JP2005309391A - Process for producing chemical product and quality inspection process for chemical used in the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To produce a silver halide photographic sensitive material with photographic materials whose qualities are guaranteed without depending on a so-called "photographic property test", that is, a small-scale production test, and to produce pharmaceuticals, agricultural chemicals or cosmetics whose qualities are guaranteed without depending on an animal test. <P>SOLUTION: A process for producing a chemical product from one or more chemicals is provided. The process includes a step of determining in advance a maximum permissible amount of an impurity peak and/or a minimum permissible amount of an effective component peak under given analytical conditions for at least one of the chemicals by means of liquid chromatography employing an electrochemical detector having a conductive diamond electrode, and a step of determining the usability of a lot of the chemical by subjecting the lot to a measurement by liquid chromatography under the above analytical conditions based on an amount of the impurity peak and/or an amount of the effective component peak of the lot. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing a chemical product. The present invention also relates to a chemical manufacturing method, an inspection method, a shipping method, and a receiving method.

  Silver halide photographic light-sensitive materials (hereinafter also simply referred to as “photographic materials”) are used in various forms in various forms, and the types of products are diverse. The photographic materials use silver halide grains as photosensitive elements for both black-and-white photographic materials and color photographic materials, and for both negative and reversal types. When recording with a photographic material, a latent image is formed only on silver halide grains exposed to radiation such as visible light, and then the silver halide is oxidized into an image according to the amount of the latent image formed. The target image is formed by the development processing by the redox reaction. In black-and-white photographic materials, silver halide is reduced to an image to form an image. In color photographic materials, an image dye formed by color development or a diffusion dye that has been released from a color material into an image form an image. Form.

  In order to provide a silver halide photographic light-sensitive material with a sufficiently long raw storage period for practical use and to stably obtain a desired image, the photographic material includes a silver halide emulsion, a dye precursor (coupler) and a coloring material. In addition to image forming materials such as these, many additives are used as photographic raw materials. Many of the additives are organic compounds, and there are various kinds of chemical sensitizers, physical sensitizers, spectral sensitizers, antifoggants, antioxidants, stabilizers and the like depending on the intended function. In general, the number of photographic raw materials used increases in the order of black and white photographic materials, color photographic materials, and instant color photographic materials, and reaches several tens of types per photographic material. Because different photographic materials are used for different types of photographic materials, photographic material manufacturing factories use nearly 1,000 kinds of photographic materials, and inspect the quality of all the photographic materials. Efforts are made day and night to ensure stable production so that there are no production failures.

Quality assurance of photographic raw materials is essential in many cases, in addition to physicochemical inspection on the raw material supply side, practicality tests on the photographic material manufacturing side. This practicality test includes a physicochemical test unique to a photographic company, but the center is a so-called “photographic test”. The photographic test is a production test for small-scale photographic materials. Using a small coating machine, which is narrower than the manufacturing machine, manufactures photographic materials using test materials and evaluates their photographic characteristics. This is a traditional method for inspecting whether a photographic raw material has the required quality. This photographic property test is a reliable test method, but is a time-consuming and time-consuming inspection method in which a light-sensitive material is actually manufactured in a dark room, developed and evaluated.
Although studies have been conducted on whether photographic tests for photographic raw materials can be replaced by appropriate physicochemical tests, no sufficient test method has yet been found in terms of impurity detection sensitivity and stability. There are many raw materials.

  Pharmaceutical products, agricultural chemicals, cosmetics, and the like are products containing various chemical substances (chemical products). In developing and manufacturing such products, it is necessary to test the biosafety of these chemicals, for example, not to induce allergic reactions. Conventionally, for example, skin sensitization is tested by dermally administering a test substance to a laboratory animal and observing the skin reaction at the site of administration (Maximization test, Bühler test, etc.). A method of examining the proliferation of lymphocytes by administering a substance transdermally (Local Lymph Node Assay method) is known. However, such an assay method requires laborious work such as administration of the test substance to the experimental animal, skin observation and blood test in addition to breeding of the experimental animal, and a period for that purpose. Therefore, it has been difficult to guarantee the quality of chemicals for each lot actually used.

  Recently, electrochemical measurement using a conductive diamond electrode doped with boron has been disclosed (see Patent Documents 1 to 5). Specifically, an example of analyzing an object to be analyzed by voltammetry using a diamond electrode as a metal or alloy (see Patent Document 1), an example of analyzing histamine using a flow cell using a diamond electrode (see Patent Document 2), an anode Example of measuring uric acid using oxidized diamond electrode (Patent Document 3), Example of analyzing thiol using diamond electrode (Patent Document 4), and measuring glucose concentration using diamond electrode An example of this is disclosed (Patent Document 5).

  There have been scientific reports on the electrochemical oxidation of NADH (dihydronicotinamide adenine dinucleotide) using a diamond electrode, or uric acid detection (see Non-Patent Documents 1 and 2).

JP 2001-21521 A JP 2001-50924 A JP 2001-147 211 A JP 2002-189016 A JP 2002-310977 A T.A. N. Rao, I.D. Yagi, T .; Miwa, D.M. A. Tryk and A.M. Fujishima, Ana. Chem. 1999, 71, 2506-2511 Elena Popa, Y.M. Kubota, D.H. A. Tryk and A.M. Fujishima, Ana. Chem. 2000, 72, 1724-1727

The problem to be solved by the present invention is to produce a silver halide photographic light-sensitive material using a photographic raw material whose quality is guaranteed without relying on the above-mentioned “photographic test”, that is, a small-scale production test. Furthermore, another problem to be solved by the present invention is to produce a pharmaceutical product, agrochemical product, or cosmetic product with guaranteed quality regardless of animal tests.
Other objects of the present invention will become apparent from the following disclosure of the invention.

