DE10148608A1 - Method and device for assessing a liquid dosing process - Google Patents

Method and device for assessing a liquid dosing process

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Publication number
DE10148608A1
DE10148608A1 DE2001148608 DE10148608A DE10148608A1 DE 10148608 A1 DE10148608 A1 DE 10148608A1 DE 2001148608 DE2001148608 DE 2001148608 DE 10148608 A DE10148608 A DE 10148608A DE 10148608 A1 DE10148608 A1 DE 10148608A1
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DE
Germany
Prior art keywords
state variable
range
characterized
error
liquid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
DE2001148608
Other languages
German (de)
Inventor
Johann Camenisch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hamilton Bonaduz AG
Original Assignee
Hamilton Bonaduz AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DE10111423 priority Critical
Application filed by Hamilton Bonaduz AG filed Critical Hamilton Bonaduz AG
Priority to DE2001148608 priority patent/DE10148608A1/en
Priority claimed from EP20020727371 external-priority patent/EP1412759B1/en
Priority claimed from DE2002505365 external-priority patent/DE50205365D1/en
Publication of DE10148608A1 publication Critical patent/DE10148608A1/en
Withdrawn legal-status Critical Current

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Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1009Characterised by arrangements for controlling the aspiration or dispense of liquids
    • G01N35/1016Control of the volume dispensed or introduced

Abstract

A method for assessing a liquid dosing process in a vessel which is at least partially filled with a gas is proposed, in which method a time profile of at least one state variable (p) of a medium present in the vessel is recorded over the entire duration of the dosing process, in which furthermore, the time course (40; 40 ') of the at least one state variable (p) with a predetermined state quantity target range (42; 42'; 242) is compared graphically or mathematically by means of a correlation method and in which, depending on the comparison result, an assessment result (S6 , S14, S16) is output.

Description

The present invention relates to a method and an apparatus for Assessment of a liquid dosing process in at least one partially filled with a gas.

Dosing processes of liquids are often part of mixing or analytical methods in which exact doses of liquids are made Quantities of liquid removed and mixed together, for example become. Dosing processes of liquids are in chemical, phar pharmaceutical, medical and human biological processes at the Agenda. Many of these dosing processes are part of one Manufacturing process for the production of pharmaceutical or medicinal active ingredients and remedies or contribute to medical diagnosis of diseases. Undetected faulty liquid doses can therefore lead to products that are beneficial for the health of living organisms, especially of humans, are questionable or even dangerous. But even if at an operational or clinical quality assurance level incorrect fluid doses are still detected the risk of being worth unnecessarily numerous reject dosages full and possibly only limited available substances wasted become.

It is therefore of great importance to do liquid metering operations like this as early as possible with the greatest possible certainty that the process is error-free to be able to judge.  

From the prior art, for example, for an aspiration gang, d. H. for sucking in a liquid, and for a dispenser tion process, d. H. for dispensing a liquid when pipetting various methods for assessing a liquid dosage known.

In the case of an aspiration process, the pipette tip is first inserted into the increasing liquid immersed. This makes one through in one Delimited pipette tip opening, inner pipette tip and plunger Liquid intake space existing gas quantity completed and by the gas volume of the environment separated, so that in the pipette tip approximate amount of gas present, d. H. apart from evaporation and Condensation processes, remains constant. With a suction movement of the pipetting plunger away from the pipetting tip becomes the volume of the completed gas volume increases, causing the pressure of the gas in the liquid intake space sinks. Above a certain pressure differentiated between the gas pressure in the liquid receiving space and that of Liquid begins to flow through the pipette tip opening into the environment Incoming liquid intake space. Due to the inflowing liquid speed, the gas volume change rate and thus the gas decrease rate of pressure change in the fluid intake space.

In the known methods for assessing a liquid dosage process is monitored to determine whether the gas pressure in the liquid intake space falls below a predetermined limit. With some procedures in addition to falling below a limit, the change rate Speed of the pressure of the trapped in the liquid receiving space observed a gas, i. H. it is checked whether the gas pressure in the Liquid intake space by a predetermined time agreed amount changes. This test can be done graphically by comparison the slope of a pressure-time curve with a predetermined slope or  also analytically by comparing corresponding pressure-time value pairs respectively.

For the dispensing process in which the volume is between an absorbed liquid and the pipetting flask included NEN amount of gas by pushing the pipetting piston out If the pipetting opening is reduced, the assessment described above applies division procedure accordingly. It is generally accepted that the dosage gang is judged to be error-free if the pressure of the fluid in the included gas reaches a certain limit or falls below or exceeds or / and if the time change of the Pressure reaches or falls below or exceeds a certain limit tet.

A disadvantage of this prior art method is that the Assessment of whether the liquid dosing process was carried out without errors or not, based only on a few metrics that are usually too Be measured at the beginning of the dosing process. A mistake after when the gas pressure limit is reached, this ver drive no longer recorded. Such an error can occur, for example occur when the pipette tip opening during the inflow of Liquid into the pipette tip through one present in the liquid Solid is clogged. This can be the case when dosing blood if there are coagulated components in the liquid blood.

It is therefore an object of the present invention to provide a teaching which enables the person skilled in the art to perform liquid dosing processes to be judged reliably and faulty with regard to their successful operation Detect doses early.

According to a first aspect of the present invention, the Task solved by a procedure for assessing a liquid dose  tion process in an at least partially with a gas, preferably with air, filled vessel, especially an aspiration or / and dispenser tion process when pipetting, which method is a temporal one Course of at least one state variable of one present in the vessel Medium essentially over the entire duration of the dosing process is recorded, in which the essentially total temporal Course of the at least one state variable with a predetermined one State variable setpoint range is compared, and at which in Depending on the comparison result, an assessment result is output becomes.

