DE102019102010A1 - Compensation of a caused by Schaltartefakte a fluid valve faulty volume of a mobile phase - Google Patents

Abstract

A fluid supply device (100) for providing a mobile phase for a sample separation device (10), wherein the fluid supply device (100) at least one fluid valve (102, 151), which allows or prevents at least a portion of the mobile phase depending on its switching state, a fluid delivery device (20) for conveying mobile phase transmitted by the at least one fluid valve (102, 151), and control means (70) for controlling the at least one fluid valve (102, 151) and / or controlling a delivery characteristic of the fluid delivery device (20) characterized in that a by a switching operation of the at least one fluid valve (102, 151) triggered volume error of at least part of the mobile phase is at least partially compensated.

Description

TECHNICAL BACKGROUND

The present invention relates to a fluid supply device, a sample separation device and a method for providing a mobile phase for a sample separation device.

In an HPLC, a liquid (mobile phase) is typically run at a very precisely controlled flow rate (for example in the range of microliters to milliliters per minute) and at a high pressure (typically 20 to 1000 bar and beyond, currently up to 2000 bar). , in which the compressibility of the liquid can be felt, by a so-called stationary phase (for example, in a chromatographic column), moved to separate individual fractions of a sample liquid introduced into the mobile phase from each other. 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 the EP 0,309,596 B1 same Applicant, Agilent Technologies, Inc.

For liquid chromatography and other sample separation applications, it is necessary to make a mixture of different fluids, for example different solvents, to produce a mobile phase. The mixed fluid composition of these fluids should be formed as accurately defined as possible. However, it has been found that during operation of a fluid supply device for generating a mobile phase, volume errors of the fluids to be mixed can occur.

EPIPHANY

It is an object of the invention to produce a mobile phase with as accurate a composition as possible. The object is achieved by means of the independent claims. Further embodiments are shown in the dependent claims.

According to an exemplary embodiment of the present invention, a fluid supply device is provided for providing a mobile phase for a sample separation device, wherein the fluid supply device at least one (in particular, active or passive switchable) fluid valve, which allows or prevents passing at least a portion of the mobile phase depending on its switching state , a fluid conveying device for conveying mobile phase transmitted by the at least one fluid valve, and a control device for controlling the at least one fluid valve and / or for controlling a conveying characteristic of the fluid conveying device such that a volume error of at least one part triggered by a switching operation of the at least one fluid valve the mobile phase is at least partially (preferably completely) compensated.

According to another exemplary embodiment, there is provided a sample separation apparatus for separating a fluidic sample, the sample separation apparatus comprising a fluid supply apparatus having the above-described features for providing a mobile phase to which the fluidic sample is to be injected and a sample separation means arranged to separate the in the mobile phase injected fluidic sample is set up in fractions.

According to yet another exemplary embodiment, a method of providing a mobile phase to a sample separator is provided, the method comprising switching at least one fluid valve that permits or inhibits passage of at least a portion of the mobile phase depending on its switching state at least one fluid valve passed through mobile phase by means of a fluid conveyor, and controlling the at least one fluid valve and / or a delivery characteristic of the fluid conveyor such that a triggered by a switching operation of the at least one fluid valve volume error at least part of the mobile phase is at least partially compensated.

In the context of the present application, the term "switching of a fluid valve" can be understood to mean, in particular, a process by which the fluid valve is transferred between an open state and a closed state or transferred between different orifice states with different fluid flow rates. Such switching may be actively performed by a controller, for example by applying a control signal to the fluid valve. However, such switching may also be passive, for example by changing the pressure ratios between two fluid ports of a passive fluid valve and therefore opening, closing or changing the gradual opening state of the appropriate fluid valve.

In the context of the present application, the term "fluid" can be understood in particular to mean a liquid and / or a gas or a substance in the supercritical state, optionally having solid particles. Such a fluid can be used in the context of the operation of a sample separation as operating fluid, which during the separation process by fluid lines of the sample separation device by means of a Fluid conveyor (for example, a high-pressure pump) is promoted. As such a working fluid may be considered a mobile phase (ie, a solvent or a solvent composition) which may be a carrier medium in the course of sample separation and / or which may provide a functional contribution to sample separation. This means that the mobile phase can promote a fluid sample to be separated as a carrier medium, but also (for example as part of a chromatographic separation process) can make a functional contribution to the fractional detachment of a previously collected on a sample separator or retarded thereby fluidic sample.

According to an exemplary embodiment of the invention, in a fluid supply device in which a mobile phase is driven by a fluid delivery device and is passed through at least one switchable fluid valve, the accuracy of the solvent composition is improved by providing artifacts regarding the delivered volume triggered by switching operations of the fluid valve will be compensated in whole or in part. Prior to the invention, it has been found that when fluid valves of a fluid supply device are switched, volume errors of the fluids to be mixed may occur, so that the exact amount and composition of the mobile phase is sometimes unclear or inaccurate. The described parasitic effects lead to erroneous volumes of the fluids to be mixed and in consequence of the mobile phase. If a fluid valve performs switching operations during the assembly of a mobile phase from a plurality of solvent components, it may come to a positive pressure surge or during the opening process in particular during the closing process to a vacuum surge. Associated with this are volume errors of the conveyed mobile phase or solvent components of such a mobile phase. In order to prevent undesired effects of such volume errors on the accuracy of sample separation, for example for a sample separation device such as a liquid chromatography device, switching of the fluid valve and / or adjustment of the delivery characteristic of the fluid delivery device can be adjusted such that such volume errors occur according to an exemplary embodiment of the invention be at least partially offset. Clearly, the operation of a fluid supply device can thus be adapted to completely or partially compensate for volume errors of a switching fluid valve. As a result, in particular when generating a mobile phase, the accuracy of the composition can be increased.

In addition, additional embodiments of the fluid supply device, the method and the sample separation device will be described.

According to one exemplary embodiment, the control device for controlling the at least one fluid valve and / or for controlling the delivery characteristic of the fluid delivery device can be configured such that an additional volume of at least part of the mobile phase triggered (at least positive) by a closing operation of the at least one fluid valve is at least partially compensated , When a fluid valve is switched from an open state in which fluid can pass the fluid valve to a closed state in which the fluid is prevented from passing the fluid valve, overpressure and thus excessive volume flow may occur during the closing operation , As a result, an incorrect volume can be coupled into a downstream fluidic system, for example a chromatographic separation path of a sample separation device. This in turn has undesirable effects on the accuracy of the separation of the fluidic sample. By compensating for the overshoot of the pressure caused by the closing operation by adjusting the amount of injected volume, the accuracy of sample separation can be improved.

According to one exemplary embodiment, the control device for controlling the at least one fluid valve and / or for controlling the delivery characteristic of the fluid delivery device can be configured such that the additional volume triggered by the closing operation of the at least one fluid valve is removed from the mobile phase and / or in a subsequent delivery cycle reduced volume of mobile phase is promoted. For example, the excess additional volume of the mobile phase, which is undesirably conveyed by the closing process through the fluid delivery device into the connected fluidic system, can be removed before it reaches the separation path. Alternatively or additionally, in a subsequent conveying cycle correspondingly less mobile phase can be promoted to compensate for the overshoot.

According to one exemplary embodiment, the control device for controlling the at least one fluid valve and / or for controlling the delivery characteristic of the fluid delivery device can be configured such that a missing volume of at least part of the mobile phase triggered (at least negative) by an opening process of the at least one fluid valve is at least partially compensated , During an opening process of a fluid valve, a undershoot may occur, and thus to a negative one Additional volume. In other words, an opening operation of the fluid valve can cause the promotion of too small a volume amount of the mobile phase. To compensate for this effect in whole or in part, additional mobile phase can be promoted, for example by shifting the switching timing of a fluid valve and / or by increasing the pumping pressure. It is also possible to promote in a subsequent delivery cycle correspondingly more mobile phase to compensate for the undershoot. Thus, the control device for controlling the at least one fluid valve and / or for controlling the delivery characteristic of the fluid delivery device can be set up in such a way that the mobile phase fault volume triggered by the opening process of the fluid valve is added and / or in a subsequent delivery cycle an increased volume of mobile phase is encouraged. While excessive mobile phase can be dissipated during a closing operation of the fluid valve or the opening interval of the fluid valve can be reduced accordingly, additional mobile phase can be promoted to compensate for a negative error volume when opening a fluid valve, for example by extending the opening interval.

