EP1069938A1 - Membranes organiques selectives d'ions - Google Patents

Membranes organiques selectives d'ions

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Publication number
EP1069938A1
EP1069938A1 EP99914252A EP99914252A EP1069938A1 EP 1069938 A1 EP1069938 A1 EP 1069938A1 EP 99914252 A EP99914252 A EP 99914252A EP 99914252 A EP99914252 A EP 99914252A EP 1069938 A1 EP1069938 A1 EP 1069938A1
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EP
European Patent Office
Prior art keywords
membrane
ion
selective
membranes
solvent
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EP99914252A
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German (de)
English (en)
Inventor
Martin J. Patko
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Individual
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Individual
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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/333—Ion-selective electrodes or membranes
    • G01N27/3335—Ion-selective electrodes or membranes the membrane containing at least one organic component
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
    • C08J5/20—Manufacture of shaped structures of ion-exchange resins
    • C08J5/22—Films, membranes or diaphragms
    • C08J5/2206—Films, membranes or diaphragms based on organic and/or inorganic macromolecular compounds
    • C08J5/2275—Heterogeneous membranes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2327/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers
    • C08J2327/02—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers not modified by chemical after-treatment
    • C08J2327/04—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a halogen; Derivatives of such polymers not modified by chemical after-treatment containing chlorine atoms
    • C08J2327/08—Homopolymers or copolymers of vinylidene chloride

Definitions

  • the present invention relates to ion-selective membranes and methods of their preparation. Specifically it relates to improved properties of polymer membranes that are formed without the use of solvents.
  • Ion-selective membranes have uses in numerous applications, particularly in biosensors and analytical devices. Typically, such membranes are used to separate a test solution from a reference solution, allowing electrochemical measurements of the differences in ion concentration across the membrane. Recent theoretical advances have created prospects for a marked increase in the detection limits of such devices. Chemical and Engineering News, November 24, 1997, p. 13. However, presently available ion-selective membranes impose significant limitations on overall sensitivity. These membranes also have other characteristics that seriously limit their long-term stability in aqueous solutions. A major use of ion-selective membranes is in the field of disposable biosensors.
  • membranes made for these devices would have a long shelf life, low detection limits, and could be manufactured rapidly and efficiently in large scale.
  • membranes because of the means by which conventional ion-selective membranes are made, such membranes have inherent limitations on shelf life, detection limits, and efficiency of high volume manufacture.
  • Ion-selective membranes that have long-term stability in contact with aqueous solutions.
  • Ion-selective membranes of the prior art are manufactured by dissolving the required components in a common solvent and then casting the mixture into a suitable tool to form it into the shape utilized in the electrode. There are many general problems associated with this technology.
  • Another disadvantage is that the casting process must be repeated many times to produce a reasonable thickness of membrane that can be handled with tools. This repeated process can increase the accumulation of bubbles with each repeated step, thus disabling an increasingly larger area of the membrane.
  • the evaporation of solvents requires energy, which is extracted from the vicinity of the membrane, it can cause cooling of the membrane. This temperature reduction can cause water vapor deposition, altering the membrane surface and inhibiting the adhesion of the next layer of membrane material to the previously deposited portion of the membrane.
  • the traditional casting process also requires precise measurement of the volume of the solvent mixture and prevention of solvent evaporation from the casting solution prior to the deposition of each new layer, in order to avoid changes in viscosity and component concentrations in the mixture.
  • a glass ring is adhered to a glass or metal plate.
  • a polymer/solvent solution is then poured into the ring.
  • the ring is covered by a larger chamber and evaporation is allowed to proceed at a relatively slow rate. After the solvent evaporates, the membrane can be cut into discs with a punch.
  • the membranes utilized in the automated production of sensors must be very uniform within a production lot, must also have a long shelf life, and must perform in a predictable manner. Because of the numerous inherent problems in forming electrode membranes by a solvent evaporation process, manufacturers are forced to produce membranes in relatively small production lots. Making membranes in small lots reduces the waste associated with a failed process, but it also puts very restrictive limits on efficiency and production capacity in the membrane formation process.
