5-aminolevulinic acid or salt thereof, and method for producing same

Abstract

The purpose of the present invention is to provide 5-aminolevulinic acid or a salt thereof and a method for producing the same, the 5-aminolevulinic acid or salt thereof having suppressed discoloration and fewer impurities and residual solvents than in the prior art. Provided is 5-aminolevulinic acid or a salt thereof, in which the ratio of the content of individual impurities to the content of the 5-aminolevulinic acid or salt thereof is 0.0007 or less, and the total of the ratios of the contents of the individual impurities to the content of the 5-aminolevulinic acid or salt thereof is 0.0016 or less, based on the peak areas obtained by HPLC analysis.

Description

5-aminolevulinic acid or its salt and method for producing same

[0001] The present disclosure relates to 5-aminolevulinic acid or a salt thereof and a method for producing the same.

[0002] 5-aminolevulinic acid (hereinafter also abbreviated as 5-ALA) is an amino acid that plays an important role in the body, and is a useful substance in fields such as medicine, agriculture, and cosmetics.

[0003] Methods for producing 5-aminolevulinic acid or a salt thereof include chemical synthesis and fermentation (see, for example, Patent Documents 1 to 5). Fermentation production of 5-aminolevulinic acid or a salt thereof has the advantages of lowering the environmental load compared to chemical synthesis and enabling high yields by utilizing microorganisms with a specific metabolic pathway.

[0004] When 5-aminolevulinic acid or its salts are crystallized in an organic solvent, the organic solvent may remain in the powder of 5-aminolevulinic acid or its salts. According to the standards set by the Ministry of Health, Labour and Welfare under the Industrial Safety and Health Act, if the ethanol concentration in a product is 1000 ppm or higher, it is considered a "hazardous or harmful substance that requires the name, etc., to be displayed or notified (substances subject to the obligation to display labels and provide safety data sheets)." Since the use of labeled 5-aminolevulinic acid products requires ensuring occupational safety, this may affect purchaser motivation.

[0005] The concentrations of other impurities mixed in during the manufacturing process of 5-aminolevulinic acid may also be problematic. According to the guidelines for impurities in drug substances containing new active ingredients stipulated in Notification No. 1216001 of the Pharmaceutical and Medical Devices Agency, safety confirmation is required if the content of any individual impurity in the drug substance exceeds 0.05% by mass when the intake exceeds 2 g / day, which may hinder drug application.

[0006] Japanese Patent No. 2997979 Japanese Patent No. 4520219 Japanese Patent No. 4915723 Japanese Patent No. 4989153 Japanese Patent No. 5845203

[0007] As described above, the production of 5-aminolevulinic acid or a salt thereof involves problems such as the organic solvent remaining in the crystallization step (hereinafter also referred to as "residual organic solvent") and impurities mixed in during the production process. In fact, the present inventors examined the residual ethanol levels in five lots of powders of 5-aminolevulinic acid or a salt thereof (hereinafter also referred to as "marketed products") supplied by two companies, and found that several lots had ethanol concentrations exceeding the standard value of 1,000 ppm.

[0008] Furthermore, since the impurities have a structure similar to that of amino acids, it was assumed that their molar absorption coefficients would be equivalent to that of 5-aminolevulinic acid or its salts, which are used as standards in high-performance liquid chromatography (HPLC) measurements. As a result, the peak areas of the impurities in the competitor's products were measured using an HPLC equipped with an ultraviolet-visible absorbance detector. As a result, lots containing a large amount of unknown impurities, whose peak area ratios to 5-aminolevulinic acid or its salts exceeded 0.0005, were identified.

[0009] Here, a ratio of the peak area of ​​an impurity to the peak area of ​​5-aminolevulinic acid exceeding 0.0005 is synonymous with a content of each impurity in a powder containing 5-aminolevulinic acid or a salt thereof exceeding 0.05% by mass, and indicates a deviation from the reference value of the guidelines for impurities in drug substances.

