flow may function as a curtain flow preventing the entry of additional primary exhaust fluid. At the same time, undiluted primary exhaust fluid may begin to refill loop 50′″ near primary tee 30′″. FIG. 33 generally illustrates the embodiment after being held in the fill state for approximately half the fill time. The system is held in such a filled state until the loop 50''' is nearly filled (see, for example, FIG. 29), and the cycle is repeated.

[0078] In the above-described embodiments, it was noted that pulse shaping advantages in the overfilled / underdrained mode may be realized, for example, by trimming or clipping leading and trailing pulse edges. In underfilled / overdrained mode embodiments, such pulse edges may not be trimmed or clipped. However, a higher flow rate may be provided to flush the loop in the underfilled / overdrained mode, which may be, for example, up to two times (or more) higher than the flow rate used to flush the loop in the overfilled / underdrained mode. Such a higher flow rate associated with the underfilled / overdrained mode may be particularly useful in reducing or minimizing pulse broadening caused by the “unclipped” leading and trailing edges of the pulse. In embodiments of the present disclosure, it has been found that the underfilled / overdrained mode may produce pulses that are only 10% wider than their theoretical minimum.

[0079] Furthermore, in embodiments, a single modulator may be used in conjunction with either an overfill / underdrain mode or an underfill / overdrain mode. For example, in the overfill / underdrain mode, the auxiliary carrier flow may be operated near a minimum (e.g., 3 mL / min, greater than F2) to rapidly switch between fill and injection states, with the primary column pushed into the loop to shorten the effective loop length. The underfill / overdrain mode may be established by withdrawing the primary column to the rear of the loop and operating at a higher auxiliary flow (e.g., near 30 mL / min). In embodiments, the overfill / underdrain mode may, for example, produce relatively slightly sharper pulses, while the underfill / overdrain mode may, for example, provide relatively better quantification accuracy, especially when modulating narrow primary column peaks.

[0080] Some embodiments described thus far have involved systems with three union tees and two lengths of tubing (see, for example, the loop and connecting tube in FIG. 15 ). However, the inventive concepts are not limited to such configurations, and other potentially advantageous embodiments can be constructed, including, but not limited to, other configurations mentioned below.

[0081] For example, without limitation, one way to reduce the potential for leaks that may be associated with a three-tee modulator is to provide a primary tee 200 and replace the exhaust tee, connecting tube, and secondary tee with a single cross-union (see, for example, single cross-union 210 generally shown in FIG. 34). In such an embodiment, cross-union 210 may include straight through-holes connecting loop port 220 and secondary column port 230, and may include "staggered" orthogonal positions such that exhaust port 240 and switch flow port 250 connect to the through-holes. In such an embodiment, exhaust port 240 may connect to the through-hole closer to loop port 220, and switch flow port 250 may connect to the closer to secondary column port 230. The inlet of the secondary column may then be positioned between exhaust port 240 and the switch flow connection point. Advantages of such an embodiment include the ability to reduce the number of fittings from three to two, increase the mechanical strength of the modulator (e.g., by eliminating the connecting tube), and / or reduce the risk of leakage by eliminating the two compression seals associated with the connecting tube.

[0082] FIG. 35 generally illustrates an embodiment of a modulator including a primary T-joint 300 and a cross-union 310 with an overinsertion associated with a secondary column. The modulator may include a loop port 320 and a secondary column port 330, and may also include an exhaust port 340 and a switch flow port 350. This configuration of overinserting a secondary column into a standard cross-joint can effectively mimic a staggered cross-joint. This configuration may allow such a modulator / system to mimic the benefits of a modulator / system with two T-joints and a connecting capillary, but use one (e.g., replacing the exhaust T-joint, connecting capillary, and secondary T-joint with a single cross-joint). Examples of flow patterns generated in such a cross-joint (overinserted into a secondary column) during the fill and inject states are generally illustrated in FIG. 36. As generally illustrated, this secondary column overinsertion can be filled with an auxiliary carrier during the fill state and not filled with primary exhaust fluid. During the inject state, primary exhaust fluid can enter the secondary column. In embodiments, inserting a secondary column (e.g., about 1 mm) into the opposite port can provide a modulator that functions equivalently to a 3T joint modulator (e.g., such as the embodiment shown in FIG. 15). However, as noted above, some potential advantages of such an approach are that the number of joints can be reduced and mechanical strength can be increased. In embodiments, the risk of analytes being adsorbed to the outside of the tip of the secondary column can be minimized by coating the outer surface of the tip of the secondary column with a deactivating material, including, for example, in the form of a layer of deactivating material.