  The above problem is about at least one chemical product of a chemical product produced from one or more chemical products by liquid chromatography equipped with an electrochemical detector (Electro-Chemical Detector: ECD) having a conductive diamond electrode. Pre-determining the maximum permissible amount of impurity peaks and / or the minimum permissible amount of active ingredient peaks under certain analytical conditions, and the above analysis for the lot to be used of the chemical Achieved by a method for producing a chemical product, comprising a step of performing liquid chromatography measurement under conditions and determining whether or not the lot can be used based on the impurity peak amount and / or active ingredient peak amount of the lot. It was done.

  Another object of the present invention is to provide a liquid chromatograph equipped with an electrochemical detector having a conductive diamond electrode, to allow the maximum amount of impurity peaks and / or active ingredients under certain analytical conditions of the chemical. Including the step of predetermining the minimum acceptable amount of peak and the step of measuring the chemical product by liquid chromatography under the above analytical conditions, the impurity peak amount and / or active ingredient peak amount of the chemical product Based on the above, the present invention has been achieved by a method for producing a chemical characterized in that the synthesis reaction and / or purification process of the chemical is controlled.

  The subject of the present invention is also a step of preparing a conductive diamond electrode and a counter electrode, a step of using a chemical as a component separated and eluted by liquid chromatography, and the conductive diamond electrode and the counter electrode eluted from the liquid chromatography. A method for inspecting the quality of chemicals, comprising the steps of contacting components, applying a voltage causing an oxidation reaction between the conductive diamond electrode and the counter electrode, and measuring a current under the voltage Achieved by.

  Taking a photographic material production method as an example, raw materials with quality assurance are used without relying on so-called coating tests, so production efficiency is excellent, and high-quality photographic raw materials and photographic photosensitive materials can be obtained stably. It was. For pharmaceuticals, agricultural chemicals, and cosmetics, an effect of efficiently providing a safe product can be obtained by using raw materials that are replaced with animal experiments or quality-guaranteed by a test that supplements them. The present invention can also be applied to the production of other chemical products. Furthermore, the present invention can be applied to a method for producing a chemical product.

  The method for producing a chemical product of the present invention provides a specific method for at least one chemical product produced from one or more chemical products by liquid chromatography with an electrochemical detector having a conductive diamond electrode. A step of predetermining the maximum allowable amount of impurity peaks and / or the minimum allowable amount of active ingredient peak under the analytical conditions of It includes a step of measuring by liquid chromatography and determining whether or not the lot can be used based on the impurity peak amount and / or the active ingredient peak amount of the lot.

The chemical product of the present invention is a product made of one or more kinds of chemical substances (chemical products). Chemical products include cosmetics and photographic materials in which the active ingredient is a composition of a large number of chemicals, from a single pharmaceutical or agricultural chemical.
The present invention relates to a method for producing a chemical product using a raw material subjected to quality inspection by liquid chromatography equipped with an electrochemical detector having a conductive diamond electrode.
As a representative example, the present invention relates to a method for producing a silver halide photographic light-sensitive material or the like using a photographic raw material subjected to quality inspection by liquid chromatography using an electrochemical detector having a conductive diamond electrode as a detector. Related. The present invention can also be applied to the manufacture of pharmaceuticals, agricultural chemicals and cosmetics.

  Furthermore, the method for producing a chemical product of the present invention comprises a liquid chromatograph equipped with an electrochemical detector having a conductive diamond electrode, and an acceptable maximum amount of impurity peaks and / or under certain analytical conditions of the chemical product. Or a step of predetermining an acceptable minimum amount of the peak of the active ingredient, and a step of measuring the chemical product by liquid chromatography under the above-described analytical conditions, and the impurity peak amount and / or effective amount of the chemical product The synthesis reaction and / or purification process of the chemical product is managed based on the component peak amount.

Another aspect of the present invention is the step of preparing a conductive diamond electrode and a counter electrode, the step of using a chemical as a component separated and eluted by liquid chromatography, and the conductive diamond electrode and the counter electrode eluted from the liquid chromatography. A chemical quality comprising: contacting the components; applying a voltage causing an oxidation reaction between the conductive diamond electrode and the counter electrode; and measuring a current under the voltage. Related to the inspection method.
Further, the quality inspection method may include: an acceptable maximum amount of impurity peaks and / or an impurity peak under certain analytical conditions by liquid chromatography with an electrochemical detector having a conductive diamond electrode. A step of predetermining the minimum allowable amount of the active ingredient peak, and measurement of the lot of the chemical by liquid chromatography under the above analytical conditions, and the impurity peak amount and / or active ingredient peak amount of the lot It is preferable to include a step of judging the quality of the lot based on the above.

  Here, the chemical product includes chemical substances (raw materials) constituting the chemical product, as well as the reaction solvent, etc. in addition to the pre-reaction raw materials (reactants) used in the process of manufacturing the chemical product (product). Solvents used as are also included.

  The quality inspection includes a shipping inspection by a manufacturer that manufactures a chemical product, and an acceptance inspection by a manufacturer of a chemical product that uses the raw material.

A conductive diamond electrode is a diamond electrode that is imparted with conductivity to an originally insulating diamond by doping an appropriate conductive dopant, and is a chemical vapor deposition method (especially chemical vapor deposition using plasma). It can be produced by chemical vapor-deposition (CVD).
Examples of the conductive dopant include Group 3 and Group 5 atoms, preferably B, N, P, and As. Among them, nitrogen (N) and boron (B) are preferable, and B is particularly preferable. A p-type semiconductor diamond or a metal-like conductive diamond can be obtained and used as an electrode. The conductivity can be controlled by the amount of doping, and it is preferable that the amount of doping into diamond gives a conductivity of about 1 × 10 ⁻² to 10 ⁻⁶ Ωcm.
Although it is possible to use conductive diamond itself as an electrode without supporting the substrate, it is preferable to form a thin film of conductive diamond on the conductive substrate.