  • the membranes may be formed in situ from a dissolved membrane-forming mixture.
  • this requires expensive equipment capable of repeatedly dispensing small amounts of high viscosity solutions, subsequent protection against water deposition, controlled evaporation of the solvent to minimize bubble formation, long parking time in the equipment, and excessive delay in the manufacturing process.
  • a problem, perhaps even more severe, with solvent-based ion-selective membranes is the fact that such membranes are inherently unstable when in contact with aqueous solutions. This is because as the solvent leaves the membrane structure by evaporation, it leaves behind pores, channels, and other irregularities in the membrane structure. These artifacts of solvent evaporation are readily attacked by water, which causes rapid distortion of membrane structure and electrochemical function.
  • This phenomenon inhibits the formation of, and distorts the magnitude of, an electrical potential across the membrane, and can, within a short time, lead to a complete loss of potential as the aqueous solution moves through the membrane. This is because the infiltration of water into the membrane causes the movement and diffusion of previously immobilized active ingredients within the membrane, thus carrying with them the ions responsible for formation of the potential.
  • the disadvantages of solvent-based, ion-selective membranes include both inefficiencies of production and irregularities in performance.
  • Such membranes have an inherently short shelf life, particularly in the presence of any form of humidity, and are thus not optimal for disposable biosensors that may require long shelf life.
  • Such membranes are also wholly unsuitable for use in implantable biosensor devices, both because of their rapid physical and performance degradation in contact with aqueous solutions, and because of the biocompatibility problems commonly associated with implanted plastics.
  • Disclosed herein are membranes exhibiting highly desirable physical properties, as well as methods of their manufacture that represent a vast improvement over the methods disclosed in the prior art.
  • the present invention provides a method of producing an ion-selective membrane.
  • membrane components including a polymer and at least one additive are combined to form a mixture without addition of a solvent.
  • a superior ion-selective membrane may be formed from this mixture.
  • the polymer may be vinyl chloride.
  • the polymer may also be polyvinyl chloride or it may be a copolymer of vinyl chloride, such as, for example vinyl acetate and/or vinyl alcohol.
  • the additive may be a plasticizer.
  • Suitable plasticizers may include, for example, one or more of the following: aromatic ethers, aliphatic-aromatic ethers, adipic acid esters, sebasic acid esters, phthaiic acid esters, lauric acid esters, glutaric acid esters, and phosphoric acid esters.
  • the additive may also be an ion-selective agent.
  • the membrane components may include more than one additive.
  • the membrane components may include a plasticizer and an ion-selective agent.
  • the membrane components further may include an additive such as, for example, plasticizer modifiers, active ingredients, ion mobility enhancers, heat stabilizers, light stabilizers, surface activity modifiers, iipophilizers, and intermediary immobilizers.
  • the combining step may include mixing the components in a homogenizer. It may also include heating the components.
  • the forming step of the method may include extruding the mixture onto a device adapted for use with the membrane.
  • the membrane may also be formed by injection molding the mixture.
  • the invention also contemplates reacting a biomolecule with the components of the membrane to form a bond between the biomolecule and the membrane at the membrane's surface. Biomoiecules that may be thus reacted include, for example, enzymes, receptors, hormones, nucleic acids and antibodies.
  • the method of the invention may further include contacting a surface of the membrane with an aqueous material that may contain a biomolecule, to form a two-layer ion-selective membrane having a solvent-free layer and an aqueous layer.
  • the biomoiecules may be, for example, enzymes, receptors, hormones, nucleic acids and antibodies.
  • a solvent-free ion-selective membrane made of a polymer and at least one additive, wherein the membrane is formed without a solvent.
