Analysis device and analysis method

Abstract

Provided are an analysis device and an analysis method that make it possible to suppress contamination due to an electrolyte leaching from a reference electrode when the analysis device is not in operation, and to increase an interval during which continuous use is possible without the need for an initial operation. An analysis device (10) is characterized by comprising a flow path (130), a flow-type sensor (110), a reference electrode (120), a liquid feed mechanism (141), and a device control unit (240), wherein, after an analysis mode and before a standby mode for waiting until the next analysis mode, the device control unit (420) controls the liquid feed mechanism (141) to fill a liquid contact portion of the flow path (130) with a liquid, and performs a gas suction sequence for dividing the liquid filling the liquid contact portion by means of a gas in at least one of a portion of the flow path between the flow-type sensor (110) and the reference electrode (120) and a portion of the flow path on the side of the reference electrode (120) on the opposite side to the flow-type sensor, the liquid contact portion being a portion of the flow path (130) where the reference electrode (120) makes contact with the liquid.

Description

Analysis apparatus and analysis method

[0001] The present invention relates to an analysis apparatus and an analysis method for analyzing a specimen that is a liquid.

[0002] Electrochemical measurement refers to a method of electrochemically measuring the properties of chemical substances. Among the analysis apparatuses for performing electrochemical measurement, a flow-type electrochemical measurement apparatus has a structure in which a working electrode and a reference electrode are arranged so as to be electrically in contact with the liquid in the flow path. Among these electrodes, since the reference electrode serves as a reference for the potential, it is required that the potential does not change with time or external factors. The reference electrode is generally composed of an ion-sensitive electrode and a reference solution, and various configurations have been proposed so far. For example, Non-Patent Document 1 discloses a stick-type reference electrode in which the reference solution flows out in the direction of gravity through a bicor glass. Further, Patent Document 1 discloses a reference electrode in which the liquid junction member has a cylindrical shape and is made of porous ceramic, and a configuration in which the electrolyte enclosed in the housing of the reference electrode from the liquid junction member gradually leaks out.

[0003] Rene E.Dohner et al., Reference electrode with free-flowing free-diffusion liquid junction, Analytical Chemistry 1986, 58(12), 2585-2589, DOI:10.1021 / ac00125a053

[0004] Japanese Patent Laid-Open No. 62-231154

[0005] In flow-type electrochemical analyzers, the reference electrode continuously leaks electrolytes from its housing over time while in contact with liquids such as samples or internal standard solutions. This electrolyte leak occurs regardless of whether the device is operating (analysis mode) or not (standby mode). However, during operation, this does not pose a particular problem because the sample or internal standard solution flows continuously in a constant direction through the flow path. On the other hand, during non-operation, the electrolyte leaked from the reference electrode can accumulate in the liquid within the flow path, potentially contaminating the flow path and working electrode, and shortening the interval during which the device can be used continuously without initial operation.

[0006] Therefore, the object of the present invention is to provide an analytical apparatus and analytical method that can suppress contamination by electrolyte seeping from the reference electrode when not in operation, and that can extend the interval during which continuous use is possible without the need for initial operation.

[0007] To solve the aforementioned problems, the analytical apparatus according to the present invention comprises a flow path through which a liquid to be analyzed flows, a flow-type sensor for analyzing the liquid flowing through the flow path, a reference electrode for measuring the potential of the liquid flowing through the flow path, a liquid delivery mechanism for delivering the liquid in the flow path, and at least an apparatus control unit for controlling the liquid delivery mechanism. After an analysis mode in which the concentration of a specific substance in the liquid is calculated based on data acquired from the flow-type sensor and the reference electrode, and before a standby mode in which the apparatus control unit waits until the next analysis mode, the apparatus control unit controls the liquid delivery mechanism to fill the wetted portion of the reference electrode in the flow path with liquid, and to perform a gas suction sequence in which the liquid filling the wetted portion with gas in at least one of the flow path between the flow-type sensor and the reference electrode, and the flow path on the opposite side of the flow-type sensor from the reference electrode.

[0008] According to the present invention, it is possible to provide an analytical apparatus and analytical method that can suppress the amount of electrolyte seeping from the reference electrode and the extent of contamination when the apparatus is not in operation, reduce the number of flow path cleaning operations when transitioning to a non-operational state, and increase the service life of the reference electrode.

[0009] This is an overall configuration diagram of the analyzer according to the first embodiment. This is a schematic cross-sectional view showing the internal structure of the reference electrode according to the first embodiment. This is an enlarged configuration diagram of the flow path, ion-selective electrode, and a modified reference electrode according to the first embodiment. This is a flowchart of the analysis method according to the first embodiment. This is a configuration diagram of the analyzer when the gas is dividing the liquid in the gas suction sequence of the first embodiment. This is a configuration diagram of the analyzer when the gas is not dividing the liquid in the gas suction sequence of the first embodiment. This is a configuration diagram of the flow-type sensor and reference electrode of the analyzer according to the second embodiment. This is a graph showing the change in potential difference between the potassium ion-selective electrode and the reference electrode after 24 hours in standby mode. This is a block diagram of the computer constituting the control unit.

[0010] The analytical apparatus and analytical method according to the present invention will be described below with reference to the first and second embodiments. In describing the second embodiment, the configurations common to the previously described embodiments will be omitted, and the description will focus on the differing configurations.

