An automated system for on-line detection of organic molecular impurities in semiconductor-grade chemicals.

Abstract

One embodiment of an analytical system can include an initial multiport valve, at least one intermediate multiport valve, an additional multiport valve, and a time-of-flight mass spectrometer (TOF-MS). The initial multiport valve can be configured to receive a sample. The at least one intermediate multiport valve can be fluidly connected to the initial multiport valve and configured to receive a sample from the initial multiport valve. A given intermediate multiport valve can have an ion exchange column associated with it. A given intermediate multiport valve can be selectively configured to direct a sample through its associated ion exchange column (speciation mode) or to bypass the ion exchange column (injection mode). The additional multiport valve can be fluidly connected to the at least one intermediate multiport valve and configured to receive a sample therefrom. The time-of-flight mass spectrometer (TOF-MS) can be fluidly connected to the additional multiport valve.

Description

[Technical Field]

[0001] (Related Applications) This application claims domestic priority to U.S. Provisional Patent Application No. 62 / 949,411, filed December 17, 2019, entitled "AUTOMATED SYSTEM FOR ONLINE DETECTION OF ORGANIC MOLECULAR IMPURITIES IN SEMICONDUCTOR GRADE CHEMICALS." [Background technology]

[0002] Sample introduction systems can be employed to introduce liquid samples into various analytical instruments, such as ICP analyzers (e.g., inductively coupled plasma mass spectrometers (ICP / ICP-MS), inductively coupled plasma atomic emission spectrometers (ICP-AES)), time-of-flight (TOP) mass spectrometers, triple quadrupole (QQQ) mass spectrometers, and other types of sample detectors or analytical instruments for analysis. For example, a sample introduction system can remove an aliquot of liquid sample from a container and then transfer the aliquot to a nebulizer, which converts the aliquot into a polydisperse aerosol suitable for ionization in a plasma by an ICP spectrometer instrument. The aerosol is then sorted in a nebulization chamber to remove larger aerosol particles. Upon exiting the nebulization chamber, the aerosol is introduced into the plasma by the plasma torch assembly of the ICP-MS or ICP-AES instrument for analysis. [Brief explanation of the drawings]

[0003] The detailed description will be made with reference to the accompanying drawings, in which any dimensions included are for illustrative purposes only and are not meant to limit the disclosure.

[0004] [Figure 1] 1 is a schematic diagram of an analysis system according to an exemplary embodiment of the present disclosure. [Figure 2] FIG. 2 is a schematic front view of the central analyzer unit of the analysis system of FIG. 1. [Figure 3]FIG. 1 is a partial schematic diagram of an analytical system selectively used in injection mode or speciation mode, according to an exemplary embodiment of the present disclosure. [Figure 4] 1 is a data table showing percent transfer recovery of 5 ppb spiked samples performed using a procedure according to an embodiment of the present disclosure. [Figure 5] 1 is a data table showing the results of a semi-quantification experiment for phthalic acid conducted using a procedure according to an exemplary embodiment of the present disclosure. [Figure 6] 1 is a data plot of percentage counts over time for speciation mode detection of phthalate plasticizers in isopropyl alcohol (IPA) performed using a procedure according to an exemplary embodiment of the present disclosure. [Figure 7] 1 is a series of data plots for speciation mode detection of sub-ppb phthalates performed using a procedure according to an exemplary embodiment of the present disclosure. [Figure 8] 10 is a set of comparative plots showing results with the gas line to the reference atomizer open and closed, performed using a procedure according to an exemplary embodiment of the present disclosure. [Figure 9] 1 is a plot of count-collection time performed using a procedure according to an exemplary embodiment of the present disclosure. [Figure 10] 1 is a plot of the difference in m / z- versus baseline values ​​for two different grades of 10% H2SO4 performed using a procedure according to an exemplary embodiment of the present disclosure. [Figure 11] 1 is a series of schematic diagrams illustrating an analytical system configured to achieve automatic dilution and / or automatic spiking, according to an exemplary embodiment of the present disclosure, to facilitate adding both reference ions and compound calibration ions to the same sample and injecting the same sample via a single nebulizer. [Figure 12] 1A-1C are a series of schematic diagrams illustrating an analytical system configured to achieve automatic dilution and / or automatic spiking, according to exemplary embodiments of the present disclosure. [Figure 13]1A-1C are a series of schematic diagrams illustrating an analytical system configured to achieve automatic dilution and / or automatic spiking, according to exemplary embodiments of the present disclosure. [Figure 14] 1A-1C are a series of schematic diagrams illustrating an analytical system configured to achieve automatic dilution and / or automatic spiking, according to exemplary embodiments of the present disclosure. [Figure 15] 1 is a data table showing sensitivity by chemical type analyzed using TOF MS, performed using a procedure according to an exemplary embodiment of the present disclosure. [Figure 16] 1 is a data table showing sensitivity by chemical type analyzed using QQQ MS. [Figure 17] 1 is a data table and plots for matrix effects in isopropyl alcohol (IPA) performed using a procedure according to an exemplary embodiment of the present disclosure. [Figure 18] 1 is a data table and plot for matrix suppression in water (H2O) performed using a procedure according to an exemplary embodiment of the present disclosure. [Figure 19] 1 is a data table for matrix effects for a series of chemicals analyzed using TOF using a procedure according to an exemplary embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0005] Aspects of the present disclosure will be described more fully hereinafter with reference to the accompanying drawings, which form a part hereof and which show illustrative features. These features may, however, be embodied in many different forms and should not be construed as limited to the combinations set forth herein, but rather these combinations are provided so that this disclosure will be thorough and complete and will carry its full scope.

