Analytical systems and methods involving switching between liquid chromatography fluid streams

Abstract

The present disclosure relates to an analysis system (100), which includes a liquid chromatography (LC) system (10), the liquid chromatography (LC) system (10) including a plurality of fluid streams (11, 12, 13, Sn-1, Sn, Sn+1) that can be alternately connected to a common detector (60) via a stream selection valve (20), the stream selection valve (20) being connected to the detector (60) via a valve-detector conduit (30). The analysis system (100) further includes a cleaning pump (40), which is fluidically connected to the stream selection valve (20) and configured to be connected to the valve-detector conduit (30) between two consecutive fluid streams to wash out the liquid of the previous fluid stream from the valve-detector conduit (30) before the liquid of the subsequent fluid stream enters the valve-detector conduit (30). An analysis method is also disclosed, which includes switching between fluid streams (11, 12, 13, Sn-1, Sn, Sn+1) and cleaning between them.

Description

Technical Field

[0001] The present disclosure relates to analytical systems comprising a plurality of fluid streams that are alternately connectable to a common detector, and to analytical methods comprising switching between the fluid streams. Background Art

[0002] There is growing interest in implementing mass spectrometry, and more specifically liquid chromatography (LC)-MS / MS, in clinical laboratories. However, the lack of standardized and automated procedures and the complexity of the analytical setup limit its implementation.

[0003] Sample processing with LC-MS also usually follows a batch method, in which a batch of samples prepared in advance under the same preparation conditions are subjected to consecutive chromatographic separation runs under the same separation conditions. However, this method cannot achieve high throughput and is not flexible, for example, it cannot process samples in a random order as they arrive. Batch processing also cannot be rescheduled (i.e., the predetermined processing order is changed) because, for example, an urgent sample arrives that has a higher priority and must be processed first.

[0004] U.S. Patent Application Publication 2018 / 0292368 A1 describes a system comprising multiple LC fluid streams arranged in parallel and alternately connectable to a mass spectrometer, and a method capable of automated random-access sample preparation and LC separation, thereby utilizing LC-mass spectrometry technology suitable for clinical diagnosis.

[0005] For high-throughput applications requiring many sequential injection cycles, and especially for random-access analysis of different samples that may require different injection conditions and different LC separation conditions, greater flexibility and speed in quickly changing and adjusting conditions for each sample in a planned sequence is important.

[0006] In particular, solvents / eluents used for LC separations may have to be frequently exchanged within the same fluid stream and between parallel fluid streams. Liquid exchange is the process of repeated dilution of previously used liquid by newly used liquid, which can result in long equilibrium and signal stabilization times due to the nature of pump operation, internal dead volumes, and fluidic and surface effects. Therefore, such a process may present a bottleneck if the goal is to achieve high-throughput random-access sample processing, especially if the goal is to maintain a regular pace of injection and analysis regardless of the sample sequence and separation / analysis conditions. Summary of the invention

[0007] It is against the foregoing background that embodiments of the present disclosure provide certain non-obvious advantages and advances over the prior art.In particular, the inventors have recognized a need for improved analytical systems and methods for switching between liquid chromatography fluid streams.

[0008] Although the embodiments of the present disclosure are not limited to specific advantages or functions, it is noted that the present disclosure provides an analytical system and method that is capable of more quickly and efficiently exchanging the liquid of a previous LC fluid stream with the liquid of a subsequent LC fluid stream in a fluid conduit leading from a logistics selection valve to a detector, thereby shortening the clearing (signal stabilization) time and thereby improving the throughput in random access sample analysis.

[0009] Another advantage of the systems and methods disclosed herein is that carryover is minimized, thereby reducing baseline drift and improving sensitivity.

[0010] Another advantage of the systems and methods disclosed herein is that no-flow conditions can be prevented during system standby or liquid chromatography interruptions, thereby minimizing surface adsorption effects and helping to keep the valve-detector conduits cleaner, thereby also minimizing maintenance costs and system downtime.

[0011] Another advantage of the systems and methods disclosed herein is the ability to perform automated cleaning procedures at a convenient time and independent of the liquid chromatography system, thereby also extending the life of some system components.

[0012] Another advantage of the systems and methods disclosed herein may be the standardization of initial conditions at each fluid stream switch, such as by always introducing the same liquid between them.

[0013] Another advantage of the systems and methods disclosed herein is that it is possible to determine whether the final blockage is located in the fluid conduit leading to the detector or elsewhere.

[0014] In particular, an analytical system according to an embodiment of the present disclosure includes a liquid chromatography system, which includes a plurality of fluid streams that can be alternately connected to a common detector via a stream selection valve, wherein the stream selection valve is connected to the detector via a valve-detector conduit. The analytical system further includes a cleaning pump, which is fluidically connected to the stream selection valve and configured to be connected to the valve-detector conduit between two consecutive fluid streams to wash out the liquid of the previous fluid stream from the valve-detector conduit before the liquid of the subsequent fluid stream enters the valve-detector conduit.

[0015] "Liquid chromatography or LC" is an analytical method that subjects a sample injected via an injector to a chromatographic separation through an LC column, for example to separate analytes of interest from matrix components, e.g. residual matrix components after sample preparation (which may still interfere with subsequent detection, e.g. mass spectrometry), and / or to separate analytes of interest from each other so that they can be detected individually. "High performance liquid chromatography" or HPLC, "ultra-high performance liquid chromatography" or UHPLC, "micro-liquid chromatography" or µLC and "small-pore liquid chromatography" or small-pore LC are forms of liquid chromatography performed under pressure.

