Method and control unit for monitoring and preventing inhibitor failure

Abstract

Methods and control units for monitoring and preventing suppressor failures are provided. The eluent used in IC separation contains non-volatile salts incompatible with electrospray ionization-mass spectrometry (ESI-MS). A suppressor is required to convert these non-volatile salts into water or a volatile acid form (i.e., acetic acid). When the suppressor fails, the non-volatile salts enter the MS, causing extensive shutdowns and maintenance of the mass spectrometer. The suppressor voltage derivative is used to: assess the most common suppressor failure modes, including interruption of regenerant flow and excessive back pressure on the suppressor due to downstream blockage; and to trigger the eluent pump to stop eluent flow or trigger an auxiliary valve to switch the flow to the mass spectrometer from eluent to water.

Description

Background Technology

[0001] Ion chromatography (IC) is a well-established analytical technique and has been the preferred method for determining inorganic and small organic anions for the past 40 years. IC is also widely used for determining inorganic cations, as well as carbohydrates and amino acids.

[0002] Suppressors are components of an IC system. Their function is to reduce the background conductivity of the eluent and increase the conductivity of the analyte through an ion exchange process, thereby improving the response of subsequent conductivity detection. The most popular commercial suppressors employ a three-channel sandwich design, in which the eluent channel for delivering the sample is separated from the regenerant channel located on the sides by two ion exchange membranes. A flat electrode is placed in each regenerant channel. A constant current flows between the two electrodes. Electrolysis of water in the regenerant channel generates hydrogen and hydroxide ions, which are used for eluent suppression. A continuous water supply in the regenerant channel is crucial for the stability of the suppressor's performance.

[0003] In recent years, mass spectrometry (MS) has become the most widely accepted instrument for selective and sensitive detection. When coupled with liquid chromatography (including IC), atmospheric pressure ionization (API) MS (primarily in the form of electrospray ionization (ESI)) is a powerful tool for identifying compounds by determining the molecular weight or characteristic fragments of analytes. IC, at the intersection of MS and MS, plays an important role in multiple fields, including trace analysis of molecular weight inorganic and organic anions via IC-ESI / MS, speciation and metallomics, mass isotope measurements of ionic species, trace organic analysis of molecular weight analytes, and analysis of polysaccharides and other complex carbohydrates.

[0004] The eluent used in IC separation contains non-volatile salts incompatible with ESI-MS. The suppressor is a critical component used to convert these non-volatile salts into water or a volatile acid form (i.e., acetic acid (HOAc)). Specifically, for the analysis of polysaccharides and other complex carbohydrates, various complex gradients using high-concentration sodium acetate (NaOAc) / sodium hydroxide (NaOH) eluents are typically required. When the suppressor fails, these non-volatile salts will enter the MS, causing extensive shutdowns and maintenance of the mass spectrometer. The most common suppressor failures involve water loss in the regenerant channel due to no water flow from the reservoir, pump shutdown, or damaged connecting pipes, as well as suppressor leakage due to excessive downstream back pressure. Summary of the Invention

[0005] A method for monitoring suppressor status, which automatically prevents eluent from reaching the mass spectrometer in the event of suppressor failure. The suppressor voltage derivative is used to monitor suppressor status. The most common suppressor failure modes have been shown to include interruption of regenerator flow and excessive back pressure on the suppressor due to downstream blockage, which can be used to trigger the eluent pump to stop eluent flow or trigger an auxiliary valve to switch the flow to the mass spectrometer from eluent to water. The method requires no additional sensors, thus eliminating the need for complex setups and additional peak dispersion associated with MS detection. The method is applicable to both high-performance anion exchange chromatography (HPAE) systems with manually prepared sodium acetate / sodium hydroxide eluents and reagent-free ion chromatography (RFIC) systems with electrolytically generated eluents coupled to the MS.

[0006] A method for detecting a suppressor malfunction, the suppressor being fluidly coupled to a chromatographic column, the method comprising the steps of: flowing eluent from the chromatographic column to the suppressor; applying a current between the negative and positive electrodes of the suppressor; measuring a voltage across the negative and positive electrodes of the suppressor; calculating a monitored value; and determining a suppressor malfunction when the monitored value is detected to be higher than a threshold value.

[0007] A system control unit for a chromatography system, the chromatography system including a chromatographic column fluidly coupled to a suppressor, wherein the system control unit is configured to: measure a voltage across the negative and positive electrodes of the suppressor; calculate a monitored value; and determine that a suppressor malfunction exists when the monitored value is detected to be higher than a threshold.

[0008] The monitored value is one of the following: a) the time derivative of the voltage. b) the time derivative of the moving average voltage, wherein the moving average voltage is the average voltage of 2 to 20 measurements. c) the moving average of the time derivative of the voltage, wherein the moving average of the time derivative is the average time derivative of 2 to 20 time derivatives. d) the moving average of the time derivative of the moving average of the voltage. e) the higher-order time derivative of the voltage. f) the higher-order time derivative of the moving average voltage. g) the moving average of the higher-order time derivative of the voltage.

[0009] These and other objects and advantages will become apparent from the accompanying drawings and their description. Attached Figure Description

[0010] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments and, together with the general description given above and the detailed description of the embodiments given below, serve to explain the principles of this disclosure.

[0011] Figure 1This is a schematic flowchart of an embodiment of an ion chromatography-mass spectrometry (IC-MS) system with an auxiliary valve.

