JPH0339582B2 - - Google Patents

Description

〔Technical field〕

The present invention relates to a PH sensor, and particularly to a PH sensor that can measure hydrogen ion concentration in liquids such as serum and blood using electrode potential response or current response. [Prior Art and Problems] Measuring the concentration of specific ions, particularly hydrogen ions, in body fluids or similar electrolytes is important in the diagnosis and treatment of diseases. Currently, many devices that measure the pH of solutions use glass electrodes as working electrodes. However, when glass electrodes are used to measure the pH of liquids, blood and other foreign substances present in the liquid tend to adhere to the glass membrane, making the measurement operation complicated, and the resistance of the glass membrane is high. The disadvantage was that it was practically impossible to measure. Purpose of the Invention Therefore, the purpose of the present invention is to easily and accurately measure the hydrogen ion concentration of body fluids such as blood and serum.
Our goal is to provide PH sensors. According to the present invention, the above-mentioned object is achieved by the use of a nitrogen-containing aromatic compound derived from at least one fluorine-containing aromatic compound selected from the group consisting of nitrogen-containing aromatic compounds and hydroxyaromatic compounds each having a fluorine atom. This is accomplished by providing a PH sensor in which a composite film is deposited directly on the surface of an electrical conductor. As used herein, the term "polymer" is meant to include both homopolymers and interpolymers (eg, dipolymers, terpolymers). In addition, the interpolymer includes not only a copolymer of two or more of the above-mentioned fluorine-containing aromatic compounds, but also at least one of the above-mentioned fluorine-containing aromatic compounds and other suitable monomers (for example, fluorine-containing aromatic compounds). Also included are copolymers with at least one of nitrogen-containing aromatic compounds and hydroxyaromatic compounds that do not contain elementary atoms. That is, this polymer has at least one type of unit derived from the above-mentioned fluorine-containing aromatic compound. Fluorine-containing aromatic compounds have the general formula (Here, Ar is an aromatic nucleus, R ⁰ is a substituent having a fluorine atom, R ¹ is a substituent having hydrogen or no fluorine, l, m and n are each an integer of 1 or more, and l+m+n is an Ar does not exceed the effective valence number of .However, if Ar contains a fluorine atom, m is 0.
). Examples of such fluorine-containing aromatic compounds include 2-, 3- or 4-aminobenzotrifluoride, 2,2-bis-(4-aminophenyl)hexafluoropropane, 2,2-bis-[ 4-(4'-aminophenoxy)phenyl]hexafluoropropane, or It is. Alternatively, fluorine-containing aromatic compounds can be expressed by the general formula (Here, Ar is an aromatic nucleus, R ⁰ is a substituent having a fluorine atom, R ¹ is a substituent having hydrogen or no fluorine, l, m and n are each an integer of 1 or more, and l+m+n is an Ar (However, if Ar contains a fluorine atom, m may be 0). Examples of such fluorine-containing aromatic compounds include 2-, 3-
or 4-hydroxybenzotrifluoride,
2,2-bis-(4'-hydroxyphenyl)hexafluoropropane, or It is. The polymer may be an interpolymer of a fluorine-containing aromatic compound and a fluorine-free aromatic compound, as described above. Such fluorine-free aromatic compounds have the general formula (HO)- _p Ar-(R ¹ ) _q (where Ar is an aromatic nucleus, R ¹ is hydrogen or a non-fluorine substituent, p and q is an integer of 1 or more, and p+q does not exceed the effective valence number of Ar). Examples of such fluorine-containing aromatic compounds include phenol, dimethylphenol, 2-, 3- or 4-hydroxypyridine, o- or m-benzyl alcohol,
o-, m- or p-hydroxybenzaldehyde, o-, m- or p-hydroxyacetophenone, o-, m- or p-hydroxypropiophenone, o-, m- or p-benzophenol, o- , m or p-hydroxybenzophenone, o-, m- or p-carboxyphenol, diphenylphenol, 2-methyl-8-hydroquinoline, 5-hydroxy-1,4-naphthoquinone, 4-(p-hydroxy phenyl)-2-butanone, 1,5-dihydroxy-1,2,3,4