[0016] A "liquid chromatography system or LC system" is an analytical device or module for performing liquid chromatography, or a unit in an analytical device. An LC system may be embodied as a single-channel or multi-channel system, which may comprise one or more LC columns arranged in parallel and / or in series. An LC system may further comprise elements such as injectors, valves, liquid sources, fluid connections and components such as for mixing, degassing, tempering etc. liquids, one or more sensors such as pressure sensors, temperature sensors etc., in particular at least one LC pump. This list is not exhaustive.

[0017] According to one embodiment, the detector can be a mass spectrometer connected to the valve-detector conduit via an ionization source. However, the detector can be something other than a mass spectrometer, such as an optical detector, such as an ultraviolet or fluorescence detector, an impedance detector, a conductivity detector, etc.

[0018] According to one embodiment, the LC system can be configured as an analysis module designed to prepare samples for mass spectrometry and / or transfer prepared samples to a mass spectrometer, particularly for separation of relevant analytes prior to detection by a mass spectrometer. In particular, typically, during an LC run, a mass spectrometer can be set to scan a specific mass range. LC / MS data can be presented by adding the ion currents in each mass scan and plotting the "total" ion current as intensity points relative to time. The resulting graph looks like an HPLC UV trace with analyte peaks.

[0019] "Fluid stream" is a fluid path through which a liquid can flow, in particular, a sample from an injection point can be transferred to a detector, for example, to a mass spectrometer or other detector, and the sample can undergo a chromatographic process. The fluid connection through different parts of the fluid stream may be discontinuous. This is because the fluid stream may include elements such as a switching valve, which can establish alternating connections and regulate the flow of fluid between different parts of the fluid stream at different times. The fluid stream may include at least one capillary and / or LC column, which includes a stationary phase selected according to the type of one or more samples and the relevant analyte, and the mobile phase is pumped through it so that under selected conditions, for example, as is well known, according to their polarity or log P value, size or affinity, capture and / or separate and elute and / or transfer relevant analytes. The at least one LC column may be replaceable. In particular, the LC system may include more LC columns than the fluid stream, wherein a plurality of LC columns may be selectable, for example, interchangeably coupled to the same fluid stream. Capillaries can also be used to bypass LC columns. The fluid stream may include multiple substreams.

[0020] In particular, an LC system according to one or more embodiments of the present disclosure may include multiple fluid streams connected to a stream selection valve to direct flow from one fluid stream at a time to a detector.

[0021] "LC column" can refer to any of the columns, cartridges, capillaries, etc., used to perform separations of chromatographic properties. The column is usually filled or loaded with a stationary phase, through which the mobile phase is pumped, so as to capture and / or separate and elute and / or transfer related analytes under selected conditions, such as, as is well known, according to their polarity or log P value, size or affinity. This stationary phase can be particulate or beaded or a porous monolith. However, the term "column" can also refer to a capillary or channel that is not filled or loaded with a stationary phase but relies on the surface area or geometry of the inner capillary wall to achieve separation. An example is provided by column array chromatography, in which a separation bed is formed by etching away interstitial volumes from a solid silicon wafer to leave a column array. The resulting channel can be folded into a small footprint by connecting bed segments to an optimized flow distributor that limits peak dispersion. This creates a stationary phase support structure organized in a reproducible, ordered pattern.

[0022] The LC column may be replaceable and / or operate in parallel or sequentially with one or more other LC columns. The LC column may be, for example, a fast capture and elution LC column or simply a "capture column", an HPLC column or a UHPLC column, and may be of any size, including micro LC columns and small pore LC columns, or a column array LC column, with an inner diameter of 1 mm or less. In the case of a capture column, a stationary phase may be selected that retains the analyte of interest, while any salts, buffers, detergents, and other matrix components are not retained and washed away. This process is usually followed by elution of the analyte with a different mobile phase or solvent gradient, for example in a backwash mode. Depending on the analyte, separation of some analytes may be expected in some cases. On the other hand, when the analytes have the same mass (isobaric) and / or have overlapping daughter ion spectra in multiple reaction monitoring (MRM), a more extensive chromatographic separation may be typical when mass spectrometry is involved. In this case, separation in an HPLC or UHPLC column may be advantageous.

[0023] A "liquid chromatography pump or LC pump" is a high pressure pump that may have varying pressurization capabilities but produces a consistent and reproducible volume flow through the LC channel. Pressures in HPLC may typically be up to 60 MPa or approximately 600 atmospheres, while UHPLC and µ-LC systems have been developed to operate at higher pressures, e.g. up to 140 MPa or approximately 1400 atmospheres, thus enabling the use of much smaller particle sizes (<2 μm) in LC columns. LC pumps may be configured as binary pumps or even quaternary pumps, e.g. in cases where conditions require the use of an elution gradient by gradually changing the ratios between up to four elution solvents.

[0024] According to one embodiment, the LC pump may generate a pressure of 60 MPa to 140 MPa, typically 75 MPa to 100 MPa, more typically 80 MPa.

[0025] According to one embodiment, the LC pump can be configured to operate at a flow rate of 1 μl / min to 500 μl / min or higher, typically up to 1500 μl / min, more typically 100 μl / min to 300 μl / min and an accuracy of, for example, about ± 5% or less.

