DE102015112235A1 - Correcting an operating point shift of a sample separator caused by an axial temperature distribution - Google Patents

Abstract

Apparatus (100) for adjusting an operating point of a sample separation device (30) for separating a fluidic sample, the device (100) having a control device (70) arranged, based on information regarding an instantaneous axial temperature distribution along the sample separation device (30). in particular based on information regarding a temperature difference between different positions along the sample separation device (30), a temperature control of the sample separation device (30) and / or a temperature control of the sample separation device (30) to be supplied to the mobile phase to be adapted with optionally contained components of the fluidic sample in order to at least partially compensate for an operating point shift caused by the axial temperature distribution, in particular operating point drift, of the sample separation device (30).

Description

TECHNICAL BACKGROUND

 The present invention relates to an apparatus and a method for setting a working point of a sample separator for separating a fluidic sample, as well as a sample separator.

 In an HPLC, a liquid (mobile phase) is typically run at a very accurately controlled flow rate (for example in the range of microliters to milliliters per minute) and at a high pressure (typically 20 bar to 1000 bar and beyond, currently up to 2000 bar ), in which the compressibility of the liquid is detectable and measurable, is moved through a stationary phase (for example, enclosed in a chromatographic separation column) to separate individual components of a sample liquid introduced into the mobile phase. In a flow cell of a liquid chromatography device, the detection of the separated fractions of the sample then takes place. For this purpose, the fluidic sample is guided from a capillary downstream of the separation column into a detector, especially, for example, into a flow cell of a detector. As the fluidic sample passes the flow cell, detection may be performed on the sample, such as by fluorescence measurement, whereby the individual fractions of the sample can be identified or quantified.

Such an HPLC system is for example from EP 0,309,596 B1 by the same Applicant, Agilent Technologies, Inc.

 While the mobile phase passes through a sample separator, for example a chromatographic separation column, there sometimes occurs a significant pressure drop, for example from 1000 bar to atmospheric pressure, especially when fine-grained packing materials are used for the sample separator. Phenomena that occur due to this pressure drop can have an effect on sample separation.

EPIPHANY

 It is an object of the invention to enable a reproducible sample separation. The object is achieved by means of the independent claims. Further embodiments are mentioned in the dependent claims.

 According to an exemplary embodiment of the present invention, an apparatus for adjusting an operating point (in particular a thermal operating point) of a sample separator is provided for separating a fluidic sample (ie, a sample that is liquid and / or gaseous, optionally comprising solid particles) Control device (for example, a processor or a part of a processor), which is established based on previously known (in particular metrologically detected and / or empirically determined and / or theoretically derived) information regarding an axial temperature distribution along the sample separation device (in particular based on information a temperature difference between at least two different positions along the sample separation device) a temperature control of the sample separation device and / or a temperature control for the flow through the sample separation Direction to be supplied mobile phase with optionally contained therein components of the fluidic sample (in particular a fluidic mobile phase containing fluidic sample) to adapt to at least partially compensate for a caused by the axial temperature distribution operating point shift (in particular operating point drift) of the sample separation device.

 According to another exemplary embodiment, a sample separation device (for example, a liquid chromatography device) is provided for separating a fluid sample in a mobile phase (in particular a solvent or a solvent composition), the sample separation device comprising a fluid pump (in particular a high-pressure pump) for driving at least one of the mobile phase and the fluidic sample through the sample separator, a sample separator (in particular a chromatographic separation column) downstream of the fluid pump for separating the sample in the mobile phase, and a device with the above-described features for controlling a temperature distribution along the sample separator for setting a working point the sample separator.

According to yet another exemplary embodiment, a method of adjusting a working point (in particular, a temperature operating point or a temperature regime or thermal regime operating point) of a sample separator for separating a fluidic sample is provided, wherein the method comprises controlling the temperature of the sample separator and / or tempering of mobile phase to be supplied for flowing through the sample separator with optionally contained components of the fluidic sample based on known information regarding an axial temperature distribution along the sample separator (in particular based on information regarding a temperature difference between at least two different positions along the sample separation device) is adapted such that an operating point shift (in particular working point drift) of the sample separation device caused by the axial temperature distribution is at least partially compensated.

 In the context of the present application, the term "operating point of a sample separator" is used in particular to specify a parameter (for example a temperature value at a specific position of the sample separator or a parameter set (for example a plurality of temperature values at different positions or a temperature profile along the axial extent of the sample separator). or the value of a mathematical function of a parameter or of a parameter set (for example a weighted average of the temperature values at different positions along the axial extent of the sample separator), the operation of the sample separator, in particular with respect to an event to be detected, a peak to be detected or defines, determines or influences a fraction of the fluidic sample to be detected.

 In the context of the present application, the term "working point shift" (in particular "working-point drift") is understood to mean, in particular, a change in the operating point of the sample separation device over time (in particular occurring over successive separation cycles). A corresponding shift in operating point has an undesirable effect on the reproducibility or comparability of different separation procedures on the same sample.

 In the context of the present application, the term "at least partial compensation of the operating point shift, in particular operating point drift" means in particular that a recognized change or shift of the operating point (in particular between successive executions of a separation process or a separation cycle, and further particularly with respect to one and the same fraction the fluidic sample) is wholly or partially reduced, eliminated or corrected. In particular, an actual operating point can be corrected specifically in the direction of a desired operating point.

 In the context of the present application, the term "axial temperature distribution" is understood to mean, in particular, a temperature profile adjusting in the flow direction of the mobile phase (in particular a mobile phase with a fluidic sample contained therein) by the sample separation device, according to which a temperature of a specific section of the mobile phase, in particular with a fluidic sample located therein, as it progresses through the sample separation device. This term is to be distinguished from a radial temperature distribution, which refers to a possible temperature profile perpendicular to the flow direction of the fluidic sample through the sample separator.

 In the context of the present application, the term "mobile phase" is understood in particular to mean a fluid and / or gas-containing fluid (more particularly a solvent composition) which passes through the sample separation device. Mobile phase may include a carrier medium for transporting a fluidic sample. In the context of the present application, the term "fluidic sample" is understood in particular to mean liquid which, for example, can be brought from outside the measuring system and can be analyzed. Such a liquid may be formed of a plurality of components, such as a sample solvent (which may constitute a major portion) and analytes or sample components (i.e., analyte-relevant portions). For analysis, a part (portion) of the fluidic sample can be drawn. This portion can be introduced, for example, by means of an injector in a fluidic path of the system, where it is initially present as a compact package and is also moved as such. When the fluidic sample has arrived at the sample separator, the separation process begins. First, as a rule, the sample components are retained on the stationary phase, while the sample solvent is further transported unrestrained with (or from) the mobile phase through the sample separator. At this stage, a fluidic sample is adsorbed on the stationary phase of the sample separator. "Mobile phase with the components of the fluidic sample contained therein" thus particularly denotes a liquid content of the sample separation device (in particular a chromatographic column).