[0011] [Analytical Apparatus According to the First Embodiment] Figure 1 is an overall configuration diagram of the analytical apparatus 10 according to the first embodiment. The analytical apparatus 10 is broadly composed of a measurement unit 100 and a control unit 200. The analytical apparatus 10 is a device that can measure the concentration of a specific substance in a sample using the potential difference between electrodes by alternately performing analysis of a sample and analysis of an internal standard solution, and using the potential difference and calibration curve, and is also called a so-called "flow-type electrochemical measuring device". The measurement unit 100 of the analytical apparatus 10 mainly comprises an ion-selective electrode 110, a reference electrode 120, a flow path 130, a syringe pump for liquid delivery 141, a syringe pump for diluent 142, a syringe pump for internal standard solution 143, electromagnetic valves 151 to 157, a bottle for diluent 161, a bottle for internal standard solution 162, a supply tank 163, a drain tank 164, and a vacuum pump 171. The following describes the configuration of the measurement unit 100 of the analytical apparatus 10 according to the first embodiment.

[0012] (Ion-Selective Electrode) The ion-selective electrode 110 is a component that analyzes the concentration of a specific substance in the liquid flowing through the channel 130 and corresponds to a "flow-type sensor". The ion-selective electrode 110 consists of a chloride ion-selective electrode 111 equipped with a chloride ion-sensitive membrane, a potassium ion-selective electrode 112 equipped with a potassium ion-sensitive membrane, and a sodium ion-selective electrode 113 equipped with a sodium ion-sensitive membrane. The chloride ion-selective electrode 111, potassium ion-selective electrode 112, and sodium ion-selective electrode 113 are arranged along the channel 130 such that their respective ion-sensitive membranes are in contact with the liquid flowing through the channel 130. Note that the ion-selective electrode 110 is not limited to the configuration comprising the three electrodes 111, 112, and 113 described above, and may be other electrodes, and the number of electrodes may be one or more.

[0013] (Reference Electrode) The reference electrode 120 is an electrode that serves as the reference for potential. The reference electrode 120 is positioned downstream of the ion-selective electrode 110 and upstream of the liquid delivery syringe pump 141 (described later), so as to be in contact with the liquid flowing through the channel 130. Figure 2 is a schematic cross-sectional view showing the internal structure of the reference electrode 120. The reference electrode 120 comprises a resin housing 121 having an opening, a liquid junction member 122 provided to seal the opening of the housing 121, and a silver-silver chloride electrode 123 provided at a location opposite the opening of the housing 121. The inside of the housing 121 of the reference electrode 120 is filled with an internal liquid 124 which is a saturated potassium chloride-silver chloride aqueous solution, potassium chloride powder 125, and silver chloride powder 126.

[0014] The liquid junction member 122 is rod-shaped, with one end exposed to the outside of the housing 121 and in contact with the liquid flowing through the channel 130, and the other end in contact with the internal liquid 124 filled inside the housing 121. With this configuration, the internal liquid 124 filled inside the housing 121 seeps out to the outside only through the liquid junction member 122. Furthermore, compared to the liquid junction member shown in Patent Document 1, which is cylindrical and has an inner surface in contact with the liquid, the liquid junction member 122 has a smaller contact area with the liquid, thus extending the service life of the reference electrode 102. The liquid junction member 122 only needs to be configured to allow the internal liquid 124 filled inside the housing 121 to seep into the channel 130, and examples include porous ceramic, porous resin, gel, and ultrafine channels.

[0015] When the reference electrode 120 is positioned so that the liquid junction member 122 is on the upper side (as shown in Figure 3), the lower end of the liquid junction member 122 is immersed in the internal liquid 124. With this configuration, the liquid junction member 122 becomes wet in the internal liquid 124 due to capillary action, and the internal liquid 124 seeps into the flow path 130.

[0016] The internal liquid 124 filled in the housing 121 is maintained at a saturation concentration until the potassium chloride powder 125 and silver chloride powder 126 are depleted, so the reference electrode 120 can obtain a stable potential. Note that the internal liquid 124 is not limited to a saturated potassium chloride and silver chloride aqueous solution, but can be any aqueous solution containing a combination of anions and cations with similar transport rates, and the type of electrode inside the housing 121 can be changed according to these combinations.

[0017] (Flow path) The flow path 130 is a pipe through which liquids such as the sample to be analyzed and internal standard solutions flow. A sample suction nozzle 181 capable of drawing liquid from the supply tank 163 is connected to the upstream end of the flow path 130. The downstream side of the flow path 130 is configured to drain liquid into the drain tank 164 via an electromagnetic valve 151, a liquid delivery syringe pump 141, and an electromagnetic valve 152. Figure 3 is an enlarged view of the flow path 130, the ion-selective electrode 110, and the reference electrode 120. The chloride ion-selective electrode 111, potassium ion-selective electrode 112, sodium ion-selective electrode 113, and reference electrode 120 are connected in a continuous sequence from the upstream side to the downstream side of the flow path 130. In addition, the flow path 130 has a branching passage 131 formed at the location where the reference electrode 120 is installed, so that the tip of the liquid junction member 122 comes into contact with the liquid. As will be described in detail later in the analysis method, in the gas suction sequence, gas is introduced in at least one of the two channels of the channel 130: channel 132 between the ion-selective electrode 110 and the reference electrode 120, and channel 133 downstream of the reference electrode 120.