According to an embodiment, the fluid supply device may include at least one sensor for detecting information indicative of a characteristic of at least a part of the mobile phase and transmitting the information to the controller as a basis for controlling the delivery characteristic of the fluid delivery device and / or for adjusting the valve timing. For example, such a sensor can detect a pressure overshoot when closing a fluid valve or a pressure undershoot when opening the fluid valve. The corresponding information can then be used for compensation. It should be noted, however, that as an alternative or in addition to the provision of one or more sensors as the basis for the control for compensating the volume artifact, other information may also be included. Thus, for example, the behavior of the fluid valve and the associated effects on the volume flow can be modeled and compensation based on this model can be made. It is also possible to adjust the control of the fluid valve based on expert knowledge or historical data to perform the volume compensation.

According to an embodiment, at least one of the at least one sensor may comprise one of a group consisting of a pressure sensor and a flow rate sensor. However, alternatively or additionally, other sensors may also be used, for example temperature sensors.

According to an exemplary embodiment, at least one of the at least one sensor may be arranged downstream of at least one of the at least one fluid valve, in particular downstream of a proportioning valve, and upstream of the fluid conveying device. A flow sensor downstream of the proportioning valve may detect channel independent information relating to the mobile phase as a whole. Compensation of a volume flow can therefore be carried out in particular based on corresponding sensor signals.

According to an exemplary embodiment, at least one of the at least one sensor may be arranged upstream of the at least one fluid valve, in particular upstream of a proportioning valve. Sensors in the flow direction upstream of the proportioning valve can detect channel-specific information relating to a respective component of the mobile phase. In particular, such sensors may be implemented in supply lines connected to fluid containers for providing a respective fluid component. For example, such sensors may detect special events or malfunctions in individual channels. Integrating sensors into the supply lines, which may be located between respective solvent containers and a proportioning valve, may provide important information about volume flow correction for the elimination of switching artifacts.

According to one exemplary embodiment, at least one of the at least one sensor can be set up for the time-dependent acquisition of the information, in particular information that is detected over an entire delivery cycle of the respective fluid valve. By sensory detection of the entire cycle, a particularly accurate correction of the described volume artifact can be made possible.

According to one exemplary embodiment, at least one of the at least one sensor can be calibrated or calibratable by means of the fluid delivery device, in particular calibrated or calibrated to different solvents. The fluid delivery device or a primary piston of such a fluid delivery device can be embodied as a high-precision pump with which the sensors (for example a calorimetric design) designed, for example, as flow sensors can also be calibrated to different solvents.

According to one exemplary embodiment, the control device may be configured to analyze, evaluate and / or monitor a provided mobile phase based on sensor data provided by at least one of the at least one sensor. In particular, as a flow sensor trained and downstream of a Proportionierventils arranged sensor (see reference numerals 108 ' in 2 ) are used to evaluate the ready-mixed solvents. This allows for precise monitoring of a compound mobile phase.

According to one exemplary embodiment, the control device may be configured to analyze, evaluate and / or monitor individual solvents from which the mobile phase is composed, based on sensor data provided by at least one of the at least one sensor. The individual solvents can through the sensors upstream of a Proportionierventils (see reference numerals 108 in 2 ) for expected solvent properties, even during an analysis. As a result, a malfunction or the risk of mistakenly changed bottles can be reduced.

According to one exemplary embodiment, the control device for controlling the at least one fluid valve and / or for controlling the delivery characteristic may be configured such that immediately after an opening operation of the fluid valve, a time-aspiration volume characteristic of the mobile phase is left-curved. By a left curvature or such a disproportionately rapid increase in the time-intake volume characteristic, a controlled acceleration can take place at the beginning of a suction phase.

According to one exemplary embodiment, the control device for controlling the at least one fluid valve and / or for controlling the delivery characteristic may be configured such that a time-intake volume characteristic of the mobile phase is right-curved immediately before a closing operation of the fluid valve. By adjusting or adjusting a right-hand curvature of the time-aspiration volume characteristic of the mobile phase, controlled deceleration may occur at the end of a suction phase. A transition to a suction-free phase can thus be particularly gentle.

According to one embodiment, the time-aspiration volume characteristic of the mobile phase may be linear between the left-curved time range and the right-curved time range, in particular with continuous transition of the linear time range to the left-curved portion and / or the right-curved time range. The left curvature, right curvature and interposed linear characteristic can be clearly referred to as an S-curve. Clearly, the river can first be gently accelerated, then subjected to a linear characteristic, and finally gently braked to stabilize the river in a right-curved area. As a result, unwanted oscillations can be avoided. The slope in the linear region can be used as a design parameter for adjusting the operating characteristic of the fluid supply device. Advantageously, however, the slope should not exceed a predefinable maximum value, which corresponds to a maximum intake speed or a maximum volume flow which the respective fluid valve just barely cope with.

According to one embodiment, the fluid delivery device may be configured to deliver a first fluid component of the mobile phase faster with a first volume fraction than a second fluid component of the mobile phase with a second volume fraction, wherein the first volume fraction is greater than the second volume fraction. Clearly, a high degree of precision in the setting of the correct amount of this solvent component can then be achieved even for small solvent components, since with an artificial extension of the supply times for such low solvent components switching periods play no greater role than for other solvent components with a larger volume contribution. In order to make this adjustment separately for each solvent component, the slope can be adjusted accordingly in the time interval designated in the preceding paragraph as a linear time range.

According to one exemplary embodiment, the control device for controlling the at least one fluid valve and / or for controlling the delivery characteristic may be configured such that after completion of an intake operation for aspirating at least part of the mobile phase and before a closing operation of the fluid valve, a waiting time until the completion of a flow stabilization is waited, in particular determined based on at least one sensor detected information. By waiting until equilibrium is reached after completion of a suction phase, flow stabilization can be achieved resulting in a particularly precise solvent composition.

According to one embodiment, the control device for controlling the at least one fluid valve and / or for controlling the delivery characteristic may be configured such that in a period before the at least one fluid valve is opened, the fluid delivery device does not perform a suction movement, in particular determined based on information acquired by at least one sensor. Clearly, a piston pump can be prevented from pulling as long as an upstream fluid valve is still closed. As a result, a pressure surge when switching can be avoided or mitigated.

According to one embodiment, the control device for controlling the at least one fluid valve and / or for controlling the delivery characteristic may be configured such that in a period after closing the at least one fluid valve, the fluid delivery device performs a pressure adjustment, in particular determined based on at least one sensor detected information. By means of the sensors, the pressure conditions can be detected after closing. In the case of a determined too low pressure against a target pressure, a piston of the fluid conveyor can be moved forward to build up an additional pressure. Conversely, if too great a pressure is detected, a piston of the fluid conveyor can be retracted to reduce the pressure. Thereby, the pressure can be suitably adjusted before a subsequent suction of another component. The target pressure may, for example, have a different or specific value for each solvent channel. It is also possible that a pressure from a preceding pump cycle is specified as the target pressure.

In one embodiment, the fluid supply device may include a plurality of supply lines fluidly coupled to the fluid valve and each fluidly fluidly coupled to a respective one of a plurality of fluid component sources for providing a respective fluid from which the mobile phase is formed. In this way, by connecting a proportioning valve downstream of the plurality of supply lines, a sequence of serially arranged fluid pacts with different solvents can be achieved (for example, water, an organic solvent such as methanol or acetonitrile, etc.). At each switching operation of the proportioning valve, a solvent component of the mobile phase may pass through this fluid valve. By successively switching the individual supply lines through the fluid valve, a sequence of solvent components can occur, which can be processed into a homogeneous mobile phase by diffusion, active mixing and / or compression in the fluid delivery device.

According to an embodiment, the fluid supply device may have a merge point at which fluid packets from the fluid component sources are combined to form the mobile phase. In the context of the present invention, the term "packets of fluids" is understood in particular to be a temporal and spatial sequence of sections of fluids flowing in succession or sequentially in a fluid line. These sections may differ from one another with respect to the substance of the respective fluid package. For example, a proportioning device (eg, a proportioning valve) may fluidly couple a line carrying the solvent composition to different supply lines, and from a respective supply line, couple and convey a respective fluid packet into that line. This results in a sequence of initially slightly mixed and separate fluid packages, which can then be mixed. At the fluidic junction, the fluid packets from the fluid component sources flow together. Thereby, the mobile phase is obtained with the desired composition, which can be adjusted by the opening intervals of the fluid valve or valves with respect to the respective supply lines. The merge point may be configured, for example, as a fluidic T-point, fluidic Y-point, fluidic X-point, etc.