[0006] (overview) Determining trace element concentrations or amounts in a sample can provide an indication of the purity of the sample or the acceptability of the sample for use as a reagent, reactive component, etc. For example, in certain production or manufacturing processes (e.g., semiconductor manufacturing, pharmaceutical processing, etc.), the tolerances for impurities can be very strict, e.g., on the order of parts per billion. For example, semiconductor processes may require the detection of organic molecular impurities in processing chemicals. Failure to detect impurities in such processing chemicals can degrade the quality of the process and ruin semiconductor wafers.

[0007] Various types of organic molecular contaminants can adversely affect semiconductor processes. Plasticizers, such as dibutyl phthalate and dioctyl phthalate, can slow silicon dioxide growth. Organic phosphoric acids can cause unintended doping. Amines can neutralize photogenerated acids. Antioxidants, such as butylated hydroxytoluene and butylated hydroxyanisole, can decompose gate oxide structures on wafers. Surfactants, such as cetrimonium bromide and sodium dodecyl sulfate, can impart hydrophilic properties to wafers.

[0008] Furthermore, the use of volatile additives is considered best practice in liquid chromatography-mass spectrometry (LC-MS). Nonvolatile additives have been shown to precipitate salts in the ion source, suppressing signal. To make matters worse, inorganic acids can be corrosive to stainless steel components commonly found in LC-MS sample ionization. Furthermore, high concentrations of mineral acids are generally considered incompatible with electrospray ionization-mass spectrometry (ESI-MS) due to their nonvolatility and potential harm to the sample introduction site. By selectively removing the anions of mineral acids, other components of the matrix can be analyzed. These considerations have led to methods of sulfate removal from samples, including the use of anion-exchange chromatography for this purpose. Sulfate removal can improve the system's ability to detect organic additives.

[0009] Accordingly, the present disclosure relates to systems and methods for automated online detection of organic molecular impurities in chemical samples, such as semiconductor-grade chemical samples.

[0010] The system can employ one or more remote sampling and preparation modules with pneumatic transfer to a central detection device (e.g., a mass spectrometer) that can detect organic analyte impurities in a sample by generating and detecting molecular ions or molecular ion fragments from one or more impurities. In an embodiment, the ion source is electrospray, and the detection device includes a mass spectrometer (MS), such as a time-of-flight (TOF) mass spectrometer or a triple quadrupole (triple quad or QQQ) mass spectrometry instrument. In one embodiment, the system can employ a gas chromatography-mass spectrometry (GC-MS) analysis unit (e.g., alone or in combination with other analysis units). One or more remote sampling and preparation modules can be located at various sampling points within a manufacturing facility and can be sequentially sampled and analyzed or randomly accessed for analysis. In one embodiment, a central analysis unit can sample and analyze up to 40 remote sampling points. In one embodiment, organic-based cleaning solutions can be used (e.g., in the line and / or in any columns), as organic solvents (e.g., methanol, isopropyl alcohol, etc.) tend to dissolve organic compounds better than water. Organic compounds are generally relatively non-polar, meaning that they are not soluble in water.

[0011] In embodiments, the system can operate in at least two modes. For example, in a first mode, the system injects the sample directly into the ion source without chromatographic separation from the sample matrix or from other impurities from the analyte. In one embodiment, the injection mode is a fast process that can be used for the direct analysis of a given chemical. For example, the injection mode can use TOF contaminant identification by exact m / z (mass-to-charge ratio) or QQQ contaminant identification by exact m / z and fragmentation.

[0012] In the second or speciation mode, analytes are first partially or completely separated from the sample matrix or other sample components using chromatography. In one embodiment, speciation mode can confirm chemical composition through a combination of retention time via chromatography (i.e., retention time on an ion exchange column) and accurate m / z measurements via TOF-MS, and can be performed with extremely low detection limits. In one embodiment, speciation mode can result in the elimination of matrix-induced suppression. In embodiments, speciation of multiple organic contaminants can facilitate a fully automated organic impurity monitoring system, providing near real-time monitoring for each chemical. In embodiments, speciation can provide sub-parts-per-billion (sub-ppb) detection limits for most organic contaminants. In embodiments, selection of a secondary analysis in speciation mode is based on initial data from the injection mode analysis. In embodiments, the system can be calibrated using standard addition. The system can be calibrated using external calibration with an offset factor to adjust for sensitivity of the injected sample.

[0013] In embodiments, each of the remote samples can be directed to multiple mass spectrometers to provide complementary information, for example, using TOF to detect one or more known analytes and QQQ-MS to identify unknown analytes.

[0014] In one aspect, the present disclosure relates to methods for remote sample preparation, system component materials, and / or system cleaning. In one embodiment, the system can be configured to incorporate multiple remote sampling points (e.g., up to 40) to monitor many chemicals with a single mass spectrometer. In one embodiment, one or more transfer lines can be fabricated from a specific material, such as fluoropolymer tubing for testing for metal components or PEEK (polyetheretherketone) or fused silica tubing for testing for organics, thereby minimizing potential adverse effects that the transfer line material may have on testing for a specific material class. In one embodiment, organic cleaning solutions (e.g., methanol, isopropyl alcohol, etc.) for transfer and / or central lines and / or column cleaning can be employed, as organic solvents tend to dissolve organic compounds better than water. In one embodiment, the system can mitigate ionization suppression of mineral acids, thereby improving detection of organic contaminants in online monitoring. In one embodiment, the system can be configured for automatic cleaning of air transfer lines after chemical transfer to prevent cross-contamination. The connections associated with the system can accommodate units that are more than 300 meters (m) away from the system's central analyzer.

