Multidimensional liquid chromatography system

Abstract

Described herein are multi-dimensional liquid chromatography (MDLC) systems and methods of performing MDLC. The MDLC systems include a valve configuration that enables modulation of a flow containing an analyte in an eluent of a first dimension liquid chromatography system such that the analyte can be captured in a fluidic circuit and subsequently provided to a second dimension liquid chromatography system. Various system embodiments are provided with small instrument size, including the option of using the same detector for both the first and second dimensions, enabling improved valve timing operations, and reduced magnitude and impact of pressure pulses. Additionally, the modulator can enable dilution of the analyte, and the use of incompatible mobile phases and mobile phase flow rates on the first and second dimensions.

Description

[0001] Related applications

[0002] This patent application claims the benefit of the earlier filing date of U.S. Provisional Patent Application Serial No. 63 / 021,396 entitled “Multidimensional Liquid Chromatography System”, filed on May 7, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates generally to liquid chromatography systems, and more specifically to systems and methods for performing multidimensional liquid chromatography. Background Technology

[0004] Multidimensional liquid chromatography (MDLC) is commonly used to solve chromatographic separation problems arising from challenging chemical separations. Nevertheless, limitations remain that hinder the widespread deployment and acceptance of MDLC. For example, conventional MDLC systems may have multiple system modules, leading to instrument size. Additionally, MDLC systems typically include separate dedicated detectors for the first and second dimensions. Therefore, even if the detectors are of the same type, modulation efficiency cannot be accurately measured due to subtle differences in detector response. Furthermore, systems configured for MDLC-MS (mass spectrometry) with MS in the second dimension are used only for MDLC-MS separations and require repiping to switch between MDLC-MS and single-dimensional LCMS operations.

[0005] Another common problem with MDLC systems is the timing associated with the switching of the modulation valve. The actuation of the modulation valve must take into account the volume of the interconnecting tubing between the detector and the collection device. Additionally, valve actuation can generate pressure pulses, which may cause detector baseline interference.

[0006] The modulator section of an MDLC system can limit the types of separators that can be coupled together. More specifically, different dimensions of mobile phases and / or flow velocities may be incompatible within an MLDC system.

[0007] In addition to the above, creating methods for MDLC systems is also challenging. Control of such systems is typically limited to expert users. Summary of the Invention

[0008] In one aspect of this disclosure, a multidimensional liquid chromatography system includes: a switching valve operable in at least two valve states; a detector; a path selection valve; and a first fluid loop valve. The detector is connected to the switching valve via a first fluid path, and the path selection valve is connected to the switching valve via a second fluid path. The first fluid loop valve is connected to the path selection valve via a third fluid path. The volume of the first fluid path is equal to the sum of the volumes of the second and third fluid paths.

[0009] The first fluid circuit valve may have multiple sample fluid circuits, each of which is connected to a corresponding pair of ports of the first fluid circuit switching valve.

[0010] The multidimensional liquid chromatography system may include a second fluid loop valve connected to the path selection valve via a fourth fluid route, wherein the volume of the first fluid route is equal to the sum of the volumes of the second and fourth fluid routes. The volume of the third fluid route may be equal to the volume of the fourth fluid route. The second fluid loop valve may have multiple sample fluid loops, each connected to a corresponding pair of ports of the second fluid loop switching valve.

[0011] The fluid path may be defined by a tube. The tube may be a fused silica tube. The difference between the volume of the first fluid path and the sum of the volumes of the second and third fluid paths may not exceed the volume variation based on the manufacturing tolerances of the tube. The diameter of the tube in one of the fluid paths may differ from the diameter of the tube in the other fluid path.

[0012] When the switching valve is in the first valve state, the liquid received at the first port of the switching valve can flow to the detector, and when the switching valve is in the second valve state, the liquid received at the first port can flow to the path selection valve.

[0013] The multidimensional liquid chromatography system may include a first-dimensional column and a second-dimensional column, which are connected to the switching valve through the first port and the second port of the switching valve, respectively.

[0014] A portion of the path selection valve, as well as the first fluid loop valve and the second fluid loop valve, may be formed in a diffusion-bonded stator array. Attached Figure Description

[0015] The above and other advantages of the present invention can be better understood by referring to the following description in conjunction with the accompanying drawings, in which the same reference numerals indicate the same elements and features in each drawing. For clarity, not every element is labeled in every drawing. The drawings are not necessarily drawn to scale, but are intended to illustrate the principles of the technology.