According to one embodiment, the fluid valve may be configured as a proportioning valve for proportioning fluid packages supplied by the supply lines of the respective one of the fluids. As already described, by switching the proportioning valve such that fluid packages of specific lengths can be fed from the individual supply lines to the individual solvent components, any desired mobile phase solvent composition can be adjusted. With respect to a chromatographic gradient run, over time the solvent composition may be varied to fractionally disburse fluidic sample adsorbed on a chromatographic separation column for each fraction separately for a particular solvent composition. However, it is also possible to keep the solvent composition constant over time, for example in an isocratic chromatographic separation mode.

According to one embodiment, the fluid valve may be formed as a multi-channel gradient valve. For example, the fluid valve may be designed as a four-channel gradient valve, that is, as a quaternary valve.

According to one embodiment, the fluid valve may comprise a bidirectional fluid valve, which may in particular be designed as an active bidirectional fluid valve or passive unidirectional fluid valve. Such a bidirectional valve may be positioned between a proportioning device and the fluid delivery device. The at least one fluid valve may in particular have an active or passive inlet valve. This can in particular be arranged downstream of a proportioning valve for proportioning fluid packages supplied by the supply lines of the respective fluid and / or immediately upstream of the fluid delivery device.

According to one exemplary embodiment, the control device for controlling the switching state of at least two fluid valves may be designed such that a volume error of at least part of the mobile phase triggered by a switching operation of the fluid valves is at least partially compensated. Both the above-described proportioning valve and the above-described intake valve for the fluid delivery device can therefore be made the subject of the described control in order to suppress volume errors due to switching artifacts. According to one embodiment, said fluid valves may thus be a proportioning valve for proportioning fluid packets and a unidirectional fluid valve between the proportioning valve and the fluid conveying device.

According to one embodiment, the control device may be designed to control the switching state of the fluid valves and to regulate the delivery characteristic of the fluid delivery device by means of a feedback loop. Such a regulation may, with effect for the future, control the at least one fluid valve and / or the fluid delivery device such that information from the past operation is used for this future control.

According to one embodiment, the fluid delivery device may be configured to pull the mobile phase. For example, the fluid delivery device may comprise a piston pump or a plurality of serial or parallel piston pumps, in particular a double piston pump. In particular, the fluid delivery device may be selected from a group consisting of a binary pump, a quaternary pump and a multi-channel pump. For example, the fluid delivery device may include a primary piston pump and a downstream secondary piston pump. The primary piston pump can return its piston to aspirate mobile phase from the at least one fluid valve and transfer it to its piston space. Thereafter, the primary piston pump can compress the mobile phase by advancing the piston. The compressed mobile phase can be transferred from the primary pump to the secondary pump by a combined retraction of the piston of the primary piston pump and a simultaneous advancement of the piston of the secondary pump. Subsequently, the secondary piston pump can promote the already precompressed mobile phase by advancing its piston into a separation path, that is, toward a sample separator (eg, a chromatography column). However, it should be noted that alternative fluid handling devices are possible, for example two non-serial but parallel piston pumps or a single piston pump. Other pump types can also be used, for example a peristaltic pump.

According to one embodiment, the fluid delivery device for conveying the mobile phase with a pressure of at least 500 bar, in particular at least 1200 bar, be set up. In other words, the fluid delivery device may be a high-pressure pump. In other words, the fluid delivery device can provide high and highest pressures, as is desirable, for example, for the requirements of a liquid chromatography sample separation device, particularly HPLC. At the high pressures mentioned, even small volume errors of the mobile phase can lead to significant influences on a separation result.

According to one embodiment, the fluid whose constituents are to be mixed may be a mobile phase into which the fluidic sample to be separated is to be introduced during (in particular chromatographic) sample separation. In particular, such a mobile phase may be a solvent or a constant or variable solvent composition which co-promotes the actual fluid sample to be separated along the fluid lines of the sample separator. In a chromatographic separation experiment, for example, in a gradient operation after adsorbing fractions of the fluidic sample on a stationary phase of a sample separator, the mobile phase may fractionally detach the fractions from the sample separator (such as a chromatographic separation column) by successively changing the mobile phase solvent composition. Alternatively, for example, an isocratic mode is also possible in which the solvent composition can remain constant over time. The exact composition of the mobile phase has an influence on the flow rate or a volume of fluid delivered. This influence in turn influences the accuracy of the separation result, in particular the position and amplitude (in particular height) of peaks in a chromatogram. By increasing the accuracy of the composition of the mobile phase, better comparable separation data can be obtained, and the separation result (for example, a chromatogram in a chromatographic separation method) can be specified.

According to one embodiment, a degasser may be arranged between the plurality of fluid component sources and the fluid delivery device. A degasifier may optionally contain gas from the associated liquid in the solvents conveyed by the individual fluid component sources (in particular solvent containers) through the fluid delivery device remove. Such gas bubbles in a liquid solvent can affect the accuracy of a fluid composition. For example, such degasser may fluidly couple the solvent to be delivered through a permeable membrane with an exchange medium such that gas bubbles in the liquid solvent diffuse into the exchange medium.

According to one embodiment, the fluid supply device may include one or more pressure sensors for detecting a value indicative of a pressure in a respective one of the delivery lines. Alternatively or additionally, the fluid supply device may have at least one pressure sensor downstream of the junction point. The provision of pressure sensors (or alternatively flow sensors for detecting a flow rate, ie volume flow or mass flow of an associated fluid per unit time) allows monitoring of the trouble-free operation of the fluid supply device. In this way, the operation of the fluid supply device can be made even more reliable.

According to one embodiment, the mobile phase or composition may comprise at least a first solvent, in particular water, and a second solvent, in particular an organic solvent.

The sample separation device may be a microfluidic measuring device, a life science device, a liquid chromatography device, a HPLC (High Performance Liquid Chromatography), a UHPLC system or an SFC (Supercritical Liquid Chromatography) device. However, many other applications are possible.

According to one embodiment, the sample separation device can be designed as a chromatographic separation device, in particular as a chromatography separation column. In a chromatographic separation, the chromatographic separation column may be provided with an adsorption medium. At this, the fluidic sample can be stopped and only then fractionally dissolved again in the presence of a specific solvent composition, whereby the separation of the sample is accomplished in their fractions.

For example, the pumping system may be configured to deliver the fluid or mobile phase through the system at a high pressure, for example, from a few hundred bars up to 1000 bars or more.

The sample separator may include a sample injector for introducing the sample into the fluidic separation path. Such a sample injector may comprise a syringe-dockable injection needle in a corresponding fluid path, which needle may be withdrawn from that seat to receive sample, wherein upon reintroduction of the needle into the seat, the sample is in a fluid path which, for Example, by switching a valve, can be switched into the separation path of the system, which leads to the introduction of the sample in the fluidic separation path.

The sample separator may include a fraction collector for collecting the separated components. Such a fraction collector may carry the various components of the separated sample, for example, into different liquid containers. The analyzed sample can also be fed to a drain tank.

Preferably, the sample separation device may comprise a detector for detecting the separated components. Such a detector may generate a signal which can be observed and / or recorded and which is indicative of the presence and amount of sample components in the fluid flowing through the system.

list of figures

• 1 zeigt ein HPLC-System mit einer Fluidversorgungsvorrichtung gemäß einem exemplarischen Ausführungsbeispiel der Erfindung.
• 2 zeigt eine Fluidversorgungsvorrichtung gemäß einem exemplarischen Ausführungsbeispiel der Erfindung.
• 3 zeigt ein Diagramm, das eine Zeit-Ansaugvolumen-Charakteristik einer Fluidversorgungsvorrichtung gemäß einem exemplarischen Ausführungsbeispiel der Erfindung darstellt.
• 4 zeigt ein Diagramm, das eine Zeit-Druck-Charakteristik eines Fluidventils einer Fluidversorgungsvorrichtung darstellt.
• 5 zeigt ein Diagramm, das eine Zeit-Flussrate-Charakteristik eines Fluidventils einer Fluidversorgungsvorrichtung gemäß einem exemplarischen Ausführungsbeispiel der Erfindung darstellt.
• 6 zeigt ein anderes Diagramm, das eine Zeit-Flussrate-Charakteristik eines Fluidventils einer Fluidversorgungsvorrichtung gemäß einem anderen exemplarischen Ausführungsbeispiel der Erfindung darstellt.
• 7 zeigt Ansaugzyklen für unterschiedliche Architekturen zum Zusammensetzen von mobiler Phase während eines Ansaugzeitraums.
• 8 zeigt ein kaskadiertes Regelungssystem eines Probentrenngeräts mit einer Fluidversorgungsvorrichtung gemäß einem exemplarischen Ausführungsbeispiel der Erfindung.

