Chloride ion sensor

Abstract

Described herein are chloride ion-selective electrode membranes having an epoxy component, a hardener component, and one or more polyurethanes. Also described herein are chloride ion-selective electrode membranes having an epoxy component, a hardener component, one or more polyurethanes, and silica. The present disclosure also relates to a chloride ion-selective electrode having a substrate with a chloride ion-selective electrode membrane on a surface thereof and a method of making the same.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 565,346, filed March 14, 2024, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure generally relates to the field of chloride ion selective electrode membranes, chloride ion selective electrodes incorporated in the membranes, and methods for manufacturing the same. Background Technology

[0004] Ion-selective electrodes play an important role in various diagnostic assays for the detection and / or quantification of certain ions, such as sodium (Na₂O₃), in biological samples. + ), potassium (K) + ), magnesium (Mg²) + ), calcium (Ca²) + ) and chloride ions (Cl - However, the use of ion-selective electrodes in this situation becomes complicated by the influence of interfering ions (i.e., components in the sample that may provide positive or negative bias to the ions of interest). Chloride ion-selective electrodes are particularly susceptible to the significant effects of interfering ions such as bromide, citrate, iodide, and thiocyanate ions. Therefore, there is a need in the art for chloride ion-selective electrodes that can withstand common interfering ions. Summary of the Invention

[0005] This document discloses a chloride ion selective electrode membrane comprising an epoxy resin component, a curing agent component, and at least one polyurethane. It also discloses a chloride ion selective electrode membrane comprising an epoxy resin component, a curing agent component, at least one polyurethane, and silica. This disclosure further relates to a chloride ion selective electrode having a substrate on which a chloride ion selective electrode membrane is disposed. Methods for manufacturing the chloride ion selective electrode membrane and the chloride ion selective electrode as described herein are further disclosed. Attached Figure Description

[0006] Figure 1A This is a cross-sectional view of a first exemplary chloride ion selective electrode according to various aspects of this disclosure.

[0007] Figure 1B This is a cross-sectional view of a second exemplary chloride ion selective electrode according to various aspects of this disclosure.

[0008] Figure 1C This is a cross-sectional view of a third exemplary chloride ion selective electrode according to various aspects of this disclosure.

[0009] Figure 2AThis is a cross-sectional view of an exemplary potential measurement cell assembly according to various aspects of this disclosure.

[0010] Figure 2B Is it about Figure 2A A top view of the described potentiometric cell assembly.

[0011] Figure 3A These are microscopic images of an exemplary chloride ion selective electrode membrane prepared according to Example I.

[0012] Figure 3B This is a confocal top view of the chloride ion selective electrode membrane prepared according to Example I.

[0013] Figure 3C This is a cross-sectional view of the chloride ion selective electrode membrane prepared according to Example I.

[0014] Figure 4 As described in Example II, on the first day of the test, a graphical representation of the sensitivity of the chloride ion selective electrode membrane alone and the chloride ion selective electrode membrane in the presence of whole blood with different concentrations of chloride ions is shown, where the Y-axis is the sensor output in microvolts and the X-axis is time.

[0015] Figure 5 As described in Example II, on the second day of testing, a graphical representation of the sensitivity of the chloride ion selective electrode membrane alone and in the presence of whole blood without added interfering anions, whole blood with added bromide ions, and whole blood with added iodide ions is provided, where the Y-axis represents the sensor output in microvolts and the X-axis represents time.

[0016] Figure 6 As described in Example II, on the third day of testing, a graphical representation of the sensitivity of the chloride ion selective electrode membrane alone and in the presence of whole blood without added interfering anions, whole blood with added bromide ions, and whole blood with added iodide ions is provided, where the Y-axis represents the sensor output in microvolts and the X-axis represents time.

[0017] Figure 7 This is a graphical representation of the sensitivity of the chloride ion selective electrode membrane in mV / dec over three days in the presence of whole blood, bromide ions, and iodide ions, as described in Example II.

[0018] Figure 8 The table showing the effect of bromide ion interference on the chloride ion selective electrode membrane is as described in Example II.

[0019] Figure 9 yes Figure 8 The data shown is a graphical representation comparing it with a reference blood gas analyzer.

[0020] Figure 10 As described in Example III, on the first day of testing, a graphical representation of the sensitivity of the chloride ion selective electrode membrane alone and in the presence of whole blood in an aqueous system, whole blood without added interfering anions, whole blood with added bromide ions, and whole blood with added iodide ions is presented, where the Y-axis represents the sensor output in microvolts and the X-axis represents time.

[0021] Figure 11A As described in Example III, on the second day of testing, a graphical representation of the sensitivity of the chloride ion selective electrode membrane alone and in the presence of whole blood in an aqueous system, whole blood without added interfering anions, whole blood with added bromide ions, and whole blood with added iodide ions is presented, where the Y-axis represents the sensor output in microvolts and the X-axis represents time.

[0022] Figure 11B As described in Example III, on the second day of testing, a graphical representation of the sensitivity of the chloride ion selective electrode membrane alone and in the presence of whole blood in an aqueous system, whole blood without added interfering anions, whole blood with added bromide ions, and whole blood with added iodide ions is presented, where the Y-axis represents the sensor output in microvolts and the X-axis represents time.

[0023] Figure 12A As described in Example III, on the third day of testing, a graphical representation of the sensitivity of the chloride ion selective electrode membrane alone and the chloride ion selective electrode membrane in the presence of whole blood, bromide ions and iodide ions is shown, where the Y-axis is the sensor output in microvolts and the X-axis is time.

[0024] Figure 12B As described in Example III, on the third day of testing, a graphical representation of the sensitivity of the chloride ion selective electrode membrane alone and the chloride ion selective electrode membrane in the presence of whole blood, bromide ions and iodide ions is shown, where the Y-axis is the sensor output in microvolts and the X-axis is time.

[0025] Figure 13 This is a graphical representation of the sensitivity of the chloride ion selective electrode membrane in mV / dec over the entire three days in the presence of whole blood, bromide ions, and iodide ions, as described in Example III. Detailed Implementation

[0026] This document discloses a chloride ion selective electrode membrane comprising an epoxy resin component, a curing agent component, and at least one polyurethane. It also discloses a chloride ion selective electrode membrane comprising an epoxy resin component, a curing agent component, at least one polyurethane, and silica. This disclosure further relates to a chloride ion selective electrode having a substrate on which a chloride ion selective electrode membrane is disposed. Methods for manufacturing the chloride ion selective electrode membrane and the chloride ion selective electrode as described herein are further disclosed.