[0012] Figure 2 This is a schematic flowchart of an embodiment of a high-performance anion exchange chromatography-mass spectrometry (HPAE-MS) system with an auxiliary valve for the analysis of complex carbohydrates.

[0013] Figure 3 This is a schematic flowchart of an embodiment of a reagent-free ion chromatography-mass spectrometry (RFIC-MS) system with an auxiliary valve for cation / anion analysis.

[0014] Figure 4 This is a schematic diagram of an HPAE system coupled to a conductivity detector used in a feasibility study.

[0015] Figure 5 These are conductivity, suppressor voltage, and voltage derivative curves under isocratic elution conditions. Elution flow rate: 0.25 mL / min; Suppressor: Thermo Scientific Dionex ERD500 2-mm. Elution solution: 50 mM NaOAc / 100 mM NaOH; Elution flow rate: 0.25 mL / min; Regenerant: Deionized water; Suppressor current: 150 mA. Sudden loss of regenerant flow rate: Regenerant flow rate: 1.5 mL / min, 0–5 min; 0 mL / min during 5–25 min; 1.5 mL / min during 25–30 min. Gradual loss of regenerant flow rate: Regenerant flow rate: 1.5 mL / min, 0–5 min; 1.5–0 mL / min during 5–10 min; 0 mL / min during 10–25 min; 1.5 mL / min during 25–30 min.

[0016] Figure 6 These are conductivity, suppressor voltage, and voltage derivative curves under isocratic elution conditions. Elution flow rate: 0.25 mL / min; Suppressor: Thermo Fisher Scientific Dionex ERD 500 2-mm. Elution solution: 100 mM NaOAc / 100 mM NaOH; Elution flow rate: 0.25 mL / min; Regenerant: Deionized water; Suppressor current: 150 mA. Sudden loss of regenerant flow rate: Regenerant flow rate: 1.5 mL / min, 0–5 min; 0 mL / min during 5–25 min; 1.5 mL / min during 25–30 min. Gradual loss of regenerant flow rate: Regenerant flow rate: 1.5 mL / min, 0–5 min; 1.5–0 mL / min during 5–10 min; 0 mL / min during 10–25 min; 1.5 mL / min during 25–30 min.

[0017] Figure 7 These are conductivity, suppressor voltage, and voltage derivative curves under isocratic elution conditions. Elution flow rate: 0.25 mL / min; Suppressor: Thermo Fisher Scientific Dionex ERD 500 2-mm. Elution solution: 250 mM NaOAc / 100 mM NaOH; Elution flow rate: 0.25 mL / min; Regenerant: Deionized water; Suppressor current: 200 mA. Sudden loss of regenerant flow rate: Regenerant flow rate: 2 mL / min 0-5 min; 0 mL / min during 5-25 min; 2 mL / min during 25-30 min. Gradual loss of regenerant flow rate: Regenerant flow rate: 2 mL / min 0-5 min; 2-0 mL / min during 5-10 min; 0 mL / min during 10-25 min; 2 mL / min during 25-30 min.

[0018] Figure 8 These are conductivity, suppressor voltage, and voltage derivative curves under isocratic elution conditions. Elution flow rate: 0.25 mL / min; Suppressor: Thermo Fisher Scientific Dionex ERD 500 2-mm. Elution solution: 100 mM NaOH; Elution flow rate: 0.25 mL / min; Regenerant: Deionized water; Suppressor current: 150 mA. Sudden loss of regenerant flow rate: Regenerant flow rate: 1.5 mL / min, 0–5 min; 0 mL / min during 5–25 min; 1.5 mL / min during 25–30 min. Gradual loss of regenerant flow rate: Regenerant flow rate: 1.5 mL / min, 0–5 min; 1.5–0 mL / min during 5–10 min; 0 mL / min during 10–25 min; 1.5 mL / min during 25–30 min.

[0019] Figure 9(A) shows the conductivity, suppressor voltage, and voltage derivative curves of the NaOAc / NaOH gradient eluent with normal regenerant flow rate. Eluent: 10 mM NaOAc / 100 mM NaOH for 0–5 minutes; 10 mM NaOAc to 100 mM NaOH containing 100 mM NaOAc for 5–20 minutes; 100 mM NaOAc / 100 mM NaOH for 20–50 minutes; eluent flow rate: 0.25 mL / min; normal regenerant flow rate: 1.5 mL / min; suppressor: Thermo Fisher Scientific Dionex ERD 500 2-mm; suppressor current: 150 mA.

[0020] Figure 9(B) shows the conductivity, suppressor voltage, and voltage derivative curves of the NaOAc / NaOH gradient eluent with a sudden loss of regenerant flow. Eluent: 10 mM NaOAc / 100 mM NaOH for 0–5 min; 10 mM NaOAc to 100 mM NaOH containing 100 mM NaOAc for 5–20 min; 100 mM NaOAc / 100 mM NaOH for 20–50 min; eluent flow rate: 0.25 mL / min; regenerant flow rate: 1.5 mL / min for 0–10 min; 0 mL / min for 10–40 min; 1.5 mL / min for 40–50 min; suppressor: Thermo Fisher Scientific Dionex ERD 5002-mm; suppressor current: 150 mA.