Other objects and many of the attendant advantages of embodiments of the present invention will be readily appreciated and become better understood by reference to the following more particular description of embodiments taken in conjunction with the accompanying drawings. Features that are substantially or functionally the same or similar are given the same reference numerals.

• 1 shows an HPLC system with a fluid supply device according to an exemplary embodiment of the invention.
• 2 shows a fluid supply device according to an exemplary embodiment of the invention.
• 3 FIG. 12 is a diagram illustrating a time-suction volume characteristic of a fluid supply device according to an exemplary embodiment of the invention. FIG.
• 4 FIG. 12 is a diagram illustrating a time-pressure characteristic of a fluid valve of a fluid supply device. FIG.
• 5 FIG. 10 is a diagram illustrating a time-flow rate characteristic of a fluid valve of a fluid supply device according to an exemplary embodiment of the invention. FIG.
• 6 FIG. 14 is another diagram illustrating a time-flow rate characteristic of a fluid valve of a fluid supply device according to another exemplary embodiment of the invention. FIG.
• 7 Figure 4 shows aspiration cycles for different architectures for assembling mobile phase during a priming period.
• 8th shows a cascaded control system of a sample separation device with a fluid supply device according to an exemplary embodiment of the invention.

The illustration in the drawing is schematic.

Before describing exemplary embodiments with reference to the figures, some basic considerations will be summarized based on which exemplary embodiments of the invention have been derived.

According to an exemplary embodiment of the invention, a fluid supply device is provided for providing a mobile phase for a sample separation device in which volume errors of a switching fluid valve are at least partially compensated. When such a fluid valve switches, there may be overshoots or undershoots in the pressure-time curve both when closing and when opening the fluid valve. This can lead to volume errors of the solvent composition formed as a mobile phase. According to an exemplary embodiment of the invention, such and other volume errors may be at least partially compensated by one or more switching fluid valves. This can be done by the valve control or the control of a fluid delivery device (for example, a high-pressure pump) for conveying the mobile phase is adjusted accordingly or become.

1 shows the basic structure of an HPLC system as an example of a liquid chromatography sample separation device 10 according to an exemplary embodiment of the invention, as can be used for example for liquid chromatography. A fluid delivery device 20 containing solvents from a feeder 25 supplied drives a mobile phase through a sample separator 30 (such as a chromatographic column) containing a stationary phase. The feeder 25 includes a first fluid component source 114 for providing a first fluid or a first solvent component A (for example water) and a second fluid component source 115 for providing another second fluid or component B (For example, an organic solvent). An optional degasser 27 may be the means of the first fluid component source 114 and by means of the second fluid component source 115 degasified solvent before this the fluid conveyor 20 be supplied. A sample application unit 40 , which may also be referred to as an injector, is between the fluid delivery device 20 and the sample separator 30 arranged to introduce a sample liquid or fluidic sample in the fluidic separation path. For this purpose, an injector valve 90 be switched accordingly. The stationary phase of the sample separator 30 is intended to separate components of the sample. A detector 50 which may comprise a flow cell, detects separated components of the sample, and a fractionating device 60 may be provided to dispense separated components of the sample in dedicated containers. Liquids no longer needed can be dispensed into a drain tank or into a waste (not shown).

While a fluid path between the fluid conveyor 20 and the sample separator 30 is typically under high pressure, the sample liquid under normal pressure is first in a separate area from the liquid path, a so-called sample loop (English: Sample Loop), the sample application unit 40 or the injector input, which then in turn introduces the sample liquid in the high-pressure liquid path. During the connection of the sample liquid, which is initially under normal pressure, in the sample loop into the high-pressure liquid path, the content of the sample loop becomes the system pressure of the sample separation device designed as HPLC 10 brought. A control device 70 controls the individual components 20 . 30 . 40 . 50 . 60 . 90 and a fluid valve described in more detail below 102 of the sample separator 10 ,

1 also shows a liquid chromatography fluid supply device 100 for providing a mixture of several different fluids as a solvent composition or mobile phase for the liquid chromatography sample separation device 10 , The fluid supply device 100 has in the embodiment shown two supply lines 110 . 111 each of which fluidly communicates with a respective one of the two as fluid component sources 114 . 115 designated solvent container for providing a respective one of the fluids and solvent components A and B is fluidically coupled. The respective fluid or the respective solvent component A respectively. B is through the respective supply line 110 respectively. 115 , through the degasser 27 to a fluid valve 102 promoted as Proportioniereinrichtung, where the fluids or solvent components A or B from the supply lines 110 . 111 be united with each other, which through a union point 87 is shown. On the formed as Proportionierventil fluid valve 102 the fluid packets flow out of the supply lines 110 . 111 ie together to form a homogeneous solvent composition. The latter becomes the fluid delivery device 20 fed.

In the 1 illustrated fluid supply device 100 So serves to provide a mobile phase for the sample separation device 10 , For this purpose, the fluid supply device 100 the switchable fluid valve 102 which permits or prevents passage of at least part of the mobile phase, depending on its switching state. The control device 70 functions to control the switching state of the fluid valve 102 and for controlling a delivery characteristic of the fluid delivery device 20 such that a by a switching operation of the fluid valve 102 triggered volume error of at least part of the mobile phase is at least partially compensated.

This means that in the case of the control or regulation logic used by the control device 70 according to 1 is executed when controlling or regulating the switching state of the fluid valve 102 and the conveying characteristic of the fluid conveying device 20 Schaltartefakte the fluid valve 102 be taken into account. For this purpose, the fluid valve 102 and / or the fluid delivery device 20 are parameterized with respect to the respective functionality, and the corresponding parameters can be adapted to correct the volume flow. This can cause volume errors due to switching of the fluid valve 102 occur in a closed state or in an open state, by the control device 70 be compensated in whole or in part. As a result, the solvent composition of the mobile phase leading to the injector 40 and subsequently the sample separator 30 is promoted by Schaltartefakten the fluid valve 102 be completely or partially freed. As a result, also the solvent composition and finally the separation result, with the sample separator 10 according to 1 can be achieved, become more precise.

2 shows the more detailed construction of a fluid supply device 100 according to an exemplary embodiment of the invention. 2 has various components of 1 on, so in this context supplementary to the description of 1 is referenced.

Structurally, the fluid supply device 100 four supply lines 110 - 113 on, with the designed as Proportionierventil fluid valve 102 are fluidically coupled. Further, each of the four supply lines 110 - 113 fluidically with a respective one of four fluid component sources 114 - 117 is fluidically coupled to provide a respective fluid. From these four fluids, the mobile phase can be formed. Further, at the outlet of the fluid valve 102 a fluidic junction 87 formed on the fluid packets from the fluid component sources 114 - 117 to unify the mobile phase. The fluid valve 102 So can as Proportionierventil for proportioning by means of the supply lines 110 - 113 supplied fluid packets of the respective fluids, more specifically as a multi-channel gradient valve.

The fluid delivery device 20 serves to pull the mobile phase and to promote the mobile phase with a pressure of, for example, at least 1200 bar. The fluid delivery device 20 For example, an arrangement of two serial piston pumps 118 . 120 be, ie be designed as a double piston pump. More specifically, the fluid delivery device 20 from a primary piston pump 118 and a downstream secondary piston pump 120 formed, also from the control device 70 to be controlled. This allows the reciprocating of the pistons of the piston pumps 118 . 120 be coordinated with each other. The fluid delivery device 20 according to 2 can be designed as an isocratic pump or as a gradient pump.

2 shows in detail how four solvents from solvent containers 114 - 117 through the supply lines 110 - 113 first by degasser 27 to free the solvent components of gas and subsequently into the fluid valve designed as a quaternary valve 102 be encouraged. sensors 108 , each of which is in one of the supply lines 110 - 113 are located, detect flow rate or pressure at their respective position. The fluid valve 102 can be controlled by the controller 70 can be switched and depending on the switching state in each case a fluid package according to the solvent from the solvent containers 114 - 117 through fluid valve 102 through or not. Another sensor 108 ' , which may also be a pressure sensor or a flow rate sensor, is downstream of the fluid valve 102 and upstream of an active or passive inlet valve as another fluid valve 151 implemented.