[0083] FIG. 37 generally illustrates another embodiment. In such an embodiment, all of the discrete union tee fittings can be replaced with a single five-port modulator manifold. FIG. 37 generally illustrates an embodiment of a five-port manifold 400. The five-port manifold embodiment may be configured, for example, from a single unit component (e.g., a single, unit-formed body / housing structure 410) and may further include a liner 420, for example, a ported, inert liner (which may be constructed, for example, of silanized glass) that can be inserted down the length of the manifold. In an embodiment, such a liner may include one or more small exhaust ports drilled through the liner wall, for example, near the location of the outward exhaust pipe. The apparatus / system illustrated in FIG. 37 may include a primary column 430, a secondary column 440, a line or tubing leading to an exhaust flow regulator 450, a normally open line from a selector valve 460, and a normally closed line from a selector valve 470.

[0084] The liner 420 may include one or more seals 480 and may include a drain hole 490 positioned for fluid communication with the drain port. In embodiments, the liner 420 may be connected and / or sealed to the inner body of the manifold at least two locations, for example, (i) between the upstream switch flow port 500 and the drain port 510, and (ii) between the drain port 510 and the downstream switch flow port 520. The inlet of the secondary column may be located slightly downstream from the liner drain port(s). In embodiments, the drain port may be provided by replacing the perforated liner with two pieces of tubing butted against each other. For example, the end of one tube may include a small radial groove that can function as a drain port when the two pieces of tubing are placed (e.g., pressed) in an end-to-end configuration. Furthermore, the "internal liner" embodiment of the modulator may offer certain advantages, such as, for example, the modulator may have high mechanical strength; the primary exhaust fluid that ultimately enters the secondary column only contacts the inner surface of the liner, so that only the liner needs to be inactivated; if the modulator becomes fouled by low-volatility sample components, the performance of the modulator can be restored by simply replacing the liner; and / or the internal dimensions of the linear section may be tailored to the specific needs of the current separation, while the remaining hardware may not require significant modification.

[0085] It should be noted that, in modulator embodiments such as those generally shown in FIG. 15 , some embodiments can be operated in a reverse-fill / drain mode, for example, by swapping the positions of the primary column and exhaust fluid regulator (e.g., elements 70″ and 90″). FIG. 38 generally illustrates one embodiment of a modulator 500 operable in a reverse-fill / drain mode. The coaxiality / configuration of the secondary column 510 and the coupling tube 520 allows the effective length of the coupling tube 520 in such embodiments to be adjusted simply by varying the insertion depth of the secondary column 510 into the coupling tube 520. This adjustability is advantageous when operating in RFF mode in view of the small curtain flow typically associated with RFF mode. For example, the leading edge of the secondary column 510 can be moved away from the primary tee 530 toward the secondary tee 540, thereby increasing the effective length of the coupling tube 520 and reducing diffusive transport of the primary exhaust fluid to the inlet of the secondary column 510. 38 may also employ a conduit 550 associated with an exhaust tee 560 that leads to an exhaust fluid regulator. In an embodiment, the conduit 550 may be narrow enough to allow for coaxial insertion into the loop conduit 570. The depth of insertion of the flow regulator conduit 550 may be varied to provide an adjustable effective loop length, a beneficial feature when operating the modulator under overfill conditions, for example.

[0086] Various examples / embodiments relating to various devices, systems, and / or methods are described herein. Numerous specific details are set forth to provide a thorough understanding of the overall structure, function, manufacture, and use of the examples / embodiments as described herein and illustrated in the accompanying drawings. However, those skilled in the art will understand that the examples / embodiments may be practiced without such specific details. In other examples, well-known operations, components, and elements have not been described in detail so as not to obscure the examples / embodiments described herein. Those skilled in the art will understand that the examples / embodiments described and illustrated herein are non-limiting examples, and thus, specific structural and functional details disclosed herein may be typical and do not necessarily limit the scope of the embodiments.