[0010] On the other hand, 5-aminolevulinic acid or a salt thereof may become discolored during storage. For example, if impurities remain, a reaction may occur between 5-aminolevulinic acid or a salt thereof and the remaining impurities, or between the remaining impurities themselves, resulting in the production of a discolored substance, which may affect storage stability and product quality. Therefore, in order to improve storage stability and product quality, it is necessary to remove impurities as much as possible and obtain high-purity 5-aminolevulinic acid or a salt thereof with reduced discoloration.

[0011] However, there is no uniform method that can suppress residual organic solvents, impurities, or coloration not only in 5-aminolevulinic acid or a salt thereof but also in various other compounds. Therefore, various methods have been investigated to suppress these, and it is extremely difficult to find 5-aminolevulinic acid or a salt thereof that suppresses these problems.

[0012] Therefore, an object of the present disclosure is to provide a powder of 5-aminolevulinic acid or a salt thereof in which impurities, residual solvents, or coloring are suppressed compared to conventional powders, and a method for producing the same.

[0013] The present inventors have found that, in the production of 5-aminolevulinic acid or a salt thereof, by controlling the parameters during crystallization, 5-aminolevulinic acid or a salt thereof can be obtained with reduced impurities, residual solvents, or coloration compared to conventional methods, and have completed the present invention.

