Analysis device and analysis method

Abstract

An analysis device according to the present invention includes a membrane filtration device that comprises a microfiltration membrane or an ultrafiltration membrane, a flow injection system that analyzes sample water from the reaction between a substance to be detected that is included in the sample water and a reagent that is included in carrier water and reacts with the substance to be detected, first piping through which concentrated water in which the substance to be detected has been concentrated by the membrane filtration device flows to the flow injection system as the sample water, and a sample water pump that pressurizes the sample water at the first piping. The piping inner diameter of an outlet pipe of the flow injection system is smaller than the piping inner diameter of the first piping.

Description

Analytical device and analytical method

[0001] The present disclosure relates to an analytical device and an analytical method.

[0002] Japanese Patent Laid-Open No. 62-280652 describes a flow injection analysis (hereinafter abbreviated as "FIA") method in which a liquid-liquid mixture consisting of an organic phase and an aqueous phase is introduced into the inner tube of a double tube consisting of an inner tube made of a porous polymer membrane and an outer tube that surrounds the inner tube, or into a region surrounded by the inner tube and the outer tube, and only the organic phase is allowed to permeate through the wall surface of the inner tube made of a porous polymer membrane to separate the organic phase from the aqueous phase, and the obtained organic phase is introduced into a detection section to analyze the analyte element.

[0003] In Japanese Patent Laid-Open No. 2022-011525, the inventors have performed low-concentration analysis of endotoxins and the like using an FIA method that uses fluorescent substances, but it has been difficult to measure the low concentrations required for online measurement.

[0004] In general, endotoxin is a pyrogen that should not be contained in pharmaceutical water such as purified water and water for injection (WFI). Therefore, when producing purified water, water for injection (WFI), etc., it is necessary to remove endotoxin as much as possible, and online monitoring is also required. Online measurement is required to be able to quantify endotoxin down to low concentrations, and to perform accurate and stable measurement.

[0005] When analyzing bacterial-derived substances containing endotoxins using an online analysis device and analysis method that uses the FIA ​​method, it is difficult to perform quantitative analysis even when the concentration of the bacterial-derived substance is low.

[0006] An object of the present disclosure is to improve the quantitativeness of analysis in an online analysis device and analysis method using the FIA ​​method.

[0007] The analytical device of the first embodiment comprises a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, a flow injection system that analyzes sample water through the reaction between a detection target contained in the sample water and a reagent contained in carrier water that reacts with the detection target, a first pipe through which concentrated water in which the detection target has been concentrated by the membrane filtration device flows into the flow injection system as the sample water, and a sample water pump that pressurizes the sample water in the first pipe, and the inner diameter of the outlet pipe in the flow injection system is smaller than the inner diameter of the first pipe.

[0008] In this analytical device, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing the water to be analyzed through the membrane filtration device, concentrated water in which the target substance is concentrated is obtained. The concentrated water is pressurized by a sample water pump in the first pipe and flows into a flow injection system as sample water. In the flow injection system, the sample water is analyzed through a reaction with a reagent contained in carrier water. In this way, the concentrated water in which the target substance is concentrated by the membrane filtration device is sent to the flow injection system as sample water, thereby improving the quantitativeness of the analysis of the sample water for target substances derived from bacteria, including endotoxins.

[0009] Furthermore, in this analytical device, the inner diameter of the outlet pipe in the flow injection system is smaller than the inner diameter of the first pipe.

[0010] This allows the water pressure of the sample water downstream of the pump in the first pipe to be maintained higher than the water pressure of the sample water upstream of the pump, stabilizing the flow rate of the sample water discharged from the pump and increasing the concentration ratio of the target substance in the sample water.

[0011] The analytical device of the second embodiment includes a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, a flow injection system that analyzes sample water through the reaction between the target substance contained in the sample water and a reagent contained in carrier water that reacts with the target substance, a first pipe through which concentrated water in which the target substance has been concentrated by the membrane filtration device flows into the flow injection system as the sample water, a second pipe through which at least a portion of the permeate water from the membrane filtration device flows into the flow injection system as the carrier water, and a sample water pump that pressurizes the sample water in the first pipe.

[0012] In this analytical device, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing the water to be analyzed through the membrane filtration device, concentrated water in which the target substance is concentrated is obtained. The concentrated water is pressurized by a sample water pump in the first pipe and flows into a flow injection system as sample water. In the flow injection system, the sample water is analyzed through a reaction with a reagent contained in carrier water. In this way, the concentrated water in which the target substance is concentrated by the membrane filtration device is sent to the flow injection system as sample water, thereby improving the quantitativeness of the analysis of the sample water for target substances derived from bacteria, including endotoxins.

[0013] Furthermore, this analytical device includes a second pipe through which at least a portion of the permeate from the membrane filtration device flows as carrier water into the flow injection system.

[0014] Therefore, no device for obtaining carrier water is required, and the configuration of the analysis device can be simplified.

[0015] The analytical device of the third aspect comprises a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, a flow injection system that analyzes sample water from the reaction between a detection target contained in the sample water and a reagent contained in carrier water that reacts with the detection target, a first pipe through which concentrated water in which the detection target has been concentrated by the membrane filtration device flows into the flow injection system as the sample water, a second pipe through which the carrier water flows into the flow injection system, and a sample water pump that pressurizes the sample water in the first pipe, and the membrane filtration device has a connection port to which the second pipe is connected.

