Ion-selective membranes comprising a combination of plasticizers

Abstract

Provided is an ion-selective membrane comprising a combination of plasticizers. The ion-selective membrane is used in ion-selective electrodes, sensors and analysers, and in a method for determining the concentration of components in a sample, in particular a blood sample.

Description

[0001] ION-SELECTIVE MEMBRANES COMPRISING A COMBINATION OF PLASTICIZERS

[0002] TECHNICAL FIELD

[0003] An ion-selective membrane is provided comprising a combination of plasticizers. The ion- selective membrane is used in ion-selective electrodes, sensors and analysers, and in a method for determining an ion, urea or CO2concentration in a sample, in particular a blood sample.

[0004] BACKGROUND

[0005] Ion-selective membranes are used in selective electrodes, such as ion-selective electrodes (ISE) or CO2-selective electrodes. By allowing interaction with a particular ion or small molecule, the selective electrodes can be used for real-time analysis of liquids, such as blood. Such electrodes, and sensors comprising such electrodes, are thus particularly useful as a screening, diagnostic or monitoring tool in medical situations.

[0006] Ion-selective membranes are typically based on an organic polymer matrix, which is often based on poly(vinyl chloride), PVC. Various additional substances are incorporated into the polymer matrix, to promote the selectivity required by the membrane.

[0007] Ion-selective membranes comprise one or more ionophores in the membrane, to promote selective interaction between an ion species and the membrane. The organic polymer matrices of ion-selective membranes also suitably comprise a plasticizer. The most common plasticizers used in today's commercially available ion-selective membrane-based sensors are phthalate-based plasticizers, such as diethylhexyl phthalate, DEHP.

[0008] Concerns have been raised regarding the toxicological profile of phthalates in humans and animals. Specifically, diethylhexyl phthalate has been identified as harmful to humans. Therefore, there is a need to address potential toxicity issues of known selective membranes comprising phthalate plasticizers, such as specifically ion-selective membranes comprising diethylhexyl phthalate.

[0009] SUMMARY

[0010] The present inventors have developed an ion-selective membrane that may have a reduced toxicity and a comparable durability relative to membranes previously described in the art. The membranes provided are stable, resistant to interference and drift and have a rapid hydration time.

[0011] In a first aspect, the present invention relates to an ion-selective membrane comprising : an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), at least one primary plasticizer, being a trimellitate tri-ester, cyclohexyl diester, a phthalate diester or a terephthalate diester, wherein said trimellitate tri-ester, cyclohexyl diester, phthalate diester or terephthalate diester has alkyl-ester moieties (Ri) each comprising > 8 carbon atoms, at least one secondary plasticizer and / or at least one tertiary plasticizer, wherein the at least one secondary plasticizer is an adipate, trimellitate tri-ester, cyclohexyl diester, phthalate diester or a terephthalate diester, said trimellitate tri-ester, cyclohexyl diester, phthalate diester or terephthalate diester having alkyl-ester moieties (R2) each comprising <8 carbon atoms, and wherein the at least one tertiary plasticizer is a 2-nitroalkylphenyl ether, said 2- nitroalkylphenyl ether having an alkyl-ether moiety (R3) comprising > 8 carbon atoms.

[0012] In a second aspect, the present invention relates to an ion-selective electrode comprising one or more ion-selective membranes as disclosed herein.

[0013] In a third aspect, the present invention relates to a potentiometric sensor comprising the ion- selective electrode as disclosed herein and at least one reference electrode.

[0014] In a fourth aspect, the present invention relates to a blood gas analyser for analysis of a bodily fluid comprising the potentiometric sensor as disclosed herein.

[0015] In a fifth aspect, the present invention further relates to a method for determining an ion, urea or CO2concentration in a liquid sample, preferably a blood sample, said method comprising : contacting said liquid sample with a potentiometric sensor as disclosed herein, and determining the ion, urea or CO2concentration in said liquid sample based on a signal provided by said potentiometric sensor.

[0016] In a sixths aspect, the present invention relates to the use of a mixture of plasticizer in a ion- selective membrane, wherein the mixture of plasticizers comprises (i) tris(2-ethylhexyl) trimellitate (TOTM), and (ii) di-isopentyl terephthalate (DiPT), and optionally (iii) 2- nitrophenyl octyl ether (o-NPOE).

[0017] Further aspects of the invention are provided in the dependent claims, and the following description text and figures.

[0018] LEGENDS TO THE FIGURE

[0019] Fig. 1 shows plasticizer parameters, i.e. Hansen solubility parameters given as 6p (delta-p) as a function of 6h (delta-h) for selected primary and secondary plasticizers.

[0020] Fig. 2 shows Hansen solubility parameters, 6p (delta-p) as a function of 6h (delta-h), for a selected primary and secondary plasticizer, and a combination thereof.

[0021] Fig. 3 shows Hansen solubility parameters, 6p (delta-p) as a function of 6h (delta-h), for selected primary and secondary plasticizers, and a combination thereof.

[0022] Fig. 4 shows Hansen solubility parameters, 6p (delta-p) as a function of 6h (delta-h), for selected primary phthalates / terephthalates and selected secondary phthalates / terephthalates.

[0023] Fig. 5 shows Hansen solubility parameters, 6p (delta-p) as a function of 6h (delta-h), for a selected primary and secondary plasticizer, and a combination thereof.

[0024] Fig. 6 shows Hansen solubility parameters, 6p (delta-p) as a function of 6h (delta-h), for a selected primary secondary and tertiary plasticizer, and for the combination of a specific combination thereof.

[0025] Fig 7. shows the sensitivity over time for ion-selective sensors prepared from membranes plasticized with diethylhexyl phthalate (DEHP) and with TOTM: DiPT, where TOTM is tris(2- ethylhexyl) trimellitate and DiPT is di-isopentyl terephthalate.

[0026] Fig 8. shows the sensor sensitivity stability over a test period for DEHP based sensors, TOTM based sensors, TOTM: DiPT based sensors and TOTM: DiPT:o-NPOE based sensors, where o- NPOE is 2-nitrophenyl octyl ether.

[0027] Fig 9. shows the sensitivity over time for ion-selective sensors prepared from membranes plasticized with diethylhexyl phthalate (DEHP) and with TOTM:o-NPOE. Fig 10. shows the sensitivity over time for ion-selective sensors prepared form membranes plasticized with diethylhexyl phthalate (DEHP) and with TOTM:o-NPOE:DEA, where DEA is diethyl adipate.

[0028] DETAILED DISCLOSURE

[0029] Definitions

[0030] The term "ion-selective membrane" when used herein refers to a barrier having a preference for a particular ion or molecule. "Ion-selective" when used herein does not mean absolute or exclusive selectivity.

[0031] The term "polymer" refers to a macromolecule composed of repeating monomers. In the context of "organic polymer", the monomers are rich in carbon atoms, and are based on chains of carbon atoms.

[0032] When used herein in connection with a polymer, the term molecular weight refers to the weight average molecular weight, calculated by: Mw= ZWiMi, wherein Wi, is the weight fraction of polymer with molecular weight Mi.

[0033] The term "matrix" refers to the bulk material of the membrane in which active components of the membrane e.g. ionophore, lipophilic salt and / or plasticizer are embedded.

[0034] When used herein, the term "ionophore” refers to a compound that reversibly binds ions.

[0035] The term "lipophilic" when used herein, in particular in the context of a "lipophilic compound", refers to the ability of a chemical compound to dissolve in fats, oils, lipids, or non-polar solvents. Lipophilicity is determined by partitioning the compound between water and oil. A parameter which is typically available is the partition coefficient Kowbetween water and octanol. For diethylhexyl phthalate (DEHP) Logio(Kow) is 7.60 while it for tris(2-ethylhexyl) trimellitate (TOTM) is 11.59 and for 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) it is greater than 6.2 (cf. Databook of plasticizers 2ndedition Anna Wypych ISBN: 978-1-895198-96-6).

[0036] The term "salt" when used herein refers to a deprotonated form of an anionic species together with a cationic species to counterbalance the negative charge hereof. In the context of "lipophilic salt", either the cation or the anion has lipophilic moieties. Non-limiting examples of lipophilic salts include potassium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate and potassium tetrakis(4-chlorophenyl)borate.

[0037] The term "plasticizer" refers to a chemical compound that by its presence has the ability to change the mechanical properties of the matrix e.g. soften the matrix.

[0038] The term "slow leaching plasticizer" refers to a plasticizer which stays within the polymer matrix.

[0039] When referring to chemical groups, the terms "alkyl", "aryl", "alkenyl" and "alkynyl" have their usual meaning in the art. The term "branched alkyl" refers to an alkyl group which is not fully linear, i.e. has at least one side-chain. The term "cyclic alkyl" refers to an alkyl group in which the hydrocarbon chain binds to itself to form a ring. The term "straight-chain" refers to an alkyl group which is fully linear i.e. has no side-chains.

[0040] The term "isomers" is used herein to refer to molecules with the same molecular formula but distinct arrangement of atoms within the molecule, such as to refer to different branching patterns of carbon moieties.

[0041] The term "alkyl-ester moiety" is used herein, to specifically refer to alkyl moieties covalently bound to the primary and / or secondary plasticizers by carboxylic acid groups having been esterified with alkyl moieties.

[0042] The term "alkyl-ether moiety" is used herein, to specifically refer to alkyl moieties covalently bound to the tertiary plasticizers by the ether bond.

[0043] The term "concentration" when used herein in the context of determining a concentration of ions, such as calcium ions, in a sample, refers to the stoichiometric concentration of the ion in a standardized solution matrix (reference scale) having an ion activity which is equal to that of the measured sample, cf. IFCC guidelines (Ben Rayana et al. (2008) Clin Chem Lab Med 46(1):21).

[0044] The term "electrode" when used herein refers to an electrical conductor used to make contact with a non-metallic part of a circuit e.g. an electrolyte and / or an ion-selective membrane.

[0045] The term "reference electrode" when used herein refers to an electrode, which has a well- known electrode potential. The term "potentiometric sensor" when used herein refers to an electrochemical sensor with no current passage, which is used to determine the analytical concentration of some ion or compound of an analyte solution or gas.

[0046] The term "blood gas analyser" when used herein refers to an instrument which measures the amount of a gases e.g. O2or CO2, as well as ions and metabolites in a blood sample.

