Method for testing and calibrating the delivery volume of a pump and apparatus for testing and / or calibrating the pump

Abstract

The invention relates to a method for testing the delivery volume of a pump for delivering a liquid, comprising the following steps: i) providing a sample container with a known container volume of a defined volume; ii) delivering a predetermined, desired delivery volume of a system liquid to the sample container by means of a pump; iii) measuring a first liquid level of the sample container and calculating the actual delivery volume in the sample container therefrom; iv) sucking out a predetermined, desired suction volume from the sample container by means of a pump; v) measuring a second liquid level of the sample container and calculating the suction volume actually sucked out in step iv); vi) comparing the actual volume measured in steps iii) and v) with the desired theoretical delivered volume of steps ii) and iv); vii) checking whether the measured value deviation from the desired theoretical value determined in step vi) is within a specified tolerance range. This makes it possible to verify the currently delivered pump volume and calibrate the pump automatically and in a targeted and optimized manner without the need for additional equipment.

Description

Technical Field

[0001] The invention relates to a method for testing the delivery volume of a pump for delivering a fluid, in particular a liquid, a method for calibrating or recalibrating the delivery volume of a pump by such a test of the current pump delivery volume, and a device for testing the delivery volume of a pump and / or calibrating the delivery volume of a pump according to one of the methods.

[0002] Such testing and readjustment methods and the equipment required therefor have been known for decades, are common in laboratory work and the relevant equipment is commercially available.

[0003] The invention relates generally to the field of testing and calibrating fluid pumps with respect to their actual delivery volume. Such pumps are often used in laboratories when liquids are to be tested and / or processed or reprocessed. This may, for example, primarily involve the collection of eluate fractions from devices for liquid chromatography, but often also involve the regular extraction and testing of liquid fractions from continuously monitored chemical reactions, where the testing can be carried out by analytical measurements, in particular by nuclear magnetic resonance imaging. Background Art

[0004] The preparation of such liquid samples is increasingly being automated using XYZ liquid handlers (= "Liquid Handler"). This results in a higher throughput and better reproducibility of results than with manual preparation. For human medical samples that must be prepared under S2 conditions, such as serum or plasma, automated processing is even required for the safety of laboratory personnel.

[0005] NMR (= Nuclear Magnetic Resonance) imaging is a widely used measurement method with which chemical compounds can be analyzed. In NMR imaging, the sample to be measured is usually introduced into a sampling probe in a test tube and measured in an NMR imager. In NMR, sample preparation mainly involves adding and mixing substances that induce the desired reaction (e.g. protein bonding reaction) to the original sample or adding deuterated solvents in order to obtain a stable lock for the NMR measurement. For this purpose, transfer from the sample container to an NMR tube or directly to an NMR flow cell is also carried out after preparation.

[0006] A prerequisite for reproducible and precise sample preparation is that the pumps used have the correct delivery volume. All pump types are subject to a certain amount of wear and should be checked at regular intervals and, if necessary, recalibrated in order to obtain correct and comparable results.

[0007] Furthermore, the actually delivered pump volume depends to a certain extent, depending on the specific design, on the properties of the delivered medium and the resulting pressure conditions.

[0008] For diaphragm pumps and gear pumps, the delivery flow depends, for example, to a large extent on the viscosity and density of the solution used, but also on the ambient temperature. Piston and jet pumps are less sensitive to this, but also show smaller volume deviations in the event of system changes.

[0009] It follows that when changing to a lower viscosity application, e.g. from water to acetonitrile, a pump calibrated on water will achieve a delivery of less than 98%. For a 50:50 H2O / methanol mixture, the delivery becomes more than 105% relative to pure water due to the increased viscosity of the mixture.

[0010] When exchanging capillaries or needles with different axial lengths and / or internal diameters, the internal pressure conditions also change and can lead to relevant deviations in the delivered volume.

[0011] In order to obtain similar results even after several years, regular checking and, if necessary, correction of the pump volume parameters is necessary.

[0012] Currently, this process can only be performed manually. A certain volume is entered into a weighed container or a certain volume is drawn out of the container and weighed. The currently necessary correction factor can be determined from the known density (e.g. 0.996 g / ml for water at 21°C) and this can be taken into account in the correction factor corresponding to the pump parameters and the test can be repeated.