[0027] As used herein, a chloride ion-selective electrode is a type of ion-selective electrode, or "ISE," which refers to a potentiometric electrochemical sensor whose potential corresponds to the activity of selected ions contained in the sample in contact with the ISE. It should be understood that a chloride ion-selective electrode is therefore an ISE whose potential corresponds to the activity of chloride ions in the sample.

[0028] As used herein, a chloride ion-selective electrode membrane is a type of ion-selective electrode membrane that provides selective transfer of selected ions. Therefore, it should be understood that a chloride ion-selective electrode membrane refers to an ion-selective electrode membrane that provides selective transfer of chloride ions. The selective transfer of selected ions (e.g., chloride ions) from the sample to the ion-selective electrode membrane generates an electrical response. Together with an external reference electrode, an ISE having an ion-selective electrode membrane can form a potentiometric cell assembly, allowing the potential difference between the ISE and the reference electrode to be measured. In this way, the selected ions in the sample can be quantified.

[0029] The chloride ion selective electrode membrane of this disclosure may include an epoxy resin component. As used herein, "epoxy resin component" refers to a component having one or more curable resins, each curable resin containing one or more epoxy groups, referred to herein as an epoxy resin. The epoxy resin of this disclosure may be independently saturated or unsaturated, linear or branched, aliphatic, alicyclic, aromatic or heterocyclic, and / or may include one or more substituents that do not substantially interfere with the curing of the epoxy resin. According to some aspects, the epoxy resin may include polyglycidyl ethers of polyphenols. In some non-limiting examples, the epoxy resin may include epichlorohydrin-4,4'-isopropylidene diphenol resin; 2,2-bis(4-hydroxyphenyl)propane (bisphenol-A); 2,2-bis(4-hydroxy-3-tert-butylphenyl)propane; 1,1-bis(4-hydroxyphenyl)ethane; 1,1-bis(4-hydroxyphenyl)isobutane; 1,1-bis(4-hydroxy-3-alkylphenyl)ethane; or combinations thereof. Additionally or alternatively, epoxy resins may include: RP bisphenol F-epimylohydrin resin; reaction products of bisphenol-A-(epimylohydrin) with epoxy resin; polymers of methyl 2-methylacrylate with 1,3-butadiene, butyl 2-acrylate and vinylbenzene; 2,2'-[methylenebis(p-phenoxymethylene)]bisepoxyethylene; dodecane-1-thiol; or combinations thereof. In some non-limiting examples, epoxy resins may additionally or alternatively include diphenols (bisphenol F) obtained by reacting phenols with aldehydes such as formaldehyde.

[0030] According to some aspects, the epoxy resin component may include one or more secondary components. These secondary components may include components that provide one or more properties to the chloride ion selective electrode membrane, such as moisture resistance and / or impact resistance and reduction of membrane stress. Non-limiting examples of secondary components include, but are not limited to, ferric oxide, pyrolytic silica, and combinations thereof.

[0031] Depending on some aspects, epoxy resin components may include medical-grade epoxy resins. As used herein, “medical-grade” means a biocompatible composition. For example, a medical-grade epoxy resin may be a biocompatible epoxy resin that meets the requirements of ISO 10993. Non-limiting examples of medical-grade epoxy resins are medical-grade epoxy resins such as Loctite EA M-121HP medical device adhesive manufactured by Henkel, LOCTITE® EA M-31CL manufactured by Henkel, LOCTITE® EA M-121HP manufactured by Henkel, LOCTITE® EA M-21HP manufactured by Henkel, EPO-TEK® 302 manufactured by Epoxy Technology Inc., and EPO-TEK® MED-353ND manufactured by Epoxy Technology Inc., which are commercial adhesives containing medical-grade epoxy resin mixed with a curing agent component, as will be described herein.

[0032] According to some aspects, the chloride ion selective electrode membrane may contain about 10% w / w to 30% w / w of epoxy resin component, optionally about 15% w / w to 25% w / w and optionally about 20% w / w of epoxy resin component. Depending on some aspects, the chloride ion selective electrode membrane may contain an epoxy resin component of about 10% w / w to 50% w / w, optionally about 20% w / w to 40% w / w, optionally about 20% w / w to 30% w / w, optionally about 25% w / w to 35% w / w, optionally about 30 w / w to 40% w / w, optionally about 29 w / w to 30% w / w, optionally about 34% w / w to 35% w / w, optionally about 29% w / w, optionally about 30% w / w, optionally about 31% w / w, optionally about 32% w / w, optionally about 33% w / w, optionally about 34% w / w, optionally about 35% w / w, optionally about 36% w / w, optionally about 37% w / w, optionally about 38% w / w, optionally about 39%. w / w and optionally about 40% w / w epoxy resin component.

[0033] The epoxy resin disclosed herein can be cured by a curing agent component having one or more curing agents sufficient to at least partially cure the epoxy resin. According to some aspects, the one or more curing agents may include one or more substituted aminophenols, aliphatic polyamines, aromatic polyamines, acid anhydrides, fatty acids, polyamides, tertiary and secondary amines, imidazoles, polythiols, polysulfides, boron trifluoride-amine complexes, dicyandiamide, organic acid hydrazides, light-curing agents, and ultraviolet-curing agents, and combinations thereof. Non-limiting examples of curing agents include 2,4,6-tris(dimethylaminomethyl)phenol, bis[(dimethylamino)methyl]phenol, diethylenetriamine, triethylenetetramine, tetraethylenepentamine, aminoethylpiperazine, amine-epoxy resin adducts, polyethylene polyamine, m-phenylenediamine, diaminodiphenyl sulfone, diethyltoluenediamine, methylnadic anhydride, hexahydrophthalic anhydride, trimellitic anhydride, dodecenylsuccinic anhydride, phthalic anhydride, methylhexahydrophthalic anhydride, tetrahydrophthalic anhydride, methyltetrahydrophthalic anhydride, and combinations thereof. Additionally or alternatively, curing agents may include C18 fatty acid dimers, tall oil fatty acids, triethylenetetramine polymers, 3,6,9-triazazyndexamethylenediamine, 3,6-diazaoctanethylenediamine, or combinations thereof.