  • the polymer of the membrane may be, for -5- example, vinyl chloride, polyvinyl chloride, or a copolymer of vinyl chloride, such as vinyl acetate and/or vinyl alcohol.
  • the additive may be a plasticizer.
  • Useful plasticizers include, for example, aromatic ethers, aliphatic-aromatic ethers, adipic acid esters, sebasic acid esters, phthalic acid esters, iauric acid esters, glutaric acid esters, and phosphoric acid esters.
  • the additive also may be an ion-selective agent.
  • Membrane components may also include more than one additive, such as a plasticizer and an ion-selective agent.
  • the membrane components further may include one or more additives such as, for example, plasticizer modifiers, active ingredients, ion mobility enhancers, heat stabilizers, light stabilizers, surface activity modifiers, iipophilizers, and intermediary immobilizers.
  • additives such as, for example, plasticizer modifiers, active ingredients, ion mobility enhancers, heat stabilizers, light stabilizers, surface activity modifiers, iipophilizers, and intermediary immobilizers.
  • the ion-selective membranes of this aspect of the invention may have a curing mass loss less than 10%, or in some embodiments less than 1 %.
  • the membranes may have a water absorption index less than 0.5%, or in some embodiments less than 0.1 %.
  • a biomolecule may be bound to a surface of the membrane.
  • Useful biomoiecules may include, for example, enzymes, receptors, hormones, nucleic acids and antibodies.
  • the membranes may also have a layer of aqueous material in contact with a surface of the membrane, and the aqueous material may contain a biomolecule.
  • an improved biosensor device including an electrode, wherein the electrode has an ion-selective membrane.
  • the improvement is a solvent-free ion-selective membrane made up of a polymer and at least one additive, wherein the improved membrane is formed without a solvent.
  • the membranes of the present invention are formed without the use of extraneous solvents.
  • An extraneous solvent is a solvent that is added to increase the solubility of the components, which solvent is later removed as part of the formation of the membrane.
  • the membranes of the invention do not employ extraneous solvents, they do not require evaporation steps. And since these membranes are formed without evaporation of a solvent, they exhibit structural and physical properties that are distinct from prior art membranes. Among the most important of those properties is a greatly reduced degree and rate of water absorption. Because the membranes of the present invention do not readily absorb water, they are not subject to the rapid distortions in structure, composition, and electrochemical properties that have plagued membranes of the prior art.
  • Aqueous solutions may include solutions with any appreciable water content, including, for example, beverages, pharmaceutical solutions or suspensions, culture or fermenter media, blood, plasma, urine, cerebrospi ⁇ al fluid, mucous secretions, and the like.
  • membranes of the present invention are capable of lower limits of ion detection, more rapid response, more accurate and reproducible measurements over time, and greater mechanical strength, such as would be beneficial for use under positive pressure or vacuum. Additionally, because of -b- their greatly reduced water absorption, the membranes of the present invention are much more effective in immobilizing membrane components. That is, important additives in the membrane, as discussed below, do not tend to leach out of the membrane, as is commonly the case with membranes of the prior art.
  • the membranes of the present invention are made without solvents; they are instead made by combining a polymer, a plasticizer, and other optional ingredients, which are mixed mechanically to form a mixture for membrane formation.
  • mechanical mixing may employ a high speed blender or homogenizer, which is well known in the plastics industry.
  • Components may be added individually or in groups into the base polymer.
  • Such components can be plasticizers, heat stabilizers, UV absorbers, gamma ray stabilizers, anti static agents, ion-selective agents and other ligands, conductive agents, waxes, hydrophobic agents, flow reduction agents, and the like.
  • membranes of the invention can be formed to virtually any desired thickness, eliminating the need to form membranes in a series of thin-layer depositions with controlled evaporation steps in between.
  • the solvent-free mixture of membrane components can be pre-granulated or it can be directly fed into an extruder or injection molding machine. With extrusion, a ribbon of nascent membrane material can be fed easily into high speed production equipment. In this manner, membranes with new characteristics or mixtures of characteristics may be produced, many of which mixtures were heretofore impossible with previously known ion-selective membrane technology.