In the context of the present application, the term "mobile phase with any components of the fluidic sample contained therein" is understood in particular to mean a mobile phase which may temporarily contain components of the fluidic sample and may be free from the fluidic sample in other periods. As part of a sample separation mobile phase can be promoted by the sample separation device, without the fluidic sample has already been injected into the mobile phase. Already in this phase a temperature control of the mobile phase is possible. Subsequently, the fluidic sample can be injected into the mobile phase so that the mobile phase then temporarily carries fluid sample with it. Also in this phase, a temperature control of the mobile phase including fluidic sample is possible. after the fluid sample is adsorbed on the sample separator, mobile phase (in particular with a time-varying solvent composition, for example, according to a gradient profile) can be conveyed through the sample separator to remove the fluidic sample fractionally from the sample separator. Also in this phase, a temperature of the fluid is possible.

 According to an exemplary embodiment of the invention, information regarding a temperature distribution along the sample separator (in particular information regarding a temperature gradient in the axial flow direction of the mobile phase and the fluid sample contained therein by the sample separator) is consulted to determine the influence of such a temperature profile along the sample separator on the reproducibility to consider a separation process. A developing temperature profile can have an undesirable effect on the results of a separation. The reproducibility is influenced by temporal development or changes in the temperature profile. By a control procedure, which can be carried out by means of a control device recognizes working point shifts of the sample separator due to the formation, development or change of such temperature gradients and at least partially actively compensates, but without necessarily a complete suppression of the temperature gradient itself to target, caused by an operating point shift reproducibility losses quite or partially compensated for and the associated undesirable influences on the separation result are suppressed or excluded. The working point correction of the sample separation device can be tailored in particular to a specific fraction of the fluidic sample of interest and can specifically unify their (usually temperature-dependent) retention behavior in different successive separation sequences or make it more reproducible.

 In particular, exemplary embodiments of the invention are based on the finding that by a significant pressure drop along the sample separator in the case of HPLC application (upstream of the sample separator, a high pressure of at least several 100 bar prevail, whereas downstream of the sample separator a low pressure of the order of atmospheric pressure prevails can) upon passing the fluidic mobile phase (which may be fluidic sample) through the sample separation medium of the sample separator frictional heat may arise, resulting in a higher temperature of the mobile phase (in particular the mobile phase with fluidic sample therein) at the sample separator output in Compared to a nominal (in particular lower) temperature of the mobile phase (especially with fluidic sample therein) can lead to the sample separator input. The consideration of such effects allows a specific active countersteering in order to ensure a more stable or completely stable operating point characteristic by an active intervention in the time-dependent temperature management of the sample flowing into and flowing through the sample separator and thus to avoid negative influences on the reproducibility.

 In the following, embodiments of the device, the method and the sample separation device will be described.

 According to one embodiment, the device may comprise a temperature detection device, which is set up to detect indicative data for at least one temperature on the sample separation device and to provide the data as the previously known information to the control device. For example, it may be sufficient to detect only one exit temperature at the exit of the sample separator assuming that the inlet temperature at the inlet of the sample separator is known by a preheater (eg, a column temper unit). According to the embodiment described, a temperature or a temperature profile along the axial extent of the sample separation device, which corresponds in particular to a flow direction of the mobile phase with optionally contained components of the fluidic sample during the separation process (or a direction opposite thereto), by means of at least one temperature sensor metrologically detected or detected. As a result, the information indicative of a temperature distribution and course can be determined experimentally in terms of time and / or location and used as a basis for the control or regulation.

According to one exemplary embodiment, the temperature detection device can be designed to detect indicative data for several temperatures at different positions, in particular at different positions along the flow direction of the mobile phase with optionally contained components of the fluidic sample through the sample separation device, as the previously known information. If a plurality of temperature values are determined as a function of location along the sample separation device, in particular time-resolved, the development can be monitored spatially and / or temporally with respect to the temperature distribution and by tracking or adjusting the supply or removal thermal energy to be answered. In particular, the detection of the plurality of temperature values can take place at the sections of the fluidic path which abut the sample separation device. A temperature detection at the inlet and outlet is a particularly advantageous choice.

 According to an embodiment, the different positions may include an inlet and an outlet of the sample separator. An inlet of the sample separation device is understood to mean, in particular, a fluidic connection thereof through which the mobile phase with optionally contained components of the fluidic sample flows into the sample separation device from a position upstream of the sample separation device (coming from an injector, for example). By contrast, an outlet of the sample separation device may, in particular, be understood as meaning a fluidic connection of the sample separation device at which the fluidic sample separated into fractions flows out of the sample separation device and, for example, flows into a detector for detecting the individual fractions downstream of the sample separation device. Often, especially in liquid chromatography applications, a monotonic (in the mathematical sense) temperature gradient along the flow direction of the mobile phase with optionally contained components of the fluidic sample in the sample separator (especially under the influence of hydraulic frictional heat), so that inlet and outlet often the extreme values a temperature range along the sample separator represent. Often, such a temperature gradient only increases initially until it has fully developed. After that, he can be essentially constant, and then does not change anymore. In other words, the temperature at the inlet of the sample separator may have a minimum value and the temperature at the outlet of the sample separator may have a maximum value along the extent of the sample separator. An example of the control logic could be to determine the inlet and outlet values and to adjust the thermal management of the mobile phase flowing into the sample separator, along with fluidic sample, based on these measurements so that the (time-increasing) temperature difference between inlet and outlet associated working point shifts are reduced or eliminated. For example, by weighting the determined temperature values at the inlet and at the outlet, control information regarding an intermediate position between inlet and outlet can be obtained.

 According to one embodiment, temperature sensors at the inlet and outlet at a the mobile phase, in particular mobile phase with optionally contained components of the fluidic sample, leading capillary (for example, a steel capillary) and / or at the inlet and at the outlet on a fluidic sample separating Pillar (which may contain the actual separation medium) may be appropriate. Temperature sensors for detecting the temperature values at the inlet and outlet can preferably be coupled to a capillary through which the mobile phase with optionally contained components of the fluidic sample is introduced into the sample separator or by means of which the mobile phase with optionally contained components of the fluidic sample the sample separator is removed. As a result, a high accuracy of the detected temperature values in relation to the mobile phase with optionally contained therein components of the fluidic sample is given, while avoiding disturbances during the sample separation due to the temperature measurement. It is more convenient to measure the temperature at the terminals that belong to the device or stay in the device, than at the column, which is replaced or changed more frequently. Another measuring method which proves to be precise is to carry out temperature measurements on the separation column itself and thus as close as possible to the sample separation medium of the sample separation device. Preferably, the temperature sensors may be mounted at the described positions (and / or at other positions) of the sample separation device so that the thermal coupling with the environment is as small as possible and as narrow as possible with the sample separation device or especially with the mobile phase. As a result, high precision can be achieved. This can be accomplished, for example, by wirelessly communicating temperature sensors or by wired temperature sensors (which should then be thermally isolated as best as possible from the environment).