[0013] For this process, it is necessary to have a precision balance spatially located near or on the XYZ liquid processor in order to keep evaporation losses as small as possible.

[0014] In addition to the manual weighing of the volume determined, output or inhaled as described above, there are also automatic volume determination methods, which automatically set the correction factor. In the last mentioned case, the liquid is directly transferred into the container, which is placed on a balance, which is placed on the working surface of the liquid treatment machine and the weighing result is used for the coefficient correction. As long as the balance is placed on the working area, other work / preparation cannot be carried out. The balance occupies the main area of ​​the working area. Therefore, it is more unreasonable to use the balance as a permanent component of the working surface. In addition, this solution also potentially has evaporation problems and may cause distortion of the results.

[0015] Specific prior art

[0016] EP 2 933 613 B1 (= reference [1]) describes a method and a device for automatically grading liquids and for automatically adapting preset settings of a capacitive liquid level measurement. This involves detecting the liquid grading by using a cLLD function (cLLD = capacitve Liquid Level Detection), but does not involve using this cLLD function to test the pump volume or to make corrections if necessary.

[0017] US 2013 / 0319108 A1 (=reference [2]) describes the filling of a container and the testing of the liquid level in order to avoid overfilling of the corresponding container. To this end, a defined volume of liquid is repeatedly introduced into the container and the liquid level is measured until a predetermined level is reached. However, there is no description of the calibration of the delivery pump.

[0018] The complete dispensing system described in US 2012 / 0024055 A1 (=reference [3]) uses a capacitive LLD not only for detecting the liquid level, but also for checking whether the pipette needle is inserted or ejected. The relevant electronic equipment is described in detail. However, this document does not mention the correctness of the volume output by the fluid pump, nor does it describe the calibration of the pump based on the corresponding results.

[0019] US 20011 / 0102004 A1 (= reference [4]) describes the functional principle of an LLD with capacitive electronics. Although a "self-test" by simulation is mentioned, this self-test only involves the electronics with a reference oscillating circuit and not a specific pump volume. However, this does not allow calibration of a changing pump volume.

[0020] Furthermore, none of the documents discussed above mentions calibrated containers, such as, for example, NMR tubes. In particular, none of these prior art techniques give any indication of using calibrated containers to determine the detection volume for a fluid pump used for delivery by cLLD.

[0021] Disadvantages of the methods known hitherto for testing the delivery volume of a pump and / or for calibrating the delivery volume of a pump, as well as of the devices for carrying out said methods, are the lack of automatability or the need for extensive and expensive additional devices and the general complexity of such methods and devices. Summary of the invention

[0022] In contrast, the present invention, which is more demanding and complex in detail, aims to improve a method of the type described above for testing the current delivery volume of a fluid pump, and a method for calibrating or recalibrating the pump delivery volume by means of such a test, using uncomplicated, easily available or already available as standard at the user's disposal, and also to improve a device for carrying out said test and / or for calibration, so that a substantially automated and also targeted optimization-based test or verification of the currently actually delivered pump volume and, if necessary, a recalibration of the pump can be realized based on the actual value measured for the delivery volume in a very simple manner and without the need for expensive additional tools. Here, the properties already provided by, in particular, commercially available liquid handling machines should be utilized in a new way.

[0023] Brief Description of the Invention

[0024] The object is achieved by the invention in a likewise surprisingly simple and effective manner with regard to the testing and verification method by the following steps:

[0025] i) providing a sample container of defined volume, said sample container having a known container volume,

[0026] ii) outputting a predetermined desired output volume of system liquid to the sample container via the pump,

[0027] iii) measuring a first liquid level in the sample container and calculating therefrom the actual output volume in the sample container,

[0028] iv) aspirating a predetermined, desired aspiration volume from the sample container by means of the pump,

[0029] v) measuring a second fill level in the sample container and calculating therefrom the aspirated volume actually aspirated in step iv),

[0030] vi) comparing the actual volume measured in steps iii) and v) with the desired theoretically delivered volume of steps ii) and iv),

[0031] vii) Testing whether the measured value deviation from the theoretically expected value determined in step vi) is within a predefined tolerance range.