-tetrahydronaphthalene, or bisphenol. Alternatively, fluorine-containing aromatic compounds have the general formula ( _H2N ) _-rAr- ( ^R1 ) _s , where Ar is an aromatic nucleus, ^R1 is hydrogen, or a substituent without fluorine, r and Each of s is an integer of 1 or more, and r+s does not exceed the effective valence number of Ar.However, if Ar contains a nitrogen atom, r may be 0). Examples of such fluorine-free aromatic compounds include 1,2-diaminobenzene, aniline, 2-
aminopyridine, 2,3-diaminopyridine,
4,4'-diaminodiphenyl ether, 4,4'-
Methylene dianiline, tyramine, N-(o-hydroxybenzyl)aniline or pyrrole. In either case, the polymer is preferably an electrolytically oxidized polymer. Preferably, at least the surface of the conductor is made of platinum. DETAILED DESCRIPTION OF THE INVENTION The present invention will now be described in detail with reference to the accompanying drawings. As shown in FIG. 1, the PH sensor according to the present invention has a conductive base 11 having an arbitrary shape, for example, a wire shape.
The exposed tip surface 11 is covered with an insulator 13 such as polyolefin or Teflon (registered trademark).
A predetermined polymer film 12 is directly applied and fixed to a. It is preferable that platinum is formed on at least the surface portion of the conductor 11 to which the polymer film 12 is adhered. Therefore, it is possible to form the entire conductor base 11 from platinum, or form the main body from another metal (iron, stainless steel, etc.) and deposit a platinum layer on the required surface portions by vapor deposition, sputtering, etc. preferable. The latter method is advantageous from an economic point of view. The polymer film 12 deposited on the exposed surface of the conductor base 11 contains at least one fluorine selected from the group consisting of nitrogen-containing aromatic compounds and hydroxyaromatic compounds each containing a fluorine atom. derived from containing aromatic compounds. That is,
This fluorine-containing aromatic compound is an aromatic compound containing a fluorine atom and a nitrogen atom, and an aromatic compound containing a fluorine atom and a hydroxyl group. The former fluorine-containing aromatic compound has the following general formula () (Here, Ar is an aromatic nucleus, such as a monocyclic ring (benzene nucleus, pyridine nucleus, etc.), a polycyclic ring, that is, a condensed ring (naphthalene nucleus, quinoline nucleus, naphthoquinone nucleus, etc.), a bridged ring (bisphenyl nucleus, Terphenyl nucleus, methyl chain bridged bisphenyl nucleus, -0
-bridged bisphenyl nucleus, ( _-CF2 ) _-3-5 bridged bisphenyl nucleus); ^R0 is a substituent having a fluorine atom; ^R1 is a substituent having hydrogen or no fluorine; l, m and n are each integers of 1 or more, and l+m+n does not exceed the effective valence number of Ar. However, when Ar contains a fluorine atom (for example, (-CF ₂ ) _3-5 bridged bisphenyl nucleus), m is 0
). Examples of R ⁰ include a fluorine atom and a fluoroalkyl group (eg, trifluoromethyl). Also,
Examples of R ¹ include alkyl groups such as methyl groups,
Examples include aryl groups such as phenyl groups, alkyl or arylcarbonyl groups, hydroxyalkyl groups, carboxyl groups, aldehyde groups, hydroxyl groups, hydroxyhexafluoroisopropyl groups, and the like. Specific examples of the fluorine-containing aromatic compound represented by the general formula () include 2-, 3- or 4-aminobenzotrifluoride, 2,2-bis-(4
-aminophenyl)hexafluoropropane,
2,2-bis-[4-(4'-aminophenoxy)phenyl]hexafluoropropane, and It is. As a hydroxy aromatic compound having a fluorine atom, the following general formula () is used. (Here, Ar, R ⁰ , R ¹ , l, m and n are as described above). Specific examples of the compound represented by the general formula () include 2-, 3-, or 4-hydroxybenzotrifluoride, 2,2-bis-(4'-hydroxyphenyl)hexafluoropropane, and It is. The polymers deposited on the surface 11a of the conductive substrate 11 are homopolymers and interpolymers of fluorine-containing compounds represented by the general formulas () and (), and interpolymers of these and other monomers. It is a combination. A suitable compound that forms an interpolymer with the compound represented by the general formula () is the following general formula () (HO) - _p Ar - (R ¹ ) _q () (where Ar and R ¹ are as described above). As shown, p and q are each an integer of 1 or more, and p+q is Ar
fluorine-free hydroxyaromatic compounds. General formula ()
Examples of hydroxyaromatic compounds represented by are phenol, dimethylphenol (e.g.
2,6- and 3,5-dimethylphenol),