[0016] In this analytical device, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing the water to be analyzed through the membrane filtration device, concentrated water in which the target substance is concentrated is obtained. The concentrated water is pressurized by a sample water pump in the first pipe and flows into a flow injection system as sample water. In the flow injection system, the sample water is analyzed through a reaction with a reagent contained in carrier water. In this way, the concentrated water in which the target substance is concentrated by the membrane filtration device is sent to the flow injection system as sample water, thereby improving the quantitativeness of the analysis of the sample water for target substances derived from bacteria, including endotoxins.

[0017] Furthermore, the analytical device has a second pipe through which at least a portion of the permeate from the membrane filtration device flows as carrier water into the flow injection system.

[0018] Therefore, no device for obtaining carrier water is required, and the configuration of the analysis device can be simplified.

[0019] Furthermore, in this analytical device, the membrane filtration device has a connection port to which the second pipe is connected.

[0020] By connecting the second pipe to the connection port of the membrane filtration device, the permeate water from the membrane filtration device can be sent to the second pipe as carrier water without being exposed to the outside air, thereby preventing foreign matter from being mixed into the carrier water.

[0021] The analytical device of the fourth aspect comprises a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, a flow injection system that analyzes sample water through the reaction between a detection target contained in the sample water and a reagent contained in carrier water that reacts with the detection target, a first pipe through which concentrated water in which the detection target has been concentrated by the membrane filtration device flows into the flow injection system as the sample water, and a sample water pump that pressurizes the sample water in the first pipe, wherein the pressure on the inlet side of the membrane filtration device is smaller than the pressure at the outlet of the sample water pump and is 0.05 MPa or more.

[0022] In this analytical device, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing the water to be analyzed through the membrane filtration device, concentrated water in which the target substance is concentrated is obtained. The concentrated water is pressurized by a sample water pump in the first pipe and flows into a flow injection system as sample water. In the flow injection system, the sample water is analyzed through a reaction with a reagent contained in carrier water. In this way, the concentrated water in which the target substance is concentrated by the membrane filtration device is sent to the flow injection system as sample water, thereby improving the quantitativeness of the analysis of the sample water for target substances derived from bacteria, including endotoxins.

[0023] Furthermore, in this analytical device, the pressure on the inlet side of the membrane filtration device is lower than the pressure at the outlet of the sample water pump and is 0.05 MPa or higher.

[0024] By setting the pressure on the inlet side of the membrane filtration device in this way, the quantitative analysis of the sample water can be improved.

[0025] The analytical device of the fifth aspect is the second or third aspect, wherein the membrane filtration device is provided with a discharge section that is open to the outside and from which permeated water that has permeated the microfiltration membrane or the ultrafiltration membrane is discharged, and the linear velocity of the permeated water discharged from the discharge section is 0.1 m / sec or more and 2.0 m / sec or less.

[0026] By discharging most of the permeated water that has permeated the ultrafiltration membrane of the membrane filtration device from the discharge section, the amount of permeated water discharged per unit time in the membrane filtration device can be increased, and the concentration of the concentrated water can be increased.

[0027] Furthermore, by setting the linear velocity of the permeate in this manner, a sufficient amount of permeate can be obtained, and endotoxin can be sufficiently concentrated in the membrane filtration device.

[0028] The analytical apparatus of a sixth aspect is the first or fourth aspect, wherein the membrane filtration device is provided with a discharge section that is open to the outside and from which permeated water that has permeated the microfiltration membrane or the ultrafiltration membrane is discharged, the linear velocity of the permeated water discharged from the discharge section is 0.1 m / sec or more and 2.0 m / sec or less, and further includes a second pipe through which at least a portion of the permeated water flows as the carrier water into the flow injection system.

[0029] By discharging most of the permeated water that has permeated the ultrafiltration membrane of the membrane filtration device from the discharge section, the amount of permeated water discharged per unit time in the membrane filtration device can be increased, and the concentration of the concentrated water can be increased.

[0030] Furthermore, by setting the linear velocity of the permeate in this manner, a sufficient amount of permeate can be obtained, and endotoxin can be sufficiently concentrated in the membrane filtration device.

[0031] Since the second pipe is provided, a device for obtaining carrier water is not required, and the configuration of the analysis device can be simplified.

[0032] The seventh aspect of the analytical method involves producing sample water in which the target substance is concentrated using a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, pressurizing the sample water using a sample water pump and sending it to a flow injection system, and analyzing the sample water in the flow injection system from the reaction between the target substance and a reagent contained in carrier water that reacts with the target substance, wherein the water pressure downstream of the sample water pump is higher than the water pressure upstream of the sample water pump.

[0033] In this analysis method, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing the water to be analyzed through the membrane filtration device, concentrated water containing the target substance is obtained. The concentrated water is pressurized by a sample water pump and sent to a flow injection system as sample water. In the flow injection system, the target substance is analyzed through a reaction with a reagent contained in carrier water. In this way, the concentrated water in which the target substance has been concentrated by the membrane filtration device is sent to the flow injection system as sample water, thereby improving the quantitative analysis of the target substance, which is a bacterial substance containing endotoxin.