[0032] This results in a test method which detects the actual volume actually delivered by the delivery pump in a container of calibrated volume by means of a simple level sensor and compares it with the theoretically expected delivery volume. If necessary, a recalibration or recalibration is then also carried out. The method according to the invention is purely volume-based and is not even related in principle to the prior art discussed above.

[0033] The detection of pump variations is independent of the specific gravity and viscosity of the system fluid. The delivered volume varies as a function of the type of pump (e.g. piston pump, gear pump, centrifugal pump, diaphragm pump, jet pump) and its entrainment performance as well as the system fluid used. By means of the described detection of pump errors in pressure and suction mode at a given delivery volume, the errors can be readjusted in a simple manner by adaptively adjusting the pump factor in order to achieve the correct volume.

[0034] With regard to the regulation or readjustment of the pump delivery volume, the above object of the invention is achieved in that, after carrying out the test method according to the invention, in a further step, the setting parameters of the pump, preferably the pump parameters for the liquid volume to be sucked in and delivered, are adaptively adjusted as a function of the measured value deviation between the measured actual volume and the theoretically desired volume determined in step vi).

[0035] With regard to a device for testing the delivery volume of a pump and / or calibrating the delivery volume of a pump according to one of the methods according to the invention described above, the object of the invention is achieved by the combination of the following features:

[0036] - Pumps for delivering liquids through a needle

[0037] - XYZ liquid treatment machine

[0038] - at least one volume-calibrated sample container (ie a defined container, the volume of which can be determined directly by means of the filling level),

[0039] - A level sensor for detecting the liquid level in the sample container

[0040] - an electronic evaluation and control device, which is suitable for controlling the output volume of the pump and detecting the information of the level sensor and calculating the volume with the help of the inner surface (inner diameter) of the container and relating the calculated volume to the control volume of the pump.

[0041] Particular advantages of the purely volume-based measurement method according to the invention:

[0042] 1. Automatically check the volume delivered by the pump without the need for additional equipment, such as a scale;

[0043] 2. Automatically check the volume sucked in by the pump without the need for additional equipment, such as a scale;

[0044] 3. When using the capacitive liquid sensor (cLLD) function inside the system, the pump can be quickly checked between two preparations without additional location requirements;

[0045] 4. The measurement is independent of the pump type, since it only involves the volume delivered;

[0046] 5. The measurement is independent of the liquid medium or the mixing ratio of solvent mixtures, such as water and acetonitrile;

[0047] 6. The measurement is independent of environmental influences (temperature, air humidity, etc.);

[0048] 7. When there is a deviation from the expected volume, the pump parameters can be automatically corrected;

[0049] 8. Check the delivery volume in both delivery mode and suction mode to take mechanical delays into account;

[0050] 9. The accuracy of the measurement can be increased relatively easily by using a smaller inner diameter (ID) in the measuring vessel: a volume-calibrated sample vessel (NMR tube) of 5.0 mm corresponds to an inner diameter of 4.2 mm, i.e. a volume of 12.5 µl / mm and an accuracy of + / -1.2 µl at a variation of + / -0.1 mm in the Z direction; for a volume-calibrated sample vessel of 4.0 mm, an ID of 3.3 mm corresponds to a volume of 4.5 µl / mm and an accuracy of + / -0.45 µl at a variation of + / -0,1 mm in the Z direction.

[0051] This function can easily identify the blockage of the needle or flow path, thereby significantly improving the operational reliability of the liquid processing machine. For high-value samples, the administration can be quickly interrupted and an alarm can be issued to the user to prevent more unfavorable situations.

[0052] Preferred embodiments and improvements of the present invention

[0053] A preferred embodiment of the method according to the invention is characterized in that the sample container is completely emptied before carrying out step ii) in order to define a starting point.

[0054] Alternatively, for example in the case of sample containers with rounded bottoms, a minimum volume can be filled after emptying until the volume-calibrated range is reached. The needles usually have an opening which does not extend all the way to the bottom, so that liquid residues are often still present in the sample container, which can distort the measurement. Therefore, segmented filling is advantageous.