[0015] In one aspect, the present disclosure relates to software implemented in connection with the system. In one embodiment, the software can import m / z (mass-to-charge ratio) data for organic matter (e.g., both expected and unexpected components and / or contaminants), thereby facilitating testing a larger range of materials / components. Mass spectrometers can only detect ions that are not neutrally charged compounds. m / z refers to the ion mass observed for a particular compound and its associated charge carriers. For example, C3H9N may be observed by the instrument as C3H9N(H+) at +60.0808 because the compound (+H) has a mass of 60.0808 and a charge of +1. m / z detection can be used to identify previously unobserved compounds, thereby automatically detecting such compounds. In one embodiment, the software can be configured to automatically assign chemical formulas based on high-resolution mass (±0.0001 amu) spectroscopy analysis to facilitate the identification of unknown contaminants.

[0016] In one embodiment, the software can be programmed and configured to simultaneously detect multiple organic contaminants and / or components. In one embodiment, the software can be configured to perform semi-quantitative testing (e.g., estimation) on unknown contaminants. In one embodiment, the software can be configured, for example, to classify one or more unknown organic components (e.g., by formula) into a particular class and compare them with compounds from the same class. In one embodiment, the software can be programmed and configured for semi-quantitative calibration of unknown contaminants using high-resolution m / z formulas to classify compounds into classes because compounds within a class (e.g., amines) tend to have similar ionization potentials. In one embodiment, the software can be configured to express unknown compounds as a percent deviation from a baseline, for example, using uncalibrated organic contaminant detection and semi-quantitative intensity expressions according to the deviation from a previous baseline.

[0017] Further aspects of the present disclosure can relate to the implemented software. In one embodiment, the software can be configured to take polarity into account (e.g., to facilitate testing for metals and / or organics). In one embodiment, the software for the central analyzer can be programmed and configured to automatically select a predetermined transfer line for organic or metal contaminants (e.g., send one portion to an organic MS and another portion to an ICPMS for metal and particle detection). In one embodiment, the software can automatically determine whether a contaminant is known (previously observed) or new, and can automatically add newly observed and identified contaminants / materials to a predetermined database or library, if desired.

[0018] In one aspect, the present disclosure relates to automated calibration and / or dilution in the central analyzer of the system. In one embodiment, the central analyzer is configured to simultaneously auto-calibrate organic compounds using in-line syringe dilution for the electrospray mass spectrometer. In one embodiment, automated external calibration can be employed, for example, using in-line syringe dilution. In one embodiment, metals and organics can be analyzed using the same sampling system. In one embodiment, simultaneous detection of organic and metal contaminants can be achieved using automated sampling to two different mass spectrometers (e.g., as part of the central analyzer). In one embodiment, a given sample can be diluted using flow injection (e.g., 4 μl dilution with a carrier). In one embodiment, the central analyzer can be configured to automatically spike samples using the method of standard addition (MSA) to compensate for different chemical matrices. In one embodiment, the central analyzer can be configured to automatically spike samples with one or more analytes that are out of range to bring the sample into range (e.g., with water, methanol, IPA (isopropyl alcohol), or other chemicals). In one embodiment, a remote sample preparation system can be used to maintain sensitivity and transport efficiency, for example, by remotely diluting samples with water or other chemicals (e.g., 10% by volume), improving the transfer and recovery of organic contaminants. In one embodiment, the system can be configured for automated spiking of reference, accurate mass-corrected calibration standards into samples and sensitivity standards for each compound analytical response (sensitivity) calibration. In one embodiment, these steps can be accomplished using a single sprayer for the introduction of both the sample and the mass calibration standard. In one embodiment, these steps can result in measurement sensitivity that is 2-10 times higher than previously achievable. In one embodiment, the central analyzer can be configured to express changes in organic sensitivity as a percentage change from an established baseline.

[0019] In one aspect, the present disclosure relates to sample preparation performed by the present system. In one embodiment, chemical introduction can be controlled. In one embodiment, ion exchange columns (e.g., one or more high-performance liquid chromatography (HPLC) columns) can be employed for both organic and mineral solvents (e.g., tetramethylammonium hydroxide (TMAH) and sulfuric acid). In one embodiment, the present system can be configured to define the difference between mass-accurate reference ions and compound calibrations. In one embodiment, the central analyzer can use a single sprayer (as part of the TOF-MS) for both mass correction and sample introduction. In one embodiment, the central analyzer can be configured to selectively select between injection mode or speciation mode, where a speciation column is not used during injection mode and a speciation column is used during speciation mode. In one embodiment, a platinum (Pt) sprayer can be employed as part of the TOF-MS / central analyzer (e.g., the inert nature of Pt ensures that additional contaminants are not introduced through the use of the sprayer, even at high temperatures). In one embodiment, positive and negative compounds can be selectively analyzed using the present system.