[0014] That is, the present disclosure is as follows. 1. 5-aminolevulinic acid or a salt thereof that satisfies at least one of the following (A1) and (A2) based on the peak area determined by HPLC analysis: (A1) The ratio of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (1), is 0.0007 or less. (A2) The sum of the ratios of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (2), is 0.0016 or less. Ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof = Peak area of ​​each impurity quantifiable by HPLC / Peak area of ​​5-aminolevulinic acid or a salt thereof...formula (1) Sum of the ratios of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof = Σ (Peak area of ​​each impurity quantifiable by HPLC / Peak area of ​​5-aminolevulinic acid or a salt thereof)...formula (2) 2. 5-aminolevulinic acid or a salt thereof that satisfies the following (B1) and (B2): (B1) The transmittance of light at a wavelength of 430 nm is 98.8% or more. (B2) The transmittance of light at a wavelength of 430 nm measured by a severe stability test under the following conditions is 92.0% or more. Conditions for the severe stability test: The 5-aminolevulinic acid or a salt thereof is stored at a temperature of 70°C ± 2°C for 2 days, and then the transmittance of light at a wavelength of 430 nm is measured with a spectrophotometer. 3. 5-aminolevulinic acid or a salt thereof according to 1 or 2 above, wherein the content of residual organic solvent contained in the 5-aminolevulinic acid or a salt thereof is 1000 ppm or less. 4. 5-aminolevulinic acid or a salt thereof according to 1 or 2 above, wherein the content of arsenic contained in the 5-aminolevulinic acid or a salt thereof is less than 0.3 ppm. 5. 5. The 5-aminolevulinic acid or a salt thereof according to 1 or 2 above, wherein the 5-aminolevulinic acid or a salt thereof is 5-aminolevulinic acid phosphate. 6. A method for producing 5-aminolevulinic acid or a salt thereof, comprising the following steps [1] to [3]:[1] A step of preparing a solution containing 5-aminolevulinic acid or a salt thereof, and adding water to the solution or concentrating the solution to prepare a crystallization stock solution having a concentration of 200 to 700 g / L, calculated as 5-aminolevulinic acid monophosphate; [2] A step of adjusting the temperature of the crystallization stock solution obtained in [1] to 5 to 25°C; [3] A step of adding a first organic solvent to the crystallization stock solution obtained in [2] to precipitate 5-aminolevulinic acid or a salt thereof. 7. The method described in 6 above, wherein the 5-aminolevulinic acid or a salt thereof satisfies at least one of the following (A1) and (A2) based on peak areas determined by HPLC analysis: (A1) The ratio of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (1), is 0.0007 or less; (A2) The total ratio of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (2), is 0.0016 or less. Ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof=peak area of ​​each impurity quantifiable by HPLC / peak area of ​​5-aminolevulinic acid or a salt thereof...Equation (1) Sum of the ratios of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof=Σ(peak area of ​​each impurity quantifiable by HPLC / peak area of ​​5-aminolevulinic acid or a salt thereof)...Equation (2) 8. The method according to 6 above, which satisfies the following (B1) and (B2): (B1) The transmittance of light at a wavelength of 430 nm is 98.8% or more. (B2) The transmittance of light at a wavelength of 430 nm measured by a severe stability test under the following conditions is 92.0% or more. Conditions for the severe stability test: The 5-aminolevulinic acid or a salt thereof is stored at a temperature of 70°C ± 2°C for 2 days, and then the transmittance of light at a wavelength of 430 nm is measured using a spectrophotometer. 9. 9. The method according to 6 above, wherein the 5-aminolevulinic acid or salt thereof has a residual organic solvent content of 1000 ppm or less. 10. The method according to 6 above, wherein the 5-aminolevulinic acid or salt thereof has an arsenic content of less than 0.3 ppm. 11. The method according to 6 above, wherein the 5-aminolevulinic acid or salt thereof is 5-aminolevulinic acid phosphate.12. The method according to item 6, further comprising adding seed crystals to the crystallization stock solution to a content of 0.01 to 5.0 mass% in [3]. 13. The method according to item 12, further comprising adding the seed crystals to the crystallization stock solution and then stirring for less than 360 minutes to mature the crystals in [3]. 14. The method according to item 6, further comprising adding the first organic solvent in an amount of 0.50 v / v or less relative to the volume of the crystallization stock solution in [3]. 15. The method according to item 12, further comprising adding a second organic solvent to the crystallization stock solution after adding the seed crystals in [3]. 16. The method according to item 15, further comprising adding the second organic solvent at an addition rate of 0.4 to 5.0 v / v / h relative to the volume of the crystallization stock solution. 17. The method according to item 15, further comprising adding the first organic solvent and the second organic solvent in a total amount of 2 v / v or less relative to the volume of the crystallization stock solution. 18. The method according to item 6, comprising separating and drying the precipitate obtained in item [3] to obtain a powder, wherein the content of residual organic solvent in the powder is 1000 ppm or less. 19. The method according to any one of items 6 to 18, wherein the first organic solvent in item [3] is at least one selected from methanol, ethanol, isopropanol, normal propanol, acetone, and acetonitrile. 20. The method according to any one of items 15 to 18, wherein the second organic solvent in item [3] is at least one selected from methanol, ethanol, isopropanol, normal propanol, acetone, and acetonitrile. 21. The method according to item 19, wherein the first organic solvent in item [3] is ethanol. 22. The method according to item 20, wherein the second organic solvent in item [3] is ethanol. 23. A solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA is dissolved in Na. ＋24. A method for producing 5-aminolevulinic acid or a salt thereof, comprising treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with at least one of a phosphoric acid-type and an acetate-type strongly basic anion exchange resin. 25. A method for producing 5-aminolevulinic acid or a salt thereof, comprising the following x1) to x3) in any order: x1) treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with a strongly acidic cation exchange resin. x2) treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with a weakly acidic cation exchange resin. x3) treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with a strongly basic anion exchange resin. 26. A method for producing 5-aminolevulinic acid or a salt thereof, comprising the following y1) to y4) in this order: y1) treating solution A containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with a strongly acidic cation exchange resin to obtain solution B; y2) treating solution B with a weakly acidic cation exchange resin to obtain solution C; y3) treating solution C with a strongly basic anion exchange resin to obtain solution D; and y4) adjusting the pH of solution D to obtain solution E. 27. The strongly acidic cation exchange resin is a polystyrene-based resin having sulfonic acid groups as functional groups, and the ion type is Na ＋28. The method according to any one of 24 to 26, wherein the strongly basic anion exchange resin is a polystyrene resin having dimethylethanolammonium groups as functional groups, and the ionic form is at least one of acetate and phosphate. 29. The method according to 26, wherein in y1), the recovery conditions for obtaining solution B are initiated by a change in Brix and terminated by a change in pH. 30. The method according to 26, wherein in y2), the recovery conditions for obtaining solution C are initiated by a change in Brix and terminated by a change in Brix. 31. The method according to 26, wherein in y3), the recovery conditions for obtaining solution D are initiated by a change in Brix and terminated by a change in Brix.