[0018] The points where gas is introduced into the channels 132 and 133 (points where the channels are divided by gas) are equipped with a gas retention mechanism that can maintain the state of liquid division by gas. In other words, the gas retention mechanism is a mechanism that makes it easy for three phases—gas, liquid (internal standard liquid), and solid (inner wall surface of the channel)—to coexist simultaneously. An example of such a gas retention mechanism is a mechanism in which the inner wall surfaces of the channels 132 and 133 exhibit hydrophobicity, and in particular, a mechanism in which the contact angle between the inner wall surfaces of the channels 132 and 133 and water is 90° or more is preferred. Specifically, examples of such a gas retention mechanism include a mechanism in which the channels 132 and 133 are made of Teflon, or a mechanism in which the inner wall surfaces of the channels 132 and 133 are treated with a water-repellent coating. Furthermore, gas retention mechanisms may include, for example, a mechanism in which the flow paths 132 and 133 at the point where gas is introduced are positioned higher vertically than the surrounding flow paths, or a mechanism in which the inner diameter is reduced to increase the aspect ratio of the gas when it is introduced (long side of the gas cross-section / short side of the gas cross-section in the direction of liquid delivery). By providing such a gas retention mechanism, the introduced gas in the flow paths 132 and 133 can appropriately divide the liquid.

[0019] Figure 4 is an enlarged view of the flow path 130, the ion-selective electrode 110, and a modified example, the reference electrode 120a (in which the liquid junction member 122a has a cylindrical shape that covers the flow path 130). In the case of Figure 4, as in the case of Figure 3, the flow path 130 has a chloride ion-selective electrode 111, a potassium ion-selective electrode 112, a sodium ion-selective electrode 113, and a reference electrode 120 formed in a continuous manner from the upstream side to the downstream side, and the flow paths 132a and 133a where the gas is introduced are equipped with a gas-holding mechanism.

[0020] (Liquid Transfer Syringe Pump) The liquid transfer syringe pump 141 is a mechanism for transferring liquid in the flow path 130 and corresponds to the "liquid transfer mechanism". The liquid transfer syringe pump 141 can be any conventionally known syringe pump and is not particularly limited as long as it is a mechanism that can transfer liquid from the supply tank 163 to the drain tank 164 via the flow path 130.

[0021] (Other components of the measuring unit) In addition to the above-mentioned components, the measuring unit 100 also includes a supply tank 163 for storing the liquid to be supplied, a diluent bottle 161 for containing the diluent, a syringe pump 142 for sending the diluent from the diluent bottle 161 to the supply tank 163, an internal standard solution bottle 162 for containing the internal standard solution, an internal standard solution syringe pump 143 for sending the internal standard solution from the internal standard solution bottle 162 to the supply tank 163, electromagnetic valves 151 to 157 for controlling the flow rate of fluid in each flow path, a vacuum pump 171 for sending residual liquid remaining in the supply tank 163 to the drain tank 164, and the like.

[0022] (Control Unit) The control unit 200 of the analyzer 10 according to the first embodiment mainly comprises a potential measurement unit 210, a concentration calculation unit 220, a judgment unit 230, an apparatus control unit 240, an output unit 250, and an input unit 260. The potential measurement unit 210 acquires the potential difference between the ion-selective electrode 110 (chloride ion-selective electrode 111, potassium ion-selective electrode 112, sodium ion-selective electrode 113) and the reference electrode 120, as well as the potential difference in the conductive part. The concentration calculation unit 220 calculates the concentration of a specific substance in the liquid based on the data acquired by the potential measurement unit 210. The judgment unit 230 executes the judgment sequence described later based on the data acquired by the potential measurement unit 210. The apparatus control unit 240 performs control over the measurement unit 100, including the liquid delivery syringe pump 141. The output unit 250 is a display for outputting the calculation results from the concentration calculation unit 220. The input unit 260 is an interface for inputting various data and commands to the device control unit 240.

[0023] The processing of the control unit 200 is realized by program execution processing by the CPU (Central Processing Unit) or by dedicated circuits, etc. It may also be equipped with a memory unit (not shown), and the memory unit can be made up of general storage devices such as RAM (Random Access Memory), ROM (Read Only Memory), HDD (Hard Disk Drive), or flash memory. The hardware configuration of the control unit 200 will be described later with reference to Figure 9. Note that the control lines and information lines of the control unit 200 in Figure 1 are only shown if they are considered necessary for explanation, and the connection method is not particularly limited, and all parts may be interconnected. Furthermore, the configuration of each part of the control unit 200 is not particularly limited, and for example, the judgment unit 230 may be omitted by having the concentration calculation unit 220 or the device control unit 240 perform the functions of the judgment unit 230.

[0024] (Liquid used in the analytical apparatus) The liquid used in the analytical apparatus 10 according to the first embodiment is not particularly limited as long as it is a liquid whose concentration of a specific substance you wish to analyze. Examples include specimens (also called test samples) such as blood, urine, and cerebrospinal fluid, which are diluted with a diluent as appropriate before being used for analysis. Another example of a liquid used in the analytical apparatus 10 is an internal standard solution necessary for quantifying a specific substance. The specific substance contained in the specimen is not particularly limited, but examples include chloride ions (Cl － ), potassium ions (K ＋ ), sodium ions (Na ＋ Examples include the following. Furthermore, the diluent used to dilute the sample is not particularly limited as long as it is a liquid with a lower concentration of the specific substance than the sample, but examples include pure water and buffer solutions. In addition, the internal standard solution is not particularly limited as long as it is a liquid with a concentration of the specific substance close to that of the diluted sample, and any liquid with a known concentration of the specific substance will suffice.