[0020] (Example) 1 illustrates a schematic diagram of an analytical system 100 configured to analyze samples transported over long distances, according to an exemplary embodiment of the present disclosure. The analytical system 100 may include, for example, a central analytical equipment unit 102, multiple remote units 104 (e.g., remote sample preparation units), a chemical supply and monitoring unit 106, a large fluid container 108 (e.g., a tank, tote, or drum), an arriving chemical monitoring vehicle 110, and multiple fluid lines 112 that facilitate fluid interconnection between the various units. FIG. 2 illustrates the central analytical equipment unit 102 in more detail. The central analyzer unit 102 can include, for example, an exhaust enclosure 114, a dual containment tray 116, a TOF MS unit 118, multiple TOF cartridges 120, multiple reservoirs 122 (e.g., fabricated from a high-purity fluoropolymer such as high-purity perfluoroalkoxyalkane (PFA)), at least one leak sensor 124, multiple syringe dilution and valve modules 126, multiple TOF modules 128, on / off and emergency off (EMO) switches 130, an electronics and control computer 132, and a status indicator 134 (e.g., a multicolor light). The analytical system 100 can be configured to analyze organic compounds (e.g., organic contaminants) and metal or mineral constituents (e.g., metal contaminants). In one embodiment, the analytical system 100 can be configured to monitor many chemicals using a single mass spectrometer (e.g., TOF MS unit 118) with access to multiple remote sampling points (e.g., remote unit 104). In one embodiment, a given remote unit 104 may be configured to sample a given chemical to be tested and / or prepare the sample for testing (e.g., adjust the concentration, introduce a diluent, and / or provide an internal standard). In one embodiment, the present analytical system 100 may be known by applicant as a "Scout Carbon" analytical system, or simply as a "Scout" analytical system.

[0021] According to one embodiment of the present disclosure, the analytical system 200 (e.g., used as part of or in conjunction with a central analytical unit) can operate in at least two modes, namely, injection mode and speciation mode, as shown in FIG. 3. To facilitate use in the two modes, in one embodiment, analytical system 200 includes multiple multiport valves 250A-250E, at least one sample source 252, at least one carrier bottle 254, an anion exchange column 256, a cation exchange column 258, a first wash fluid source 260 (e.g., 5% (by weight) NHOH reconditioning agent, other basic solvent, or ultrapure water (UPW)), a second wash fluid source 262 (e.g., 10% (by weight) HNO reconditioning agent, other acidic solvent, or UPW), one or more waste (W) locations 264, a tuning solution source 266, a TOF MS 268, and, as needed, multiple fluid lines 270 providing fluid interconnections between multiport valves 250A-250E and / or other system components. Each of multiport valves 250A-250E can include multiple individual ports 272 (e.g., 4-6 ports 272) to allow fluid flow through, into, or out of a given multiport valve 250A-250E. In one embodiment, multiport valves 250A and 250E can be V6HP valves, multiport valve 250B can be a PL-4 valve, and multiport valves 250C and 250D can be PM6 valves. Multiport valves 250C and 250D can be considered intermediate multiport valves 250B and 250E, with multiport valve 250E being considered the final multiport valve and providing connection to TOF-MS 268 (e.g., at the end of the flow path for a given sample).

[0022] When operating in speciation mode, analytes are first partially or completely separated from the sample matrix or other sample components using chromatography, and ion exchange columns (e.g., anion exchange column 256 and cation exchange column 258) are used to remove matrix material (e.g., an acid such as sulfuric acid or a base such as TMAH) from the sample before directing the sample to TOF-MS 268. For either matrix material, the sample (e.g., 4 μL of sample) can be loaded into multiport valve 250B and pushed into multiport valve 250C. For acid matrices such as sulfuric acid, the sample can be pushed inline through anion exchange column 256 supported by multiport valve 250C, directed to bypass cation exchange column 258 as it travels through multiport valve 250D, and delivered to TOF-MS 268 via multiport valve 250E. For basic matrices such as TMAH, the sample is forced through multiport valve 250C, bypassing its in-line anion exchange column 256, and is directed into multiport valve 250C and its cation exchange column 258, and then through multiport valve 250E to TOF-MS 268.

[0023] Flushing or cleaning of the system may be performed periodically or after each use of a given ion exchange column 256, 258. UPW or a suitable reconditioning agent may be used to flush one or more fluid lines and / or a given ion exchange column 256, 258. For example, UPW and / or an acid reconditioning agent may be used to clean, flush, and / or recondition the cation exchange column 258 and / or multiport valve 250D, while a basic reconditioning agent may be used to clean, flush, or recondition the anion exchange column 256 and / or multiport valve 250C.

[0024] In certain embodiments, organic cleaning fluids, UPW, or other fluids (e.g., solvents) may be used to flush and clean any of the various fluid channeling components (e.g., fluid lines 112, 270 and / or multiport valve 250) of analytical system 100, 200. Analytical system 100, 200 can be configured to automatically clean air transfer lines after chemical transfer to prevent cross-contamination. In certain embodiments, analytical system 100 can automatically clean transfer and central lines (e.g., 112, 270) using organic cleaning fluids. In one embodiment, a sample can be loaded (e.g., 18 mL) into a loop and transferred from a given remote unit 104 to the central analyzer unit 102 using an air transfer line (e.g., 112, 270). Once the sample has been transferred, the same loop can be provided (e.g., filled) with an organic wash solution (e.g., 18 mL), and the organic wash solution can be transferred via the same air transfer line. Finally, the organic wash solution can be rinsed by transferring a similar volume (e.g., 18 mL) of UPW.

[0025] When operating in injection mode, the sample can be delivered from multiport valve 250B through multiport valves 250C and 250D and then through multiport valve 250E without passing through any exchange columns 256 and 258 before finally reaching TOF-MS 268. In some embodiments, the sample can be delivered directly from multiport valve 250B to multiport valve 250E when tested using injection mode (e.g., completely bypassing multiport valves 250C and 250D).

