Flow module selector

Abstract

In one aspect, a system for adjusting a flow rate of a mobile phase delivered to at least one liquid chromatography (LC) column is disclosed, the system comprising a first plurality of pre-calibrated flow modules, each flow module configured to receive a first mobile phase at an inlet thereof and provide a first mobile phase having a pre-calibrated range of output flow rates at an outlet thereof, wherein the first plurality of flow modules are configured to provide the first mobile phase having different ranges of output flow rates, the system further comprising a selector valve in fluid communication with the first plurality of flow modules for selecting from among the first plurality of pre-calibrated flow modules to selectively deliver the first mobile phase into the LC column to adjust the flow rate of the first mobile phase delivered to the LC column.

Description

[0001] Related applications

[0002] This patent application claims priority to U.S. Provisional Patent Application No. 63 / 160,626, filed March 12, 2021, the disclosure of which is incorporated herein by reference in its entirety. Background Technology

[0003] This teaching generally relates to methods and systems for delivering analytes into LC columns in mass spectrometry systems.

[0004] Liquid chromatography-mass spectrometry (LC / MS) is an analytical technique used for the qualitative and quantitative determination of the elemental composition of test substances. LC / MS can be effectively applied to identify unknown mixtures, determine the structure of a specific mixture by observing its fragmentation, and quantitatively measure the amount of a specific mixture in a sample. For example, a sample can be introduced into an LC column and fragmented into multiple fractions, which are then eluted from the LC column in a time-separated sequence. The eluents can then be ionized, and the resulting ions can be analyzed downstream by a material analyzer to obtain information on the composition and structure of the substituents in the sample under investigation.

[0005] In many traditional LC / MS systems, the flow rate of the sample introduced into the LC column can be controlled by a calibrated fluid flow module, typically in the form of a flow restrictor. More specifically, flow rate measurement can be performed by measuring the pressure difference across the calibrated fluid flow module. Due to limitations in the range, accuracy, and precision of pressure measurements, the effective usability of the flow module is restricted. Different calibrated flow restrictors are typically used to handle different flow rate ranges (e.g., from nanoliters per minute to microliters per minute). For example, different instrument models may include different fluid flow restrictors providing different flow rates. In other examples, user-replaceable cartridges with different flow rates can be provided, allowing users to change the flow rate by replacing one cartridge with another.

[0006] Such traditional practices require hardware modifications, which limits the instrument's flow range and flexibility. Furthermore, adjusting flow rates by using different cartridges can be time-consuming and may introduce new problems such as leaks and blockages.

[0007] Therefore, there is a need for systems and methods that allow for easy changes in the flow rate of a sample introduced into an LC / MS column. Summary of the Invention

[0008] In one aspect, a system for adjusting the flow rate of at least one mobile phase delivered to a liquid chromatography (LC) column is disclosed, comprising a first plurality of pre-calibrated flow modules, each flow module configured to receive the first mobile phase at its inlet and provide the first mobile phase at its outlet with an output flow rate having a pre-calibrated range, wherein the first plurality of flow modules are configured to provide the first mobile phase with different ranges of output flow rates. The system further includes a selector valve in fluid communication with the first plurality of pre-calibrated flow modules for selecting from the first plurality of pre-calibrated flow modules to selectively deliver the first mobile phase into the LC column, thereby adjusting the flow rate of the first mobile phase delivered to the LC column.

[0009] In some embodiments, the system includes a first container for storing a first mobile phase, the first container being in fluid communication with a first plurality of pre-calibrated flow modules for delivering the first mobile phase to the first plurality of pre-calibrated flow modules.

[0010] In some embodiments, the system may further include a first pump for delivering a first mobile phase from a first container to a first plurality of fluid flow modules.

[0011] In some embodiments, the system may further include a controller for adjusting the speed of the first pump to regulate the flow rate of the first mobile phase delivered to the first plurality of fluid flow modules.

[0012] In some embodiments, the first selector valve may include a first plurality of inlets and a first outlet, wherein each inlet is in fluid communication with an outlet of one of the first plurality of fluid flow modules, wherein a first mobile phase exits the first selector valve via the first outlet.

[0013] In some embodiments, the system may further include a second plurality of pre-calibrated fluid flow modules, wherein each fluid flow module is configured to receive a second mobile phase at its inlet and provide a second mobile phase with an output flow rate having a pre-calibrated range at its outlet, wherein the second plurality of fluid flow modules are configured to provide a second mobile phase with an output flow rate having a different range.

[0014] In some embodiments, the system may include a second container for storing a second mobile phase, the second container being in fluid communication with a second plurality of pre-calibrated fluid flow modules for delivering the second mobile phase to the second plurality of pre-calibrated fluid flow modules.

[0015] In some embodiments, the selector valve is fluidly coupled to a second plurality of pre-calibrated flow modules for selecting from the second plurality of pre-calibrated flow modules to deliver a second mobile phase into the LC column, thereby regulating the flow rate of the second mobile phase delivered to the LC column.