[0047] As used herein, the term "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated member, integer or step but not the exclusion of any other non-stated member, integer or step, unless the context requires otherwise. The term "consist of" is a particular or preferred embodiment of the term "comprise", wherein any other non-stated member, integer or step is excluded. In the context of the present invention, the term "comprise" encompasses the term "consist of". The term "comprising" thus encompasses "including" as well as "consisting of" e.g, a composition "comprising" X may consist exclusively of X or may include something additional e.g., X + Y.

[0048] As used herein, the term "about" in relation to a numerical value x means x ± 10 %, preferably x ± 5 %, even more preferably x ± 2 %, most preferably x ± 1 %.

[0049] Ion-selective membrane

[0050] In a first aspect, the invention relates to an ion-selective membrane comprising an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), at least one primary plasticizer, being a trimellitate tri-ester, cyclohexyl diester, a phthalate diester or a terephthalate diester, wherein said trimellitate tri-ester, cyclohexyl diester, phthalate diester or terephthalate diester has alkyl-ester moieties (Ri) each comprising > 8 carbon atoms, at least one secondary plasticizer and / or at least one tertiary plasticizer, wherein the at least one secondary plasticizer is an adipate, trimellitate tri-ester, cyclohexyl diester, phthalate diester or a terephthalate diester, said trimellitate tri-ester, cyclohexyl diester, phthalate diester or terephthalate diester having alkyl-ester moieties (R2) each comprising <8 carbon atoms, and wherein the at least one tertiary plasticizer is a 2- nitroalkylphenyl ether, said 2-nitroalkylphenyl ether having an alkyl-ether moiety (R3) comprising > 8 carbon atoms. The combination of at least one primary plasticizer with the at least one secondary plasticizer and / or at least one tertiary plasticizer as listed is in part a result of the realization that suitable plasticizer combinations can be identified by considering the Hansens solubility parameters of the primary, the secondary and / or tertiary plasticizers. Generally, Hansens solubility parameters indicate the compatibility of molecules such as to predict if a molecular species will dissolve in another.

[0051] Hansens solubility parameters comprises three parameters; 6d relating to the energy from dispersion forces between molecules, 6Prelating to the energy from dipolar intermolecular forces between molecules and 6h relating to the energy from hydrogen bonds between molecules. The Hansens solubility parameters for a molecule can be considered coordinates for a point in a three-dimensional Hansen space. When considering the compatibility of two molecules, such as to predict if one molecular species will dissolve in another, the coordinates for the point of the first molecule (molecule 1) in a three-dimensional Hansen space is compared to the coordinates for the point of the second molecule (molecule 2). The closer the points are, the more likely they are to dissolve into each other. Hansens solubility parameters such as for multiple plasticizers are additive and may be represented by a single point in the three-dimensional Hansen space.

[0052] Hansens solubility parameters may be determined empirically and experimentally for a molecule 1 such as a polymer by evaluating its solubility in selected solvents, wherein the solvent dissolving the polymer will have Hansens solubility parameters closer to those of the molecule, hence have parameters inside the Hansen sphere for molecule 1. Alternatively, Hansens solubility parameters may be determined using computational methods such as computational methods comprising means of multiresponse optimization algorithms optionally including both an optimization routine and a Derringer's desirability function. Such computational methods are known in the art. As specific examples, Hansens solubility parameters has been determined using Microsoft Excel with Solver add-in, wherein several solving methods are available e.g. Simplex LP, GRG Nonlinear and Evolutionary Solver, further including problem size limits of 200 decision variables and 100 constraints in addition to bounds on the variables. Alternatively, optimization algorithms have been implemented in a variety of computational platforms such as MatLab and Maple, and further a suitable algorithm optimization approach has been included in the software HSPiP.

[0053] Herein, Hansen solubility parameters are used in the context of identifying replacement(s) for plasticizers, hence the idea that if the replacing plasticizer or replacing plasticizer combination will dissolve the reference plasticizer, the replacing plasticizer or replacing plasticizer combination will be suitable for substituting the reference plasticizer. Components of the Ion-selective membrane

[0054] A preferred composition of an ion-selective membrane comprises 0.5-5 wt% ionophore, 0.5-5 wt% lipophilic salt, 10-50 wt% organic polymer matrix such as PVC, and 30-80 wt% plasticizer such as 60-80 wt% plasticizer, wherein the wt% is of the dry mass of the membrane (i.e. the mass of the components before mixing in solvent). Preferably, the ion- selective membrane is selective towards at least one ion selected from Na+, K+, Ca2+Mg2+, NH4+, H+, ions or a combination thereof. lonophore(s)

[0055] The ion-selective membrane comprises an ionophore, such as one or more ionophores. The role of an ionophore is to bind a specific ion or compound, when the specific ion or compound enters the ion-selective membrane, hence an ionophore enables reversible binding of ion(s) / compound(s). Consequently, the selectivity of the ion-selective membrane stems from the choice of ionophore or from the combination of ionophores and plasticizers.

[0056] The ionophore can be charged or uncharged (neutral). Ionophores are preferably lipophilic to ensure that they can be dissolved in an organic polymer matrix. Many suitable ionophores have been described in the art. For example, the ionophore may be a tertiary amine, particularly a tertiary amine comprising long-chain (C5-Ci8) alkyl moieties, such as tridodecylamine. An alternative ionophore is (-)-(R,R)-N,N'-Bis-[ll- (ethoxycarbonyl)undecyl]-N,N',4,5-tetramethyl-3,6-dioxaoctane-diamide. Other suitable ionophores include nactins (such as nonactin), Valinomycin 4-tert-butylcalix[4] arenetetraacetic acid tetraethyl ester, and phenanthroline.

[0057] Typically, the total mass of ionophores constitutes between 0.1 - 10 wt%, such as about 0.5- 5 wt%, e.g. about 1 wt% of the dry mass of the membrane.

[0058] Lipophilic salt(s)

[0059] The ion-selective membrane comprises a lipophilic salt such as one or more lipophilic salts. The lipophilic salt dissolves in the membrane because of the high content of lipophilic groups. The role of the lipophilic salt is - in combination with the ionophore - to buffer the primary ion (i.e. the ion said membrane is selective towards) and thus improve the selectivity of the membrane. Without being bound by any specific theory, it is hypothesized that in a combination of an ionophore and plasticizers in an organic polymer matrix, the additional ionic groups induced with the lipophilic salt facilitate effective binding of the primary ion in the membrane. Suitable lipophilic salts are described in e.g. W02020 / 007623 and the references therein, which is hereby incorporated by reference.

[0060] The organic polymer matrix

[0061] The ion-selective membrane comprises an organic polymer matrix comprising poly(vinyl chloride). The poly(vinyl chloride) gives the membrane structural integrity as it provides a three-dimensional network, wherein the polymer is homogeneously distributed in a plasticizer phase and additional active components e.g. ionophores and / or lipophilic salt.

[0062] Typically, the total mass of organic polymer constitutes between 10-50 wt% such as 20-40 wt% such as 30-35 wt% of the dry mass of the membrane such as 33 wt% of the dry membrane mass.

[0063] The organic polymer matrix may comprise above 75 wt% poly(vinyl chloride), such as above 85 wt% and such as above 95 wt% poly(vinyl chloride). Most preferably, the organic polymer matrix is a poly(vinyl chloride) matrix. Specifically, the molecular weight of said poly(vinyl chloride) may be from 150,000 to 500,000, preferably 200,000 to 300,000 such as around 245,000 g / mol.

[0064] The organic polymer matrix may comprise a co-polymer made from vinyl acetate, urethane and / or vinyl alcohol. Non-limiting examples of polymers and co-polymers that may be used include poly(vinyl chloride), polyurethane, poly(vinyl chloride-co-vinyl acetate), poly(vinyl chloride-co-vinyl alcohol), poly(vinyl chloride-co-vinyl acetate-co-vinyl alcohol) and combinations of any of these. The organic polymer matrix may comprise poly(vinyl chloride) co-polymers with hydroxypropyl acrylate, acrylic acid, and / or acid anhydrides. The organic polymer matrix may comprise a polymer blend.

[0065] Plasticizers

[0066] The role of the plasticizers is to keep other components, such as the organic polymers comprised in the organic polymer matrix, the ionophore(s) and lipophilic salt, dissolved and mobile. Hence, the plasticizers enable high mobility of ions and other compounds in the membrane and allow for good processing and flexibility of the ion-selective membrane. The plasticizer also allows the membrane to maintain its properties in the temperature ranges under which the membrane is manufactured, stored and used (typically from around +2°C to +37°C). Additionally, the plasticizers may contribute to effective binding of a specific ion in the ion-selective membrane. The provided ion-selective membrane is obtained by embedding at least one primary plasticizer, being a trimellitate tri-ester, cyclohexyl diester, a phthalate diester or a terephthalate diester, wherein said trimellitate tri-ester, cyclohexyl diester, phthalate diester or terephthalate diester has alkyl-ester moieties (Ri) each comprising > 8 carbon atoms, together with at least one secondary plasticizer and / or at least one tertiary plasticizer in the matrix. More specifically, the at least one secondary plasticizer is an adipate, trimellitate triester, cyclohexyl diester, phthalate diester or a terephthalate diester, said trimellitate triester, cyclohexyl diester, phthalate diester or terephthalate diester having alkyl-ester moieties (R2) each comprising <8 carbon atoms and the at least one tertiary plasticizer is a 2-nitroalkylphenyl ether, said 2-nitroalkylphenyl ether having an alkyl-ether moiety (R3) comprising > 8 carbon atoms.

[0067] Having a primary plasticizer combined with at least one secondary plasticizer and / or at least one tertiary plasticizer in the matrix provides membranes with durability, which is comparable to membranes previously described in the art. Additionally, the provided combinations have the potential to make phthalate-based plasticizers such as diethylhexyl phthalate (DEHP) redundant. Further, the ion-selective membranes comprising the provided combination of plasticizers have a suitable softness for use in an ion-selective electrode.

[0068] Combinations of plasticizers

[0069] The ion-selective membrane comprises at least one primary plasticizer, being a trimellitate tri-ester, cyclohexyl diester, a phthalate diester or a terephthalate diester, wherein said trimellitate tri-ester, cyclohexyl diester, phthalate diester or terephthalate diester has alkyl- ester moieties (Ri) each comprising > 8 carbon atoms. The at least one primary plasticizer has a high molecular weight, such as equal to or higher than that of DEHP. The at least one primary plasticizer may be a slow leaching plasticizer within the organic polymer matrix as this provides the favourable mobility within the ion-selective membrane.