Although an assessment ver driving a pipetting process has been described is the fiction methods are not limited to pipettes as vessels, but to any vessel applicable. By capturing at least one State variable of a medium present in the vessel over essentially Information about is available for the entire duration of the dosing process the filling state of the vessel essentially for the whole Dosing process is available and can be used to assess it get dressed by. By comparing the essentially whole time course of the at least one state variable with a The state variable setpoint range can be selected at any time abnormal values of at least one occurring during dosing State variable found and thus reliably assess the dosing process be shared.

The state variable setpoint range can be, for example, a u. U. with an idealized state variable curve provided with a tolerance allowance.

The state variable can be in any one present in the vessel Medium are detected. For example, the state variable of the hydro static pressure of the dosed into an open cup or bottle  Be liquid that is at the lowest point of the cup or bottle will measure. However, vessels are often used for liquid dosing a gas space closed during the metering process applies, such as when pipetting with pipetting tips of the Case is. In such vessels, at least one can be detected State variable of the gas present in the vessel a particularly ge exact result can be obtained because the gas trapped in the vessel quantity almost in contrast to the inflowing or outflowing liquid is finally influenced by the liquid to be dosed and a Influence from the surroundings of the vessel is almost impossible.

Another advantage of detecting at least one state variable of the in the gas present in the vessel lies in the fact that this also means dosing operations with lower dosage amounts can be assessed as upon detection of a state variable of the metered liquid itself, because the liquid to a greater extent than the gas adhesion or / and Rei interactions with the vessel wall. This interaction Consequences are only considered from a certain minimum amount of liquid lässigbar.

The method according to the invention can be used with any type of gas, i. H. in every Kind of gas atmosphere, feasible. In the simplest and most common case the dosing process is carried out in ambient air, which is why the In this case, the vessels are filled with air. However, it is also conceivable that liquids must be dosed, their contact with air or oxygen is not desired. In this case, the method according to the invention even when dosed in an inert or quasi-inert atmosphere such as B. argon, nitrogen or carbon dioxide atmosphere used become.

As already described, the state variable comes in for a measurement the liquid in the vessel the hydrostatic pressure, for a  Measurement in gas the gas pressure and / or the temperature in question. Since the in Amount of gas present in the vessel, d. H. the gas mass, with many dosing vessels remains approximately constant during the dosing process, however the volume of the gas quantity is changed by moving a piston, change with the volume of pressure and, depending on the version of the Dosing process, including the temperature of the gas. With particularly long Seed gas volume changes in the vessel can be approximated by one isothermal volume change can be assumed. In this case measuring only the pressure sense. With particularly fast volumes Changes can be approximated by an adiabatic change of state are assumed, which is why with knowledge of the gas assigned Adiabatic exponents either the pressure or the temperature as Zu stand size can be recorded. The highest accuracy and security Unit is obtained, however, if one pressures both the pressure and the temperature of the Gases detected, as a result of a mutual control of the function efficiency of the state quantity detection sensors can take place.

To record a state variable, it is sufficient to record a quantity sen, which changes in a known relationship with the state quantity.

The state variable setpoint range is advantageously at least for defines the total duration of the liquid dosing process. In this In case it is possible, the liquid dosing process is not only in be agreed periods of time, but actually at any time of the day To assess the dosing process.

However, this does not mean that the state variable setpoint range only defined for the duration of the change in the amount of liquid in the vessel is. It can also make sense to set the state variable before or / and after the phase of changing the amount of liquid in the vessel capture and accordingly also the state variable setpoint range to extend to these periods. So any transportation  phase between the aspiration phase and the dispensing phase via to be awake B. on fluid loss due to droplet formation and Loss of drops or even loss of the pipette tip (pipette tip).

The exact procedure for registering such liquid dosing Upstream and downstream processes are explained below using an exec Example are described.

According to a first preferred embodiment of the present invention The state variable setpoint range can follow a set curve be defined, and then to assess the dosing process it is averaged whether the time course of the at least one state variable is within the state variable setpoint range, and depending an assessment result is output from the result of the investigation. It han is a very easy comparison to make the dosing process can be reliably assessed.

For the sake of clarity and simplicity Understanding of the assessment results obtained can be the condition size setpoint range can advantageously be defined such that the liquid dosing process is judged to be error-free as long as the recorded temporal course of the at least one state variable within the Zu range and that it is judged to be faulty if it is determined that the recorded time profile of the at least one State variable at least in sections outside the state variable Target range is.

For example, a pipette opening can be temporarily opened by a Solid body clogged or narrowed in cross section, the Solid after a pause by the inflowing or outflowing Liquid is washed away. In this case the gas pressure would be inside the pipette tip, for example during an aspiration process  drop (or / and the gas temperature would drop sharply), so the State variable leaves its setpoint range. After removing the Fault, the state variable can again assume values that are within of the setpoint range. However, since during the occurrence of the interference Undefined flow conditions existed at the pipette tip it makes sense to assess a pipetting as faulty if: it is determined that the recorded time profile of the at least one State variable at least in sections outside the state variable Setpoint range.

Another advantage of the method according to the invention lies in the possibility ability to assess the correct course of the dosing process In addition, in the event of an error, this with regard to its Diagnose type of error. It is advantageous that if the time course of the at least one state variable as at least from recorded in sections lying outside the target state range is determined, whether the course of the at least one state variable at least in sections in at least one error range of one A plurality of error ranges, one outside the target state variable range of state variables. Dependent on of the at least one error area that has been passed through then becomes one Error message issued.

If the time course of the at least one state variable leaves the State variable setpoint range, so is the time course of the at least one state variable in a state variable outside the State value value range lying within the setpoint range. Kick usually different types of errors occur at different times or / and lead to different deviations in the state variables value from the state variable setpoint range. It is therefore possible that the State variable setpoint range surrounding state variable valuesbe range in at least one error range, preferably a plurality of  To divide areas of error. Each area of error is more advantageous exactly one error, but possibly also a plurality of Errors. In the case of several error areas, these are temporal or / and by time-variable state variable threshold values of delimited from each other.