[0026] An LC pump may include more than one pump head. For example, a binary pump includes two pump heads, each of which typically includes a primary pump head and a secondary pump head that cooperate with each other to pump liquid while maintaining a substantially constant pressure of the liquid within the pump head. In particular, the primary pump head and the secondary pump head are each typically a syringe-like pump that includes a syringe-like cylinder having an inner wall surface and a plunger that can translate through the cylinder to leave a gap between the inner wall surface and the plunger as the plunger translates through the cylinder.

[0027] The term "liquid" with respect to a fluid stream refers to a liquid commonly used in liquid chromatography, eg as a solvent or solvent mixture, which is used, for example, as a mobile phase or eluent (elution solvent) and as known in the art.

[0028] A "purge pump" is an auxiliary pump that is at least functionally different from an LC pump, and its main or sole function is to promote and accelerate the exchange of liquids in the valve-detector conduit. Generally speaking, a purge pump is a pump with lower pressure and higher volume (higher flow) than an LC pump, and is connected to a logistics selection valve independently of the LC system fluid. Typically, a purge pump according to the present disclosure is also a pump with lower precision than an LC pump, and is therefore simpler and cheaper to construct. According to one embodiment of the present disclosure, the purge pump is a positive pressure pump. Any pump suitable for generating a positive pressure can be used to actively pump a purge liquid from a purge liquid source through a valve-detector conduit via a logistics selection valve, such as a membrane / diaphragm pump, a single plunger high-speed pump, a syringe piston pump, a gear pump, etc. According to one embodiment, positive pressure and active pumping can be achieved by applying pneumatic pressure to a sealed liquid container connected to an upstream inlet valve, such as by pressurized gas, such as by nitrogen supply.

[0029] According to one embodiment, the purge pump is configured to pump the purge fluid through the valve-detector conduit at a flow rate (e.g., several times, such as 5 times, 10 times, 20 times, or more) higher than the flow rate of the fluid stream. For example, in the case of a µ-LC with a typical flow rate of about 1 µL / min, a purge pump flow rate of 5 µL / min may be beneficial. In the case of a flow rate of the fluid stream of about 100 µL / min, the effective flow rate of the purge pump is about 500 – 1000 µL / min or more. According to some embodiments, purge pump flows of up to 5000 µL / min are possible.

[0030] A "cleaning liquid" is a liquid suitable for washing away, and therefore dissolving, final traces of sample in the valve-detector conduit, while still being compatible with the detector used, for example a mass spectrometer. Thus, the cleaning liquid may be the same or similar to the elution solvent used for chromatography, which may be different depending on the type of sample and analyte. For example, for analytes that are typically subjected to reverse phase chromatography, suitable solvents may be organic solvents such as methanol, acetonitrile, tetrahydrofuran and / or isopropanol. These solvents may also be mixed with each other and / or with water. Acidic or basic additives may be added to adjust the pH. Typical additives may include formic acid, ammonium formate, ammonium acetate, and the like. For example, for analytes that are typically subjected to normal phase chromatography, suitable solvents may include solvents such as hexane, heptane mixed with polar organic solvents such as ethyl acetate, chloroform or 2-propanol.

[0031] The term "valve" refers to a flow regulating device for controlling, redirecting, limiting or shutting off flow, in particular an LC switching valve, i.e. a multi-way valve that controls the flow between elements connected to a port. This is usually achieved by moving one or more valve conduits to switch the communication between different elements. The elements may be fluidically connected to the port via further conduits, such as pipes, tubing, capillaries, microfluidic channels, etc., and by fittings, such as screws / nuts and ferrules, or alternative liquid-tight seals (which are held in place, for example, by a clamping mechanism). LC switching valves are typically able to allow liquid pressures of the order of magnitude used for HPLC or higher.

[0032] In particular, the stream selection valve may include a port for each fluid stream from the LC system, a port for the valve-detector conduit, and a plurality of waste ports.

[0033] According to one embodiment of the present disclosure, the stream selection valve has one or more inner valve conduits with an inner diameter of less than 0.6 mm, typically about 0.5 mm to 0.2 mm, more typically about 0.4 mm, and even more typically about 0.25 mm. However, the inner valve conduits may have any other diameter within the commonly used range.

[0034] According to one embodiment of the present disclosure, the stream selection valve has a typical switching time of about 500 ms or less. However, the switching time may also be longer than 500 ms.

[0035] A "mass spectrometer (MS)" is an analytical module that includes a mass analyzer designed to further separate and / or detect analytes based on their mass-to-charge ratio. According to one embodiment, the mass spectrometer is a fast scanning mass spectrometer. According to one embodiment, the mass spectrometer is a tandem mass spectrometer capable of selecting a parent molecular ion, generating fragments by collision-induced fragmentation, and separating the fragments or daughter ions according to their mass-to-charge ratio (m / z). According to one embodiment, the mass spectrometer is a triple quadrupole mass spectrometer as known in the art. In addition to quadrupoles, other types of mass analyzers may also be used, including time-of-flight, ion traps, or combinations thereof.

[0036] An "ionization source (IS)" is an interface coupling the LC to the MS, configured to generate charged analyte molecules (molecular ions) and to transfer charged analyte molecules from the liquid phase to the gas phase. According to certain embodiments, the ionization source is an electrospray ionization (ESI) source, or a heated electrospray ionization (HESI) source, or an atmospheric pressure chemical ionization (APCI) source, or an atmospheric pressure photoionization (APPI) or atmospheric pressure laser ionization (APLI) source. However, the LC / MS interface may include a dual ionization source, such as an ESI and APCI source, or a module-exchangeable ionization source.