[0070] The ion-selective membrane may preferably comprise at least one primary plasticizer, being a trimellitate tri-ester. A trimellitate tri-ester is based on trimellitic acid (i.e., 1,2,4- benzenetricarboxylic acid) in which all carboxylic acid groups are esterified with alkyl moieties, i.e. alkyl-ester moieties, Ri. Hence, the chemical structure of a trimellitate tri-ester is according to formula 1 :

[0071] The ion-selective membrane may comprise at least one primary plasticizer being a cyclohexyl diester, a phthalate diester or a terephthalate diester. A cyclohexyl diester is based on cyclohexyl 1,2-dicarboxylic acid or cyclohexyl 1,3-dicarboxylic acid in which the two carboxylic acid groups are esterified with alkyl moieties, i.e. alkyl-ester moieties, Ri.

[0072] Similarly, a phthalate diester is based on phthalic acid (i.e., benzene-l,2-dicarboxylic acid) in which the two carboxylic acid groups are esterified with alkyl moieties, i.e. alkyl-ester moieties, Ri and a terephthalate diester is based on terephthalic acid (i.e., benzene-1,4- dicarboxylic acid) in which both carboxylic acid groups are esterified with alkyl moieties, i.e. alkyl-ester moieties Ri.

[0073] Preferably, wherein the at least one primary plasticizer is a trimellitate tri-ester, the trimellitate tri-ester comprises three alkyl-ester moieties, and wherein the at least one primary plasticizer is a cyclohexyl diester, phthalate diester or terephthalate diester the cyclohexyl diester, phthalate diester or terephthalate diester comprises two alkyl-ester moieties.

[0074] The at least one primary plasticizer being a trimellitate tri-ester may further be specified to comprise three alkyl-ester moieties (Ri) and the at least one primary plasticizer being a cyclohexyl diester, phthalate diester or terephthalate diester may further be specified to comprise two alkyl-ester moieties (Ri). Specifically, the at least one primary plasticizer comprises alkyl-ester moieties, preferably where each alkyl-ester moiety (Ri) is independently defined by comprising > 8 carbon atoms, preferably all Ri moieties are the same, and / or comprises a C8-Ci8alkyl-ester moiety such as a C8-Ci3alkyl-ester moiety, and / or is branched alkyl-ester, such that the longest straight alkane chain in each Ri moiety is independently selected from octyl, such as n-octyl; nonyl; or decyl, such as n- decyl.

[0075] Having one or more Ri moieties being a branched alkyl-ester provide steric hinderance, which may reduce leaching of the primary plasticizer from the ion-selective membrane. Preferably, when the primary plasticizer is a phthalate, Ri comprises > 8 carbon atoms. The phthalate may further be specified such that each Ri moiety may comprise a C9-Ci8alkyl-ester moiety, such as a C9-Ci3alkyl-ester moiety.

[0076] Most preferably, the ion-selective membrane comprises at least one primary plasticizer, wherein the primary plasticizer is selected from the group comprising: tris(octyl) trimellitate, tris(nonyl) trimellitate, tris(decyl) trimellitate , di-nonyl phthalate, di-decyl phthalate, diundecyl phthalate, di-dodecyl phthalate, di-tridecyl phthalate, di-octyl terephthalate, di-nonyl terephthalate, di-decyl terephthalate, di-undecyl terephthalate, di-dodecyl terephthalate or di-tridecyl terephthalate, 1,2-cyclohexane dicarboxylic acid di-octyl ester, 1,2-cyclohexane dicarboxylic acid di-nonyl ester, 1,2-cyclohexane dicarboxylic acid di-decyl ester, 1,2- cyclohexane dicarboxylic acid di-undecyl ester, 1,2-cyclohexane dicarboxylic acid di-dodecyl ester or 1,2-cyclohexane dicarboxylic acid di-tridecyl ester, preferably tris(2-ethylhexyl) trimellitate or di-isononyl phthalate (DINP), 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH).

[0077] Specifically, the tris(2-ethylhexyl) trimellitate plasticizer has been found to: be readily miscible with other membrane components such as ionophores, lipophilic salts, poly(vinyl chloride) and solvent, have exceptional low leaching in general and in adjacent polymer materials i.e. slow leaching within the polymer matrix, have very low solubility in water with Kow partition coefficient of 11.59, hence very low solubility in aqueous solutions e.g. rinse solutions. have a relative dielectric constant comparable to current DEHP, i.e. around 5.

[0078] Specifically, the ion-selective membrane may comprise a tridodecylamine ionophore and at least one trimellitate tri-ester having alkyl-ester moieties (Ri) each comprising > 8 carbon atoms such as tris(2-ethylhexyl) trimellitate combined with at least one secondary plasticizer and / or at least one tertiary plasticizer, and be selective towards H+.

[0079] Alternatively, the ion-selective membrane may comprise an (-)-(R,R)-N,N'-Bis-[ll- (ethoxycarbonyl)undecyl]-N,N',4,5-tetramethyl-3,6-dioxaoctane-diamide ionophore and at least one trimellitate tri-ester having alkyl-ester moieties (Ri) each comprising > 8 carbon atoms such as tris(2-ethylhexyl) trimellitate combined with at least one secondary plasticizer and / or at least one tertiary plasticizer, and be selective towards calcium ions (Ca2+).

[0080] Alternatively, the ion-selective membrane may comprise a 4-tert-butylcalix[4] arenetetraacetic acid tetraethyl ester ionophore and at least one trimellitate tri-ester having alkyl- ester moieties (Ri) each comprising > 8 carbon atoms such as tris(2-ethylhexyl) trimellitate combined with at least one secondary plasticizer and / or at least one tertiary plasticizer, and be selective towards sodium ions (Na+).

[0081] Alternatively, the ion-selective membrane may comprise a Valinomycin ionophore and at least one trimellitate tri-ester having alkyl-ester moieties (Ri) each comprising > 8 carbon atoms such as tris(2-ethylhexyl) trimellitate combined with at least one secondary plasticizer and / or at least one tertiary plasticizer, and be selective towards potassium ions (K+).

[0082] Alternatively, the ion-selective membrane may comprise a phenantroline ionophore and at least one trimellitate tri-ester having alkyl-ester moieties (Ri) each comprising > 8 carbon atoms such as tris(2-ethylhexyl) trimellitate combined with at least one secondary plasticizer and / or at least one tertiary plasticizer, and be selective towards magnesium ions (Mg2+).

[0083] Alternatively, the ion-selective membrane may comprise a nonactin ionophore and at least one trimellitate tri-ester having alkyl-ester moieties (Ri) each comprising > 8 carbon atoms such as tris(2-ethylhexyl) trimellitate combined with at least one secondary plasticizer and / or at least one tertiary plasticizer, and is selective towards ammonium (NH4+).

[0084] The ion-selective membrane comprises at least one secondary plasticizer and / or at least one tertiary plasticizer, wherein the at least one secondary plasticizer is an adipate, trimellitate tri-ester, cyclohexyl diester, phthalate diester or a terephthalate diester, said trimellitate triester, cyclohexyl diester, phthalate diester or terephthalate diester having alkyl-ester moieties (R2) each comprising <8 carbon atoms. The at least one secondary plasticizer has a low molecular weight, such as equal to or lower than the molecular weight of DEHP. The at least one secondary plasticizer may be a plasticizer having a high mobility within the organic polymer matrix.

[0085] The ion-selective membrane may comprise at least one secondary plasticizer being a trimellitate tri-ester, cyclohexyl diester, phthalate diester or a terephthalate diester, said diesters being based on acids in which all carboxylic acid groups are esterified with alkyl moieties as described above. Additionally or alternatively, the ion-selective membrane may comprise at least one secondary plasticizer being an adipate, where an adipate is based on adipic acid in which all carboxylic acid groups are esterified with alkyl moieties, i.e. alkyl- ester moieties. An alkyl-ester moiety comprised in a secondary plasticizer is referred to as alkyl-ester moiety, R2. Specifically, the secondary plasticizer differs from the primary plasticizer by the size of the alkyl-ester moieties (R2) comprising fewer carbon atoms than the alkyl-ester moieties (Ri) of the primary plasticizer.

[0086] The secondary plasticizer being a trimellitate tri-ester may further be specified to comprise three alkyl-ester moieties (R2) and the secondary plasticizer being an adipate, cyclohexyl diester, phthalate diester or terephthalate diester may further be specified to comprise two alkyl-ester moieties (R2). Specifically, where the secondary plasticizer comprises alkyl-ester moieties, preferably each alkyl-ester moiety (R2) is independently defined by comprising < 8 carbon atoms, preferably wherein all R2moieties are the same, and / or is independently a branched, cyclic or straight-chain, preferably wherein each R2moiety is branched.

[0087] Branched alkyl-ester moieties (R2) may provide lower mobility and diffusion in the polymer matrix. For ion-selective membranes comprising a secondary plasticizer, where the secondary plasticizer comprises alkyl-ester moieties, the longest straight alkane chain in each R2moiety may be independently selected from propyl, butyl, pentyl, or hexyl. In this way, the alkyl- ester moieties (R2) may be isomers comprising said longest straight alkane chains. Having one or more R2moieties being a branched alkyl-ester provide steric hinderance, which may reduce leaching of the secondary plasticizer from the ion-selective membrane.

[0088] Specifically, for the ion-selective membrane comprising a secondary plasticizer being an adipate, each R2may comprise 1 or 2 carbon atoms, hence be selected from dimethyl adipate or diethyl adipate, preferably diethyl adipate.

[0089] More specifically, for the ion-selective membrane comprising a secondary plasticizer, the secondary plasticizer may be selected from dimethyl adipate, diethyl adipate, tris(butyl) trimellitate, tris(pentyl) trimellitate, tris(hextyl) trimellitate, tris(heptyl) trimellitate, 1,2- cyclohexane dicarboxylic acid di-butyl ester, 1,2-cyclohexane dicarboxylic acid di-pentyl ester, 1,2-cyclohexane dicarboxylic acid di-hexyl ester, 1,2-cyclohexane dicarboxylic acid diheptyl ester, di-butyl terephthalate, di-pentyl terephthalate, di-hexyl terephthalate, di-heptyl terephthalate, di-butyl phthalate, di-pentyl phthalate, di-hexyl phthalate, di-heptyl phthalate (DiHP), preferably di-isopentyl terephthalate (DiPT). The advantage of terephthalates is that they may be of less concern than the phthalates.