The chemical vapor deposition method of diamond is performed by using a mixture of a carbon source and hydrogen as a source gas, exciting it with an excitation source, and supplying and depositing it on a substrate.
A diamond electrode is an electrode imparted with conductivity by doping conductive atoms such as boron in the course of chemical vapor deposition (CVD). An organic compound such as methane or methanol is used as the carbon source. Examples of the excitation source include a hot filament, microwave, high frequency, direct current arc discharge, direct current glow discharge, and combustion flame, and microwave is preferable.
A diamond thin film manufactured by a CVD method grows in a polycrystalline state on a substrate. Examples of the substrate include single crystal silicon, Mo, W, Nb, Ti, Fe, Au, Ni, Co, alumina, silicon carbide, and graphite. A conductive silicon substrate can be preferably used. The silicon substrate preferably has a conductivity of about 0.1 Ωm or more, and can be obtained by doping an appropriate conductive dopant when manufacturing the silicon substrate.

One process of CVD will be described below, but those skilled in the art can easily make appropriate changes with reference to Non-Patent Document 1 or 2 and the literature cited therein.
Prior to the CVD process, the surface of the silicon substrate is preferably mechanically polished. For example, if the silicon (100) surface is polished with a fine diamond powder having an average particle size of 0.5 μm, the nucleus growth of the diamond crystal can be facilitated. The polished surface is cleaned with acetone. An acetone / methanol (9: 1 v / v) mixture is used as a carbon source, and B ₂ O ₃ is dissolved in the mixture as a boron source so that the B / C ratio is about 1 mol%. As a microwave CVD system, Applied Science and Technology, Inc. A microwave plasma chemical vapor deposition system such as ("ASTeX") (Woburn, Mass., USA) can be used. When high purity hydrogen is used as a carrier gas and grown at a substrate temperature of 800 to 900 ° C. under a pressure of 115 Torr and a microwave output of 5 kW for about 10 hours, a polycrystalline diamond is deposited as a thin film with a thickness of about 40 μm. The resistance value according to the four-point sample method is 10 ⁻³ Ωcm. From the Raman absorption spectrum at 1200 cm ⁻¹ , it can be confirmed that boron was doped.
Although the thickness of a diamond thin film is not specifically limited, The thickness of 1-100 micrometers can be used, Preferably it is 5-50 micrometers.

The diamond thin film surface can be oxidized as necessary.
After forming conductive diamond on a conductive silicon substrate, the back surface of the electrode is coated with a conductive metal such as titanium (Ti) and / or gold and used as an electrode.

FIG. 1 shows a schematic example of the structure of a diamond electrode. FIG. 1A is a cross-sectional view of a diamond electrode 1 , which is composed of a conductive diamond thin film 3 formed on a substrate 2, and a conductive wire 5 is made of gold, for example, on the conductive diamond thin film 3. Connected through the coating 4. FIG. 1B is a perspective view of the diamond electrode 1 , which is composed of a conductive diamond thin film 3 formed on a substrate 2, and further a gold coating 4 for using the conductive diamond thin film 3 as an electrode. The conducting wire 5 is connected through the cable.

  The conductive diamond electrode is a relatively newly developed electrode as seen in Patent Documents 1 to 5 and Non-Patent Documents 1 and 2, and can be used for cyclic voltammetry, rotating disk electrode, amperometric measurement, and the like. . A typical electrochemical measurement used in the present invention is an amperometric measurement. In the present invention, it is preferable that the chromatography is an amperometric method, and a raw material composed of an organic compound is separated into components containing impurities by ordinary liquid chromatography, particularly preferably by a high performance liquid chromatography (HPLC) apparatus. Elution is performed, and a diamond electrode is used as a detector for quantifying the eluted components, and electrochemical quantification is performed.

  Specifically, a diamond electrode and a counter electrode are brought into contact with a solution of an HPLC elution component, a voltage causing an oxidation reaction is applied between the diamond electrode and the counter electrode, and a current value under this voltage is measured. In this HPLC-ECD method (method of measuring by ECD having a diamond electrode connected to HPLC), when the main component (active component) and impurities contained in the test sample are separated and eluted, the component is oxidized and reduced by the diamond electrode ( The redox reaction is detected, and the amount of current accompanying the redox reaction is detected as a change over time. In the test results, the horizontal axis represents the elution time, and the vertical axis represents the current change associated with oxidation / reduction of the eluted components as an independent peak group. The peak area is proportional to the elution amount, and the elution time is specific to the eluted component. If necessary, the elution component can be identified by separately checking the elution time corresponding to the standard sample. Alternatively, the detector can be switched to a mass spectrometer and the components can be identified directly by LC-MS.

  In the present invention, high performance liquid chromatography (HPLC) is preferably used as the liquid chromatography, but detailed description thereof is omitted because HPLC is a common analytical method. For example, the outline is described in the Chemical Society of Japan, Chemical Handbook, 6th edition, Applied Chemistry I, Maruzen Co., Ltd., published in 2003, pages 342-343. In high performance liquid chromatography, an absorptiometer (ultraviolet spectrophotometer (UV)) has been widely used as a normal detector.

The liquid chromatography (LC) connecting the electrochemical detector used in the present invention ranges from general-purpose LC to semi-micro LC. The capacity of the amperometric cell is preferably 1 to 10 μL.
Conventionally known materials and conditions can be used for the LC column, mobile phase, column temperature, flow rate, injection amount, and the like. Electrochemical detectors can be used, either connected in series or replaced after the commonly used ultraviolet (such as 240 nm), visible or refractive index detectors.