[0055] In an advantageous variant of the method according to the invention, the sample container is aspirated and / or filled by means of a needle or a pipette which is introduced into the sample container, preferably up to the bottom of the sample container.

[0056] These method variants can be improved in that the needle or the pipette is rinsed after aspiration of the sample container and / or before filling, so that there are no longer any air bubbles in the capillary or the needle which could distort the measurement result.

[0057] In an advantageous embodiment, the sample container can be aspirated and / or filled by output in tracking mode (= “tracking mode”).

[0058] In tracking mode, only the needle tip is in contact with the liquid surface and not the entire sleeve is wetted with liquid, which could also distort the measurement due to possible droplets adhering to the needle surface.

[0059] Particularly preferred is an embodiment of the invention in which, in step iii) and / or v), the current fill level value of the sample container is measured capacitively (= “cLLD”) by a fill level sensor, using ultrasound, by an air overpressure sensor or optically.

[0060] The following improvement of these method variants is advantageous, in which, in step iii) and / or v), a capacitive cLLD level sensor for detecting the liquid level present in the XYZ liquid processing machine is used to measure the current liquid level value in the sample container. In this improvement, the functions of the liquid processing machine present in batches can be used without having to carry out additional further upgrades for implementing the method according to the invention.

[0061] Preferably, a level sensor is used which has a measuring accuracy of ±0.1 mm in the Z direction.

[0062] The liquid is sucked in or out by the pump at a sufficiently low delivery rate so that no air bubbles are formed in the pumped liquid volume or in the calibration tube.

[0063] The scope of the present invention also includes a method for calibrating or recalibrating the pump delivery volume by testing the current pump delivery volume according to the above-mentioned test method, wherein, in a further step, the setting parameters of the pump, preferably the pump parameters for the intake and discharge volume of the liquid, are adaptively adjusted depending on the measured value deviation between the measured actual volume and the theoretical, desired volume determined in step vi).

[0064] Setting the pump parameters refers in particular to the number of steps for adjusting the volume delivered per time. Depending on the type of pump, this can be the number of steps when using a stepper motor, the number of strokes for a diaphragm pump or the number of revolutions for each volume delivery for a gear pump. Another setting parameter is the delivery speed, since, especially when (fast) aspirating liquids, bubbles can also form in the capillary due to possible negative pressures in the supply line, which can be avoided by reducing the delivery speed.

[0065] Particularly preferred are variants of the calibration method in which different setting parameters are respectively adapted for discharge and intake.

[0066] In an alternative or supplementary embodiment of the calibration method according to the invention, in order to verify whether the adaptation was successful, after the setting parameters of the pump have been adapted, the test method according to the invention is performed again, and when the presence of an inadmissible measured value deviation is confirmed in step vii), the setting parameters of the pump are adapted again.

[0067] Also within the scope of the invention is a device for testing the delivery volume of a pump and / or calibrating the delivery volume of a pump according to one of the above-mentioned methods, comprising:

[0068] - pumps for delivering liquids through a needle,

[0069] - XYZ liquid treatment machine,

[0070] - at least one volume-calibrated sample container (ie a defined container, the volume of which can be determined directly by means of the filling level),

[0071] - a level sensor for detecting the liquid level in the sample container,

[0072] An electronic evaluation and control device is suitable for controlling the output volume of the pump and detecting the information of the level sensor and calculating the volume with the aid of the inner surface of the container, and for associating the calculated volume with the control volume of the pump.

[0073] Embodiments of the device according to the invention are particularly preferred in which the sample container is designed in an axisymmetric manner, preferably in a cylindrically symmetrical manner, in particular as a tube open on one side.

[0074] The following embodiment of the device according to the invention has proven itself in practice, in which the sample container has an internal diameter of 2 mm to 10 mm.

[0075] An embodiment of the volume-calibrated sample container is advantageous in which the liquid surface is small and has a diameter of 2 mm to 10 mm, particularly preferably a diameter of between 3 mm and 5 mm, since the smaller the liquid surface, the more precise the measurement of the volume formed. Furthermore, since some liquids, such as acetone or ether, evaporate quickly and thus falsify the measurement result, the liquid surface should also be minimized.