[0037] Typical components of an ionization source are a nebulizer and a sampling capillary, which are usually arranged orthogonally or coaxially with each other. The LC eluate leaving the LC stream is directed through a probe comprising a spray needle or capillary. In this way, the LC eluate is atomized in a volume downstream of the nebulizer capillary, where ionization occurs and the charged analyte molecules obtained thereby enter the gas phase. A sampling device (e.g., a sampling capillary or orifice) is provided to collect ions in the gas phase and direct them into a mass spectrometer.

[0038] The ionization source may further include providing a curtain gas, also known as a counter gas (e.g., N 2 ) assembly that reduces background ions (e.g., solvent clusters) from entering the MS. The assembly may have a curtain plate and orifice assembly to provide a curtain gas. The ionization source may further include an assembly that provides an auxiliary gas (also called a heater gas).

[0039] To optimize ionization conditions, the solvent composition can also be adjusted by adding a make-up stream directly before the ionization source to adjust the pH, salts, buffers, or organic content.

[0040] Such ionization sources are known in the art and will not be further elucidated here.

[0041] According to one embodiment, the ionization source comprises a nebulizer capillary forming part of the valve-detector conduit. Thus, liquids from the fluid streams, including LC eluate, and wash liquids between the fluid streams flow alternately through the nebulizer capillary fluidically connected to the stream selection valve.

[0042] The analysis system may include a controller configured to manage the fluid stream connection time, i.e., the connection time between each fluid stream and the valve-detector conduit, and the cleaning pump connection time, i.e., the connection time between the cleaning pump and the valve-detector conduit, by controlling the switching of the stream selection valve. The controller may also be configured to control the cleaning pump so that the cleaning fluid is pumped only during the cleaning pump connection time.

[0043] The term “controller” used herein may refer to a processing unit such as a microprocessor, a microcontroller, a reduced instruction set circuit (RISC), an application specific integrated circuit (ASIC), a logic circuit, and any other circuit or processor capable of performing the functions / methods described herein.

[0044] The controller may be integrated into the analysis system, or may be a separate logical entity that communicates with the analysis system via a network interface device, either directly or indirectly via a wired or wireless communication network, such as a wide area network, such as the Internet or a local area network or intranet of a healthcare provider. In some embodiments, the processor may be integrated with a data management unit, such as implemented on a computing device, such as a desktop computer, a laptop computer, a smart phone, a tablet computer, a PDA, etc. It may include a server computer and / or be distributed / shared between multiple analysis systems. In addition, the analysis system may include remote devices, servers, and cloud-based elements that communicate with the controller via wired or wireless means (e.g., infrared, cellular, Bluetooth®), or remote PC / server or cloud-based systems. The controller may also be configured to control the analysis system in a manner that one or more workflows and one or more workflow steps are executed by the analysis system. In particular, the processor can communicate and / or collaborate with a scheduler and / or a data manager to take into account input test orders and / or received test orders in conjunction with managing fluid logistics connection times and cleaning pump connection times, controlling the switching of logistics selection valves and the action of cleaning pumps, and many planned process operations associated with the execution of test orders.

[0045] According to one embodiment, the fluid logistics connection time is fixed and is the same for each fluid logistics. In addition, the cleaning pump connection time is fixed and is a part of the fluid logistics connection time, thereby at least temporarily switching continuously with a regular pace. If the cleaning pump connection time is 20% or shorter of the fluid logistics connection time, usually 10% or shorter, or more usually 5% or shorter and thus adjust the cleaning pump in terms of flow and / or cleaning fluid conditions to minimize the cleaning pump connection time, it is particularly beneficial. In terms of absolute value, the cleaning pump connection time may be as short as a few seconds, usually 5s or shorter, more usually 3s or shorter.

[0046] According to one embodiment, the controller may be configured to adjust a set of parameters of the detector and / or ionization source from a previous configuration associated with the previous fluid stream to a subsequent configuration associated with the subsequent fluid stream during the cleaning pump connection time before switching to the subsequent fluid stream. In this way, by the time the stream selection valve is switched again, the detector is ready for the subsequent fluid stream, which can also reduce the fluid stream connection time, thereby further improving the throughput. According to one embodiment, this set of parameters may include any one or more of the air curtain gas pressure, the nebulizer gas pressure, the auxiliary gas pressure, the nebulizer capillary voltage, the sampling capillary voltage, etc., including any parameters that can be adjusted before starting to detect the eluate from the fluid stream.

[0047] According to one embodiment, the controller can be configured to extend the cleaning pump connection time while pumping cleaning liquid through the valve-detector conduit when the switching interruption between the fluid logistics or when the system is on standby. Otherwise, when the switching interruption between the fluid logistics or when the system is on standby, the liquid from the last fluid logistics may evaporate and the fluid conduit or a part thereof, in particular the sprayer capillary may dry up, so that the final sample traces or mobile phase additives, such as salt concentration, deposition or even crystallization, may cause blockage and / or require special maintenance procedures, such as replacing the severe contamination of the capillary sprayer. Considering that the ion source is usually heated, evaporation may occur relatively quickly. Therefore, the continued use of the cleaning pump can be beneficial to prevent this evaporation by maintaining a continuous liquid flow.

[0048] According to one embodiment, the analysis system includes a pressure gauge for measuring liquid pressure between the purge pump and the logistics selection valve, and the controller is configured to compare the liquid pressure measured during the purge pump connection time with the liquid pressure measured when the purge pump fluid is connected to the waste, and determine whether there is a blockage in the valve-detector conduit based on this comparison.