According to one exemplary embodiment, the control device can be set up to adjust a temperature control of a preheater for preheating the mobile phase with optionally contained components of the fluidic sample upstream of the sample separator. Thus, for subsequent separation cycles and associated sections of fluidic sample upstream of the sample separation device, a temperature correction can be made with respect to preceding separation sequences and associated other sections of fluidic sample, which counteracts a work-point displacement detected in the sample separation device. In a chromatographic separation column (as an example of a sample separation device), for example, a storage of the separation column in an oven (also referred to as column oven), wherein the upstream of the sample separation device, the mobile phase with optionally contained therein components of the fluidic Sample passes through a preheater (with adjustable heating or cooling capacity), in which the mobile phase with optionally contained therein components of the fluidic sample to a desired (nominal) set temperature preheated (in particular preheated) is. If the control device thus influences the heating characteristics of the preheater in a time-resolved manner (and thereby even more or less heated or even cooled), it is possible to attenuate or completely or partially compensate for corresponding thermal operating point offsets on the downstream sample separating device or counteract threatening operating point offsets in advance ,

 According to one exemplary embodiment, the control device can be set up to adjust a temperature control of a furnace over a spatial region in a location-dependent manner for operating point correction, in which the sample separation device is arranged. For example, the furnace can be subdivided into different spatial sections or sections in the flow direction of the sample, in which different furnace temperatures can be set. It is also possible to set a continuously spatially but also temporally changing temperature profile along the furnace in order to bring, for example, a preheating device and / or different sections of the sample separation device to a respective different starting temperature. As an alternative or in addition to the previously described control of a preheating device, the control device can thus adjust the temperature of the sample separation device and thus the mobile phase with optionally contained components of the fluidic sample by means of the furnace to suppress a working point shift, whereby the fluidic sample axially corrected spatially resolved corrective thermal energy or can be withdrawn. As a result, an undesirable shift in the thermal operating point caused by an axial temperature profile along the sample separation device can at least be mitigated, preferably eliminated, without undesirably generating additional equipment, without undesirably generating a pronounced radial temperature profile.

 According to an embodiment, the control means may be arranged to adjust a temperature control of direct heating (i.e., setting an elevated temperature on the direct heater by correspondingly driving the direct heater, for example by correspondingly supplying the direct heater with electrical energy) to at least a portion of the sample separator for operating point correction. For example, an input area of the sample separator can be heated or cooled in a targeted and spatially resolved manner by means of such direct heating, whereas an outlet area of the sample separator can thermally float (so that the temperature can freely set there), ie. can be free of a targeted energy input by means of direct heating. In this context, a direct heating of the sample separation device is understood as meaning a heating device which acts directly, specifically or exclusively on the sample separation device in order to supply or dissipate energy there (in particular axially depending on location). Such a direct heating of the sample separation device can be effected, for example, by a complete or partial coating of an outer wall of the sample separation device with a heating device (for example a heating coil). Alternatively, direct heating of the sample separation device can also be realized by means of irradiation of selected regions of the sample separation device with electromagnetic radiation (for example thermal radiation), preferably in a spatially resolved manner. This has the advantage that the mobile phase flowing axially through the sample separation device with components of the fluidic sample possibly contained therein can be impressed with particularly specific and precise temperature profiles along the sample separation device in order to counteract an operating point shift or to initially impress the expected profile, so that subsequently the separation device in FIG their natural regime can be operated without a shift in operating point occurs. The exemplary embodiment relating to the direct heating of the sample separating device can be carried out alternatively or in addition to the adaptation by influencing the furnace and / or preheating device.

According to an embodiment, the controller may be configured to use as the information at least one selected from a group consisting of empirical knowledge regarding the behavior of the sample separator and a theoretical model regarding the behavior of the sample separator. As an alternative or in addition to ascertaining the information in a metrological manner by detecting temperature values at one or more specific positions of the sample separation device, it is thus possible to use previously known experimental knowledge or a theoretical model of the behavior of the sample separation device to determine empirically determined measurement data or a theoretical model Modeling of the thermal conditions within the sample separator to predict or anticipate the emergence of temperature profiles or operating point shifts in the operation of the sample separation device and to use this assumed temperature profile information as the basis for the control. Dynamic acquisition of temperature information during the Operation of the sample separator and the sample separator may then be dispensable.

 According to one embodiment, the control device may be configured to at least partially compensate for the operating point shift caused by the axial temperature distribution, in particular working point drift, by adjusting a temperature control of the fluidic sample such that different effects of the axial temperature distribution on a separation result in at least for a given fraction of the fluidic sample successive separation cycles are at least partially compensated. If successive different fluidic portions of a fluidic sample in the sample separator are separated into their fractions, it may happen that the individual separation results are not reliably reproducible and therefore no longer directly comparable (for example, if the temperature-induced selectivity changes enter). Rather, these separation results may then diverge, for example, for a particular fraction of the fluidic sample currently of particular interest to a user due to the shift in the operating point. The adjustment of the operating point can be done selectively to avoid the phenomena described so as to reduce or eliminate the reproducibility problems specific to that fraction. In particular, obtaining reproducible separation results for a particular fraction of the fluidic sample may be facilitated by having a specific temperature (ie, a target temperature that results in reproducible separation results for that particular fraction) at a very particular axial position along the sample separator (e.g. just midway between inlet and outlet, or at a position that is X percent (for example 60 percent) away from the inlet and 100 X percent (eg 40 percent) away from the outlet). To achieve reproducibility specifically for a fraction of interest, the balancing action of the controller may focus on that fraction. According to the described embodiment, axial temperature profiles which reproduce a successive heating of the mobile phase with optionally contained components of the fluidic sample during passage through the sample separator can be compensated for at a specific position or in a certain spatial area of the sample separator.

 Advantageously, according to an exemplary embodiment of an undesirable, leading to a radial temperature distribution, complete compensation of the temperature profile along the entire sample separation device will be omitted. This could reduce the separation efficiency.

 In particular, the control device can be set up as the separation result to at least partially compensate for a time retention of a retention parameter indicative of a retention of the predetermined fraction of the fluidic sample, in particular a retention time or a retention volume. In other words, the balancing action of the controller may be adjusted such that in a chromatographic separation, the retention time (ie, the time required for a particular fraction to reach a detector) or the retention volume (ie, a volume of solvent that the sample separator uses) flow through until a particular fraction is released from the sample separator and then flows to a detector) for a given fraction is always the same for different separation sequences. A peak of interest then always appears in a chromatogram at the same position regardless of an existing or even time-varying temperature profile along the sample separator.

 According to one embodiment, the control device may be configured to at least partially offset the different effects of the axial temperature distribution on the separation result for the selected fraction of the fluidic sample in the successive separation sequences. Such an axial temperature distribution can be based on frictional heat, in particular on frictional heat dependent on a solvent of the fluidic sample, as a result of a drop in pressure of the mobile phase with optionally contained components of the fluidic sample as it flows through the sample separator. During the passage of the sample separation device, the mobile phase is optionally exposed to pressure drop components of the fluidic sample in chromatographic separation systems, wherein upstream of the sample separator a high pressure is generated by a fluid pump and downstream of the sample separator is connected to normal or ambient pressure. This pressure drop is accompanied by the generation of frictional heat, which can lead to continuous heating of the mobile phase, including the fluidic sample, on the one hand during the passage of the sample separation device and on the other hand during the performance of different sequential fluidic separation sequences on the same sample separation device. By compensating for such an effect (especially with respect to a specific fraction of the fluidic sample or a specific peak in a chromatogram), the accuracy of the sample separation can be increased.