[0021] Figure 9(C) shows the conductivity, suppressor voltage, and voltage derivative curves of the NaOAc / NaOH gradient eluent as the regenerant flow rate gradually decreased. Eluent: 10 mM NaOAc / 100 mM NaOH for 0–5 min; 10 mM NaOAc to 100 mM NaOH containing 100 mM NaOAc for 5–20 min; 100 mM NaOAc / 100 mM NaOH for 20–50 min; eluent flow rate: 0.25 mL / min; regenerant flow rate: 1.5–0 mL / min for 0–10 min, 0 mL / min for 10–40 min, and 1.5 mL / min for 40–50 min; suppressor: Thermo Fisher Scientific Dionex ERD500 2-mm; suppressor current: 150 mA.

[0022] Figure 10(A) shows the conductivity, suppressor voltage, and voltage derivative curves of the NaOH gradient eluent with normal regenerator flow rate. Eluent: 10 mM NaOH for 0–5 min; 10 mM–100 mM NaOH for 5–20 min; 10 mM NaOH for 20–50 min; eluent flow rate: 0.25 mL / min; normal regenerator flow rate: 1.5 mL / min; suppressor: Thermo Fisher Scientific Dionex ERD 500 2-mm; suppressor current: 150 mA.

[0023] Figure 10(B) shows the conductivity, suppressor voltage, and voltage derivative curves of the NaOH gradient eluent with a sudden loss of regenerant flow. Eluent: 10 mM NaOH for 0–5 min; 10 mM–100 mM NaOH for 5–20 min; 10 mM NaOH for 20–50 min; eluent flow rate: 0.25 mL / min; regenerant flow rate: 1.5 mL / min for 0–10 min; 0 mL / min for 10–40 min; 1.5 mL / min for 40–50 min; suppressor: Dionex ERD 500 2-mm, Thermo Fisher Scientific; suppressor current: 150 mA.

[0024] Figure 10(C) shows the conductivity, suppressor voltage, and voltage derivative curves of the NaOH gradient eluent with gradual loss of regenerant flow. Eluent: 10 mM NaOH for 0–5 min; 10 mM–100 mM NaOH for 5–20 min; 10 mM NaOH for 20–50 min; eluent flow rate: 0.25 mL / min; regenerant flow rate: 1.5–0 mL / min for 0–10 min, 0 mL / min for 10–40 min, and 1.5 mL / min for 40–50 min; suppressor: Dionex ERD 500 2-mm, Thermo Fisher Scientific; suppressor current: 150 mA.

[0025] Figure 11 This is a schematic diagram of a reagent-free ion chromatography (RFIC) system used for feasibility studies.

[0026] Figure 12 These are conductivity, suppressor voltage, and voltage derivative curves under gradient eluent conditions generated by electrolysis during a sudden loss of regenerant flow in an RFIC system. Eluent generator: Dionex EGC 500 KOH; Eluent: 10 mM KOH for 0-10 minutes, 10-100 mM for 10-30 minutes, and 100 mM KOH for 30-60 minutes; Eluent flow rate: 0.25 mL / min; Normal regenerant flow rate: 0.25 mL / min; Regenerant flow rate: 0.25 mL / min for 0-20 minutes, 0 mL / min for 20-50 minutes, and 0.25 mL / min for 50-60 minutes; Suppressor: Dionex ADRS 6002-mm; Suppressor current: 62 mA.

[0027] Figure 13(A) shows the conductivity traces for different regenerant flows. Eluent: 100 mM NaOH containing 100 mM NaOAc; Eluent flow rate: 0.25 mL / min; Normal regenerant flow rate: 1.5 mL / min; Suppressor: Dionex ERD 500 2-mm; Suppressor current: 150 mA. X represents the reduced regenerant flow rate, and the value of X is indicated in the legend.

[0028] Figure 13(B) shows the conductivity traces for different regenerant flows. Eluent: 100 mM NaOH; Eluent flow rate: 0.25 mL / min; Normal regenerant flow rate: 1.5 mL / min; Suppressor: Dionex ERD 500 2-mm; Suppressor current: 150 mA. X represents the reduced regenerant flow rate, and the value of X is indicated in the legend.

[0029] Figure 14 These are the conductivity, suppressor voltage, and voltage derivative curves of the 100 mM NaOAc / 100 mM NaOH eluent with a sudden loss of regenerant flow. Eluent flow rate: 0.25 mL / min; Regenerant flow rate: 1.5 mL / min during 0–5 min, 0 mL / min during 5–95 min, and 1.5 mL / min during 95–100 min; Suppressor: Dionex ERD500 2-mm; Suppressor current: 150 mA.

[0030] Figure 15(A) shows the conductivity, suppressor voltage, and voltage derivative curves under different NaOAc / NaOH gradient elution conditions. Elution: 10 mM NaOAc for 0–5 min, 10 mM NaOAc to 100 mM NaOH containing 100 mM NaOAc for 5–20 min, and 100 mM NaOAc for 20–50 min; Elution flow rate: 0.25 mL / min; Regenerant flow rate: 1.5 mL / min; Suppressor: Dionex ERD 500 2-mm; Suppressor current: 150 mA.

[0031] Figure 15(B) shows the conductivity, suppressor voltage, and voltage derivative curves under different NaOAc / NaOH gradient eluent conditions with a sudden decrease in regenerant flow rate. Eluent: 10 mM NaOAc for 0–5 min, 10 mM NaOAc to 100 mM NaOH containing 100 mM NaOAc for 5–20 min, and 100 mM NaOAc for 20–50 min; Eluent flow rate: 0.25 mL / min; Regenerant flow rate: 1.5 mL / min for 0–10 min, 1.0 mL / min for 10–40 min, and 1.5 mL / min for 40–50 min; Suppressor: Dionex ERD 500 2-mm; Suppressor current: 150 mA.