[0034] Also, in this analysis method, the water pressure downstream of the pump is higher than the water pressure upstream of the pump.

[0035] This stabilizes the flow rate of the sample water discharged from the pump, thereby increasing the concentration rate of the target substance in the sample water.

[0036] The analytical method of the eighth aspect involves producing sample water in which the target substance is concentrated using a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, pressurizing the sample water using a sample water pump and sending it to a flow injection system, sending at least a portion of the permeated water that has permeated the microfiltration membrane or the ultrafiltration membrane in the membrane filtration device to the flow injection system as carrier water, and analyzing the sample water in the flow injection system from the reaction between the target substance and a reagent contained in the carrier water that reacts with the target substance.

[0037] In this analysis method, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing water to be analyzed through the membrane filtration device, sample water is obtained as concentrated water in which the analyte is concentrated. The sample water is pressurized by a sample water pump and sent to a flow injection system. At least a portion of the permeate that passes through the microfiltration membrane or ultrafiltration membrane in the membrane filtration device is sent to the flow injection system as carrier water. In the flow injection system, the analyte in the sample water is analyzed through a reaction with a reagent contained in the carrier water. Since the concentrated water in which the analyte is concentrated by the membrane filtration device is sent to the flow injection system as sample water, the quantitative analysis of the analyte, including bacterial-derived substances, can be improved.

[0038] Furthermore, since at least a portion of the permeate that has passed through the microfiltration membrane or ultrafiltration membrane in the membrane filtration device is sent to the flow injection system as carrier water, no device is required to obtain carrier water, and the configuration of the analytical device can be simplified.

[0039] The ninth aspect of the analytical method involves producing sample water in which the target substance is concentrated using a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, pressurizing the sample water using a sample water pump and sending it to a flow injection system, setting the pressure on the inlet side of the membrane filtration device to be lower than the pressure at the outlet of the sample water pump and to be 0.05 MPa or more, and analyzing the sample water in the flow injection system from the reaction between the target substance and a reagent contained in carrier water that reacts with the target substance.

[0040] In this analysis method, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing the water to be analyzed through the membrane filtration device, sample water is obtained as concentrated water in which the target substance is concentrated. The sample water is pressurized by a sample water pump and sent to a flow injection system. In the flow injection system, the target substance in the sample water is analyzed through a reaction with a reagent contained in carrier water. Since the concentrated water in which the target substance has been concentrated by the membrane filtration device is sent to the flow injection system as sample water, the quantitative analysis of the target substance, including bacterial-derived substances including endotoxins, can be improved.

[0041] Furthermore, by making the pressure on the inlet side of the membrane filtration device lower than the pressure at the outlet of the sample water pump and at 0.05 MPa or higher, the quantitative analysis of the sample water can be improved.

[0042] The analytical method of the tenth aspect is the eighth aspect, wherein in the membrane filtration device, permeated water that has permeated the microfiltration membrane or the ultrafiltration membrane is discharged from a discharge portion of the membrane filtration device to the outside in an unpressurized state and at a linear velocity of 0.1 m / sec or more and 2.0 m / sec or less.

[0043] By setting the linear velocity of the permeate in this manner, a sufficient amount of permeate can be obtained, and endotoxin can be sufficiently concentrated in the membrane filtration device.

[0044] An eleventh aspect of the analytical method is the seventh or ninth aspect, wherein in the membrane filtration device, permeated water that has permeated the microfiltration membrane or the ultrafiltration membrane is discharged from a discharge portion of the membrane filtration device to the outside in an unpressurized state and at a linear velocity of 0.1 m / sec or more and 2.0 m / sec or less, and at least a portion of the permeated water that has permeated the microfiltration membrane or the ultrafiltration membrane in the membrane filtration device is sent to the flow injection system as carrier water.

[0045] By setting the linear velocity of the permeate in this manner, a sufficient amount of permeate can be obtained, and endotoxin can be sufficiently concentrated in the membrane filtration device.

[0046] Furthermore, since at least a portion of the permeate that has passed through the microfiltration membrane or ultrafiltration membrane in the membrane filtration device is sent to the flow injection system as carrier water, no device is required to obtain carrier water, and the configuration of the analytical device can be simplified.

[0047] The technology disclosed herein makes it possible to improve the quantitativeness of analysis in an analysis device and analysis method using the FIA ​​method.

[0048] Fig. 1 is a configuration diagram showing an analytical device of a first embodiment, Fig. 2 is a configuration diagram showing an analytical device of a modified example of the first embodiment, and Fig. 3 is a configuration diagram showing an analytical device of Example 8.

[0049] An analysis device 12 according to a first embodiment will be described below with reference to the drawings. As shown in FIG. 1 , the analysis device 12 analyzes water obtained from a water treatment system (not shown) or water in the process of being treated. In this embodiment, the analysis device 12 analyzes endotoxins contained in the analysis target. Endotoxins are an example of a bacterial-derived substance and also an example of a detection target in the disclosed technology. That is, the analysis device 12 and analysis method of the disclosed technology detect bacterial-derived substances containing endotoxins. The detection target is not limited to endotoxins, i.e., lipopolysaccharides used to constitute the cell walls of gram-negative bacteria, but may also be, for example, various fungi (the bacteria themselves).