  • the thickness of the membrane may be controlled with tooling or extrusion dies.
  • the membrane thus produced may be rolled in quantities for prolonged production shifts of days or weeks. Since there are no solvents involved, the membranes display many superior properties over prior art membranes discussed above. The per-unit production cost is very low, and high volume automated production is relatively simple.
  • plasticizers are capable of solubilizing polymers in many cases. Accordingly, in some publications (e.g. Suzuki, et al., Anal. Chem. 1989, 61:382-384) plasticizers themselves have been misdesignated as solvents. More correctly, and for the purposes of this application, a distinction is drawn between a true solvent and a plasticizer in membrane production. A true (extraneous) solvent is used to dissolve the components of the membrane and is then, either in whole or in part, removed from the membrane as it cures. The removal of the solvent generally is accomplished by means of evaporation, the disadvantages of which have been discussed above.
  • Examples of true solvents that commonly have been used in solvent-based polymeric membranes of the prior art include cyclohexanone, methylene chloride, propyiene carbonate, tetrahydrofuran, toluene, methanol, and water.
  • the membranes of the present invention are thus made without addition of these or any other extraneous solvents, and have the benefit of being highly resistant to degradation caused by contact with water or solutions containing water.
  • a plasticizer may also be used to dissolve membrane components, but it remains part of the membrane and does not require any evaporation steps, nor does it produce the structural artifacts of evaporation.
  • a solvent-based membrane solution that is cast to form a membrane will lose significant mass during the process of solvent evaporation.
  • a solvent-free mixture used to form a membrane will not lose significant mass during the manufacturing process.
  • much more important than issues of loss of mass are the resultant disadvantages of solvent evaporation, such as structural distortions and membrane porosity, water deposition on the curing membrane, elaborate control of evaporation parameters and/or the long delays and equipment downtime associated with curing by means of evaporation.
  • Membranes of the invention being solvent-free, permit greatly increased rates of production, require significantly less control over environmental variables such as humidity, avoid the expense and environmental regulation difficulties associated with using and removing large amounts of organic solvents, and ultimately produce membranes having a degree of water absorption that is a small fraction of the water absorption of membranes of the prior art.
  • Water absorption by membranes of the present invention compared with ion-selective membranes of the prior art, thus may be reduced by a factor of 5, 10, 100, or more.
  • the final density of a cured membrane provides a distinction between the solvent-based ion-selective membranes of the prior art and the solvent-free ion-selective membranes of the present invention.
  • solvent evaporation creates artifacts in the membrane, causing undesirable irregularities of structure and membrane porosity.
  • solvent-free membranes do not display artifacts of evaporation, and are essentially non-porous.
  • bulk porosity is defined as the "dead space" within a membrane, and is calculated by weighing a membrane sample of known volume, and comparing its density with the overall density of the base polymer and any additives that may be present.
  • high bulk porosity is a desirable condition.
  • ion-selective membranes would ideally approach zero bulk porosity -they are ideally non-porous.
  • MDR Membrane Density Ratio
  • the membranes of the present invention may contain a polymer, typically polyvinylchloride (PVC) or a PVC copolymer; plasticizers; plasticizer modifiers; active ingredients; ion mobility enhancers; heat stabilizers; light stabilizers; surface activity modifiers; lipophilizers; intermediary immobiiizers; and/or other components.
  • PVC polymers or copolymers include low, medium, high and ultra-high molecular weight PVC.
  • copolymers of vinyl chloride such as vinyl chloride/vinyl acetate, vinyl chloride/vinyl alcohol, and vinyl chloride/vinyl acetate/vinyl alcohol.
  • Another suitable polymer is carboxylated polyvinyl chloride.
  • plasticizers may be used.
