JPH1123549A - Liquid chromatograph with liquid leakage detecting mechanism - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a liquid chromatograph with high reproducibility and reliability by measuring the passing quantity of a liquid on the suction side of a liquid feed pump and on the foul solution side of a detector. SOLUTION: A mobile phase 2 in a solvent sump 1 is introduced into a first liquid meter 6 located at the lower position via a solenoid valve 4 by gravitational force. When the mobile phase 2 is accumulated to the height of the sensor at the uppermost section of the liquid meter 6, the solenoid valve 4 is closed, and a liquid feed pump 8 is started to suck the mobile phase 2. The decrease of the liquid level height of the liquid meter 6 is detected by the sensors provided in the vertical direction in sequence, and the liquid flow on the suction side of the liquid feed pump 8 is detected based on the time from the start of the liquid feed pump 8 to the outputs of the sensors. A passage from a three-way joint 16 to a foul solution sump through solenoid valves 26, 29 and a passage to the foul solution sump through the second liquid meters 20, 33 are provided, and the liquid flow on the foul solution side of a detector 14 is continuously detected. Both flows are compared, and a liquid leakage and a defect of the liquid feed pump 8 can be easily detected.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a liquid chromatographic apparatus, and more particularly, to a liquid chromatograph system in which a liquid flow rate in a liquid chromatographic system is compared by comparing a suction liquid amount of a liquid supply pump and a liquid discharge amount from a detector. The present invention relates to a liquid chromatograph apparatus which keeps constant or detects and warns a liquid leak in a liquid chromatograph system.

[0002]

2. Description of the Related Art Liquid chromatographs have been frequently used for qualitative / quantitative analysis of trace components. However, liquid chromatographs are used for liquid reservoirs for mobile phases, liquid sending pumps, separation columns, detectors, and pipes for communicating these components. The flow rate of the liquid flowing in the liquid chromatograph system thus constituted only depends on the setting of the liquid sending amount by the liquid sending pump.

[0003]

However, there is no guarantee that the set flow rate of the feed pump and the flow rate of the liquid in the system actually match. In particular, for example, when a problem occurs in the liquid feed pump and the liquid flow rate changes, there is a concern that measurement may be performed at an unexpected liquid flow rate because the problem cannot be detected immediately.

In particular, in a liquid chromatograph, the qualitativeness of an unknown component in an unknown sample is often determined by the elution time of a known component in a standard sample and those peaks, that is, whether or not the elution volume coincides. Therefore, when the liquid flow rate in the liquid chromatograph system changes, reproducibility is deteriorated, and there is a risk that erroneous qualification may be performed.

[0005] Rarely, a liquid flow meter is installed after the detector,
Although the waste liquid flow rate may be measured, even if a decrease in the flow rate value is detected in the liquid chromatograph device having such a configuration, whether the set liquid flow rate has not been achieved due to a failure in the liquid feed pump, or for example, It is difficult to determine whether the measured flow rate value has decreased due to the occurrence of a liquid leak in the liquid chromatograph system. In order to facilitate this determination, for example, it is conceivable to attach a liquid leak detector to a place where liquid leakage is likely to occur, but in a complicated liquid chromatograph system, it is necessary to attach a large number of sensors, and in practice, Not valid.

Accordingly, it is an object of the present invention to provide a liquid balance in a liquid chromatograph system,
That is, by monitoring the difference between the liquid flow rate on the suction side of the liquid feed pump and the liquid flow rate on the waste liquid side of the detector, a change in the liquid flow rate due to a malfunction of the liquid feed pump and a liquid leak in the liquid chromatograph system can be immediately detected. An object of the present invention is to provide a liquid chromatograph device which detects, reproduces, and has high reliability.