[0015] The 5-aminolevulinic acid or a salt thereof of the present disclosure contains fewer impurities and residual organic solvents and is suppressed in coloration compared to conventional products, and therefore has excellent storage stability and can facilitate quality control and quality assurance.

[0016] FIG. 1 shows the results of measuring residual EtOH in powder in Example 1-1. FIG. 2 shows the results of measuring residual EtOH in powder in Example 1-2. FIG. 3 shows the results of measuring residual EtOH in powder in Example 1-3. FIG. 4 shows the results of measuring residual EtOH in powder in Example 2-6. FIG. 5 shows the results of powder X-ray diffraction measurement using 5-aminolevulinic acid phosphate powder. FIG. 6 is a flowchart showing the process in one embodiment of the manufacturing method of the present disclosure. FIG. 7 is a flowchart showing the process in one embodiment of the manufacturing method of the present disclosure.

[0017] The present disclosure will be described in detail below, but these are examples of preferred embodiments and the present disclosure is not limited to these contents.

[0018] The "to" in a numerical range means a range that includes the numerical values ​​before and after it. For example, "0% by mass to 100% by mass" means a range that is 0% by mass or more and 100% by mass or less.

[0019] 5-aminolevulinic acid and salts thereof of the present disclosure will be described below based on embodiments, but the production method of the present disclosure is not limited thereto. 5-aminolevulinic acid and salts thereof of the present disclosure include 5-aminolevulinic acid and salts thereof of the first and second embodiments described below.

[0020] 1. 5-Aminolevulinic Acid or Salts Thereof In the present disclosure, salts of 5-aminolevulinic acid include, for example, salt forms such as phosphate, hydrochloride, nitrate, etc. Among these, from the viewpoint of use in foods and the like, phosphate is preferred because it has excellent storage stability and is less irritating.

[0021] The 5-aminolevulinic acid or a salt thereof in the present disclosure may be in the form of a powder. Specifically, powders containing 5-aminolevulinic acid or a salt thereof include crystalline powders containing 5-aminolevulinic acid or a salt thereof, or amorphous powders obtained by freeze-drying, spray-drying, or the like. The method for producing the powder is not particularly limited as long as a powder can be obtained; for example, the powder can be obtained by crystallization. The powder obtained by crystallization may be further purified, as needed, by vacuum drying, forced air drying, heat drying, or by dissolving it again in an aqueous solution and then subjecting it to general purification procedures such as desalting, decolorization, crystallization, spray-drying, or freeze-drying. Therefore, in the present disclosure, the 5-aminolevulinic acid or a salt thereof obtained by crystallization and the 5-aminolevulinic acid or a salt thereof precipitated from the crystallization stock solution may both be crystalline, amorphous, or a mixture thereof.

[0022] [First Embodiment] <Impurities> In the first embodiment of the present disclosure, 5-aminolevulinic acid or a salt thereof is characterized in that it satisfies at least one of the following (A1) and (A2) based on the peak area determined by HPLC analysis: (A1) The ratio of the content of each impurity quantifiable by HPLC to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (1), is 0.0007 or less. (A2) The total ratio of the content of each impurity quantifiable by HPLC to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (2), is 0.0016 or less. Ratio of the content of each impurity quantifiable by HPLC to the content of 5-aminolevulinic acid or a salt thereof=peak area of ​​each impurity quantifiable by HPLC / peak area of ​​5-aminolevulinic acid or a salt thereof...formula (1) Sum of the ratios of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof=Σ(peak area of ​​each impurity quantifiable by HPLC / peak area of ​​5-aminolevulinic acid or a salt thereof)...formula (2) In formula (2), Σ( ) represents the sum of the values ​​in parentheses.