  • suitable plasticizers are aromatic ethers; aliphatic-aromatic ethers; esters of adipic acid, sebasic acid, phosphoric acid, glutaric acid, phthalic acid, and/or lauric acid; and long chain aliphatic alcohols.
  • plasticizer modifiers are halogenated paraffins such as chloroparaffins, long chain aliphatic alcohols, substituted nitrobenzenes, and acetophenones.
  • Active ingredients that may be used in membranes of the present invention include, among others, antibiotics, liquid ion exchangers, neutral carriers, substituted amines, organo-ammonium salts, crown ethers, hormones, enzymes, antigens, antibodies, DNA binding factors, nucleic acids, and the like.
  • Ion mobility enhancers -8- include, for example, salts of stearic acid, long chain alcohols, and waxes including but not limited to paraffin waxes.
  • useful heat stabilizers are salts of stearic acid, organo-metallic compounds, and chlorine receptors.
  • Light stabilizers can include both UV absorbers and light-to-heat converters.
  • Examples of surface activity modifiers are cellulose triacetate, polyacrylamide, organo-ammonium salts, and the like.
  • the membrane components are mixed by combining the polymer, the plasticizer, and any other optional additives.
  • a plasticizer may also function as an active ingredient, or an active ingredient may function as a plasticizer.
  • the invention contemplates solvent-free membranes made from as few as two components, as well as membranes made from a combination of numerous components.
  • Mixing may be facilitated with a high speed blender or by heat gelation and diffusion. Mixing may occur at ambient temperature, or an alternative temperature may be selected based on the particular combination and properties of the components. For example, where antibodies or other proteins are among the additives to the membrane, elevated temperatures may cause problems of protein de ⁇ aturation, and would therefore dictate limits on the temperature that could be used in forming the membrane. Other considerations in selecting membrane formation temperature include the desired working viscosity of the membrane mixture, temperature tolerances of other components of disposable devices onto which the membranes may be formed, and the like.
  • the membranes may be formed by extrusion and stamping, including in situ extrusion directly onto an electrode device.
  • the membranes may also be formed by injection molding or capillary extrusion, either in situ onto a device, or in a separate fabrication step. Additional means of membrane formation include, for example, vacuum forming, vacuum molding, compression molding, blow molding, and calendaring. Membranes may be formed to virtually any useful thickness.
  • the invention also contemplates solvent-free membranes as described herein with aqueous-active molecules adhered or bound to their surface.
  • catalysts including enzymes, may function at the surface of the membrane to modify a chemical species which is not directly detectable into a product which can be detected with the electrode of the device.
  • other molecules, structures, or complexes may function at the membrane surface to enhance or modify the function of the membrane or the electrode device as a whole.
  • Advantageous molecules, structures, or complexes include, for example, hormones, antibodies, antigens, nucleic acids, receptors, binding proteins, pharmaceutical preparations, crystalline substances, and the like.
  • an enzyme such as urease
  • a membrane electrode that is capable of detecting an ionic species such as ammonium to also indirectly detect a non-ionic species such as urea. That is, as urea molecules in a test solution come into contact with the urease enzyme immobilized at the surface of the solvent-free membrane, the enzyme catalyzes the breakdown of urea to produce ammonium ions, which are detected by the electrode.
  • a receptor complex with ATPase activity may be immobilized at the surface of a solvent-free membrane sensitive to phosphate ions, to indirectly measure presence of the receptor's ligand.
  • phosphate ions are released from ATP and these ions are detected by the electrode.
  • This type of indirect detection of analytes assisted by soluble biomoiecules held at or near the surface of a solvent-free membrane has broad applicability that will be appreciated by those of skill in the art.
  • a solvent-free membrane is formed as disclosed herein.
  • a selected molecule or structure is chemically linked to the membrane via active moieties within the polymer or co-polymer of the membrane.
  • an amine group may be reacted to a chlorine group on a polyvinyl chloride membrane in a coupling reaction driven by silver ions as a catalyst.