[0090] The ion-selective membrane may comprise the specific combinations of tris(2-ethylhexyl) trimellitate and one secondary plasticizer, such that the plasticizer combination is selected from of tris(2-ethylhexyl) trimellitate combined with dimethyl adipate, or tris(2-ethylhexyl) trimellitate combined with diethyl adipate, or tris(2-ethylhexyl) trimellitate combined with dibutyl phthalate, or tris(2-ethylhexyl) trimellitate combined with di-pentyl phthalate, or tris(2- ethylhexyl) trimellitate combined with di-hexyl phthalate or tris(2-ethylhexyl) trimellitate combined with di-isoheptyl phthalate. Alternatively the ion-selective membrane comprises tris(2-ethylhexyl) trimellitate combined with di-heptyl terephthalate or tris(2-ethylhexyl) trimellitate combined with di-hexyl terephthalate or tris(2-ethylhexyl) trimellitate combined with di-pentyl terephthalate or tris(2-ethylhexyl) trimellitate combined with dibutyl terephthalate, preferably tris(2-ethylhexyl) trimellitate combined with di-isopentyl terephthalate. Another specifically preferred combination is tris(2-ethylhexyl) trimellitate combined with diethyl adipate.

[0091] In a specifically preferred embodiment, the ion-selective membrane comprises: an ionophore, a lipophilic salt, organic polymer matrix comprising poly(vinyl chloride), at least one primary plasticizer being tris(2-ethylhexyl) trimellitate, at least one secondary plasticizer being di-isopentyl terephthalate.

[0092] Specifically, the ion-selective membrane may comprise tridodecylamine ionophore, tris(2- ethylhexyl) trimellitate and di-isopentyl terephthalate, and be selective towards hydrogen ions (H+).

[0093] Alternatively, the ion-selective membrane may comprise (-)-(R,R)-N,N'-Bis-[ll- (ethoxycarbonyl)undecyl]-N,N',4,5-tetramethyl-3,6-dioxaoctane-diamide ionophore, tris(2- ethylhexyl) trimellitate and di-isopentyl terephthalate, and be selective towards calcium ions (Ca2+).

[0094] Alternatively, the ion-selective membrane may comprise 4-tert-butylcalix[4] arenetetraacetic acid tetraethyl ester ionophore, tris(2-ethylhexyl) trimellitate and di-isopentyl terephthalate, and be selective towards sodium ions (Na+).

[0095] Alternatively, the ion-selective membrane may comprise Valinomycin ionophore, tris(2- ethylhexyl) trimellitate and di-isopentyl terephthalate, and be selective towards potassium ions (K+).

[0096] Alternatively, the ion-selective membrane may comprise a phenantroline ionophore, tris(2- ethylhexyl) trimellitate and di-isopentyl terephthalate, and be selective towards magnesium ions (Mg2+).

[0097] Alternatively, the ion-selective membrane may comprise a nonactin ionophore, tris(2- ethylhexyl) trimellitate and di-isopentyl terephthalate, and be selective towards ammonium (NH4+).

[0098] In another preferred embodiment, the ion-selective membrane comprises: an ionophore, a lipophilic salt, organic polymer matrix comprising poly(vinyl chloride), at least one primary plasticizer being tris(2-ethylhexyl) trimellitate, at least one secondary plasticizer being diethyl adipate.

[0099] The ion-selective membrane may comprise tridodecylamine ionophore, tris(2-ethylhexyl) trimellitate and diethyl adipate, and be selective towards hydrogen ions (H+).

[0100] Alternatively, the ion-selective membrane may comprise (-)-(R,R)-N,N'-Bis-[ll- (ethoxycarbonyl)undecyl]-N,N',4,5-tetramethyl-3,6-dioxaoctane-diamide ionophore, tris(2- ethylhexyl) trimellitate and diethyl adipate, and be selective towards calcium ions (Ca2+).

[0101] Alternatively, the ion-selective membrane may comprise 4-tert-butylcalix[4] arenetetraacetic acid tetraethyl ester ionophore, tris(2-ethylhexyl) trimellitate and diethyl adipate, and be selective towards sodium ions (Na+).

[0102] Alternatively, the ion-selective membrane may comprise Valinomycin ionophore, tris(2- ethylhexyl) trimellitate and diethyl adipate, and be selective towards potassium ions (K+).

[0103] Alternatively, the ion-selective membrane may comprise a phenanthroline ionophore, tris(2- ethylhexyl) trimellitate and diethyl adipate, and be selective towards magnesium ions (Mg2+).

[0104] Alternatively, the ion-selective membrane may comprise a nonactin ionophore, tris(2- ethylhexyl) trimellitate and diethyl adipate, and be selective towards ammonium (NH4+).

[0105] The ion-selective membrane comprises at least one secondary plasticizer and / or at least one tertiary plasticizer, wherein the at least one tertiary plasticizer is a 2-nitroalkylphenyl ether, said 2-nitroalkylphenyl ether having an alkyl-ether moiety (R3) comprising > 8 carbon atoms. Said alkyl-ether moiety (R3) may be branched, cyclic or a straight-chain.

[0106] Specifically, the tertiary plasticizer may be 2-nitrophenyl octyl ether, 2-nitrophenyl nonyl ether, 2-nitrophenyl decyl ether or (12-(4-ethylphenyl)dodecyl) 2-nitroalkylphenyl ether, preferably 2-nitrophenyl octyl ether. The effect of including at least one 2-nitrophenylalkyl ether, and specifically 2-nitrophenyl octyl ether is an increase in selectivity specifically where the membrane is selective towards Ca2+or Mg2+. Additionally, the presence of said tertiary plasticizer may further eliminate or reduce impedance and prolong sensitivity and stability over time for such membranes selective towards Ca2+or Mg2+.

[0107] In a specifically preferred embodiment, the ion-selective membrane comprises: an ionophore, a lipophilic salt, organic polymer matrix comprising poly(vinyl chloride), at least one primary plasticizer being tris(2-ethylhexyl) trimellitate, at least one tertiary plasticizer being 2-nitrophenyl octyl ether.

[0108] Such membrane may advantageously be selective towards at least Ca2+. Specifically, the ion- selective membrane may comprise the ionophore (-)-(R,R)-N,N'-Bis-[ll- (ethoxycarbonyl)undecyl]-N,N',4,5-tetramethyl-3,6-dioxaoctane-diamide, tris(2-ethylhexyl) trimellitate, 2-nitrophenyl octyl ether, and be selective towards calcium ions (Ca2+).

[0109] In a more specifically preferred embodiment, the ion-selective membrane comprises: an ionophore, a lipophilic salt, organic polymer matrix comprising poly(vinyl chloride), at least one primary plasticizer, being tris(2-ethylhexyl) trimellitate, at least one secondary plasticizer being di-isopentyl terephthalate and at least one tertiary plasticizer being 2-nitrophenyl octyl ether.

[0110] Such membrane may advantageously be selective towards at least Ca2+. Specifically, the ion- selective membrane may comprise the ionophore (-)-(R,R)-N,N'-Bis-[ll- (ethoxycarbonyl)undecyl]-N,N',4,5-tetramethyl-3,6-dioxaoctane-diamide, tris(2-ethylhexyl) trimellitate, di-isopentyl terephthalate, 2-nitrophenyl octyl ether, and be selective towards calcium ions (Ca2+).

[0111] Hansens solubility parameters for the primary, secondary and tertiary plasticizer

[0112] In the specific case, where the plasticizer combination is to replace diethylhexyl phthalate (DEHP), the primary plasticizer preferably has Hansens solubility coordinates comprising a 6P< 6P-DEHP and 6h < Sh-DEHP (6P-DEHP and Sh-DEHP being parameter values for DEHP) and preferably the secondary and / or tertiary plasticizer have coordinates comprising 6P> 6P.DEHP and 6h > 6h- DEHP. Further, the at least one primary plasticizer may have Hansen solubility parameters within the DEHP Hansen sphere. Additionally or alternatively, the at least one secondary and / or tertiary plasticizer(s) may have a 6P> 6P.DEHP and 6h > Sh-DEHP. Where the plasticizer combination comprises at least one secondary plasticizer, the at least one secondary plasticizer may have Hansen solubility parameters within the DEHP Hansen sphere. Additionally or alternatively, the at least one secondary plasticizer may have Hansen solubility parameters within the Hansens sphere of the organic matrix. Where the plasticizer combination comprises at least one tertiary plasticizer, the at least one tertiary plasticizer may have Hansen solubility parameters within the Hansens sphere of the organic polymer matrix. In general, a good plasticizer and especially a good combination of plasticizers for replacing DEHP has / have Hansen solubility parameters within the DEHP Hansen sphere. Hansen solubility parameters are not known for all plasticizers, e.g. no Hansens solubility parameters exist in the literature for terephthalates. Herein the primary and / or the secondary plasticizer may be a terephthalate. However, Hansen solubility parameters are known for the corresponding phthalates; hence these values may be used as substitutes. This is suitable because the only difference between terephthalates and the corresponding phthalates i.e. phthalates with the same alkyl-chains / radicals lengths, is the substitution positions at the benzene ring, and the substitution position is not a necessary factor when computational methods are used for calculating Hansen solubility parameters e.g. using the Group Contribution Method. The Hansen solubility parameters of known phthalates are thus used as substitutes for the corresponding terephthalates.

[0113] In this way, DEHP in the ion-selective membrane may be substituted by at least one primary plasticizer, combined with at least one secondary plasticizer and / or at least one tertiary plasticizer.

[0114] Concentration of plasticizers in the ion-selective membrane

[0115] The ion-selective membrane may further be specified such that the total amount of plasticizer present in the membrane is 30-80 wt%, preferably 60-80 wt%, by dry mass of the membrane. The total amount of plasticizer may preferably refer to the total amount of external plasticizer, wherein external plasticizer(s) also known as free plasticizer specifies plasticizer(s) not covalently bound to the organic polymer matrix. Alternatively, the ion- selective membrane may comprise the plasticizers as internal plasticizer(s) or as a combination of external and internal plasticizer(s), wherein internal plasticizer(s) also referred to as immobilized plasticizers specifies plasticizers being covalently bound to polymers comprised in the organic polymer matrix. Having the provided interval of total amount of plasticizer in the membrane may result in a suitable mobility of ions and other compounds within said ion-selective membrane.

[0116] Where the membrane is selective towards at least K+, the total amount of plasticizer present in the membrane may comprise 60-80 wt% of the dry mass of the membrane, and more preferably 68-74 wt% such as 71 wt% of the dry mass of the membrane.