[0007]

A liquid chromatograph apparatus according to the present invention, which has been made to solve the above problems, has a separation column and a detector, and supplies a liquid to the separation column by a liquid feed pump. In the apparatus, a first side and a second side capable of measuring a liquid passing amount are respectively provided on a suction side of the liquid sending pump and a waste liquid side of the detector.
Is a liquid chromatograph apparatus provided with the liquid measuring means of (1). Here, the first and second liquid measuring means include, for example, a liquid reservoir and a sensor for measuring the liquid level in the liquid reservoir. In addition to the above configuration, the control means for calculating the liquid flow rate on the suction side of the liquid feed pump and the liquid flow rate on the waste liquid side of the detector from the liquid passing amount measured by the first and second liquid measuring means is provided. The provided liquid chromatograph apparatus is preferable because the control means can automatically calculate the liquid flow rate in the system.

Further, the control means detects the calculated liquid flow rate on the suction side of the liquid feed pump, the liquid flow rate on the waste liquid side of the detector, or a difference between these, and based on the values set in advance. If the calculated tolerance is exceeded,
A function to stop the liquid chromatograph apparatus and issue a warning and / or a liquid leak warning in the liquid chromatograph system, a calculated liquid flow rate at the suction side of the liquid supply pump, a calculated liquid flow rate at the waste side of the detector, or If these differences are detected, and if they exceed an allowable range calculated based on a value set in advance, the amount of liquid sent by the liquid sending pump in the liquid chromatograph apparatus is increased or decreased to reduce the difference to the allowable range. Provide a liquid chromatograph device that can automatically perform liquid chromatography with improved reproducibility by adding a function to provide feedback inside the liquid chromatograph, and can quickly respond to problems such as liquid leakage. can do. Here, the value set in advance is, for example, to detect a malfunction of the liquid feed pump, preferably a set value of the liquid feed amount of the liquid feed pump in the liquid chromatograph device, and to detect a liquid leak. Is preferably zero.

The liquid chromatograph of the present invention includes at least a separation column, a detector, and first and second liquid measuring means for a liquid sending pump. The first liquid measuring means is disposed on a suction side of the liquid sending pump, that is, in a pipe from the liquid reservoir to the liquid sending pump when, for example, the liquid chromatograph apparatus has a liquid reservoir for a mobile phase. Is preferred. The second liquid measuring means is disposed on a waste liquid side of the detector, that is, on a pipe extending from the detector to the waste liquid reservoir when, for example, the liquid chromatograph device includes a waste liquid reservoir that has been detected by the liquid chromatograph device. Is preferred. The first liquid measuring means may be installed between the liquid sending pump and the inlet for injecting the sample to measure the amount of liquid discharged from the liquid sending pump. This is because the measurement result may change depending on the degree of compression and the liquid property in the compressed state. The second liquid measuring means may be installed between the separation column and the detecting means to measure the amount of eluate from the separation column. However, the second liquid measuring means measures the liquid passing amount. Due to the minimum volume (dead volume) required for the separation, a part of the components separated by the separation column may not be provided to the detection means, which may deteriorate the separation ability.

[0010] The separation column, detector, liquid feed pump and the like are not particularly limited as long as they are used in a usual liquid chromatograph.

Examples of the separation column include columns packed with various packing materials for liquid chromatography such as size exclusion chromatography, ion exchange, reverse phase chromatography, affinity chromatography and the like. In this specification, for convenience, a separation column is described, but the content is not limited to a separation column, and may be, for example, an adsorption column, a guard column, a sample concentration column, or the like. Further, two or more columns may be arranged in series.

The detector may be appropriately selected in relation to components in a sample to be qualitatively and quantitatively measured by a liquid chromatograph. For example, an absorbance detector, a fluorescence detector, a light emission detector, a transmitted light detector and the like can be exemplified. In addition, a part of the pipe in the liquid chromatograph is configured as a so-called flow cell for detection by the detector. That is, the eluate eluted from the separation column is guided to a flow cell configured as a part of a pipe, and detection is performed while flowing the eluate. Therefore, the flow cell in the present specification may be, for example, one in which a part of a pipe is formed of a transparent or translucent member, or a normal flow cell.

The liquid feed pump may be, for example, a pump using a piston or a syringe, but may be a peristaltic pump, for example.