[0034] The curing agent component may further include an accelerator. As used herein, the term "accelerator" refers to a component that accelerates the rate of curing of the epoxy resin relative to the curing rate in the absence of an accelerator. In some non-limiting examples, the accelerator may include polythiols, such as pentaerythritol tetra(3-mercaptopropionate), trimethylolpropane tri(3-mercaptopropionate), ethylene glycol bis(3-mercaptopropionate), or combinations thereof.

[0035] The hardener component may further include one or more secondary components. These secondary components may include components that provide one or more properties to the chloride ion selective electrode membrane, such as improved adhesion, flexural strength, improved Young's modulus, crack resistance and / or reduced biofouling, and modulated heat resistance and electrical resistance. Non-limiting examples of secondary components include metals, their oxides, and combinations thereof. Exemplary, non-limiting metals useful according to this disclosure include aluminum, titanium, silver, copper, and combinations thereof. In some non-limiting examples, one or more secondary components may be provided in particulate form, including nanoparticles.

[0036] In some non-limiting examples, the chloride ion selective electrode membrane of this disclosure may further comprise an ion support. Non-limiting examples of ion supports useful according to this disclosure include a meso-tetraphenylporphyrin manganese(III)-chloride complex; 4,5-dimethyl-3,6-dioctyloxy-o-phenylene-bis(mercuric trifluoroacetate), ETH 9009; 3,6-bisdodecyloxy-4,5-dimethyl-o-phenylene-bis(mercuric chloride), ETH 9033; 4,5-bis-[N'-(butyl)thiourea]-2,7-di-tert-butyl-9,9-dimethylxanthene; and combinations thereof.

[0037] In some non-limiting examples, the chloride ion selective electrode membrane of this disclosure may further comprise an ion exchange component, including a trialkylammonium ion exchanger. Non-limiting examples of trialkylammonium ion exchangers include chloride salts of tripropylammonium, tributylammonium, tripentylammonium, trihexylammonium, trioctylammonium, and tri(dodecyl)ammonium, as well as combinations thereof.

[0038] Depending on some aspects, the chloride ion selective electrode membrane may contain about 30% w / w to 50% w / w of a curing agent component, optionally about 35% w / w to 45% w / w and optionally about 40% w / w of a curing agent component.

[0039] According to some aspects, the chloride ion selective electrode membrane may contain a curing agent component of about 10% w / w to 30% w / w, optionally about 15% w / w to 25% w / w, optionally about 20% w / w to 25% w / w, optionally about 21% w / w to 22% w / w, optionally about 15% w / w, optionally about 16% w / w, optionally about 17% w / w, optionally about 18% w / w, optionally about 19% w / w, optionally about 20% w / w, optionally about 21% w / w, optionally about 22% w / w, optionally about 23% w / w, optionally about 24% w / w, and optionally about 25% w / w.

[0040] According to some aspects, the chloride ion selective electrode membrane may comprise an epoxy resin component and a curing agent component in a weight ratio of about 1:1.9 to 1:3, optionally about 1:1.9 to 1:2.5, and optionally about 1:2. According to some aspects, the chloride ion selective electrode membrane may comprise an epoxy resin component and a curing agent component in a weight ratio of about 1:1 to 2:1, optionally about 1.4:1 to 1.8:1, optionally about 1.2:1, optionally about 1.3:1, optionally about 1.4:1, optionally about 1.5:1, optionally about 1.6:1, optionally about 1.7:1, and optionally about 1.8:1.

[0041] The chloride ion selective electrode membrane of this disclosure may further comprise one or more polyurethanes. In some non-limiting examples, the one or more polyurethanes may each independently have one or more hydrophilic functional groups, one or more hydrophobic functional groups, or combinations thereof. Exemplary hydrophobic functional groups include, but are not limited to, hydrophobic diols, polyester hydrophobic polyols, and combinations thereof. Non-limiting examples of polyurethanes useful according to this disclosure include those described in U.S. Patent Publication No. 2015 / 368392 and U.S. Patent No. 8,802,770, the contents of which are expressly incorporated herein by reference.

[0042] According to some aspects, each of one or more polyurethanes may have a certain water absorption rate. As used herein, "water absorption rate" refers to the ability of a material to absorb liquids such as water. According to some aspects, the water absorption rate may be expressed as the amount of water absorbed by the material, which is expressed as a percentage of the material's dry weight. In some non-limiting examples, each of one or more polyurethanes may independently have a water absorption rate of about 10% to 110%, optionally about 10% to 50%, optionally about 10% to 30%, optionally about 15% to 25%, and optionally about 20%.

[0043] In some non-limiting examples, each of one or more polyurethanes may independently include Tecophilic™ thermoplastic polyurethanes manufactured by Lubrizol, such as HP-60D-20, HP-60D-35, HP-60D-60, HP-93A-100, or combinations thereof.

[0044] According to some aspects, the chloride ion selective electrode membrane may comprise one or more polyurethanes of about 20% w / w to 60% w / w, optionally about 25% w / w to 55% w / w, optionally about 30% w / w to 50% w / w, optionally about 35% w / w to 45% w / w, optionally about 43% w / w to 44% w / w, optionally about 35% w / w, optionally about 36% w / w, optionally about 37% w / w, optionally about 38% w / w, optionally about 39% w / w, optionally about 40% w / w, optionally about 41% w / w, optionally about 42% w / w, optionally about 43% w / w, optionally about 44% w / w, and optionally about 45% w / w.

[0045] The chloride ion selective electrode membrane disclosed herein may comprise silicon dioxide. The silicon dioxide may comprise silicon dioxide nanoparticles, alternatively referred to as "nano-silica." According to some aspects, the silicon dioxide may comprise pyrolytic silicon dioxide, non-pyrolytic silicon dioxide, or a combination thereof.