[0087] Throughout this specification, references to "an example," "in an example," "with examples," "various embodiments," "in an embodiment," or "embodiment" or the like mean that a particular feature, structure, or characteristic described in connection with an example / embodiment is included in at least one embodiment. Thus, the appearances of phrases such as "by example," "in an example," "with examples," "various embodiments," "in an embodiment," or "embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more example / embodiment. Thus, a particular feature, structure, or characteristic illustrated or described in connection with one embodiment / example may be combined, in whole or in part, without limitation, with features, structures, functions, or characteristics of one or more other embodiments / examples, provided that such a combination is not illogical or non-functional. Furthermore, many modifications may be made to adapt a particular situation or material to the teachings of the present disclosure without departing from its scope.

[0088] It should be understood that a reference to a single element is not necessarily so limited and may include one or more of such elements. Any directional references (e.g., plus, minus, up, down, above, below, left, right, leftward, rightward, up, down, above, below, vertical, horizontal, clockwise, and counterclockwise) are used for identification purposes only to aid the reader in understanding this disclosure and are not intended to create limitations as to the location, orientation, or use of any particular example / embodiment.

[0089] Joined references (e.g., attached, coupled, connected, etc.) should be interpreted broadly and may include intermediate members between the connection of elements and relative movement between the elements. As such, joined references do not necessarily imply that two elements are directly connected / coupled and in a fixed relationship to each other. The use of "for example" herein should be interpreted broadly and is used to provide non-limiting examples of embodiments of the present disclosure, and the present disclosure is not limited to such examples. The use of "and" and "or" should be interpreted broadly (e.g., treated as "and / or"). For example, but not limited to, the use of "and" does not necessarily require all listed elements or features, and the use of "or" is inclusive unless such a configuration is illogical.

[0090] Although processes, systems, and methods may be described herein with reference to one or more steps in a particular order, it should be understood that such methods may be practiced in a different order of steps, with certain steps simultaneously, with additional steps, and / or with certain described steps omitted.

[0091] All matter contained in the above description or shown in the accompanying drawings is to be interpreted as illustrative only and not limiting. Changes in detail or structure may be made without departing from the present disclosure.