The liquid measuring means in the present invention is not limited as long as it can measure the amount of liquid passing therethrough. Above all, a liquid measuring means composed of a liquid reservoir and a sensor for measuring the liquid level in the liquid reservoir is preferable because it can measure a liquid passing amount relatively accurately with a simple configuration. . More specifically, for example, as shown in FIG. 2, a part of the side wall has a cylindrical part having a known capacity formed of a transparent member, and an optical sensor is attached to the transparent part at regular intervals. Examples can be given. According to this liquid measuring means, it is possible to measure whether or not the liquid is detected by each sensor, that is, the liquid level in the liquid reservoir. Therefore, by arranging a control means to be described later and measuring the time required until an output signal is obtained from each of these sensors, and associating with which sensor the output signal was obtained, the liquid flow rate per unit time can be obtained. It becomes possible to know. Needless to say, the first and second liquid measuring means may include the time measuring means, and the liquid flow rate may be displayed only continuously or intermittently, for example. In a configuration in which the control means is preferably disposed, the flow rate of the liquid sent from the liquid reservoir or the like to the liquid chromatograph system can be known by the first liquid measurement means and the control means, and the detection can be performed by the second liquid measurement means and the control means. Of the liquid that is drained out of the liquid chromatograph system after the
By calculating the liquid flow rate detected by the second liquid measuring means and the difference between them, it is possible to immediately detect a liquid leak or the like in the liquid chromatograph system. That is, when a liquid leak occurs in the liquid chromatograph system, a large change does not usually appear in the liquid flow rate calculated by the first liquid measuring means and the control means, but is calculated by the second liquid measuring means and the control means. Only the liquid flow rate is reduced. On the other hand, when a malfunction occurs in the liquid feed pump, the flow rates of both liquids increase and decrease similarly.

As the control means for calculating the liquid flow rate from the measurement result of the liquid measuring means described above and comparing the two liquid flow rates, for example, a microchip or a commercially available computer can be used. For example, when obtaining the difference between the two liquid flow rates, the process as shown in FIG. 4 may be performed.

The liquid flow rate and the difference between the two liquid flow rates (or the magnitude of the difference, that is, the absolute value) are constant or zero in an ideal state, but the first and second liquids such as a mobile phase are used. Differences in the time required to reach the liquid measurement means, the size of the pipe inner diameter in the liquid chromatograph system,
It increases or decreases depending on slight fluctuations in the liquid feed rate due to elasticity or pulsation in the liquid feed pump. Therefore, the control means sets an allowable range based on a value set in advance, and detects whether the magnitude of the liquid flow rate or the difference between the two liquid flow rates belongs to the allowable range. Is preferred. For example, it is possible to exemplify the use of a liquid sending amount set value of a liquid sending pump as a value set in advance. The permissible range itself can be calculated, for example, by adding a constant value to the liquid supply amount set value of the liquid supply pump as a reference or subtracting a constant value, but the specific value to be added or subtracted is a value of the liquid chromatograph device. Since the value is unique to the device depending on the performance of the liquid feed pump, the elasticity of the piping, and the like, it is preferable to set the value empirically by conducting a preliminary experiment. Thereby, the liquid flow rate on the suction side of the liquid sending pump and the waste liquid side of the detector is
If the difference does not change significantly, but exceeds the allowable range, it can be determined that there is a problem with the liquid feed pump.On the other hand, if the difference exceeds the allowable range, a liquid leak has occurred. I can judge. Note that the allowable range is
A range for the liquid flow rate on the suction side of the liquid sending pump and a waste liquid side of the detector and an allowable range for the difference between the two liquid flow rates may be separately determined.

As described above, in the liquid chromatograph apparatus of the present invention preferably provided with the control means, the difference between the values detected by the first and second liquid measuring means in the control means, for example, falls within the allowable range. In case of exceeding, etc., a function to output a signal to stop the liquid chromatograph device, especially the liquid feed pump, or to warn that a problem has occurred in the liquid pump or liquid leak has occurred in the liquid chromatograph system May be added. As described above, the malfunction of the liquid feed pump and the occurrence of liquid leakage in the liquid chromatograph system can be detected by calculating the liquid flow rate and / or the difference between the two liquid flow rates. An output signal may be determined in advance, and display according to the signal may be performed. Thus, if any of these problems occurs during the execution of liquid chromatography, the cause can be quickly known.