In one embodiment, the apparatus may include a heat recovery device configured to at least partially recycle heat (particularly frictional heat) released as it flows through the sample separator to a position upstream of the release of the heat. Such a heat recovery device can advantageously utilize the effect of the release of frictional heat in order (at least partially) to apply a heating power for heating the mobile phase with optionally contained components of the fluidic sample. This reduces the energy consumption during operation of the sample separator. As described above, passing a sample separator through a mobile phase results in the generation of frictional heat, which increases continuously with the distance traveled by the mobile phase.

 According to one embodiment, the position upstream of the release of the heat (in particular frictional heat) may be associated with a preheater for preheating the mobile phase with optionally contained components of the fluidic sample upstream of the sample separator. It is therefore advantageously possible to transfer the released heat of friction at least partially to a preheater upstream of the sample separator, so that their energy consumption can be reduced. Further, it is possible to supply at least a part of the released frictional heat to a furnace for heating the sample separator (and also the preheater).

 According to one embodiment, the working point displacement caused by the axial temperature distribution, in particular operating point drift, may be a change in a predetermined operating point of the sample separator due to a change in the axial temperature distribution in successive separation sequences, wherein successive sections of the fluidic sample are separated in the successive separation sequences by means of the sample separator. If different quantities or portions of a fluidic sample are individually and sequentially subjected to separation sequences on the same sample separation device (in particular on the same chromatography separation column), it may be due to the frictional heat described above and / or other thermal effects (for example in connection with adiabatic relaxation) come that changes a temperature profile and / or an average temperature of the sample separator. This can be referred to as an operating point shift, which can undesirably affect the reproducibility of the separation results. By, in particular with respect to one or more fractions of the fluidic sample of interest, this operating point shift is targeted corrected or compensated, in particular based on the one or more fractions of interest, an improved comparability of different partial measurements can be achieved. It may be advantageous to refrain from bringing the entire sample separator to a uniform temperature, which could lead to undesirable radial temperature gradients and a concomitant deterioration of the separation performance.

 According to one exemplary embodiment, the control device may be set up to at least partially compensate for a deviation of an actual operating point defined by the information regarding a current axial temperature distribution from a predetermined desired operating point for at least partially compensating the operating point shift, in particular operating point drift. The actual operating point can be determined by measuring the temperature of the mobile phase with optionally contained components of the fluidic sample in the region of the sample separator (for example at the inlet and at the outlet of the sample separator). The desired operating point corresponds to a desired state or desired thermal conditions, which is or are desirable for achieving reproducibility. The change in the thermal properties of the mobile phase with optionally contained therein components of the fluidic sample can be such that the deviating from the desired operating point actual operating point is approaching the desired operating point or even reached this.

According to one embodiment, the operating point may correspond to the axial temperature distribution along the sample separator (or a part thereof), in particular determined by a relation between temperatures at an inlet and at an outlet of the sample separator. For example, the operating point may be determined by an arithmetic mean of temperatures at an inlet and at an outlet of the sample separator. In particular, a temporal course of the measured temperatures and / or the knowledge about the previous history (flow value history, solvent composition history, pressure value history, etc.) can be used to create the forecast and thus a desired or necessary correction or improve. Although keeping the arithmetic mean of the two inlet and outlet temperatures constant with little effort gives good results, other relationships between inlet and outlet temperatures are possible. Examples include a weighting of the two temperatures (for example, taking into account the temperature at the inlet with a Weighting coefficients of 2/3, whereas the temperature at the outlet is taken into account only with a weighting coefficient of 1/3) or an exponential function or a polynomial function, in which the two temperatures enter.

 According to one exemplary embodiment, the control device can be set up to at least partially compensate the working point drift, in particular working point drift, by keeping a temperature at least one predetermined position along the sample separation device constant for successive separation cycles for separating the fluidic sample. In contrast, the control device may well allow a variation of temperatures at different axial positions along the sample separation device from the predetermined position and thus generally a change in a temperature profile along the sample separation device. This can be advantageous, in particular, if the keeping constant of a temperature at a specific position of the sample separation device (for example due to previously known expert knowledge or carried out measurements) leads to a reproducibility of the separation (in particular based on a specific fraction of the fluidic sample).

 According to one embodiment, the control device can be set up, the expected shift of the working point of the sample separation device based on at least one property of the mobile phase in a fluidic sample (in particular a flow rate of the liquid from the mobile phase and the fluidic sample therein) and / or a mobile phase solvent composition (which may be composed, for example, of an organic solvent and water with variable contributions during a gradient run) to predict (for example, model, calculate, etc.) and, based on this data, counteract this shift. The effect of the frictional heat described above is different for example for an organic solvent than for water. The consideration of the solvent composition therefore allows a particularly high degree of precision in the correction carried out by means of the control device. Also, the flow rate has an influence on the thermal effects, which can lead to an operating point shift, so that taking into account the current value of the flow rate for the correction also brings about a further improvement of the reproducibility.

 The sample separator may include a pump for moving a mobile phase. Such a pump may, for example, be adapted to pump the mobile phase through the system at a high pressure, for example from a few hundred bars up to 1000 bars or more. Alternatively or additionally, the sample separation device may have a Probeninjektor for injection of the sample into a mobile phase. Such a sample injector may include a needle in a seat of a corresponding fluid pathway that may extend out of that seat to receive sample and which, upon reintroduction into the seat, injects the sample into the system. Alternatively or additionally, the sample separation apparatus may include a sample fractionator for fractionating the separated components. Such a fractionator may carry the various components, for example, into different liquid containers. The analyzed sample can also be fed to a waste container.

BRIEF DESCRIPTION OF THE FIGURES

 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 as an example of a sample separation apparatus according to an exemplary embodiment of the invention.

2 to 5 show apparatus for adjusting an operating point of a sample separator for separating a fluidic sample according to exemplary embodiments of the invention.

6 and 7 show two arrangements of temperature sensors in the region of a sample separator of a sample separator according to exemplary embodiments of the invention.

8th 12 shows a first diagram schematically illustrating the formation of a spatially and temporally successive amplifying temperature profile along a sample separator during the performance of multiple separation sequences, and FIG. 12 shows a second diagram schematically illustrating the correction of the temperature profile for operating point stabilization during the execution of the separation sequences according to an exemplary initial example represents the invention.

9 shows a three-dimensional coordinate system, along whose axes a temperature at the entrance of the sample separator, a Temperature at the exit of the sample separator and a retention time are shown, and shows two spatial surfaces, which illustrate schematically actual and target operating points.

The illustration in the drawing is schematic.

1 shows the basic structure of an HPLC system as an example of a sample separator 10 as it can be used for example for liquid chromatography. A pump 20 containing solvents from a supply unit 25 supplied drives a mobile phase through a sample separator 30 (such as a chromatographic column) containing a stationary phase. A degasser 27 can degas the solvents before these the pump 20 be supplied. A sample application unit 40 is between the pump 20 and the sample separator 30 arranged to in a corresponding switching state of a fluid valve 95 to introduce a sample liquid into the mobile phase. The stationary phase of the sample separator 30 is intended to separate components of the sample fluid. A detector, see flow cell 50 , detects separated components of the fluidic sample, and a fractionation device (not shown) may be provided to dispense separated components of the sample fluid into dedicated containers. Waste liquids that are no longer needed can be stored in waste containers 60 be issued.