  • covalent bonds are formed between the biomolecule and the polymer of which the membrane is formed.
  • one or more selected biomoiecules are solubilized in water, and then a water soluble polymerizing agent is added to form a solution.
  • the solution is contacted in a thin layer with a preformed solvent-free membrane according to the invention.
  • the aqueous layer polymerizes and forms a thin layer bound to the solvent-free membrane, which thin layer immobilizes the biomoiecules or other structures it contains.
  • two separate membranes are formed.
  • the first is a solvent-free membrane as described extensively herein.
  • the second is a water-based membrane containing one or more water soluble active ingredients, such as biomoiecules or other complexes or structures.
  • the thickness of the water-based membrane would typically be 1 to 100 microns, although a membrane layer of any useful thickness may be applied to the solvent-free membrane. When the water-based membrane comes into contact with the solvent-free membrane it approximates and immobilizes the biomoiecules or other complexes or structures at or near the surface of the solvent- free membrane.
  • the end result is a membrane having the desirable water-excluding properties of the solvent-free membranes of the invention, while also having immobilized thereon molecules that may require water to perform their desired function.
  • the invention is not limited merely to solvent-free membranes that may contain one or more active ingredients, but also encompasses solvent-free membranes that may bear one or more desirable water soluble molecules on their surface.
  • the water soluble molecules thus immobilized may function as enzymatic catalysts to convert a non-measurable species into a measurable species. They may also perform other useful functions, such as concentration of desirable particles, exclusion of undesirable particles, initiation of biochemical pathways leading to a desirable and/or measurable product, and the like. Examples
  • a solvent-free membrane, selective for calcium ions was prepared according to the following formulation:
  • Comparative Example 1 Conventional calcium-selective membrane A conventional formulation was used to prepare a solvent-based calcium-selective membrane for comparison to the calcium-selective membrane of the invention.
  • the membrane was made using: N,N,N',N'-tetracyclo-3- oxapentanediamide, 10 mg; 2-nitrophenyl-octyl ether, 655 mg; potassium tetrakis(4-chlorophenyl)borate, 6 mg; PVC, high molecular weight, 328 mg. All components were dissolved in 8.0 ml (11,256 mg) tetrahydrofuran. Thus, the total mass of the formulation, prior to evaporation of the solvent, was 12,255 mg-about 8% solids and about 92% solvent.
  • the membranes were cast and cured using conventional techniques, and the resulting membranes were functionally selective for calcium ions.
  • a solvent-free membrane, selective for potassium ions was prepared according to the following formulation: PVC, ultra high molecular weight, 100.00 parts; dioctyl adipate, 150.00 parts; valinomycin (potassium ion selective ligand), 2.85 parts; sodium tetraphenylborate, 2.00 parts; stearic acid, 1.00 parts. All components were mixed to homogeneity and the membrane was formed to a thickness of about 1-3 mils (25-75 microns). After 6 h at 85-115°C, the membrane was fully solidified and functionally selective for potassium ions. Membranes of this formulation were then compared with conventional potassium-selective membranes. The results of such comparisons are provided and discussed below. Comparative Example 2. Conventional potassium-selective membrane
  • a conventional formulation was used to prepare a solvent-based potassium-selective membrane for comparison to the potassium-selective membrane of the invention.
  • the membrane was made using: valinomycin, 10 mg; bisd-butylpentyl) decane-1,10-diyl diglutarate, 650 mg; potassium tetrakis(4-chlorophenyl)borate; 5 mg; PVC, high molecular weight, 330 mg. All components were dissolved in 8.0 ml (11,256 mg) tetrah ⁇ drofuran. Thus, the total mass of the formulation, prior to evaporation of the solvent, was 12,251 mg-about 8% solids and about 92% solvent.
  • the membranes were cast and cured using conventional techniques, and the resulting membranes were functionally selective for potassium ions.