[0050] Examples of water obtained by the water treatment system include, but are not limited to, water for injection, pharmaceutical water, etc. Specific examples of the water treatment system include facilities for producing pharmaceutical water such as purified water and water for injection (WFI).

[0051] The analyzer 12 includes a preconcentration section 12A, a reagent mixing section 12B, and a detection section 12C.

[0052] In the illustrated example, the preconcentration section 12A includes a preconcentration pump 14 and a membrane filtration device 16. Water to be analyzed is sent to the preconcentration pump 14 from the water treatment system. The preconcentration pump 14 pressurizes the water to be analyzed and sends it to the downstream membrane filtration device 16 through piping 18. Note that, for example, when the analyzer 12 is directly attached to the sampling line of a purified water production system or an ultrapure water production system for online measurement, the preconcentration pump 14 is not necessary if the pressure in the sampling line is appropriate. Furthermore, if the pressure in the sampling line is higher than the appropriate pressure, a pressure reducing means such as a pressure reducing valve can be installed instead of the preconcentration pump 14.

[0053] The membrane filtration device 16 has an outer cylinder 20. An inlet section 22 is provided at one longitudinal end of the outer cylinder 20, and an outlet section 24 is provided at the other end. Furthermore, a discharge section 26 and a water supply section 28 are provided on the outer periphery of the outer cylinder 20. A pipe 18 extending from the pre-concentration pump 14 is connected to the inlet section 22. A first pipe 32, which will be described later, is connected to the outlet section 24.

[0054] A plurality of hollow fiber ultrafiltration membranes 30 are disposed inside the outer cylinder 20. Sample water flowing into the outer cylinder 20 from the inlet 22 is filtered by the ultrafiltration membranes 30. Specifically, endotoxins do not permeate the ultrafiltration membranes 30, and concentrated endotoxin-containing concentrate water is generated and reaches the outlet 24. The pore size of the ultrafiltration membranes 30 is approximately 0.01 to 0.001 μm. When detecting bacterial-derived substances containing endotoxins as in the technology disclosed herein, it is preferable to use an ultrafiltration membrane 30 having such a pore size in order to concentrate the target substance and obtain concentrated water, given the size of the bacterial-derived substances. Note that a microfiltration membrane may be used instead of an ultrafiltration membrane. As the ultrafiltration membrane or microfiltration membrane, a membrane with a removal rate of the target substance of 90% or more is more preferable, and a membrane with a removal rate of 95% or more is even more preferable.

[0055] In this embodiment, cellulose acetate, polyacrylonitrile, polysulfone, polyethersulfone, modified polyethersulfone, polyvinylidene fluoride, etc. can be used as the material of the ultrafiltration membrane 30. In particular, modified polyethersulfone is preferable as the material of the ultrafiltration membrane 30 because it is less likely to adsorb endotoxins.

[0056] As the membrane filtration device to be used, for example, KROSFLO 20CM 5K MPES manufactured by Repligen, etc. can be used without any limitation.

[0057] The permeate that has passed through the ultrafiltration membrane 30 contains no endotoxin or only a very small amount of endotoxin. In other words, this permeate is endotoxin-free water. The endotoxin-free water is discharged to the outside of the membrane filtration device 16 from the discharge section 26 and the water supply section 28. The membrane filtration device 16 concentrates the sample water 10 to 100,000 times. From the viewpoint of measurement accuracy, a concentration ratio of 1,000 to 100,000 times is more preferable.

[0058] The discharge port of the discharge section 26 is open. The permeated water is substantially discharged in an unpressurized state from the discharge section 26. This unpressurized state means that atmospheric pressure acts on the permeated water discharged from the discharge section 26, but no pressure exceeding this atmospheric pressure acts on the permeated water.

[0059] One end of a first pipe 32 is connected to the outlet 24 of the membrane filtration device 16. Concentrated water in which endotoxin has been concentrated in the membrane filtration device 16 flows through the first pipe 32 as sample water.

[0060] In this embodiment, the water supply unit 24 and the pump 42 are directly attached. That is, because no storage unit is provided between the water supply unit 24 and the pump 42, there is no risk of contamination of the sample water in the storage unit or evaporation of the sample water. Furthermore, to reduce the effects of contamination and evaporation in the storage unit, it is necessary to take measures such as increasing the flow rate to the storage unit and discharging some of the sample water from the storage unit. However, in this case, the concentration ratio decreases, which could result in a decrease in measurement accuracy. In this embodiment, there is no such risk, and accurate measurement is possible.

[0061] One end of a second pipe 34 is connected to the water supply section 28 of the membrane filtration device 16. Endotoxin-free water, from which endotoxins have been removed in the membrane filtration device 16, flows as carrier water through the second pipe 34. The water supply section 28 is an example of a connection port to which the second pipe 34 is connected.

[0062] The flow injection system 40 includes a pump 42. In this embodiment, the pump 42 is a plunger pump. In this plunger pump, a plunger reciprocates within a pump housing to pressurize and send a fluid from the upstream side to the downstream side. In particular, in the example shown in FIG. 1 , a double plunger pump having two plungers arranged in parallel is used as the pump 42, and is provided in common with the first pipe 32 and the second pipe 34. This allows the pump 42 to synchronously pressurize the sample water and carrier water and send them downstream. Note that a peristaltic pump, a syringe pump, or a solenoid pump may also be used as the pump 42. A plunger pump is more preferable.