[0026] In some embodiments, automated software can be used when analyzing using the injection mode. The computer 132 or other control unit for the central analyzer unit 102 can be programmed or configured to automatically import data files from the TGF-MS, extract the m / z and their individual intensities, and display these values ​​for the user to view. In some embodiments, the software can be programmed to facilitate the simultaneous detection of multiple organic contaminants or other components. In some embodiments, the software can use m / z detection to address unobserved compounds, thereby allowing these previously unobserved compounds to be automatically detected. The software can automatically determine whether a contaminant is known (previously observed) or a new contaminant. If it is a new contaminant, the software can be configured to automatically add it to, for example, a SECS-GEM (Semiconductor Equipment Communication Standard) / GEM (Generic Equipment) report or material library.

[0027] In one embodiment, software associated with the current analytical system (e.g., resident on the computer 132 of the system 100) can be configured to perform semi-quantitative calibration for unknown contaminants using injection mode. The TOF MS unit 118 can generate high-resolution masses (±0.0001 amu). Using these high-resolution masses, molecular formulas can be calculated and assigned to observed m / z values. An algorithm can be used to classify these generated molecular formulas for semi-quantitation (also referred to as "SEMI-QUANT"). These generated molecular formulas can then be analyzed for molecular structure (e.g., inclusion of specific elements (e.g., N, Cl, P, or S) or fitting specific molecular formula patterns (e.g., C n+8 H 2n+6 O4, but if n>0 or n=2, C 10 H 10 O4)) can be classified based on

[0028] It has been observed that similar compounds within a class ionize to similar (but not exact) intensities (measured in ppb). This is why this technique is semi-quantitative. For example, amines can be ionized using ESI-MS in the same way as other amines, and organophosphates can be ionized using ESI-MS in the same way as other organophosphates, but amines do not ionize in the same way as organophosphates. Each class can have at least one standard compound that is quantified using the automated dilution and calibration capabilities of the analytical system 100. All other compounds within the class can be calibrated according to these standard compounds. When compounds fall into multiple classes, semi-quantitative concentration ranges may be proposed.

[0029] In one embodiment, semi-quantification can be achieved using a set of steps. First, known organic compounds for a class can be calibrated (e.g., establish class X) in the organic central analyzer unit 102 using auto-dilution and auto-calibration. Then, a calibration curve can be automatically generated, and a linear slope and Y-intercept value (R 2 >0.995) can be determined. A new sample can then be run and observed for that unknown m / z value. A mass-accurate molecular formula can be generated based on the high-resolution mass of the unknown m / z. The m / z can be classified based on the molecular formula according to the software (e.g., Class X). The Class X standard slope and Y-intercept values ​​can be applied to obtain a semi-quantified concentration of the unknown m / z. Finally, the semi-quantized concentration can be reported in the software (e.g., for display and / or storage in a data library).

[0030] In one example, the semi-quantitative process involves the determination of dibutyl phthalate (DBF,C 16 H 22 O4) and dioctyl phthalate (DOP,C 24 H 38O4). The analytical system 100 classified both as "phthalates" based on the molecular formulas generated. Each was run on a calibration curve, and the intensities (counts) of each were applied to the other calibration curve for high accuracy of concentration. However, it should be understood that dibutyl phthalate could be quantified with high success using the dioctyl phthalate calibration curve, and vice versa. Figure 5 shows a table of data related to these experiments. Figures 6 and 7 show plots related to speciation mode detection of phthalates.

[0031] In some embodiments, a given remote sample preparation unit 104 can be configured to dilute a given sample in the given remote sample preparation unit 104 with water (e.g., UPW) or other chemicals (e.g., solvents) to improve sample transfer and recovery of any organic components / contaminants. In some embodiments, dilution can range from 5-15% (volume), up to 10% (volume), or 10% (volume). In some embodiments, the analytical system 100 can be configured to automatically prepare samples in the given remote sample preparation unit 104 based on a matrix to ensure high transfer recovery of organic contaminants. Certain chemicals have been found to perform better when diluted with other chemicals. This dilution step can be performed automatically in the remote unit 104 without manual sample preparation prior to transfer. For example, isopropyl alcohol (IPA) exhibits higher air transfer recovery when diluted to 90% (volume) (the remaining 10% is UPW). FIG. 4 provides data showing the improved recovery achieved for the transfer rate of a 5 PPB spiked sample when diluted IPA was used.

[0032] In some embodiments, the analytical system 100 can be configured to allow a given remote sample preparation unit 104 to selectively transfer a sample to a selected one of multiple central analytical units (e.g., 102) for testing, for example, for organic or metal contaminants. In some embodiments, a portion of the sample can be sent to an organic MS, and another portion can be sent to an ICPMS for metal and / or particle detection. To facilitate such selective transfer, differently configured transfer lines (e.g., 112, 270) may be required given the type of testing performed at a given central analytical unit 102. For example, an organic central analytical unit 102 (e.g., "ScoutCarbon" central) can be fabricated from a material such as PEEK or fused silica and have associated (internal, inlet, or outlet) transfer lines (e.g., 112, 270). For example, a metal / particle central analytical unit 102 (e.g., "ScoutDX" or "ScoutNano" central) can be fabricated from a fluoropolymer and have associated transfer lines (e.g., 112). In some embodiments, to support such selective transfer, a given remote sample preparation unit 104 may be provided with an additional multiport valve (e.g., an ESI "P3" valve) to select a transfer location (e.g., which central) and thereby direct a given sample or sample portion via an appropriately configured transfer line (e.g., 112). For example, when a multiport valve is placed in the "load" position, it can connect with one transfer line (e.g., a fluoropolymer line leading to a central using ICPMS). Also, in this example, when the multiport valve is switched to the "inject" position, it can connect with another transfer line (e.g., a PEEK line leading to a central using organic MS).