According to 2 can the sensors 108 be used for channel-specific fault diagnosis. In particular, an online monitoring of each channel 110 - 113 through a respective one of the sensors 108 be made. Captures a sensor 108 For example, a pressure drop, this may be an error in an associated channel or an indication of a depleted Solvent containers 114 - 117 give. On the other hand, the sensor 108 ' Channel-specific, the operation of the entire fluid supply device 100 specify. For example, a sudden pressure increase or pressure drop may occur at the position of the sensor 108 ' indicate that a filter is clogged or cracked. sensor 108 ' is clearly an online monitoring of the collecting channel downstream of the fluid valve 102 and upstream of the fluid conveyor 20 accomplish.

The fluid valve 151 is in the flow direction immediately before the fluid conveyor 20 arranged. The fluid valve 151 For example, it may be formed as an active or passive unidirectional valve, which provides a connection between the proportioning valve according to reference numbers 102 and the fluid delivery device 20 allows or prohibits.

In operation, the control device 70 Sensor signals of the sensors 108 . 108 ' obtained and based on a control of the fluid valves 102 . 151 and the fluid delivery device 20 make.

When mobile phase is formed, its composition by switching the fluid valves 102 . 151 and by the fluid delivery device 20 It can be determined when switching the fluid valves 102 . 151 (that is, when transferring the fluid valves 102 . 151 from an open state to a closed state and vice versa), pressure fluctuations may occur which may affect the volume composition of the mobile phase formed. To compensate for such effects, the control device 70 the control of the fluid delivery device 20 and switching the fluid valves 102 . 151 adjust so that such effects are compensated in whole or in part.

Attributes of a fluid valve to be switched 102 . 151 In particular, an opening time, a closing time, a maximum flow, through the fluid valve 102 . 151 pumped volume when the fluid valve 102 . 151 is open or closed, heat input of the solvent and the number of maximum cycles. In addition, according to exemplary embodiments for refined control, one or more other parameters may be used that are described in U.S. Pat 3 to 7 are shown and explained in more detail below.

The exact switching times of the fluid valves 102 . 151 are not known exactly a priori. In particular, a respective fluid valve switches 102 . 151 due to valve-internal phenomena not necessarily to a certain and predetermined switching time, but somewhat delayed. Also, artefacts can occur during switching, which can lead to errors in a solvent composition. Such artifacts can be particularly pronounced in highly dynamic solvent flows. According to an exemplary embodiment of the invention, the functionality or switching characteristic of the fluid valves 102 and or 151 be parameterized and the parameters can be adjusted accordingly to compensate for such artifacts in whole or in part. In the context of such a parameterization, in particular the timing during operation of the fluid valves 102 and or 151 adjusted to improve the precision of a solvent composition. Valve artifacts can clearly be compensated away. Furthermore, it is possible to operate the fluid valves 102 . 151 with each other and / or with the fluid delivery device 20 to synchronize or coordinate. The entire pumping system can be clearly adjusted based on the valve characteristics. In this case, feedback can also advantageously take place, that is to say the implementation of a (preferably closed) control loop.

About trends or tendencies of sensory readings by the sensors 108 . 108 ' conclusions can be drawn for the control of the fluid supply device 100 to be pulled. For example, a sudden pressure drop may be an indication that a solvent container 114 - 117 has run dry. A sudden increase in pressure can be an indication that a filter is clogged.

Within the scope of the described control or regulation, it is possible, for example, based on the measured values of the sensors 108 . 108 ' to capture what volume errors in a particular channel 110 - 113 occurred due to valve circuit phenomena. For the next channels 110 - 113 can then be calculated how much additional or reduced solvent must be promoted to correct the composition of the solvent. This allows a correct mixing ratio to be set. If necessary, it can lead to an absolutely too high total flow. In a chromatographic sample separation, however, the correct solvent composition is much more important than a total amount of solvent delivered. In addition, in subsequent cycles, a total too high or too low flow of solvent can be compensated to compensate for such an absolute volume error completely or partially.

Thus, the compensation of Schaltartefakten the fluid valves 102 and or 151 to compensate for errors in the solvent composition. Alternatively or additionally, however, it is also possible to carry out a correction of the total volume. Compensation of an artificial solvent composition can be, for example take place within a pumping cycle. The compensation of a total volume can preferably be carried out in a subsequent cycle by promoting more or less solvent in a subsequent cycle in order to compensate previously insufficient or over-promoted mobile phase. Furthermore, it is possible, given a slightly too high or slightly too low amount of solvent, based on the measured values of the sensors 108 . 108 ' can be determined to correct an evaluation of a separation result (in particular a chromatogram) accordingly. This can be done in particular if a volume-based retention of the measurement result is evaluated, ie a determination of the retention does not take place on the basis of retention times, but on the basis of retention volumes.

3 shows a diagram 200 , which has a time-intake volume characteristic 203 a fluid supply device 100 according to an exemplary embodiment of the invention.

A controller according to a conventional approach is shown in FIG 3 with a dashed line 201 shown. A control according to an exemplary embodiment is shown in FIG 3 with a line according to reference number 203 shown. The diagram 200 has an abscissa 202 along which the time t is plotted. Along an ordinate 204 is one of the fluid conveyor 20 suctioned volume applied. The control architecture according to reference numerals 203 takes into account physical limitations of the fluid valve 102 , which can be considered for the adjustment of the suction curve. Like the diagram 200 according to 3 can be seen, according to exemplary embodiments, a control of the fluid valve 102 or the fluid delivery device 20 (see curve corresponding to reference numerals 203 ) compared to a conventional control principle (see curve corresponding reference numerals 201 ) are adapted, modified or changed, as will be described in more detail below.

In one phase 208 the dynamic intake curve corresponding to reference numerals 203 becomes the fluid valve 102 prepared to open in relation to a particular channel. Meanwhile, there is no suction movement of the primary piston of the fluid conveyor 20 , While with reference numerals 208 marked period takes place no or at least approximately no suction. This ensures that the right fluid is always sucked in. The length of the time interval according to reference character 208 is an adjustable control parameter for control by the controller 70 , As 3 represents, has the control curve in the reference numeral 208 corresponding time interval a horizontal course. Clearly no solvent is sucked in during this period. In other words, the fluid delivery device pulls 20 no solvent, as long as the fluid valve 102 closed is.

Then the fluid valve 102 open. In one with reference numerals 210 phase shown is now a suction of a fluid. Advantageously, the control device 70 for controlling the fluid valve 102 and the conveying characteristic of the fluid conveying device 20 in phase 210 be set up so that immediately after an opening operation of the fluid valve 102 the time-aspiration volume characteristic of the mobile phase is left-curved, see reference numeral 211 , Furthermore, the control device 70 be configured for controlling the switching state and the conveying characteristic such that immediately before a closing operation of the fluid valve 102 the time-aspiration volume characteristic of the mobile phase is right-curved, see reference numerals 213 , The time-aspiration volume characteristic of the mobile phase between the left-curved time range and the right-curved time range may be linear (see reference numeral 212 ) and can be formed with continuous transition of the linear time domain between the left-curved portion and the right-curved time range. As in 3 As shown, the flow is gently accelerated using an approximately S-shaped configuration. In the 3 shown S-curve is from the period 211 with left curvature, the linear period 212 and the subsequent period 213 composed with right-curved characteristic. This intake characteristic reduces or even minimizes oscillations. While calculating the intake curve according to reference numerals 203 can be a maximum allowed intake speed Q _max be used as a control parameter or be considered a hard upper limit. This means that the fluid valve 102 can always be operated so that is sucked in with reasonable speed and acceptable pressure drop. At the end of the with reference numerals 210 phase shown, the fluid in period 213 subjected to a negative acceleration. This in turn avoids unwanted oscillations. As a control parameter for the described phase, the length of the period t_saug can be used. In reference 211 corresponding time interval, the piston movement of the primary piston of the fluid conveyor 20 controlled accelerated to then in a linear range (see reference numeral 212 ). At the end of the intake phase there is a controlled braking of the piston of the primary pump of the fluid delivery device 20 (see reference numeral 213 ) so that the control curve turns into a horizontal course.