2-, 3- and 4-hydroxypyridine, o-
and m-benzyl alcohol, o-, m- and p-hydroxybenzaldehyde, o-, m-
and p-hydroxyacetophenone, o-, m
- and p-hydroxypropiophenone, o
-, m- and p-benzophenol, o-, m
- and p-hydroxybenzophenone, o-,
m- and p-carboxyphenols, diphenylphenols (e.g. 2,6- and 3,5-
diphenylphenol), 2-methyl-8-hydroquinoline, 5-hydroxy-1,4-naphthoquinone, 4-(p-hydroxyphenyl)-2-butanone, 1,5-dihydroxy-1,2,3, 4-
These include tetrahydronaphthalene and bisphenol A. In addition, as a suitable compound that forms an interpolymer with the compound represented by the general formula (), the following general formula () (H ₂ N) − _r Ar − (R ¹ ) _s () (where Ar and R As mentioned above, ¹ is an integer of 1 or more, and r+s is Ar.
does not exceed the effective valence of However, if Ar contains a nitrogen atom, r may be 0)
There is a fluorine-free, nitrogen-containing aromatic compound shown by Specific examples of such nitrogen-containing aromatic compounds include 1,2-diaminobenzene, aniline 2-aminopyridine, 2,3-diaminopyridine, 4,4'-diaminophenyl ether, 4,
4'-methylene dianiline, tyramine, N-(o-
hydroxybenzyl)aniline and pyrrole. Now, in order to directly apply the polymer film 12 to the surface 11a of the base 11, a fluorine-containing aromatic compound is applied onto the surface of the base 11 by electrolytic oxidation polymerization, if necessary together with other monomer compounds. methods, methods in which a pre-synthesized polymer is dissolved in a solvent, and this solution is fixed on the conductor surface by dipping/coating and drying; A method of directly fixing it to the surface of the conductor through treatment can be adopted. The most convenient of the above deposition methods is by electrolytic oxidative polymerization. This electrolytically oxidized polymer is produced by electrolytically polymerizing a fluorine-containing aromatic compound, optionally with other monomers, in a suitable solvent (for example, methanol containing sodium hydroxide) to obtain the desired conductivity as a working electrode. A polymer film is applied to the surface of the body. A polymer film deposited by electrolytic oxidative polymerization has extremely good adhesion stability and a smooth film surface. The thickness of the polymer film is not particularly limited, but approximately 0.01μ to 1μ is appropriate. Specific Functions of the Invention The functions of the coated electrode having the above structure will be explained in detail below. (1) Response as an ion sensor Using the ion sensor shown in Figure 1,
To measure PH, as shown in Figure 2,
Sample solution (e.g. blood,
Body fluid (such as serum) 22 is added, and the PH sensor 23 of the present invention, a silver-silver chloride electrode as a reference electrode 24, a saturated calomel electrode, etc. are immersed in this solution. Then, the potential difference (electromotive force) between the PH sensor 23 and the reference electrode 24 is measured by the potentiometer 26 . At this time, it is preferable to stir the sample solution 22 with a stirrer 25. Then, the PH of the sample solution is read from the correlation diagram between electromotive force and PH prepared in advance. The relationship between the electromotive force and PH by the PH sensor of this invention shows a linear relationship with a gradient of approximately 59 mV/PH in a wide PH range, and is expressed by the formula E=E ₀ + RT/Fln [H ⁺ ] (where E is It almost satisfies the Nernst equation expressed by the starting force (mV), E ₀ is a constant potential (mV), R is the gas constant, T is the absolute temperature, F is the Faraday constant, and [H ⁺ ] is the hydrogen ion concentration. Examples of this invention will be described below. Example 1 The periphery of a stainless steel wire (SUS304, diameter 1 mm) serving as the conductive basic body was insulated with Teflon, and the exposed end surface was covered with silicon carbide (particle size: approximately 8.0 μm) paper and alumina powder (particle size: 0.3 μm). )
It was polished and smoothed, washed with water and methanol, and dried. A basic body was fabricated by depositing platinum to a thickness of 0.05 μm on the exposed tip surface of this basic body by a sputtering method (200 W x 15 seconds). Next, desired electrolytic oxidative polymerization was carried out using a conventional three-electrode cell under the following conditions. Electrolyte: 2,2-bis-(4'-hydroxyphenyl)hexafluoropropane (BHFP) 10