[0032] Figure 15(C) shows the conductivity, suppressor voltage, and voltage derivative curves under different NaOAc / NaOH gradient eluent conditions with a sudden decrease in regenerant flow rate. Eluent: 10 mM NaOAc for 0–5 min, 10 mM NaOAc to 100 mM NaOH containing 100 mM NaOAc for 5–20 min, and 100 mM NaOAc for 20–50 min; eluent flow rate: 0.25 mL / min; regenerant flow rate: 1.5–1 mL / min for 0–10 min, 1.0 mL / min for 10–40 min, and 1.5 mL / min for 40–50 min; suppressor: Dionex ERD 500 2-mm; suppressor current: 150 mA.

[0033] Figure 16(A) shows the conductivity, suppressor voltage, and voltage derivative curves under different NaOH gradient eluent conditions with normal regenerant flow rates. Eluent: 10 mM NaOH for 0–5 min, 10 mM–100 mM NaOH for 5–20 min, and 100 mM NaOH for 20–50 min; Eluent flow rate: 0.25 mL / min; Regenerant flow rate: 1.5 mL / min; Suppressor: Dionex ERD 500 2-mm; Suppressor current: 150 mA.

[0034] Figure 16(B) shows the conductivity, suppressor voltage, and voltage derivative curves under different NaOH gradient eluent conditions with a sudden decrease in regenerant flow rate. Eluent: 10 mM NaOH for 0–5 min, 10 mM–100 mM NaOH for 5–20 min, and 100 mM NaOH for 20–50 min; Eluent flow rate: 0.25 mL / min; Regenerant flow rate: 1.5 mL / min for 0–10 min, 1.0 mL / min for 10–40 min, and 1.5 mL / min for 40–50 min; Suppressor: Dionex ERD 500 2-mm; Suppressor current: 150 mA.

[0035] Figure 16(C) shows the conductivity, suppressor voltage, and voltage derivative curves under different NaOH gradient eluent conditions with gradual loss of regenerant flow rate. Eluent: 10 mM NaOH for 0–5 min, 10 mM–100 mM NaOH for 5–20 min, and 100 mM NaOH for 20–50 min; Eluent flow rate: 0.25 mL / min; Regenerant flow rate: 1.5–1 mL / min for 0–10 min, 1.0 mL / min for 10–40 min, and 1.5 mL / min for 40–50 min; Suppressor: Dionex ERD 500 2-mm; Suppressor current: 150 mA.

[0036] Figure 17 The curves show conductivity, system pressure, suppressor voltage, and voltage derivative. Eluent: 100 mM KOH; Eluent flow rate: 0.25 mL / min; Suppressor: Thermo Fisher Scientific Dionex ADRS 2-mm; Suppressor current: 62 mA; Regenerant flow rate: 0.25 mL / min.

[0037] Figure 18 The curves show conductivity, system pressure, suppressor voltage, and voltage derivative. Eluent: 10 mM KOH for 0-10 minutes, 10-100 mM for 10-30 minutes, 100 mM KOH for 30-40 minutes, and 10 mM KOH for 40-60 minutes; Eluent flow rate: 0.25 mL / min; Suppressor: Thermo Fisher Scientific Dionex ADRS 2-mm; Suppressor current: 62 mA; Regenerant flow rate: 0.25 mL / min.

[0038] Figure 19The curves show conductivity, system pressure, suppressor voltage, and voltage derivative. Eluent: 100 mM NaOAc / 100 mM NaOH for 0-5 minutes; 250 mM NaOAc / 100 mM NaOH for 5-55 minutes; 100 mM NaOAc / 100 mM NaOH for 55-60 minutes; eluent flow rate: 0.25 mL / min; suppressor: Thermo Fisher Scientific Dionex ERD 500 2-mm; suppressor current: 250 mA; regenerant flow rate: 4 mL / min. Detailed Implementation

[0039] The eluent used in IC separation contains non-volatile salts incompatible with electrospray ionization-mass spectrometry (ESI-MS). A suppressor is required to convert the non-volatile salts into water or a volatile acid form (e.g., acetic acid). When the suppressor fails, the non-volatile salts enter the MS, causing extensive shutdowns and maintenance of the mass spectrometer. The described method provides a means of detecting when a suppressor fails, allowing intervention to prevent damage to the MS. The method uses the time derivative of the suppressor voltage to capture the most common suppressor failure modes, which include interruption of regenerant flow and excessive suppressor back pressure due to downstream blockage. Once a suppressor failure mode is identified, it may trigger the eluent pump to stop the eluent flow or trigger an auxiliary valve to switch the mass spectrometer flow from the eluent to another liquid. The method requires no additional sensors, thus eliminating the need for complex setups and additional peak dispersion associated with MS detection.

[0040] For self-regenerating suppressors, a constant current is applied to the electrodes to induce water electrolysis, thereby providing a continuous supply of hydrogen or hydroxide ions to the eluent. The voltage across the channels in the suppressor is affected by various factors, such as eluent concentration, eluent and regenerator flow rates. The voltage is affected when the water supply in the regenerator channel is interrupted, for example, if no water flows out of the reservoir or the pump shuts off, or if flow is interrupted (either eluent or regenerator flow) due to excessive back pressure caused by downstream blockage.