Likewise, the state variable setpoint range can be defined by an upper and a lower threshold curve from the rest of the state variable value range be delimited. The threshold curve is the upper threshold curve denotes which increases the state variable setpoint range State quantity values limited. The lower threshold curve is that accordingly, the state variable setpoint range to lower Zu threshold curve limiting the size of the standpoints. The threshold course ven can be and are usually functions of time the state variable setpoint range usually a non-trivial setpoint curve follows. In this case, it can be determined whether the temporal course of the at least one state variable within the predetermined state size setpoint range lies in a simple manner by a Comparison of the course over time with the upper threshold curve and the lower threshold curve.

As an alternative to this, the determination as to whether the temporal course of the we at least one state variable within the predetermined state quantity ß-setpoint range is also carried out by image processing become. An image processing investigation procedure is invented by the inventor Processes in accordance with the invention are favored insofar as those in the process data bases used, such as B. time course of at least one State variable, state variable setpoint range and if desired a plurality of error areas particularly good for a graphic Presentation and evaluation are suitable.  

The quality of the assessment achieved with the method according to the invention Division of the liquid dosing process largely depends on that used for the assessment of the state variable setpoint range. If the state variable setpoint range is very broad, there is Danger that already incorrect dosing processes are still error-free be assessed. Conversely, a very narrow state Setpoint range the risk that error-free dosing processes as errors be judged.

One especially for the assessment of liquid dosing processes suitable range of state variables for a certain liquid dosing can be obtained by essentially Chen same liquid dosing process using the essentially Lichen same process parameters repeatedly and the temporal course of the at least one state variable recorded. The Ver The phrase "essentially the same process parameters" means that if possible the same liquid (or at least a liquid essentially the same viscosity, surface tension etc.) at im Essentially the same ambient temperature in the essentially same vessel, d. H. a vessel of the same type, e.g. B. the same order number of the same manufacturer, in essentially the same gas atmosphere sphere with essentially the same operating settings of a dose dosing device. To the operating settings of a dosing device counts, for example, the dosing speed in liquid volume per unit of time or liquid weight per unit of time.

The scatter that occurs during practical use of a dosing device or to be traced back to a copy of the metering device end of the process parameters such. B. measuring temperature, dosing speed speed and, as already mentioned, the shape of the vessel, it should be under "essentially equal ", so that the setpoint range determined in this way this parameter spread is taken into account.  

After performing the liquid dosing process several times, provided that each individual dosing process was carried out without errors, a group of temporal courses of the at least one state variable, their envelopes further passages of this liquid metering can initially be used as the state variable setpoint range. Depending on the safety relevance of the metered amount of liquid or after the envelope of the plurality of temporal courses of the at least one state variable by a tole margin can be increased or decreased and the reduced envelope can be used as the setpoint range.

Alternatively, the group of time courses of the at least a state variable can also be combined into a reference curve by, for example, by averaging. This so predetermined refer enzkurve can be provided with a tolerance field on both sides (± n-6), also serve as a state variable setpoint range.

According to a further preferred embodiment of the invention essen procedure, can then from the time course of at least a state variable by means of correlation calculation methods degree of temporal progression of the at least one state variable the predetermined reference curve is determined and as a function of the determination result of an assessment of the dosing process be issued. By using correlation calculation methods very precise comparisons of the time course of the at least one zu stand size possible with the predetermined reference curve. Moreover can be carried out by performing a correlation calculation method and by Hin establishing a reference curve for certain operating parameters of the Storage of the state variable setpoint range required storage space and that for comparison with a current state variable curve required computing time can be reduced. This can also be used to assess  dividing dosing run faster. The calculated correlation crude can serve as a quality indicator.

Known methods such as e.g. B. the fast Fourier transformation, polynomial regression, regression methods in space mean, wavelets and difference formation in question.

Correlation calculation methods of this type give the degree of agreement between two curves or point courses usually as numerical Value. The dosing process to be examined can, for example then be judged to be faulty if the determined match Degree of achievement outside a predetermined degree of conformity range of values. By comparing a numerical value with The result of the evaluation can in particular be in a predetermined value range be obtained quickly, given the fact that in industrial doses short available times of great importance action is.

Furthermore, an error that occurs when the over Degree of attunement as outside the predetermined correspondence degree setpoint range is recorded horizontally by a further Diagnostic comparison methods are examined in more detail. In particular this determines whether the degree of conformity is within an error range a plurality of error areas one out of match degree setpoint range lying degree of agreement value range lies. Depending on the area of error in which the match an error message is then issued. That’s it possible, a systematic error in the dosing system quickly and reliable detection and remedy. For example, in Try error areas within the overall match level Value range determined and this specific errors or error groups  assigned, which may result in a statement about it it is possible how critical the respective error is.

In order to be able to save further computing time and further storage space it is sufficient if the correlation calculation method is used as the input variable Bases from the time course of the at least one state size and used from the reference curve. With enough little The distance between the bases can be the computing time and the required Storage space can be significantly reduced without accuracy in the appraisal division result is lost.

In another aspect of the invention, the foregoing Task also solved by a device for assessing a Process of metering liquid in an at least partially with gas, preferably filled with air, using the previously be The method described, the device comprising: at least one Sensor for detecting the time course of the at least one zu stand size, a data memory for storing a predetermined State variable target range of state variables detected by the sensor evaluate and, if desired, the times of recording the individual state variable values, a data processing unit for comparison the time course of the at least one state variable with the previous one determined state variable setpoint range and an output unit for Output of an assessment result depending on the result the comparison by the data processing unit.

The at least one sensor is used to record the time profile of the at least one state variable. This acquisition can be continuous or at intervals of individual measurements take place, the distance between two individual measurements in comparison to the total duration of the liquid dosing process is small.  

The predetermined state variable setpoint range is in the data memory saved. Furthermore, the state variables detected by the sensor values stored in the data memory.

From a plurality of individual measurements, for example, one can temporal course are formed that one for each measurement one for the Dosing process characteristic machine or vessel state, at for example, the position of a movable piston relative to the rest Vessel, assigned. The position of the piston is at least during the Phase in which the piston is moved, equivalent to a point in time.