In a subsequent phase, the reference numeral 214 can be represented, a Stabilization of the river can be done. The control device 70 In this case, for controlling the switching state and the conveying characteristic, it may be arranged such that after completion of the suction process for aspirating mobile phase (ie at the end of the period 210 ) and before a closing operation of the fluid valve 102 a wait t wait until the completion of a flux stabilization. The waiting time t_wait can be based, for example, on using the sensors 108 . 108 ' of acquired information. The remaining oscillations take some time to drop to an acceptable level. The sensors 108 . 108 ' can monitor this timing. Using the parameter t_wait, a corresponding adaptation of curve 203 be made. The end of the intake phase of a particular channel is given at the beginning of the period t_wait. The parameter t_wait can be set so long that transients have subsided.

In a subsequent phase, the reference numeral 216 is shown, the fluid valve 102 be prepared for a subsequent closing. Clearly, the fluid valve is needed 102 a certain amount of time to close in a defined way. The parameter t_zu_1 can be set to achieve this. During the reference 216 corresponding time interval t_zu_1 is thus waited during the closing process of the associated fluid valve 102 he follows.

In a subsequent phase, the reference numeral 218 is shown, a pressure adjustment can take place. In one with reference number 217 shown time interval, for example, by means of the sensor 108 ' the pressure after closing the fluid valve 102 be measured without a piston movement takes place. Thereafter, it may in the control curve according to reference numerals 203 to a forward or backward movement of the primary piston of the fluid conveyor 20 come when the pressure measurement has given an overpressure or a negative pressure (see reference numeral 219 or reference numerals 221 ). With reference number 223 illustrated is the fact that - optionally but advantageously - by a further advance or retraction of the primary piston of the fluid conveyor 20 an adjustment to a (higher or lower) target pressure of the next channel 110 - 113 can be made at the beginning of the reference numeral 220 time interval t_auf_2 is started. Thereby, the operating conditions of the fluid supply device 100 already for a next channel 110 - 113 be set favorably. The with reference numerals 219 respectively. 221 represented ancestors or retraction of the primary piston of the fluid conveyor 20 For example, it may be done until the pressure after closing is equal to the pressure before closing. As a result, the primary piston can be used to compensate for volume errors. The channel-by-channel adaptation of a target pressure can be based on sensor information obtained by means of the channel-specific sensors 108 can be detected.

At the beginning of the time interval 220 with the designation t_auf_2 can be switched from a supply line (for example, 110) to the next supply line (for example, 111). Then the control or rule course, as for the time intervals 208 . 210 . 214 . 216 . 218 described, be repeated for the next channel. phase 220 thus corresponds to the beginning of the opening of the next channel of the fluid valve 102 , A new aspiration from another channel or supply line can begin.

Illustratively, the control or regulating curve according to reference numerals 203 from 3 the time course of the suction movement of the primary piston of the fluid conveyor 20 again. Illustratively, a parameterization of fluid valve 102 and fluid delivery device 20 be done so that Schaltartefakte can be suppressed or compensated. In particular, using measurements of the sensors 108 and or 108 ' Information can be obtained, which allows a setting or shifting of the time until a gradient of a solvent composition assumes a predetermined target value. It is alternatively possible, however, such a setting without the provision of sensors 108 . 108 ' , for example iteratively. It is also possible in future cycles to adapt the control of fluid delivery equipment 20 and / or fluid valve 102 to the effect that artefacts that have occurred in a current or past cycle are only subsequently compensated.

Again referring to 3 For example, t_to_1 and t_zu_1 are design parameters that improve the performance of the fluid supply device 100 can be adjusted accordingly. Also, the slope Q _P in the reference 210 associated time interval, a design parameter that can be adjusted accordingly to suppress switching artifacts. However, should Q _P be less than a predetermined value Qmax, which denotes the maximum suction velocity or the maximum volume flow during suction, the fluid valve 102 coped. The slope Q _P can be adapted or fitted, but should not exceed Qmax. Thus, too Q _P a design parameter to improve performance and increase operational safety. By adjusting the parameter Q _P For example, a balance of aging effects of a fluid supply device 100 respectively.

4 shows a diagram 230 , which is a time-pressure characteristic of a fluid valve 102 . 151 a fluid supply device 100 according to an exemplary embodiment of the invention.

The diagram 230 according to 4 again has an abscissa 202 along which time t is shown. Along an ordinate 232 is a curve of the pressure p during operation of the fluid valve 102 respectively. 151 shown. The diagram 230 can be seen that an opening of the fluid valve 102 respectively. 151 leads to a negative pressure surge, see reference numeral 234 , Conversely, closing the fluid valve 102 respectively. 151 to a positive pressure surge 236 that is, an overshoot in the pressure-time characteristic.

To the in 4 In accordance with an exemplary embodiment, the control device can compensate for artifacts represented 70 for controlling the delivery characteristic of the fluid delivery device 20 and for switching the fluid valves 102 . 151 be set up such that a by a closing operation of the respective fluid valve 102 . 151 conditional unwanted additional volume (see reference numeral 238 ) of the mobile phase is at least partially compensated. For example, the control device 70 a by a closing operation of the respective fluid valve 102 . 151 dissipate released additional volume of the mobile phase or nachfördern in a later pumping cycle correspondingly less mobile phase. Also, the control device 70 a by an opening operation of the respective fluid valve 102 . 151 triggered missing volume (see reference numeral 240 ) of the mobile phase. For example, such negative overhead volume may be added to the mobile phase later, for example in a subsequent pump cycle.

Illustratively, according to exemplary embodiments, an undesirable additional volume, which in diagram 230 schematically with reference numerals 238 is shown to be discharged to the positive pressure surge when closing the fluid valve 102 respectively. 151 to compensate. It is also possible, the negative pressure surge when opening the fluid valve 102 respectively. 151 to compensate, adding a missing volume, in 4 schematically with reference numerals 240 is shown, is additionally coupled.

The pressure surge according to reference numerals 238 means that something is too much mobile phase to the fluid conveyor 20 arrives. The primary piston pump 118 according to 2 can be operated as a metering device with a feedback loop, with sensors 108 Is provided. Therefore, the shortage volume may be corresponding to reference numerals 238 measured or at least estimated. Also, the reverse event can be measured or estimated, namely, that too little of the desired fluid is injected into the path.

For an active compensation of the positive fault volume 238 and / or the negative false volume 240 a feedback loop can be implemented. The piston of the primary piston pump 118 can perform an additional aspiration process of just the specific parasitic amount of mobile phase until the pressure is at stagnation pressure. It can be the sensor data of the sensors 108 at the entrance of the fluid valve 102 be used for the control. In particular, a feedback loop can be used for a feed-forward control. The additional parasitic aspiration from a fluid channel may be stored to recalculate the next run. In other words, this value can be stored as an offset. It is also possible to recalculate subsequent aspirations to adjust the desired solvent composition. This can make it possible to eliminate or at least suppress an occurring error from the outset.

4 illustrated with reference numerals 235 a residual pressure drop in the fluid valve 102 respectively. 151 after completion of the opening operation corresponding to reference numerals 234 , Like reference numbers 236 shows, it also comes when closing the fluid valve 102 respectively. 151 to a dynamic dynamic pressure and a resulting pressure increase. In the area of reference numerals 234 and reference numerals 236 There is therefore a compensation requirement for the illustrated valve artifacts. One possibility is the use of a valve type, which in with reference numerals 239 illustrated characteristic shows, for example, a rocker valve. Such a valve can mitigate the closing shock.

5 shows a diagram 250 , which is a time-flow rate characteristic of a fluid valve 151 a fluid supply device 100 according to an exemplary embodiment of the invention. 6 shows another diagram 270 , which is a time-flow rate characteristic of a fluid valve 151 a fluid supply device 100 according to another exemplary embodiment of the invention. The in the diagrams 250 . 270 The characteristic shown can be from a sensor designed as a flow sensor 108 ' be measured as he is in 2 is shown. This refers to 5 on a designed as an active inlet valve fluid valve 151 while, on the other hand 6 to a designed as a passive inlet valve fluid valve 151 refers. Along an abscissa 202 the time is up. Along an ordinate 252 is a represented linear flux. The same applies to the diagram 270 according to 6 ,

It is particularly advantageous to know at which time an inlet valve (see fluid valve 151 in 2 ) in front of the primary piston pump 118 opens and closes. A calculation can benefit from a precise knowledge of these times. These times can be measured using a sensor 108 ' be detected, which may be a pressure and / or flow sensor. The measured curves according to 5 refer to the use of a flow sensor. The measurement according to 5 refers to an opening movement of the active inlet valve as a fluid valve 151 , 5 So shows results of a flow sensor between the fluid valve 102 and the active inlet valve 151 at the primary head of the fluid conveyor 20 , A negative peak 306 indicates the opening time.

