US-12618812-B2 - Fluid mixing by fluid supply lines with line-specific fluid pumps for liquid chromatography

US12618812B2US 12618812 B2US12618812 B2US 12618812B2US-12618812-B2

Abstract

A liquid chromatography fluid supply apparatus, for providing a mixture of a plurality of different fluids as a mobile phase for a liquid chromatography sample separation apparatus, includes a plurality of supply lines, a plurality of fluid pumps, and a combining point. Each of the supply lines is fluidically coupled to a respective one of a plurality of fluid component sources for providing a respective one of the fluids. Each of the fluid pumps is associated with a respective one of said supply lines. The fluids from the supply lines are to be merged at the combining point. Each of the fluid pumps conveys or does not convey a respective fluid from a respective one of the fluid component sources to the combining point, depending on a respective switching state of the fluid supply apparatus.

Inventors

Clemens Plachetka

Assignees

AGILENT TECHNOLOGIES, INC.

Dates

Publication Date: 20260505
Application Date: 20190301
Priority Date: 20180302

Claims (16)

1 . A fluid supply apparatus for providing a mixture of a plurality of different fluids as a mobile phase for a sample separation apparatus, the fluid supply apparatus comprising: a plurality of supply lines, each of which is fluidically coupled to a respective one of a plurality of fluid component sources, configured to provide a respective one of the plurality of different fluids; a plurality of fluid pumps, each of which is associated with a respective one of the supply lines; a combining point downstream of the fluid pumps and configured to combine the fluids from the supply lines to output combined fluids, wherein each one of the plurality of fluid pumps is switchable such that a respective fluid pump, depending on its respective switching state, pushes or does not push a respective fluid from a respective one of the fluid component sources to the combining point; a switching configuration comprising a plurality of switching valves, each switching valve communicating with a respective one of the supply lines and each switching valve positioned between a respective one of the fluid pumps and the combining point, wherein each switching valve is switchable between an open state that allows the respective fluid pump to convey a respective fluid from a respective one of the fluid component sources to the combining point, and a closed state that prevents the respective fluid pump from conveying the respective fluid; a fluid conveying device downstream of the combining point and configured as a metering device to convey the combined fluids to a chromatographic sample separation device, wherein: the plurality of fluid pumps is configured to bring the respective fluids to a normalized initial pressure; and the fluid conveying device is configured to further pressurize the combined fluids output from the combining point to a system pressure; and a control unit configured to control pushing and not pushing by the fluid pumps, and/or control the switching of the switching valves, to controllably define a composition of the combined fluids exiting the combining point.
2 . The fluid supply apparatus according to claim 1 , wherein each one of the plurality of fluid pumps runs continuously in operation such that, depending on a switching state of a respective switching valve downstream from a respective fluid pump, the respective fluid pump conveys or does not convey a respective fluid from a respective one of the fluid component sources to the combining point.
3 . The fluid supply apparatus according to claim 2 , wherein at least one fluidic capacity is arranged, as a fluid reservoir, between the plurality of fluid pumps and the plurality of switching valves.
4 . The fluid supply apparatus according to claim 1 , wherein the fluid conveying device comprises a feature selected from the group consisting of: one or more pumps; one or more piston pumps; a binary pump; a quaternary pump; and a multi-channel pump.
5 . The fluid supply apparatus according to claim 1 , wherein the fluid supply apparatus is free from a proportioning device.
6 . The fluid supply apparatus according to claim 1 , comprising at least one of the following features: wherein each one of the fluid pumps is configured to, in an active switching state, actively convey a respective fluid from a respective one of the fluid component sources to the combining point; wherein each one of the fluid pumps is configured to, in an inactive switching state, not convey a respective fluid from a respective one of the fluid component sources.
7 . The fluid supply apparatus according to claim 1 , wherein each of the fluid pumps is selected from the group consisting of: a piston pump; a gear pump; a peristaltic pump; and a membrane pump.
8 . The fluid supply apparatus according to claim 1 , comprising at least one pressure sensor for detecting a value, which is indicative for a pressure in a respective one of the supply lines.
9 . The fluid supply apparatus according to claim 1 , comprising at least one pressure sensor downstream of the combining point.
10 . The fluid supply apparatus according to claim 1 , comprising a non-return valve downstream of the combining point, which is configured to prevent a backflow of conveyed fluids in the direction back to the combining point.
11 . The fluid supply apparatus according to claim 1 , comprising at least one sound sensor configured to detect a switching noise for monitoring the switching state of the fluid supply apparatus.
12 . A sample separation apparatus for separating a fluidic sample by liquid chromatography, the sample separation apparatus comprising: the fluid supply apparatus according to claim 1 for providing the mobile phase in the form of the fluids to be combined at the combining point; an injector downstream of the fluid conveying device and configured to inject the fluidic sample into the mobile phase; and the chromatographic sample separation device, which is configured to separate the fluidic sample injected into the mobile phase into fractions.
13 . A method of providing a mixture of a plurality of different fluids as a mobile phase for a sample separation apparatus, the method comprising: providing a plurality of supply lines, each of which is fluidically coupled to a respective one of a plurality of fluid component sources for providing a respective one of the plurality of different fluids; providing a plurality of fluid pumps, each of which is associated with a respective one of the supply lines; providing a combining point downstream of the fluid pumps and configured to combine the fluids from the supply lines to output combined fluids, wherein each one of the plurality of fluid pumps is switchable such that a respective fluid pump, depending on its respective switching state, pushes or does not push a respective fluid from a respective one of the fluid component sources to the combining point; operating the fluid pumps to bring respective ones of the fluids to a normalized initial pressure; sequentially supplying the fluids from the supply lines to the combining point such that each one of the plurality of fluid pumps, depending on a respective switching state, pushes or does not push a respective fluid from a respective one of the fluid component sources to the combining point, wherein the sequentially supplying comprises operating a switching configuration comprising a plurality of switching valves, each switching valve communicating with a respective one of the supply lines and each switching valve positioned between a respective one of the fluid pumps and the combining point, wherein each switching valve is switchable between an open state that allows the respective fluid pump to convey a respective fluid from a respective one of the fluid component sources to the combining point, and a closed state that prevents the respective fluid pump from conveying the respective fluid; controlling pushing and not pushing by the fluid pumps, and/or controlling the switching of the switching valves, to controllably define a composition of the combined fluids exiting the combining point; and operating a fluid conveying device downstream of the combining point as a metering device to further pressurize the combined fluids output from the combining point to a system pressure and to convey the combined fluids to a chromatographic sample separation device.
14 . The method according to claim 13 , wherein the system pressure is selected from the group consisting of: at least 500 bar; at least 1000 bar; and at least 1200 bar.
15 . The fluid supply apparatus according to claim 1 , wherein the switching configuration comprises a proportioning device for proportioning packages of the respective fluids supplied by the supply lines.
16 . The fluid supply apparatus according to claim 1 , wherein the fluid conveying device is configured to draw the fluids starting from the combining point.