The device can also comprise a clock. If you can then, alternatively or in addition to the aforementioned machine states, also the points in time assigned to a state variable acquisition itself get saved. A storage of state variables together with the acquisition times assigned to them or these equivalents Machine status is necessary, for example, if the acquisition of Zu Stand size values by at least one sensor not constant Intervals. On the other hand, state quantity values are constant ten time intervals, so the storage of acquisition time points do not apply because the time of entry from the sequence position a state quantity value in a series of state quantity values is determinable.

Furthermore, the device comprises a data processing unit, which Data stored in the data memory for the comparison of the time course the at least one state variable with the state quantity setpoint values draws rich.

Finally, an output unit is used to output an evaluation result nisses, which depends on the result of the comparison by the Data processing unit is obtained. The output unit can be alphanu  meric characters and / or graphic elements, such as. B. colored or / and structured lines and / or areas, to output the assessment result nisses and, if desired, to show the time course of the Use the state variable and the state variable setpoint range.

In addition to the state variable setpoint range, in the data memory cher further stored a plurality of predetermined error ranges chert be, each error area at least one possible error of the Dosing process is assigned. This allows data processing unit or errors in the dosing process in question diagnose.

Furthermore, the device for creating the desired state variable area include an editing unit, for example, starting from a state from a bevy of temporal courses of state variables size setpoint range can be created.

For this purpose, the editing unit can have an input unit connected to it believe it. Numerical values can be entered using this input unit are entered, which define tolerance ranges around which one Envelope of the family of temporal courses compared to the family ver is widened or narrowed.

Alternatively or in addition, the output unit of the device be a graphical output unit, then via the input unit a state variable setpoint range can also be defined graphically can. This graphic process, in which, for example, the family of temporal courses of the state variable and a state quantity setpoints area is made visible together, represents a special simple, yet very effective way to get a to to create the standard size setpoint range. With the editing unit but also graphically from the bevy of temporal courses  a reference course or a reference curve are created. With bigger However, this can be done with accuracy using calculation methods.

According to the preferred embodiments of the The method according to the invention can be the data processing unit average whether the time course of the at least one state variable is internal is half of the predetermined state setpoint range. Alternatively or in addition to this, the data processing unit can also be designed for this be a correlation calculation method for determining a match Degree of the temporal course of the at least one state variable with a predetermined reference curve as a state variable setpoint perform richly. Then it is advantageous if in the data memory a predetermined degree of conformity setpoint range is stored, with which the determined degree of agreement can be compared. So can be determined whether the determined degree of agreement within of the predetermined degree of conformity setpoint range.

The previously mentioned error areas that are in the data memory Error diagnostics can be stored, for example, can match ranges of mood values. Then a certain area a certain error or a be agreed error group assigned.

At this point it should be expressly pointed out that the two mentioned preferred embodiments to increase the assessment safety combined on one and the same dosing process can be applied.

As has already been said, the method according to the invention for Assessment of a liquid dosing process with any vessels, any liquids and in any gas atmosphere be turned. The same applies to the device described above. Beson  However, this method is also suitable for pipetting processes, which is why the device according to the invention preferably on a pipetting system for The method according to the invention is preferably used Pipetting process assessed on a pipetting system.

It is conceivable that the method or the device in addition to a mere assessment in the case of a dosage judged to be incorrect Measures initiated or carried out. This includes, for example Stopping a certain dosing process replacing certain pipetting tips, discarding a dispensing z. B. Aspiration and repetition of this dosing process.

The present invention is described below with reference to the accompanying Drawings explained in more detail. They represent:

Fig. 1a-1e phases of a Aspirationsvorgangs pipetting,

Fig. 2 is a method of evaluating a Flüssigkeitsdosierungsvor transfer according to the prior art,

Fig. 3 is a graphical representation of a time course of the pressure of a peak in the fluid receiving space of a pipetting gas present in an aspiration and a Dispensationsvorgang, a state variable setpoint range in accordance with the first preferred embodiment of the invention, as well as the desired range of values surrounding the error ranges,

Fig. 4 is a flow chart describing the first preferred embodiment of the method according to the invention,

Fig. 5 is a diagram illustrating the occurrence of state variable setpoint value ranges of the preferred embodiments of the present invention.

Referring to Figs. 1a to 1e will be briefly described with reference to schematic Imaging Logo gene is a the embodiment of the present invention zugrundelie gender aspiration of a liquid during pipetting explained.

Fig. 1a shows a schematic cross section of a pipette tip 10 , which is moved in the direction of arrow 12 to the liquid level 14 a of a liquid 14 . In the liquid receiving space, a pressure detection sensor 22 is arranged, which detects the pressure of the gas present in the liquid receiving space 20 .

In Fig. 1b, the opening 10 a of the pipette tip 10 has reached the liquid mirror 14 a. Thereby, the pipette tip of the abge 10 separates known amount of gas from the ambient air in the liquid holding space 20 and is apart from evaporation and Kondensationsvor passageways substantially constant. The pipette tip 10 is further lowered in the direction of arrow 12 .

In Fig. 1c, the pipette tip 10 reaches its drop point and remains immersed with the opening 10 a in the liquid 14. The piston 16 is now moved in the direction of the arrow 18 . Due to friction and surface tension effects, no liquid has yet flowed into the liquid receiving space 20 .

In Fig. 1d is seen that the uptake of liquid 14 through the pipette tip 10 has already begun to pass through the opening 10 a. Then the piston 16 is no longer moved ( FIG. 1 d ′), so that the volume of the liquid receiving space 20 of the pipette tip 10 is not increased any further. Due to the negative pressure in the liquid receiving space 20 with respect to the environment, however, liquid 14 continues to flow into the liquid receiving space 20 until an equilibrium has been established.

In Fig. 1e the aspiration process has ended. The pipette tip 10 was lifted out of the liquid 14 . In the liquid receiving space 20 of the pipette tip 10 there is a certain volume of the liquid 14 , which is held there with respect to the environment by the negative pressure of the gas enclosed between the piston 16 and the liquid volume. In addition, friction and adhesion effects between the liquid volume and the wall of the pipette tip 10 also contribute to the liquid volume remaining in the pipette tip 10 .