  In the present invention, an electrochemical detector having a conductive diamond electrode is used as a detector for liquid chromatography. It is preferable to use an electrochemically stable electrode for the electrochemical detector. Conventionally, noble metal electrodes such as silver, gold and platinum have been used and provided as various analytical instruments. However, the conventional noble metal electrode lacks stability, and it is difficult to apply to the process of predetermining the maximum allowable amount of impurity peaks and / or the minimum allowable amount of active ingredient peaks as in the present invention. there were. The conductive diamond electrode is superior to the conventionally used electrode in terms of its stability, high detection sensitivity, and many kinds of detection impurities. The conductive diamond electrode is also simply referred to as “diamond electrode” in the present specification. For quality inspection, measurement by a flow injection method using a flow cell is preferable.

Conductive diamond electrodes have higher detection sensitivity and superior reproducibility and stability compared to conventional electrodes.
Since the conductive diamond electrode has a small background current and a small amount of noise and drift, it can detect a small amount of impurities. The detection sensitivity is high, and even a sample with a sub-μM concentration can be detected. Since the potential region (potential window) where water electrolysis does not occur is wide, it is possible to detect compounds that have been difficult to measure. Since measurement at a high potential is possible, even raw materials that are difficult to be oxidized and reduced can be detected. For example, sulfur compounds such as thiol and disulfide can be detected in an aqueous solution system. In addition, the time required for stabilization from operation until measurement can be shortened.
Since the oxidation product is not irreversibly adsorbed to the electrode, the electrode is stable and reproducible.

The basic specifications of the electrochemical detector are as follows.
The amperometric method is used for the measurement, and a conductive diamond electrode is used as a working electrode in the electrolytic cell. The counter electrode (reference electrode) is not particularly limited, but a saturated calomel electrode (SCE), preferably a silver-silver chloride (Ag / AgCl) electrode can be used. The reference electrode is preferably a platinum foil.
The conductive diamond electrode is preferably subjected to a regeneration treatment after being used for a predetermined number of measurements. This regeneration process can be recovered online without removing the electrode from the flow cell. The regeneration treatment is preferably performed by anodic oxidation.

  The electrochemical detector provided with the diamond electrode which can be used for this invention can illustrate electrochemical detector ED703 manufactured by GL Sciences Inc. (Shinjuku-ku, Tokyo).

In the present invention, a method for producing a silver halide photographic light-sensitive material will be described as a representative example.
Maximum allowable amount of impurities and / or active ingredients under certain analytical conditions for raw materials that have been able to ensure normal photographic properties by liquid chromatography with an electrochemical detector using a conductive diamond electrode The minimum allowable amount is predetermined. That is, stable production is possible by using a raw material that has only a change in the type and content of components within a certain range as compared with the content of the raw material (standard) that can ensure normal photographic properties. . In some cases, anomalies may be observed in photographic properties corresponding to components of impurities that cannot be detected from the standard product, and photographic properties may deteriorate due to a decrease in the active ingredients of the standard product. In either case, comparing the chromatogram of one or more standard products with clear photographic properties and correspondence with the raw material lot (test sample) to be used will not cause any abnormality in photographic properties. The raw material can be selected by electrochemical detection. Further, the desired photographic material can be stably produced using one or more kinds of these normal photographic materials. This will be described in detail below.

  One of the simplest examples as a photographic raw material is an organic solvent. Among alcohols, methyl alcohol (methanol) is used as a solvent for dissolving many photographic additives. Methanol used in the manufacture of photographic materials must not contain impurities that cause abnormal photographic performance. Contamination may occur in the process of transporting distilled and purified methanol from the distillation vessel through the piping system to the photographic factory by some means. For example, when transported by a tank truck or transported by a drum, unexpected contaminants due to dirt on the piping system, dirt on the container, etc. may be mixed into the methanol. Conventionally, a photographic factory inspected the quality by performing a coating test. However, a high-performance liquid chromatography equipped with an electrochemical detector having a conductive diamond electrode according to the present invention contains contaminants in the production of photographic materials. Whether or not quality inspection can be performed.

  In addition, a high-quality chemical product can be produced by managing a synthesis reaction and / or a purification process using a high-performance liquid chromatography equipped with an electrochemical detector having a diamond electrode of the present invention. As the chemical, a photographic raw material is preferable.

  Traditionally, photographic raw materials, especially organic compounds, have been known to cause photographic characteristics failures depending on the production lot, even though there are no abnormalities in normal physicochemical tests, but the cause is unknown. there were. Photographic failures range from severe to mild. Examples of mild failures include (1) a spot failure only in a specific product, and (2) limited production conditions for light-sensitive materials (e.g. dissolution time of silver halide emulsion). )), And (3) normal use is normal, but low illuminance sensitivity is abnormal, etc., and the cause of these quality problems is unclear. There were many cases where direct measures could not be taken in the manufacturing and purification process.

In the present invention, according to the quality inspection using HPLC-ECD, it has been found that the cause of the above (1) is caused by a specific impurity peak of an antifoggant (Antifoggant: AF agent). It became possible to avoid failures in advance. It has also been found that the cause of the above (2) is related to the amount of a specific impurity peak contained in another AF agent.
When these cases are analyzed, they are impurities contained only in a trace amount, but due to their strong reducing power, there are cases where they act strongly on silver halide grains in photographic materials and cause failures. Even if such impurities are below the detection limit in the UV detector, they can be detected as impurities in the ECD, so that quantitative determination is possible.