[0025] [Analysis Method According to the First Embodiment] Next, the analysis method according to the first embodiment will be described. The analysis method according to the first embodiment is an analysis method using the analysis apparatus 10 according to the first embodiment described above, and as shown in Figure 5, it has an analysis mode S1 and a standby mode S4, and a gas suction sequence S2 and a decision sequence S3 are performed between the analysis mode S1 and the standby mode S4. Various processes in each mode and each sequence are performed by the control unit 200 (more specifically, the device control unit 240) controlling the measurement unit 100 of the analysis apparatus 10. In the present invention, standby mode refers to a state other than when the device is performing an analysis cycle, and includes all non-operational states, from relatively short waiting periods in a sample waiting state to long periods of inactivity such as on weekends. The following describes each mode and each sequence.

[0026] (Analysis Mode) Analysis mode S1 is a mode in which the concentration of a specific substance in a liquid is calculated using data acquired from the ion-selective electrode 110 and the reference electrode 120 (diluted sample data and internal standard solution data), and can also be described as the operation of the analyzer 10. The details are as follows.

[0027] (Analysis Mode: Acquisition of Diluted Sample Data) Referring to Figure 1, in analysis mode S1, first, the sample is placed in the supply tank 163. The electromagnetic valve 153 is opened, and the diluent contained in the diluent bottle 161 is filled into the diluent syringe pump 142. The electromagnetic valve 153 is closed and the electromagnetic valve 154 is opened to operate the diluent syringe pump 142, injecting the diluent into the supply tank 163, after which the electromagnetic valve 154 is closed. Next, the sample suction nozzle 181 is lowered to near the bottom of the supply tank 163, the electromagnetic valve 151 is opened, and the liquid delivery syringe pump 141 is operated, so that the sample diluted in the supply tank 163 (referred to as the diluted sample) is drawn into the pump 141. At this time, the diluted sample in the flow path 130 is delivered from the upstream side to the downstream side while in contact with each sensitive membrane of the ion-selective electrode 110 and the liquid junction member 122 of the reference electrode 120. When the diluted sample is in simultaneous contact with each sensitive membrane of the ion-selective electrode 110 and the reference electrode 120, the aspiration by the liquid delivery syringe pump 141 is stopped. In this state, the potential measurement unit 210 acquires the potential difference between each ion-selective electrode 110 and the reference electrode 120 and stores it in the concentration calculation unit 220 as "diluted sample data". Subsequently, the electromagnetic valve 151 is closed and the electromagnetic valve 152 is opened to operate the liquid delivery syringe pump 141, thereby sending the diluted sample after measurement to the drain tank 164. Also, the vacuum nozzle 182 is lowered to near the bottom of the supply tank 163, the electromagnetic valve 157 is opened, and the vacuum pump 171 is operated to send the diluted sample remaining in the supply tank 163 to the drain tank 164. Then, the electromagnetic valve 157 is closed and the vacuum nozzle 182 is raised.

[0028] (Analysis mode: Acquisition of internal standard solution data) Next, the electromagnetic valve 155 is opened, and the internal standard solution contained in the internal standard solution bottle 162 is filled into the internal standard solution syringe pump 143. The electromagnetic valve 155 is closed and the electromagnetic valve 156 is opened to operate the internal standard solution syringe pump 143, injecting the internal standard solution into the supply tank 163, after which the electromagnetic valve 156 is closed. Next, the sample suction nozzle 181 is lowered to near the bottom of the supply tank 163, the electromagnetic valve 151 is opened, and the liquid delivery syringe pump 141 is operated, so that the internal standard solution injected into the supply tank 163 is drawn towards the pump 141. At this time, the internal standard solution in the flow path 130 is delivered from the upstream side to the downstream side while in contact with each sensitive membrane of the ion-selective electrode 110 and the liquid junction member 122 of the reference electrode 120. When a single mass of internal standard solution is simultaneously in contact with each sensitive membrane of the ion-selective electrode 110 and the reference electrode 120, the aspiration by the liquid delivery syringe pump 141 is stopped. In this state, the potential measurement unit 210 acquires the potential difference between each ion-selective electrode 110 and the reference electrode 120, and stores it in the concentration calculation unit 220 as "internal standard solution data". The subsequent operation is the same as in the case of acquiring the diluted sample data described above.

[0029] (Analysis mode: Calculation of concentration) Based on the "diluted sample data" and "internal standard solution data" obtained by the above method, the concentration calculation unit 220 calculates the concentration of the specific substance in the sample and outputs it to the output unit 250. The method for calculating the concentration of the specific substance can be carried out using a conventionally known method, for example, by using Henderson's equation or Nernst's equation.