[0023] In a first embodiment, the 5-aminolevulinic acid or salt thereof of the present disclosure has a peak area ratio of each impurity to the peak area of ​​5-aminolevulinic acid or a salt thereof represented by formula (1) (A1) of 0.0007 or less, based on the peak area in HPLC analysis, thereby improving storage stability and product quality. In the first embodiment, the ratio is preferably 0.0006 or less, and more preferably 0.0005 or less. In second to sixth embodiments, the ratio is preferably 0.0015 or less, more preferably 0.0010 or less, even more preferably 0.0007 or less, and most preferably 0.0005 or less.

[0024] In a first embodiment, the 5-aminolevulinic acid or salt thereof of the present disclosure can improve storage stability and product quality by having the sum of the ratios of the peak areas of the individual impurities represented by formula (2) (A2) to the content of 5-aminolevulinic acid or a salt thereof, expressed by formula (2), be 0.0016 or less, based on the peak area determined by HPLC analysis. In the first embodiment, the ratio is preferably 0.0015 or less, and more preferably 0.0014 or less. In second to sixth embodiments, the ratio is preferably 0.0022 or less, more preferably 0.0020 or less, even more preferably 0.0017 or less, and most preferably 0.0016 or less.

[0025] In the 5-aminolevulinic acid or salt thereof of the present disclosure, the ratio of the peak area of ​​each impurity to the peak area of ​​5-aminolevulinic acid or a salt thereof represented by formula (1) and the sum of the ratios of the peak area of ​​each impurity to the content of 5-aminolevulinic acid or a salt thereof represented by formula (2) can be freely combined, based on the peak areas determined by HPLC analysis. As for the combination, preferably, the ratio of the peak area of ​​each impurity to the peak area of ​​5-aminolevulinic acid or a salt thereof is 0.0020 or less, and the sum of the ratios of the peak area of ​​each impurity to the content of 5-aminolevulinic acid or a salt thereof is 0.0022 or less. More preferably, the ratio of the peak area of ​​each impurity to the peak area of ​​5-aminolevulinic acid or a salt thereof is 0.0015 or less, and the sum of the ratios of the peak area of ​​each impurity to the content of 5-aminolevulinic acid or a salt thereof is 0.0020 or less. More preferably, the ratio of the peak area of ​​each impurity to the peak area of ​​5-aminolevulinic acid or a salt thereof is 0.0010 or less, and the sum of the ratios of the peak area of ​​each impurity to the content of 5-aminolevulinic acid or a salt thereof is 0.0017 or less. Most preferably, the ratio of the peak area of ​​each impurity to the peak area of ​​5-aminolevulinic acid or a salt thereof is 0.0007 or less, and the sum of the ratios of the peak area of ​​each impurity to the content of 5-aminolevulinic acid or a salt thereof is 0.0016 or less.

[0026] In the present disclosure, more specific methods for calculating the "ratio of the peak area of ​​each impurity to the peak area of ​​5-aminolevulinic acid or a salt thereof" and the "sum of the ratios of the peak area of ​​each impurity to the peak area of ​​5-aminolevulinic acid or a salt thereof" include the methods in the analytical examples and examples described below.

[0027] In the formulas (1) and (2), in one embodiment, the term "impurities quantifiable by HPLC" refers to, for example, impurities whose peak area in 5-aminolevulinic acid or a salt thereof is equal to or greater than the quantification limit by HPLC.