Description

RELATED APPLICATIONS This application is the national stage under 35 U.S.C. 371 of International Application No. PCT/IB2019/051661, filed Mar. 1, 2019, which claims priority to German Application No. DE 10 2018 104 842.4, filed Mar. 2, 2018, the entire contents of both of which are incorporated by reference herein. TECHNICAL BACKGROUND The present invention relates to a liquid chromatography fluid supply apparatus, a liquid chromatography sample separation apparatus and a method for providing a mixture of several different fluids as a mobile phase for a liquid chromatography sample separation apparatus. In an HPLC system, a liquid (mobile phase) is typically moved through a so-called stationary phase (for example in a chromatographic column) at a very precisely controlled flow rate (for example in the range of microlitres to millilitres per minute) and at a high pressure (typically 20 to 1000 bar and beyond, currently up to 2000 bar), at which the compressibility of the liquid may be perceptible, in order to separate from one another individual fractions of a sample liquid that has been introduced into the mobile phase. After passing through the stationary phase, the separated fractions of the fluidic sample are detected in a detector. Such an HPLC system is known for example, from EP 0,309,596 B1 of the same applicant, Agilent Technologies, Inc. For liquid chromatography and other applications of sample separation, it is necessary to perform a mixture of different fluids, for example different solvents, wherein the mixed fluid composition should be formed from these fluids in a well-defined manner. Upstream of a fluid drive and/or a fluid conveying device (in particular a high-pressure chromatographic pump) there are plural solvent containers, from which solvents (such as water and ethanol) are provided for a chromatographic separation run (for example a gradient run). These fluids and/or solvents are accelerated under the influence of gravity when they move through fluid lines, through a proportioning device, to a mixing or combining point to the point of the high-pressure pump. Thus, gravitational effects and also the inertia of the fluid influence, in particular, the path between the solvent containers and the mixing point and/or the inlet of the high pressure pump. The filling level of the solvent containers can only be estimated if the flow carried out is integrated. Due to the described effects, the accuracy of the fluid composition depends on the storage height of the solvent containers and on their filling level. This also means that the accuracy of the operation of a liquid chromatography apparatus can deteriorate, if the height of the bottles relative to a mixing point or the tube geometry changes. Therefore, the height and filling level of the solvent containers are correlated with the precision of a separation experiment using a liquid chromatography sample separation apparatus. For reproducible results, it would therefore be necessary for users to always arrange solvents at a same elevated position. This impairs the flexibility of the operation of a sample separation instrument as well as the reproducibility of separation results. The described gravitational effects as well as viscosity fluctuations of the fluids and the inertia of the fluids therefore thus lead to an inaccuracy in the solvent composition and consequently in the sample separation. In addition, it has been found that in the described configuration, volume errors of the fluids to be mixed can occur upon switching the proportioning device. Therefore, the precise amount of liquid, which is supplied from a fluid line at the mixing or combining point, is sometimes unclear or inaccurate. It has also been found that in the described configuration, fluid can be diverted between fluid lines in an undesirable manner. The described parasitic effects lead to missing (or incorrect) volumes of the fluids to be mixed. In particular, pressure ratios between the solvent containers and the pump head may be undefined. SUMMARY It is an object of the invention to generate a composition of plural fluids to be mixed for the liquid chromatography under reproducible and defined conditions. According to an exemplary execution example of the present invention, there is established a liquid chromatography fluid supply apparatus for providing a mixture of a plurality of different fluids as a mobile phase for a liquid chromatography sample separation apparatus, wherein the fluid supply apparatus has a plurality of supply lines, each of which is fluidically coupled to a respective one of a plurality of fluid component sources for providing a respective one of the fluids, a plurality of fluid pumps, each of which is associated with a respective one of said supply lines, and a combining point (or merging point, or point of union), at which the fluids from said supply lines are to be combined (or merged), wherein each of said plurality of fluid pumps conveys or