5 clearly shows the time course of a sensor signal from the sensor 108 ' is determined when the fluid valve 151 as active (ie as by means of the control device 70 actively switched) fluid valve is formed. A period of time with reference numerals 300 is therefore approximately equal to one cycle. sensor events 302 denote events associated with the switching of the fluid valve 102 related. reference numeral 304 shows a sensor event associated with an opening burst of the active fluid valve 151 stands. On the other hand, refers to another sensor event 306 a phenomenon related to the switching of the active fluid valve 151 in connection with the fluid delivery device 20 stands. The reference number 306 appropriate time can as a decompensation point of the fluid conveyor 20 be used. This knowledge can be used to control the fluid supply device 100 be used. In conventional approaches, this is the sensor event 306 corresponding date unknown. Due to the provision of the sensor 108 ' This time can now be determined exactly, starting from the active fluid valve 151 is actually open. On this basis, the fluid supply device 100 to be controlled.

Referring now to the diagram 270 according to 6 are measurement results of a flow sensor (see sensor 108 ' ) between the fluid valve 102 and a passive fluid valve 151 at the primary head of the fluid conveyor 20 shown. A passive fluid valve 151 Switches off, ie without externally supplied control signal. Positive values according to 6 mark the start time or the end time of a suction cycle. A mark 272 indicates a malfunction of the passive intake valve. Upon detection of such events, operation of the fluid supply device may occur 100 be marked as not valid.

6 shows clearly 5 corresponding diagram 270 for another embodiment, wherein the fluid valve 151 is designed as a passive valve. That of the sensor 108 ' then detected signal is in 6 shown. In the area of reference numerals 272 There is a loss of volume in terms of a faulty volume, which by a corresponding control or readjustment of the primary piston of the fluid conveyor 20 can be compensated in whole or in part. From a point in time, the reference number 310 corresponds, the suction of solvent by the primary piston of the fluid conveyor begins 20 , In other words, the time corresponds according to reference numerals 310 with the beginning of the time interval 210 according to 3 , At a time with reference numerals 312 is shown, the suction is completed.

7 Figure 4 shows aspiration cycles for different architectures for assembling mobile phase during a priming period 290 ,

Conventionally, a sequence of fluid packages for assembling a mobile phase can be promoted in a time proportional manner as in 7 with reference number 291 shown. This means that - in the example shown - for a 95% composition of a solvent component A and a 5% composition of the solvent component B to 95% of the time fluid from a fluid conduit with the solvent component A is sucked. The 5% remainder of the time is used to aspirate the solvent component B. This results in that when conveying the low solvent component B due to the short delivery time switching periods 295 make up a relatively large proportion of time. This leads to a particularly strong inaccuracy with respect to the solvent component B. By a time-proportional suction according to reference numerals 291 Therefore, only a limited accuracy can be achieved. When low levels of solvents from feed lines 110 - 113 are needed, they only get a short period of time. This is in opposition to oscillations and may result in the solvent composition of the mobile phase not being exactly as specified. According to the reference number 291 In the conventional approach shown, only a very short suction period is used to draw solvent B, the length of which represents the relatively small amount of solvent B (5% in the case shown). However, this has the disadvantage that due to the short intake period Schaltartefakte the or the valves involved beat particularly strong book. In other words, by the reference numeral 291 represented conventional approach a poor error ratio.

In contrast, in the context of a dynamic timing for assembling a mobile phase according to an exemplary embodiment of the invention, an improvement in the accuracy of a solvent composition can be achieved. With reference number 293 FIG. 3 illustrates a non-time proportional intake cycle with dynamic timing according to an exemplary embodiment of the invention. Such a non-time proportional suction according to reference numerals 293 causes smaller portions to receive longer periods of time. This results in a higher accuracy. Different strategies for distributing the timing can be used. For example, a strategy of uniform weight can be used: each feed channel 110 to 113 receives the same amount of time. Another embodiment may implement an algorithm that treats dynamic sampling rates as an optimization problem with respect to timing. The suction rate associated with the results of the composition obtained by a detector may then be for control by the controller 70 be used.

As with the reference number 293 illustrated control concept according to an exemplary embodiment of the invention, the solvent A (which provides a large contribution to the total volume, 95% in the illustrated case) is promoted very quickly. Referring to 3 This can be achieved by a corresponding increase of Q _P be achieved. On the other hand, slower pumping can be carried out for the solvent component B with less contribution (that is, the slope Q _P be set smaller than for solvent component A). Referring to reference numerals 291 and reference numerals 293 promoted relative amounts of the solvent components A and B are identical. However, according to reference numerals 293 for the solvent components with a lower contribution to the fluid composition, a slower delivery process is set than for the solvent component A with a larger composition. Switching artifacts then have no greater impact on solvent component B than on solvent component A. For example, if a contribution of a solvent component (B in the illustrated example) is less than 10% of the total volume, a faster wicking of this solvent component can be established.

This can be done using the in 7 shown slope parameters Q _P1 and Q _P2 expressed by the following equation: Q _P2 << Q _P1 ≤Q _max . It should be added that the values of Q _P1 before and after feeding the solvent component B can also be set differently. Furthermore, according to a further embodiment, the stroke length of the primary piston of the fluid delivery device 20 be used as another design parameter.

In 8th is a cascaded control system 800 for the fluid supply device 100 shown.

reference numeral 802 denotes a solvent identification or a solvent characterization. reference numeral 804 illustrates a solvent cabinet. With reference number 806 are the components of in 2 illustrated fluid supply device 100 to recognize. There is also an optional extra sensor system or diagnostic system 808 as well as a mixer 810 to recognize. The fluid supply device 100 are the other components of the sample separator 10 downstream. A solvent table (see reference numeral 812 ) and an information device for providing system information, component information and timing information is also shown. An emulator 816 serves to emulate predetermined system properties. A firmware 818 can be used for control.

8th clearly shows a cascaded control system, with which the fluid supply device 100 and the entire sample separator 10 can be controlled or regulated in a coordinated manner. In particular, the reference to FIG 2 and 3 described control of the fluid valves 102 respectively. 151 , This will be according to 8th connected to other control loops to obtain a cascaded control system. Control or regulation operations are in 8th illustrated with arrows.

It should be noted that the term "comprising" does not exclude other elements and that the "on" does not exclude a plurality. Also, elements described in connection with different embodiments may be combined. It should also be noted that reference signs in the claims should not be construed as limiting the scope of the claims.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• EP 0309596 B1 [0002]

Claims (20)