[0016] Figure 1 This is a schematic block diagram representing the functions of an MDLC system.

[0017] Figure 2 It is a block diagram of an implementation scheme including a modulator for capturing and subsequently providing analyte peaks from a first dimension to a second dimension.

[0018] Figures 3 to 6 This is a schematic diagram of an implementation scheme for an MDLC system configured to perform various MDLC functions.

[0019] Figure 7 The detector response of a UV-Vis detector for an MDLC system with a pulse damper and the detector response of the same detector for an MDLC system without a pulse damper are shown.

[0020] Figures 8A to 8F It is a chromatogram of separation performed using a simple fluid T-tube, and Figures 8G to 8L This is a chromatogram obtained using a 50µL mixing T-tube.

[0021] Figures 9 to 23 This is a schematic diagram of an MDLC system configured to perform various MDLC functions. Detailed Implementation

[0022] In this specification, references to “example,” “implementation,” or “specific implementation” mean that a particular feature, structure, or characteristic described in connection with that example, implementation, or specific implementation is included in at least one implementation of this teaching. References to specific examples, implementations, or specific implementations within this specification do not necessarily refer to the same implementation.

[0023] As used herein, an analyte peak refers to an analyte present in the eluent from the column and corresponding to the analyte represented by the corresponding peak in the chromatogram. Analyte peaks resulting from chromatographic separation can be modulated for further separation using a column corresponding to a second chromatographic dimension. Modulation is the process of making a first-dimensional chromatographic separation segment compatible with the second dimension. Compatibility with the second dimension can be achieved by temporarily separating the segment from the first dimension, by exchanging the mobile phase, changing the pH, removing salts, or by diluting the segment before introducing it into the second dimension. A segment may include a portion of one or more analyte peaks overlapping in the first-dimensional chromatogram, where each peak includes an analyte different from the analyte in another peak. A segment may also not contain a peak in the first dimension but is defined by a retention time range. Segments can be collected for storage in a fluid loop or on a trapping column. Modulation devices may also include one or more fluid loops and one or more trapping columns arranged in series with associated valves for fluid path selection. In some cases, “cutouts” or “slices” of analyte peaks may be stored individually, and it should be understood herein that such analyte slices can be processed by MDLC in a manner similar to stored analyte peaks.

[0024] As used herein, a “trapping column” refers to a chromatographic column that can be used to retain and subsequently elute a sample. The sample can be one or more analytes provided by chromatographic separation. Generally, trapping columns are operated under two solvent conditions: one where the solvent strength is weak enough to allow the sample to bind with the stationary phase of the trapping column; and another where the solvent strength is sufficient to allow the sample to be eluted immediately and completely from the trapping column.

[0025] As used herein, a “fluid loop” refers to a fluid storage volume, such as a channel volume, used to temporarily hold a certain amount of liquid. For example, a fluid loop may be used to hold a liquid volume comprising an analyte peak or a slice of liquid corresponding to an analyte peak. The volume of the analyte peak or slice may be less than or equal to the volume of the fluid loop. The fluid loop may be externally coupled to a valve in the form of a pipe. Alternatively, the fluid loop may be coupled to a valve and formed as a channel or other volume within a solid structure, such as a diffusion-bonded structure as described below.

[0026] A typical MDLC system requires a large volume of instrumentation. For example, such a system might require approximately one cubic meter and a significant amount of laboratory bench space. The MLDC system described herein can have a significantly smaller volume and require significantly less bench space.

[0027] The MDLC system disclosed herein can be used as a one-dimensional liquid chromatography system, operated using either of two chromatographic columns, and can be easily reconfigured for two-dimensional chromatography when a specific sample is required. In an exemplary embodiment, the system can be used as a one-dimensional liquid chromatography system, operated using either of two chromatographic detectors, and can be easily reconfigured for two-dimensional chromatography via a control valve when a specific sample is required. Figure 1 A schematic block diagram illustrating the functionality of an MDLC system is shown, including a first-dimensional liquid chromatography module 12, a modulator 14, and a second-dimensional liquid chromatography module 16. The first-dimensional liquid chromatography module 12 and the second-dimensional liquid chromatography module 16 may each include one or more first-dimensional columns and one or more second-dimensional columns, and the modulator 14 may include one or more fluid loops and / or one or more trapping columns. The MDLC system can be used to perform two-dimensional liquid chromatography, wherein one or more analyte peaks or analyte slices separated from the first dimension are modulated via the modulator 14 such that each analyte peak or analyte slice from the first dimension is separated in the second dimension.