[0117] Where the membrane is selective towards at least H+, the total amount of plasticizer present in the membrane may comprises 60-70 wt% of the dry mass of the membrane, and more preferably 62-67 wt% of the dry mass of the membrane.

[0118] The ratio of the at least one primary plasticizer relative to the at least one secondary plasticizer; or the ratio of the at least one primary plasticizer relative to the at least one tertiary plasticizer or the ratio between the least one primary plasticizer: the at least one secondary plasticizer: at least one tertiary plasticizer may vary depending on the specific combinations of primary, secondary, and tertiary plasticizer. However, preferably, the at least one primary plasticizer is / are present in the membrane in an amount of 5 wt% to 95 wt%, preferably 40 wt% to 60 wt% by weight of the total mass of the plasticizers. Additionally, the at least one secondary plasticizer may be present in the membrane in an amount of 5 wt% to 95 wt%, preferably 40 wt% to 60 wt% by weight of the total mass of the plasticizers. Alternatively or additionally to comprising the at least one secondary plasticizer, the ion- selective membrane may further comprise the tertiary plasticizer in the membrane in an amount of 5 wt% to 50 wt% by weight of the total mass of the plasticizers.

[0119] Preferably, the ion-selective membrane may have a ratio of the primary plasticizer to the secondary plasticizer of between 40:60 to 60:40, preferably 45:55 to 55:45. Specifically, wherein the ion-selective membrane comprises tris(2-ethylhexyl) trimellitate (TOTM) and diisopentyl terephthalate (DiPT) the ratio of TOTM: DiPT may be between 40:60 to 60:40, preferably 45:55 to 55:45 such as 50:50.

[0120] In a preferred embodiment, the present invention relates to an ion-selective membrane comprising : an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), and a mixture of plasticizers comprising, preferably consisting of, (i) tris(2- ethylhexyl) trimellitate (TOTM) in an amount in the range of from about 40 % (w / w) to about 60 % (w / w) based on the total weight of the mixture of plasticizers, and (ii) di-isopentyl terephthalate (DiPT) in an amount in the range of from about 40 % (w / w) to about 60 % (w / w) based on the total weight of the mixture of plasticizers. In a further preferred embodiment, the present invention relates to an ion-selective membrane comprising : an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), and a mixture of plasticizers comprising, preferably consisting of, (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount in the range of from about 45 % (w / w) to about 55 % (w / w) based on the total weight of the mixture of plasticizers, and (ii) di-isopentyl terephthalate (DiPT) in an amount in the range of from about 45 % (w / w) to about 55 % (w / w) based on the total weight of the mixture of plasticizers. It is understood that the afore amounts of (i) tris(2- ethylhexyl) trimellitate (TOTM) and (ii) di-isopentyl terephthalate (DiPT) in the mixture of plasticizer add up to 100 % (w / w).

[0121] In a particularly preferred embodiment, the present invention relates to an ion-selective membrane comprising : an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), and a mixture of plasticizers consisting of (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount of about 50 % (w / w) based on the total weight of the mixture of plasticizers, and (ii) di-isopentyl terephthalate (DiPT) in an amount of about 50 % (w / w) based on the total weight of the mixture of plasticizers. It was found that the above combinations of the primary plasticizer being TOTM and the second plasticizer being DiPT is particularly useful in ion-selective membranes of an ion- selective electrode that is selective towards at least one ion selected from Na+, K+, H+ions (such as pH sensors and / or pCO2sensors as disclosed herein), and a combination thereof.

[0122] Alternatively, wherein the ion-selective membrane comprises tris(2-ethylhexyl) trimellitate (TOTM) and diethyl adipate (DEA), preferably the ratio of TOTM: DEA is between 90: 10 to 98:2.

[0123] Preferably, the ion-selective membrane may have a ratio of the primary plasticizer to the tertiary plasticizer of between 55:45 to 90: 10, preferably 60:40 to 80:20. Specifically, wherein the ion-selective membrane comprises tris(2-ethylhexyl) trimellitate (TOTM) and 2- nitrophenyl octyl ether (o-NPOE), preferably the ratio of TOTM:o-NPOE is 60:40 to 80:20 .

[0124] Alternatively, the ion-selective membrane may comprise tris(2-ethylhexyl) trimellitate (TOTM), di-isopentyl terephthalate (DiPT) and 2-nitrophenyl octyl ether (o-NPOE) such as in a ratio of TOTM: DiPT:o-NPOE of between 45:45: 10 to 35:35:30, preferably 40:40:20. Preferably, the 2-nitrophenyl octyl ether comprises < 35 wt% such as < 30 wt% by weight of the total mass of the plasticizers.

[0125] In other words, in a preferred embodiment, the present disclosure relates to an ion-selective membrane comprising : an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), and a mixture of plasticizers comprising, preferably consisting of, (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount in the range of from about 30 % (w / w) to about 50 % (w / w) based on the total weight of the mixture of plasticizers, (ii) di-isopentyl terephthalate (DiPT) in an amount in the range of from about 30 % (w / w) to about 50 % (w / w) based on the total weight of the mixture of plasticizers, and (iii) 2-nitrophenyl octyl ether (o-NPOE) in an amount in the range of from about 10 % (w / w) to about

[0126] 30 % (w / w) based on the total weight of the mixture of plasticizers. It is understood that the amounts of (i) tris(2-ethylhexyl) trimellitate (TOTM), (ii) di-isopentyl terephthalate (DiPT), and (iii) 2-nitrophenyl octyl ether (o-NPOE) in the plasticizer mixture add up to 100 % (w / w).

[0127] In other words, in a preferred embodiment, the present disclosure relates to an ion-selective membrane comprising : an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), and a mixture of plasticizers consisting of, (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount of about 40 % (w / w) based on the total weight of the mixture of plasticizers, (ii) di-isopentyl terephthalate (DiPT) in an amount of 40 % (w / w) based on the total weight of the mixture of plasticizers, and (iii) 2-nitrophenyl octyl ether (o- NPOE) in an amount in the range of about 20 % (w / w) based on the total weight of the mixture of plasticizers. It was found that this combination of the primary plasticizer being TOTM, the second plasticizer being DiPT, and the third plasticizer being o-NPOE is particularly useful in ion- selective membranes of an ion-selective electrode that is selective towards at least one ion selected from Ca2+, Mg2+, and combinations thereof, in particular Ca2+ions.

[0128] Alternatively, the ion-selective membrane comprising tris(2-ethylhexyl) trimellitate (TOTM), diethyl adipate (DEA) and 2-nitrophenyl octyl ether (o-NPOE) such as in a ratio of TOTM :DEA:o-NPOE of between 80: 15:5 to 60:25: 15, preferably 70:20 : 10.

[0129] Ion-selective electrode (ISE)

[0130] In a further aspect, the invention relates to an ion-selective electrode comprising the ion- selective membrane disclosed herein. The ion-selective electrode further comprises an electrode, which is connected to a potentiometer. Preferably, the ion-selective electrode is selective towards at least one ion selected from Na+, K+, Ca2+Mg2+, NH4+, H+, ions or combinations thereof. The ion-selective electrode may be positioned in a chamber or on a substrate with one or more different selective membranes. Specifically, such membranes may be arranged on the same substrate and in the same chamber.

[0131] In a preferred embodiment, the present invention relates to an ion-selective electrode comprising an ion-selective membrane, the ion selective membrane comprising : an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), and a mixture of plasticizers comprising, preferably consisting of, (i) tris(2-ethylhexyl) trimellitate (TOTM) and (ii) di-isopentyl terephthalate (DiPT), and wherein the ion-selective electrode is selective towards at least one ion selected from the group consisting of Na+, K+, H+ions, and combinations thereof.

[0132] In a preferred embodiment, the present invention relates to an ion-selective electrode comprising an ion-selective membrane, the ion selective membrane comprising : an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), and a mixture of plasticizers comprising, preferably consisting of, (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount in the range of from about 40 % (w / w) to about 60 % (w / w), preferably of from about 45 % (w / w) to about 55 % (w / w), most preferably of about 50 % (w / w), each based on the total weight of the mixture of plasticizers, and (ii) di- isopentyl terephthalate (DiPT) in an amount in the range of from about 40 % (w / w) to about 60 % (w / w), preferably of from about 45 % (w / w) to about 55 % (w / w), most preferably of about 50 % (w / w), each based on the total weight of the mixture of plasticizers, and wherein the ion-selective electrode is selective towards at least one ion selected from the group consisting of Na+, K+, H+ions, and combinations thereof. In a particularly preferred embodiment, the present invention relates to an ion-selective electrode comprising an ion-selective membrane, the ion-selective membrane comprising : an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), and a mixture of plasticizers consisting of (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount of about 50 % (w / w) based on the total weight of the mixture of plasticizers, and (ii) diisopentyl terephthalate (DiPT) in an amount of about 50 % (w / w) based on the total weight of the mixture of plasticizers, and wherein the ion-selective electrode is selective towards at least one ion selected from the group consisting of Na+, K+, H+ions, and combinations thereof.

[0133] In another preferred embodiment, the present invention relates to an ion-selective electrode comprising an ion-selective membrane, the ion-selective membrane comprising : an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), and a mixture of plasticizers comprising, preferably consisting of, (i) tris(2-ethylhexyl) trimellitate (TOTM), (ii) di-isopentyl terephthalate (DiPT), and (iii) 2-nitrophenyl octyl ether (o-NPOE), and wherein the ion-selective electrode is selective towards at least one ion selected from the group consisting of Ca2+, Mg2+, and a combination thereof.

[0134] In another preferred embodiment, the present invention relates to an ion-selective electrode comprising an ion-selective membrane, the ion-selective membrane comprising : an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), and a mixture of plasticizers comprising, preferably consisting of, (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount in the range of from about 30 % (w / w) to about 50 % (w / w) based on the total weight of the mixture of plasticizers, (ii) di-isopentyl terephthalate (DiPT) in an amount in the range of from about 30 % (w / w) to about 50 % (w / w) based on the total weight of the mixture of plasticizers, and (iii) 2-nitrophenyl octyl ether (o-NPOE) in an amount in the range of from about 10 % (w / w) to about 30 % (w / w) based on the total weight of the mixture of plasticizers, and wherein the ion-selective electrode is selective towards at least one ion selected from the group consisting of Ca2+, Mg2+, and a combination thereof.