[0030] (Gas Aspiration Sequence) The gas aspiration sequence S2 is a process performed after the analysis mode S1 and before the standby mode S4, and is a process in which the liquid filling the flow path 130 is divided by gas at a predetermined location. Referring to Figure 1, in the gas aspiration sequence S2, first, the electromagnetic valve 155 is opened and the internal standard solution contained in the internal standard solution bottle 162 is filled into the internal standard solution syringe pump 143. The electromagnetic valve 155 is closed and the electromagnetic valve 156 is opened to operate the internal standard solution syringe pump 143, injecting the internal standard solution into the supply tank 163, and then the electromagnetic valve 156 is closed. Next, the sample aspiration nozzle 181 is lowered to a position where it is immersed in the internal standard solution in the supply tank 163, the electromagnetic valve 151 is opened and the liquid delivery syringe pump 141 is operated, so that the internal standard solution injected into the supply tank 163 is drawn into the pump 141. As a result, the flow path 130, in which the ion-selective electrode 110 and the reference electrode 120 are located, is filled with the internal standard solution. Next, the sample suction nozzle 181 is raised away from the internal standard solution in the supply tank 163, and the liquid delivery syringe pump 141 is operated to perform a "gas suction process" in which gas (air in the supply tank 163) is drawn towards the pump 141. This creates a layer of gas at the upstream end of the internal standard solution filling the flow path 130. Next, the sample suction nozzle 181 is lowered to a position where it is immersed in the internal standard solution in the supply tank 163, and the liquid delivery syringe pump 141 is operated to perform an "internal standard solution suction process" in which the internal standard solution injected into the supply tank 163 is drawn towards the pump 141. This creates a layer of internal standard solution at the upstream end of the gas formed in the flow path 130 during the gas suction process described above. Furthermore, the gas suction process and the internal standard solution suction process described above are repeated. Finally, the vacuum nozzle 182 is lowered to near the bottom of the supply tank 163, and the vacuum pump 171 is operated while the electromagnetic valve 157 is opened, thereby sending the internal standard liquid remaining in the supply tank 163 to the drain tank 164. Then, the electromagnetic valve 157 is closed, the vacuum nozzle 182 is raised, and the gas suction sequence S2 is completed.By performing these processes, the wetted portion of the reference electrode 120 in the flow path 130 becomes filled with the internal standard solution, and at the same time, the internal standard solution is divided by the gas in the flow paths 132 and 133 (flow paths 132a and 133a in the case of Figure 4) where the gas is introduced as shown in Figure 3.

[0031] The gas to be introduced should be introduced at least 5 mm in length through two channels 132 and 133 (channels 132a and 133a in Figure 4), each with a diameter of 1 mm, but it is not particularly limited. Furthermore, the gas to be introduced is assumed to be the air in the supply tank 163, but it is not particularly limited to any gas with low solubility in liquid, such as nitrogen or helium. The manner in which the gas divides the liquid will be described in detail below.

[0032] (Gas suction sequence: A mode in which gas divides liquid) Figure 6A is a diagram of the analyzer's configuration when gas divides liquid in the gas suction sequence S2. When gas is properly introduced in the gas suction sequence S2 as shown in Figure 6A, first, the wetted portion of the reference electrode 120 in the flow path 130 is filled with liquid L (internal standard solution). Also, in the flow path 134 between the ion-selective electrode 110 and the reference electrode 120, liquid L is divided by gas A1. Furthermore, in the flow path 135 between the reference electrode 120 and the liquid delivery syringe pump 141, liquid L is divided by gas A2. In this way, gas A1 divides liquid L in the flow path 134, preventing the diffusion of electrolyte seeping from the reference electrode 120 to the upstream side and preventing contamination of the ion-selective electrode 110 by the seeped electrolyte. Furthermore, by dividing the liquid L in the flow path 135, gas A2 prevents the diffusion of electrolyte seeping from the reference electrode 120 downstream, thereby preventing contamination of downstream components such as the syringe pump 141 with the seeped electrolyte. In addition, by dividing the liquid L with gases A1 and A2, the amount of electrolyte seeping from the reference electrode 120 is limited. As the area where the electrolyte seeps from the reference electrode 120 becomes a minute space separated by gases A1 and A2, the concentration of the electrolyte in this minute space becomes uniform more quickly, and the diffusion rate of the electrolyte decreases according to Fick's law, thus extending the service life of the reference electrode 120. In other words, by introducing gases A1 and A2 into the flow paths 134 and 135, contamination based on electrolyte seeping from the reference electrode 120 can be prevented in the standby mode S4 (non-operational state) described later, and the interval during which the analyzer 10 can be used continuously without initial operation can be extended.

[0033] Furthermore, in order for gases A1 and A2 to properly divide liquid L, it is preferable that the opposing liquid surfaces of liquid L flanking gases A1 and A2 be as parallel as possible. In other words, it is preferable that the opposing liquid surfaces of liquid L be as perpendicular as possible to the inner wall surface of the flow path 130. To achieve this state, it is preferable that the gas holding mechanism described above be provided in the flow paths 134 and 135 where gases A1 and A2 are held.

[0034] Figure 6B is a diagram of the analyzer configuration when the gas does not divide the liquid during the gas suction sequence S2. If the gas is not properly introduced during the gas suction sequence S2 as shown in Figure 6B, gases A3 and A4 cannot divide the liquid L in the flow path 130. As a result, in the standby mode S4 described later, electrolyte seeping from the reference electrode 120 diffuses to the upstream and downstream sides, contaminating surrounding components such as the ion-selective electrode 110.

[0035] (Decision Sequence) Decision sequence S3 is a process that takes place after the gas suction sequence S2 and determines whether the liquid filling the wetted portion of the reference electrode 120 in the flow path 130 is divided by the gas. In other words, decision sequence S3 is a process that determines whether the state is "divided" as shown in Figure 6A, or "not divided" as shown in Figure 6B. Specifically, the following "Decision Method 1" and "Decision Method 2" are used as the decision methods in decision sequence S3.