[0028] In one embodiment, the "impurities quantifiable by HPLC" refer to impurities detected at a temperature of 2.2±0.2 to 42.1±0.2 in an analysis using, for example, liquid chromatography (HPLC) equipped with an ultraviolet-visible absorbance detector as described below. More specifically, the impurities are those detected in the following conditions: an HPLC equipped with an ultraviolet-visible absorbance detector, an InertSustain C18 (UP) separation column (5 μm, 4.6×250 mm, GL-Science), a 0.1% trifluoroacetic acid / 15% acetonitrile mobile phase, a mobile phase flow rate of 1.0 mL / min, a sample introduction amount of 50 μL, a column temperature of 30° C., and a detection wavelength of 216 nm. (i) RT2.2±0.2, RT2.4±0.2, RT2.8±0.2, RT3.3±0.2, RT3.4±0.2, RT3.5±0.2, RT3.9±0.2, RT4.0±0.2, RT4.1±0.2, RT4.2±0.2, RT4.3±0.2, RT4.4±0.2, RT4 .. 5±0.2, RT4.7±0.2, RT4.8±0.2, RT5.0±0.2, RT5.4±0.2, RT5.6±0.2, RT5.8±0 .2, RT5.9±0.2, RT6.0±0.2, RT6.2±0.2, RT6.5±0.2, RT6.6±0.2, RT6.8±0.2, RT7.0±0.2, RT7.2±0.2, RT7.4±0.2, RT7.7±0.2, RT7.9±0.2, RT8 .1±0.2, RT8.4±0.2, RT9.6±0.2, RT10.2±0.2, RT11.1±0.2, RT11 .. 7±0.2, RT13.3±0.2, RT14.9±0.2, RT15.3±0.2, RT16.7±0.2, RT20.2±0.2, RT 22.1±0.2, RT22.6±0.2, RT22.8±0.2, RT23.2±0.2, RT30.1±0.2, RT42.1±0.2(ii) RT2.2±0.2, RT2.4±0.2, RT3.4±0.2, RT3.9±0.2, RT4.0±0.2, RT4.1±0.2, RT4.2±0.2, RT4.3±0.2, RT4.4±0.2, RT4.5±0.2, RT4.8 ±0.2, RT5.0±0.2, RT5.8±0.2, RT6.0±0.2, RT6.2±0.2, RT6.3±0.2, RT6.5±0.2, RT6.6±0.2, RT6.8±0.2, RT7.0±0.2, RT7.2±0.2, RT7.4 ±0.2, RT7.7±0.2, RT7.9±0.2, RT8.1±0.2, RT8.4±0.2, RT9.6±0.2, RT10.2±0.2, RT10.6±0.2, RT11.1±0.2, RT11.7±0.2, RT13.3±0.2 , RT14.9±0.2, RT15.3±0.2, RT16.7±0.2, RT20.2±0.2, RT22.1±0.2, RT22.6±0.2, RT22.8±0.2, RT23.2±0.2, RT30.1±0.2, RT42.1±0.2 (iii) RT 3.4 ± 0.2, RT 4.1 ± 0.2, RT 4.2 ± 0.2, RT 4.5 ± 0.2, RT 4.8 ± 0.2, RT 5.0 ± 0.2, RT 5.8 ± 0.2, RT 6.2 ± 0.2, RT 6.5 ± 0.2, RT 6.6 ± 0.2, RT 6.8 ± 0.2, RT 7.4 ± 0.2, RT 7.9 ± 0.2, RT 8.1 ± 0.2, RT 10.2 ± 0.2, RT 22.1 ± 0.2, RT 22.6 ± 0.2, RT 22.8 ± 0.2, RT 30.1 ± 0.2, RT 42.1 ± 0.2 (The above RT means retention time, and the unit of the numbers is "minutes")

[0029] The value of ±0.2 for the "impurities quantifiable by HPLC" means ±0.2 minutes, which is caused by measurement errors due to measurement conditions such as the measuring instrument and peak reading conditions, and is preferably ±0.1, more preferably ±0.01.

[0030] In the present disclosure, the "ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof" is synonymous with the "ratio of the peak area of ​​each impurity to the peak area of ​​5-aminolevulinic acid or a salt thereof."

[0031] In the present disclosure, the term "the sum of the ratios of the contents of the individual impurities to the content of 5-aminolevulinic acid or a salt thereof" is synonymous with the term "the sum of the ratios of the peak area of ​​the individual impurities to the peak area of ​​5-aminolevulinic acid or a salt thereof."