In addition to the above-mentioned display function, the control means may be provided with, for example, a function of controlling a liquid feed pump in a liquid chromatograph apparatus.
Note that these functions described above may be added simultaneously. Specifically, for example, when a liquid leak in the liquid chromatograph system is detected, a warning of the liquid leak is displayed, and the influence of the liquid leak is minimized by increasing the liquid supply amount. For example, it is possible to exemplify a control for increasing the liquid sending amount of the liquid sending pump. Further, for example, when a problem occurs in the liquid feed pump and the amount of liquid supply fluctuates, feedback control for increasing or decreasing the amount of liquid supply so as to minimize the fluctuation can be exemplified.

[0019]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in more detail with reference to the drawings.

FIG. 1 shows an outline of a liquid chromatography apparatus according to the present invention. The mobile phase 2 in the mobile phase solution reservoir 1 is introduced via a pipe 3 and an electromagnetic valve 4 into the first liquid measuring means 6 arranged at a lower level than the liquid reservoir 1 by gravity. As shown in FIG. 2, the first liquid measuring means 6 includes a liquid measuring tube 42 having a known capacity, and a plurality of liquid level measuring light sources 4.
3. It is composed of a plurality of liquid level measuring sensors 44. When the liquid is guided from the solvent reservoir to the liquid measuring tube 42, the light intensity applied to the sensor 44 changes due to refraction, and the liquid surface position in the liquid measuring tube 42 can be detected. Although FIG. 2 illustrates seven light sources and seven sensors, it is possible to perform more accurate liquid level detection by increasing the number of light sources and sensors and shortening the distance between the sensors. .

When the control means (not shown) detects that the mobile phase has been accumulated to the detection height of the sensor located at the uppermost part of the first liquid measuring means 6, the control means closes the electromagnetic valve 4, The liquid feed pump 8 is started. As a result, the mobile phase is sucked into the liquid sending pump via the pipe 7, but at the same time, the liquid level height in the first liquid measuring means decreases and is sequentially detected by the sensor provided in the vertical direction. The control means is configured to control the liquid feed pump based on the time from the start of the liquid feed pump and the output signal from the sensor, or based on the time from when the liquid level is detected by one sensor to when the liquid level is detected by another sensor. Detect the liquid flow rate on the suction side.

The mobile phase sucked by the liquid sending pump 8 is sent to the separation column 12 via the pipe 9, the sample inlet 10, and the pipe 11. The eluate from the separation column 12 is supplied to the pipe 1
3. Through a detector (flow cell) 14 and a pipe 15, a three-way joint 16 is reached.

In the apparatus of this embodiment, the pipe 25 and the electromagnetic valve 2 are connected to the three-way joint as a normal waste liquid flow path system.
6, a path from the waste liquid pipe 38 to the waste liquid reservoir via the pipe 28 and the electromagnetic valve 29, and a path to the waste liquid reservoir via the second liquid measuring means. In this example, the liquid measuring means as shown in FIG.
So that the liquid flow rate on the waste liquid side of the detector can be continuously detected. That is, in the first path, the electromagnetic valve 26 is switched to the hermetic plug 27 side, the flow path between the pipes 25 and 28 is closed, and the eluate that has passed through the three-way joint 16 passes through the pipe 17, the electromagnetic valve 18, and the pipe 19. After that, it is led to the second liquid measuring means 20. The electromagnetic valve 18, the pipe 21, the electromagnetic valve 22, the hermetic plug 23, and the pipe 24 are flow paths for discharging the liquid in the second liquid measuring means 20, and discharge the liquid using the flow path. During this time, the liquid flow rate can be detected using the other second liquid measuring means 33. The switching between the two second liquid measuring means (20, 33) is realized by switching the electromagnetic valves 26, 29 by control means (not shown). Electromagnetic valve 31, piping 34, electromagnetic valve 35,
The hermetic plug 36 and the pipe 37 are flow paths for discharging the liquid in the second liquid measuring means 33.