[0135] In another preferred embodiment, the present invention relates to an ion-selective electrode comprising an ion-selective membrane, the ion-selective membrane comprising : an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), and a mixture of plasticizers comprising, preferably consisting of, (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount in the range of from about 35 % (w / w) to about 45 % (w / w) based on the total weight of the mixture of plasticizers, (ii) di-isopentyl terephthalate (DiPT) in an amount in the range of from about 35 % (w / w) to about 45 % (w / w) based on the total weight of the mixture of plasticizers, and (iii) 2-nitrophenyl octyl ether (o-NPOE) in an amount in the range of from about 15 % (w / w) to about 25 % (w / w) based on the total weight of the mixture of plasticizers, and wherein the ion-selective electrode is selective towards at least one ion selected from the group consisting of Ca2+, Mg2+, and a combination thereof.

[0136] In a particularly preferred embodiment, the present invention relates to an ion-selective electrode comprising an ion-selective membrane, the ion-selective membrane comprising : an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), and a mixture of plasticizers consisting of (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount of about 40 % (w / w) based on the total weight of the mixture of plasticizers, (ii) di-isopentyl terephthalate (DiPT) in an amount of about 40 % (w / w) based on the total weight of the mixture of plasticizers, and (iii) 2-nitrophenyl octyl ether (o-NPOE) in an amount of about 20 % (w / w) based on the total weight of the mixture of plasticizers, and wherein the ion- selective electrode is selective towards at least one ion selected from the group consisting of Ca2+, Mg2+, and a combination thereof.

[0137] A process for preparing the ion-selective electrode may include preparing the organic polymer matrix by mixing the components i.e. comprising ionophores, lipophilic salt(s) and plasticizers in a solvent and dispensing the resulting solution on a desired electrode and allowing the solvent to evaporate. Any suitable solvent may be used. In one embodiment, the solvent is cyclohexanone. The electrode may comprise a vanadium bronze-platinium contact.

[0138] In this way, said ion-selective electrode comprising the ion-selective membrane may be suitable for analysis of a bodily fluid, e.g. whole blood, serum or plasma, as ions and / or elements present in bodily fluids may reversibly interact with the membrane.

[0139] Potentiometric sensor

[0140] In a further aspect, the invention relates to a potentiometric sensor comprising the ion- selective electrode, where the ion selective electrode comprises the ion-selective membrane as disclosed herein and at least one reference electrode. The sensor converts the activity of a specific ion or compound into an electrical potential. It is the interaction between a specific ion or compound with the ion-selective membrane that results in the potential difference between the two sides of the membrane. The potential difference across the ion-selective membrane is described by the Nernst equation, which relates the voltage with the logarithm of the ionic activity. In accordance, the potentiometric sensor is used to measure the specific ionic concentration (or compound concentration) in an aqueous solution.

[0141] The potentiometric sensor may be a pCO2sensor such as Severinghaus pCO2sensor. Said Severinghaus pCO2 sensor may be used to measure both on aqueous solutions such as blood and on gases. The silicone membrane may be gas permeable and hence allows CO2from the sample to pass into the next layer, which is a bicarbonate-based electrolyte layer. Changes of pCO2in the surroundings change the pH in the electrolyte layer. The pH in the electrolyte layer is measured by the third layer being the ion-selective membrane. From the pH it is possible to back-calculate what the pCO2level of the sample is.

[0142] Alternatively, the potentiometric sensor may be a sensor for one or more particular ions. Preferably, said potentiometric sensor comprises a line of sensors each sensors being arranged to sense a particular ion. The potentiometric sensor may comprise a Vanadium bronze electrical contact, and one or more ion-selective membranes preferably being selective towards a series of different ions. The sample to be analysed preferably makes direct contact with one or more ion-selective membrane(s).

[0143] Details of a sensor in which the present ion-selective membranes can be used can be found in e.g. EP1986007.

[0144] Blood gas analyser

[0145] A further aspect of this invention relates to a potentiometric sensor used for a blood gas analyser. Specifically, the blood gas analyser may be suitable for measuring the amount of gases e.g. CO2, as well as ions and metabolites in a blood sample. Accordingly, the sample solution may be blood or derivatives thereof e.g. whole blood or derivatives thereof such as plasma. An alternative sample solution to be analysed may be dialysis fluid.

[0146] Specifically, the potentiometric sensor may be used to measure the partial pressure of gases e.g. CO2in a blood sample.

[0147] A method for determining the ion concentration, urea concentration or the partial pressure of CO,

[0148] A method for determining an ion concentration, urea concentration or the partial pressure of CO2in a liquid sample, preferably a blood sample is also provided, said method comprising :

[0149] - contacting said liquid sample with a potentiometric sensor as defined herein, and

[0150] - determining the ion concentration, urea concentration or the partial pressure of CO2in said liquid sample based on a signal provided by said potentiometric sensor. Suitably, the method further comprises that said liquid sample is arranged to flow to the potentiometric sensor. The method may further comprise that the potentiometric sensor is then arranged to measure on a static sample. The method may also be an in-vitro method.

[0151] Use of a mixture of plasticizers

[0152] In a sixths aspect, the present invention relates to a use of a mixture of plasticizer in a ion- selective membrane, wherein the mixture of plasticizers comprises (i) tris(2-ethylhexyl) trimellitate (TOTM), and (ii) di-isopentyl terephthalate (DiPT), and optionally (iii) 2- nitrophenyl octyl ether (o-NPOE).

[0153] In a preferred embodiment, the present invention relates to the use of mixture of plasticizer in a ion-selective membrane, wherein the ion-selective membrane is selective towards at least one ion selected from the group consisting of Na+, K+, H+ions, and combinations thereof; and wherein the mixture of plasticizers comprises, preferably consists of, (i) tris(2- ethylhexyl) trimellitate (TOTM) and (ii) di-isopentyl terephthalate (DiPT). In another preferred embodiment, the present invention relates to the use of mixture of plasticizer in a ion-selective membrane, wherein the ion-selective membrane is selective towards at least one ion selected from the group consisting of Na+, K+, H+ions, and combinations thereof; and wherein the mixture of plasticizers comprises, preferably consists of, (i) tris(2- ethylhexyl) trimellitate (TOTM) in an amount of from about 40 % (w / w) to about 60 % (w / w) based on the total weight of the mixture of plasticizers, and (ii) di-isopentyl terephthalate (DiPT) in an amount of from about 40 % (w / w) to about 60 % (w / w) based on the total weight of the mixture of plasticizers. In a further preferred embodiment, the present invention relates to the use of mixture of plasticizer in a ion-selective membrane, wherein the ion-selective membrane is selective towards at least one ion selected from the group consisting of Na+, K+, H+ions, and combinations thereof; and wherein the mixture of plasticizers comprises, preferably consists of, (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount of from about 45 % (w / w) to about 55 % (w / w) based on the total weight of the mixture of plasticizers, and (ii) di-isopentyl terephthalate (DiPT) in an amount of from about 45 % (w / w) to about 55 % (w / w) based on the total weight of the mixture of plasticizers. In a yet furtehr preferred embodiment, the present invention relates to the use of mixture of plasticizer in a ion-selective membrane, wherein the ion-selective membrane is selective towards at least one ion selected from the group consisting of Na+, K+, H+ions, and combinations thereof; and wherein the mixture of plasticizers consists of (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount of about 50 % (w / w) based on the total weight of the mixture of plasticizers, and (ii) di-isopentyl terephthalate (DiPT) in an amount of about 50 % (w / w) based on the total weight of the mixture of plasticizers. In a preferred embodiment, the present invention relates to the use of mixture of plasticizer in a ion-selective membrane, wherein the ion-selective membrane is selective towards at least one ion selected from the group consisting of Ca2+, Mg2+, and a combination thereof; and wherein the mixture of plasticizers comprises, preferably consists of, (i) tris(2- ethylhexyl) trimellitate (TOTM), (ii) di-isopentyl terephthalate (DiPT), and (iii) 2-nitrophenyl octyl ether (o-NPOE). In another preferred embodiment, the present invention relates to the use of mixture of plasticizer in a ion-selective membrane, wherein the ion-selective membrane is selective towards at least one ion selected from the group consisting of Ca2+, Mg2+, and a combination thereof; and wherein the mixture of plasticizers comprises, preferably consists of, (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount of from about 30 % (w / w) to about 50 % (w / w) based on the total weight of the mixture of plasticizers, (ii) di-isopentyl terephthalate (DiPT) in an amount of from about 30 % (w / w) to about 50 % (w / w) based on the total weight of the mixture of plasticizers, and (iii) 2-nitrophenyl octyl ether (o-NPOE) in an amount in the range of from about 10 % (w / w) to about 30 % (w / w) based on the total weight of the mixture of plasticizers. In a further preferred embodiment, the present invention relates to the use of mixture of plasticizer in a ion- selective membrane, wherein the ion-selective membrane is selective towards at least one ion selected from the group consisting of Ca2+, Mg2+, and a combination thereof; and wherein the mixture of plasticizers comprises, preferably consists of, (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount of from about 35 % (w / w) to about 45 % (w / w) based on the total weight of the mixture of plasticizers, (ii) di-isopentyl terephthalate (DiPT) in an amount of from about 35 % (w / w) to about 45 % (w / w) based on the total weight of the mixture of plasticizers, and (iii) 2-nitrophenyl octyl ether (o-NPOE) in an amount in the range of from about 15 % (w / w) to about 25 % (w / w) based on the total weight of the mixture of plasticizers. In a yet further preferred embodiment, the present invention relates to the use of mixture of plasticizer in a ion-selective membrane, wherein the ion-selective membrane is selective towards at least one ion selected from the group consisting of Ca2+, Mg2+, and a combination thereof; and wherein the mixture of plasticizers consists of (i) tris(2-ethylhexyl) trimellitate (TOTM) in an amount of about 40 % (w / w) based on the total weight of the mixture of plasticizers, (ii) di-isopentyl terephthalate (DiPT) in an amount of about 40 % (w / w) based on the total weight of the mixture of plasticizers, and (iii) 2-nitrophenyl octyl ether (o-NPOE) in an amount of about 20 % (w / w) based on the total weight of the mixture of plasticizers.

[0154] EXAMPLES

[0155] Example 1 - Hansens solubility parameters for plasticizers

[0156] In this example Hansens solubility parameters for plasticizers are investigated to determine if primary, secondary and tertiary plasticizers, and combinations of these, would provide similar Hansens solubility parameters to DEHP, DEHP being a plasticizer known to provide suitable performance in ion-selective membranes.