[0041] Since the absolute value of the suppressor voltage is affected by various factors, including manufacturing variations, the slope of the voltage, i.e. the rate of voltage change, is used to derive the voltage pattern caused by suppressor failure.

[0042] A method for detecting a suppressor malfunction, the suppressor being fluidly coupled to a chromatographic column, the method comprising the steps of: flowing eluent from the chromatographic column to the suppressor; applying a current between the negative and positive electrodes of the suppressor; measuring a voltage across the negative and positive electrodes of the suppressor; calculating a monitored value; and determining a suppressor malfunction when the monitored value is detected to be higher than a threshold value.

[0043] In some embodiments, a system control unit for a chromatography system includes a chromatographic column fluidly coupled to a suppressor, wherein the system control unit is configured to: measure a voltage across the negative and positive electrodes of the suppressor; calculate a monitored value; and determine that a suppressor malfunction exists when the monitored value is detected to be higher than a threshold.

[0044] The monitored value is one of the following: a) the time derivative of the voltage. b) the time derivative of the moving average voltage, wherein the moving average voltage is the average voltage of 2 to 20 measurements. c) the moving average of the time derivative of the voltage, wherein the moving average of the time derivative is the average time derivative of 2 to 20 time derivatives. d) the moving average of the time derivative of the moving average of the voltage. e) the higher-order time derivative of the voltage. f) the higher-order time derivative of the moving average voltage. g) the moving average of the higher-order time derivative of the voltage.

[0045] The time derivative of the voltage is the first derivative of the voltage over time. It is calculated as follows: Time derivative of voltage = (V2 – V1) / (t2-t1); where V1 and V2 are the voltages at two different time points, with V1 preceding V2; and t1 and t2 are the times when the voltage was measured. The time derivative of the moving average voltage is the first derivative of the moving average of the voltage over time. The moving average is a series of measurements, such as the average of 2 to 20 measurements. The moving average can be the moving average of voltage measurements, or it can be the moving average of a calculated time derivative or a higher-order time derivative. For example, the moving average of voltage is calculated as the sum of the voltages divided by the number of voltage measurements (the moving average of V is calculated as: V1 + V2 + … + V…). n-1 +V n The higher-order time derivative can be calculated as one or more time derivatives of the voltage. For example, the second-order time derivative of the voltage can be calculated as: Second-order time derivative of voltage = (TD2 - TD1)(tt2 - tt1); where TD1 and TD2 are the time derivatives of the voltage; and tt1 and tt2 are the times of TD1 and TD2, respectively. The higher-order time derivative can be the second, third, or fourth-order time derivative. In some embodiments, the higher-order time derivative is the second-order time derivative. The voltage is continuously measured as long as the suppressor current is on.

[0046] In some embodiments, the monitored value is selected from: a) the time derivative of the voltage; b) the time derivative of the moving average voltage, wherein the moving average voltage is the average voltage of 2 to 20 measurements; c) the moving average of the time derivative of the voltage, wherein the moving average of the time derivative is the average time derivative of 2 to 20 time derivatives; d) the moving average of the time derivatives of the moving average of the voltage; e) the higher-order time derivative of the voltage; f) the higher-order time derivative of the moving average voltage; and g) the moving average of the higher-order time derivative of the voltage. In some embodiments, the monitored value is the derivative of the voltage. In some embodiments, the monitored value is the time derivative of the moving average voltage. In some embodiments, the monitored value is the moving average of the time derivative of the voltage. In some embodiments, the monitored value is the second-order time derivative of the voltage. In some embodiments, the higher-order time derivative is the second-order time derivative.

[0047] The eluent comprises a salt. In some embodiments, a mixture of salts (e.g., NaOAc / NaOH eluent) is converted in a suppressor to a form whose composition cannot be effectively indicated using a single conductivity detector (e.g., HOAc / NaOAc). The suppression efficiency of the suppressor affects the composition of the converted form. Examples of salts include mixtures of alkali metal acetates and alkali metal hydroxides, or alkali metal hydroxides, or alkali metal carbonates, or mixtures of alkali metal carbonates and bicarbonates, or strong acids. In some embodiments, the eluent comprises a mixture of alkali metal acetates and alkali metal hydroxides. In some embodiments, the eluent comprises alkali metal hydroxides. In some embodiments, the eluent comprises alkali metal carbonates. In some embodiments, the eluent comprises a mixture of alkali metal carbonates and bicarbonates. In some embodiments, the eluent comprises a strong acid.

[0048] A suppressor malfunction is detected when the monitored value exceeds a threshold. The threshold is a predetermined value. In some embodiments, the predetermined value is a percentage of the voltage when the suppressor is operating normally, such as 5% or 10%. In some embodiments, the predetermined value or percentage is determined empirically. The threshold can be varied depending on the eluent used, the concentration gradient used, and the flow rate of the eluent in the chromatography. In some embodiments, the threshold can be changed during sample analysis. Various measures can be taken to prevent salt from flowing into the mass spectrometer when a suppressor malfunction is detected. In some embodiments, after a suppressor malfunction is detected, the pump that flows the eluent is stopped. In some embodiments, after a suppressor malfunction is detected, the flow from the suppressor to the mass spectrometer is interrupted. In some embodiments, after a suppressor malfunction is detected, the flow from the suppressor to the mass spectrometer is interrupted, and a liquid comprising water (such as deionized water) is used instead of the flow to the mass spectrometer.