In Fig. 2 is a pressure-time diagram of a method according to the prior art for assessing a liquid dosing process with 30 be distinguished. The time t is plotted on the abscissa of the diagram shown in FIG. 2 and the pressure p of the amount of gas present in the liquid receiving space 20 is plotted on the ordinate.

The liquid dosing process is assessed in such a way that it is determined whether the pressure-time curve is at least in sections Slope α reached, d. H. whether the gas pressure change rate at at least in one section a predetermined value proportional to tanα reached or / and whether the pressure in the liquid receiving space of the pipette peak falls below a predetermined limit p * during aspiration. Is close to the start of aspiration from the pressure-time diagram Period of time the gradient α reaches or / and the limit value p * is undershot the aspiration process is judged to be error-free. If one of the pre specified conditions are not met, the aspiration process is called misjudged.

In FIG. 3, in the time range A, the gas pressure in the liquid receiving space 20 of the pipetting tip 10 , which is detected by the pressure detection sensor 22 of FIGS. 1a to 1e during an aspiration process, is represented by the dotted line 40 . This time course of the pressure is plotted in a coordinate system. The time t is plotted on the abscissa and the pressure p of the gas in the liquid receiving space 20 is plotted on the ordinate.

A pressure setpoint value range 42 following a setpoint curve is also plotted in this coordinate system. Outside the pressure Sollwertebe Reich 42 are in this diagram, below the pressure Sollwertebe Reich 42 lying error ranges 44, 46 and 48 and the above the pressure set value range 42, ie, toward lying error ranges 50 to higher pressures, 52, 54, 56 and 58 .

In FIG. 3, time range A, the time profile 40 of the gas pressure lies within the entire definition range of the pressure setpoint range 42 , which is why the dosing process under consideration is judged to be error-free.

For a better understanding of the time profile 40 of the gas pressure in the liquid receiving space 20 of the pipette tip 10 from FIGS. 1a to 1e, the following is briefly explained:
The course begins at time t = 0 at ambient pressure p 0 . In the first section 40 a, the pressure remains constant. This corresponds to the state shown in Fig. 1a, in which the volume of the liquid receiving space 20 remains constant. Once the opening 10 a of the pipette tip 10 as shown in Fig. 1b, the liquid level 14 a reaches, there is currently first a slight pressure decrease due to adhesion at the contact of the liquid surface, which is then overlaid by increasing back pressure in the increasingly immersed pipette tip becomes. Both effects are comparatively small and are therefore not shown in FIG. 3.

At a time which corresponds to FIG. 1c, the piston 16 is moved upwards in the direction of the arrow 18 at a constant speed, with the result that the pressure drops drastically. This phase of the strong pressure drop represented by section 40 c ends at point 40 d, at which liquid begins to flow into the liquid space 20 of the pipette tip. In the area 40 e adjoining the point 40 d, a further increase in the gas volume of the gas volume enclosed in the liquid receiving space 20 caused by movement of the piston 16 is reduced by the liquid flowing into the liquid receiving space 20 , ie the rising piston is followed by a liquid interface. There is approximately a dynamic equilibrium between the gas volume increase caused by the piston and the gas volume reduction caused by the inflowing liquid.

The movement of the piston and thus the increase in the volume of the liquid receiving space ends at time t 1 at point 40 f ( FIG. 1d). The still present in the liquid holding space 20 under pressure of the gas with respect to the ambient gas of the pipette tip 10 also allows liquid in the liquid receiving space 20 flow in, whereby, as shown g in the section 40 rapidly reduces the volume of keitsaufnahmeraum in the liquid trapped amount of gas and its pressure correspondingly fast increases.

At point 40 h, the pipette tip 10 has already been removed from the liquid ( FIG. 1e). Shortly before, the flow of the liquid into the liquid receiving space 20 of the pipette tip 10 ends ( FIG. 1d '). At point 40 h, the amount of gas enclosed between the piston 16 and the liquid in the liquid receiving space 20 is under a negative pressure difference Δp, which is approximately proportional to the amount of liquid metered for sufficiently large amounts of liquid. With very small amounts of liquid, ie depending on the liquid in amounts less than about 30 µl, the friction and adhesion effects between the liquid and the wall of the pipette tip have such a strong effect that there is no direct proportionality between the negative pressure difference and the metered amount of liquid.

The individual error areas 44 , 46 , 48 , 50 , 52 , 54 , 56 and 58 are delimited from one another in terms of time and by pressure values or pressure value curves over time. The pressure setpoint range 40 is limited to lower pressures by the lower threshold curve 60 and to higher pressures by the upper threshold curve 62 . The lower and the upper threshold curve 60 , 62 are functions of the pressure as a function of time and can be set individually. The following errors can be assigned to the various error areas:
Error area 44 : defective pressure measurement
Defect area 46 : Pipette opening blocked,
Error range 48 : aspiration time too long,
Error range 50 : defective pressure measurement
Error area 52 : Aspiration and dispensation mixed up and pipette opening is blocked,
Error area 54 : pipette tip is leaking,
Error area 56 : Aspiration process interrupted or air bubbles in the liquid,
Error range 58 : too little or no liquid in the pipette tip.

In the time domain B of FIG. 3, the time course of the gas pressure, the pressure setpoint range, as well as the pressure setpoint range surrounding defect areas depicted in Dispensationsvorgang. The dispensing process can, for example, then proceed to the previously described aspiration process. following a transport process in between (time range C). The same elements as in section A of the aspiration process are seen in section B of the dispensing process with the same, but apostrophied, reference numerals. The error areas in time period B are numbered in such a way that the areas with a corresponding error assignment are identified by the same, but apostrophic, reference symbol. With 40 'i the pressure at the time of the last drop of liquid is designated and with 40'k the equilibrium pressure which arises after the piston has come to a standstill and which arises from the ambient pressure P 0 .