[0016] In some embodiments, the system may further include a second pump for delivering a second fluid phase to a second plurality of flow modules. In some embodiments, a controller is configured to adjust the speed of the second pump to regulate the flow rate of the second fluid phase delivered to the LC column. Furthermore, in some embodiments, the second pump is configured to provide a fluid flow rate with a dynamic range different from that provided by the first pump.

[0017] In some embodiments, the controller is configured to adjust the speed of either the first pump or the second pump to dynamically change (i.e., during operation) the flow rate of either the first mobile phase or the second mobile phase delivered to the LC column. In some embodiments, such flow rate adjustment can be used to change the relative concentrations of the first mobile phase and the second mobile phase in the mixed mobile phase fed into the LC column.

[0018] In some embodiments, the selector valve may include a first plurality of inlets and a first outlet, wherein each first inlet is in fluid communication with an outlet of one of the first plurality of fluid flow modules, wherein a first mobile phase exits the selector valve via the first outlet.

[0019] In some embodiments, the selector valve may further include a second plurality of inlets and a second outlet, wherein each second inlet is in fluid communication with the outlet of one of the second plurality of flow modules to receive a second flow phase, wherein the second flow phase exits the selector valve via the second outlet.

[0020] In some embodiments, the system may further include a mixing element comprising a first inlet for receiving a first mobile phase from a first selector valve and a second inlet for receiving a second mobile phase from a second selector valve to generate a mixed mobile phase, wherein the element includes an outlet for delivering the mixed mobile phase to an LC column.

[0021] In some embodiments, the system may include a first pressure sensor disposed between a first pump and a first plurality of fluid flow modules for measuring the pressure of fluid delivered to the first plurality of fluid flow modules. In some embodiments, the system may further include a second pressure sensor disposed between a second pump and a second plurality of fluid flow modules for measuring the pressure of fluid delivered to the second plurality of fluid flow modules. Further, in some embodiments, the system may include a third pressure sensor disposed between the outlet of any of the first fluid flow module and the second plurality of fluid flow modules and a mixing element for measuring the pressure of fluid delivered from any of the first fluid flow module and the second plurality of fluid flow modules to the mixing element. In some such embodiments, the second pump is configured to provide a fluid flow rate with a dynamic range different from that output by the first pump.

[0022] In another aspect, a system for adjusting the flow rate of at least one mobile phase delivered to a liquid chromatography (LC) column is disclosed, comprising a first plurality of pre-calibrated flow modules, each flow module configured to receive the first mobile phase at its inlet and provide the first mobile phase with an output flow rate having a pre-calibrated range at its outlet. The first plurality of fluid flow modules are configured to provide the first mobile phase with different ranges of output flow rates. A first selector valve is in fluid communication with the first plurality of pre-calibrated flow modules for selecting from the first plurality of pre-calibrated fluid flow modules to selectively deliver the first mobile phase to the LC column, thereby adjusting the flow rate of the first mobile phase delivered to the LC column. The system may further include a first container for storing the first mobile phase, the first container being in fluid communication with the first selector valve to deliver the first mobile phase to the first selector valve. In some such embodiments, the first selector valve may include a first inlet for receiving the first mobile phase and a first plurality of outlets, each first outlet being fluidly coupled to one of the first plurality of flow modules. Furthermore, the system may include a second plurality of pre-calibrated flow modules, each configured to receive a second mobile phase at its inlet and provide a second mobile phase at its outlet having an output flow rate within the pre-calibrated range. The second plurality of fluid flow modules are configured to provide second mobile phases with different output flow rates.

[0023] In some embodiments, the system may include a second container for storing a second mobile phase. In some such embodiments, a first selector valve may include a second inlet for receiving the second mobile phase and a second plurality of outlets, wherein each second outlet is fluidly coupled to one of the second plurality of flow modules for selective delivery of the second fluid flow module. The system may further include a mixing element comprising a first inlet configured to receive the first mobile phase from any fluid flow module selected by the selector valve from the first plurality of fluid flow modules. The mixing element may further include a second inlet configured to receive the second mobile phase from any flow module selected by the selector valve from the second plurality of flow modules. The mixing element is configured to mix the first and second mobile phases to generate a mixed mobile phase. The mixing element may include an outlet communicating with an LC column to deliver the mixed mobile phase to the LC column.

[0024] In some embodiments, a first pressure sensor is disposed between a first pump and a selector valve to measure the pressure of a first flowing phase delivered to the selector valve. In some such embodiments, a second pressure sensor is disposed between a second pump and a selector valve to measure the pressure of a second flowing phase delivered to the selector valve. Furthermore, in some embodiments, a third pressure sensor is disposed between the outlet of any one of the first plurality of fluid flow modules and a mixing element to measure the pressure of fluid delivered from any one of the first fluid flow module and the second plurality of flow modules to the mixing element.

[0025] In some such embodiments, the first pump and the second pump are configured to provide fluid flows with different dynamic ranges. In some embodiments, the system may include a second container for storing the second mobile phase. A second plurality of pre-calibrated fluid flow modules are configured to receive the second mobile phase from the second container, wherein each of the second plurality of pre-calibrated flow modules provides the second mobile phase with an output flow rate having a pre-calibrated range.