While a fluid path between the pump 20 and the sample separator 30 typically at 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 unit 40 entered, which then introduces the sample liquid in the high-pressure liquid path. When connecting the initially under normal pressure sample liquid in the sample loop in the high-pressure liquid path, the content of the sample loop abruptly (typically in the range of milliseconds) to the system pressure of the HPLC system of the sample separation 10 brought.

Furthermore, according to 1 a preheater 90 (Preheater) for preheating fluid upstream of the sample separator 30 intended. A control device 70 (For example, a microprocessor or a CPU) controls the individual components of the sample separator 10 ,

The sample separator 10 also contains a device 100 for setting an operating point of the sample separator 30 for separating the fluidic sample. Part of the device 100 forms the control device 70 , which is arranged based on information regarding an axial temperature distribution along the sample separator 30 by appropriate control of the preheater 90 or a direct heating 99 the sample separator 30 a temperature of the sample separation device 30 adapted to a caused by the axial temperature distribution operating point shift, in particular operating point drift, the sample separator 30 at least partially offset. In order to be able to detect the temperature information addressed continuously, the device has 100 In addition, a temperature detection device 92 . 94 on which the temperature information at the sample separator 30 measures and the corresponding measurement data as temperature information to the controller 70 transmitted. In the embodiment shown, the temperature detection device 92 . 94 for detecting temperatures at two different axial positions in the direction of flow of mobile phase with optionally contained therein components of the fluidic sample through the sample separation device 30 educated. These two positions correspond to an area of an inlet 96 and an area of an outlet 98 the sample separator 30 at which an inlet temperature sensor 92 or an outlet temperature sensor 94 are arranged. More specifically, the temperature sensor 92 at the inlet 96 and the temperature sensor 94 at the outlet 98 each attached to a mobile phase with optionally contained therein components of the fluidic sample capillary, where the temperature of the sample separation device 30 flowing through mobile phase with optionally contained therein components of the fluidic sample can be measured very accurately. The control device 70 set up, a temperature of the preheater 90 for preheating the mobile phase with optionally contained components of the fluidic sample upstream of the sample separator 30 to compensate for a working point shift caused by that from the temperature sensors 92 . 94 determined temperature values is displayed and (at least also) on the generation of frictional heat during the pressure relaxation of the mobile phase with optionally contained therein components of the fluidic sample when flowing through the sample separator 30 can be attributed. Alternatively or in addition to the described driving the preheater 90 can the controller 70 to compensate for an operating point shift, in particular operating point drift, a temperature control of the direct heating 99 customize a specific spatial section of the sample separator 30 or the entire sample separator 30 can apply thermal energy.

Thus, the control device 70 arranged to compensate at least partially for a possible operating point deviation caused by an axial temperature distribution by means of adapting a temperature control of the mobile phase, including a fluidic sample. This can be carried out in a particularly advantageous manner such that, for a given fraction of the fluidic sample, different effects of the axial temperature distribution on a separation result in successive separation sequences are at least partially compensated. This will be referred to below 8th described in more detail. Due to the operating point stabilization due to the control behavior of the control device 70 may cause undesirable effects of frictional heat and / or other thermal effects inside the sample separator 30 be suppressed to the chromatographic retention time, and improved reproducibility of separation results in successive separation sequences can be obtained. The operating point drift caused by the axial temperature distribution can therefore in particular be a change in a predetermined operating point of the sample separation device 30 due to a change in the axial temperature distribution in successive separation sequences, wherein in the successive separation sequences successive, independent sections of the fluidic sample by means of the sample separation device 30 be separated. The control device 70 is arranged to compensate for at least partial compensation of the operating point shift, in particular operating point drift, a deviation of a defined by the measured temperature information with respect to a current axial temperature distribution actual operating point of a predetermined desired operating point. The operating point can be determined by the axial temperature distribution along the sample separator 30 be defined, in particular as the arithmetic mean of the temperatures at the inlet 96 and at the outlet 98 the sample separator 30 To be defined.

As in 8th described, it is particularly advantageous by means of the control device 70 the working point shift, in particular operating point drift, the sample separation device 30 by correcting, for successive separation sequences for separating successive portions of the fluidic sample, a temperature at a predetermined position along the sample separation means 30 held constant, for example, a position in the middle between inlet 96 and outlet 98 , It is particularly advantageous in the control procedure to take into account the flow rate of the mobile phase fluid sample and a respective mobile phase solvent composition, as the described artifacts also depend on both the solvent composition and the actual flow rate.

According to 1 So are the temperature sensors 92 . 94 near the inlet 96 or the outlet 98 the sample separator 30 arranged and supply the controller 70 continuous with temperature data at these two characteristic positions. Should it be to form an undesirable temperature gradient or other undesirable temperature profile along the axial extent of the sample separator 30 (that is in the fluid path between inlet 96 and the outlet 98 ), so may the controller 70 the heat input through the preheater 90 and / or the direct heating 99 to suppress or eliminate an undesirable influence of the working point shift, in particular operating point drift, on the reproducibility of the separation results.

 Before further exemplary embodiments are described in detail with reference to the further figures, a few general considerations will be described on the basis of which exemplary embodiments of the invention have been developed.

An advantageous embodiment is that a single sensor is mounted exactly at the point of the column where the operating point is to be held (for example, the middle). The control device 70 regulates the power supply to the preheater 90 then, for example, such that the working point is held.

 According to an exemplary embodiment of the invention, the temperature of a sample separator may be controlled based on temperature detection at the input and output of the sample separator. In particular, therefore, the control of a column temperature based on a multi-point temperature measurement is possible.

In particular, a temperature gradient across the sample separation device can be taken into account, which is generated by frictional heat, which usually raises the outlet temperature of a separation column during the pressurized operation of the sample separation device. Such an effect may have a magnitude of, for example, 20 ° C increase in temperature per 1000 bar pressure drop.

In modern UHPLC, a common condition is that the flow rate is raised to the limit. This can lead to a temperature increase along an HPLC column, which is due to a pressure drop along the column and with the occurrence of frictional heat can be explained.

 This increase in temperature is a "per-length" aspect that occurs hand in hand with the pressure drop along a sample separator. As a result, a gradual increase in temperature along the column bed during operation forms. The mere imposition of an isothermal regime on the column to compensate for the described effect may even be counterproductive since, in such a case, an axial gradient can be converted into a radial gradient, which leads to even poorer results with regard to the achievable HPLC performance can. In particular, this could lead to a strong dispersion of a peak, especially when columns with a relatively large inside diameter are used. In short, while a substantial axial gradient may affect retention time and selectivity, even a small radial gradient may degrade efficiency by substantial dispersion.

 It is generally noted that tempering may be heating or cooling since not only heating but also cooling may be beneficial as needed or chosen target temperature. Also, under certain conditions (for example, special media), frictional heat may actually make cooling advantageous.

 Based on the above considerations, with exemplary embodiments of the invention, original selectivity (i.e., not affected by frictional temperature increases) can be recovered by setting the temperature (eg, of the furnace) to lower values. As a rule of thumb, such an adjustment can be made so that half the temperature increase due to frictional heat is compensated. In this way, the mean column temperature can remain unchanged, whereby selectivity changes can be reduced or even minimized.