[0036] (Decision Sequence: Decision Method 1) As shown in Figure 6A, if gas A1 divides the liquid L in the flow path 134 between the ion-selective electrode 110 and the reference electrode 120, the two components do not conduct electricity, so the resistance between the two components increases and the potential difference also increases. Similarly, if gas A2 divides the liquid L in the flow path 135 between the reference electrode 120 and the liquid delivery syringe pump 141, the two components do not conduct electricity, so the resistance between the two components increases and the potential difference also increases. On the other hand, as shown in Figure 6B, if the liquid L is not divided by gas A3 in the flow path 134 between the ion-selective electrode 110 and the reference electrode 120, the two components conduct electricity, so the resistance between the two components decreases and the potential difference also decreases. Similarly, if the liquid L is not divided by gas A4 in the flow path 135 between the reference electrode 120 and the liquid delivery syringe pump 141, the two components will conduct electricity, resulting in a smaller resistance and potential difference between them. Therefore, in determination method 1, conductive parts are provided at positions that sandwich the points where the liquid is divided by the gas (flow paths 134 and 135) from both sides, the potential measurement unit 210 acquires data (potential difference) from the conductive parts, and the determination unit 230 can determine, based on this data, that the liquid is "divided" if the potential difference is ≥ X, and "not divided" if the potential difference is < X. Alternatively, if the data obtained from the conductive parts is a resistance value, the determination may be made as follows: "divided" if the resistance value is ≥ Y, and "not divided" if the resistance value is < Y. The conductive parts may be the ion-selective electrode 110, the reference electrode 120, and the liquid delivery syringe pump 141, but a conductive component may also be provided in the flow path 130 to serve as a conductive part. Furthermore, while the potential measurement unit 210 may acquire data from the conductive part, it is also possible to acquire it separately using a dedicated resistance meter or potential measuring instrument.

[0037] (Decision Sequence: Decision Method 2) As shown in Figure 6A, if the liquid L (internal standard solution) is divided by gas A1 in the flow path 134, the potential difference between the ion-selective electrode 110 and the reference electrode 120 obtained by the potential measurement unit 210 will be a value significantly different from the value of the internal standard solution data acquired in analysis mode S1. On the other hand, as shown in Figure 6B, if the liquid L is not divided by gas A3 in the flow path 134, the potential difference between the ion-selective electrode 110 and the reference electrode 120 obtained by the potential measurement unit 210 will be approximately the same as the value of the internal standard solution data acquired in analysis mode S1. Therefore, in decision method 2, if the difference when comparing the "internal standard solution data acquired in decision sequence S3" with the "internal standard solution data acquired in analysis mode S1 (internal standard solution data when the flow path 130 is completely filled with the internal standard solution)" is outside the range of ±1%, it can be determined that the liquid is "divided," and if it is within the range of ±1%, it can be determined that the liquid is "not divided."

[0038] (Recovery Sequence) Recovery sequence S10 is a series of processes consisting of gas suction sequence S2 and judgment sequence S3. In recovery sequence S10, judgment sequence S3 is performed simultaneously with the completion of gas suction sequence S2. If judgment sequence S3 determines that "disconnection" has occurred, the system transitions to standby mode S4; if judgment sequence S3 determines that "non-disconnection" has occurred, the system transitions back to gas suction sequence S2. If judgment sequence S3 repeatedly determines that "non-disconnection" has occurred, it may result in a situation where the system cannot transition to standby mode S4. To avoid such a situation, if judgment sequence S3 determines that "non-disconnection" has occurred N times (where N is an integer of 2 or more), the system may not transition to gas suction sequence S2, and instead perform the subsequent cleaning process in cleaning mode 5 more times than usual. By performing the cleaning process more times, electrolytes accumulated in the gaps of the ion-selective electrode 110 (electrolytes seeped out from the reference electrode 120) can be removed.

[0039] (Standby Mode) Standby mode S4 is a mode in which analysis is not performed continuously, and can be described as a time when the analyzer 10 is not in operation. Specifically, standby mode S4 includes short waiting periods of 1 to 30 minutes for analysis, and long waiting periods of 30 minutes or more, such as at night or on holidays.

[0040] (Washing Mode) Washing mode S5 is a mode in which a washing process is performed on the analyzer 10 after standby mode S4 and before the next analysis mode S1. Referring to Figure 1, in washing mode S5, first, the electromagnetic valve 155 is opened and the internal standard solution contained in the internal standard solution bottle 162 is filled into the internal standard solution syringe pump 143. The electromagnetic valve 155 is closed and the electromagnetic valve 156 is opened to operate the internal standard solution syringe pump 143 and inject the internal standard solution into the supply tank 163, after which the electromagnetic valve 156 is closed. Next, the sample suction nozzle 181 is lowered to near the bottom of the supply tank 163, the electromagnetic valve 151 is opened and the liquid delivery syringe pump 141 is operated so that the internal standard solution injected into the supply tank 163 is drawn to the pump 141 side. During this process, the internal standard solution in the flow path 130 is delivered from the upstream to the downstream side, while contacting each sensitive membrane of the ion-selective electrode 110 and the liquid junction member 122 of the reference electrode 120. Subsequently, the electromagnetic valve 151 is closed and the electromagnetic valve 152 is opened to activate the liquid delivery syringe pump 141, and the internal standard solution is delivered to the drain tank 164. In cleaning mode S5, this series of cleaning processes (the process of delivering the internal standard solution from the upstream to the downstream side of the flow path 130) is usually repeated 20 times to complete the process.