  • PVC ultra high molecular weight, 100.00 parts; bis(ethylhexyl) adipate, 250.00 parts; nonactin (ammonium ion selective ligand), 1.50 parts; ammonium tetraphenyl borate, 0.36 parts; stearic acid, 1.00 parts. All components were; mixed to homogeneity and the membrane was formed to a thickness of about 1-3 mils (25-75 microns). After 6 h at 85-105° C, the membrane was fully solidified and functionally selective for Ammonium ions. Membranes of this formulation were then compared with conventional ammonium-selective membranes. The results of such comparisons are provided and discussed below.
  • a conventional formulation was used to prepare a solvent-based ammonium-selective membrane for comparison to the ammonium-selective membrane of the invention.
  • the membrane was made using: nonactin, 10 mg; bis(butylpentyl)adipate, 668 mg; PVC, high molecular weight, 322 mg. All components were dissolved in 8.0 ml (11,256 mg) tetrahydrofuran. Thus, the total mass of the formulation, prior to evaporation of the solvent, was 12,256 mg-about 8% solids and about 92% solvent.
  • the membranes were cast and cured using conventional techniques, and the resulting membranes were functionally selective for ammonium ions.
  • Example 4 A conventional formulation was used to prepare a solvent-based ammonium-selective membrane for comparison to the ammonium-selective membrane of the invention.
  • the membrane was made using: nonactin, 10 mg; bis(butylpentyl)adipate, 668 mg; PVC,
  • Curing Mass Loss The membranes of the invention do not lose significant mass during curing (or solidification), because they do not contain a solvent. In contrast, prior art ion-selective membranes, since they are formed using solvents, lose substantial mass as the solvent evaporates.
  • Curing Mass Loss CML is a numerical expression of the percent loss of mass of the membrane solution during curing, and thus provides a meaningful and measurable distinction between the membranes of the invention and those of the prior art. CML can be calculated based on the relative concentrations of the components in the solvent-based mixture by subtracting the percentage concentration of the solvent from 100. This of course assumes complete solvent removal. CML also may be determined empirically by weighing a given quantity of solvent-based membrane solution before casting, and later weighing the fully cured membrane produced therefrom. Table 2 provides calculated CML for prior art membranes and for solvent-free membranes of the invention. -13-
  • Theoretical CML of the membranes of the present invention is 0%, and measured CML is generally less than 10%, preferably less than 1 %, and most preferably less than 0.1 %. Table 2. Curing Mass Loss (CML)
  • Water Absorption Index Membranes of the present invention differ significantly from prior art organic ion-selective membranes because of their greatly reduced tendency to absorb water. The functional importance of this difference has been discussed above. A useful measure of this difference is the water absorption index (WAI). WAI is determined by placing a sample of membrane having a known mass into distilled water for 24h at room temperature. After 24h, the sample is re-weighed and the mass gain, if any, is expressed as a percentage of the original mass of the membrane. Different membranes then may be compared based on the WAI of each.
  • WAI water absorption index
  • WAI is an arbitrarily selected measure of water absorption, it is a simple, universal test that is clearly proportional to and indicative of differences in water affinities of different membranes. Depending on the intended uses of particular organic ion-selective membranes, other measures similar to WAI, as defined above, may also be useful. For example, an absorption index using blood plasma as the aqueous solution, at body temperature, for a one week duration, would fairly indicate the degree to which membranes of distinct formulations would distort during one week in an implanted biosensor electrode.
  • Tests of membranes intended to be selective for a particular ion also may be conducted using a solution containing the ion and, in many cases, other additives such as chelators of undesirable ions, pH buffers, and/or solution preservatives. While WAI parameters provide a simple, universal basis for comparison, other solutions more specific for the membranes in question may be used in comparison tests to accelerate water absorption, allowing more rapid detection of differences between membranes. See Example 7.
  • Membranes of the present invention absorb water much less than organic ion-selective membranes of the prior art, and are therefore much more stable in contact with aqueous solutions, as shown below in Table 3.