[0026] In some embodiments of the above systems, a second selector valve is in fluid communication with a second plurality of pre-calibrated flow modules for selecting from the second plurality of pre-calibrated flow modules to selectively deliver a second mobile phase into the LC column, thereby adjusting the flow rate of the second mobile phase delivered to the LC column.

[0027] In some embodiments, each of the first plurality of fluid flow modules includes an inlet for receiving a first fluid phase from a first container, and an outlet in fluid communication with a first selector valve. Each of the second plurality of fluid flow modules includes an inlet for receiving a second fluid phase from a second container, and an outlet in fluid communication with a second selector valve. A mixing element has a first inlet in fluid communication with the outlet of the first selector valve to receive the first fluid phase, and a second inlet in fluid communication with the outlet of the second selector valve to receive the second fluid phase, wherein the mixing element is configured to mix the first and second fluid phases to generate a mixed fluid phase. The mixing element may include an outlet for delivering the mixed fluid phase to an LC column. A first pump may be employed to deliver the first fluid phase from the first container to the first plurality of flow modules. A second pump may be employed to deliver the second fluid phase from the second container to the second plurality of flow modules. In some such embodiments, the first and second pumps may be configured to provide fluid flow rates with different dynamic ranges.

[0028] In another aspect, a system for adjusting the flow rate of a mobile phase delivered to at least one liquid chromatography (LC) column is disclosed, comprising a container for storing a first mobile phase, a first plurality of pre-calibrated flow modules, wherein each flow module is configured to receive the first mobile phase from the container at its inlet and provide the first mobile phase with an output flow rate having a pre-calibrated range at its outlet, wherein the first plurality of fluid flow modules are configured to provide the first mobile phase with different ranges of output flow rates. A first selector valve is in fluid communication with at least a portion of the first plurality of pre-calibrated flow modules for selecting from these flow modules to selectively deliver the first mobile phase into the LC column, thereby adjusting the flow rate of the first mobile phase delivered to the LC column. At least one of the first plurality of pre-calibrated fluid flow modules is configured to provide continuous flow of the first mobile phase from the first container to the LC column.

[0029] In some embodiments, the system may include a second container for storing a second mobile phase. The system may further include a second plurality of pre-calibrated fluid flow modules, each configured to receive the second mobile phase from the second container at its inlet and provide a second mobile phase with an output flow rate having a pre-calibrated range at its outlet, the second plurality of fluid flow modules being configured to provide second mobile phases with different ranges of output flow rates. A second selector valve may be in fluid communication with at least a portion of the second plurality of pre-calibrated flow modules for selecting from these flow modules to selectively deliver the second mobile phase into the LC column, thereby adjusting the flow rate of the second mobile phase delivered to the LC column. In some such embodiments, at least one of the second plurality of pre-calibrated fluid flow modules is configured to provide continuous flow of the second mobile phase from the second container to the LC column.

[0030] In some embodiments, the system may further include a mixing element having a first inlet for receiving a continuous flow of a first mobile phase provided by one of a first plurality of flow modules, and an output flow provided by another flow module selected by a first selector valve. The element may have a second inlet for receiving a continuous flow of a second mobile phase provided by a flow module providing a second mobile phase, and an output flow provided by another flow module selected by a second selector valve. The mixing element is configured to mix the first and second mobile phases received at its first and second inlets to generate a mixed mobile phase and deliver the mixed mobile phase to the LC. Attached Figure Description

[0031] Figure 1 A system for delivering two mobile phases to a mixing element according to an embodiment of the present teaching is schematically depicted, wherein the mixing element can further deliver the mixture of mobile phases to an LC column in a mass spectrometry system.

[0032] Figure 2 A system for delivering two mobile phases to a mixing element, according to another embodiment of this teaching, is schematically depicted, wherein the mixing element can further deliver the mixture of mobile phases to an LC column in a mass spectrometry system.

[0033] Figure 3 A system for delivering two mobile phases to a mixing element, according to another embodiment of this teaching, is schematically depicted, wherein the mixing element can further deliver the mixture of mobile phases to an LC column in a mass spectrometry system.

[0034] Figure 4A system for delivering two mobile phases to a mixing element, according to another embodiment of this teaching, is schematically depicted, wherein the mixing element can further deliver the mixture of mobile phases to an LC column in a mass spectrometry system.

[0035] Figure 5A An embodiment of a selector valve according to one embodiment is schematically depicted, wherein the selector valve can operate under the control of a controller using input received from a GUI.

[0036] Figure 5B illustrative application Figure 5A The described embodiment of the controller,

[0037] Figure 6 The diagram schematically depicts an LC column and an ion trap positioned upstream of the column, where different flow rates can be used to load the ion trap and introduce the sample into the LC column.