[0076] Further particularly advantageous embodiments of the device according to the invention are characterized in that a capacitive filling level sensor is provided and that the sample container of a defined volume is surrounded by an electrically conductive metal sleeve.

[0077] When using capacitive level measurement (cLLD), it can happen that only inaccurate measurement results can be achieved for thin containers with a small inner diameter of ≤ 5 mm or for very low-viscosity system liquids, such as acetone. To remedy this, the sample container of a defined volume is surrounded by an electrically conductive metal sleeve, which increases the measurement sensitivity and thus the measurement accuracy. Even when using non-polar solvents such as chloroform, ether or the like, the metal sleeve increases the measurement sensitivity and thus the measurement accuracy of the capacitive sensor.

[0078] The method and the device according to the invention are particularly preferably used in the field of nuclear magnetic resonance, in particular in NMR imaging.

[0079] When using an XYZ liquid handling machine with an existing capacitive cLLD level sensor for detecting the liquid level, the verification or recalibration method can be performed as a quick intermediate step, since this has no effect on the preparation cycle. Only components already present in the system are used, ideally in combination with a commercially available cleaning station on the XYZ liquid handling machine.

[0080] Other advantages of the present invention are apparent from the description and the drawings. The features described above and those to be described further can be used according to the present invention individually or in any combination of multiple features. The embodiments shown and described should not be understood as an exhaustive enumeration, but rather have an exemplary nature for illustrating the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] The invention is illustrated in the drawings and will be described in detail with reference to exemplary embodiments.

[0082] in:

[0083] Figure 1 A flow chart showing the principle method process of the testing and calibration method according to the present invention;

[0084] Figure 2 Schematic diagrams showing different stages in aspirating and filling a sample container having a needle according to an embodiment described below; and

[0085] Figure 3 A schematic diagram of a device for testing the delivery volume of a pump and / or for calibrating the delivery volume of a pump using a method variant according to the invention is shown. DETAILED DESCRIPTION

[0086] The invention relates to a specially improved method for testing the delivery volume of a pump 1 for delivering a liquid, a method for calibrating or recalibrating the delivery volume of a pump by testing the current delivery volume of the pump, and a device for testing the delivery volume of a pump and / or calibrating the delivery volume of a pump according to one of the methods. The device can be, for example, a component of a liquid chromatography device with a separation column, but can also be, for example, a component of a reactor for a chemical reaction that is carried out in a controlled manner.

[0087] The core part of the present invention is such a test method, which at least comprises the following steps:

[0088] i) providing a volumetrically determined sample container 2 with a known container volume and setting a starting point in the sample container 2 , which corresponds to an initial filling level, which initial filling level may also be zero,

[0089] ii) outputting a predetermined desired output volume of system liquid into the sample container 2 via the pump 1,

[0090] iii) measuring a first liquid level in the sample container 2 and calculating the actual output volume in the sample container 2 therefrom,

[0091] iv) aspirating a predetermined, desired aspiration volume from the sample container 2 by means of the pump 1,

[0092] v) measuring a second fill level in the sample container 2 and calculating therefrom the aspirated volume actually aspirated in step iv),

[0093] vi) comparing the actual volume measured in steps iii) and v) with the desired theoretically delivered volume of steps ii) and iv),

[0094] vii) Checking whether the measured value deviation from the theoretically expected value determined in step vi) is within a predefined tolerance range.

[0095] This test method according to the invention can be used alone, but it can also be "embedded" as a "core method" in a method for calibrating or recalibrating the delivery volume of a pump. For this purpose, in a further step, the setting parameters of the pump 1, preferably the pump parameters for the intake and delivery volume of the liquid, are adapted as a function of the measured value deviation between the measured actual volume and the theoretically desired volume determined in step vi).

[0096] The principle process of the testing and calibration method according to the present invention is as follows: Figure 1 is shown as a flow chart.

[0097] Example:

[0098] The process of determining the pump volume with subsequent corrections, if necessary, comprises the following steps in a specific dimensioned embodiment:

[0099] 1. Sink the needle 3 or the dropper all the way to the bottom of a sample container 2 of defined volume with a known container volume.