Methanol solution containing 30 mM sodium hydroxide and 30 mM sodium hydroxide (sufficiently deoxidized by blowing argon gas) Counter electrode: Platinum mesh Reference electrode: Commercially available sodium chloride saturated calomel electrode (SSCE) Working electrode: The above conductor basic (electrode is distilled After washing with water and drying, the applied voltage was stopped at 1.0 V (vs. SSCE), electrolysis was performed for 3 minutes, and the desired BHFP was deposited on the basic platinum film.
electrolytically oxidized polymer (hereinafter simply referred to as poly(BHFP))
A film (0.05 μm thick) is formed, and the desired
I got a PH sensor. A cyclic voltammogram showing the initiation of this electrolytic oxidation polymerization reaction is shown in FIG. In the figure, curve a is the first scanning oxidation wave, curve b is the second scanning wave, and curve c is the third scanning wave. Note that the potential scanning speed was 100 mV/sec. Using the PH sensor thus obtained, standard serum (Versatol-A manufactured by Warner-Lambert; Cl ^- ,
PH of 25 (including Fe ^2+/3+ , Mg ²⁺ , PO ₄ ^2- , K ⁺ , Na ⁺ , Ca ²⁺ , albumin, glucose, creatinine, cholesterol, bilirubin and protein)
Measured at ±0.01℃. The concentration of standard serum was 20%, and its pH was adjusted to PH4-9.0 with phosphate buffer. The results are shown by straight line a in FIG. As can be seen from this result, the equilibrium potential value was approximately 250 mV when the PH, which corresponds to the PH of whole blood, was 7.40. Also,
The relationship between the equilibrium potential value of the same PH sensor in 0.05M phosphate buffer and PH was as shown by the straight line b in FIG. 4. From this result, the change in equilibrium potential value per PH is 56 mV (2.0≦PH≦9.0), and PH7.40
It can be seen that the equilibrium potential value at this time is 272 mV. These results show that the equilibrium potential value in phosphate buffer is approximately 22 mV higher than that in standard serum. As can be seen from the above results, this PH sensor is an excellent sensor for measuring the PH of body fluids. In addition, in order to investigate the influence of chlorine ions in the PH measurement sample solution, we used a phosphate buffer solution with a constant pH of 6.86 and measured the equilibrium potential value of the above PH sensor by changing the chlorine ion concentration (25℃± 0.1℃).
The results are shown in Figure 5. As you can see from this figure,
Chlorine ion concentration is 1 up to 10 ^-1 M.
The change in equilibrium potential per amount of activity is as small as 1.75 mV, so this PH sensor can measure PH without being interfered with by chlorine ions if the chlorine ion concentration is about the same as that contained in body fluids. can. Example 2 Electrolytic oxidation of BHFP and DAB was carried out in exactly the same manner as in Example 1, except that a methanol solution containing 5mM of BHFP, 5mM of 1,2-diaminobenzene (DAB) and 30mM of sodium hydroxide was used as the electrolyte. A PH sensor with a polymer film (approximately 0.05 μm thick) was fabricated. A cyclic voltammogram of this electrolytic oxidative polymerization is shown in FIG. In the figure, curve a is the first scanning oxidation wave, curve b is the second scanning oxidation wave, and curve c is the third scanning oxidation wave. Using the PH sensor obtained in this way, the relationship between the equilibrium potential value and PH in standard serum (black circle in Figure 7 = straight line a) and that in phosphate buffer (Figure 7) were carried out in the same manner as in Example 1. The white blank circle in the figure = straight line b) was measured. In addition, the influence of chlorine ions was also investigated in the same manner as in Example 1 (FIG. 8). Comparative Example 1 A sensor having a poly(BHFP+BPA) film was produced in the same manner as in Example 2 except that bisphenol A (BPA) was used instead of BHFP,
The relationship between the equilibrium potential value and PH value in standard serum (black triangle mark in Figure 7 = straight line c) and that in phosphate buffer (white triangle mark in Figure 7: coincides with straight line b)
was measured. The results of the sensor of Example 2 and the sensor of Comparative Example 1 are summarized in Table 1 below.