In this embodiment, only the second liquid measuring means disposed on the waste liquid side of the detecting means has been described as being provided with two means. However, it is needless to say that two first liquid measuring means are provided. It may be arranged.

FIG. 3 is a diagram showing the relationship between the control means and the liquid measuring means. FIG. 4 is a diagram showing a flow of liquid leak detection and the like. An output signal relating to the liquid level from the liquid measuring means 6, 20 (or 33) is output from the CP in the control means.
The signal is sent to U39 as a periodic signal having a period of, for example, 10 seconds. The CPU 39 that has received the signal calculates the liquid flow rate on the suction side of the liquid feed pump and the waste liquid side of the detection means from the signal, as shown in FIG. For example, assuming that the liquid level height of the first liquid measuring means 6 at time t1 is h1 and the liquid level height at time t2 is h2, the amount of liquid sucked by the liquid sending pump at time t2-t1 is h1. It corresponds to a height of -h2 minutes. Therefore, when the liquid measuring means has a columnar shape such as a columnar shape, the liquid flow rate f1 during the period of t2-t1 is (h1-h2).
× Cross-sectional area / (t2-t1).

Similarly, the liquid measuring means 20 at time t1
Assuming that the liquid level height in (or 33) is h3 and the liquid level height at time t2 is h4, the amount of liquid discharged from the detection means at time t2 to t1 corresponds to a height of h4 to h3. Therefore, when the liquid measuring means has a columnar shape such as a cylindrical shape, t2-
The liquid flow rate f2 at time t1 is (h3-h4) × cross-sectional area /
It can be calculated by (t2-t1).

If the values of f1 and f2 calculated as described above are equal or if there is a difference, if the difference is small within an allowable range, there is no liquid leakage or the like in the liquid chromatography system. I can judge. The calculated value of f1 is f
If it is smaller than 2, it is determined that a liquid leak has occurred in the liquid chromatograph system, and a warning of the liquid leak is displayed. In an ideal state, since the numerical values of f1 and f2 are equal, it is possible to exemplify that zero is set in advance as a reference value.

Apart from the above calculation process, the CPU 39
Then, the suction flow rate f1 of the liquid sending pump per unit time and the waste flow rate f2 from the detection means are calculated by the flow rate F per minute.
1 and F2, and a comparison is made with a preset value F, which is a value set in advance by the liquid supply amount setting means 40 of the liquid supply pump 8. If the value of F1 or F2 is larger than the allowable range calculated based on F, the set liquid flow rate F
It is determined that the above liquid is flowing in the system, and the liquid feeding pump 8
Of the motor rotation speed control device 41 is reduced. Conversely, when the value of F1 or F2 is smaller than the allowable range calculated based on F, it is determined that a smaller amount of liquid is flowing through the system than the set liquid flow rate, and the motor speed control of the liquid sending pump 8 is performed. An instruction to increase the number of rotations of the motor is issued to the device 41.

This control means intermittently determines whether or not F1 or F2 belongs to the allowable range, and outputs an instruction to the motor rotation speed control device when it exceeds the allowable range.
Alternatively, so-called feedback control, which is repeatedly performed while the liquid chromatograph device is operating, is performed even after F2 falls within the allowable range. Accordingly, liquid chromatography can be performed under the condition that the set flow rate of the liquid sending pump is equal to the actual liquid flow rate, and the reproducibility of measurement can be improved.

In the above example, the example in which the feed rate of the feed pump is feedback-controlled in response to the malfunction of the feed pump has been described. It is possible to control.

[0031]

According to the present invention, the liquid flow rate when a liquid such as a mobile phase is fed into a liquid chromatograph system and the liquid flow rate discharged out of the system can be measured immediately and continuously. As a result, while performing liquid chromatography, liquid leakage occurs in the liquid chromatography system,
It is possible to easily detect that a problem has occurred in the liquid feed pump, and to distinguish both of them.