[0033] In certain embodiments, software associated with the present analytical system 100 (e.g., programmed into the computer 132) can be configured to detect the polarity (e.g., positive or negative, as the case may be) of one or more components (e.g., contaminants) that the system 100 is testing for. In certain embodiments, compounds can be observed as positive or negative ions, and the software can recognize the difference based on data from the TOF-MS unit 118. Standard reports can be modified to allow for the polarity of a given component to be output using custom formulas.

[0034] In one embodiment, the analytical system 100 can be configured for automatic calibration and / or automatic dilution in the central analyzer unit 102. Automatic spiking of standards can generate accurate mass-corrected calibration standards into samples and sensitivity standards for each compound analytical response (sensitivity) calibration. In one embodiment, a single sprayer (e.g., associated with the TOF MS unit 118) can be used for both sample and mass calibration standard introduction, which can improve sensitivity by, for example, 2-10 times. Traditional use of the Agient TOF-MS is to use a second sprayer to introduce reference mass-corrected calibration standards into the electrospray (EST-MS). In this embodiment, these standards are spiked into the sample and introduced via the same sprayer. By doing so, sensitivity is increased without using or shutting off gas flow to the second sprayer. This difference is illustrated in the counts (%) vs. time (min) plot shown in Figure 8.

[0035] In some embodiments, automatic spiking of sensitivity calibration standards (MSA) or a single spike into each sample or standard can be employed. Automatic spiking using the method of standard addition (MSA) can be used to compensate for different chemical matrices. Calibration curves can be automatically generated in the sample itself, which can enable calibration in difficult matrices. The system can automatically spike different amounts of calibration standards into collected samples to generate calibration curves. Compounds with prepared calibration curves in the calibration tab can be displayed along with their concentrations when presented by the analytical system 100, eliminating the need to generate manually generated calibration samples.

[0036] In some embodiments, automatic dilution of samples with one or more analytes outside of range can be used to bring the analytes within the calibration range for accurate quantification. For example, IPA can be diluted with UPW or another chemical to bring saturated analytes into range. In some embodiments, the software may alert the user if a particular m / z saturates the detector and can automatically rerun the sample with diluent. The software can automatically account for this dilution when calculating concentration. In some embodiments, the software can be configured to apply this rule to specific masses, or the software can be configured to apply to all detected masses. In some embodiments, the data report display can indicate that such a rule has been triggered and a rerun has been performed.

[0037] In one embodiment, software can be programmed and configured to automatically and externally calibrate an organic mass spectrometer (e.g., a TOF-MS) using in-line syringe dilution for an electrospray mass spectrometer. The software can be configured to automatically generate external calibration solutions from a single standard solution. The software can also cause the analytical system 100 to automatically dilute an in-line sample to generate a calibration curve. In an exemplary process, the sample can be diluted by flow injection (e.g., 4 μL dilution with carrier) and used in conjunction with an injection mode step. In one embodiment, the sample can be captured in a multiport valve with an internal channel. This channel can have a volume of approximately 4 μL (e.g., a PL-4 valve). When the valve switches, the sample is pushed in-line with the organic / aqueous carrier solution. By the time the sample reaches the TOF-MS, it has mixed with the carrier at both the front and back ends of the sample. This results in a characteristic "peak" shape that can be automatically analyzed when performing injection mode, as shown in Figure 9. The peaks can be analyzed, for example, for organic contaminants or other components, and the data can be reported via software (eg, to a display and / or data library).

[0038] In one aspect of the present disclosure, detection and semi-quantitative intensity expression of uncalibrated organic contaminants can be achieved based on measured deviations from a previous baseline. In certain embodiments, unknown compounds can be expressed as a percentage deviation from a predetermined baseline. One way to compare two different samples of the same chemical is to subtract the intensity of each m / z from the baseline standard. This comparison can be used to create a data plot that can quickly display which m / z values ​​are found in the sample that are not found in the baseline. In certain embodiments, these values ​​can be expressed as a numeric change (i.e., sample intensity is less than baseline intensity). In certain embodiments, these values ​​can be expressed as a percentage deviation from the baseline (i.e., (sample intensity - baseline standard intensity) / baseline standard intensity x 100 = % change).

[0039] Figure 10 shows an example plot created using the numerical change relative to the baseline standard as the basis for the data plot for detecting uncalibrated organic contaminants. Each line with a value greater than 0 represents an m / z observed at a higher intensity than the baseline sample. Each of these is a potential contaminant found in the sample using 10% H2SO4 (volume).

[0040] In one aspect of the present disclosure, the difference between a mass-accurate reference ion and a compound calibration can be defined. The mass-accurate reference ion can be used by a TOF-MS (e.g., TOF MS unit 118) to accurately assign m / z values ​​to all observed ions. TOF-MS is a time-based form of MS. In this process, ions can be sent in "packages" through the flight tube of the MS, each one hitting the detector at a different time (e.g., on the order of picoseconds) due to their mass difference. The instrument can convert this time into an m / z value. A slight shift in the time difference can cause the TOF-MS to read different m / z values. In one embodiment, two ions with known m / z (currently +121 and +922 in positive mode) can be used as reference ions for the TOF-MS. Establishing the reference ion is something that is done automatically by a given TOF-MS. A typical TOF-MS achieves this using two atomizers (one for a given sample and one for the reference mass). The present analytical system 100 can accomplish this via a single sprayer for both the sample and reference mass, both reducing the number of system components employed and achieving lower detection limits relative to standard two sprayer systems.