[0046] According to some aspects, silica may comprise silica particles (e.g., nanoparticles) that have been surface-treated with one or more treatment agents. In some non-limiting examples, one or more treatment agents may be sufficient to increase the hydrophobicity of silica relative to untreated silica. Non-limiting examples of treatment agents include dimethyldichlorosilane (DDS), hexamethyldisilazane (HMDS), polydimethylsiloxane (PDMS), and combinations thereof. Non-limiting examples of surface-treated silica include treated pyrolytic silica, such as CAB-O-SIL® TS-610, CAB-O-SIL® TS-720, CAB-O-SIL® M5, and combinations thereof.

[0047] According to some aspects, the chloride ion selective electrode membrane may contain about 5% w / w to 25% w / w of silica, optionally about 10% w / w to 20% w / w, optionally about 15% w / w to 20% w / w, optionally about 17% w / w to 18% w / w, optionally about 15% w / w, optionally about 16% w / w, optionally about 17% w / w, optionally about 18% w / w, optionally about 19% w / w, and optionally about 20% w / w of silica.

[0048] According to some aspects, the chloride ion selective electrode membrane may comprise an epoxy resin component and silicon dioxide in a weight ratio of about 1:1 to 3:1, optionally about 1.5:1 to 2.5:1, optionally about 1.9:1 to 2.1:1, and optionally about 2:1.

[0049] According to some aspects, a chloride ion selective electrode membrane can provide a chloride ion selective electrode with acceptable sensitivity to chloride ions. According to some aspects, the acceptable sensitivity can be at least about 20. mV / dec, optionally at least about 21 mV / dec, optionally at least about 22 mV / dec, optionally at least about 23 mV / dec, optionally at least about 24 mV / dec, optionally at least about 25 mV / dec, optionally at least about 26 mV / dec, optionally at least about 27 mV / dec, optionally at least about 28 mV / dec, optionally at least about 29 mV / dec, optionally at least about 30 mV / dec, optionally at least about 31 mV / dec, optionally at least about 32 mV / dec, optionally at least about 33 mV / dec, optionally at least about 34 mV / dec, optionally at least about 35 mV / dec, optionally at least about 36 mV / dec, optionally at least about 37 mV / dec, optionally at least about 38 mV / dec, optionally at least about 39 mV / dec, optionally at least about 40 mV / dec, optionally at least about 41 mV / dec, optionally at least about 42 mV / dec, optionally at least about 43 mV / dec, optionally at least about 44 mV / dec, optionally at least about 45 mV / dec, optionally at least about 46 mV / dec, optionally at least about 47 mV / dec, optionally at least about 48 mV / dec, optionally at least about 49 mV / dec, optionally at least about 50 mV / dec, optionally at least about 51 mV / dec, optionally at least about 52 mV / dec, optionally at least about 53 mV / dec, optionally at least about 54 mV / dec, optionally at least about 55 mV / dec, optionally at least about 56 mV / dec, optionally at least about 57 mV / dec, optionally at least about 58 mV / dec, optionally at least about 59 mV / dec, optionally at least about 60 mV / dec, optionally about 40 to 60 mV / dec, optionally about 50 to 60 mV / dec, and optionally about 40 to 45 mV / dec.

[0050] According to some aspects, the chloride ion selective electrode membrane can provide a chloride ion selective electrode with acceptable sensitivity to chloride ions for a specific period of time following exposure to at least one sample containing chloride ions. In some non-limiting examples, this specific period of time can be at least about 1 day, optionally at least about 2 days, optionally at least about 3 days, optionally at least about 4 days, optionally at least about 5 days, optionally at least about 6 days, optionally at least about 1 week, optionally at least about 2 weeks, optionally at least about 3 weeks, and optionally at least about 4 weeks.

[0051] This disclosure also relates to a chloride ion selective electrode, and more particularly to a chloride ion selective electrode having a substrate on the surface of which a chloride ion selective electrode film is provided. According to some aspects, the substrate may include a reference electrode. Figure 1A A cross-sectional view of an exemplary chloride ion selective electrode according to various aspects of this disclosure is shown. Figure 1A As shown, the chloride ion selective electrode 100 may include a chloride ion selective electrode film 101 as described herein, provided on the surface of the contact electrode 102. According to some aspects, the contact electrode 102 may include an electrical conductor. Non-limiting examples of electrical conductors include metal-based conductors (e.g., silver, silver chloride, silver bromide, silver iodide, gold, platinum, copper, aluminum, and combinations thereof), graphite, conductive polymers, and combinations thereof.

[0052] like Figure 1A As shown, the chloride ion selective electrode 100 may further include an electrically insulating substrate 103 that at least partially surrounds the chloride ion selective electrode membrane 101. The insulating substrate 103 may comprise one or more insulating materials. As illustrated, the insulating substrate 103 may define a well for the chloride ion selective electrode membrane 101. In some non-limiting examples, the insulating material may include polymers (e.g., polyimide, liquid crystal polymer, polyvinyl chloride (PVC), polycarbonate (PC)), silicon, silicon nitride, epoxy resin, glass, ceramic, or combinations thereof. Figure 1A As shown, the insulating substrate 103 may form one or more walls of a cavity in which a contact electrode 102 (having a chloride ion-selective electrode film 101 on its surface) is provided. However, it should be understood that this disclosure is not necessarily limited to this example. It should also be understood that, although... Figure 1A The illustration shows an insulating substrate 103 forming a single cavity containing a chloride ion-selective electrode membrane 101, but this disclosure is not limited to this manner. For example, the substrate 103 may include two, three, four, five, or more cavities, each cavity independently including an electrode that is the same as or different from the electrode in another cavity. Furthermore, each cavity may contain an ion-selective electrode membrane that is the same as or different from the ion-selective electrode membrane contained in another cavity.

[0053] Figure 1A A sample 104 containing chloride ions 105, to be analyzed by a chloride ion selective electrode 100, is further illustrated. It should be understood that, as used herein, "sample" refers to any liquid containing chloride ions. Non-limiting examples of samples include biological samples, such as samples containing whole blood, serum, plasma, sputum, lymph, semen, vaginal mucus, feces, urine, cerebrospinal fluid, saliva, feces, cerebrospinal fluid, tears, mucus, biological tissue (e.g., hair, skin, sections or excised tissue) or combinations thereof. Other non-limiting examples of samples include non-biological samples, such as drinking water.