[0032] In the present disclosure, the term "impurities" refers to substances other than 5-aminolevulinic acid or a salt thereof. Examples of impurities in the present disclosure include impurities derived from the culture, by-products of decomposition of 5-aminolevulinic acid or a salt thereof, inorganic ions, inorganic acids, and inorganic metals.

[0033] Examples of impurities derived from the culture include carbon sources such as glucose and glycine, and nitrogen sources such as ammonia and ammonium chloride, which are used in fermentation production.

[0034] Many of the inorganic ions, inorganic acids, or inorganic metals are derived from components contained during fermentation production, but most of them are removed during the process of purifying 5-aminolevulinic acid or a salt thereof.

[0035] Examples of inorganic ions include inorganic cations such as sodium ions, potassium ions, calcium ions, and magnesium ions. Examples of inorganic anions include chloride ions, nitrate ions, and sulfate ions. Examples of inorganic metals include iron, arsenic, and lead.

[0036] The content of inorganic metals in the 5-aminolevulinic acid or a salt thereof of the present disclosure is not particularly limited, but the lower the content, the better. For example, the content of inorganic metals per 1 kg of powder is 10 mg or less (10 ppm or less), and the following, in order of more preferred values, are 7 ppm or less, 5 ppm or less, 3 ppm or less, and 1 ppm or less.

[0037] Among the inorganic metals, arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb), which are classified as Class 1 in the Elemental Impurities Guideline (ICH Q3D) of the International Council for Harmonisation (ICH), are particularly toxic to humans, and therefore their use in pharmaceutical manufacturing is restricted or prohibited. The arsenic (As) content in 5-aminolevulinic acid or a salt thereof in the present disclosure is less than 0.3 ppm, and is preferably 0.25 ppm or less, 0.2 ppm or less, 0.1 ppm or less, and 0.01 ppm or less, in that order.

[0038] <Residual Organic Solvent> In the present disclosure, the term "residual organic solvent" refers to an organic solvent remaining in 5-aminolevulinic acid or a salt thereof. Examples of organic solvents that may be contained in 5-aminolevulinic acid or a salt thereof of the present disclosure include organic solvents used for crystallization.

[0039] The organic solvent may be at least one selected from methanol, ethanol, isopropanol, normal propanol, acetone, and acetonitrile, and is preferably ethanol. Since the organic solvent is difficult to remove from the 5-aminolevulinic acid or a salt thereof during the separation and drying steps of the precipitate, it is preferable to reduce the content of the residual organic solvent as much as possible in the crystallization step. In the present disclosure, the precipitate may be a crystal of 5-aminolevulinic acid or a salt thereof, or an amorphous form of 5-aminolevulinic acid or a salt thereof.

[0040] In one embodiment, the 5-aminolevulinic acid or a salt thereof of the present disclosure preferably has a residual organic solvent content of 1000 ppm or less, and more preferably 1000 ppm or less, 750 ppm or less, 500 ppm or less, 300 ppm or less, and 50 ppm or less, in the following order:

[0041] <Coloration Degree> Compounds such as a representative 5-aminolevulinic acid phosphate, which is a salt of 5-aminolevulinic acid, are not colored, and powdery 5-aminolevulinic acid phosphate is white or milky white. The color of the powder of 5-aminolevulinic acid or a salt thereof of the present disclosure is preferably closer to white, and an aqueous solution obtained by dissolving the powder in water is preferably clear and colorless.

[0042] When 5-aminolevulinic acid or a salt thereof contains impurities, a Maillard reaction or the like occurs between 5-aminolevulinic acid or a salt thereof and the remaining impurities, or between the remaining impurities, leading to the formation of colored substances, and thus the powder becomes colored.

[0043] Examples of a measurement method for evaluating the coloration degree of 5-aminolevulinic acid or a salt thereof include a method using a spectrophotometer, etc. More specifically, the coloration degree of 5-aminolevulinic acid or a salt thereof can be evaluated by measuring the transmittance of short-wavelength visible light in a wavelength range adjacent to the ultraviolet range (e.g., 430 nm) using a spectrophotometer.