The following assignment of error messages and error areas applies:
Error range 46 ': pipetting opening clogged,
Error range 48 ': dispensing time too long,
Error area 52 ': aspiration and dispensation confused,
Error range 56 ': Pipette tip or pipette system is leaking.

The use of the error areas is to be understood as follows: If, for example, the pipetting opening is blocked during a dispensing, the liquid in the pipetting tip cannot or only to a limited extent escape from the pipetting tip. Due to the push-out movement of the plunger during dispensing, by means of which the volume of the liquid receiving space of the pipette tip is reduced, the gas volume enclosed in the pipette tip is compressed. This increases the gas pressure. The result of this is that the time course of the pressure leaves the target value range 42 'when its upper threshold value 62 ' is exceeded and thereby enters the error range 46 '. This is represented by the dashed line 41 'in period B in Fig. 3 Darge. In this way, not only can it be reliably recognized that an error has occurred during the liquid metering process, but the error can also be diagnosed.

Pressure monitoring can also take place in the meantime with an allowable pressure setpoint range 42 "which is slightly increased upwards and downwards to take into account permissible pressure fluctuations during transport, particularly in the case of jerky movement. If the pressure exceeds the setpoint range (error range 70 ) or falls below the setpoint range (Error area 72 ), an error is detected.

In FIG. 4 is a flow chart shows the flow of judgment is shown a liquid dosing process. The pipetting process begins at step S1, for example the aspiration process known from time segment A in FIG. 3. At the start of Flüssigkeitsdosierungsvor gangs which are relevant for the process parameters are initialized, that is, a clock is set to zero and started, by a Druckerfas sungssensor to a detection timing t erf detected pressure P erf is set to zero, as is the acquisition time t erf. Furthermore, a flag F_KI, which in the event of an error indicates whether the pressure setpoint range has been left for higher or lower pressure values, is set to zero. The Uhrmax value, which indicates the duration of the liquid dosing process, is loaded.

In the next step S2, the pressure of the gas present in the liquid receiving space is detected and the current value of the clock is loaded into the variable t erf of the time of detection. The pressure p measured at the time t erf is loaded into the variable p erf , ie the pressure detection was carried out at the time t erf .

In the following step S3, the threshold values assigned to the respective acquisition time t erf are loaded from a memory. In this case, USW denotes the lower threshold value of the pressure setpoint value range (ie the value of the lower threshold curve 60 at time t erf of FIG. 3), OSW the upper threshold value. SW 1 to SW n denote the threshold values that separate the individual fault areas. If, for example, the pressure detection is carried out at the time t erf identified by line 64 in FIG. 3, point SW 1 is the threshold value separating the error area 56 from the error area 54 and point SW 2 is the threshold value separating the error area 54 from the error area 52 . The value n indicates the maximum number of threshold values lying between two error ranges. In the example shown in FIG. 3, n = 2.

In the next step S4, it is checked whether the detected pressure p erf is equal to or greater than the lower threshold value USW, which limits the pressure setpoint value range for smaller pressure values. If this is the case, it is checked in the subsequent step S5 whether the detected pressure p erf is less than or the same size as the upper threshold value OSW which limits the pressure setpoint value range for larger pressure values. If this is also the case, it is output in a subsequent step S6 that the process is running correctly.

Step S7 represents a waiting loop, which is another print acquisition only possible if the period of time has elapsed since the last time the pressure was recorded Δt has passed.

In step S8 it is checked whether the time limit Uhrmax for the dosing process is reached or not. If the time limit is reached, the If not, the process returns to step S2 and thus to a new one Detection of the gas pressure in the liquid intake space of the pipette point back.

If it is determined in step S4 that the detected pressure p erf is lower than the lower threshold value USW, ie the time curve of the gas pressure leaves the pressure setpoint range toward lower pressure values, the flag F_KI becomes the value 1 in step S9 set. In the following step S10, the run variable k = 1 is set. If the time course of the pressure value leaves the pressure setpoint range towards higher pressure values, ie if it is determined in step S5 that the detected pressure p erf is greater than the upper threshold value OSW, step S10 is also reached, but the flag F_KI remains on its initialization value zero.

After it has already been determined that an error has occurred in the liquid metering process, this is diagnosed in the steps described below. The following convention applies: At least one error message is assigned to each error area. The error messages are defined as a one-dimensional field (= vector), with the individual entries error message (x) in the error message field being assigned to the error areas in the direction of increasing pressure, i.e. error message (0) is error area 46 , error message ( 1 ) is error area 56 , error message ( 2 ) is assigned to error area 54 and error message ( 3 ) is assigned to error area 52 . Accordingly, the one-dimensional error message field contains different numbers of entries depending on the number of error areas present at a certain point in time.

In step S11 it is now determined whether the detected pressure p erf is greater than the kth threshold value. If this is the case, the running variable k is increased by one in step S12 and a check is carried out in step S13 to determine whether k already exceeds the maximum number n of threshold values assigned from time t erf . If k does not yet exceed the number n, the step S11 is checked again, but with a run variable increased by one.

However, if k exceeds the value n after the increase by one, the checked pressure value must lie in the error range with the highest pressure value range and in step S14 the error message (k), ie error message ( 3 ) of error area 52 in the present example, output.

If the check in step S11 shows that the detected pressure p erf does not exceed the threshold value SW K , then in step S15 it is checked whether the flag F_KI has the value 1, ie whether the pressure over time leads to higher or lower pressure values has broken out of the pressure setpoint range. If the flag F_KI has the value zero, ie if the pressure setpoint range has been left for higher pressure values, the error message (k) is output. If the check in step S15 reveals, however, that the value of the flag F_KI has the value 1, ie the pressure over time has left the pressure setpoint range for lower pressure values, the error message (k-1) is generated in step S16. output. In this example, after the error message has been issued, the process jumps to the waiting loop of step S7. However, it is also possible for another process to follow the output of an error message, for example an emergency stop of a pipetting system or a replacement of a pipetting tip. However, it is often interesting to monitor the chronological course of the detected state variable until the end of the metering process even in the event of an incorrect metering process, since the chronological course of the at least one state variable can possibly reach several error ranges.