[0063] A reagent injection section 44 is provided in the second pipe 34 downstream of the pump 42. In the reagent injection section 44, a reagent that reacts with endotoxin is injected into carrier water to obtain carrier water.

[0064] In the reagent mixing section 12B, the first pipe 32 and the second pipe 34 reach the inside of the flow injection system 40. Inside the flow injection system 40, the first pipe 32 and the second pipe 34 join together to form a joining pipe 46. The joining pipe 46 is included in the detection section 12C.

[0065] The reagent in the present application may be a fluorescent reagent in which a fluorescent moiety and a recognition moiety are linked by a spacer, as described in JP 2022-011525 A, but is not particularly limited thereto.

[0066] In the confluence pipe 46, the sample water that has flowed through the first pipe 32 and the carrier water that has flowed through the second pipe 34 are combined to form combined water. In the combined water, a reaction occurs between the endotoxin contained in the sample water and the reagent contained in the carrier water.

[0067] An analyzer 48 is disposed in the confluence pipe 46. The analyzer 48 analyzes the endotoxin concentration from the reaction between the endotoxin and the reagent. In this embodiment, piping (not shown) and a quartz cell connected to the piping are disposed inside the analyzer 48. The analyzer 48 irradiates light onto the confluence water flowing through the quartz cell, and detects the endotoxin concentration from the intensity of the resulting fluorescent signal.

[0068] The analyzer 48 has an outlet pipe 50 for discharging the combined water after analysis. The inner diameter of the outlet pipe 50 is smaller than the inner diameter of the first pipe 32. This allows a state in which the pressure P2 downstream of the pump 42, for example, at the outlet, is higher than the pressure P1 on the inlet side of the pump 42, for example, upstream of the membrane filtration device 16.

[0069] In the analyzer 48, for example, quantification is performed by irradiating the sample with excitation light having a wavelength of 340 to 360 nm and observing the generated fluorescence having a wavelength of 440 to 520 nm. In the analyzer 48, the flow rate of the sample water is 0.01 to 4.00 mL / min, and by keeping the flow rate in this range, measurement accuracy is improved.

[0070] There are no particular restrictions on the materials of the first pipe 32, the second pipe 34, and the junction pipe 46, as long as they can carry the sample water, carrier water, and junction water, respectively. Similarly, there are no particular restrictions on the piping of the analyzer 48, but using, for example, fused silica tubing can suppress reactions between the piping and the junction water flowing therethrough, enabling more accurate analysis.

[0071] In this embodiment, a so-called online analysis device and online analysis method are realized in which the analyzer 48 analyzes the endotoxin concentration while continuously flowing the water to be analyzed.

[0072] Next, the operation of the analysis device 12 of this embodiment and the analysis method will be described.

[0073] Water to be analyzed, sent from a water treatment system (not shown), is pressurized by a preconcentration pump 14 and sent to a membrane filtration device 16. In the membrane filtration device 16, the water to be analyzed is filtered by an ultrafiltration membrane 30, and concentrated water in which endotoxins are concentrated and permeate water that does not contain endotoxins (endotoxin-free water) are obtained.

[0074] The permeated water is discharged from the discharge section 26 and the outlet section 24 to the outside of the membrane filtration device 16. In the analyzer 12 of this embodiment, the discharge port of the discharge section 26 is open, and the permeated water is discharged from the discharge section 26 under no pressure. That is, most of the permeated water that has passed through the ultrafiltration membrane 30 is discharged from the discharge section 26. Therefore, the flow rate that can be discharged is greater compared to a configuration in which a pressure exceeding atmospheric pressure acts on the permeated water discharged from the discharge section 26. Endotoxins can be concentrated from a larger amount of water to be treated per unit time, and the concentration of the concentrated water can be increased.

[0075] Here, it is preferable that the inner diameter of the discharge section 26 be 2 mm or more and 30 mm or less, or that the linear velocity of the permeated water flowing through the discharge section 26 be 0.1 m / sec or more and 2.0 m / sec or less. Furthermore, it is preferable that the length of the piping of the discharge section 26 (the length from the outer tube 20 to the outlet of the discharge section 26) be 30 m or less. By setting the shape of the discharge section 26 or the linear velocity of the permeated water in this manner, a sufficient amount of permeated water can be obtained, and endotoxin can be sufficiently concentrated in the membrane filtration device 16. Furthermore, the inlet pressure of the pump 42 downstream of the water supply section 28 can be maintained within an appropriate range, and the amount of reagent added in the reagent injection section 44 can be maintained appropriately, thereby further stabilizing the measured values ​​in the analyzer 48. The inner diameter of the discharge section 26 refers to the inner diameter at the portion where the cross-sectional area of ​​the flow path of the discharge section 26 is narrowest, and the above-mentioned linear flow velocity is the linear velocity at this portion.

[0076] 2 as a first modified example, the discharge section 26 may be provided by branching off from between the water supply section 28 and the pump 42. In this case, the diameter of the pipe from the water supply section 28 to the discharge section 26 is set within the above-mentioned range, and the inner diameter of the second pipe 34 between the discharge section 26 and the pump 42 is preferably, for example, 0.5 mm or more and 2.0 mm or less.