[0028] like Figure 2 As shown, in some embodiments, modulator 14 includes fluid loops 18, each of which is used to capture and subsequently provide analyte peaks from a first dimension to a second dimension. Modulator 14 may include a dilution module 20 and a trapping column 22. The dilution module 20 provides a solvent that can be combined with a stream including an analyte peak from one of the fluid loops to form a diluted analyte peak. The trapping column 22 receives the stream (or diluted stream) from the fluid loops and retains the analyte peak on the trapping column. Subsequently, a trapping elution solvent is provided to the trapping column 22 to elute the analyte peak into the stream of the second-dimensional liquid chromatography system.

[0029] Modulator 14 allows the use of a mobile phase in one dimension that may be incompatible with its use in another dimension. For example, hydrophilic interaction chromatography (HILIC) can be performed in the first dimension, while reversed-phase liquid chromatography (RPLC) can be performed in the second dimension. Furthermore, the flow rate of the mobile phase in one dimension does not affect the flow rate of the mobile phase used in the other dimension. For example, a semi-preparative column using a higher mobile phase flow rate (e.g., 10 mL / min) can be used in the first dimension, while an analytical column using a significantly lower mobile phase flow rate (e.g., 500 µL / min) can be used in the second dimension. The volume of peaks captured in the first dimension can be very large (e.g., hundreds of microliters to tens of milliliters or more).

[0030] Figure 3This is a schematic diagram of an MDLC system, which includes a first switching valve 24, a second switching valve 26, a path selection valve 28, a first fluid loop valve 30, a second fluid loop valve 32, and a trapping valve 34. As shown, these valves are implemented as rotary shear valves with stator surfaces connected to the rotor surface, although other valve types compatible with the solvent and pressure of the MDLC system may also be considered. The grooves on the rotor surface are shown as interconnected arcs and / or line segments. Each valve can be rotated clockwise or counterclockwise to change its valve state and reconfigure the fluid path through the valve.

[0031] The first switching valve 24 has two valve states. The first valve state is shown, in which the first switching valve 24 directs the eluent from the first dimension column 36 to the detector 38 and directs the flow downstream from the detector 38 to the path selection valve 28. As a non-limiting example, the detector 38 may be an optical detector, such as an ultraviolet-visible (UV-Vis) or photodiode array detector. In its second valve state (not shown), the first switching valve 24 allows the eluent from the first dimension column 36 to bypass the detector 38 and flow directly to the path selection valve 28.

[0032] A pulse damper is included in the fluid path leading to detector 38. The pulse damper includes a fluid volume that absorbs pressure pulses generated by valve actuation. The pulse damper may be located in the fluid path from detector 38 to path selection valve 28. In a non-limiting example, the pulse damper also includes a pressure relief mechanism to prevent over-pressurization of the detector. For example, Figure 7 The detector response 40 for a UV Vis detector in a system with a pulse damper is shown, as well as the detector response 42 for the same detector in a system without a pulse damper. Detector response 42 includes two peaks corresponding to two valve actuations that may cause system pressure disturbances. These two peaks degrade the detector baseline response and may limit the performance of the MDLC system, especially when the response peaks occur almost simultaneously with the presence of analytes in the flow at the detector. Alternatively, the response peaks may be interpreted as analytes or impurities in the mobile phase.

[0033] Refer again Figure 3 Within manufacturing tolerances, the total volume of the fluid path between the path selection valve 28 and the first fluid loop valve 30 is the same as the total volume of the corresponding fluid path between the path selection valve and the second fluid loop valve 32.

[0034] A solvent source (ACD loader 44) provides solvent to push the stored analyte peak from one of the twelve fluid loops (not shown) to a three-way fluid T-tube 46. The MDLC system includes a dilution solvent source 48 to achieve on-column dilution (ACD) of the analyte peak. The dilution solvent is combined with the analyte peak at the fluid T-tube 46, and the diluted analyte peak flows to the trap valve 34.