[0100] Within the scope of this exemplary embodiment, standardized NMR tubes with an outer diameter of 5 mm were used, which corresponds to an inner diameter of 4.2 mm.

[0101] 2. Empty container 2 by aspirating 600 µl in order to obtain a defined starting point.

[0102] 3. Rinse the needle 3 with more than 600 μl of system liquid from the reservoir 8, preferably discharging a volume of >1000 μl into a waste container. The needle 3 is thereby advantageously charged with the desired system liquid without air bubbles.

[0103] 4. The needle 3 is sunk all the way to the bottom of the sample container 2, so that, in particular with narrow sample containers 3, no droplets remain attached to the walls, which could distort the results.

[0104] 5. Optionally, when the sample container 2 has a rounded bottom, a defined starting point can be set by metering a small amount of liquid so that the liquid level reaches the cylindrical area of ​​the sample container 2. For a standard NMR tube, this is approximately 60 µl in order to obtain a liquid level of approximately 5 mm.

[0105] 6. Check the position of the liquid level with a level sensor 4 (capacitive, ultrasonic, optical) in order to determine the internal starting position. Capacitive measurement with cLLD is preferred, since, in particular for thin test tubes, a relatively precise measurement of up to + / - 0.1 mm is possible. Here, the needle is raised to slightly above the liquid level and lowered again until the level sensor 4 responds when the liquid surface is detected.

[0106] 7. Fill with a defined amount of liquid, e.g. 500 µl for a 5 mm NMR tube with an inner diameter of 4.19 mm + / - 0.025 mm, in Tracking Mode (tracking mode, in which the needle 3 is guided slightly below the liquid surface). This is preferably done in Tracking Mode, since droplets formed on the needle 3 can lead to volume distortions, since these droplets (approx. 1-5 µl / droplet) may not be taken into account in the calibration.

[0107] 8. The position of the liquid level is measured using the liquid level sensor 4 for detecting the final position. Here, the needle is raised to slightly above the liquid level and lowered again until the liquid level sensor 4 responds when it detects the liquid surface.

[0108] 9. Calculate the actual output volume from the measured liquid level and the inner surface (inner diameter) of the container.

[0109] 10. Internal errors are detected by comparing the theoretical volume with the actual volume. A plausibility test is then performed to determine whether the actual output volume is within the predefined tolerance range.

[0110] 11. Aspirate a volume of 500 µl in tracking mode.

[0111] 12. The filling level is tested using the filling level sensor 4 for detecting the previous starting position. Here, the needle is raised to slightly above the filling level and lowered again until the filling level sensor 4 responds when it detects the filling surface.

[0112] 13. Calculate the remaining volume from the measured liquid level when the inner diameter of the container is known.

[0113] 14. Correctness is defined by re-comparing the theoretical volume (60 µl) with the actual volume and a confidence test is performed to determine whether the aspirated volume is within the pre-defined tolerance range.

[0114] exist Figure 2 3 shows the different stages of the respective immersion depth of the needle 3 or the dropper during the aspiration and filling of the sample container 2 according to steps 2, 6-8, 11 and 12 described above.

[0115] Steps 11 to 14 are also necessary for checking the correctness of the current actual value of the pump 1, since the measured sample 9 is always sucked in with negative pressure during measurement operation with the device and is received in the connecting capillary 10 (see Figure 3 ), directly thereafter the measurement sample is output from the connecting capillary into the measuring tube by positive pressure. The physical conditions when outputting the liquid through the needle (including the hose connection structure with the pump 1) are different from those when inhaling. Positive pressure is established during output. Negative pressure, i.e. low pressure, is generated during inhalation. If the inhalation is too fast, bubbles may form in the system, which may distort the results. However, many pumps are not 100% sealed and therefore respond differently to the dispensing and drawing (= output and inhalation) actions. That is, in order to achieve 100% reliability and obtain the same results for both actions under given conditions, these two actions must also be tested. Therefore, the pumps commonly used also have two different coefficients, i.e. one coefficient for output and another coefficient for inhalation, so as to be able to compensate for the physical effects associated with the mechanical delay of the system.

[0116] The functional test according to the invention may take > 1 minute.

[0117] Calibration and verification can be completed in less than 5 minutes.