[0041] The analytical method according to the first embodiment is as described above. However, for conditions and processing details not explicitly stated, conditions and processing details adopted in general measurement methods using ion-selective electrodes may be applied, and it goes without saying that these conditions and processing details can be appropriately changed as long as the desired effect is achieved.

[0042] [Analytical Apparatus According to the Second Embodiment] Next, an analytical apparatus according to the second embodiment will be described. FIG. 7 is a configuration diagram of a flow-type sensor and a reference electrode of the analytical apparatus according to the second embodiment. The analytical apparatus 20 according to the second embodiment, also called an immunoassay apparatus, is an apparatus based on the electrochemiluminescence method. Then, the analytical apparatus 20 analyzes the concentration of a specific substance in a liquid by applying a potential to the liquid to be analyzed to generate a signal that can be optically detected. In the measurement cell 300 where measurement is performed in the analytical apparatus 20, a working electrode 320, a counter electrode 310, an optical window 330, etc. are installed on the upstream side of the flow path 130, and a reference electrode 120b is installed on the downstream side. And the combination of the working electrode 320, the counter electrode 310, and the optical window 330 corresponds to a "flow-type sensor".

[0043] The analytical apparatus 20 applies a potential to the liquid flowing in the flow path 130 based on the working electrode 320 and the counter electrode 310. By applying this potential, an optical signal is generated from the liquid, and the signal radiated through the optical window 330 is detected by a detector (a detector using a photomultiplier tube, a semiconductor, etc.). Note that the measurement cell 300 is provided with a magnet 340, and a detection target component that forms a complex with magnetic particles and a luminescent label contained in the liquid is adsorbed on the surface of the working electrode 320 by the magnet 340 during measurement to perform electrochemiluminescence by voltage application, but it is not an essential member. Also, the liquid junction member 122b of the reference electrode 120b in FIG. 7 has a cylindrical shape surrounding the flow path 130. Of course, it may have a rod-like configuration as shown in FIG. 2. And the configuration of the measurement cell 300 of the analytical apparatus 20 may apply the configuration of an apparatus based on a conventionally known electrochemiluminescence measurement method and is not limited to the configuration of FIG. 7.

[0044] The analyzer 20 according to the second embodiment is different only in the "flow-type sensor" compared with the analyzer 10 according to the first embodiment. Therefore, descriptions of other members and analysis methods will be omitted. When performing the gas suction sequence S2 using the analyzer 20 according to the second embodiment, although it depends on the inner diameter of the flow path 130 and the size of the apparatus, for example, suction processing of 15 μL of internal standard solution, suction processing of 5 μL of gas, suction processing of 15 μL of internal standard solution, suction processing of 5 μL of gas, and suction processing of 15 μL of internal standard solution may be performed. By this series of processes, the wetted portion of the reference electrode 120b in the flow path 130 is filled with the internal standard solution. Also, in the flow path 130 between the reference electrode 120b and the working electrode 320, the counter electrode 310, etc., and in the flow path 130 on the downstream side of the reference electrode 120b, the internal standard solution will be segmented by the gas.

[0045] Although the present invention has been described using the first and second embodiments, it is not limited to these embodiments and includes various modifications. Also, the first and second embodiments have been described in detail for easy understanding of the present invention, and are not necessarily limited to those having all the configurations described. And, for a part of the configurations of the first and second embodiments, addition, deletion, or replacement with other configurations is possible. The modifications are, for example, as follows.

[0046] (Modification) In the "judgment method 1" of the judgment sequence S3 in the analysis method according to the first embodiment, in the locations (flow paths 134, 135) where the gas is segmented in FIG. 6A, a conductive portion is provided at positions sandwiching each from both sides, and the "segmentation" / "non-segmentation" at two locations is judged. However, it may be configured to judge only one of the locations.

[0047] [Verification of Effects] Figure 8 is a graph showing the change in potential difference between the potassium ion selective electrode and the reference electrode after a 24-hour standby mode. Note that the graph in Figure 8 is a general representation and shows how the aforementioned potential difference changes as the number of liquid flow cycles after the standby mode increases. Data D1 in Figure 8 is the result from an analytical apparatus that does not apply the present invention, and a large potential difference is generated during liquid flow after the 24-hour standby mode, which results in a large concentration error when converted to concentration. Therefore, at least several dozen liquid flow cycles are required to suppress the concentration error and show a constant potential difference. On the other hand, data D2 in Figure 8 is the result from an analytical apparatus that applies the present invention, and a large potential difference is not generated immediately after liquid flow after the 24-hour standby mode, and a constant potential difference is shown from the beginning. Therefore, it was found that with an analytical apparatus that applies the present invention, accurate analysis is possible without generating concentration errors from immediately after the standby mode. This result is presumed to be because the ion-selective electrode was not contaminated by electrolyte seeping from the reference electrode during standby mode. In addition to the effect of extending the interval for continuous use without requiring initial operation of the analyzer, the present invention has been confirmed to exhibit other excellent effects. Therefore, it has been confirmed that the analyzer and analytical method according to the present invention are very effective in practical applications such as clinical testing.