[0035] In an alternative implementation, a hybrid T-tube is used instead of the simple three-way fluid T-tube 46. Figures 8A to 8L Chromatograms of separations performed using a simple fluid T-tube or a three-way 50µL mixer (i.e., a mixing T-tube) are shown. Figures 8A to 8F The six chromatograms shown were obtained using a simple fluid T-tube, and each chromatogram represents a specific sample. Figures 8A to 8C The chromatogram corresponds to the analyte eluted from the first dimension in 100% acetonitrile. Figures 8D to 8F The chromatogram corresponds to the same analyte eluted from the first dimension in 100% methanol. Figures 8G to 8L The six chromatograms shown are targeted using a mixed T-tube. Figures 8A to 8F The chromatograms obtained using the same samples and conditions as the corresponding chromatograms were compared. The chromatograms obtained using the fluid T-tube did not exhibit observable shoulders or tails, and the peak heights closely matched those of the chromatograms obtained using the mixed T-tube. This comparison clearly demonstrates that performance was not significantly affected by the mixing capability of the simple fluid T-tube. Therefore, the simple fluid T-tube may be preferred for some applications where the internal composition of the mixed T-tube may cause problems with interactions with one or more analytes.

[0036] Refer again Figure 3 In a preferred embodiment, portions of the path selection valve 28, the first fluid loop valve 30, and the second fluid loop valve 32 may be formed in a diffusion-bonded stator array. U.S. Patent Publication No. 2020 / 0064313 (incorporated herein by reference) discloses an example of a stator array for a multi-valve system. The stator array includes a diffusion-bonded plate comprising stator surfaces, each configured to receive a rotor surface of a corresponding rotary valve actuator. The stator array includes internal fluid channels with precisely controlled dimensions. Compared to conventional channels and fluid loops implemented using external piping, the channel volume and fluid loops between the stator ports of the stator surfaces are formed with smaller tolerances.

[0037] During operation, the eluent received at the first switching valve 24 from the first dimension column 36 is either diverted through detector 38 and then directed to path selection valve 28, or directly supplied to path selection valve 28, depending on the valve state. Path selection valve 28 is configured to supply eluent to either a first fluid loop valve 30 or a second fluid loop valve 32. The first or second fluid loop valve 30 or 32 can be configured to bypass, allowing eluent to flow back to path selection valve 28 or allowing the received eluent to pass through a sample fluid loop connected at each end to stator ports of opposite diameter. As shown, the first fluid loop valve 30 is in its bypass state and directs the flow back to path selection valve 28, which then follows the path to the second switching valve 26 and continues along the path to the mass spectrometer detector 50.

[0038] One advantage of the first switching valve 24 is its ability to perform both first-dimensional separation and second-dimensional separation using the same detector. For example, Figure 4 This shows the first switching valve 24 in the first valve state, causing the moving phase from the first dimension column 36 to flow to the detector 38, and Figure 5 The first switching valve 24 is shown in the second valve state, allowing the moving phase from the second dimension column 37 to flow to the detector 38. Advantageously, this embodiment avoids the need for a second detector, where each detector will be dedicated to only one dimension. Furthermore, since the detector responses of the two detectors may differ, even if these detectors are of the same type, using a single detector to determine the modulation efficiency avoids the need to consider different detector response factors.

[0039] The second switching valve 26 allows the mass spectrometer detector 50 to use either dimension independently. In a non-limiting example, the mass spectrometer detector 50 can be replaced by another destructive detector, such as an evaporative light scattering detector, an electrosol detector, a flame ionization detector, etc. Figure 5 The valve is shown to be configured such that the first-dimensional moving phase flows through the path selection valve 28, the first fluid loop valve 30, and the second switching valve 26 to the waste, while the second-dimensional moving phase flows through the second switching valve 26 to the mass spectrometer 50. Figure 6 An alternative configuration is shown in which the first switching valve 24 and the second switching valve 26 are reconfigured such that the first-dimensional mobile phase flows through the path selection valve 28 and the first fluid loop valve 30 (in bypass mode) to the mass spectrometer 50, while the second-dimensional mobile phase flows to waste.