 In an exemplary implementation, it is possible to determine the inlet temperature and the outlet temperature and to account for the thermal control for operating point adjustment of the sample separator. For this purpose, a first temperature sensor can be attached to one inlet end of the column and another temperature sensor to an outlet end of the column. It is particularly advantageous here to arrange the sensors near the liquid flow and therefore close to the column. In this way, it is possible not only to adapt the preheating to flow dependency and environmental conditions, but also to precisely detect the effects that frictional heat actually has under the given operating conditions.

 According to an exemplary embodiment, a customized control is possible. The thermal control of a preheater may be implemented to adjust the energy to achieve a particular weighted average of two measured values. The weight factors can enter into a chromatographic method. In a specific case, in the case of the present frictional heat and a weighting factor of 50% of temperature values according to inlet and outlet sensors for correction, the mean column temperature can be set to the arithmetic mean between the column inlet and column outlet temperatures. The mean column temperature then follows exactly the method value.

 Expressed more generally, the effect of an operating point shift, in particular working point drift, of the sample separation device can thus be corrected by adjusting the temperature control of the fluid sample flowing into the sample separation device so that a mean temperature adapted thereby can be adjusted when temperature profiles occur over the axial extent of the sample separation device Sample separator corresponds to a desired temperature according to a predetermined chromatographic method.

 According to an exemplary embodiment, an integrated solution is also possible. For this purpose, a sample separation device can be equipped with a recursively operating heating device, thus removing frictional heat occurring at the sample separation device from there and used for preheating subsequent fluidic sample. In this way, the frictional heat can be usefully used to preheat the inflowing liquid.

 According to an exemplary embodiment, bidirectional external thermal control is possible. For example, on the basis of previous experiments, it may be known in advance how the influence of frictional heat is actually (for example, after some time, in a series of gradient runs, etc.). This can then be used to preheat the column in such a way that external heat is supplied to both ends of the column to begin a sequence. Some predictive control mechanisms and active components may be used to advantage.

It is possible to consider different heating mechanisms, that is preheating the solvent and / or preheating one thermal chamber and / or direct heating of the column by a heat sleeve (the last two variants are particularly advantageous to be used for preconditioning of a column before take-off). A balance between the two heating mechanisms (both of which can be implemented in the same module) may preferably be controlled depending on an applied flow rate, with an increasing role of solvent preheating with increasing flow rate. Preferably, therefore, the adaptation can be based on a flow rate of the fluidic sample in a mobile phase. Also in the course of progress from a start to a quasi-stationary regime, the influence of the inlet solvent temperature on the regulation can be increased. This is because the inlet solvent temperature control is the preferred method of temperature control that does not produce radial temperature gradients.

 Detection systems that may be employed in accordance with exemplary embodiments of the invention include integrating or attaching wired thermal sensors to capillary terminals near the column, integrating or attaching wired thermal sensors to column terminals, and / or using wireless temperature transducers.

2 shows a device 100 for setting an operating point of a sample separator 30 and for controlling a temperature distribution along the sample separator 30 for separating a fluidic sample according to an exemplary embodiment of the invention.

According to 2 the temperature control is carried out for operating point correction of the sample separation device 30 in that the control device 70 a temperature of a preheater 90 for preheating the mobile phase with optionally contained components of the fluidic sample upstream of the sample separator 30 adapts. In the embodiment according to 2 So it is the preheater 90 upstream of the sample separator 30 arranged. Both the preheater 90 as well as the sample separator 30 are inside a furnace 200 or arranged within an insulated chamber. The oven 200 thus brings Vorheizeinrichtung 90 and sample separator 30 to a certain temperature level. The preheater 90 tempered a mobile phase and the fluidic sample contained therein, before this the sample separation device 30 to reach. Should it (for example by frictional heat due to pressure release over the axial course of the sample separator 30 away, so according to 2 from left to right) to form axial temperature profiles, so they can by means of the temperature sensors 92 . 94 detected and the control device 70 be transmitted. The control device 70 can then the preheater 90 accordingly, to leave a retention time related to a specific fraction of the fluidic sample unchanged and to change the temperature profiles accordingly (preferably by shifting the position, see US Pat 8th , bottom illustration), without necessarily completely compensating for them.

3 shows a device 100 for setting an operating point of a sample separator 30 and for controlling a temperature distribution along the sample separator 30 for separating a fluidic sample according to another exemplary embodiment of the invention.

The device 100 according to 3 differs from that according to 2 in that according to 3 the controller 70 not on the preheater 90 but on a direct heating 99 in the form of a sample separation device 30 surrounding heating mantle. As a result, its heating characteristic can be changed to an operating point shift, in particular operating point drift, the sample separation device 30 to compensate in whole or in part. Furthermore, the device differs 100 according to 3 from that according to 2 in that according to 3 the temperature sensors 92 . 94 at a respective capillary upstream of the inlet 96 or downstream of the outlet 98 the sample separator 30 are arranged. This configuration can be implemented in any of the illustrated embodiments.

4 shows a device 100 for setting an operating point of a sample separator 30 and for controlling a temperature distribution along the sample separator 30 for separating a fluidic sample according to another exemplary embodiment of the invention.

The device 100 according to 4 has a heat recovery device 400 on, for at least partial recycling of the flow through the sample separation device 30 Released frictional heat is set to a position upstream of the release of the frictional heat. The position upstream of the release of heat corresponds to 4 the preheater 90 for preheating fluidic sample upstream of the sample separator 30 ,

In the in 4 As shown, the operating point correction takes place via the axial extent of the sample separator 30 through the selective recycling thermal Energy of the sample separator 30 leaving mobile phase with optionally contained therein components of the fluidic sample to the preheater 90 and from this on nachströmende mobile phase with optionally contained therein components of the fluidic sample. The separate fluidic sample containing the sample separator 30 leaves, before feeding to a detector 50 passed through a heat exchanger, which thermally with the preheater 90 is coupled. This is at the heat recovery device 400 Transfer heat from the separate fluidic sample to the inflowing mobile phase, possibly including unseparated fluidic sample. In addition, the controller takes 70 according to an embodiment of the invention also by means of controlling the preheater 90 Influence on the temperature of the sample separator 30 ,

In 4 are not temperature sensors 92 . 94 shown. The temperature management of the sample separator 30 by the control device 70 is then done, for example, solely based on empirically known data regarding the thermal performance of the sample separation device 30 , Corresponding data is in a database 402 stored on which the control device 70 Has access. Alternatively, according to 4 temperature sensors 92 . 94 be implemented.

5 shows a device 100 for setting an operating point of a sample separator 30 and for controlling the temperature distribution along a sample separator 30 for separating a fluidic sample according to another exemplary embodiment of the invention.

According to 5 is the controller 70 set up, a tempering of the furnace 200 adapt location-dependent over a spatial area, in which also the sample separation device 30 is arranged. sections 500 . 502 . 504 of the oven 200 (here the spatial area of the preheater 80 or certain spatial areas of the sample separation device 30 are assigned) can therefore be brought to different temperatures. The device 100 according to 5 differs from that according to 2 in that according to 3 the controller 70 not just on the preheater 90 but on the stove 200 acts. As a result, its heating characteristic can be changed to the temperature profile along the sample separator 30 for suppressing an operating point shift, in particular operating point drift, of the sample separating device 30 to influence (in particular with an offset to occupy, see lower representation in 8th ).