[0038] Figure 7 An LC / MS system is schematically depicted, including a delivery system for delivering one or more mobile phases to an LC column according to embodiments of the present teachings. Detailed Implementation

[0039] This disclosure generally relates to systems and methods for delivering one or more mobile phases to an LC / MS column by employing automated valves to select from multiple pre-calibrated flow modules. As described below, systems and methods according to this teaching can provide a wide range of flow rates without any hardware changes. Various different embodiments incorporating this teaching are set forth below for providing specific target flow ranges with high accuracy, or a wide overall flow range. The embodiments described below also provide greater flexibility for generating a wide variety of mobile phase compositions, for example, by mixing different mobile phases at a variety of different concentration ratios. Although the embodiments described below relate to delivering two mobile phases to a mixing element, which in turn can generate a mixed mobile phase for delivery to the LC column, this teaching can in fact be adopted to deliver only one or more mobile phases (e.g., 3, 4, 5 or more mobile phases) to the LC column, for example, by a mixing element.

[0040] The various terms used in this document are consistent with their common meaning in the industry. The term "approximately" in this document means a fluctuation of up to 10% around the value. The term "generally" in this document means a deviation of up to 10% relative to the complete condition and / or state.

[0041] Figure 1A system 10 is schematically depicted for delivering two mobile phases (e.g., solutions containing one or more analytes to be studied) separately or in combination to a liquid chromatography (LC) column 12, and for allowing adjustment of the flow rates of these mobile phases by using multiple flow modules and at least one selector valve, wherein the multiple flow modules provide different ranges of flow rates for the mobile phases, and at least one selector valve allows selection from those flow modules to adjust the flow rate of the mobile phase delivered to the LC column, as detailed below.

[0042] More specifically, in this embodiment, system 10 includes two sets of fluid flow modules 100 and 200, wherein fluid flow module 100 is fluidly coupled to container 110 via pneumatic pump 112, and fluid flow module 200 is fluidly coupled to container 210 via pneumatic pump 212. In this embodiment, container 110 stores a first mobile phase 114, while container 210 stores a second mobile phase 214.

[0043] Continue to refer to Figure 1 In this embodiment, the fluid flow module group 100 includes three fluid flow modules 101, 102, 103 (also referred to herein as the “first plurality of fluid flow modules”) and a purge module 104, wherein each fluid flow module is configured to provide a flow rate within a pre-calibrated range, and the purge module can allow the contents of container 110 to be purged, as detailed below.

[0044] While in some embodiments the range of pre-calibrated flow rates associated with these fluid flow modules is different, in other embodiments the fluid flow rates associated with at least two fluid flow modules may partially overlap.

[0045] Fluid flow modules 101, 102, 103, and purge module 104 each include inlets 101a, 102a, 103a, and 104a for receiving a first mobile phase from container 110 via fluid conduit 111. Further, fluid flow modules 101, 102, 103, and purge module 104 each include outlets 101b, 102b, 103b, and 104b, through which the first mobile phase exits these modules. A pressure sensor PA is located between pneumatic pump 112 and the plurality of fluid flow modules 100 to measure the pressure of the first mobile phase when it is delivered to the fluid module 100 by pneumatic pump 112.

[0046] The purge module 201 and the fluid flow modules 202, 203, 204 (also referred to herein as the "second plurality of fluid flow modules") each include inlets 201a, 202a, 203a, 204a and outlets 201b, 202b, 203b, 204b, respectively, wherein the inlets are used to receive the second mobile phase 214 from the container 210, and the second mobile phase can exit the fluid flow module 200 via the outlets. A pressure sensor PB is located between the pneumatic pump 212 and the plurality of fluid module groups 200 to measure the pressure of the second mobile phase when it is delivered to the fluid module 200 by the pneumatic pump 212.

[0047] For example, in this embodiment, each fluid flow module in the fluid flow module groups 100 and 200 can be implemented using a flow restrictor. Such flow restrictors are commercially available.

[0048] System 10 further includes a selector valve 300 having a first plurality of inlets 301a, 301b, 301c and 301d, which can receive a first mobile phase from outlets 101b, 102b, 103b and 104b of fluid module 100 via a plurality of fluid conduits 100c. The selector valve also has a second plurality of inlets 302a, 302b, 302c and 302d, which can receive a second mobile phase from outlets 201b, 202b, 203b and 204b of fluid module 200 via a plurality of fluid conduits 200c.

[0049] Selector valve 300 further includes two outlets 303a and 303b. Outlets 303a and 303b are coupled to inlets 400a and 400b of mixing element 400, respectively. Outlet 303a of selector valve 300 allows output fluid flow from any fluid flow module selected by selector valve 300 in fluid flow modules 101 / 102 / 103 to reach mixing element 400, and outlet 303b of selector valve 300 allows output fluid flow from any fluid flow module selected by selector valve 300 in fluid flow modules 202 / 203 / 204 to reach mixing element 400.