[0157] Figures 1-6 show a two-dimensional representation of the Hansens space, more specifically the 6P, 6h plane of the Hansen space. In this series of examples, the reference plasticizer is di-2-ethylhexyl phthalate (DEHP) which has the Hansen solubility parameters 6d = 16.6 MPa0 5, 6P= 7.0 MPa0 5, 6h = 3.1 MPa0 5. Suitable coordinates i.e. the Hansen solubility parameters, for a combination of plasticizers is considered to be less than 2 from the centre of the DEHP sphere. Figures 1-6 show the DEHP Hansen sphere having its centre in the Hansen parameter of DEHP and a radius of 2.

[0158] Figure 1 shows a series of primary and secondary plasticizers represented in the Hansen space, 6P, 6h. Specifically, Fig. 1 shows the 6Pparameter value as a function of the 6h value for the primary and secondary plasticizers of tris(2-ethylhexyl) trimellitate (TOTM), di-tridecyl phthalate (DTDP), di-isodecyl phthalate (DiDP), di-isononyl phthalate (DiNP), di-isoheptyl phthalate (DiHP), di-hexyl phthalate (DHP), di-2-ethylhexyl phthalate (DEHP), tris(isononyl) trimellitate (TiNTM). From the figure it is seen that the primary and secondary plasticizers listed provide combinations having coordinates within the DEHP sphere (as Hansens solubility parameters for combinations of plasticizers are additive), hence provides a distance of less than 2 from the centre of the DEHP sphere. Consequently, any combination of any one of the primary with any one of the secondary plasticizer is identified as suitable combinations for an ion-selective matrix.

[0159] Figure 2 shows the primary plasticizers of TOTM represented by its 6Pparameter value as a function of the 6h value, and further the secondary plasticizers of Di-methyl phthalate (DMP) represented by its 6Pparameter value as a function of the 6h value. Additionally, the combination of TOTM and DMP in a ratio of 45:55 is also represented by the combinations 6P, 6h. The data show that the combination of TOTM and DMP in a ratio of 45:55 provides a distance of less than 2 from the centre of the DEHP sphere. Consequently, combinations of TOTM with DMP constitutes suitable combinations of plasticizers for the ion-selective membrane.

[0160] Figure 3 shows the primary plasticizers of TOTM represented by its 6Pparameter value as a function of the 6h value, and further the secondary plasticizers of dimethyl adipate (DMA) and diethyl adipate (DEA) represented by its 6Pparameter value as a function of the 6h value. Additionally, the combination of TOTM and DMA in a ratio of 45:55 is also represented by the combinations 6P, 6h. The data show that the combination of TOTM and DMA in a ratio of 45:55 provide a combination of plasticizers providing a distance of less than 2 from the centre of the DEHP sphere. Consequently, combinations of TOTM with DMA or TOTM with DEA constitutes suitable combinations of plasticizers for the ion-selective membrane. Figure 4 shows the 6Pparameter value as a function of the 6h value for selected phthalates. More specifically, Figure 4 shows the primary plasticizers of di-tridecyl phthalate (DTDP), diisodecyl phthalate (DiDP), di-isononyl phthalate (DiNP), di-2-ethylhexyl phthalate (DEHP) and the secondary plasticizers of di-isoheptyl phthalate (DiHP), Di-hexyl phthalate (DHP), di-butyl phthalate (DibP), Di-n-butyl phthalate (DnBP), Di-ethyl phathalate (DEP), Di-methyl phthalate (DMP) and butyl benzyl phthalate (BBP). The data show that a combination of a primary plasticizer with any one of the secondary plasticizers provide a combination of plasticizers providing a distance of less than 2 from the centre of the DEHP sphere. Consequently, combinations of the listed primary plasticizers with the secondary plasticizers constitutes suitable combinations of plasticizers for the ion-selective membrane.

[0161] Figure 5 shows the primary plasticizer of TOTM represented by its 6Pparameter value as a function of the 6h value, and further the secondary plasticizer of di-isopentyl terephthalate (DiPT) represented by its 6Pparameter value as a function of the 6h value. Additionally, the combination of TOTM and DiPT in a ratio of 50 :50 is also represented by the combinations 6P, 6h. The data show that the combination of TOTM and DiPT in any ratio (TOTM constituting above 0 to less than 100 wt% by dry mass of the membrane and DiPT constituting above 0 to less than 100 wt% by dry mass of the membrane) such as in a ratio of 50:50 provide a combination of plasticizers providing a distance of less than 2 from the centre of the DEHP sphere. Consequently, combinations of TOTM with DiPT constitutes a suitable combination of plasticizers for the ion-selective membrane.

[0162] Figure 6 shows the primary plasticizer of TOTM, the secondary plasticizer of di-isopentyl terephthalate (DiPT) and the tertiary plasticizer of 2-nitrophenyl octyl ether (o-NPOE) represented by their 6Pparameter values as a function of their 6h values. Additionally, the combination of TOTM: DiPT: o-NPOE in a ratio of 40 :40:20 is also represented by the combinations 6P, 6h. The data show that the combination of TOTM, DiPT and o-NPOE provide a combination of plasticizers providing a distance of less than 2 from the centre of the DEHP sphere. Consequently, combinations of TOTM, DiPT and o-NPOE constitutes a suitable combination of plasticizers for the ion-selective membrane. Specifically, preferably are combinations wherein o-NPOE is less or equal to 35 wt% (cf. Table 1).

[0163] Calculations of suitable amounts of o-NPOE for TOTM : DiPT combinations going from 100:0 wt% to 0: 100 wt%. The TOTM: DiPT combinations are represented with 10% steps in the table all % being wt% by dry mass of the membrane.

[0164] Figure 6 further provide that the primary plasticizer of TOTM in combination with the tertiary plasticizer o-NPOE provide a suitable combination of plasticizers as the combination provides a distance of less than 2 from the centre of the DEHP sphere. For example TOTM, combined with o-NPOE in a ratio of 75:25, provide a distance of less than 2 from the centre of the DEHP sphere. Preferably, the ratio of the TOTM plasticizer is between 65 wt% to less than 100 wt%, by dry mass of the membrane.

[0165] Example 2 - Experimental data

[0166] Sensor preparation Ion-selective membrane dispensing solutions were prepared by mixing the plasticizers, lipophilic salt, the respective ion-selective ionophore, PVC and solvent in a vial at room temperature and subsequently stirring the solution mixtures to ensure homogeneity.

[0167] The resulting solution was used for dispensing membranes onto a vanadium bronze electrical contact on a ceramic support. The different ion-selective membranes are dispensed in different cavities on the same ceramic board. The solvent was subsequently allowed to evaporate to obtain the plasticized ion selective membranes. Ceramic supports with the ion-selective sensors were placed in a measurement chamber, to measure ion concentrations in a blood sample by a diagnostic analyser, such as an ABL90 instrument.

[0168] In-use lifetime test of sensors

[0169] The plasticized ion-selective membranes for Na, K, Ca, pH and pCO2 described in Examples A-D were tested and compared for their ability to measure the respective ions concentrations in blood samples. Each membrane was dispensed onto five individual electrodes of an electrode substrate, which was placed into a measuring chamber in an ABL90 analyser.

[0170] The measuring chamber had fluidic contact with a reference electrode. The analyser was programmed for automatic control of liquid transport of calibration and rinse solutions, aspiration of samples, sampling of the potentiometric signal of each electrode position, and data acquisition thereof. The sensitivity of the ion-selective sensors is determined by regular two-point calibrations during the sensors in-use lifetime, and the sensor sensitivity and sensitivity stability over minimum 24 days in-use lifetime was compared to sensors plasticized with DEHP. The sensor sensitivity was followed over the in-use lifetime of the sensor.

[0171] Example A - DEHP vs TOTM + Di PT - K, Na, pCO2 and pH sensors

[0172] Plasticized ion selective membrane solutions based on tris(2-ethylhexyl) trimellitate (TOTM) and di-isopentyl terephthalate 50:50 %w / w were prepared as described using the ingredients: TOTM, DiPT, Potassiumtetrakis-3,5-bis(Trifluoromethyl)Phenyl for pH and pCO2, Potassiumtetrakis (4-chlorophenyl)borate for Na and K, the ionophore Valinomycin for K, an Na-i- ionophore for Na, and hydrogen ionophore for pH and pCO2, PVC, and Cyclohexanone. Ceramic support with the membranes was prepared as described and mounted in a measurement chamber for testing.

[0173] As a reference, identical ion-selective membrane solutions and sensors comprising the ion- selective membrane were prepared using DEHP instead of the TOTM: DiPT mixture in same total amount of plasticizer.

[0174] Figure 7 shows the sensitivity over time for ion-selective sensors prepared from membranes plasticized with diethylhexyl phthalate (DEHP) (left) and with TOTM: DiPT 50:50 (right). It is observed that the sensor sensitivities for each ion selective sensor type with membranes plasticized with TOTM : DiPT 50:50 (%w / w) and DEHP (100 % w / w) are comparable and that they are stable over 30 days in-use lifetime. Example B - DEHP vs TOTM only vs TOTM+Di PT vs TOTM+Di PT +NPOE - Ca sensor

[0175] Three plasticized calcium ion selective membrane solutions were prepared comprising the following plasticizers combination of (b) 100 %w / w TOTM, (c) TOTM : DiPT 50:50 %w / w and (d) TOTM : DiPT:o-NPOE 40:40:20 %w / w. Additionally, the ion selective membrane solutions were prepared with a calcium ionophore, Potassiumtetrakis-3,5-bis(Trifluoromethyl)Phenyl, PVC, and Cyclohexanone. Membrane solutions were dispensed on ceramic supports such to provide the sensors and tested as described. The total amount of plasticizer was held constant across all membranes.

[0176] As a reference, a fourth identical calcium ion selective membrane solution and sensors were prepared using equal amount of (a) DEHP as used in the test sensors with alternate plasticizer(s). The sensors calcium sensitivities were followed over 32 days in-use lifetime in ABL90 analysers.

[0177] In Figure 8, the sensor sensitivity stability over 32 days test period for DEHP based sensors (a) and the three alternate formulations (b, c, d) are compared. It is observed that the sensors based on 100 %w / w TOTM (b) are unstable or have significantly reduced in-use lifetime as they show a steady and too large decrease in sensitivity over the 32 days in-use time. The positive effect of incorporating DiPT to an amount of TOTM: DiPT 50:50 is shown by the sensor sensitivity over time decreasing initially but thereafter stabilizing and staying stable over the rest of the testing period (c). It was found that the initial sensitivity decrease could be further avoided or reduced, and stable sensor sensitivity could be obtained, by incorporating 20% rel. o-NPOE in the plasticizer mixture (d).