[0092] (Appendix 1) a fluid manifold comprising a primary tee, a discharge tee, a secondary tee, a loop conduit, a connecting pipe, and a flow regulator; a fluid valve having a common port, a normally open output port connected to said secondary tee, and a normally closed output port connected to said primary tee; a pressure / flow controller configured to supply a secondary fluid to the common port of the fluid valve; The fluid modulator includes a primary T-joint, a discharge T-joint, and a secondary T-joint, the primary T-joint and the secondary T-joint being located at opposite ends of the fluid manifold with the discharge T-joint disposed therebetween, the primary T-joint being connected to the discharge T-joint by the loop conduit, the discharge T-joint being connected to the secondary T-joint by the connecting pipe, the loop conduit being longer than the connecting pipe, the primary T-joint being configured to connect to a primary column, and the secondary T-joint being configured to connect to a secondary column. (Appendix 2) configured to operate in a filling state and an injecting state so as not to dilute the collected primary exhaust fluid; When operating in the packed state, a fluid valve directs a switch flow to the secondary T-joint to supply carrier gas to the secondary column, a primary column exhaust fluid fills the loop conduit, and the primary exhaust fluid and excess of the switch flow are discharged at the exhaust T-joint; 2. The fluid modulator of claim 1, wherein when operating in the injection state, the fluid valve is switched such that the switched flow is directed to the primary T-joint to direct the primary exhaust fluid from the loop conduit to the secondary column, and the excess flow is directed to the exhaust T-joint for outlet. (Appendix 3) 3. A fluid modulator as described in claim 2, wherein the duration of the filling state can be adjusted so that the total volume of the primary discharge fluid flowing into the loop conduit is less than the volume of the loop conduit (underfilled), or, if desired, so that the total volume of the primary discharge fluid flowing into the loop conduit exceeds the volume of the loop conduit (overfilled). (Appendix 4) 3. The fluid modulator of claim 2, wherein the duration of the injection state is adjustable so that the volume of the switching flow entering the loop conduit is less than the total volume of the loop conduit (under-discharge) or, if desired, so that the total volume of the switching flow entering the loop conduit exceeds the volume of the loop conduit (over-discharge). (Appendix 5) 3. The fluid modulator of claim 2, configured to provide a modulation cycle including the filling state (filling) and the injection state (draining), wherein the repetition of the filling state / injection state is one of: (i) overfilling / underdraining, (ii) underfilling / overdraining, (iii) overfilling / overdraining, or (iv) underfilling / underdraining. (Appendix 6) 10. The fluid modulator of claim 1, wherein the primary tee, the discharge tee, and the secondary tee are configured in a linear or coaxial configuration. (Appendix 7) 10. The fluid modulator of claim 1, wherein the flow regulator is connected to the outlet tee. (Appendix 8) 10. The fluid modulator of claim 1, wherein the flow regulator is selected from the group consisting of a static device, an adjustable device, and a combination of a static device and an adjustable device. (Appendix 9) 10. The fluid modulator of claim 1, wherein the flow adjuster comprises a backpressure regulator. a fluid manifold comprising a primary tee, a discharge tee, a secondary tee, a loop conduit, a connecting pipe, and a flow regulator; a fluid valve having a common port, a normally open output port connected to said secondary tee, and a normally closed output port connected to said discharge tee; a pressure / flow controller configured to supply a secondary fluid to the common port of the fluid valve; The discharge T-joint, primary T-joint, and secondary T-joint are located at opposite ends of the fluid manifold, with the primary T-joint disposed therebetween, the discharge T-joint connected to the primary T-joint by the loop conduit, the primary T-joint connected to the secondary T-joint by the connecting pipe, the loop conduit being longer than the connecting pipe, the primary T-joint configured to connect with a primary column, and the secondary T-joint configured to connect with a secondary column. (Appendix 11) configured to operate in a filling state and an injecting state; (i) in the packed state, the fluid valve directs a switching flow to the secondary T-joint to supply carrier gas to the secondary column, a primary column exhaust fluid fills the loop conduit, and the primary exhaust fluid and excess switching flow are discharged at the exhaust T-joint; 11. The fluid modulator of claim 10, wherein (ii) in the injection state, the fluid valve is switched to direct the primary exhaust fluid from the loop conduit to the secondary column in a direction opposite to the direction in which the loop conduit was filled, with the switch flow being directed to the exhaust Tee and excess switch flow being directed to an outlet exhaust Tee. (Appendix 12) 12. The fluid modulator of claim 11, wherein the duration of the filling state is adjustable so that the total volume of the primary discharge fluid flowing into the loop conduit is less than the volume of the loop conduit (underfilled), or, if desired, so that the total volume of the primary discharge fluid flowing into the loop conduit exceeds the volume of the loop conduit (overfilled). (Appendix 13) 12. The fluid modulator of claim 11, wherein the duration of the injection state is adjustable so that the volume of the switching flow entering the loop conduit is less than the volume of the loop conduit (under-discharge) or, if desired, so that the total volume of the switching flow entering the loop conduit exceeds the volume of the loop conduit (over-discharge). (Appendix 14) 12. The fluid modulator of claim 11, configured to provide a modulation cycle including the filling state (filling) and the injection state (draining), wherein the repetition of the filling state / injection state is one of: (i) overfilling / underdraining, (ii) underfilling / overdraining, (iii) overfilling / overdraining, or (iv) underfilling / underdraining. (Appendix 15) 11. The fluid modulator of claim 10, wherein the discharge tee, the primary tee, and the secondary tee are configured in a linear or coaxial configuration. (Appendix 16) 11. The fluid modulator of claim 10, wherein the flow regulator is connected to the outlet tee. (Appendix 17) 11. The fluid modulator of claim 10, wherein the flow regulator is selected from the group consisting of a static device, an adjustable device, and a combination of a static device and an adjustable device. (Appendix 18) 11. The fluid modulator of claim 10, wherein the flow adjuster comprises a back pressure regulator. (Appendix 19) 11. The fluid modulator of claim 10, wherein the discharge T-joint, the primary T-joint, and the secondary T-joint are switchable to a configuration in which the primary T-joint and the secondary T-joint are located at opposite ends of the fluid manifold and the discharge T-joint is disposed therebetween. (Appendix 20) 11. The fluid modulator of claim 1 or claim 10, comprising a single, integral five-port fluid manifold body. (Appendix 21) 11. The fluid modulator of claim 1 or claim 10, wherein the flow regulator is included in the discharge tee.