A fluid supply device (100) for providing a mobile phase to a sample separation device (10), the fluid supply device (100) comprising: at least one fluid valve (102, 151) which permits or inhibits passage of at least part of the mobile phase as a function of its switching state; a fluid conveying device (20) for conveying mobile phase, which is transmitted by the at least one fluid valve (102, 151); a control device (70) for controlling the at least one fluid valve (102, 151) and / or for controlling a delivery characteristic of the fluid delivery device (20) in such a way that a volume error of at least a part of the volume caused by a switching operation of the at least one fluid valve (102, 151) mobile phase is at least partially compensated. Fluid supply device (100) according to Claim 1 wherein the control device (70) for controlling the at least one fluid valve (102, 151) and / or for controlling the delivery characteristic of the fluid delivery device (20) is arranged such that an additional volume triggered by a closing operation of the at least one fluid valve (102, 151) At least part of the mobile phase is at least partially compensated. Fluid supply device (100) according to Claim 2 wherein the control device (70) for controlling the delivery characteristic of the fluid delivery device (20) is arranged such that the additional volume triggered by the closing operation of the fluid valve (102, 151) is removed from the mobile phase and / or a correspondingly reduced amount in a subsequent delivery cycle Volume of mobile phase is promoted. Fluid supply device (100) according to one of Claims 1 to 3 wherein the control device (70) for controlling the at least one fluid valve (102, 151) and / or for controlling the delivery characteristic of the fluid delivery device (20) is arranged such that a faulty volume triggered by an opening process of the fluid valve (102, 151) is at least one Part of the mobile phase is at least partially compensated. Fluid supply device (100) according to Claim 4 wherein the control device (70) for controlling the at least one fluid valve (102, 151) and / or for controlling the delivery characteristic of the fluid delivery device (20) is arranged such that the faulty volume of the mobile device triggered by the opening process of the fluid valve (102, 151) Phase is added and / or promoted in a subsequent delivery cycle, a correspondingly increased volume of mobile phase. Fluid supply device (100) according to one of Claims 1 to 5 sensor comprising at least one sensor (108, 108 ') for detecting information indicative of a property of at least a portion of the mobile phase, which information is provided to the controller (70) as a basis for controlling the at least one fluid valve (102, 151) and / or for controlling the conveying characteristic of the fluid conveying device (20) can be provided. Fluid supply device (100) according to Claim 6 comprising at least one of the following features: wherein at least one of the at least one sensor (108, 108 ') comprises one of a group consisting of a pressure sensor and a flow rate sensor; wherein at least one of the at least one sensor (108 ') is located downstream of at least one of the at least one fluid valve (102, 151), in particular downstream of a proportioning valve (102), and upstream of the fluid delivery device (20); wherein at least one of the at least one sensor (108) is disposed upstream of the at least one fluid valve (102, 151); wherein at least one of the at least one sensor (108) is disposed in at least one of a plurality of supply lines (110-113) that are fluidically coupled or coupleable to the at least one fluid valve (102, 151) and each of which is for providing a respective one Fluid is fluidly coupled, from which fluids the mobile phase is formed; wherein at least one of the at least one sensor (108, 108 ') is arranged for the time-dependent acquisition of the information, in particular in an entire delivery cycle of the at least one fluid valve (102, 151) and / or the fluid delivery device (20); wherein at least one of the at least one sensor (108, 108 ') is calibrated or calibratable by means of the fluid delivery device (20), in particular calibrated or calibratable to different solvents; wherein the control device (70) is designed to analyze, evaluate and / or monitor a provided mobile phase based on sensor data provided by at least one of the at least one sensor (108 '); wherein the control device (70) is designed to analyze, evaluate and / or monitor individual solvents, from which the mobile phase is composed, based on sensor data provided by at least one of the at least one sensor (108). Fluid supply device (100) according to one of Claims 1 to 7 wherein the control device (70) for controlling the at least one fluid valve (102, 151) and / or for controlling the delivery characteristic is arranged such that immediately after an opening operation of the at least one fluid valve (102, 151) a time-intake volume characteristic of mobile phase is left curved. Fluid supply device (100) according to one of Claims 1 to 8th wherein the control device (70) for controlling the at least one fluid valve (102, 151) and / or for controlling the delivery characteristic is arranged such that immediately before a closing operation of the at least one fluid valve (102, 151) a time-intake volume characteristic of mobile phase is right-curved. Fluid supply device (100) according to Claim 8 and 9 wherein the control means (70) is arranged to control the at least one fluid valve (102, 151) and / or to control the delivery characteristic such that the time-aspiration volume characteristic of the mobile phase is linear between the left-curved time range and the right-curved time range, in particular with continuous transition of the linear time range to the left-curved time range and / or to the right-curved time range. Fluid supply device (100) according to one of Claims 1 to 10 wherein the control device (70) for controlling the at least one fluid valve (102, 151) and / or for controlling the delivery characteristic is arranged such that after completion of an intake operation for sucking at least a portion of the mobile phase and before a closing operation of the at least one Fluid valve (102, 151) a waiting time (t_wait) until the completion of a flow stabilization is waiting, in particular determined based on at least one sensor (108, 108 ') detected information. Fluid supply device (100) according to one of Claims 1 to 11 comprising a plurality of supply lines (110-113) fluidly coupled to the at least one fluid valve (102, 151) and each fluidly fluidly communicating with a respective one of a plurality of fluid component sources (114-117) to provide a respective fluid is coupled, from which fluids the mobile phase is formed. Fluid supply device (100) according to one of Claims 1 to 12 wherein the at least one fluid valve (102, 151) comprises a proportioning valve (102) for proportioning fluid packets of different fluids supplied by means of a plurality of supply lines (110-113). Fluid supply device (100) according to one of Claims 1 to 13 wherein the at least one fluid valve (102, 151) comprises a multi-channel gradient valve. Fluid supply device (100) according to one of Claims 1 to 14 wherein the at least one fluid valve (102, 151) comprises an inlet valve (151), in particular active or passive, in particular downstream of a proportioning valve (102) for proportioning fluid packets supplied by supply lines (110-113) and / or immediately upstream of the fluid delivery device (20). Fluid supply device (100) according to one of Claims 1 to 15 wherein the at least one fluid valve (102, 151) comprises a bidirectional fluid valve (151), in particular arranged between a proportioning valve (102) and the fluid delivery device (20). Fluid supply device (100) according to one of Claims 1 to 16 comprising at least one of the following features: wherein the control device (70) for controlling at least two fluid valves (102, 151) is designed such that a volume error of at least part of the mobile phase triggered by a switching operation of the fluid valves (102, 151) is at least partially compensated; wherein the control device (70) is designed to control the at least one fluid valve (102, 151) and / or to regulate the delivery characteristic of the fluid delivery device (20) by means of a feedback control loop; wherein the fluid conveying means (20) is arranged to pull the mobile phase; wherein the fluid conveying device (20) is arranged to convey the mobile phase at a pressure of at least 500 bar, in particular at least 1200 bar; wherein the fluid delivery device (20) comprises a piston pump or a plurality of serial or parallel piston pumps (118, 120), in particular a double piston pump; wherein the fluid delivery means (20) is selected from a group consisting of a binary pump, a quaternary pump and a multi-channel pump; wherein the fluid delivery device (20) is configured to deliver a first fluid component (A) of the mobile phase having a first volume fraction at a higher delivery rate than a second fluid component (B) of the mobile phase having a second volume fraction, wherein the first volume fraction is greater than that second volume fraction is; wherein the control device (70) for controlling the at least one fluid valve (102, 151) and / or for controlling the delivery characteristic is set up such that in a period (t_up_1) before opening the at least one fluid valve (102, 151) the fluid delivery device (20 ) performs no intake movement, in particular determined based on at least one sensor (108, 108 ') detected information; wherein the control device (70) for controlling the at least one fluid valve (102, 151) and / or for controlling the delivery characteristic is arranged such that in a period of time (t_cond) after closing the at least one fluid valve (102, 151) the fluid delivery device (20 ) performs a pressure adjustment, in particular determined based on at least one sensor (108, 108 ') detected information. A sample separation device (10) for separating a fluidic sample, the sample separation device (10) comprising: a fluid supply device (100) according to any one of Claims 1 to 17 for providing a mobile phase, wherein the fluidic sample is to be injected into the mobile phase; a sample separator (30) adapted to separate the fluidic sample injected into the mobile phase into fractions. Sample separating device (10) according to Claim 18 further comprising at least one of the following features: the sample separation device (30) is designed as a chromatographic separation device, in particular as a chromatography separation column; the sample separation apparatus (10) is configured to analyze at least one physical, chemical and / or biological parameter of at least one fraction of the fluidic sample; the sample separation device (10) comprises at least one of the group consisting of a device for chemical, biological and / or pharmaceutical analysis, a chromatography device, in particular a liquid chromatography device, and an HPLC device; the sample separation device (10) is configured as a microfluidic device; the sample separation device (10) is configured as a nanofluidic device; the sample separation apparatus (10) has a detector (50) for detecting the separated fractions; the sample separation device (10) has an injector (40) for injecting the fluidic sample into the mobile phase; the sample separator (10) comprises a sample fractionator (60) for fractionating the separated fractions. A method of providing a mobile phase for a sample separation apparatus (10), the method comprising: Switching at least one fluid valve (102, 151) which, depending on its switching state, permits or prevents passage of at least part of the mobile phase; Conveying a mobile phase transmitted by the at least one fluid valve (102, 151) by means of a fluid delivery device (20); Controlling the at least one fluid valve (102, 151) and / or a delivery characteristic of the fluid delivery device (20) such that a volume error of at least part of the mobile phase triggered by a switching operation of the at least one fluid valve (102, 151) is at least partially compensated.

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