[Table] From the above, the PH sensor of this invention
PH measurement is possible, and the difference in equilibrium potential between phosphate buffer and serum is small, indicating that it is hardly affected by interfering ions. In particular, it is clear from FIG. 8 that there is no interference with chloride ions. On the other hand, although the PH sensor of Comparative Example 1 is capable of measuring PH in a phosphate buffer, it is not possible to measure PH in serum. Examples 3 and 4 PH with a poly(BHFP+ABTF) film was prepared in exactly the same manner as in Example 2 except that 2-aminobenzotrifluoride (ABTF) was used instead of DAB.
A sensor was produced (Example 3). Also, BHFP
A PH sensor having a poly(ABTF) film was produced in exactly the same manner as in Example 1 except that ABTF was used instead of (Example 4). Regarding these PH sensors, the relationship between the equilibrium potential value and the PH value in standard serum and phosphate buffer was investigated in the same manner as in Example 1. The results are shown in Figure 9. In the figure, straight lines a and b are poly(BHFP+
Regarding the PH sensor with ABTF) membrane, the results are shown in standard serum and phosphate buffer, respectively. Also, lines c and d show the results in standard serum and phosphate buffer, respectively, for a PH sensor with a poly(ABTF) membrane. These results are summarized in Table 2 below.

[Table] These results show that both PH sensors can measure PH without being affected by interfering ions in body fluids. Especially with a copolymer membrane
The PH sensor (Example 3) has an equilibrium potential value of Example 4.
This is higher than that of the previous method, and is better for measuring hydrogen ion concentrations in body fluids. Furthermore, the samples of Example 3 are less affected by chlorine ions than those of Example 4. Examples 5 to 7 PH sensors having corresponding copolymer membranes were produced in exactly the same manner as in Example 2, except that the copolymerizable compounds shown in Table 3 were used instead of DAB. Using these PH sensors, the relationship between the equilibrium potential value and the PH value in serum and phosphate buffer was investigated in the same manner as in Example 1. The results are also listed in Table 3.

【table】

[Table] Specific Effects of the Invention The PH sensor of the present invention described above can measure the PH of body fluids (blood, serum, etc.) almost unaffected by interfering ions present therein. The PH sensor of the present invention has a simple structure in which a film of a polymer of a fluorine-containing aromatic compound is coated on the surface of a conductor, and there is no need to provide a reference liquid chamber unlike a glass electrode. Therefore, miniaturization can be achieved up to the processing limit of the conductor. Furthermore, even if this polymer film is used repeatedly, sticky substances in body fluids will not adhere to it. Furthermore, since the polymer membrane has a low impedance, a high input impedance amplifier is not required for pH measurement.

[Brief explanation of the drawing]

FIG. 1 is an enlarged sectional view of the PH sensor of the present invention, FIG. 2 is a schematic diagram showing an example of a PH measuring device using the PH sensor of the present invention, and FIGS. 3 and 6 are PH sensor of the present invention. Cyclic voltammograms during the electrolytic oxidation reaction carried out to produce the sensor, FIGS. 4, 5, and 7 to 9 are graphs showing the characteristics of the PH sensor of the present invention. DESCRIPTION OF SYMBOLS 11... Conductor base, 11a... Surface of conductor base, 12... Polymer film, 23... PH sensor,
24... Reference electrode, 26... Potentiometer.