[0054] According to some aspects, the chloride ion selective electrode of this disclosure can be combined with an external reference electrode to form a potentiometric cell assembly. Figure 2A A cross-sectional view of an example potential measurement cell assembly 200 according to various aspects of this disclosure is shown. Figure 2A As shown, the potential measurement cell assembly 200 may include an insulating substrate 203, similar to that described above. Figure 1A The insulating substrate 103 is described. The potentiometric cell assembly 200 may further include a reference electrode 202b as described herein. Figure 2A Further illustrations are shown of chloride ion selective electrode membrane 201 and reference electrode membrane 206 as described herein, such as membranes comprising fluoropolymer-polymer copolymers based on sulfonated tetrafluoroethylene. However, it should be understood that this disclosure is not necessarily limited to this approach, as any reference electrode or dummy reference electrode, including dummy silver or silver|silver chloride electrodes, may be used, optionally in contact with a reference electrode solution (e.g., saturated KCl or NaCl) sealed using a standard reference electrode porous glass frit core.

[0055] Figure 1B Another example of a chloride ion selective electrode 100 according to various aspects of this disclosure is shown. Like Figure 1A Same, Figure 1B A contact electrode 102 and an insulating substrate 103 are shown. In this example, the contact electrode 102 and the insulating substrate 103 form substantially flat surfaces on which a chloride ion selective electrode film 101 can be provided.

[0056] Figure 1C Another example of a chloride ion selective electrode 100 according to various aspects of this disclosure is shown. In this example, the contact electrode 102 may protrude relative to the insulating substrate 103, as shown. The contact electrode 102 may include any shape suitable for a chloride ion selective electrode, such as a plate or a wire. In this example, a chloride ion selective electrode film 101 may be provided to at least partially cover the contact electrode 102.

[0057] Figure 2B As shown in the example regarding Figure 2A A top view of the described potential measurement cell assembly 200.

[0058] It should be understood that a potentiometric cell assembly 200 in contact with sample 204 can be provided to determine the concentration of chloride ions 205 contained therein, as is known in the art. In particular, the concentration of chloride ions 205 contained in sample 204 can be determined using the Nernst equation (1):

[0059] Equation (1)

[0060] in E 0 is the standard potential, R is the universal gas constant, T is the temperature in Kelvin, n is the ionic charge, F is the Faraday constant, and A1 and A2 are the ion concentrations.

[0061] This disclosure also relates to methods for manufacturing the chloride ion selective electrode membrane and chloride ion selective electrode described herein.

[0062] According to some aspects, the method may include combining an epoxy resin component, a hardener component, at least one polyurethane, a solvent, and optionally silica to provide a solution, providing the solution on a surface, and drying the solution to provide the chloride ion selective electrode membrane described herein.

[0063] It should be understood that each of the epoxy resin component, the hardener component, at least one polyurethane, and silica can be as described herein. According to some aspects, the epoxy resin component, the hardener component, at least one polyurethane, and / or silica can be combined with a solvent to provide a solution. Exemplary solvents useful according to this disclosure include, but are not limited to, organic solvents (e.g., cyclohexanone, tetrahydrofuran, dimethylacetamide). In some non-limiting examples, the solvent includes cyclohexanone and tetrahydrofuran. In some non-limiting examples, the solvent includes dimethylacetamide.

[0064] According to some aspects, the epoxy resin component may be provided in solution in an amount sufficient to provide about 1% w / w to 10% w / w, optionally about 1% w / w to 5% w / w, optionally about 1% w / w to 3% w / w, optionally about 2.5% w / w to 2.6% w / w, and optionally about 2.1% w / w of epoxy resin component in solution. According to some aspects, the epoxy resin component may be provided in solution in an amount sufficient to provide about 1% w / w to 10% w / w, optionally about 2% w / w to 9% w / w, optionally about 3% w / w to 8% w / w, optionally about 4% w / w to 7% w / w, optionally about 5% w / w to 6% w / w, and optionally about 5.6% w / w to 5.8% w / w of epoxy resin component in solution.

[0065] According to some aspects, the hardener component may be provided in solution in an amount sufficient to provide about 1% w / w to 10% w / w, optionally about 2% w / w to 6% w / w, optionally about 3% w / w to 5% w / w, optionally about 3.5% w / w to 4.5% w / w, and optionally about 4.1% w / w of hardener component. According to some aspects, the hardener component may be provided in solution in an amount sufficient to provide about 2% w / w to 5% w / w, optionally about 3% w / w to 4% w / w, and optionally about 3.5% w / w to 3.7% w / w of hardener component.

[0066] According to some aspects, one or more polyurethanes may be provided in solution in an amount sufficient to provide about 1% w / w to 10% w / w, optionally about 2% w / w to 6% w / w, optionally about 3% w / w to 5% w / w, optionally about 3.5% w / w to 4.5% w / w, and optionally about 4.1% w / w of polyurethane in solution. According to some aspects, one or more polyurethanes may be provided in solution in an amount sufficient to provide about 5% w / w to 10% w / w, optionally about 6% w / w to 9% w / w, optionally about 7% w / w to 8% w / w, and optionally about 7.1% w / w to 7.3% w / w of polyurethane in solution.

[0067] According to some aspects, silica can be provided in solution in an amount sufficient to provide about 1% w / w to 10% w / w, optionally about 1% w / w to 5% w / w, optionally about 2% w / w to 4% w / w and optionally about 2.8% w / w to 3% w / w in solution.

[0068] In some non-limiting examples, the epoxy resin component, the hardener component, at least one polyurethane, and / or silica can be mixed with the solvent at an elevated temperature. According to some aspects, the elevated temperature can be from about 30°C to 70°C, optionally from about 40°C to 60°C, optionally from about 50°C, and optionally from about 55°C. In some non-limiting examples, the epoxy resin component, the hardener component, at least one polyurethane, and / or silica can be combined with the solvent at room temperature (i.e., about 20°C to 22°C). Providing the solution may further include stirring the epoxy resin component, the hardener component, at least one polyurethane, silica, and / or solvent for a specific stirring time. In some non-limiting examples, the stirring time can be from about 10 minutes to 3 hours, optionally from about 10 minutes to 2 hours, optionally from about 10 minutes to 1 hour, optionally from about 30 minutes, and optionally from about 1 hour. It should be understood that each of the epoxy resin component, the hardener component, at least one polyurethane, and / or silica can be combined with the solvent individually, while also being combined with one or more other components. Alternatively or alternatively, each of the epoxy resin component, the hardener component, at least one polyurethane and / or silica can be individually combined with a solvent, and subsequently combined with one or more other components. Furthermore, each of the epoxy resin component, the hardener component, at least one polyurethane and / or silica can be combined with a solvent at the same temperature as or at a different temperature than the other component. Alternatively or alternatively, each of the epoxy resin component, the hardener component, at least one polyurethane and / or silica can be stirred with a solvent for the same stirring time as the other component or for a different stirring time.