Further, according to the liquid chromatograph apparatus of the present invention, in addition to the detection of the fluctuation of the liquid flow rate due to the failure of the liquid feed pump in the liquid chromatograph system and the detection of the liquid leak in the system, the influence of these is minimized. The feed pump can also be feedback-controlled in order to keep the feed pressure down.

As a result, according to the liquid chromatography apparatus of the present invention, the reproducibility of the liquid chromatography operation can be improved, and the reliability of the result can be improved.

[Brief description of the drawings]

FIG. 1 is a view schematically showing a liquid chromatograph apparatus of the present invention.

FIG. 2 is a diagram showing a specific example of a liquid measuring unit in the liquid chromatograph device of the present invention.

FIG. 3 is a diagram showing a relation between a control device and a liquid measuring unit in the liquid chromatograph device of the present invention.

FIG. 4 is a diagram showing a flow of liquid leak detection in the liquid chromatograph device of the present invention.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Solvent reservoir 2 Liquid (mobile phase) 3 Piping 4 Electromagnetic valve 5 Seal plug 6 Liquid meter 7 Piping 8 Liquid sending pump 9 Piping 10 Sample inlet 11 Piping 12 Separation column 13 Piping 14 Detection cell 15 Piping 16 3-way joint 17 Piping 18 Electromagnetic Valve 19 Piping 20 Liquid Meter 21 Piping 22 Electromagnetic Valve 23 Sealing Plug 24 Waste Liquid Piping 25 Piping 26 Electromagnetic Valve 27 Sealing 28 Piping 29 Electromagnetic Valve 30 Piping 31 Electromagnetic Valve 32 Piping 33 Liquid Meter 34 Piping 35 Electromagnetic Valve 36 Hermetic Plug 37 Waste liquid piping 38 Waste liquid piping 39 CPU 40 Flow rate setting device 41 Motor rotation speed control device 42 Liquid measuring tube 43 Light source 44 Sensor

Claims (7)

[Claims] 1. A liquid chromatograph apparatus having a separation column and a detector, wherein a liquid is supplied to the separation column by a liquid feed pump. In the liquid chromatograph apparatus, a liquid is supplied to a suction side of the liquid feed pump and a waste liquid side of the detector, respectively. A liquid chromatograph apparatus comprising first and second liquid measuring means capable of measuring a passing amount. 2. A liquid chromatograph according to claim 1, wherein said first and second liquid measuring means comprise a liquid reservoir and a sensor for measuring a liquid level in said liquid reservoir. apparatus. 3. A control means for calculating a liquid flow rate on the suction side of the liquid feed pump and a liquid flow rate on the waste liquid side of the detector from the liquid passing amount measured by the first and second liquid measuring means. Item 1. A liquid chromatograph device according to Item 1. 4. The control means detects the calculated liquid flow rate on the suction side of the liquid feed pump, the liquid flow rate on the waste liquid side of the detector, or a difference between them, and uses these values based on values set in advance. 4. The liquid chromatograph according to claim 3, wherein the liquid chromatograph apparatus has a function of stopping the liquid chromatograph apparatus when the calculated value exceeds the allowable range, issuing a warning, and / or issuing a liquid leak warning in the liquid chromatograph system. apparatus. 5. The control means detects the calculated liquid flow rate on the suction side of the liquid feed pump, the liquid flow rate on the waste liquid side of the detector, or a difference between them, and based on these values. 4. When the calculated value exceeds the allowable range, the liquid chromatograph apparatus has a function of increasing / decreasing the amount of liquid supplied by the liquid supply pump and feeding back the difference so as to be within the allowable range. Liquid chromatography equipment. 6. A liquid chromatograph apparatus according to claim 4, wherein said preset value is a set value of a liquid sending amount of a liquid sending pump in the liquid chromatograph apparatus. 7. The liquid chromatograph apparatus according to claim 4, wherein said preset value is zero.