[0050] In this embodiment, a pressure sensor PC is disposed between the outlet 303a of the selector valve 300 and the mixing element 400 to measure the pressure of the first flowing phase flowing from the outlet 303a of the selector valve to the mixing element 400. Although not shown in this embodiment, in other embodiments, the pressure sensor may also be disposed between the outlet 303b of the selector valve and the mixing element 400.

[0051] Continue to refer to Figure 1The selector valve 300 further includes two outlets 303c and 303d, which allow the first and second flow phases received by the selector valve to flow to the waste container 500 via fluid conduits 501 and 502, respectively. For example, the contents of each container in containers 112 and 212 can be purged via purge modules 104 and 201 and selector valve 300.

[0052] The mixing element mixes the received first and second mobile phases to generate a mixed mobile phase, which can be delivered to the LC column 12 through the outlet 400c of the mixing element 400.

[0053] Fluid flow module groups 100 and 200 can provide a wide range of flow rates. In some embodiments, the flow rate range provided by fluid flow module groups 100 and 200 is configured to allow for the preparation of a mixed flow phase containing a first and a second flow phase with different relative concentrations. In some embodiments, the flow rate range provided by fluid flow modules 101 / 102 / 103 is significantly different from the flow rate range provided by fluid flow modules 202 / 203 / 204. Further, as described above, in this embodiment, in each group of fluid flow modules 100 / 200, the fluid flow modules can provide flow phases with different flow rates, wherein in some cases, the different flow rate ranges provided by at least two fluid flow modules in the first and second groups may at least partially overlap.

[0054] The system for delivering one or more mobile phases to an LC column according to this teaching allows for adjustment of the concentration ratio of two or more mobile phases in a mixture of these mobile phases without hardware changes, even during operation.

[0055] Figure 2 A system 20 according to another embodiment of this teaching is schematically depicted for delivering two mobile phases (e.g., solutions containing one or more analytes to be studied) separately or in combination to a liquid chromatography (LC) column 12. In this embodiment, compared to the previous embodiment where the selector valve is located between two sets of fluid flow modules and a mixing element, the two sets of fluid flow modules are located between the selector valve and the mixing unit.

[0056] More specifically, in this embodiment, system 20 includes a selector valve 1000 having two inlets 1001 and 1002, wherein inlet 1001 receives a first mobile phase from a first container 110 via fluid conduit 111, and the second inlet 1002 receives a second mobile phase from a second container 210 via fluid conduit 211. Similar to the previous embodiment, pneumatic pumps 112 and 212 facilitate the flow of the mobile phase from containers 110 and 210 to the corresponding inlets of selector valve 1000.

[0057] Continue to refer to Figure 2 The selector valve 1000 further includes four outlets 1003, 1004, 1005, and 1006, which are fluidly connected to fluid flow modules 101, 102, and 103 via multiple fluid conduits 1007 and to purge module 104 via their inlets (not numbered in this figure for simplicity). The selector valve 1000 also includes four additional outlets 1008, 1009, 1010, and 1011, which are fluidly connected to purge module 201 via multiple fluid conduits 1012 and to multiple fluid flow modules 102, 103, and 104 via the inlets of these modules (not numbered in this figure for simplicity).

[0058] Similar to the previous embodiments, flow modules 101 / 102 / 103 / 104 include outlets 101b, 102b, 103b, and 104b, which fluidly connect the outlets of these fluid flow modules to the inlet 400a of the mixing element 400 via fluid conduit 501. Furthermore, purge module 201 and the plurality of fluid flow modules 202, 203, and 204 include a plurality of outlets 201b, 202b, 203b, and 204b, which fluidly connect these fluid modules to other inlets 400b of the mixing element 400 via fluid conduit 502.

[0059] Selector valve 1000 can be employed to selectively pressurize any module of purge and fluid flow modules 100 or 200, independently or in any desired combination of modules, for selectively delivering the mobile phase to mixing element 400. As described above, mixing element 400 mixes the received mobile phase to generate a mixed mobile phase, which can be delivered to the LC column via outlet 400c of mixing element.

[0060] In some embodiments, at least one fluid flow module in the fluid flow module can provide a direct connection between a container storing the mobile phase and a mixing element. Such an arrangement allows for maintaining a continuous flow of at least one mobile phase to the LC column, while using one or more selector valves to enhance the continuous flow of one or more mobile phases (e.g., the same or different from the continuously flowing mobile phase).

[0061] For example, Figure 3 An embodiment of such a system 30 is schematically depicted, which is similar to the system 10 described above, except that in this embodiment, two fluid flow modules in the fluid flow module directly connect each of containers 110 and 210 to the mixing element 400 to deliver a continuous flow of the first and second fluid phases (114 / 214) to the mixing element 400.

[0062] More specifically, in this embodiment, the system 30 includes a first plurality of fluid flow modules 500, which includes fluid flow modules 501, 502, 503, 504 and 505. The system 30 also includes a second plurality of fluid flow modules 600, which includes fluid flow modules 601, 602, 603, 604 and 605.