[0069] For example, the method may include first combining at least one polyurethane with a solvent at a first temperature and stirring for a first stirring time. The method may further include then combining the solvent with one or more of an epoxy resin component, a hardener component, and / or silica at a second temperature and stirring for a second stirring time to provide a solution.

[0070] According to some aspects, the method may include providing a solution on a surface. In some non-limiting examples, the surface may include an inert surface. Additionally or alternatively, the surface may include components of a chloride ion selective electrode as described herein. For example, as described herein, a solution may be provided on the surface of a reference electrode. In some non-limiting examples, the reference electrode may be provided within a cavity formed in an insulating substrate as described herein. According to some aspects, a solution may be provided on the surface in a reduced humidity environment. As used herein, the term "reduced humidity environment" may refer to an environment having RH of 30% or lower.

[0071] This method may further include drying the solution to provide the chloride ion-selective electrode membrane described herein. The solution may be dried at a drying temperature for a duration sufficient to evaporate all or part of the solvent. It should be understood that the drying temperature and drying time may depend on the concentration of the solvent in the solution and / or the amount of solution to be dried.

[0072] In some non-limiting examples, the drying temperature can be room temperature. In some non-limiting examples, the drying temperature can be elevated, such as at about 40°C to 120°C, optionally at about 40°C to 90°C, optionally at about 40°C to 80°C, optionally at about 50°C to 70°C, and optionally at about 60°C. In some non-limiting examples, the drying time can be about 10 minutes to 24 hours, optionally about 10 minutes to 12 hours, and optionally about 1 hour to 10 hours. According to some aspects, the solution can be dried in a reduced humidity environment, such as in an oven.

[0073] While the aspects described herein have been described in conjunction with the exemplary aspects outlined above, various alternatives, modifications, variations, improvements, and / or substantial equivalents (whether known, currently unforeseen, or potentially unforeseen) may become apparent to those skilled in the art. Therefore, the exemplary aspects set forth above are intended to be illustrative and not restrictive. Various changes may be made without departing from the spirit and scope of this disclosure. Thus, this disclosure is intended to cover all known or subsequently developed alternatives, modifications, variations, improvements, and / or substantial equivalents.

[0074] Therefore, the claims are not intended to be limited to the aspects shown herein, but rather to be consistent with the full scope of the language of the claims, wherein, unless specifically stated otherwise, elements in the singular form are not intended to mean “one and only one”, but rather “one or more”. All structural and functional equivalents of elements of the various aspects described throughout this disclosure that are known to or will be known hereafter by those skilled in the art are expressly incorporated herein by reference and are intended to be covered by the claims. Furthermore, nothing disclosed herein is intended to be offered to the public, whether or not such disclosure is expressly stated in the claims. No claim element is to be interpreted as means plus function unless the element is expressly stated using the phrase “means for…”.

[0075] In this document, numerical ranges described by endpoints (e.g., about 50:1 to 1:1, about 100°C to 500°C, about 1 minute to 60 minutes) include all values ​​contained within that range. For example, about 1 minute to 60 minutes includes 21, 22, 23, and 24 minutes as endpoints within the specified range. Therefore, ranges such as 22-36, 25-32, 23-29, etc., also fall within the range 1-60, depending on the starting materials used, temperature, specific application, specific embodiment, or limitations of the claims (if applicable). The examples and methods disclosed herein demonstrate that the listed ranges encompass every point within that range, as different synthetic products are produced by changing one or more reaction parameters. Furthermore, the methods and examples disclosed herein describe various aspects of the disclosed ranges and the effects when the ranges are changed individually or in combination with other listed ranges.

[0076] Furthermore, the term "example" is used herein to mean "serving as an example, instance, or illustration." Any aspect described herein as an "example" is not necessarily to be construed as preferred or advantageous over other aspects. Unless otherwise specifically stated, the term "some" means one or more. Combinations such as "at least one of A, B, or C," "at least one of A, B, and C," and "A, B, C, or any combination thereof" include any combination of A, B, and / or C, and may include multiple A, multiple B, or multiple C. Specifically, combinations such as "at least one of A, B, or C," "at least one of A, B, and C," and "A, B, C, or any combination thereof" may be only A, only B, only C, A and B, A and C, B and C, or A and B and C, wherein any such combination may include one or more members of A, B, or C. Nothing disclosed herein is intended to be offered to the public, whether or not such disclosure is expressly recited in the claims.

[0077] As used herein, the terms “about” and “approximately” are defined as close to the extent understood by one of ordinary skill in the art. In one non-limiting embodiment, the terms “about” and “approximately” are defined as within 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5%.

[0078] Therefore, based on the foregoing, this disclosure may be implemented in accordance with any of the following provisions.

[0079] Clause 1. A chloride ion selective electrode membrane comprising: an epoxy resin component, a curing agent component, and one or more polyurethanes.

[0080] Clause 2. The chloride ion selective electrode membrane according to Clause 1, wherein the one or more polyurethanes include polyurethanes having one or more hydrophobic functional groups.

[0081] Clause 3. The chloride ion selective electrode membrane according to any of the preceding clauses, wherein the one or more polyurethanes comprise polyurethanes having one or more hydrophilic functional groups.

[0082] Clause 4. The chloride ion selective electrode membrane according to any of the preceding clauses, wherein the one or more polyurethanes comprise polyurethanes having one or more hydrophilic functional groups and one or more hydrophobic functional groups.

[0083] Clause 5. The chloride ion selective electrode membrane according to any of the preceding clauses, wherein the one or more polyurethanes have a water absorption rate of about 20%.