[0049] Thresholds can be set based on the type of suppressor and system, and are used to shut off the eluent pump to prevent eluent flow to the mass spectrometer. In some embodiments, a 6-way injection valve is installed as an auxiliary valve between the suppressor (or optionally a conductivity detector) and the mass spectrometer. When the auxiliary valve is in position A, the system operates normally, with eluent flowing through the suppressor and to the mass spectrometer, and the auxiliary pump delivering deionized water regenerator to the suppressor. When the monitored value reaches a preset threshold (indicating suppressor failure), the auxiliary valve is triggered to position B, in which eluent flow is switched to the suppressor regenerator inlet, and the auxiliary pump delivers deionized water to the mass spectrometer.

[0050] Chromatographic systems can be configured with different components and various arrangements. In some embodiments, the eluent flows from the column to a suppressor and then to a conductivity cell before reaching the MS.

[0051] Changes in regenerant flow rate are represented as spikes in the slope data curve. When the regenerant flow rate remains constant or changes very little, not affecting suppression performance, the slope data appears as a flat line with uniformly distributed electronic noise. When flow is interrupted, i.e., when the regenerant flow rate is lost or reduced, a negative spike appears in the voltage slope plot over time. The amplitude of the negative spike is related to the rate of regenerant flow rate loss. When eluent flow is obstructed due to downstream blockage, a positive or negative spike (depending on the type of suppressor) appears in the voltage slope plot over time. The amplitude of the spike is related to the magnitude of the pressure increase.

[0052] In this disclosure, the singular forms “a / an” and “the” include plural referents, and unless the context clearly indicates otherwise, a reference to a particular numerical value includes at least that particular value. Thus, for example, a reference to “material” is a reference to at least one of such materials and their equivalents known to those skilled in the art, and so on.

[0053] The modifier “about” should also be considered as disclosing a range defined by the absolute values ​​of the two endpoints. For example, expressing “about 2 to about 4” also discloses the range “2 to 4”. When used to modify a single number, the term “about” can refer to the indicated number plus or minus 10%, and includes the indicated number. For example, “about 10%” can indicate a range of 9% to 11%, and “about 1” can mean 0.9 to 1.1.

[0054] If present, all ranges are inclusive and combinatorial. That is, a reference to a value stated as a range is included in every value within that range. For example, a range defined as 400 to 450 ppm includes 400 ppm and 450 ppm as independent examples. Ranges of 400 to 450 ppm and 450 to 500 ppm can be combined to form a range of 400 to 500 ppm.

[0055] When a list is presented, unless otherwise stated, it should be understood that each individual element of the list and each combination of the list will be interpreted as a separate embodiment. For example, a list of embodiments presented as “A, B, or C” will be interpreted as including embodiments “A”, “B”, “C”, “A or B”, “A or C”, “B or C”, or “A, B, or C”.

[0056] It should be understood that, for clarity, certain features of the invention described herein in the context of individual embodiments may also be provided in combination in a single embodiment. That is, unless obviously incompatible or excluded, each individual embodiment is considered to be combinable with any other embodiment, and such combination is considered another embodiment. Conversely, for brevity, various features of the invention described in the context of a single specific embodiment may also be provided individually or in any sub-combination. It should be further noted that the claims may be drafted to exclude any optional elements. Therefore, this statement is intended as a precondition for the use of exclusive terms such as “solely”, “only”, or negative limitations in the recitation of the elements of the claims. Finally, while embodiments may be described as part of a series of steps or a more general structure, each said step may also be considered an independent embodiment.

[0057] While this disclosure has been illustrated by describing several embodiments, and while illustrative embodiments have been described in considerable detail, the applicant does not intend to limit the scope of the appended claims or restrict them in any way to such details. Other advantages and modifications will readily occur to those skilled in the art. Furthermore, features from individual lists can be combined; and features from examples can be generalized to the entire disclosure.

[0058] Example

[0059] Example 1: Sudden and gradual loss of regenerant flow rate under isocratic elution conditions

[0060] On an HPAE system with manually prepared eluent, a series of eluent conditions were examined for sudden loss of regenerator water flow (simulating no water outflow from the reservoir and pump shutdown) and gradual loss (simulating channel leakage). Figure 4 Since typical eluent conditions for the separation of complex carbohydrates are different NaOAc gradients in a constant 100 mM NaOH, elution with 50 mM (NaOAc) was tested. Figure 5 ), 100 mM ( Figure 6 ) and 250 mM NaOAc ( Figure 7 The elution buffer was 100 mM NaOH. To cover the NaOH eluent system, the 100 mM NaOH eluent ( Figure 8 In a sudden loss test of regenerant water flow rate, the regenerant flow rate is set to zero at the 5th minute and then set back to normal flow rate at the 25th minute to rebalance for the next run. In a gradual loss test of regenerant water flow rate, the regenerant flow rate is set to decrease from normal flow rate to zero over a period of 5-10 minutes, and then set back to normal flow rate at the 25th minute to rebalance for the next run. The dashed line indicates the regenerant flow rate.

[0061] For sudden regenerant flow loss, the instantaneous spike in the voltage derivative signal (amplitude greater than -5 volts / minute) is as follows: Figure 5-8 All the cases shown occur at 5 minutes. Depending on the eluent concentration, the increase in conductivity in response to the cessation of regenerant flow will occur within a few minutes. The instantaneous spike in the voltage derivative can be used to trigger the eluent pump to stop before salt breakthrough begins.