[0049] According to another embodiment of the present disclosure, an automated analysis method is also described herein, the method comprising alternately connecting multiple fluid streams of a liquid chromatography (LC) system to a common detector via a logistics selection valve, the logistics selection valve being connected to the detector via a valve-detector conduit, the method further comprising connecting a cleaning pump fluid to the valve-detector conduit via the logistics selection valve between two consecutive fluid streams and washing out the liquid of the previous fluid stream from the valve-detector conduit before the liquid of the subsequent fluid stream enters the valve-detector conduit.

[0050] According to one embodiment, the method may further include automatically managing the fluid logistics connection time, i.e., the connection time between each fluid logistics and the valve-detector conduit, and the cleaning pump connection time, i.e., the connection time between the cleaning pump and the valve-detector conduit, by controlling the switching of the logistics selection valve.

[0051] According to another embodiment, the fluid stream connection time may be fixed and the same for each fluid stream, and wherein the purge pump connection time is fixed and a fraction of the fluid stream connection time, thereby performing continuous switching at least temporarily in a regular pace.

[0052] According to yet another embodiment, the method includes adjusting a set of parameters of the detector and / or ionization source (where the detector is a mass spectrometer) from a previous configuration associated with a previous fluid stream to a subsequent configuration associated with a subsequent fluid stream during a purge pump connection time prior to switching to a subsequent fluid stream.

[0053] According to yet another embodiment, the method further comprises extending the purge pump connection time while pumping the purge fluid through the valve-detector conduit in case of an interruption in switching between fluid streams or in case of system standby.

[0054] According to one embodiment, the method includes comparing the liquid pressure between the purge pump and the logistics selection valve measured during the purge pump connection time with the liquid pressure measured when the purge pump fluid is connected to the waste, and determining whether there is a blockage in the valve-detector conduit based on this comparison.

[0055] Other and further objects, features and advantages will become apparent from the following description of exemplary embodiments in conjunction with the accompanying drawings and the appended claims. It is noted that the scope of the claims is limited by the description therein rather than by the specific discussion of features and advantages given in this specification. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] The following detailed description of embodiments of the present disclosure may be best understood when read in conjunction with the following drawings, in which like structure is represented by like reference numerals and in which:

[0057] Figure 1A Schematically shown is an analytical system comprising a purge pump connected to a stream selection valve and a first step of an analytical method comprising the use of the purge pump.

[0058] Figure 1B Schematic display Figure 1A The same analysis system and the second step of the same method.

[0059] Figure 1C Schematic display Figure 1A The same analysis system and the third step of the same method.

[0060] Figure 1D Schematic display Figure 1A The same analysis system and the fourth step of the same method, which is Figure 1B same.

[0061] Figure 1E Schematic display Figure 1A The same analysis system and the fifth step of the same method.

[0062] Figure 1F Schematic display Figure 1A The same analysis system and the same method of the sixth step, which is Figure 1B and Figure 1D same.

[0063] Figure 2 Schematic diagram showing the detector-related Figures 1A-1F Further details of the analysis system.

[0064] Figure 3 A method of controlling the switching of a stream selection valve is schematically shown.

[0065] Figure 4 Includes extended cleaning Figure 3 A variation of the method.

[0066] Figure 5 is an experimental example showing what can be achieved.

[0067] Fig. 6A Schematic showing pressure gauge Figure 2 The same analysis system and the first step of the method for determining blockage based on liquid pressure measurement.

[0068] Figure 6B Schematic display Fig. 6A Continuation of the same analytical system and methods.

[0069] The skilled person will appreciate that the elements in the drawings are shown for simplicity and clarity and are not necessarily drawn to scale. For example, the dimensions of some elements in the drawings may be exaggerated relative to other elements to help improve understanding of the embodiments of the present disclosure. DETAILED DESCRIPTION

[0070] Figures 1A-1F A schematic example of an analysis system 100 is shown, which includes a liquid chromatography (LC) system 10, which includes a plurality of fluid streams 11, 12, 13 that are alternately connectable to a common detector 60 via a stream selection valve 20, which is connected to the detector 60 via a valve-detector conduit 30. The analysis system 100 further includes a purge pump 40, which is fluidly connected to the stream selection valve 20 and is configured to be connected to the valve-detector conduit 30 between two consecutive fluid streams 11, 12; 12, 13; 13, 11 to wash out liquid of the preceding fluid stream from the valve-detector conduit 30 before liquid of the subsequent fluid stream enters the valve-detector conduit 30.

[0071] In particular, the stream selection valve 20 in this case comprises fluid stream ports 21, 22, 23 for each fluid stream 11, 12, 13, respectively, waste ports 21', 22', 23' for each fluid stream 11, 12, 13, respectively, leading to waste 50, a purge pump inlet port 24 and a purge pump waste port 24' leading to waste 50. The stream selection valve 20 also comprises a valve-detector conduit port 25 connected to the valve-detector conduit 30. It is clear that this is only an example and the number of ports and connections can be adjusted as required, in particular according to the number of fluid streams.