[0077] At least a portion of the permeate that has permeated the ultrafiltration membrane 30 is sent as carrier water from the water supply unit 28 to the reagent injection unit 44 of the flow injection system 40 via the second pipe 34. There is no need to use another device to obtain carrier water, and the configuration of the analyzer 12 and the procedure of the analysis method can be simplified.

[0078] When the membrane filtration device 16 is of an internal pressure type, either the method shown in FIG. 1 or FIG. 2 can be applied, but when it is of an external pressure type, the method shown in FIG. 2 can be preferably used.

[0079] Furthermore, the second pipe 34 is connected to the discharge part 26, and the permeated water is not exposed to the outside air. This makes it possible to prevent foreign matter from being mixed into the permeated water (carrier water) as endotoxin-free water.

[0080] The carrier water is pressurized by a pump 42 and sent downstream. Downstream of the pump 42, a reagent is injected by a reagent injector 44.

[0081] The concentrated water obtained by the membrane filtration device 16 is sent as sample water from the outlet 24 through the first pipe 32 to the reagent injection section 44 of the flow injection system 40. The sample water is then pressurized by the pump 42 and sent downstream. In the analyzer 12 of this embodiment, the concentrated water in which endotoxin has been concentrated to a high concentration by the membrane filtration device 16 is used as sample water, and the endotoxin concentration can be analyzed by the flow injection system 40. Compared to using sample water with a low endotoxin concentration without using the membrane filtration device 16, the quantitative accuracy of endotoxin analysis can be improved.

[0082] The first pipe 32 is connected to the outlet 24, and the concentrated water is not exposed to the outside air. This makes it possible to prevent foreign matter from being mixed into the concentrated water (sample water).

[0083] The sample water in the first pipe 32 and the carrier water in the second pipe 34 are joined at a joining pipe 46 to form joined water. Then, a reaction occurs between the endotoxin contained in the sample water and the reagent contained in the carrier water. The joined water is then sent to an analyzer 48. The analyzer 48 obtains the endotoxin concentration from the reaction between the endotoxin and the reagent and analyzes the sample water.

[0084] In the analyzer 12 of this embodiment, the inner diameter of the outlet pipe 50 of the analyzer 48 is smaller than the inner diameter of the first pipe 32. This achieves a state in which the pressure P2 at the outlet portion downstream of the pump 42 is higher than the pressure P1 at the upstream side of the membrane filtration device 16 upstream of the pump 42. Because the discharge pressure at the outlet side of the pump 42 is higher than the water pressure at the inlet side of the pump 42, the pump 42 is less affected by the water pressure at the inlet side when it is driven. In other words, the water pressure at the outlet side dominates the effect on the flow rate of the sample water discharged from the pump 42. Because the flow rate of the sample water discharged from the pump 42 is not affected by pressure fluctuations at the inlet side, the flow rate at the outlet side can be stabilized and maintained within a constant range. This results in a higher concentration rate of endotoxin in the sample water compared to when the discharge pressure at the outlet side of the pump 42 is lower than the water pressure at the inlet side of the pump 42. Furthermore, as the concentration rate of endotoxin increases, the signal intensity at the analyzer 48 also increases. That is, in the flow injection system 40, it is possible to improve the quantitativeness of endotoxin analysis.

[0085] Next, the technology of the present disclosure will be described in more detail with reference to examples and comparative examples, although the technology of the present disclosure is not limited to the contents of the examples shown below.

[0086] In the examples and comparative examples, the analyzer 12 of the first embodiment was used to analyze the endotoxin concentration of sample water in which endotoxin was injected into carrier water so that the endotoxin concentration was 10 nM. Specifically, the range of measurement values ​​of the endotoxin concentration of the sample water obtained by the analyzer 48 was verified.

[0087] In the examples and comparative examples, the measurement conditions were an excitation wavelength of 350 nm, a detection fluorescence wavelength of 500 nm, a fluorescent reagent Zn-dpa-C2OPy (see chemical formula (1) below), and a fluorescent reagent concentration of 10 μM in the reagent injection port.

[0088]

[0089] In the examples and comparative examples, the measurement conditions were an excitation wavelength of 350 nm and a detection fluorescence wavelength of 500 nm.

[0090] Table 1 shows, for each of the examples and comparative examples, the pressure P1 at the inlet side of the membrane filtration device 16, the pressure P2 at the outlet of the pump 42, and the measurement range of the analyzer 48. This measurement range is the range of values ​​actually measured as the endotoxin concentration by the analyzer 48, and specifically, the maximum and minimum values ​​obtained from five measurements are shown.

[0091] The pressure P1 at the inlet side of the membrane filtration device 16 can be set to a desired pressure value by a water treatment system (not shown) arranged upstream of the analysis device 12 and the pre-concentration pump 14.

[0092] In Examples 1 to 7 and Comparative Examples 1 to 3 shown in Table 1, the settings of the pressure P1 and pressure P2 in the analyzer 12 shown in FIG. 1 were changed and the measurement ranges were verified.