[0118] Optional pump recalibration

[0119] The method steps of the test method according to the invention can be supplemented, if necessary, by the following (re)calibration steps:

[0120] 15. Calibrate Pump 1 by adapting the pump factors for suction and delivery.

[0121] In the above step 10 or 14, it is only checked whether the pump 1 is still delivering within the permissible range. If the deviation is within the permissible range, the operation can be continued immediately. However, the calibration is an intervention in the pump parameters, since the pump coefficients are corrected thereby. Therefore, after this correction, the test is carried out again as described above in steps 1-14 in order to verify this correction.

[0122] 16. Repeat steps 6 through 14 to verify calibration step 15 for a given system fluid.

[0123] The cLLD function that is present in XYZ liquid handling machines 5 is usually used to detect the liquid surface. Alternatively, other technologies can also be used, such as ultrasonic measurement of the liquid level. This ensures that the needle 3 does not have to move to the bottom of the container in order to aspirate the liquid, or that only a few millimeters of the needle tip come into contact with the liquid when the liquid is discharged through the needle 3. This significantly reduces the risk of contamination or volume loss due to droplets adhering to the needle surface.

[0124] The Z position of the needle of the liquid handling machine can be read with an accuracy of + / - 0.1 mm. If volume calibrated containers are used, such as 5.0 mm NMR tubes with very narrow internal dimensions (ID 4.19 mm + / - 0.025 mm), the volume introduced or aspirated can be calculated very accurately via the filling height. 0.1 mm corresponds to a volume of 1.2 µl in the NMR tube described above. For a pipetting volume of 500 µl, this + / - 1.2 µl corresponds to a fluctuation of + / - 0.24%. This accuracy is well within the range of a high-precision laboratory balance.

[0125] Since the OD of 5 mm (< 0.2 mm 2 ) and the very short time between pipetting and cLLD measurement, losses due to evaporation can be almost avoided. This time advantage makes it possible to perform such volume determination even for liquids that evaporate easily or have low viscosity, such as acetone, for example.

[0126] exist Figure 3Schematically shows an embodiment of a device for testing the delivery volume of a pump and / or calibrating the delivery volume of a pump using one of the above-described method variants according to the invention. The device comprises:

[0127] - a pump 1 for delivering a liquid using a needle 3,

[0128] - XYZ liquid treatment machine 5,

[0129] - at least one volume-calibrated sample container 2 (that is to say a defined container, the volume of which can be determined directly by means of the filling level of the container),

[0130] - a liquid level sensor 4 for detecting the liquid level in the sample container 2,

[0131] - an electronic evaluation and control device 6, which is suitable for controlling the delivery volume of the pump 1 and detecting the information of the level sensor 4 and calculating the volume with the aid of the inner surface of the container and which associates the calculated volume with the control volume of the pump 1. The evaluation and control device 6 is also designed to set the parameters of the pump in the delivery and intake mode, that is, the number of steps per delivery volume and / or the delivery rate can be adjusted.

[0132] If a capacitive filling level sensor 4 is used, the sample container 2 of a certain volume can be surrounded by an electrically conductive metal sleeve 7 in order to increase the measuring sensitivity of the capacitive sensor and thus the measuring accuracy.

[0133] exist Figure 3 In FIG. 8 , the two-way communication between the evaluation and control device 6 and the pump 1 is indicated by a dotted double arrow 61 , and the two-way communication between the control device 6 and the XYZ liquid processing machine 5 including the liquid level sensor 4 is indicated by a dotted double arrow 65 .

[0134] Reference numerals list

[0135] 1 Pump

[0136] 2 Sample container with defined volume

[0137] 3 needles or droppers

[0138] 4 Liquid level sensor

[0139] 5XYZ liquid treatment machine

[0140] 6Evaluation and control device

[0141] 7Conductive metal sleeve

[0142] 8Reservoir container with system fluid

[0143] 9. Measuring samples

[0144] 10 Connecting capillaries

[0145] 61 Control device-pump two-way communication

[0146] 65 Control Unit - Two-way communication for XYZ liquid handling machine

[0147] Reference list

[0148] Publications examined for patentability:

[0149] [1] EP 2 933 613 B1

[0150] [2] US 2013 / 0319108 A1

[0151] [3] US 2012 / 0024055 A1

[0152] [4] US 20011 / 0102004 A1

Claims

1. A method for testing the delivery volume of a pump (1) for delivering a liquid, comprising the following steps: i) providing a sample container (2) with a defined volume, said sample container having a known container volume, ii) outputting a predetermined desired output volume of system liquid to the sample container (2) through the pump (1), iii) measuring a first liquid level in the sample container (2) and calculating therefrom the actual output volume in the sample container (2), iv) aspirating a predetermined, desired aspiration volume from the sample container (2) by means of the pump (1), v) measuring a second fill level in the sample container (2) and calculating therefrom the aspirated volume actually aspirated in step iv), vi) comparing the actual volume measured in steps iii) and v) with the desired theoretically delivered volume of steps ii) and iv), vii) checking whether the measured value deviation from the theoretically expected value determined in step vi) is within a predefined tolerance range, It is characterized in that The following additional step is added between step i) and step ii): ia) metering a small amount of system liquid into the sample container (2) by means of the pump (1) in order to set the liquid level to a determined starting point, and ib) Measuring the starting position of the liquid level.

2. The method according to claim 1, characterized in that The sample container (2) is completely emptied before performing step ii).

3. The method according to claim 1 or 2, characterized in that: The sample container (2) is aspirated and / or filled by means of a needle (3) or a dropper introduced into the sample container (2).

4. The method according to claim 3, characterized in that After aspirating the sample container (2) and / or before filling the sample container, the needle (3) or the dropper is rinsed.

5. The method according to claim 3, characterized in that: The sample container (2) is aspirated and / or filled by means of a discharge in tracking mode.

6. The method according to claim 1, characterized in that In steps iii) and / or v), the current fill level value of the sample container ( 2 ) is measured capacitively by a fill level sensor ( 4 ), using ultrasound, by an air overpressure sensor or optically.

7. The method according to claim 6, characterized in that In step iii) and / or v) for measuring the current liquid level value in the sample container (2), a capacitive liquid level sensor (4) for identifying the liquid surface in the XYZ liquid processing machine (5) is used.

8. The method according to claim 6 or 7, characterized in that: A liquid level sensor (4) with a measurement accuracy of ±0.1 mm in the Z direction is used.

9. Method for calibrating or recalibrating a pump delivery volume by testing the current pump delivery volume according to the method according to any one of claims 1 to 8, characterized in that In a further step, setting parameters of the pump (1) are adapted as a function of the measured value deviation between the measured actual volume and the theoretical, desired volume determined in step vi).

10. The method according to claim 9, characterized in that For suction and output adaptability to different setting parameters.

11. The method according to claim 9 or 10, characterized in that: In order to verify whether the adaptation is successful, after the setting parameters of the pump (1) are adapted, the method according to any one of claims 1 to 8 is performed again, and when the presence of an inadmissible measured value deviation is confirmed in step vii), the setting parameters of the pump (1) are adapted again.

12. Device for testing the delivery volume of a pump (1) according to the method according to any one of claims 1 to 8 and / or for calibrating the delivery volume of a pump according to the method according to any one of claims 9 to 11, comprising: - a pump (1) for delivering a liquid using a needle (3), - XYZ liquid processing machine (5), - at least one volume-calibrated sample container (2), that is to say a defined container, the volume of which can be determined directly by means of the filling level of the container, - a liquid level sensor (4) for detecting the liquid level in the sample container (2), - an electronic evaluation and control device (6) which is suitable for controlling the output volume of the pump (1) and detecting the information of the level sensor (4) and calculating the volume with the help of the inner surface of the container and for associating the calculated volume with the control volume of the pump (1).

13. The device according to claim 12, characterized in that The sample container (2) is configured as an axisymmetric tube.

14. The device according to claim 12 or 13, characterized in that The sample container (2) has an inner diameter of 2 mm to 10 mm.

15. The device according to claim 12 or 13, characterized in that A capacitive level sensor (4) is provided, and a sample container (2) of a certain volume is surrounded by an electrically conductive metal sleeve (7).

Images