Also according to 5 can the controller 70 access data in the database 402 are stored. These data include empirical and / or theoretical information about which thermal effects the sample separator 30 usually during operation of the sample separator 10 is exposed. In other words, this data allows the database 402 to which the controller 70 Has access to anticipate which temperature profiles actually exist under which operating conditions (for example, flow rate, set temperatures, a particular chromatographic method, etc.). With or without (see 4 ) Temperature measurement can thus control the device 70 make an adjustment using this information or data to compensate for working point shifts. Optionally, the empirical and / or theoretical data can be obtained with experimentally measured data (then, for example, using temperature sensors 92 . 94 ) be combined.

6 shows an arrangement of one of two wire components 600 . 602 a thermocouple formed temperature sensor 92 (or 94 ) in the area of a sample separator 30 a sample separator 10 according to an exemplary embodiment of the invention. The two wire components 600 . 602 are to a mobile phase with optionally contained therein components of the fluidic sample perpendicular to the paper plane of 6 in a lumen 610 leading capillary 604 (for example made of steel) thermally and mechanically coupled. A voltmeter 606 detects an electrical voltage between the wire components 600 . 602 which is indicative of the temperature value at the position shown. The capillary 604 is of an electrical isolation structure 608 jacketed.

7 shows another arrangement of a temperature sensor 92 (or 94 ) in the area of a sample separator 30 a sample separator 10 according to another exemplary embodiment of the invention. According to 7 are the wire components 600 . 602 of the thermocouple and is the lumen 610 on or as part of a laminate arrangement of bonded (in particular metallic) and partially structured layers 700 . 702 . 704 intended. The wire components 600 . 602 are opposite the lumen 610 isolated attached.

8th shows a first diagram 800 schematically illustrating the formation of a spatially and temporally successive reinforcing temperature profile along a sample separator 30 while performing multiple separation sequences, and shows a second diagram 850 , the schematically illustrates the correction of the temperature profile for operating point stabilization during the execution of the separation sequences according to an exemplary embodiment of the invention.

Along an abscissa 802 the diagrams 800 . 850 is the axial position x along a sample separator 30 applied, wherein an inlet of the sample separator 30 a position x ₁ and an outlet corresponds to a position x ₂ . Along an ordinate 804 the diagrams 800 . 850 is a temperature profile along the sample separator 30 applied as it is (especially due to a pressure drop along the sample separator 30 coherent frictional heat) during a flow through the sample separator 30 through the mobile phase, including the fluidic sample. This not only results in the formation of a temperature profile during a separation sequence, but in addition to forming a successively increasing temperature profile during successive separation sequences. The temperature profiles during successive separation sequences I, II, III, IV and V (which are traversed in the time order I->II->III->IV-> V) are in 8th drawn here as a momentary state recorded at the beginning of each separation sequence.

diagram 800 refers to a state without correction of the operating point continuously shifting with the separation sequences I, II, III, IV and V. In the example shown, the operating point is the temperature at a position x _{0 of} the sample separation device 30 defined under the conditions shown as an arithmetic mean of the temperatures at the positions x ₁ and x ₂ . This operating point shifts, as with arrow 810 is indicated, in the course of the separation sequences I, II, III, IV and V continuously, which affects the reproducibility of the chromatographic separation results due to the temperature dependence of the retention time.

The scenario shown further relates to one in which a certain fraction or peak of the chromatographic separation result is reproducibly found in a chromatogram when, at the position x _0, the operating point and therefore the temperature are stabilized. With the present invention it has been recognized that for reproducible separation results, therefore, no complete compensation of the temperature profiles along the sample separation device 30 is necessary, but that the working point stabilization in a specific subarea (for example, at one point) may be sufficient for this purpose. On the contrary, a complete compensation of the temperature profiles along the sample separator 30 would lead to the formation of a radial temperature profile, which would degrade the efficiency (peak width) of the separation. In view of these preliminary considerations, according to an exemplary embodiment, the correction of the axial temperature profile is carried out in such a way that the operating point is stabilized at the position x ₀ . As in diagram 850 This can be shown by correcting or adjusting the temperature of the mobile phase with optionally contained components of the fluidic sample at the inlet x _{1 of} the sample separator 30 be accomplished, which is progressively reduced with progressive separation sequences (ie in the chronological order I->II->III->IV-> V), so that during operation the temperature at the position x ₀ remains at least almost constant (see reference numeral 870 ). In particular, this temperature of the mobile phase, including fluidic sample, by the preheater 90 be set. This leads to an operating point stabilization and consequently to reproducible separation results.

9 shows a three-dimensional coordinate system 900 , along its axes 902 . 904 . 906 a temperature Te at the input x _{1 of} the sample separator 30 (see reference numeral 902 ), a temperature Ta at the output x _{2 of} the sample separator 30 (see reference numeral 904 ) and an operating point AP (see reference numeral 906 ), represented for example by a target temperature of the sample separator 30 at a uniform temperature distribution across these, and showing two spatial surfaces 908 . 910 , which schematically shows a dependence of an actual operating point (see reference numeral 908 ) of Ta and Te, and a plane (see reference numeral 910 ), which is a target operating point of a sample separator 30 as a Z-axis value illustrate target operating point. In this case, an actual operating point should be understood as a value which determines the retention time of a sample component of interest. Thus, based on the area 908 For each pair of Te and Ta values, a corresponding operating point can be read off. However, this representation is to be regarded as a schematic, since the area 908 can be more than three-dimensional, if, for example, further parameters such as a function of the history of the Te and Ta values or a further temperature value are associated with a further position of the separating device. It should also be noted that the graphical representation is for illustrative purposes only and that the embodiment may operate on approximately analytical or tabular values.

A controller according to an exemplary embodiment of the invention is the system on a section line between the two surfaces according to reference numerals 908 and reference numerals 910 respectively. This corresponds to a stabilized operating point, ie for example in In the case of an embodiment where the correcting control of the operating point is effected by influencing the Te value, that the Ta value is read in each case and the Te value is tracked such that the point of this Te, Ta value pair on the surface 908 is always on the cut line and thus remains at a constant AP value, thereby achieving constancy or at least a reduction in the variation in the retention time of the sample component of interest.