[0084] Clause 6. The chloride ion selective electrode membrane according to any of the preceding clauses further comprises an ion carrier, an ion exchange component, a metal, a metal oxide, or a combination thereof.

[0085] Clause 7. The chloride ion selective electrode membrane according to any of the preceding clauses further comprises silicon dioxide.

[0086] Clause 8. The chloride ion selective electrode membrane according to any of the preceding clauses, wherein the silica comprises surface-treated pyrolytic silica.

[0087] Clause 9. The chloride ion selective electrode membrane according to any of the preceding clauses, wherein at least one of the epoxy resin component and the curing agent component is medical grade.

[0088] Clause 10. A chloride ion selective electrode, comprising: a substrate having a chloride ion selective electrode film on its surface, wherein the chloride ion selective electrode film comprises: an epoxy resin component, a curing agent component, and one or more polyurethanes.

[0089] Clause 11. The chloride ion selective electrode according to Clause 10, wherein the one or more polyurethanes comprise polyurethanes having one or more hydrophobic functional groups.

[0090] Clause 12. The chloride ion selective electrode according to any of the preceding clauses, wherein the one or more polyurethanes comprise polyurethanes having one or more hydrophilic functional groups.

[0091] Clause 13. The chloride ion selective electrode according to any of the preceding clauses, wherein the one or more polyurethanes comprise polyurethanes having one or more hydrophilic functional groups and one or more hydrophobic functional groups.

[0092] Clause 14. The chloride ion selective electrode according to any of the preceding clauses, wherein the one or more polyurethanes have a water absorption rate of about 20%.

[0093] Clause 15. The chloride ion selective electrode according to any of the preceding clauses, wherein the chloride ion selective electrode membrane further comprises silicon dioxide.

[0094] Clause 16. The chloride ion selective electrode according to any of the preceding clauses, wherein the silica comprises surface-treated pyrolytic silica.

[0095] Clause 17. The chloride ion selective electrode according to any of the preceding clauses, wherein at least one of the epoxy resin component and the hardener component is medical grade.

[0096] Clause 18. A chloride ion selective electrode according to any of the preceding clauses, wherein the chloride ion selective electrode membrane further comprises an ion carrier, an ion exchange component, a metal, a metal oxide, or a combination thereof.

[0097] Clause 19. A method of manufacturing a chloride ion selective electrode membrane, comprising: combining an epoxy resin component, a curing agent component, at least one polyurethane and a solvent to provide a solution, providing the solution on a surface, and drying the solution to provide the chloride ion selective electrode membrane.

[0098] Clause 20. The method according to Clause 19, wherein the surface includes a contact electrode.

[0099] Example

[0100] Example I: Preparation of Chloride Ion Selective Electrode Membrane

[0101] First, four solutions comprising an epoxy resin component, a hardener component, a polyurethane component, and a solvent were prepared. Each solution contained the epoxy resin component as shown in Table 1.

[0102] Table 1

[0103] Each solution contains the hardener components shown in Table 2: Table 2

[0104] Each solution also contains polyurethane with a higher or lower hydrophilicity level, as well as solvents containing cyclohexanone and tetrahydrofuran. The epoxy resin components, hardener components, polyurethane, and solvents were combined as shown in Table 3 and stirred at 20°C for approximately one hour.

[0105] Table 3

[0106] As shown in Table 4, a total of four solutions were obtained.

[0107] Table 4

[0108] Sufficient solutions from each of Table 4 are provided to fill each of the two cavities formed in the insulating substrate having a conductive bottom surface, and drying is allowed at room temperature to provide a total of eight chloride ion selective electrode membranes. Figure 3A This is a microscopic image of the chloride ion selective electrode membrane prepared according to Example I. Figure 3B A top microscopic view of a chloride ion selective electrode membrane is shown. Figure 3C A cross-sectional view of a chloride ion selective electrode membrane is shown.

[0109] Example II: Analysis of Chloride Ion Selective Electrode

[0110] The performance of the chloride ion selective electrode membrane prepared according to Example I was analyzed over three days. Specifically, the chloride ion selective electrode membrane was exposed to a calibration aqueous solution containing 100 mM chloride ions, and to analytes (whole blood) containing different concentrations of chloride ions (85 mM, 130 mM, and 150 mM) with and without the addition of interfering bromide or iodide ions. The calibration solution containing 100 mM chloride ions served as the “baseline” chloride ion concentration in all these exemplary tests.

[0111] Figures 4 to 7 The results of this study are presented. In particular, Figure 4 The sensitivity of the chloride ion selective electrode membrane after one day is shown, where the Y-axis represents the sensor output in microvolts and the X-axis represents time. Figure 5 The sensitivity of the chloride ion selective electrode membrane after two days is shown, where the Y-axis represents the sensor output in microvolts and the X-axis represents time. Figure 6 The sensitivity of the chloride ion selective electrode membrane after three days is shown, where the Y-axis represents the sensor output in microvolts and the X-axis represents time. Figure 7 The graph shows the sensitivity of the chloride ion selective electrode membrane in mV / dec over the entire three days. As shown, the Unibond extrusion-grade samples (UG-EG-1 and UD-EG-2) were stable over the entire three days.

[0112] The performance of the chloride ion selective electrode membrane prepared according to Example I was then compared with that of commercial chloride ion selective electrode membranes of two commercial blood gas analyzers (referred to as reference blood analyzers 1 and 2). Figure 8This is a table showing the effect of high (10 mM) and low (2 mM) bromide ion concentrations on chloride ion measurements in calibration solutions with high (150 mM) and low (86 mM) chloride ion concentrations. Specifically, Figure 8 The chloride ion concentrations measured in a standalone calibration solution (i.e., without bromide ion interference) and in a calibration solution with bromide ion interference are shown. Figure 8 As shown, the Unibond extrusion-grade electrodes exhibit significantly less interference at high concentrations of bromide ions (i.e., 7 mM and 8 mM) than the interference observed in commercial chloride ion selective electrode membranes (e.g., >10 mM, 17 mM, 18 mM and 15 mM).

[0113] Figure 9 yes Figure 8 A graphical representation of the data shown in the table.