[0072] The cleaning pump 40 is connected to four cleaning liquid containers in this example, which contain respective cleaning liquids 41, 42, 43, 44, such as water, acetonitrile, methanol, tetrahydrofuran or isopropanol, which can be pumped individually or mixed with each other in any combination and ratio, depending on, for example, the LC conditions, the type of sample and / or analyte flowing therebetween, and the desired cleaning effect. In particular, the cleaning pump 40 is configured to pump the cleaning liquid through the valve-detector conduit 30 at a flow rate 45 that is higher than the flow rate 15 of the fluid streams 11, 12, 13.

[0073] The analysis system 100 further includes a controller 90, which is configured to manage the fluid logistics connection time, i.e., the connection time between each fluid logistics 11, 12, 13 and the valve-detector conduit 30, and the cleaning pump connection time, i.e., the connection time between the cleaning pump 40 and the valve-detector conduit 30, by controlling the switching of the logistics selection valve 20.

[0074] Continue to refer Figures 1A-1F , also schematically shows an automated analysis method, which includes alternately connecting multiple fluid streams 11, 12, and 13 of a liquid chromatography (LC) system 10 to a common detector 60 via a logistics selection valve 20, and the logistics selection valve 20 is connected to the detector 60 via a valve-detector conduit 30. The method further includes connecting a cleaning pump 40 fluid to the valve-detector conduit 30 via the logistics selection valve 20 between two consecutive fluid streams 11, 12; 12, 13; 13, 11 and washing out the liquid of the previous fluid stream from the valve-detector conduit 30 before the liquid of the subsequent fluid stream enters the valve-detector conduit 30.

[0075] In particular, Figure 1A The first step of the method is shown in which stream selection valve 20 is switched to connect fluid stream 11 to valve-detector conduit 30, while the other fluid streams 12, 13 are connected to waste ports 22', 23' respectively. Purge pumps 40 are also connected to respective purge pump waste ports 24'.

[0076] Figure 1B The second step of the method is shown, wherein the stream selection valve 20 is switched to connect the purge pump 40 to the valve-detector conduit 30, while all fluid streams 11, 12, 13 are directed to waste 50 via waste ports 21', 22', 23' respectively.

[0077] Figure 1C The third step of the method is shown in which stream selection valve 20 is switched to connect fluid stream 12 to valve-detector conduit 30, while the other fluid streams 11, 13 are connected to waste ports 21', 23' respectively. Purge pumps 40 are also connected to respective purge pump waste ports 24'.

[0078] like Figure 1D The fourth step of the method shown in Figure 1B The second step is the same.

[0079] Figure 1E The fifth step of the method is shown in which stream selection valve 20 is switched to connect fluid stream 13 to valve-detector conduit 30, while the other fluid streams 11, 12 are connected to waste ports 21', 22' respectively. Purge pumps 40 are also connected to respective purge pump waste ports 24'.

[0080] At the beginning again Figure 1A Before the first step, Figure 1F The sixth step of the method shown in Figure 1B The second step and Figure 1D The fourth step is the same.

[0081] Continue to refer Figures 1A-1F , the controller 90 may be configured to control the cleaning pump 40 so that the cleaning fluid is only in the process of the cleaning pump connection time, that is, only in Figure 1B , 1D , 1F, the second, fourth and sixth steps, thereby preventing large volumes of cleaning fluid waste caused by higher flow rates. The controller 90 may be further configured to control the selection and or ratio of each cleaning fluid 41, 42, 43, 44.

[0082] Of course, variations of the method are possible, wherein there are different numbers of fluid streams and / or wherein the order between the fluid streams may be different. In particular, the method can be adapted to switch between any two or more or all of the plurality of fluid streams and in any order depending on the analytical method, as long as the method includes switching to purge the pump between two consecutive fluid streams.

[0083] Figure 2 Schematic display Figures 1A-1F An embodiment of an analytical system, wherein the detector 60 is a mass spectrometer connected to the valve-detector conduit 30 via an ionization source 61, such as an electrospray ionization (ESI) source, the ionization source 61 including a sprayer capillary 62 forming part of the valve-detector conduit 30 and being cleaned with a cleaning fluid from a cleaning pump 40.

[0084] and Figures 1A-1F Related, Figure 3 According to some embodiments, Figures 1A-1FFurther aspects of the method. According to one aspect, the method includes automatically managing the fluid logistics connection times t-Sn-1, t-Sn, t-Sn+1, i.e., the connection time between each fluid logistics 11, 12, 13 and the valve-detector conduit 30, and the cleaning pump connection time, i.e., the connection time between the cleaning pump 40 and the valve-detector conduit 30, by the controller 90 by controlling the switching of the logistics selection valve 20. The fluid logistics connection times t-Sn-1, t-Sn, t-Sn+1 are fixed and are the same for each fluid logistics 11, 12, 13. The cleaning pump connection time tW is also fixed and is a part of the fluid logistics connection times t-Sn-1, t-Sn, t-Sn+1, thereby performing continuous switching at least temporarily at a regular pace. According to another aspect, the controller 90 is configured to adjust a set of parameters of the detector 60 and / or the ionization source 61 from a previous configuration Config. n-1 associated with a previous fluid flow Sn-1 to a subsequent configuration Config. n associated with a subsequent fluid flow Sn, and so on from Config. n to Config. n+1 during a cleaning pump connection time tW before switching to a subsequent fluid flow.

[0085] In the case where the controller 90 is configured to control the wash pump 40 to pump the wash liquid only during the wash pump connection time tW, a portion of the wash pump connection time tW may be required to start and stop the pumping action by the wash pump 40, and a slightly longer wash pump connection time tW is ultimately required to compensate for this time lag while still achieving the same cleaning effect. In the case where the controller 90 is configured to control the wash pump 40 to continuously pump the wash liquid while directing the wash liquid to waste during the fluid logistics connection time, the entire wash pump connection time tW can be used for cleaning, and the wash pump connection time tW can ultimately be reduced while still achieving the same cleaning effect.