Representative compounds of photographic raw materials to which the present invention can be applied are listed below: couplers, anti-fogging agents, anti-fading agents, stabilizers / scavengers, dispersants, solvents, UV degradation inhibitors, surfactants, dura maters A wide range of agents, filter dyes, etc.
Typical photographic materials include color paper, color negative, color reversal, diffusion transfer method material, black and white photosensitive material, and photothermographic material.
Photographic materials and additives are listed in Research Disclosure, September 1997, pages 613-650, literature number 40145. The present invention can be applied as a method for inspecting, receiving, and manufacturing at least one of these materials by the method of the present invention. The present invention can also be applied to a method for producing a photographic light-sensitive material using raw materials manufactured, inspected or received in this way.
Photographic material production standards, including conventional coating tests, can be changed to production standards that rely on testing with the electrochemical detector of the present invention.

  In the present invention, a raw material whose quality inspection is effective by HPLC-ECD includes a photographic raw material that has oxidation-reduction properties and, as a result, may contain impurities that hinder photographic properties. In particular, since the silver halide photographic light-sensitive material is subjected to a development process that selectively reduces silver halide grains having a latent image, even if a trace amount of reducing impurities is present, it may cause a photographic failure. It was revealed.

The photographic raw material includes a raw material that does not dissolve in an organic solvent or an aqueous organic solvent that is a mixture of the organic solvent and water. These raw materials can be measured by HPLC-ECD using test samples obtained by appropriate pretreatment. Some examples are described.
For example, in the case of an aqueous suspension of polymer particles, the supernatant liquid can be analyzed by centrifugation. In the case of a water-soluble polymer solution, the filtrate obtained by ultrafiltration is measured. Moreover, the oil-soluble raw material can analyze the water extract obtained by water extraction operation.

  The present invention also relates to a method for producing a photographic raw material, wherein the amount of impurity peaks is constant in an amperometric chromatogram obtained by high performance liquid chromatography equipped with an electrochemical detector using a conductive diamond electrode. The synthesis reaction and / or purification process is controlled so that the amount is less than the amount or the active ingredient peak is within a predetermined range.

  The present invention also relates to a production method including a step of determining whether or not a lot is a quality assurance unit of a chemical synthesized and / or purified under a specific condition.

  The present invention also relates to a method for inspecting a photographic raw material, and relates to a photographic inhibitory impurity peak in an amperometric chromatogram obtained by high performance liquid chromatography equipped with an electrochemical detector using a conductive diamond electrode. The photographic raw material is inspected so that the amount is a certain amount or less or the active ingredient peak is within a predetermined range.

  The present invention also relates to a method for accepting a photographic raw material. In the amperometric chromatogram obtained by high performance liquid chromatography equipped with an electrochemical detector using a conductive diamond electrode, It is characterized in that the photographic raw material whose amount is below a certain amount or whose active ingredient peak is within a predetermined range is inspected and accepted.

  The present invention also relates to a method for producing a pharmaceutical product characterized by producing according to a production standard including detection of health-inhibiting impurities or detection of active ingredients by liquid chromatography equipped with an electrochemical detector.

  The present invention also relates to a method for producing a cosmetic product, characterized by being produced according to a production standard including detection of quality-inhibiting impurities or detection of active ingredients by liquid chromatography equipped with an electrochemical detector.

  EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to these.

Through the following examples, the HPLC apparatus was a 10A type manufactured by Shimadzu Corporation, and the measurement was performed by combining the following conditions.
HPLC conditions:
(1) Liquid feed pump: LC10Ai
(2) Autosampler: SIL10Ai
(3) System controller: SCL10A
(4) Column thermostat: CTO10Avp
(5) Ultraviolet detector: SPD10Ai made by Shimadzu Corporation (6) ECD detector: GL Sciences Co., Ltd. ED703 type is used. Used in series. All separation columns were manufactured by GL Science Co., Ltd., Inertsil ODS-3, having a particle size of 5 μm, and an inner diameter of 4.6 mm and a length of 150 mm or 250 mm were selected and used. The column temperature was 40 ° C. All eluent flow rates were measured at 1 ml / min. The electrode temperature of ECD was set to 35 ° C.
FIGS. 2A, 2B to 7A, 7B show the HPLC profile by ECD ((A) series) and the HPLC profile by ultraviolet detector ((B) series).

(Example 1)
Antifoggant AF1 (chemical structural formula is shown below), which is a photographic raw material, was subjected to HPLC-ECD measurement under the following conditions.
AF1

Column size: 4.6 mm inner diameter × 250 mm length Eluent: 0.05% phosphoric acid aqueous solution Test solution: 25 mg sample was dissolved in 5 ml eluent, and 5 μl thereof was injected.
ECD condition: Applied voltage 1.2V vs Ag / AgCl
Ultraviolet detection conditions: detection wavelength 200 nm
A peak appearing at a retention time of 3.99 minutes observed in a chromatogram obtained by ECD connected to HPLC (hereinafter also referred to as HPLC-ECD chromatogram) is a cause of photographic inhibition (spot failure in color reversal film). It corresponded to impurities (see FIG. 2). By using AF1 having no impurity peak, a normal color reversal film (ISO 100) having no failure could be produced.

(Example 2)
Antifoggant AF2 (chemical structural formula is shown below), which is a photographic raw material, was subjected to HPLC-ECD measurement under the following conditions.
AF2

Column size: 4.6 mm inner diameter × 150 mm length Eluent: A / B / C = 150/50/1 (vol ratio) mixed solution A: acetonitrile B: 0.03 M tetramethylammonium chloride and 0.03 M dihydrogen phosphate Aqueous solution containing 1 potassium C: Phosphoric acid Test solution: A 5 mg sample was dissolved in 4 ml of an eluent, and 2 μl thereof was injected.
ECD condition: Applied voltage 1.2V vs Ag / AgCl
Ultraviolet detection conditions: detection wavelength 200 nm
The peak appearing at a retention time of 54.35 minutes observed in the HPLC-ECD chromatogram corresponded to impurities causing photographic inhibition (spot failure in color reversal film) (see FIG. 3). In addition, this peak could not be observed with a UV detector. By using AF2 having no impurity peak, a normal color reversal film (ISO 100) having no failure could be produced.