[0041] Compound calibration can be achieved for unknown compounds by TOF-MS prior to analysis. They are injected into the TOF-MS and observed at a specific m / z value with a certain intensity relative to their concentration. This concentration can be varied via external calibration or MSA to obtain a calibration curve for that specific compound. As noted above, a single sprayer can be used for both the reference ion and the compound calibration ion. In certain embodiments, the analytical system (e.g., system 100) can exhibit auto-dilution and auto-spiking capabilities, allowing both reference ions and compound calibration ions to be added to the same sample, which can be injected at the same time via a single sprayer.

[0042] 11-14 illustrate an apparatus and simultaneous method for achieving automatic dilution and / or automatic spiking, as well as facilitating the addition of both reference ions and compound calibration ions to the same sample and injection of the same sample via a single nebulizer, in accordance with an embodiment of the present disclosure. The analytical system 300 generally includes a plurality of multiport valves 350A-350L, a plurality of injectable fluid sources 352 (e.g., shown as S1, S2, S3, etc., serving as fluid sources for, e.g., test sample, MSA, sample carrier, and diluent, respectively), at least one carrier bottle 354, an anion exchange column 356, a cation exchange column 358, a first wash fluid source 360 ​​(e.g., 5% (wt) NHOH reconditioning agent, other basic solvent, or ultrapure water (UPW)), a second wash fluid source 362 (e.g., 10% (wt) HNO reconditioning agent, other acidic solvent, or UPW), one or more waste (W) locations 364, a tuning solution source 366, a TOF-MS 368, and, as needed, a plurality of fluid lines 370 providing fluid interconnections between the multiport valves 350A-350L and / or other system components. Each of the multiport valves 350A-350L can include multiple individual ports 372 (e.g., 4-12 ports 372) to allow fluid flow to be directed through, into, or out of a given multiport valve 350A-350L. Multiport valve 350D may be considered a "sample-sense" multivalve. The analytical system 300 can further include one or more UPW manifolds 374 and multiple sample loops 376, each of which is associated with a selected multiport valve 350A-350L, as shown. Similar named components in the various embodiments can be expected to be similarly configured and function similarly, unless otherwise noted.

[0043] The process for using analytical system 300 is best seen in FIGS. 12-14. As seen in FIG. 12, sample, MSA additive, diluent, and / or internal standard (e.g., from fluid source 352) can be introduced into multiport valve 350D via multiport valve 350E. The sample, MSA additive, diluent, and / or internal standard can all be pushed into select ports 372 of multiport valve 350D and into sample loop 376 (e.g., a 1 ml loop) associated with multiport valve 350G (e.g., a PM6 valve). As seen in FIG. 13, the sample from sample loop 376 of multiport valve 350G can be captured by multiport valve 350H (e.g., a PL-4 valve). As further seen in FIG. 13, multiport valve 350F can be configured to introduce one or more of pressurized inert gas (e.g., argon (Ar)), other fluids, and / or UPW into multiport valve 350G. As can be seen from FIG. 14, the sample in the sample loop 376 of the multiport valve 350G can ultimately be injected into the TOF-MS 368 for analysis either by injection mode (which bypasses any of the ionization columns (e.g., avoiding the HPLC column) as shown) or by speciation mode (following the LCMS procedure as discussed in connection with FIG. 3).

[0044] Figures 15-19 show comparative data associated with processes performed using the present analytical systems 100, 200, and 300. Figures 15 and 16 demonstrate the sensitivity achievable for the analysis of various organics using TOF-MS and QQQ-MS. Figures 17-19 demonstrate the effect of various carrier and / or matrix materials on various TOF-MS measurements.

[0045] In embodiments, the system controller 118 (e.g., the computer 132 of the analysis system 100) can include a processor, memory, and a communications interface 124. The processor provides at least the processing functionality for the controller and can include any number of processors, microcontrollers, circuits, field programmable gate arrays (FPGAs), or other processing systems, as well as resident or external memory for storing data, executable code, and other information accessed and generated by the controller. The processor can execute one or more software programs embodied in non-transitory computer-readable media that implement the techniques described herein. The processor is not limited by the material from which it is formed or the processing mechanisms employed therein, and as such can be implemented by semiconductors and / or transistors (e.g., using electronic integrated circuit (IC) components), etc.

[0046] The memory is one example of a tangible, computer-readable storage medium that provides storage capability for storing various data and / or program code (e.g., software programs and / or code segments that instruct the processor, or other data) related to the operation of the controller, and possibly other components of systems 100, 200, 300, to perform the functions described herein. Thus, the memory can store data (e.g., programs of instructions for operating the system (including its components)). It should be noted that while a single memory is described, a wide variety of types and combinations of memory (e.g., tangible, non-transitory memory) can be employed. The memory can be integrated with the processor, comprise stand-alone memory, or a combination of both.

[0047] Some examples of memory may include removable and non-removable memory components, e.g., random access memory (RAM), read-only memory (ROM), flash memory (e.g., Secure Digital (SD) memory cards, mini-SD memory cards, and / or micro-SD memory cards), magnetic memory, optical memory, universal serial bus (USB) memory devices, hard disk memory, external memory, removable (e.g., server and / or cloud) memory, etc. In an example implementation, the memory may include memory provided by a removable integrated circuit card (ICC) memory, e.g., a subscriber identity module (SIM) card, a universal subscriber identity module (USIM) card, a universal integrated circuit card (UICC), etc.