[0040] Typically, accurate understanding of the time delay is required. This time delay is defined as the time from when the analyte peak arrives at detector 38 to when the analyte peak arrives at the valve used to redirect or "capture" the peak in the fluid loop. This time delay is used to determine when to actuate the first fluid loop valve 30 or the second fluid loop valve 32. In some operating modes, the MDLC system first determines... Figure 3 The configuration shown performs "scouting separation" to simplify the timing requirements of the MDLC system. As used herein, scouting separation refers to a separation performed to determine the start and end times when one or more analyte peaks arrive at and leave detector 38. These start and end times are used for subsequent capture separation of similar analyte samples performed while bypassing detector 38, where flow is passed from first switching valve 24 to first fluid loop valve 30. As used herein, "capture separation" refers to a separation performed to collect one or more analyte peaks in one or more fluid loops coupled to first fluid loop valve 30 or second fluid loop valve 32, or a separation performed to collect slices (parts) of one or more analyte peaks, where each slice is stored within a fluid loop. Analyte peak detection at detector 50 is not required during capture separation because the timing of valve actuation is determined based on an earlier scouting separation, which will be described in more detail below.

[0041] The MDLC system is configured such that the sum of the volumes of the fluid routes from the first switching valve 24 to the detector 38 is equal to the sum of the volumes of the fluid routes from the first switching valve 24 to the path selection valve 28 and from the path selection valve 28 to the first fluid loop switching valve 30 or the second fluid loop switching valve 32. This can be achieved, for example, by using external pipe sections such that the total internal volume of the pipe sections for each set of fluid routes is equal to the total internal volume of the pipe sections for the other sets of fluid routes. As a specific example, fused silica tubes may be preferred over steel tubes because the internal volume variability of fused silica tubes is typically reduced by more than an order of magnitude compared to steel tubes, thus more accurately matching the resulting delay volume. Alternatively, tubes with smaller tolerances, as described above, can be used, provided that the pipe sections are evaluated to ensure accurate delay volume matching. Matching sets of pipe sections can be provided to installers in kit form to achieve the matched delay volume, thereby simplifying installation and setup.

[0042] During the exploratory separation, the times when the analyte in the eluent from the first-dimensional column 36 is first detected and last detected at detector 38 are determined. In other words, the start and end times at which the analyte peak is sensed at detector 38 are determined. The start and end times of other analytes of interest in the eluent can be determined similarly. Due to the volume matching of the fluid path, the determined time delay for each analyte from the first switching valve 24 to detector 38 is substantially equal to the time delay when the MDLC system, as described above, is used. Figure 5The illustrated configuration shows the time delay for each corresponding analyte to traverse to the first fluid loop valve 24, where the first switching valve is in its alternative valve state. Therefore, when the MDLC system is operated for capture separation, the user does not need to know the exact volume of each fluid path, nor does it need to consider additional timing offsets for the operation of the first fluid loop valve 24. Thus, the user avoids providing known delay times or volumes to the system operating software.

[0043] The trapping valve 34 includes a trapping column 52 connected between two valve ports. When the trapping valve 34 is configured in the alternative state shown in the figure, the contents of one of the twelve fluid loops can be ejected by solvent from the ACD loader 44, diluted by diluter 48 at the fluid T-tube 46, and then flow to the trapping column 52. Subsequently, the trapping valve 34 is reconfigured to the valve state shown, and the eluting solvent elutes the analyte peak or slice from the trapping column 52 without separation, such that the analyte peak is included in the flow to the second dimension column 37. The mobile phase flow from the second dimension column 37 passes through the first switching valve 24 and then flows to the second switching valve 26, as shown in the figure. Figure 9 As shown, this allows detector 38 to be used to monitor the second-dimensional separation. Alternatively, if switching valves 24 and 26 are in their alternative valve states, the eluent from the second-dimensional column 37 flows through the first switching valve 24 and the second switching valve 26, and flows to the mass spectrometer detector 50, as shown. Figure 10 As shown. Switching valves 24 and 26 can be configured to connect the outlet of the second dimension column 37 to the optical detector 38 or the mass spectrometer 50, or both the optical detector 38 and the mass spectrometer 50, or not connect the outlet of the second dimension column to the optical detector 38 and the mass spectrometer 50.

[0044] Advantageously, the flow rate of the diluted analyte peak to the trap column 52 can be controlled independently of other flow rates in the system. Similarly, the flow rate of the mobile phase in the second dimension is controllable independently of other system flow rates. Therefore, the MDLC system is not prohibited from operating the first and second dimensions with significantly different mobile phase flow rates. Furthermore, mobile phases incompatible in one dimension can be used in the other. Additionally, segments collected from the first dimension that are typically incompatible with the second dimension due to volumetric or mobile phase incompatibility can be used in the second dimension.