(Example 3)
Antifoggant AF3 (chemical structural formula is shown below), which is a photographic raw material, was subjected to HPLC-ECD measurement under the following conditions.
AF3

Column size: 4.6 mm inner diameter × 150 mm length Eluent: A / B / C = 50/50 / 0.2 (vol ratio) mixture
A: Acetonitrile
B: Water
C: Phosphoric acid Test solution: A 50 mg sample was dissolved in a total volume of 50 ml with an eluent, and 10 μl thereof was injected.
ECD condition: Applied voltage 1.2V vs Ag / AgCl
Ultraviolet detection conditions: detection wavelength 200 nm
The peak appearing at a retention time of 3.15 minutes observed in the HPLC-ECD chromatogram corresponded to impurities that caused photographic inhibition (sensitivity abnormality in photographic properties) (see FIG. 4). By using AF3 having no impurity peak, a normal color negative film (ISO400) having no failure could be produced.

Example 4
Antifoggant AF4 (chemical structural formula is shown below), which is a photographic raw material, was subjected to HPLC-ECD measurement under the following conditions.
AF4

Column size: 4.6 mm inner diameter × 150 mm length Eluent: A / B / C = 70/30 / 0.2 (vol ratio) mixture
A: Acetonitrile
B: Water
C: Phosphoric acid Test solution: Dissolve 50 mg sample with eluent in a total volume of 50 ml, and inject 10 μl of it.
ECD condition: applied voltage 1.05V vs Ag / AgCl
Ultraviolet detection conditions: detection wavelength 254 nm
The peak appearing at a retention time of 6.91 minutes observed in the HPLC-ECD chromatogram corresponded to impurities that caused photographic inhibition (sensitivity failure in emulsion production) (see FIG. 5). By using AF4 having no impurity peak, a normal color reversal film (ISO 100) having no failure could be produced.

(Example 5)
Methanol, which is a solvent used for photo production, was subjected to HPLC-ECD measurement under the following conditions.

Column size: 4.6 mm inner diameter × 150 mm length Eluent: A / B / C = 80/20 / 0.2 (vol ratio) mixture
A: Acetonitrile
B: Water
C: Phosphate Test solution: 10 μl of sample was directly injected.
ECD condition: Applied voltage 1.2V vs Ag / AgCl
Ultraviolet detection conditions: detection wavelength 210 nm
Three peaks appearing at a retention time of 6.31 to 8.57 minutes observed in the HPLC-ECD chromatogram corresponded to impurities causing photographic inhibition (fogging failure) (see FIG. 6). By using methanol having no impurity peak, a normal color reversal film (ISO 100) having no failure could be produced.

(Example 6)
Coupler 1 (chemical structural formula shown below) used for photo production was subjected to HPLC-ECD measurement under the following conditions.
Coupler 1

Column size: 4.6 mm inner diameter × 150 mm length Eluent: A / B / C / D = 950/50/2/2 (vol ratio) mixture
A: Acetonitrile
B: Water
C: Acetic acid
D: Phosphoric acid Test solution: 10 μl of the sample was directly injected.
ECD condition: applied voltage 1.5V vs Ag / AgCl
Ultraviolet detection conditions: detection wavelength 254 nm
A peak appearing at a retention time of 13.89 minutes observed in the HPLC-ECD chromatogram corresponded to impurities that caused photographic inhibition (fogging failure) (see FIG. 7). By using the coupler 1 having no impurity peak, a normal color reversal film (ISO 100) having no failure could be produced.

(Example 7)
The UV-absorber UV-1 (chemical structural formula shown below), which is a photographic raw material, was subjected to HPLC-ECD measurement under the following conditions.
UV-1

(HPLC-ECD conditions)
Column size: 4.6 mm inner diameter × 250 mm length Eluent: A / B / C = 990/10/2 (vol ratio) mixture
A: Acetonitrile
B: Water
C: Phosphoric acid Test solution: 25 mg of sample was dissolved in 1 ml of ethyl acetate, and the total amount was adjusted to 100 ml with acetonitrile, and 10 μl thereof was injected.
ECD condition: Applied voltage 1.2V vs Ag / AgCl
Ultraviolet detection conditions: detection wavelength 210 nm

(Representative HPLC profile)
FIG. 8 shows a typical ECD (A) and ultraviolet (B) HPLC profile of UV-1. The component having a retention time of 14.4 minutes in FIG. 8A is the main component, and in the HPLC-ECD chromatogram, the proportion of the main component in the eluted components after 3 minutes based on the integrated area is 96% or more. It showed good performance. By using UV-1 having a main component ratio of 96% or more, a normal color paper having no failure could be produced.

(Example 8)
Ultraviolet absorber UV-2 (chemical structural formula is shown below), which is a photographic raw material, was measured under the following conditions.
UV-2

(Extraction condition)
5 g of the UV-2 sample was dissolved in 50 ml of chloroform by stirring for about 10 minutes at room temperature. Similarly, 10 ml of 0.2% aqueous phosphoric acid solution was added to the UV-2 solution at room temperature, and the mixture was vigorously stirred and mixed for 30 minutes.
Then, it left still at room temperature for 1 hour, the chloroform layer and the water layer were isolate | separated, and one part was extract | collected with the pipette from the upper water layer, and it was set as the test solution for HPLC analysis.