Claims (1)

[Scope of Claims] 1. A polymer film derived from at least one fluorine-containing aromatic compound selected from the group consisting of nitrogen-containing aromatic compounds and hydroxyaromatic compounds each having a fluorine atom. A PH characterized by being formed by directly depositing on the surface of a conductor.
sensor. 2 Fluorine-containing aromatic compounds have the general formula (Here, Ar is an aromatic nucleus, R ⁰ is a substituent having a fluorine atom, R ¹ is a substituent having hydrogen or no fluorine, l, m and n are each an integer of 1 or more, and l+m+n is an Ar does not exceed the effective valence number of .However, if Ar contains a fluorine atom, m is 0.
The PH sensor according to claim 1, which may be 3 The fluorine-containing aromatic compound is 2-, 3- or 4-aminobenzotrifluoride, 2,2-bis-(4-aminophenyl)hexafluoropropane, 2,2-bis[-(4'-aminophenoxy)
phenyl]hexafluoropropane, or It is. PH sensor according to claim 2. 4 Fluorine-containing aromatic compounds have the general formula (Here, Ar is an aromatic nucleus, R ⁰ is a substituent having a fluorine atom, R ¹ is a substituent having hydrogen or no fluorine, l, m and n are each an integer of 1 or more, and l+m+n is an Ar (However, if Ar contains a fluorine atom, m may be 0). 5 The fluorine-containing aromatic compound is 2-, 3-, or 4-hydroxybenzotrifluoride, 2,2
-bis-(4-'hydroxyphenyl)hexafluoropropane, or The PH sensor according to claim 4. 6. The PH sensor according to any one of claims 1 to 5, wherein the polymer is an interpolymer of a fluorine-containing aromatic compound and a fluorine-free aromatic compound. 7 Fluorine-containing aromatic compounds have the general formula (HO)- _p Ar- (R ¹ ) _q (where Ar is an aromatic nucleus, R ¹ is hydrogen or a substituent without fluorine, and p and q are each 1 or more, and p+q does not exceed the effective valence number of Ar)
PH sensor. 8 The fluorine-free aromatic compound is phenol, dimethylphenol, 2-, 3- or 4-hydroxypyridine, o- or m-benzyl alcohol, o-, m- or p-hydroxybenzaldehyde, o-, m- or p-hydroxyacetophenone, o-, m- or p-hydroxypropiophenone, o-, m- or p-benzophenol, o-, m- or p-hydroxybenzophenone, o-, m- or p -carboxyphenol, diphenylphenol, 2-methyl-8-
Hydroquinoline, 5-hydroxy-1,4-naphthoquinone, 4-(p-hydroxyphenyl)-2-
Butanone, 1,5-dihydroxy-1,2,3,
8. The PH sensor according to claim 7, which is 4-tetrahydronaphthalene or bisphenol A. 9 Fluorine-free aromatic compounds have the general formula (H ₂ N) - _r Ar - (R ¹ ) _s (where Ar is an aromatic nucleus, R ¹ is hydrogen, or a substituent without fluorine, r and s is an integer of 1 or more, and r+s does not exceed the effective valence number of Ar. However, if Ar contains a nitrogen atom, r may be 0). PH sensor described in Section 6. 10 The fluorine-free aromatic compound is 1,2-diaminobenzene, aniline, 2-aminopyridine,
2,3-diaminopyridine, 4,4'-diaminodiphenyl ether, 4,4'-methylene dianiline, tyramine, N-(o-hydroxybenzyl)
The PH sensor according to claim 9, which is aniline or pyrrole. 11. The PH according to any one of claims 1 to 10, wherein the polymer is an electrolytically oxidized polymer.
sensor. 12. The PH sensor according to any one of claims 1 to 11, wherein at least the surface of the conductor is made of platinum.