[0045] An example of a method for operating an MDLC system such as described above is now described. This method includes performing exploratory separation, performing first-dimensional separation, transferring the captured analyte peak from the first-dimensional separation to a second dimension, and performing second-dimensional separation. For each additional captured analyte peak stored in one fluid loop, the steps of transferring the captured analyte peak and performing second-dimensional separation can be repeated. Control of the MDLC system is achieved by appropriately configuring the valve state of each valve and by actuating the valves to change their valve states at appropriate times.

[0046] Now for reference Figures 11 to 22 , Figures 11 to 22 Another example of a method for operating an MDLC system is depicted, in which a series of valve state reconfigurations are performed. Chromatographic separation is performed in a first liquid chromatography dimension, and the analyte peaks in the first dimension eluent are stored in anticipation of injection into a second liquid chromatography dimension. Unlike the operation of the MDLC system described above, this example method does not perform exploratory separations; instead, it controls the actuation of various valves based on the detection of the start and end times of the analyte peaks at detector 38.

[0047] Figure 11 An MDLC system with valve states configured during method startup is shown. A first-dimensional moving phase flows through a first-dimensional column 36 and through a detector 38, then reaches a first switching valve 24. The moving phase flows to a path selection valve 28 and then to a second fluid loop valve 32, which is configured to bypass. Therefore, the moving phase does not flow through any of the fluid loops, but instead returns to the path selection valve 28 and flows through the second switching valve 26 to waste. In the valve states shown, the first fluid loop valve 30 directs any flow at its inlet port through the fluid loops connected between the ports.

[0048] exist Figure 12 In the first switching valve 24, the path selection valve 28 switches to its alternative state, causing the moving phase to flow through the fluid loop between the ports, return to the path selection valve 28, and then through the second switching valve 26 to the waste. Next, the path selection valve 28 switches back to its initial state, and the moving phase is guided through the second fluid loop valve 32, which is in its bypass state, and flows to the waste, as... Figure 13 As shown. The path selection valve 28 is first determined as follows: Figure 12 Configure as shown, then as follows Figure 13 The reconfiguration time shown is such that the entire volume of the analyte peak to be stored is captured within the volume of the fluid loop. The specific time in the example shown is based on the start and end times of the analyte peak sensed by detector 38 and the knowledge of the delayed volume of the fluid path.

[0049] Figure 14This illustrates how the MDLC system can be configured at a point after the termination of a previous analyte capture event. The first fluid loop valve 30 switches to its next valve state to allow storage in the second fluid loop connected between ports 2 and 8. Similar to the process of storing the first analyte peak, the path selection valve 28 is then actuated to direct flow at its inlet port through the first fluid loop valve 30 and the second fluid loop, and then switches back to its previous state to complete the storage of the second analyte peak. Additional analyte peaks can be captured by repeating this process using different fluid loops. For example, Figure 15 A first fluid loop valve 30 is shown, configured in a valved state to capture analyte peaks in the fluid loop connected between ports 6 and 12. Other fluid loops available for storage include those between ports 3 and 9, ports 4 and 10, and the fluid loop between ports 5 and 11.

[0050] exist Figure 16 In the middle, the path selection valve 28 is switched to direct the moving phase to the second fluid loop valve 32, which is in a bypass state, so that the moving phase flows back to the path selection valve 28 and flows to the waste. Next, the first fluid loop valve 30 is switched to its bypass state (e.g., Figure 17 (as shown), and then switch the path selection valve 28 to its alternative state (as shown). Figure 18 As shown), the moving phase now flows through the first fluid loop valve 30 and then to the waste. The second fluid loop valve 32 is then actuated to direct the flow received at its inlet port through the first fluid loop connected between the ports, as shown. Figure 19 As shown. Figure 20 This illustrates how to switch path selection valve 28 to guide the moving phase through the first fluid circuit connected to the second fluid circuit valve 32, and Figure 21 This illustrates how to switch path selection valve 28 back to its previous valve state to guide the moving phase through the first fluid loop valve 30 and flow to waste. Therefore, from when... Figure 20 The valve shown was first configured at the time when... Figure 21 The valve shown is first configured to capture the analyte peak in the first fluid loop. Figure 22 This illustrates how the second fluid loop valve 32 can be configured to prepare for capturing another analyte peak in a second fluid loop connected to ports 2 and 8. The second fluid loop valve 32 can similarly be configured to use a fluid loop connected to other port pairs on the second fluid loop valve 32 to capture the analyte peak.