  • -14- membranes of the invention have a WAI of less than 0.5%, preferably less than 0.1 %, and most preferably less than 0.05%.
  • the membranes of the invention would weigh between 1000 and 1002 mg after 24h in water, while a conventional potassium-selective membrane would weigh 1009.5 mg after 24h in water.
  • Example 6 Water Mass Loss
  • membranes of the invention Another benefit of the membranes of the invention is that, since they do not absorb water to an appreciable degree, they likewise are not subject to loss of membrane components due to the leaching effects caused by water absorption and/or permeability. In contrast, conventional solvent-based ion-selective membranes actually lose mass, presumably due to the leaching out of internal membrane components during 24h contact with water.
  • the membranes of the invention would weigh between 1000 and 998 mg after 24h in water followed -15- by 24h of air drying, while a conventional potassium-selective membrane would weigh 993.9 mg after 24h in water followed by 24h of air drying.
  • Ion solution absorption was determined by placing membrane samples in solutions containing 4 m eq of the ion for which the membrane is selective. Membranes were left in the ion solution for 24h at room temperature, then were blotted dry and weighed. Prior art membranes exhibited significantly increased mass, while mass increases in the membranes of the invention were at or near detection limits. Table 5. Ion Solution Absorption (ISA)

Abstract

L'invention concerne des membranes sélectives d'ions, fabriquées sans utilisation de solvants étrangers, ainsi que des procédés de fabrication de ces membranes, lesquelles sont moins poreuses, plus inertes par rapport à l'eau, possèdent une durée de vie plus longue et sont conçues pour être efficacement fabriquées en grandes quantités.
EP99914252A 1998-04-06 1999-03-29 Membranes organiques selectives d'ions Withdrawn EP1069938A1 (fr)

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US5589598A 1998-04-06 1998-04-06
US55895 1998-04-06
PCT/US1999/006832 WO1999051330A1 (fr) 1998-04-06 1999-03-29 Membranes organiques selectives d'ions

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EP1069938A1 true EP1069938A1 (fr) 2001-01-24

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EP (1) EP1069938A1 (fr)
JP (1) JP2002510540A (fr)
CN (1) CN1302223A (fr)
AU (1) AU3214199A (fr)
CA (1) CA2330463A1 (fr)
WO (1) WO1999051330A1 (fr)
ZA (1) ZA200006298B (fr)

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DE102004044299A1 (de) * 2004-09-10 2006-03-30 Forschungszentrum Jülich GmbH Vorrichtung und Verfahren zum Nachweis von geladenen Makromolekülen
CN103336044B (zh) * 2013-06-18 2015-03-11 南京普朗医疗设备有限公司 一种全固态离子选择电极及其制备方法和应用
WO2016156941A1 (fr) * 2015-04-03 2016-10-06 Diasys Diagnostics India Private Limited Biocapteur d'électrolyte à l'état solide
CN112601956B (zh) * 2018-07-04 2024-04-02 雷迪奥米特医学公司 离子选择性膜及其制备
US20210262972A1 (en) * 2018-07-04 2021-08-26 Radiometer Medical Aps Magnesium ion selective pvc membranes
JP7212135B2 (ja) * 2018-07-04 2023-01-24 ラジオメーター・メディカル・アー・ペー・エス マグネシウムイオン選択性膜
CN114778646A (zh) * 2022-03-24 2022-07-22 南京工业大学 一种铵离子选择性电极敏感膜及其制备方法和应用

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See references of WO9951330A1 *

Also Published As

Publication number Publication date
AU3214199A (en) 1999-10-25
JP2002510540A (ja) 2002-04-09
WO1999051330A1 (fr) 1999-10-14
CN1302223A (zh) 2001-07-04
ZA200006298B (en) 2001-11-07
CA2330463A1 (fr) 1999-10-14

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