(HPLC-ECD conditions)
Column size: 4.6 mm inner diameter × 250 mm length Eluent: 0.2% phosphoric acid aqueous solution Test solution: 10 μl of the test solution described in the extraction conditions was injected.
ECD condition: Applied voltage: 1.2V vs Ag / AgCl
Ultraviolet detection conditions: detection wavelength 210 nm

(Representative HPLC profile)
FIG. 9 shows an HPLC-ECD profile of UV-2 extracted water (A) containing a component that photographically reduces sensitivity and UV-2 extracted water (B) that does not photographically affect sensitivity.
The three components observed in the chromatogram of (A) after the retention time of 13 minutes were components that deteriorated sensitivity (sensitivity failure of color paper). By using UV-2 which does not have these impurity peaks, a color paper without a decrease in sensitivity could be produced.

Example 9
Samples before and after purification of cyan coupler CP-2 (chemical structural formula shown below), which is a photographic raw material, were measured under the following conditions.
CP-2

(Purification conditions)
35 g of unpurified crystals (A) were collected, and 90 ml of ethanol was added and dissolved by heating. Thereafter, 700 ml of hexane was added and the mixture was cooled, and the precipitated crystals were separated by filtration to obtain sample (B).

(HPLC-ECD conditions)
Column size: 4.6 mm inner diameter × 250 mm length Eluent: A / B / C = 900/100/4
A: Acetonitrile
B: Water
C: Phosphoric acid Test solution: 10 mg of (A) and (B) was dissolved in 50 ml of eluent, and 10 μl thereof was injected.
ECD condition: Applied voltage 0.8V vs Ag / AgCl
Ultraviolet detection condition: 254 nm

(Correlation with typical HPLC profile and photographic performance)
FIG. 10 shows the HPLC-ECD profile of CP-2 unpurified crystals (A) containing components that reduce photographic sensitivity and the level (B) from which components that reduce photographic sensitivity were removed by the purification operation.
The four components from the retention time 3.6 minutes to 7.4 minutes observed in the chromatogram of (A) were components (sensitivity failure of the color negative photosensitive material) that lowered the photographic sensitivity. With UV detection, no difference in the corresponding retention time could be detected. By using CP-2 subjected to this purification treatment, a color negative sensitive material with good sensitivity could be produced.

  The quality inspection of the chemical products of Examples 1 to 9 could be carried out as shipping inspection and / or acceptance inspection. Furthermore, the process of determining whether or not a chemical product can be used in Examples 1 to 9 can be implemented as a shipping inspection of a person who supplies the chemical product and / or an acceptance inspection of the manufacturing plant of the chemical product in the manufacture of the chemical product. It was.

(Example 10)
Surfactant W-1 (mixture represented by chemical structural formulas A and B), which is a cosmetic raw material, was subjected to HPLC-ECD measurement under the following conditions.
W-1

Ｒ₁：炭素数９〜１３のアルキル基

R ₁ : an alkyl group having 9 to 13 carbon atoms

Ｒ₂：炭素数９〜１３のアルキル基

R ₂ : an alkyl group having 9 to 13 carbon atoms

(HPLC-ECD conditions)
Column size: 4.6 mm inner diameter × 250 mm length Eluent: A / B = 1000/2 (vol ratio) mixed solution
A: Methanol
B: Phosphate Test solution: 0.5 g of sample was dissolved in methanol to make a total volume of 50 ml, and 10 μl thereof was injected.
ECD condition: Applied voltage 1.6V vs Ag / AgCl
Ultraviolet detection conditions: detection wavelength 220 nm

(Skin sensitization test)
The test was performed according to the GPMT method (guinea pig maximization test) based on the OECD guidelines (OECD TG406).

(Representative HPLC profile)
FIG. 11 shows representative ECD (A) and UV (B) HPLC profiles of W-1.
It was found that the skin sensitization of the one having a high two peaks near the retention time of 3.7 minutes observed in the chromatogram of FIG. By applying the HPLC-ECD method, the skin sensitization of the surfactant can be rapidly evaluated.

(Example 11)
A UV-absorber UV-3 (chemical structural formula is shown below), which is a raw material for paints or cosmetics, was subjected to HPLC-ECD measurement under the following conditions.
UV-3

(HPLC-ECD conditions)
Column size: 4.6 mm inner diameter × 250 mm length Eluent: A / B / C = 990/10/2 (vol ratio) mixture
A: Acetonitrile
B: Water
C: Phosphoric acid Test solution: A 25 mg sample was dissolved in 1 ml of ethyl acetate, and the total amount was adjusted to 100 ml with acetonitrile, and 10 μl thereof was injected.
ECD condition: Applied voltage 1.4V vs Ag / AgCl
Ultraviolet detection conditions: detection wavelength 210 nm

(Skin sensitization test)
The skin sensitization test was performed as described above.

(Representative HPLC profile)
FIG. 12 shows typical ECD (A) and UV (B) HPLC profiles of UV-3.
It was found that the skin sensitization became stronger with the increase of the three peak components detected in the retention time of 5 to 9 minutes observed in the chromatogram of FIG.
By applying the HPLC-ECD method, the skin sensitization property of the raw material can be rapidly evaluated.