[0063] Fluid flow module 500 receives a first mobile phase 114 from container 110 via fluid conduit 111 through fluid flow module inlets 501a, 502a, 503a, 504a, and 505a, and fluid flow module 600 receives a second mobile phase 214 from container 210 via fluid conduit 211 through fluid flow module inlets 601a, 602a, 603a, 604a, and 605a. Two pressure sensors PA and PB allow measurement of the pressure of the first and second mobile phases delivered to the first and second fluid flow modules 500 / 600.

[0064] In this embodiment, fluid flow module 501 provides direct fluid coupling between container 111 and mixing element 400 to provide continuous flow of a first mobile phase to the mixing element. Further, fluid flow module 601 provides direct fluid coupling between container 211 and mixing element 400 to provide continuous flow of a second mobile phase to the mixing element. More specifically, outlet 501b of fluid flow module 501 is directly connected to inlet 401 of mixing element 400, and outlet 601b of fluid flow module 601 is directly connected to inlet 402 of mixing element 400. This allows for continuous flow of a first and a second mobile phase to the mixing element, wherein the flow rate of the first mobile phase introduced into the mixing element is determined by the flow rate provided by fluid flow module 501, and the flow rate of the second mobile phase introduced into the mixing element is determined by the flow rate provided by fluid flow module 601.

[0065] The outlets 502b, 503b, 504b, and 505b of fluid flow modules 502, 503, 504, and 505 are fluidly connected to the first plurality of inlets 1, 2, 3, and 4 of fluid selector valve 2000, and the outlets 602b, 603b, 604b, and 605b of fluid modules 602, 603, 604, and 605 are fluidly connected to the second plurality of inlets 5, 6, 7, and 8 of fluid selector valve 2000. The outlet 9 of selector valve 2000 is fluidly connected to the first inlet 401a of mixing element, and the outlet 10 of selector valve is fluidly connected to the second inlet 401b of mixing element.

[0066] The selector valve can be employed to select from fluid flow modules 502b, 503b, 504b and 505b and 602b, 603b, 604b and 605b, independently or in different combinations (e.g., from one fluid flow module in fluid flow module group 500 and from one fluid flow module in fluid flow module group 600). This allows for enhanced fluid flow provided by fluid modules 501 and 601, which provide continuous flow of the first and second fluid phases. The system offers a high degree of flexibility in adjusting the flow of the first and second fluid phases to the mixing element and the LC column. For example, by activating only fluid flow module 501 or 601, the system allows for continuous flow of only the first or second fluid phase to the mixing element and subsequently the LC column. Alternatively, by activating both fluid flow modules 501 and 601 simultaneously, continuous flow of both the first and second fluid phases to the mixing element and subsequently the LC column can be provided. Furthermore, as described above, the fluid flow provided by any of the fluid flow modules in the continuous fluid flow modules 501 or 601 can be enhanced by using a selector valve to activate any one of the other fluid flow modules in the first plurality of fluid flow modules and the second plurality of fluid flow modules 500 / 600.

[0067] Although the above embodiment uses only one selector valve, other embodiments may utilize multiple selector valves to select from different banks of fluid flow modules. For example, Figure 4 An embodiment of such a system 40 is schematically depicted, wherein the system 40 includes a first plurality of fluid flow modules 700 and a second plurality of fluid flow modules 800, wherein the fluid flow modules 700 receive a first mobile phase 114 from a first container 110 via fluid conduits 111 through a plurality of inlets 701, and the fluid flow modules 800 receive a second mobile phase 214 from a second container 210 via fluid conduits 211 through a plurality of inlets 801.

[0068] In this embodiment, the fluid flow module group 700 includes a plurality of outlets 702, which are fluidly connected to a plurality of inlets 3000a of a selector valve 3000. The selector valve 3000 includes an outlet 3000b, which is in fluid communication with an inlet 401a of a mixing element 400. The selector valve 3000 can be employed to select from a plurality of fluid flow modules 700 to fluidly connect the selected fluid flow module to the mixing element, thereby adjusting the flow rate of the first mobile phase introduced into the mixing element.

[0069] Continue to refer to Figure 4The fluid flow module assembly 800 includes multiple outlets 802, the outlet fluids being connected to multiple inlets 4000a of another selector valve 4000. The selector valve 4000 includes an outlet 4000b, the outlet fluids being connected to another inlet 401b of the mixing element 400.

[0070] The selector valve 4000 can be employed to select from a plurality of fluid flow modules 800 to fluidly connect the selected fluid flow module to the mixing element, thereby adjusting the flow rate of the second flow phase introduced into the mixing element.

[0071] The mixing element can then mix the first and second mobile phases to generate a mixed mobile phase, which can be delivered to the LC column 12 through the outlet 401c of the mixing element 400. A selector valve allows adjustment of the flow rates of the first and second mobile phases delivered to the mixing element, thereby adjusting the concentration ratio of the first and second mobile phases in the mixed mobile phase delivered to the LC column.