[0086] Figure 4 yes Figure 3 An adjustment of , which shows another aspect of the analysis system and method, according to which the controller 90 is configured to extend the cleaning pump connection time tW while pumping the cleaning liquid through the valve-detector conduit 30 in the event of an interruption in switching between fluid streams or in the event of system standby. Depending on the duration of the interruption or the system standby time, the controller 90 can be configured to control the cleaning pump 40 to pump the cleaning liquid continuously or intermittently, and eventually reduce the flow rate, as long as it is prevented that the valve-detector conduit 30 becomes dry.

[0087] Figure 5 An example of the effects that can be achieved by performing a purge under specific conditions between successive fluid streams is shown. In particular, Figure 5Show by being coupled to mass spectrometer by valve-detector conduit 30 via ESI source and continuously measure the chromatogram of two superposition series that the liquid flow that flows out from valve-detector conduit 30 obtains.In first series 70, directly follow the liquid flow from second fluid stream S2 after the liquid flow from first fluid stream S1, then follow the liquid flow from first fluid stream S1.The first liquid flow from first fluid stream S1 is the reference blank solution of continuous infusion, and volume ratio is 5: 95 acetonitrile: water, to provide stable and regular background signal.The second liquid flow from second fluid stream S2 is volume ratio is 5: 95 identical acetonitrile: aqueous solution, it contains the testosterone of concentration 50 pg / mL and generates the background signal that strengthens and has noise compared with reference signal.In second series 80, the order of liquid flow and solution used are identical with series 70, except between S1 and S2 and between S2 and S1, cleaning solution W is pumped through valve-detector conduit 30. The cleaning liquid used is water:methanol in a volume ratio of 50:50, and the cleaning time or cleaning pump connection time tW is 1.2 seconds, which is a part of the 28.2 seconds of fluid flow connection time t-S2 for S2 in the second series 80. The flow rate of the fluid streams S1, S2 is 100 μL / min, and the flow rate of the cleaning liquid is 1 mL / min. It is also noted that the fluid flow connection time t-S2 for S2 in the first series 70 is longer than that in the second series 80, because a part of the total time is used for cleaning in the second series 80. In other words, t-S2 in the first series 70 is equal to t-S2 + tW in the second series 80. The connection time t-S1 for the second fluid stream in the first series 70 is also equal to t-S1 + tW in the second series 80. In other words, compared with the first series 70, the starting points of the fluid flow connection times t-S2 and t-S1 are delayed by tW in the second series 80, while their end points are the same in the first series 70 and the second series 80.

[0088] Importantly, in Figure 5 It can be observed that when switching from a fluid stream S2 with an elevated analyte concentration to a fluid stream S1 using a reference solution, there is a significant difference between the first series 70 and the second series 80. In particular, in the first series 70, the S1 background signal after S2 takes much longer to return to the same level as S1 before S2. In contrast, by introducing a cleaning step between S2 and S1 in the second series 80, the S1 background signal immediately returns to the same level as S1 before S2. Thus, not only is the significant time loss tW spent on cleaning compensated, but additional time gain is also obtained due to the much faster signal stabilization (clearing time).

[0089] Fig. 6A and Figure 6B The schematic diagram shows the pressure gauge 46. Figure 2 The same analysis system 100 and the method of automatically determining the blockage based on the liquid pressure measurement by the controller 90. In particular, the pressure gauge 46 is located between the cleaning pump 40 and the logistics selection valve 20, and the controller 90 is configured to Figure 6B The liquid pressure P2 measured during the cleaning pump connection time (tW) is Fig. 6A 47, and based on this comparison 47, for example, by determining that P2 is significantly greater than P1, it is determined whether there is a blockage 31 in the valve-detector conduit 30 ( Figure 6B ).

[0090] In the foregoing description, many specific details are set forth to provide a thorough understanding of the present disclosure. However, it is apparent to one of ordinary skill in the art that it is not necessary to use the specific details to practice the present teachings. In other cases, well-known materials or methods are not described in detail to avoid obscuring the present disclosure.

[0091] In particular, modifications and variations of the disclosed embodiments are certainly possible in light of the above description.It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described in the examples described above.

[0092] Reference throughout the foregoing specification to "one embodiment", "an embodiment", "an example" or "an instance", "an aspect" or "an aspect" means that a particular feature, structure or characteristic described in relation to that embodiment or example or aspect is included in at least one embodiment. Thus, the appearance of the phrases "in one embodiment", "in an embodiment", "an example" or "an instance", "an aspect" or "an aspect" in various places in this specification are not necessarily all referring to the same embodiment or example or aspect.

[0093] Furthermore, the particular features, structures or characteristics may be combined in any suitable combinations and / or subcombinations in one or more embodiments or examples or aspects.