FIG. 1 is a schematic view showing a structural example of a diamond electrode. FIG. 1A is a cross-sectional view of a diamond electrode 1 , and this electrode is composed of a conductive diamond thin film 3 formed on a substrate 2. (B) is a perspective view of the diamond electrode 1 , and is composed of a conductive diamond thin film 3 formed on a substrate 2. FIG. 2 (A) shows an example of a chromatogram obtained by an electrochemical detector (ECD) connected to the high performance liquid chromatography (HPLC) used in the present invention. (B) is a chromatogram by a UV detector connected to the same HPLC as a comparative example. FIG. 3A shows an example of a chromatogram obtained by an electrochemical detector (ECD) connected to high performance liquid chromatography (HPLC) used in the present invention. (B) is a chromatogram by a UV detector connected to the same HPLC as a comparative example. FIG. 4A shows an example of a chromatogram obtained by an electrochemical detector (ECD) connected to high performance liquid chromatography (HPLC) used in the present invention. (B) is a chromatogram by a UV detector connected to the same HPLC as a comparative example. FIG. 5A shows an example of a chromatogram obtained by an electrochemical detector (ECD) connected to high performance liquid chromatography (HPLC) used in the present invention. (B) is a chromatogram by a UV detector connected to the same HPLC as a comparative example. FIG. 6A shows an example of a chromatogram obtained by an electrochemical detector (ECD) connected to high performance liquid chromatography (HPLC) used in the present invention. (B) is a chromatogram by a UV detector connected to the same HPLC as a comparative example. FIG. 7A shows an example of a chromatogram obtained by an electrochemical detector (ECD) connected to high performance liquid chromatography (HPLC) used in the present invention. (B) is a chromatogram by a UV detector connected to the same HPLC as a comparative example. FIG. 8A shows an example of a chromatogram obtained by an electrochemical detector (ECD) connected to high performance liquid chromatography (HPLC) used in the present invention. (B) is a chromatogram by a UV detector connected to the same HPLC as a comparative example. 9A and 9B show an example of a chromatogram obtained by an electrochemical detector (ECD) connected to the high performance liquid chromatography (HPLC) used in the present invention. (A) shows an example of a chromatogram of extracted water (A) from UV-2 containing a component that photographically reduces sensitivity. (B) shows an example of a chromatogram of extracted water (B) of UV-2 that does not affect the sensitivity photographically. FIGS. 10A and 10B show an example of a chromatogram obtained by an electrochemical detector (ECD) connected to high performance liquid chromatography (HPLC) used in the present invention. (A) shows an example of a chromatogram of unpurified crystals (A) of CP-2 containing a component that lowers the photographic sensitivity. (B) shows an example of a CP-2 chromatogram of the level (B) from which a component that lowers the photographic sensitivity is removed by a purification operation. FIG. 11A shows an example of a chromatogram obtained by an electrochemical detector (ECD) connected to high performance liquid chromatography (HPLC) used in the present invention. (B) is a chromatogram by a UV detector connected to the same HPLC as a comparative example. FIG. 12A shows an example of a chromatogram obtained by an electrochemical detector (ECD) connected to high performance liquid chromatography (HPLC) used in the present invention. (B) is a chromatogram by a UV detector connected to the same HPLC as a comparative example.

Explanation of symbols

1 : Diamond electrode 2: Base material 3: Conductive diamond thin film 4: Gold coating 5: Conductor 1: Impurity peak that inhibits photographic properties (detectable by HPLC-ECD)
10: Main component (active ingredient)
20: Skin sensitizing ingredient

Claims (12)

For at least one chemical of a chemical product produced from one or more chemicals by liquid chromatography with an electrochemical detector having a conductive diamond electrode,
Predetermining the maximum allowable amount of impurity peaks and / or the minimum allowable amount of active ingredient peaks under certain analytical conditions; and
Measuring a lot to be used of the chemical by liquid chromatography under the analytical conditions described above, and determining whether or not the lot can be used based on the impurity peak amount and / or active ingredient peak amount of the lot. A method for producing a chemical product, comprising: The method for producing a chemical product according to claim 1, wherein the chemical product is a silver halide photographic light-sensitive material. The method for producing a chemical product according to claim 1, further comprising a step of determining whether or not the lot can be used for a lot of the chemical synthesized and / or purified under a specific condition. The method for producing a chemical product according to claim 1, wherein the two steps are performed using a test sample obtained by pretreatment of the chemical product. The chromatography is amperometric;
The manufacturing method of the chemical product as described in any one of Claims 1-4. A method for producing a chemical product,
Liquid chromatography with an electrochemical detector with a conductive diamond electrode allows the maximum allowable amount of impurity peaks and / or the minimum allowable amount of active ingredient peaks under certain analytical conditions of the chemical. A predetermined step, and
The chemical product includes a step of performing measurement by liquid chromatography under the above analysis conditions,
A method for producing a chemical product, comprising managing a synthesis reaction and / or purification step of the chemical product based on an impurity peak amount and / or an active ingredient peak amount of the chemical product.   The method for producing a chemical product according to claim 6, wherein the chemical product is a photographic raw material. Preparing a conductive diamond electrode and a counter electrode;
A process of converting chemicals into components separated and eluted by liquid chromatography,
Contacting the components eluted from the liquid chromatography with a conductive diamond electrode and a counter electrode;
Applying a voltage that causes an oxidation reaction between the conductive diamond electrode and the counter electrode; and
A method for inspecting a quality of a chemical product, comprising a step of measuring a current under the voltage. Liquid chromatography with an electrochemical detector with a conductive diamond electrode allows the chemical to have an acceptable maximum amount of impurity peaks and / or an acceptable minimum of active ingredient peaks under certain analytical conditions. Pre-determining the amount; and
The method according to claim 8, further comprising the step of measuring the lot of the chemical by liquid chromatography under the analysis conditions and determining the quality of the lot based on the impurity peak amount and / or active ingredient peak amount of the lot. The quality inspection method for the described chemical product. The chemical quality inspection method according to claim 8 or 9, wherein the chemical product is a chemical product used in a production process of a silver halide photographic light-sensitive material.   A chemical product subjected to quality inspection by the quality inspection method according to any one of claims 8 to 10.   A chemical product produced using one or more of the chemical products according to claim 11.

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