[0093] Example 8 shown in Table 1 is an example in which the analytical device 52 shown in Figure 3 is used. In this analytical device 52, a small tank 54 is further installed between the outlet 24 and the pump 42 in addition to the components of the analytical device 12 shown in Figure 1. In this case, the sample water concentrated by the membrane filtration device 16 is temporarily stored in the tank 54, and this stored sample water is sucked up by the pump 42. The capacity of the tank 54 is 10 ml.

[0094]

[0095] As can be seen from Table 1, in Examples 1 to 7, the relationship P1 < P2 is satisfied, and measurement values ​​obtained within the measurement range are approximately equivalent to the endotoxin concentration in the supply water. That is, in Examples 1 to 7, quantitative measurement of the endotoxin concentration in the sample water is possible. This is because, in Examples 1 to 7, the flow rate of the sample water flowing through first pipe 32 is appropriately controlled, and the flow rate ratio between this sample water and the carrier water flowing through second pipe 34 is an appropriate value. Furthermore, the high endotoxin concentration in the concentrated water allows analyzer 48 to function properly.

[0096] In the case of Example 8, the pressures P1 and P2 are set to specified values, and the relationship P1<P2 is satisfied. In Example 8, the values ​​in the measurement range tend to be larger than in the other examples. This is because contamination occurs in the tank 54 when the sample water is received in the tank 54. In this way, in the case of Example 8, it is known in advance that the values ​​in the measurement range will be measured to be larger than the actual values. To deal with this, for example, a predetermined correction coefficient may be obtained and the measured values ​​may be multiplied by the correction coefficient.

[0097] In the eighth embodiment, the tank 54 prevents the pressure in the upstream stage of the tank 54 from affecting the pressure in the downstream stage of the tank 54, and therefore has the advantage that the pressure P1 can be freely set.

[0098] In particular, the value of pressure P1 preferably satisfies the above condition of P1<P2 and is P1≧0.03 MPa, and more preferably P1≧0.05 MPa. By setting the lower limit of the pressure P1 in this manner, concentration can be sufficiently performed at the ultrafiltration membrane 30, thereby improving measurement accuracy. In each example shown in Table 1, the smallest value of pressure P1 is 0.03 MPa, and the next smallest value is 0.06 MPa. However, in practice, concentration can be sufficiently performed at the ultrafiltration membrane 30 as long as pressure P1 satisfies P1≧0.05 MPa.

[0099] In contrast, in Comparative Examples 1 to 3, the relationship P1≧P2 holds, and the measurement range is a smaller value than the endotoxin concentration of the supply water. This is because, in Comparative Examples 1 to 3, a large amount of sample water flows through the first pipe 32, and the flow rate ratio between this sample water and the carrier water flowing through the second pipe 34 is not appropriate, so the reagent concentration in the junction pipe 46 becomes diluted or the concentration is unstable. Furthermore, because the amount of sample water flowing through the first pipe 32 is unstable and the endotoxin concentration cannot be maintained high, the measurement value does not reach the appropriate measurement range of the analyzer 48.

[0100] 3, it is also possible to install a pressure adjustment valve instead of the tank 54. However, this method cannot be implemented because there are no commercially available valves that can adjust the pressure at such a flow rate.

[0101] The following supplementary notes are further disclosed. (Supplementary Note 1) An analytical device comprising: a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; a flow injection system for analyzing sample water through a reaction between an analyte contained in the sample water and a reagent contained in carrier water that reacts with the analyte; a first pipe through which concentrated water in which the analyte has been concentrated by the membrane filtration device flows as the sample water into the flow injection system; and a pump for pressurizing the sample water in the first pipe. (Supplementary Note 2) The analytical device according to Supplementary Note 1, wherein the inner diameter of an outlet pipe in the flow injection system is smaller than the inner diameter of the first pipe. (Supplementary Note 3) The analytical device according to Supplementary Note 1 or Supplementary Note 2, wherein the membrane filtration device has a discharge part that is open to the outside and through which permeated water that has permeated the ultrafiltration membrane is discharged. (Supplementary Note 4) The analytical device according to Supplementary Note 3, wherein the membrane filtration device has a discharge part that is open to the outside and through which permeated water that has permeated the ultrafiltration membrane is discharged. (Appendix 5) The analytical device according to Appendix 4, wherein the membrane filtration device has a connection port to which the second pipe is connected. (Appendix 6) The analytical device according to Appendix 1, wherein the pressure on the inlet side of the membrane filtration device is lower than the pressure at the outlet of the pump and is 0.05 MPa or higher. (Appendix 7) An analytical method comprising: producing sample water in which a target substance is concentrated using a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; pressurizing the sample water with a pump to send it to a flow injection system; and analyzing the sample water in the flow injection system from the reaction between the target substance and a reagent contained in carrier water that reacts with the target substance. (Appendix 8) The analytical method according to Appendix 7, wherein the water pressure downstream of the pump is higher than the water pressure upstream of the pump. (Appendix 9) The analytical method according to Appendix 7 or Appendix 8, wherein the permeated water that has permeated the ultrafiltration membrane in the membrane filtration device is discharged outside the membrane filtration device in an unpressurized state. (Supplementary Note 10) The analytical method according to Supplementary Note 9, wherein at least a portion of the permeate from the membrane filtration device is sent to the flow injection system as the carrier water.(Supplementary Note 11) The analytical method according to Supplementary Note 7, wherein the pressure on the inlet side of the membrane filtration device is set to be lower than the pressure at the outlet of the pump and to be 0.05 MPa or higher.