The device in which the method according to the invention runs can for example an electronic data processing system, in particular a personal computer or process-controlling microcontroller. This Data processing system with at least one sensor on the pipette connected to the temporal course of at least one state size, for example the pressure. The data storage can a hard disk, a CD-ROM, an internal RAM memory or a memory of a PC connected to the microcontroller. at for example, the state variable setpoint range can be stored on a CD-ROM be saved. The CPU of the data processing system forms the data processing unit, and a screen or a printer turns off unit of the device. The CPU can also be an editing unit form, the data processing system then performing a  Editing the state variable setpoint range using a keyboard or Includes mouse or the like as an input unit.

The evaluation of the state variable measurements accompanying the dosing process solution can, for example, correspond to that described above Flow chart take place in which a numerical exit of the momenta NEN measured value from the tolerance range is detected. One is also conceivable graphic evaluation (e.g. pattern recognition technique) to determine whether and where the tolerance band is left by the current measurement curve.

FIG. 5 shows the establishment of state variable setpoint ranges for the preferred embodiments of the invention. In FIG. 5a, a statistically significant group 70 of pressure-time profiles is shown in a pressure-time diagram (the time is plotted on the abscissa, the pressure is plotted on the ordinate), which is based on one of identical operating parameter settings with identical operating means performed dosing were measured. In Fig. 5b, a state variable setpoint range or pressure setpoint range 142 is shown for. B. is limited by envelope of the blade 70 of Fig. 5a to higher and lower pressure values. In contrast, a reference curve 242 is shown in Fig. 5c, which results from the group 70, for example, by averaging.

This reference curve 242 can be determined by correlation calculation methods such as e.g. B. spectral analysis method, preferably Fast Fourier Transformation or / and Wavelets method and / or numerical convolution, can be compared with a currently measured pressure-time curve, which was measured during a metering process to be assessed. Depending on the resulting degree of agreement, the quality of the respective dosing process can be assessed (Numerical Mathematics, HR Schwarz, Teubner Verlag Stuttgart; "Engineer Analysis" 1 and 2 Christian Blatter, Springer Verlag 1996).

The degree of agreement is usually a number that normalizes in this way will have a value between 0 and 1, where 1 is the value for is identical match. A degree of compliance setpoint rich, for example ranging from 0.9 to 1, indicates the range of values for whose degree of agreement values a dosing process as error-free is judged. In a range of values from, for example, 0.4 to 0.9 a questionable quality of the pipetting is assumed, whereby in The individual case has to be decided whether the pipetting should be discarded or not In the remaining value range (in the example: 0 to 0.4), a serious one Incorrect pipetting detected.

Claims (25)