Claims

1. A fluid modulator for controlling flow balance and pressure within the fluid modulator, comprising: a fluid manifold comprising a primary tee, a discharge tee, a secondary tee, a loop conduit, a connecting pipe, and a flow regulator connected to the discharge tee; a fluid valve having a common port, a normally open output port connected to said secondary tee, and a normally closed output port connected to said discharge tee; a pressure / flow controller configured to supply a substantially constant flow rate of auxiliary fluid to the common port of the fluid valve; the discharge T-joint, primary T-joint, and secondary T-joint are located at opposite ends of the fluid manifold with the primary T-joint disposed therebetween, the discharge T-joint is connected to the primary T-joint by the loop conduit, the primary T-joint is connected to the secondary T-joint by the connecting pipe, the loop conduit is longer than the connecting pipe, the primary T-joint is configured to connect with a primary column, and the secondary T-joint is configured to connect with a secondary column; A fluid modulator, wherein the flow regulator is configured to do at least one of the following: (i) balancing the outlet pressure of the primary column with the inlet pressure of the secondary column to control the flow balance within the fluidic modulator; or (ii) controlling the flow balance in the fluid modulator to control the outlet pressure of the primary column and the inlet pressure of the secondary column;

2. configured to operate in a filling state and an injecting state; (i) in the packed state, the fluid valve directs a switching flow to the secondary T-joint to supply carrier gas to the secondary column, a primary column exhaust fluid fills the loop conduit, and a primary exhaust fluid and an excess switching flow are discharged at the exhaust T-joint; 2. The fluid modulator of claim 1, wherein (ii) in the injection state, the fluid valve is switched to direct the primary exhaust fluid from the loop conduit to the secondary column in a direction opposite to the direction in which the loop conduit was filled, with the switch flow being directed to the exhaust Tee and excess switch flow being directed to an outlet exhaust Tee.

3. 3. The fluid modulator of claim 2, wherein the duration of the filling state is adjustable so that the total volume of the primary discharge fluid flowing into the loop conduit is less than the volume of the loop conduit (underfilling) or so that the total volume of the primary discharge fluid flowing into the loop conduit exceeds the volume of the loop conduit (overdischarge).

4. 3. The fluid modulator of claim 2, wherein the duration of the injection state is adjustable so that the volume of the switching flow flowing into the loop conduit is less than the volume of the loop conduit (under-discharge) or so that the total volume of the switching flow flowing into the loop conduit exceeds the volume of the loop conduit (over-discharge).

5. 3. The fluid modulator of claim 2, configured to provide a modulation cycle including the filling state (filling) and the injection state (draining), wherein the repetition of the filling state / injection state is one of: (i) overfilling / underdraining, or (ii) underfilling / overdraining.

6. The fluid modulator of claim 1 , wherein the discharge tee, the primary tee, and the secondary tee are configured in a linear or coaxial configuration.

7. 10. The fluid modulator of claim 1, wherein the flow regulator is selected from the group consisting of a static device, an adjustable device, and a combination of a static device and an adjustable device.

8. The fluid modulator of claim 1 , wherein the flow adjuster comprises a backpressure regulator.

9. 2. The fluid modulator of claim 1, wherein the exhaust tee, the primary tee, and the secondary tee are switchable to a configuration in which the primary tee and the secondary tee are located at opposite ends of the fluid manifold and the exhaust tee is disposed therebetween.

10. 10. The fluid modulator of claim 1 comprising a single, integral five-port fluid manifold body.

11. The fluid modulator of claim 1 , wherein the flow adjuster is included in the discharge tee.

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