[0062] For gradual regenerant flow loss, a consistent spike greater than -1 V / min is observed approximately 10 minutes before or after the flow eventually stops. Within minutes, conductivity begins to increase, indicating salt breakthrough. Therefore, a threshold can be used to trigger the mechanism.

[0063] Example 2: Sudden and gradual loss of regenerant flow rate under gradient elution conditions

[0064] Under manually prepared eluent gradient conditions, the effects of sudden loss (simulating no water outflow from the reservoir and pump shutdown) and gradual loss (simulating channel leakage) of regenerator water flow were also examined in NaOAc / NaOH (Fig. 9(A)-9(C)) and NaOH (Fig. 10(A)-10(C)) eluent systems, respectively. Figure 4 The normal regenerant flow rates for NaOAc / NaOH and NaOH are depicted in Figures 9(A) and 10(A), respectively. In the sudden loss test of regenerant water flow rate, the regenerant flow rate was set to zero at 10 minutes and then set back to normal flow rate at 40 minutes to rebalance for the next run, as shown in Figures 9(B) and 10(B). In the gradual loss test of regenerant water flow rate, as shown in Figures 9(C) and 10(C), the regenerant flow rate was set to decrease from normal flow rate to zero during the 0-10 minute period and then set back to normal flow rate at 40 minutes to rebalance for the next run (indicated by the green dashed line in Figure 9).

[0065] For a sudden loss of regenerant flow, in both Figures 9(B) and 10(B), an instantaneous spike in the voltage derivative (amplitude greater than -5 V / min) appears at the 10-minute mark. Conductivity shows a significant increase over the minutes. Therefore, the spike in the voltage derivative is effective in indicating flow interruption.

[0066] For gradual regenerant flow loss, a consistent spike greater than -1 V / min was observed before and at the 10-minute mark before the flow finally stopped. Within minutes, conductivity began to increase, indicating salt breakthrough. Therefore, using -1 V / min as the threshold for valve switching remains effective. In the case of Figure 10(C), the eluent was 100 mM NaOH, and the conductivity curve did not change due to the interruption of regenerant flow. The suppressor's ability to suppress relatively low eluent concentrations was demonstrated, and the spike shown on the voltage derivative plot still effectively indicated the interruption of regenerant flow and can be used as a trigger mechanism.

[0067] The impact of regenerant flow interruption was also examined on the RFIC system, where the KOH eluent was generated by a Dionex EGC500 KOH cartridge. Figure 11 ). For example in Figure 12 As shown, when the regenerant flow stops at the 20th minute, a transient negative spike appears in the voltage derivative plot, which can be used to trigger a mechanism to protect the MS. In this example, due to the loss of regenerant flow, the suppressor voltage reaches its maximum setting and stops operating at approximately the 35th minute.

[0068] Example 3: The impact of reduced regenerant flow rate on suppressor performance (test boundary conditions)

[0069] To examine the effect of reduced regenerant flow rate on suppressor performance, a range of regenerant flow rates were tested. In the tests, the regenerant flow rate was set to decrease to various rates ranging from 1.4 to 0 mL / min (value X). As shown in Figures 13(A) and 13(B), in both the NaOAc / NaOH (Figure 13(A)) and NaOH (Figure 13(B)) eluent systems, the conductivity response did not change significantly with variations in regenerant flow rate, except at zero flow.

[0070] To examine whether a reduced regenerant flow rate over a prolonged period would affect suppressor performance, a longer test duration of 90 minutes was conducted. (As in...) Figure 14 As shown, the regenerant flow rate decreased by 30% at minute 5 and continued to operate for 90 minutes before recovering to 100% at minute 95. The sudden flow rate drop produced a spike in the voltage derivative greater than -5 V / min that could be used to trigger the mechanism, while the eluent was still effectively suppressed.

[0071] Sudden and gradual decreases in flow rate were also examined under gradient conditions. As shown in Figures 15(A)-15(C), with eluents containing 10–100 mM NaOAc, and as shown in Figures 16(A)-16(C), with eluents containing 10–100 mM NaOH, when the regenerant flow rate suddenly decreased from 1.5 mL / min to 1 mL / min at minute 10, instantaneous spikes greater than -1 V / min were observed in the voltage derivative. The amplitude of the peak in the conductivity trace generated by the eluent gradient shows a higher peak than under normal regenerant flow rate conditions, indicating some salt breakthrough due to the reduced regenerant flow rate. The voltage derivative spike was effective for triggering the mechanism. When the flow rate gradually decreased from 1.5 mL / min to 1 mL / min during the 0–10 minute period, the effect on the voltage derivative was not significant (i.e., less than -1 V / min), making it difficult to use it to indicate changes in regenerant flow rate. However, as indicated in the conductivity traces, eluent inhibition is unaffected under these conditions, similar to the case of reduced regenerant flow in Figures 13 and 14, and is therefore harmless to MS.

[0072] Example 4: Increased back pressure in the eluent channel

[0073] One of the most common suppressor failure modes is suppressor leakage, which is caused by excessive back pressure downstream of the suppressor outlet due to particulate blockage of the pipe or ESI capillary.

[0074] In the following example, to simulate an increase in back pressure of the suppressor, a flow limiter (Idex adjustable BPR, P-880) was placed at the outlet of the conductivity detector to supply power to the RFIC system at approximately 21 minutes and 34 minutes, respectively. Figure 11 The suppressor (Dionex ADRS 600 2-mm) applies a back pressure of 400-600 psi, as in Figure 17 As shown in the system pressure trace. The duration of the flow restriction is approximately 2.5 minutes each time it is applied. (As shown in...) Figure 17 As shown, positive spikes were observed at the 21st and 34th minutes in response to the increased back pressure. This demonstrates the effectiveness of the voltage derivative method in indicating elevated back pressure applied to the suppressor, which leads to impaired device performance.