[0114] Example III: Analysis of Chloride Ion Selective Electrode

[0115] The study described in Example II was repeated. Figures 10 to 13 The results of this replication study are shown. In particular, Figure 10 The sensitivity of the chloride ion selective electrode membrane after one day is shown, where the Y-axis represents the sensor output in microvolts and the X-axis represents time. Figure 11A and Figure 11B The sensitivity of the chloride ion selective electrode membrane after two days is shown, where the Y-axis represents the sensor output in microvolts and the X-axis represents time. Figure 12A and Figure 12B The sensitivity of the chloride ion selective electrode membrane after three days is shown, where the Y-axis represents the sensor output in microvolts and the X-axis represents time. Figure 13 The graph represents the sensitivity of the chloride ion selective electrode membrane over the entire three days, expressed in mV / dec.

[0116] Example IV: Preparation of Chloride Ion Selective Electrode Membrane

[0117] First, a solution containing an epoxy resin component, a hardener component, polyurethane, silica, and a solvent was prepared according to Table 5. The epoxy resin component and hardener component were provided as a medical-grade commercial product, LOCTITE® EAM-21HP manufactured by Henkel. The polyurethane consisted of Tecophilic™ HP-60D-20 manufactured by Lubrizol, the silica consisted of CAB-O-SIL® TS-720, and the solvent consisted of dimethylacetamide. To prepare the solution, the polyurethane was first dissolved in the solvent by stirring at 55°C for one hour. Then, the epoxy resin component, hardener component, and silica were added at room temperature. The solution was then stirred for another hour.

[0118] Table 5

[0119] Then, sufficient solution from Table 5 is provided to fill the cavity formed in the insulating substrate with a conductive bottom surface, and drying is allowed at room temperature to provide a selective electrode film.

[0120] Example V: Preparation of Chloride Ion Selective Electrode Membrane

[0121] First, a solution containing an epoxy resin component, a hardener component, a polyurethane component, and a solvent was prepared as described in Table 6. The epoxy resin component and the hardener component were provided as a medical-grade commercial product, LOCTITE® EA M-21HP manufactured by Henkel. The polyurethane comprised Tecophilic™ HP-60D-20 manufactured by Lubrizol, and the solvent comprised dimethylacetamide. To prepare the solution, the polyurethane was first dissolved in the solvent by stirring at 55°C for one hour. Then, the epoxy resin component and the hardener component were added at room temperature. The solution was then stirred for another hour.

[0122] Table 6

[0123] Then, sufficient solution from Table 6 is provided to fill the cavity formed in the insulating substrate with a conductive bottom surface, and drying is allowed at room temperature to provide a selective electrode film.

Claims

1. A chloride ion selective electrode membrane, comprising: Epoxy resin components Hardener components, and One or more polyurethanes.

2. The chloride ion selective electrode membrane according to claim 1, wherein the one or more polyurethanes comprise polyurethanes having one or more hydrophobic functional groups.

3. The chloride ion selective electrode membrane according to any of the preceding claims, wherein the one or more polyurethanes comprise polyurethanes having one or more hydrophilic functional groups.

4. The chloride ion selective electrode membrane according to any of the preceding claims, wherein the one or more polyurethanes comprise polyurethanes having one or more hydrophilic functional groups and one or more hydrophobic functional groups.

5. The chloride ion selective electrode membrane according to any of the preceding claims, wherein the one or more polyurethanes have a water absorption rate of about 20%.

6. The chloride ion selective electrode membrane according to any of the preceding claims further comprises an ion carrier, an ion exchange component, a metal, a metal oxide, or a combination thereof.

7. The chloride ion selective electrode membrane according to any of the preceding claims further comprises surface-treated pyrolytic silicon dioxide.

8. The chloride ion selective electrode membrane according to claim 7, wherein the chloride ion selective electrode membrane comprises: The hardener component is approximately 15% w / w to 25% w / w. The epoxy resin component comprises approximately 25% w / w to 35% w / w. About 35% w / w to 45% w / w of one or more of the aforementioned polyurethanes, and / or The surface treatment of pyrolytic silica is approximately 10% w / w to 20% w / w.

9. The chloride ion selective electrode membrane according to any of the preceding claims, wherein at least one of the epoxy resin component and the curing agent component is medical grade.

10. A chloride ion selective electrode, comprising: A substrate having a chloride ion-selective electrode film on its surface, wherein the chloride ion-selective electrode film comprises: Epoxy resin components Hardener components, and One or more polyurethanes.

11. The chloride ion selective electrode according to claim 10, wherein the one or more polyurethanes comprise polyurethanes having one or more hydrophobic functional groups.

12. The chloride ion selective electrode according to claim 10 or 11, wherein the one or more polyurethanes comprise polyurethanes having one or more hydrophilic functional groups.

13. The chloride ion selective electrode according to any one of claims 10 to 12, wherein the one or more polyurethanes comprise polyurethanes having one or more hydrophilic functional groups and one or more hydrophobic functional groups.

14. The chloride ion selective electrode according to any one of claims 10 to 13, wherein the one or more polyurethanes have a water absorption rate of about 20%.

15. The chloride ion selective electrode according to any one of claims 10 to 14, wherein the chloride ion selective electrode film further comprises surface-treated pyrolytic silicon dioxide.

16. The chloride ion selective electrode according to claim 15, wherein the chloride ion selective electrode membrane comprises: The hardener component is approximately 15% w / w to 25% w / w. The epoxy resin component comprises approximately 25% w / w to 35% w / w. About 35% w / w to 45% w / w of one or more of the aforementioned polyurethanes, and / or The surface treatment of pyrolytic silica is approximately 10% w / w to 20% w / w.

17. The chloride ion selective electrode according to any one of claims 10 to 16, wherein at least one of the epoxy resin component and the hardener component is medical grade.

18. The chloride ion selective electrode according to any one of claims 10 to 17, wherein the chloride ion selective electrode membrane further comprises an ion carrier, an ion exchange component, a metal, a metal oxide, or a combination thereof.

19. A method for manufacturing a chloride ion selective electrode membrane, comprising: An epoxy resin component, a hardener component, at least one polyurethane, and a solvent are combined to provide a solution. The solution is provided on the surface, and The solution is dried to provide the chloride ion selective electrode membrane.

20. The method of claim 19, wherein the surface comprises a contact electrode.

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