[0051] The above description Figures 11 to 22 This relates to how to capture analyte peaks in an MDLC system for later infusion into the second dimension. The following description pertains to how to provide the stored analyte peaks to column 37 of the second dimension.

[0052] Figure 23 An MDLC system is illustrated in which the mobile phase from the first dimension is directed from path selection valve 28 and the second fluid loop valve 32 (in bypass mode) to waste. Simultaneously, the solvent flow from the ACD loader 44 is directed by path selection valve 28 to the port of the first fluid loop valve 30, such that the analyte peak stored in the fluid loop between the ports is pushed toward the fluid T-tube 46, in which the analyte peak may optionally be combined with the flow of dilution solvent from the ACD diluter module 48.

[0053] In the embodiments disclosed above, the various valves are shown as having a specific arrangement and number of ports and internal fluid routes. It should be understood that these valves may alternatively be implemented according to alternative embodiments with different arrangements and / or numbers of ports and internal fluid routes to achieve similar switching functionality and fluid path selection.

[0054] Although the present technology has been shown and described with reference to specific embodiments, those skilled in the art will understand that various changes in form and detail may be made without departing from the scope of the claims.

Claims

1. A multidimensional liquid chromatography system, the multidimensional liquid chromatography system comprising: A switching valve, which is capable of operating in at least two valve states; The detector is in communication with the switching valve via a first fluid route, the first fluid route being defined by a channel for connecting the switching valve to the detector having a first end connected to a port of the switching valve and a second end connected to the detector; A path selection valve, which is in communication with the switching valve via a second fluid route defined by a channel for connecting the switching valve to the path selection valve, having a first end connected to another port of the switching valve and a second end connected to the first port of the path selection valve; and A first fluid loop valve is connected to the path selection valve via a third fluid route, the third fluid route being defined by a channel having a first end connected to a second port of the path selection valve and a second end connected to the first fluid loop valve for connecting the path selection valve to the first fluid loop valve. The volume of the first fluid path is equal to the sum of the volumes of the second fluid path and the third fluid path.

2. The multidimensional liquid chromatography system according to claim 1, further comprising a second fluid loop valve, the second fluid loop valve being connected to the path selection valve via a fourth fluid route, the fourth fluid route being defined by a channel connecting the path selection valve to the second fluid loop valve, and wherein the volume of the first fluid route is equal to the sum of the volumes of the second fluid route and the fourth fluid route.

3. The multidimensional liquid chromatography system according to claim 2, wherein the volume of the third fluid path is equal to the volume of the fourth fluid path.

4. The multidimensional liquid chromatography system according to claim 1, wherein the fluid route is defined by a tube.

5. The multidimensional liquid chromatography system according to claim 4, wherein the tube is a fused silica tube.

6. The multidimensional liquid chromatography system of claim 4, wherein the difference between the volume of the first fluid path and the sum of the volumes of the second and third fluid paths does not exceed the volume variation based on the manufacturing tolerances of the tube.

7. The multidimensional liquid chromatography system according to claim 4, wherein the tube of one fluid path has a diameter different from the diameter of the tube of the other fluid path.

8. The multidimensional liquid chromatography system according to claim 1, wherein, When the switching valve is in the first valve state, the liquid received at the first port of the switching valve flows to the detector, and when the switching valve is in the second valve state, the liquid received at the first port flows to the path selection valve.

9. The multidimensional liquid chromatography system according to claim 1, wherein the multidimensional liquid chromatography system further comprises a first-dimensional column and a second-dimensional column, the first-dimensional column and the second-dimensional column being connected to the switching valve through a first port and a second port of the switching valve, respectively.

10. The multidimensional liquid chromatography system according to claim 1, wherein the first fluid loop valve has a plurality of sample fluid loops, each of the plurality of sample fluid loops being connected to a corresponding pair of ports of the first fluid loop valve.

11. The multidimensional liquid chromatography system according to claim 2, wherein the second fluid loop valve has a plurality of sample fluid loops, each of the plurality of sample fluid loops being connected to a corresponding pair of ports of the second fluid loop valve.

12. The multidimensional liquid chromatography system of claim 2, wherein a portion of the path selection valve and the first fluid loop valve and the second fluid loop valve are capable of being formed in a diffusion-bonded stator array.

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