[0075] In the following example, a flow restriction is applied to the outlet of the conductivity detector to apply a back pressure of approximately 560 psi to the suppressor during the slope gradient. The duration of the flow restriction is approximately 2.5 minutes. As shown in Figure 15, in addition to the positive spike at approximately 19.5 minutes corresponding to the increase in back pressure, a positive peak also exists at approximately 42.5 minutes due to the gradient in steps from 100 mM KOH to 10 mM KOH. To avoid erroneous signals on the voltage derivative, a second derivative is applied. As shown in the second derivative plot of the suppressor voltage, the positive peak at 42.5 minutes is minimized, while the spike at 19.5 minutes remains distinct. This indicates that applying more than one derivative can effectively eliminate erroneous indications caused by conditions unrelated to suppressor failure.

[0076] In the following example, to simulate an increase in back pressure of the suppressor, a series of limiting tubes were placed at the outlet of the conductivity detector to supply power to the HPAE system at approximately 10 minutes, 15 minutes, 20 minutes, 25 minutes, and 30 minutes, respectively. Figure 4 The suppressor (Dionex ERD 500 2-mm) applies a back pressure of 300-800 psi, as in Figure 19 As shown in the system pressure trace. The duration of the flow restriction is approximately 2 minutes each time it is applied. The system pressure trace shows that the pressure increase reading is lower than the theoretical pressure reading calculated based on the pipe inner diameter and length, especially when a higher back pressure is applied. The suppressor begins to leak as the back pressure increases, thus dissipating the increased system pressure. As shown in Figure 19 As shown, a negative spike response was observed to the increased back voltage. This demonstrates the effectiveness of the voltage derivative method in indicating the increased back voltage applied to the suppressor, which causes performance degradation in the device.

Claims

1. A method for detecting a suppressor malfunction, the suppressor being fluidly coupled to a chromatographic column, the method comprising: The eluent flows from the column to the suppressor; A current is applied between the negative and positive terminals of the suppressor; Measure the voltage across the negative and positive terminals of the suppressor; The monitored value is calculated as one of the following: a) The time derivative of the voltage b) The time derivative of the moving average voltage, wherein the moving average voltage is the average voltage of 2 to 20 measurements. c) The moving average of the time derivative of the voltage, wherein the moving average of the time derivative is the average time derivative of 2 to 20 time derivatives. d) The moving average of the time derivative of the moving average of the voltage. e) The higher-order time derivative of the voltage f) The higher-order time derivative of the moving average voltage, and g) The moving average of the higher-order time derivative of the voltage; and When the monitored value is detected to be higher than the threshold, a suppressor malfunction is determined.

2. The method according to claim 1, wherein the monitored value is the second time derivative of the voltage.

3. The method according to claim 1, wherein the higher-order time derivative is the second-order time derivative.

4. The method according to claim 1, wherein the eluent comprises a mixture of alkali metal acetate and alkali metal hydroxide, or alkali metal hydroxide, or alkali metal carbonate, or a mixture of alkali metal carbonate and bicarbonate, or a strong acid.

5. The method of claim 1, wherein when a suppressor malfunction is determined, the pump that supplies the eluent is stopped.

6. The method of claim 1, further comprising: The eluent is allowed to flow from the suppressor to the mass spectrometer; When a suppressor malfunction is detected, the flow from the suppressor to the mass spectrometer is interrupted.

7. The method of claim 6, further comprising, when the flow is interrupted, supplying a liquid comprising water to the mass spectrometer in place of the eluent.

8. The method of claim 1, further comprising allowing the eluent to flow from the chromatographic column or the suppressor to a conductivity cell.

9. A system control unit for a chromatography system, the chromatography system including a chromatographic column fluidly coupled to a suppressor, wherein the system control unit is configured to: The voltage is measured across the negative and positive terminals of the suppressor; The monitored value is calculated as one of the following: a) The time derivative of the voltage b) The time derivative of the moving average voltage, wherein the moving average voltage is the average voltage of 2 to 20 measurements. c) The moving average of the time derivative of the voltage, wherein the moving average of the time derivative is the average time derivative of 2 to 20 time derivatives. d) The moving average of the time derivative of the moving average of the voltage. e) The higher-order time derivative of the voltage f) The higher-order time derivative of the moving average voltage, and g) The moving average of the higher-order time derivative of the voltage; and When the monitored value is detected to be higher than the threshold, a suppressor malfunction is determined.

10. The system control unit according to claim 9, wherein the monitored value is the second time derivative of the voltage.

11. The system control unit of claim 9, wherein the system control unit is configured to stop the pump that flows the eluent when a suppressor failure is determined to exist.

12. The system control unit of claim 9, wherein in the chromatography system, the suppressor is fluidly coupled to the mass spectrometer; The system control unit is configured to interrupt the flow from the suppressor to the mass spectrometer when a suppressor malfunction is detected.

13. The system control unit of claim 12, wherein the system control unit is configured to supply a liquid comprising water to the mass spectrometer in place of the eluent when the flow is interrupted.

14. The system control unit of claim 9, wherein the conductivity cell is fluidly coupled to the suppressor.

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