[0178] Example C - DEHP vs TOTM+NPOE - Ca, K, Na, pCO2 sensors

[0179] Plasticized ion selective membrane solutions based on tris(2-ethylhexyl) trimellitate (TOTM) and o-Nitrophenyl Octylether (o-NPOE) 75:25 %w / w were prepared as described using the ingredients: TOTM, o-NPOE, Potassiumtetrakis-3,5-bis(Trifluoromethyl)Phenyl, the respective ionophores i) calcium ionophore for Ca, ii) Valinomycin for K, iii) Na+ ionophore for Na, and iv) hydrogen ionophore for pCO2, PVC, and Cyclohexanone. Ceramic support with the membranes was prepared as described and mounted in a measurement chamber for testing.

[0180] As a reference, identical ion selective membrane solutions and sensors were prepared using DEHP instead of the TOTM:o-NPOE mixture in same total amount of plasticizer.

[0181] Sensitivities of Ca, K, Na and pCO2sensors containing the plasticizer DEHP or the plasticizers TOTM + o-NPOE (75:25) (%w / w) were measured over 30 days in ABL90 analysers. In Figure 9, it is observed that the mixture provides nearly as stable sensitivity over in-use lifetime as for the sensors with DEHP plasticized membranes, and it is seen that the behaviour for the pCO2with an initial increase and then small decrease is reproduced for the alternate plasticizer mixture.

[0182] Example D - DEHP vs TOTM+NPOE+DEA - K and Na sensors

[0183] Plasticized Sodium and Potassium ion selective membrane solutions based on TOTM:o- NPOE:DEA 70:20: 10 %w / w were prepared using the ingredients: TOTM, o-NPOE, DEA, Potassiumtetrakis-3,5-bis(Trifluoromethyl)Phenyl, the respective ionophores i) calcium ionophore for Ca, ii) Valinomycin for K, iii) Na+ ionophore for Na, and iv) hydrogen ionophore for pCO2, PVC, and Cyclohexanone. Ceramic support with the membranes was prepared and tested as described. The total amount of plasticizer was held constant across all membranes.

[0184] As a reference, identical sodium and potassium ion selective membrane solution and sensors were prepared using equal amount of DEHP as used in the test sensors with the alternate plasticizer mixture.

[0185] The sodium and potassium sensor sensitivities were followed over 23 days in-use lifetime in ABL90 analysers.

[0186] From Figure 10, it is observed that the sensor sensitivity with the alternate plasticizer mixture is stable over time, as stable as for DEHP.

Claims

CLAIMS1. An ion-selective membrane comprising: an ionophore, a lipophilic salt, an organic polymer matrix comprising poly(vinyl chloride), at least one primary plasticizer, being a trimellitate tri-ester, cyclohexyl diester, a phthalate diester or a terephthalate diester, wherein said trimellitate tri-ester, cyclohexyl diester, phthalate diester or terephthalate diester has alkyl-ester moieties (Ri) each comprising > 8 carbon atoms, at least one secondary plasticizer and / or at least one tertiary plasticizer, wherein the at least one secondary plasticizer is an adipate, trimellitate tri-ester, cyclohexyl diester, phthalate diester or a terephthalate diester, said trimellitate tri-ester, cyclohexyl diester, phthalate diester or terephthalate diester having alkyl-ester moieties (R2) each comprising <8 carbon atoms, and wherein the at least one tertiary plasticizer is a 2-nitroalkylphenyl ether, said 2- nitroalkylphenyl ether having an alkyl-ether moiety (R3) comprising > 8 carbon atoms.

2. The ion-selective membrane according to claim 1, wherein the at least one primary plasticizer being a trimellitate tri-ester comprises three alkyl-ester moieties (Ri) and the at least one primary plasticizer being a cyclohexyl diester, phthalate diester or terephthalate diester comprises two alkyl-ester moieties (Ri), preferably where each alkyl-ester moiety (Ri) is independently defined by comprising > 8 carbon atoms, preferably all Ri moieties are the same, and / or comprises a C8-Ci8alkyl-ester moiety such as a C8-Ci3alkyl-ester moiety, and / or is branched alkyl-ester, such that the longest straight alkane chain in each Ri moiety is independently selected from octyl, such as n-octyl; nonyl; or decyl, such as n- decyl.

3. The ion-selective membrane according to any one of the preceding claims, wherein, when the at least one primary plasticizer is a phthalate, Ri comprises > 8 carbon atoms, and preferably each Ri moiety may comprise a C9-Ci8alkyl-ester moiety, such as a C9-Ci3alkyl- ester moiety.

4. The ion-selective membrane according to any one of the preceding claims, wherein primary plasticizer is selected from the group comprising : tris(octyl) trimellitate, tris(nonyl) trimellitate, tris(decyl) trimellitate , di-nonyl phthalate, di-decyl phthalate, di-undecyl phthalate, di-dodecyl phthalate, di-tridecyl phthalate, di-octyl terephthalate, di-nonylterephthalate, di-decyl terephthalate, di-undecyl terephthalate, di-dodecyl terephthalate or di-tridecyl terephthalate, 1,2-cyclohexane dicarboxylic acid di-octyl ester, 1,2-cyclohexane dicarboxylic acid di-nonyl ester, 1,2-cyclohexane dicarboxylic acid di-decyl ester, 1,2- cyclohexane dicarboxylic acid di-undecyl ester, 1,2-cyclohexane dicarboxylic acid di-dodecyl ester or 1,2-cyclohexane dicarboxylic acid di-tridecyl ester, preferably tris(2-ethylhexyl) trimellitate or di-isononyl phthalate (DINP), 1,2-cyclohexane dicarboxylic acid diisononyl ester.

5. The ion-selective membrane according to any one of the preceding claims, wherein the secondary plasticizer being a trimellitate tri-ester comprises three alkyl-ester moieties (R2) and the secondary plasticizer being an adipate, cyclohexyl diester, phthalate diester or terephthalate diester comprises two alkyl-ester moieties (R2), wherein when the secondary plasticizer comprises alkyl-ester moieties, preferably each alkyl-ester moiety (R2) is independently defined by comprising < 8 carbon atoms, preferably wherein all R2moieties are the same, and / or is independently a branched, cyclic or straight-chain, preferably wherein each R2moiety is branched.

6. The ion-selective membrane according to any one of the preceding claims, wherein the secondary plasticizer is selected from dimethyl adipate, diethyl adipate, tris(butyl) trimellitate, tris(pentyl) trimellitate, tris(hextyl) trimellitate, tris(heptyl) trimellitate, 1,2- cyclohexane dicarboxylic acid di-butyl ester, 1,2-cyclohexane dicarboxylic acid di-pentyl ester, 1,2-cyclohexane dicarboxylic acid di-hexyl ester, 1,2-cyclohexane dicarboxylic acid diheptyl ester, di-butyl terephthalate, di-pentyl terephthalate, di-hexyl terephthalate, di-heptyl terephthalate, di-butyl phthalate, di-pentyl phthalate, di-hexyl phthalate, di-heptyl phthalate, preferably di-isopentyl terephthalate.

7. The ion-selective membrane according to any one of the preceding claims, wherein the tertiary plasticizer is 2-nitrophenyl octyl ether, 2-nitrophenyl nonyl ether, 2-nitrophenyl decyl ether or (12-(4-ethylphenyl)dodecyl) 2-nitroalkylphenyl ether, preferably 2-nitrophenyl octyl ether.

8. The ion-selective membrane according to any one of the preceding claims, comprising : an ionophore, a lipophilic salt, organic polymer matrix comprising poly(vinyl chloride), at least one primary plasticizer being tris(2-ethylhexyl) trimellitate, at least one secondary plasticizer being di-isopentyl terephthalate, orthe ion-selective membrane according to any one of the preceding claims, comprising : an ionophore, a lipophilic salt, organic polymer matrix comprising poly(vinyl chloride), at least one primary plasticizer being tris(2-ethylhexyl) trimellitate, at least one tertiary plasticizer being 2-nitrophenyl octyl ether, or the ion-selective membrane according to any one of the preceding claims, comprising : an ionophore, a lipophilic salt, organic polymer matrix comprising poly(vinyl chloride), at least one primary plasticizer, being tris(2-ethylhexyl) trimellitate, at least one secondary plasticizer being di-isopentyl terephthalate and at least one tertiary plasticizer being 2-nitrophenyl octyl ether.

9. The ion-selective membrane according to any one of the preceding claims, wherein the total amount of plasticizer present in the membrane is 30-80 wt%, preferably 60-80 wt%, by dry mass of the membrane.

10. The ion-selective membrane according to any one of the preceding claims, wherein the at least one primary plasticizer is / are present in the membrane in an amount of 5 wt% to 95 wt%, preferably 40 wt% to 60 wt% by weight of the total mass of the plasticizers wherein the at least one secondary plasticizer is / are present in the membrane in an amount of 5 wt% to 95 wt%, preferably 40 wt% to 60 wt% by weight of the total mass of the plasticizers and / or, wherein the tertiary plasticizer is present in the membrane in an amount of 5 wt% to 50 wt% by weight of the total mass of the plasticizers.

11. The ion-selective membrane according to any one of the preceding claims, where the ion-selective membrane is selective towards at least one ion selected from Na+, K+, Ca2+Mg2+, NH4+, H+ions or a combination thereof.

12. An ion-selective electrode comprising one or more ion-selective membranes according to any one of claims 1-11, preferably wherein said ion-selective electrode is selective towards at least one ion selected from Na+, K+, Ca2+Mg2+, NH4+, H+ions or a combination thereof.

13. A potentiometric sensor comprising the ion-selective electrode of claim 12 and at least one reference electrode.

14. A blood gas analyser for analysis of a bodily fluid, such as whole blood, serum or plasma comprising the potentiometric sensor according to claim 13.

15. A method for determining an ion concentration, urea concentration or the partial pressure of CO2in a liquid sample, preferably a blood sample, said method comprising : contacting said liquid sample with a potentiometric sensor according to claim 13, and determining the ion concentration, urea concentration or the partial pressure of CO2in said liquid sample based on a signal provided by said potentiometric sensor.

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