[0048] The communication interface can be configured to operate to communicate with components of the system 100, 200, 300. For example, the communication interface can be configured to transmit data for storage by the system 100, 200, 300 and to retrieve data from storage within the system 100. The communication interface can also be communicatively coupled to the processor to facilitate data transfer between the components of the system 100, 200, 300 and the processor. While the communication interface is described as a component of the controller, it should be noted that one or more components of the communication interface can be implemented as external components communicatively coupled to the system 100, 300 or its components via wired and / or wireless connections. The system 100, 300 or its components can include and / or be coupled to one or more input / output (I / O) devices (e.g., via the communication interface), such as a display, a mouse, a touchpad, a touchscreen, a keyboard, a microphone (e.g., for voice commands), etc.

[0049] The communications interface and / or processor may be configured to communicate with a variety of different networks (e.g., a wide area cellular telephone network (e.g., a 3G cellular network, a 4G cellular network, a 5G cellular network, or a Global System for Mobile Communications (GSM) network), a wireless computer communications network (e.g., a WiFi network (e.g., a wireless local area network (WLAN) operated using the IEEE 802.11 network standard), an ad hoc wireless network, the Internet, a wide area network (WAN), a local area network (LAN), a personal area network (PAN), a wireless personal area network (PAN) operated using the IEEE 802.15 network standard, etc.) The communication interface may be configured to communicate with a wireless personal computer (WPAN), a public telephone network, an extranet, an intranet, etc. However, this list is provided by way of example only and is not meant to limit the present disclosure. Additionally, the communication interface may be configured to communicate with a single network or multiple networks via different access points. In certain embodiments, the communication interface may transmit information from the controller to an external device (e.g., a mobile phone, a computer connected to a WiFi network, cloud storage, etc.). In other certain embodiments, the communication interface may receive information from an external device (e.g., a mobile phone, a computer connected to a WiFi network, cloud storage, etc.).

[0050] Although the subject matter has been described in language specific to structural features and / or methodological acts, it is to be understood that the subject matter defined in the appended claims is not necessarily limited to the specific features or acts described above. Rather, the specific features and acts described above are disclosed as example forms of implementing the claims.

Claims

1. an initial multiport valve configured to accept a sample; at least one intermediate multiport valve fluidly connected to the initial multiport valve and configured to receive a sample from the initial multiport valve, a given intermediate multiport valve having an ion exchange column attached thereto, the given intermediate multiport valve being selectably configured to either a) direct the sample through the ion exchange column attached thereto or b) bypass the ion exchange column, wherein in a) case the sample is directed through the selected ion exchange column as part of a speciation mode of operation to remove matrix material from the sample, while in b) case the sample is directed to bypass any ion exchange column as part of an injection mode of operation; an additional multiport valve in fluid communication with the at least one intermediate multiport valve and configured to receive a sample from the at least one intermediate multiport valve; a time-of-flight mass spectrometer (TOF-MS) fluidly connected to an additional multiport valve; 1. Software configured to perform semi-quantitative testing for previously unknown components using high-resolution mass-to-charge ratios (m / z), the software comprising: i) acquiring high-resolution mass-to-charge ratios (m / z) of previously unknown components in a sample by TOF-MS; ii) assigning molecular formulas associated with the previously unknown components based on the high-resolution mass-to-charge ratios (m / z); iii) assigning the molecular formulas to the high-resolution mass-to-charge ratios (m / z); iv) classifying the molecular formulas to fit a particular molecular formula pattern or based on molecular structure; and v) applying the high-resolution mass-to-charge ratios (m / z) of the previously unknown components in the sample to a calibration curve of known compounds corresponding to the classified molecular formulas of the previously unknown components in the sample to obtain semi-quantitative concentrations of the previously unknown components in the sample; When operating in speciation mode, the analytical system is configured to ascertain the chemical composition of a sample by a combination of retention time in a given ion exchange column and the exact mass-to-charge ratio (m / z) determined by TOF-MS.

2. 10. The analytical system of claim 1, wherein the ion exchange column of a given intermediate multiport valve is one of a cation exchange column or an anion exchange column.

3. 10. The analytical system of claim 1, further comprising a source of an organic-based cleaning solution for cleaning at least one of a given ion exchange column or one or more fluid interconnections with the analytical system.

4. further comprising one or more transfer lines; a predetermined transfer line used to test for one or more metal components is fabricated from fluoropolymer tubing; 10. The analytical system of claim 1, wherein a given transfer line used to test for one or more organic components is fabricated from PEEK (polyetheretherketone) or fused silica tubing.

5. 10. The analytical system of claim 1, comprising software configured to simultaneously detect multiple organic components.

6. The analytical system of claim 1 , wherein the software is configured to express unknown compounds based on deviations from a baseline.

7. 10. The analytical system of claim 1, including software configured to take into account the polarity of a given component.

8. 10. The analytical system of claim 1, including software configured to add newly observed components to the database.

9. The analytical system of claim 1 , configured to perform at least one of autocalibration or autodilution.

10. The analytical system of claim 1 , wherein the TOF-MS is configured to use one nebulizer for both mass correction and sample introduction.

11. The analytical system of claim 1 , wherein the TOF-MS employs a platinum atomizer.

12. The analytical system of claim 1 , further comprising a sample preparation unit configured to dilute the sample by up to 10% by volume to improve at least one of sample transfer or recovery of organic components.

13. further comprising an inductively coupled plasma mass spectrometer (ICP-MS) configured to detect at least one metal or particulate component; The analytical system of claim 1 , wherein the TOF-MS is configured to detect at least one organic component.

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