Claims

1. An analysis system (100), comprising a liquid chromatography (LC) system (10), the liquid chromatography (LC) system (10) comprising a plurality of fluid streams (11, 12, 13, Sn-1, Sn, Sn+1) which can be alternately connected to a common detector (60) via a stream selection valve (20), the stream selection valve (20) being connected to the detector (60) via a valve-detector conduit (30), wherein the analysis system (100) further comprises a cleaning pump (40) which is fluidically connected to the stream selection valve (20) and is configured to be connected to the valve-detector conduit (30) between two consecutive fluid streams to wash out liquid of a previous fluid stream from the valve-detector conduit (30) before liquid of a subsequent fluid stream enters the valve-detector conduit (30), characterized in that The analysis system (100) includes a controller (90), which is configured to manage the fluid logistics connection time (t-Sn-1, t-Sn, t-Sn+1), that is, the connection time between each fluid logistics (11, 12, 13, Sn-1, Sn, Sn+1) and the valve-detector conduit (30), and the cleaning pump connection time (tW), that is, the connection time between the cleaning pump (40) and the valve-detector conduit (30) by controlling the switching of the logistics selection valve (20), wherein the controller (90) is configured to adjust a set of parameters of the detector (60) and / or the ionization source (61) from a previous configuration related to the previous fluid logistics to a subsequent configuration related to the subsequent fluid logistics during the cleaning pump connection time (tW) before switching to the subsequent fluid logistics, and / or wherein the controller (90) is configured to extend the cleaning pump connection time (tW) while pumping the cleaning liquid through the valve-detector conduit (30) when the switching between the fluid logistics is interrupted or the system is on standby.

2. The analysis system (100) according to claim 1, wherein the detector (60) is a mass spectrometer connected to the valve-detector conduit (30) via an ionization source (61).

3. The analytical system (100) according to claim 2, wherein the ionization source (61) comprises a nebulizer capillary (62) forming part of the valve-detector conduit (30).

4. An analytical system (100) according to any of the preceding claims, wherein the cleaning pump (40) is configured to pump the cleaning liquid (41, 42, 43, 44) through the valve-detector conduit (30) at a flow rate (45) higher than the flow rate (15) of the fluid flow 11, 12, 13.

5. The analysis system (100) according to any one of claims 1-3, wherein the controller (90) is configured to control the cleaning pump (40) so that the cleaning liquid (41, 42, 43, 44) is pumped only during the cleaning pump connection time (tW).

6. An analysis system (100) according to any one of claims 1-3, wherein the fluid logistics connection time (t-Sn-1, t-Sn, t-Sn+1) is fixed and is the same for each fluid logistics (11, 12, 13, Sn-1, Sn, Sn+1), and wherein the cleaning pump connection time (tW) is fixed and is part of the fluid logistics connection time (t-Sn-1, t-Sn, t-Sn+1), thereby performing continuous switching at least temporarily at a regular pace.

7. The analysis system (100) according to any one of claims 1-3, wherein the set of parameters includes any one or more of curtain gas pressure, nebulizer gas pressure, auxiliary gas pressure, nebulizer capillary voltage, and sampling capillary voltage.

8. An analysis system (100) according to any one of claims 1-3, comprising a pressure gauge (46) for measuring liquid pressure between the cleaning pump (40) and the logistics selection valve (20), wherein the controller (90) is configured to compare the liquid pressure (P2) measured during the cleaning pump connection time (tW) with the liquid pressure (P1) measured when the cleaning pump (40) fluid is connected to the waste (50), and based on this comparison (47) determine whether there is a blockage (31) in the valve-detector conduit (30).

9. An automated analysis method, comprising alternately connecting a plurality of fluid streams (11, 12, 13, Sn-1, Sn, Sn+1) of a liquid chromatography (LC) system (10) to a common detector (60) via a stream selection valve (20), wherein the stream selection valve (20) is connected to the detector (60) via a valve-detector conduit (30), the method further comprising fluidically connecting a purge pump (40) to the valve-detector conduit (30) via the stream selection valve (20) between two successive fluid streams and washing out liquid of a preceding fluid stream from the valve-detector conduit (30) before liquid of a succeeding fluid stream enters the valve-detector conduit (30), Features The method includes automatically managing the fluid logistics connection time (t-Sn-1, t-Sn, t-Sn+1), i.e., the connection time between each fluid logistics (11, 12, 13, Sn-1, Sn, Sn+1) and the valve-detector conduit (30), and the cleaning pump connection time (tW), i.e., the connection time between the cleaning pump (40) and the valve-detector conduit (30) by controlling the switching of the logistics selection valve (20), wherein the method includes, during the cleaning pump connection time (tW) before switching to the subsequent fluid logistics, adjusting a set of parameters of the detector (60) and / or, when the detector (60) is a mass spectrometer, the ionization source (61) from a previous configuration related to the previous fluid logistics to a subsequent configuration related to the subsequent fluid logistics, and / or wherein the method includes extending the cleaning pump connection time (tW) while pumping cleaning liquid through the valve-detector conduit (30) when the switching between fluid logistics is interrupted or the system is on standby.

10. A method according to claim 9, wherein the fluid logistics connection time (t-Sn-1, t-Sn, t-Sn+1) is fixed and is the same for each fluid logistics (11, 12, 13, Sn-1, Sn, Sn+1), and wherein the cleaning pump connection time (tW) is fixed and is part of the fluid logistics connection time (t-Sn-1, t-Sn, t-Sn+1), thereby performing continuous switching at least temporarily at a regular pace.

11. A method according to claim 9 or 10, comprising comparing the liquid pressure (P2) between the cleaning pump (40) and the logistics selection valve (20) measured during the cleaning pump connection time (tW) with the liquid pressure (P1) measured when the cleaning pump (40) is fluidically connected to the waste (50), and determining whether there is a blockage (31) in the valve-detector conduit (30) based on this comparison (47).

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