[0072] Similar to the embodiments described above, pressure sensor PA measures the pressure of the first flowing phase delivered to fluid flow module 700, and pressure sensor PB measures the pressure of the second flowing phase delivered to fluid flow module 800. Further, pressure sensor PC measures the pressure of the first flowing phase delivered to mixing element 400 via selector valve 3000. Although not shown in this embodiment, pressure sensors may be used to measure the pressure of the second flowing phase delivered to mixing element.

[0073] The system for delivering one or more mobile phases to an LC column in a liquid chromatography-mass spectrometry system according to this teaching can offer several advantages. For example, without requiring hardware changes, such a system can allow one or more mobile phases to be introduced into the LC column at a range of flow rates. For instance, Figure 5A Examples of selector valves 5000 used in different embodiments of this teaching are schematically depicted, which can provide flow rates in nanoliters per minute (N / min) systems, low microliters per minute (µL / min) systems, and high microliters per minute (µL / min) systems. In this example, the selector valve 5000 can also, for example, provide access to a waste container using the methods described above.

[0074] Continue to refer to Figure 5A The controller 5001 is employed to set the selector valve 5000 to different operating modes corresponding to different flow rates. Furthermore, a graphical user interface (GUI) 5002 is provided to allow the user to interact with the controller 5001 to set the desired operating mode of the selector valve. Similar controllers and GUIs can be employed in the above embodiments for controlling the operation of the selector valve.

[0075] The controller and GUI can be implemented using techniques known in the industry as described in this teaching. In an embodiment, Figure 5B An example implementation of controller 5001 is schematically depicted. In this embodiment, controller 5001 includes, among other elements known in the prior art, a processor 5003, permanent memory 5004, random access memory (RAM) 5005, and a communication module 5006 and a communication bus 5007, the communication bus 5007 allowing the processor to interact with other components of the controller. The communication module 5006 can provide wired or wireless communication to GUI 5002, such as... Alternatively, a suitable protocol may be used to receive instructions from the user. Instructions for operating the selector valve can be stored in permanent memory 5004 and loaded into RAM 5005 for execution at runtime.

[0076] In some embodiments, the selector valve may operate based on a preset process to adjust the flow rate of the mobile phase delivered to the LC column.

[0077] As described above, the system according to this teaching can be employed to select different workflows (e.g., direct injection, ion well / elution, nanoliters / minute, or microliters / minute delivery flow rates) associated with delivering one or more mobile phases to the LC column of the liquid chromatography-mass spectrometry system. In embodiments, Figure 6 An embodiment of a system for delivering one or more mobile phases to an LC column, according to embodiments of the present teachings, is illustrated schematically. In this embodiment, one or more mobile phases (e.g., a mixture of mobile phases) are first introduced into an ion well column and then into an LC column. The system according to the present teachings can be employed to load the mobile phase into the ion well column at a higher flow rate and then switch to a lower flow rate for chromatography.

[0078] The system for delivering one or more mobile phases to an LC column according to this teaching can be incorporated into a wide variety of mass spectrometry systems. For example, such a system may include a mass spectrometer using multiple types of mass spectrometers, such as one or more quadrupole mass spectrometers, time-of-flight mass spectrometers, and combinations thereof.

[0079] Figure 7An embodiment of a mass spectrometry system 6000 is schematically depicted, including a system for delivering one or more mobile phases according to the present teachings. More specifically, the illustrated system 6000 includes a mobile phase delivery system 6001 according to an embodiment of the present teachings, as described above. The output of the mobile phase delivery system is introduced into a liquid chromatography (LC) column 6002, and the eluent from the LC column is introduced into an ion source 6003 for ionizing analytes contained in a sample received from the LC column. These ions are then transferred to one of the mass spectrometers or a mass spectrometer analyzer 6004. An ion detector 6005, arranged downstream of the mass spectrometer analyzer 6004, can detect ions passing through the mass spectrometer analyzer and generate a detection signal in response to ion detection. An analysis module 6006 can receive the signal generated by the ion detector 6005 and analyze the signal to generate a mass spectrum of the generated ions.

[0080] Various types of mass spectrometers can be used in the mass spectrometry system 6000. In terms of range, the mass spectrometer can be a quadrupole or a time-of-flight mass spectrometer. For example, in some embodiments, multiple tandem quadrupole mass spectrometers can be employed to perform tandem mass spectrometry (MS / MS) analysis. In some such embodiments, one or more quadrupole mass spectrometers can be employed to select a parent ion with a mass-to-charge ratio (m / z) within a desired range. Furthermore, in some such embodiments, the selected parent ion can undergo collision-induced fragmentation in a collision cell, and the fragment ions can then be placed downstream of the collision cell for mass spectrometry analysis.

[0081] Those skilled in the art should understand that various modifications can be made to the above embodiments without departing from the scope of protection of the present invention.

Claims

1. A system for adjusting the flow rate of at least one mobile phase delivered to a liquid chromatography (LC) column, comprising: A plurality of pre-calibrated flow modules, wherein each of the plurality of pre-calibrated flow modules is configured to receive a first mobile phase at its inlet and provide the first mobile phase at its outlet with an output flow rate having a pre-calibrated range, wherein the plurality of pre-calibrated flow modules are configured to provide the first mobile phase with different ranges of output flow rates, and A first selector valve, fluidly connected to the first plurality of pre-calibrated flow modules, is used to select from the first plurality of pre-calibrated flow modules to selectively deliver the first mobile phase to the LC column, thereby adjusting the flow rate of the first mobile phase delivered to the LC column.