[0102] The disclosure of Japanese Patent Application No. 2023-210477, filed on December 13, 2023, is incorporated herein by reference in its entirety. All documents, patent applications, and technical standards described herein are incorporated herein by reference to the same extent as if each individual document, patent application, and technical standard was specifically and individually indicated to be incorporated by reference.

Claims

1. An analytical apparatus comprising: a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; a flow injection system that analyzes sample water through a reaction between a detection target contained in the sample water and a reagent contained in carrier water that reacts with the detection target; a first pipe through which concentrated water in which the detection target has been concentrated by the membrane filtration device flows into the flow injection system as the sample water; and a sample water pump that pressurizes the sample water in the first pipe, wherein the inner diameter of the outlet pipe in the flow injection system is smaller than the inner diameter of the first pipe.

2. An analytical apparatus comprising: a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; a flow injection system for analyzing sample water through a reaction between a detection target contained in the sample water and a reagent contained in carrier water that reacts with the detection target; a first pipe through which concentrated water in which the detection target has been concentrated by the membrane filtration device flows into the flow injection system as the sample water; a second pipe through which at least a portion of the permeated water from the membrane filtration device flows into the flow injection system as the carrier water; and a sample water pump for pressurizing the sample water in the first pipe.

3. An analytical device comprising: a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; a flow injection system for analyzing sample water through a reaction between a detection target contained in the sample water and a reagent contained in carrier water that reacts with the detection target; a first pipe through which concentrated water in which the detection target has been concentrated by the membrane filtration device flows into the flow injection system as the sample water; a second pipe through which the carrier water flows into the flow injection system; and a sample water pump for pressurizing the sample water in the first pipe, wherein the membrane filtration device has a connection port to which the second pipe is connected.

4. An analytical apparatus comprising: a membrane filtration device equipped with a microfiltration membrane or ultrafiltration membrane; a flow injection system that analyzes sample water through a reaction between a detection target contained in the sample water and a reagent contained in carrier water that reacts with the detection target; a first pipe through which concentrated water in which the detection target has been concentrated by the membrane filtration device flows into the flow injection system as the sample water; and a sample water pump that pressurizes the sample water in the first pipe, wherein the pressure on the inlet side of the membrane filtration device is lower than the pressure at the outlet of the sample water pump and is 0.05 MPa or higher.

5. The analytical apparatus according to claim 2 or 3, wherein the membrane filtration device is provided with a discharge section that is open to the outside and from which permeated water that has permeated the microfiltration membrane or the ultrafiltration membrane is discharged, and the linear velocity of the permeated water discharged from the discharge section is 0.1 m / sec or more and 2.0 m / sec or less.

6. The analytical apparatus of claim 1 or claim 4, wherein the membrane filtration device is provided with a discharge section that is open to the outside and from which permeated water that has permeated through the microfiltration membrane or the ultrafiltration membrane is discharged, the linear velocity of the permeated water discharged from the discharge section is 0.1 m / sec or more and 2.0 m / sec or less, and further provided with a second piping through which at least a portion of the permeated water flows into the flow injection system as the carrier water.

7. An analytical method comprising the steps of: producing sample water in which the target substance is concentrated using a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; pressurizing the sample water using a sample water pump and sending the sample water to a flow injection system; analyzing the sample water in the flow injection system from the reaction between the target substance and a reagent contained in carrier water that reacts with the target substance; and the water pressure downstream of the sample water pump being higher than the water pressure upstream of the sample water pump.

8. An analytical method comprising the steps of: producing sample water in which the target substance is concentrated using a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; pressurizing the sample water using a sample water pump and sending it to a flow injection system; sending at least a portion of the permeated water that has permeated the microfiltration membrane or the ultrafiltration membrane in the membrane filtration device to the flow injection system as carrier water; and analyzing the sample water in the flow injection system from the reaction between the target substance and a reagent contained in the carrier water that reacts with the target substance.

9. An analytical method comprising the steps of: producing sample water in which the target substance is concentrated using a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; pressurizing the sample water using a sample water pump and sending it to a flow injection system; setting the pressure on the inlet side of the membrane filtration device to be lower than the pressure at the outlet of the sample water pump and to be 0.05 MPa or more; and analyzing the sample water in the flow injection system from the reaction between the target substance and a reagent contained in carrier water that reacts with the target substance.

10. The analytical method described in claim 8, wherein in the membrane filtration device, the permeate that has permeated the microfiltration membrane or the ultrafiltration membrane is discharged from the discharge portion of the membrane filtration device to the outside under no pressure and at a linear velocity of 0.1 m / sec or more and 2.0 m / sec or less.

11. The analytical method described in claim 7 or claim 9, wherein in the membrane filtration device, the permeate that has permeated the microfiltration membrane or the ultrafiltration membrane is discharged from a discharge portion of the membrane filtration device to the outside under no pressure and at a linear velocity of 0.1 m / sec or more and 2.0 m / sec or less, and at least a portion of the permeate that has permeated the microfiltration membrane or the ultrafiltration membrane in the membrane filtration device is sent to the flow injection system as carrier water.

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