1. A method for assessing a liquid dosing process in a vessel which is at least partially filled with a gas, preferably with air, in particular an aspiration and / or dispensing process during pipetting, in which method a time course of at least one state variable (p) one in the vessel existing medium is recorded essentially over the entire duration of the dosing process, during which the essentially entire time profile ( 40 ; 40 '; 40 ") of the at least one state variable (p) with a predetermined state quantity target value range ( 42 ; 42 '; 242 ) is compared, and with which, depending on the comparison result, an evaluation result (S6, S14, S16) is output.
2. The method according to claim 1, characterized in that the Medium is the gas present in the vessel.
3. The method according to claim 1 or 2, characterized in that the state variable of the pressure (p) and / or the temperature of the medium is over.
4. The method according to any one of the preceding claims, characterized in that the state variable setpoint range ( 42 ; 42 '; 242 ) is defined at least for the entire duration of the liquid metering process, preferably also for the duration of an interim transport process.
5. The method according to any one of the preceding claims, characterized in that the state variable setpoint range ( 42 ; 42 '; 242 ) of a liquid dosing process on a plurality of bushings ( 70 ) of the substantially same liquid dosing process using the substantially same process parameters based.
6. The method according to any one of claims 1 to 5, characterized in that the predetermined state variable target value range ( 42 ; 42 ') follows a target curve, and that it is determined whether the time profile ( 40 ; 40 ') of the at least one state variable (p) lies within the predetermined state variable target value range ( 42 ; 42 ') following a target curve, and that, depending on the result of the determination, an assessment result (S6, S14, S16) is output.
7. The method according to claim 6, characterized in that the liquid dosing process is judged to be faulty if it is determined that the recorded time profile ( 40 ; 40 ') of the at least one state variable (p) at least in sections outside the state quantity setpoint range ( 42 ; 42 ').
8. The method according to claim 6 or 7, characterized in that when the time profile ( 40 ; 40 ') of the at least one state variable (p) lies at least in sections outside the state variable setpoint range ( 42 ; 42 ') is determined whether the course of the at least one state variable (p) at least in sections in at least one error area from a plurality of error areas ( 44 , 46 , 48 , 50 , 52 , 54 , 56 , 58 ; 46 ', 48 ', 52 ', 56 ') of a state variable value range lying outside the state variable target value range ( 42 ; 42 '), and an error message is output as a function of the at least one error range ( 46 ') which has been passed through.
9. The method according to any one of claims 6 to 8, characterized in that the determination of whether the temporal course of the at least one state variable (p) lies within the predetermined state size setpoint range ( 42 ; 42 ') by comparing the course ( 40 ; 40 ') with an upper threshold curve ( 62 ; 62 ') which limits the state variable setpoint range ( 42 ; 42 ') to larger state variable values and with an upper threshold curve which limits the state variable setpoint range to smaller state variable values limit the lower threshold curve ( 60 ; 60 ') is carried out.
10. The method according to claim 6 or 7, characterized in that the determination as to whether the temporal profile ( 40 ; 40 ') of the at least one state variable (p) lies within the predetermined state quantity target value range ( 42 ; 42 '), by image processing tion is carried out.
11. The method according to any one of claims 1 to 5, characterized in that by means of correlation computing a degree of correspondence of the time course of the at least one state variable (p) with a predetermined reference curve ( 242 ) is determined as the state variable setpoint range ( 142 ), and that Depending on the result of the determination, an assessment result is output.
12. The method according to claim 11, characterized in that the Degree of agreement as a result of the determination a numerical value where the liquid dosing process is judged to be faulty, if the degree of conformity is outside a predetermined Degree of conformity setpoint range.
13. The method according to any one of claims 11 and 12, characterized records that if the degree of match is outside of the predetermined degree of conformity setpoint range  is detected, it is determined whether the degree of conformity in a Defect area from a plurality of defect areas except one half of the match target range mood level range of values, and that depending on the area of error in which the degree of agreement lies, one Error message is issued.
14. The method according to any one of claims 11 to 13, characterized records that the correlation calculation method as an input variable Bases from the time course of the at least one Zu stand size (p) and from the reference curve.
15. A device for assessing a process of a liquid dosage in an at least partially filled with gas, preferably air, using the method according to one of the preceding claims, wherein the device comprises:
at least one sensor for detecting the time profile ( 40 ; 40 ') of at least one state variable (p),
a data memory for storing a predetermined state variable target value range ( 42 ; 42 '; 242 ) and for storing state variable values (p) detected by the sensor,
a data processing unit for comparing the time profile ( 40 ; 40 ') of the at least one state variable (p) with the predetermined state variable setpoint range ( 42 ; 42 '),
an output unit for outputting a judgment result (S6, S14, S16) depending on the result of the comparison by the data processing unit.
16. The apparatus according to claim 15, characterized in that a plurality of predetermined error ranges ( 44 , 46 , 48 , 50 , 52 , 54 , 56 , 58 ; 46 ', 48 ', 52 ', 56 ') are also stored in the data memory , with each error range ( 44 , 46 , 48 , 50 , 52 , 54 , 56 , 58 ; 46 ', 48 ', 52 ', 56 ') being assigned at least one possible error in the dosing process.
17. Device according to one of claims 15 and 16, characterized records that the device continues to an editing unit for Er Position of the state variable setpoint range includes.
18. The apparatus according to claim 17, characterized in that the Device an input unit connected to the editing unit includes.
19. The apparatus according to claim 18, characterized in that the Output unit is a graphic output unit, and that about the input unit graphically represents a state variable setpoint range is definable.
20. Device according to one of claims 15 to 19, characterized in that the data processing unit determines whether the temporal course ( 40 ; 40 ') of the at least one state variable (p) within the predetermined state variable setpoint value range ( 42 ; 42 ' ) lies.
21. The device according to one of claims 15 to 19, characterized in that the data processing unit carries out a correlation calculation to determine a degree of correspondence between the time course of the at least one state variable and a predetermined reference curve ( 242 ) as a state variable setpoint range ( 142 ) ,
22. The apparatus according to claim 21, characterized in that in the data memory a predetermined degree of conformity value range is saved.
23. The device according to claim 21 and 22, characterized in that that the data processing unit determines whether the match degree of compliance within the predetermined degree of agreement Setpoint range.
24. Pipetting system with an assessment device according to one of the Claims 15 to 23.
25. Pipetting system, in which a pipetting process by a method is assessed according to one or more of claims 1 to 14.
DE2001148608 2001-03-09 2001-10-02 Method and device for assessing a liquid dosing process Withdrawn DE10148608A1 (en)

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DE10111423 2001-03-09
DE2001148608 DE10148608A1 (en) 2001-03-09 2001-10-02 Method and device for assessing a liquid dosing process

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
DE2001148608 DE10148608A1 (en) 2001-03-09 2001-10-02 Method and device for assessing a liquid dosing process
EP20020727371 EP1412759B1 (en) 2001-03-09 2002-03-07 Method and device for evaluating a liquid dosing process
AT02727371T AT313805T (en) 2001-03-09 2002-03-07 Method and device for assessing a liquid dosage process
DE2002505365 DE50205365D1 (en) 2001-03-09 2002-03-07 Method and device for assessing a liquid dosage process
US10/471,242 US6938504B2 (en) 2001-03-09 2002-03-07 Method and device for evaluating a liquid dosing process
PCT/EP2002/002521 WO2002073215A2 (en) 2001-03-09 2002-03-07 Method and device for evaluating a liquid dosing process
JP2002572425A JP4328531B2 (en) 2001-03-09 2002-03-07 Method and apparatus for evaluating process of dispensing predetermined amount of liquid
ES02727371T ES2250644T3 (en) 2001-03-09 2002-03-07 Procedure and device for evaluating a liquid dosage process.
HK04108465A HK1067407A1 (en) 2001-03-09 2004-10-28 Method and device for evaluating a liquid dosing process

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2525231A1 (en) 2011-05-16 2012-11-21 Brinkhaus Management GmbH Method and device for monitoring a liquid metering procedure using cylinder stroke pipettes
DE102012209314A1 (en) * 2012-06-01 2013-12-05 Albert-Ludwigs-Universität Freiburg Device and method for dispensing or receiving a liquid volume

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2525231A1 (en) 2011-05-16 2012-11-21 Brinkhaus Management GmbH Method and device for monitoring a liquid metering procedure using cylinder stroke pipettes
WO2012156492A1 (en) 2011-05-16 2012-11-22 Ymatron Ag Device and method for monitoring a liquid metering process in piston-stroke pipettes
DE102012209314A1 (en) * 2012-06-01 2013-12-05 Albert-Ludwigs-Universität Freiburg Device and method for dispensing or receiving a liquid volume
DE102012209314B4 (en) * 2012-06-01 2015-04-02 Albert-Ludwigs-Universität Freiburg Device and method for dispensing or receiving a liquid volume
US9459128B2 (en) 2012-06-01 2016-10-04 Hahn-Schickard-Gesellschaft Fuer Angewandte Forschung E.V. Device and method for dispensing or receiving a liquid volume

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