2. The system of claim 1, further comprising a first container for storing the first mobile phase, the first container being in fluid communication with the first plurality of pre-calibrated flow modules for delivering the first mobile phase to the first plurality of pre-calibrated flow modules.

3. The system of claim 2, further comprising a first pump for delivering the first mobile phase from the first container to the first plurality of pre-calibrated flow modules.

4. The system of claim 3, further comprising a controller for adjusting the speed of the first pump to regulate the flow rate of the first mobile phase delivered to the first plurality of pre-calibrated flow modules.

5. The system according to any one of claims 1-4, wherein the first selector valve includes a first plurality of inlets and a first outlet, wherein each first inlet is in fluid communication with the outlet of one of the first plurality of pre-calibrated flow modules, wherein a first mobile phase exits the first selector valve via the first outlet.

6. The system of claim 4, further comprising a second plurality of pre-calibrated flow modules, wherein each of the second plurality of pre-calibrated flow modules is configured to receive a second mobile phase at its inlet and provide a second mobile phase having an output flow rate having a pre-calibrated range at its outlet, wherein the second plurality of pre-calibrated flow modules is configured to provide a second mobile phase having an output flow rate having a range different from the flow rate provided by the first plurality of pre-calibrated flow modules for the first mobile phase.

7. The system of claim 6, further comprising a second container for storing the second mobile phase, the second container being in fluid communication with the second plurality of pre-calibrated flow modules for delivering the second mobile phase to the second plurality of pre-calibrated flow modules.

8. The system of claim 7, wherein the first selector valve is fluidly coupled to the second plurality of pre-calibrated flow modules for selecting from the second plurality of pre-calibrated flow modules to deliver a second mobile phase to the LC column, thereby adjusting the flow rate of the second mobile phase delivered to the LC column.

9. The system of claim 7, further comprising a second pump for delivering the second mobile phase from the second container to the second plurality of pre-calibrated flow modules.

10. The system of claim 9, wherein the controller is configured to adjust the speed of the second pump for regulating the flow rate of the second mobile phase.

11. The system of claim 9, wherein the second pump is configured to provide a fluid flow rate with a dynamic range different from that provided by the first pump.

12. The system of claim 11, wherein the controller is configured to adjust the speed of either the first pump or the second pump to dynamically change the flow rate of the fluid delivered to the LC column during operation.

13. The system of claim 12, wherein the first selector valve includes a first plurality of inlets and a first outlet, wherein each first inlet is in fluid communication with the outlet of one of the first plurality of pre-calibrated flow modules, wherein the first mobile phase exits the first selector valve via the first outlet.

14. The system of claim 13, wherein the first selector valve further includes a second plurality of inlets, wherein each second inlet is in fluid communication with an outlet of one of the second plurality of pre-calibrated flow modules to receive the second flow phase, and the first selector valve further includes a second outlet, wherein the second flow phase exits the first selector valve via the second outlet.

15. The system of claim 14, further comprising a mixing element having a first inlet for receiving the first mobile phase from the first outlet of the first selector valve and a second inlet for receiving the second mobile phase from the second outlet of the first selector valve to generate a mixed mobile phase, the mixing element having an outlet for delivering the mixed mobile phase to an LC column.

16. The system of claim 3, further comprising a first pressure sensor disposed between the first pump and the first plurality of pre-calibrated flow modules for measuring the fluid pressure delivered to the first plurality of pre-calibrated flow modules.

17. The system of claim 9, further comprising a second pressure sensor disposed between the second pump and the second plurality of pre-calibrated flow modules for measuring the fluid pressure delivered to the second plurality of pre-calibrated flow modules.

18. The system of claim 15, further comprising a third pressure sensor disposed between an outlet of any one of the first plurality of precalibrated flow modules and the second plurality of precalibrated flow modules and the mixing element, for measuring the pressure of fluid delivered from any one of the first plurality of precalibrated flow modules and the second plurality of precalibrated flow modules to the mixing element.

19. The system of claim 18, wherein the second pump is configured to provide a fluid flow with a dynamic range different from that provided by the first pump.

20. The system of claim 6, further comprising a second selector valve in fluid communication with the second plurality of pre-calibrated flow modules for selecting from the second plurality of pre-calibrated flow modules to selectively deliver the second mobile phase to the LC column.

21. The system of claim 20, further comprising a mixing element having a first inlet for receiving a first mobile phase from a first selector valve, and the mixing element having a second inlet for receiving a second mobile phase from a second selector valve.

22. The system of claim 21, wherein the mixing element includes an outlet for delivering the mixed mobile phase to the LC column, wherein the mixed mobile phase comprises a mixture of the received first and second mobile phases.

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