 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 [0003]

Claims (20)

Contraption ( 100 ) for setting an operating point of a sample separator ( 30 ) for separating a fluidic sample, wherein the device ( 100 ) comprises: a control device ( 70 ), which is set up, based on information regarding an instantaneous axial temperature distribution along the sample separation device ( 30 in particular based on information regarding a temperature difference between different positions along the sample separation device ( 30 ), a temperature of the sample separation device ( 30 ) and / or a temperature of for flowing through the sample separation device ( 30 ) to be fed to the mobile phase to be optionally contained therein components of the fluidic sample to a caused by the axial temperature distribution operating point shift, in particular operating point drift, the sample separation device ( 30 ) at least partially offset. Contraption ( 100 ) according to claim 1, comprising a temperature detection device ( 92 . 94 ) for detecting at least one temperature at the sample separation device ( 30 indicative data and to provide the data as the information to the controller ( 70 ) is set up. Contraption ( 100 ) according to claim 2, wherein the temperature detection device ( 92 . 94 ) for detecting for several temperatures at different positions, in particular at different axial positions in the flow direction of the mobile phase with optionally contained therein components of the fluidic sample through the sample separation device ( 30 ), the sample separation device ( 30 ) indicative data is set up as the information. Contraption ( 100 ) according to claim 3, wherein the different positions comprise at least one inlet ( 96 ) and an outlet ( 98 ) of the sample separation device ( 30 ) contain. Contraption ( 100 ) according to one of claims 2 to 4, wherein the temperature detection device ( 92 . 94 ) has at least one, in particular a plurality of temperature sensors which is or are attached to a capillary carrying the mobile phase with optionally contained components of the fluidic sample and / or on a separation column separating the fluidic sample. Contraption ( 100 ) according to one of claims 1 to 5, comprising at least one of the following features: the control device ( 70 ) is arranged, for at least partially compensating the operating point shift, in particular operating point drift, a temperature control of a preheater ( 90 ) for preheating the mobile phase with optionally contained components of the fluidic sample upstream of the sample separation device ( 30 ) to adapt; the control device ( 70 ) is arranged, for at least partially compensating the operating point shift, in particular operating point drift, a temperature control of a furnace ( 200 ) or a thermally insulated chamber, at least over a spatial region, in a location-dependent manner, in which the sample separation device ( 30 ) is arranged; the control device ( 70 ) is arranged to at least partially compensate for the operating point shift, in particular operating point drift, a temperature control of a direct heating ( 99 ) at least a portion of the sample separation device ( 30 ). Contraption ( 100 ) according to one of claims 1 to 6, wherein the control device ( 70 ) is arranged to compensate at least partially for the operating point shift caused by the axial temperature distribution, in particular operating point drift, by adjusting a temperature of the mobile phase with optionally contained components of the fluidic sample that different effects of the axial temperature distribution or at least for a given fraction of the fluidic sample Differences of effects of changing axial temperature distribution on a separation result in successive separation cycles are at least partially offset. Contraption ( 100 ) according to claim 7, wherein the control device ( 70 ) is set up as the separation result to at least partially compensate for a retention parameter indicative of a retention of the predetermined fraction of the fluidic sample, in particular a retention time or a retention volume, by adapting the temperature for successive separation cycles. Contraption ( 100 ) according to claim 7 or 8, wherein the control device ( 70 ) is adapted to at least partially offset the different effects of the axial temperature distribution on the separation result for the predetermined fraction of the fluidic sample in the successive separation cycles, which axial temperature distribution at least in part on frictional heat, in particular on a solvent of the mobile phase and / or the fluidic Sample-dependent frictional heat, due to a pressure drop of the mobile phase with optionally contained therein components of the fluidic sample during flow through the sample separation device ( 30 ). Contraption ( 100 ) according to any one of claims 1 to 9, comprising a Heat recovery device ( 400 ) for at least partially recycling the flow through the mobile phase with optionally contained therein components of the fluidic sample through the sample separation device (US Pat. 30 ) released heat, in particular frictional heat, is set to a position upstream of the release of the heat. Contraption ( 100 ) according to claim 10, wherein the heat recovery device ( 400 ) is arranged, at least a portion of the heat released to a preheater ( 90 ) for preheating mobile phase with optionally contained components of fluidic sample upstream of the sample separation device ( 30 ). Contraption ( 100 ) according to one of claims 1 to 11, wherein the operating point displacement caused by the axial temperature distribution, in particular working point drift, a change of a predetermined operating point of the sample separation device ( 30 ) due to a change in the axial temperature distribution in successive separation cycles, wherein in the successive separation cycles successive independent sections of the fluidic sample by means of the sample separation device ( 30 ) are separated. Contraption ( 100 ) according to one of claims 1 to 12, wherein the control device ( 70 ) is arranged for at least partially balancing the operating point shift, in particular operating point drift, at least partially offset a deviation of an actual operating point that can be determined or displayed by the information relating to the current axial temperature distribution from a predetermined desired operating point. Contraption ( 100 ) according to claim 12 or 13, wherein the operating point is determined by the axial temperature distribution along the sample separation device ( 30 ), in particular by a relation between temperatures at an inlet ( 96 ) and at an outlet ( 98 ) of the sample separation device ( 30 ), in particular by an arithmetic mean of temperatures at an inlet ( 96 ) and at an outlet ( 98 ) of the sample separation device ( 30 ) is determined. Contraption ( 100 ) according to one of claims 1 to 14, wherein the control device ( 70 ), the working point displacement, in particular operating point drift, of the sample separation device ( 30 ), that for successive separation sequences for separating successive independent sections of the fluidic sample a temperature at at least one predetermined position along the sample separation device ( 30 ) is kept constant. Contraption ( 100 ) according to claim 15, wherein the control device ( 70 ), a variation of temperatures at different axial positions from the predetermined position along the sample separation device (US Pat. 30 ). Contraption ( 100 ) according to one of claims 1 to 16, wherein the control device ( 70 ), the working point displacement, in particular operating point drift, of the sample separation device ( 30 ) based on at least one property of the mobile phase fluid sample, in particular a flow rate of the mobile phase fluid sample and / or a mobile phase solvent composition. Sample Separator ( 10 ) for separating a mobile phase in a fluidic sample, wherein the sample separation device ( 10 ) comprises: a fluid pump ( 20 ) for driving at least one of the mobile phase and the fluidic sample through the sample separation apparatus ( 10 ); a sample separator ( 30 ) downstream of the fluid pump ( 20 ) for separating the sample in the mobile phase; a device ( 100 ) according to one of claims 1 to 17 for controlling a temperature distribution along the sample separation device ( 30 ) for setting an operating point of the sample separation device ( 30 ). Sample Separator ( 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 separator ( 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 separator ( 10 ) comprises at least one of the group consisting of a detector device, a chemical, biological and / or pharmaceutical analysis device, a liquid chromatography device and an HPLC device; the fluid pump ( 20 ) is configured to drive the mobile phase at a high pressure; the fluid pump ( 20 ) is configured to drive the mobile phase at a pressure of at least 100 bar, in particular at least 500 bar, more particularly at least 1000 bar; the sample separator ( 10 ) is configured as a microfluidic device; the sample separator ( 10 ) is configured as a nanofluidic device; the sample separator ( 10 ) has an injector device ( 40 ) for introducing the fluidic sample into a fluidic path between the fluid pump ( 20 ) and the sample separation device ( 30 ) on; the sample separator ( 10 ) has a detector ( 50 ) for detecting the separated fractions; the sample separator ( 10 ) has a sample fractionator ( 60 ) to fractionate the separated fractions. Method for setting a working point of a sample separator ( 30 ) for separating a fluidic sample, the method comprising: adjusting a temperature of the sample separation device ( 30 ) and / or a temperature of for flowing through the sample separation device ( 30 ) to be supplied to the mobile phase with optionally contained therein components of the fluidic sample based on information regarding an instantaneous axial temperature distribution along the sample separation device ( 30 in particular based on information regarding a temperature difference between different positions along the sample separation device ( 30 ), such that an operating point displacement, in particular working point drift, caused by the axial temperature distribution, of the sample separation device ( 30 ) is at least partially offset.

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