[0048] Figure 9 is a block diagram of the computer 980 that constitutes the control unit 200. The control unit 200 described above is equipped with one or more computers 980 as shown in Figure 9. In Figure 9, the computer 980 includes a CPU 981, a storage unit 982, a communication port 983, an input / output port 984, and a media port 985. Here, the storage unit 982 includes a RAM 982a, a ROM 982b, and an SSD (Solid State Drive) 982c. The communication port 983 is connected to a communication circuit 986. The input / output port 984 is connected to an input / output device 987. The media port 985 reads and writes data to and from the recording medium 988. The ROM 982b stores the IPL (Initial Program Loader) and the like, which are executed by the CPU. The SSD 982c stores application programs and various data. The CPU 981 implements various functions by executing application programs and the like that loaded from the SSD 982c into the RAM 982a. In Figure 1 shown above, the control unit 200, including the potential measurement unit 210 and the concentration calculation unit 220, is shown as a block that primarily represents functions implemented by application programs and the like.

[0049] 10 Analytical apparatus according to the first embodiment 20 Analytical apparatus according to the second embodiment 100 Measurement unit 110 Ion-selective electrode (flow-type sensor) 111 Chloride ion-selective electrode 112 Potassium ion-selective electrode 113 Sodium ion-selective electrode 120 Reference electrode 130 Flow channel 141 Syringe pump for liquid delivery (liquid delivery mechanism) 142 Syringe pump for diluent 143 Syringe pump for internal standard solution 151-157 Solenoid valve 161 Bottle for diluent 162 Bottle for internal standard solution 163 Supply tank 164 Drainage tank 171 Vacuum pump 200 Control unit 210 Potential measurement unit 220 Concentration calculation unit 230 Judgment unit 240 Device control unit 250 Output unit 260 Input unit

Claims

1. An analytical apparatus comprising: a flow path through which a liquid to be analyzed flows; a flow-type sensor for analyzing the liquid flowing through the flow path; a reference electrode for measuring the potential of the liquid flowing through the flow path; a liquid delivery mechanism for delivering the liquid in the flow path; and a device control unit for controlling at least the liquid delivery mechanism, wherein, after an analysis mode in which the concentration of a specific substance in the liquid is calculated based on data acquired from the flow-type sensor and the reference electrode, and before a standby mode in which the device control unit waits until the next analysis mode, the device control unit controls the liquid delivery mechanism to fill the wetted portion of the reference electrode in the flow path with liquid, and performs a gas suction sequence in which the liquid filling the wetted portion with gas in at least one of the flow path between the flow-type sensor and the reference electrode, and the flow path on the opposite side of the flow-type sensor from the reference electrode.

2. The analytical apparatus according to claim 1, characterized in that the point of division by the gas is the flow path between the flow-type sensor and the reference electrode.

3. The analytical apparatus according to claim 2, characterized in that the point of division by the gas is the flow path on the opposite side of the flow-type sensor when viewed from the reference electrode.

4. The analytical apparatus according to any one of claims 1 to 3, characterized in that it is provided with a gas holding mechanism that can maintain the state of liquid separation by gas at the point where the gas is used for separation.

5. The analytical apparatus according to claim 4, characterized in that the gas holding mechanism is a mechanism in which the inner wall surface of the flow path exhibits hydrophobicity.

6. The analytical apparatus according to claim 5, characterized in that the gas holding mechanism is a mechanism in which the contact angle between the inner wall surface of the flow path and water is 90° or more.

7. The analytical apparatus according to claim 4, characterized in that the gas holding mechanism is a mechanism in which the flow path at the point of division by the gas is positioned at a higher vertical position than the flow path surrounding that point.

8. The analytical apparatus according to any one of claims 1 to 3, further comprising a determination unit for determining whether or not the liquid filling the wetted portion is divided by the gas.

9. The analytical apparatus according to claim 8, wherein conductive parts are provided at positions that sandwich the portion to be divided by the gas from both sides, and the determination unit determines whether or not the portion is divided based on data from the conductive parts.

10. The analytical apparatus according to claim 9, characterized in that one of the conductive parts is the flow-type sensor.

11. The analytical apparatus according to claim 8, characterized in that the determination unit determines to perform the gas suction sequence again when it determines that the liquid filling the wetted portion is not divided by the gas.

12. The analytical apparatus according to claim 11, characterized in that when the determination unit determines N times (where N is an integer of 2 or more) that the liquid filling the wetted portion is not divided by the gas, it determines to perform the cleaning process in the cleaning mode after the standby mode and before the next analysis mode more times than usual without performing the gas suction sequence further.

13. An analytical method using an analytical apparatus comprising: a flow path through which a liquid to be analyzed flows; a flow-type sensor for analyzing the liquid flowing through the flow path; a reference electrode for measuring the potential of the liquid flowing through the flow path; and a liquid delivery mechanism for delivering the liquid in the flow path, the analytical method comprising: an analysis mode for calculating the concentration of a specific substance in the liquid based on data acquired from the flow-type sensor and the reference electrode; and a standby mode for waiting until the next analysis mode, wherein, after the analysis mode and before the standby mode, the liquid delivery mechanism is controlled to fill the liquid-contacting portion of the flow path with liquid, and a gas suction sequence is performed in which the liquid filling the liquid-contacting portion is divided by gas in at least one of the flow path between the flow-type sensor and the reference electrode, and the flow path on the opposite side of the flow-type sensor from the reference electrode.

14. The analytical method according to claim 13, characterized in that, after the gas suction sequence, a determination sequence is performed to determine whether or not the liquid filling the wetted area is divided by the gas.

15. The analytical method according to claim 14, characterized in that, in the judgment sequence, if it is determined that the liquid filling the wetted part is not divided by the gas, the gas suction sequence is performed again.

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