[0044] [Second Embodiment] In a second embodiment of the present disclosure, 5-aminolevulinic acid or a salt thereof is characterized in that it satisfies the following (B1) and (B2): (B1) The transmittance of light at a wavelength of 430 nm measured with a spectrophotometer is 98.8% or more. (B2) The transmittance of light at a wavelength of 430 nm measured in a severe stability test under the following conditions is 92.0% or more. Conditions for the severe stability test: 5-aminolevulinic acid or a salt thereof is stored at a temperature of 70°C ± 2°C for 2 days, and then the transmittance of light at a wavelength of 430 nm is measured with a spectrophotometer.

[0045] The decrease in light transmittance at a wavelength of 430 nm measured with a spectrophotometer is due to a yellow coloring component. In the second embodiment, 5-aminolevulinic acid or a salt thereof according to the present disclosure has (B1) a light transmittance at a wavelength of 430 nm of 98.8% or more, thereby reducing the amount of the yellow coloring component and suppressing coloration. The light transmittance at a wavelength of 430 nm is, in order of preference, 98.8% or more, 98.9% or more, 99.0% or more, 99.5% or more, and 99.9% or more.

[0046] As conditions for evaluating the degree of coloration of 5-aminolevulinic acid or a salt thereof according to the present disclosure, it is preferable to create an environment in which 5-aminolevulinic acid is likely to deteriorate and compare the results before and after deterioration, since the presence or absence of coloration clearly occurs. An example of an environment in which 5-aminolevulinic acid or a salt thereof is likely to deteriorate is a severe stability test in which 5-aminolevulinic acid or a salt thereof is stored under heated conditions at 70±2°C for two days or more.

[0047] In a second embodiment, 5-aminolevulinic acid or a salt thereof according to the present disclosure has (B2) a light transmittance at a wavelength of 430 nm measured by a severe stability test under the following conditions of 92.0% or more, in order of preference 93.0% or more, 97.0% or more, 98.0% or more, and 99.0% or more. A light transmittance of 92.0% or more indicates excellent stability. Conditions for the severe stability test: 5-aminolevulinic acid or a salt thereof is stored at a temperature of 70°C ± 2°C for two days, and then the light transmittance at a wavelength of 430 nm is measured using a spectrophotometer.

[0048] The spectrophotometer is not particularly limited as long as it can evaluate the degree of coloration, and examples thereof include U-5100, U-3900 / U-3900H, and UH5300 manufactured by Hitachi High-Tech Science Corporation, Agilent Cary 60 UV-Vis spectrophotometer and Agilent Cary 3500 UV-Vis spectrophotometer manufactured by Agilent Technologies, and GENESYS 50 UV-visible spectrophotometer, Biomate160 UV-visible spectrophotometer, and GENESYS 180 UV-visible spectrophotometer manufactured by Thermo Fisher Scientific.

[0049] <Diffraction Angle by Powder X-ray Diffraction> The 5-aminolevulinic acid or a salt thereof of the present disclosure may be crystalline or amorphous. Furthermore, the 5-aminolevulinic acid or a salt thereof of the present disclosure can be applied regardless of whether it is crystalline or a crystalline polymorph. Therefore, the diffraction angle 2θ of the 5-aminolevulinic acid or a salt thereof of the present disclosure measured by powder X-ray diffraction varies depending on the resulting crystalline polymorph, but it is preferable that the diffraction angle 2θ of the 5-aminolevulinic acid or a salt thereof measured by powder X-ray diffraction exhibits characteristic peaks at 7.9°±0.2, 15.8°±0.2°, 18.9°±0.2°, 20.7°±0.2°, 21.1°±0.2°, 21.4°±0.2°, 22.9°±0.2°, 23.0°±0.2°, 27.8°±0.2°, and 33.2°±0.2°.

[0050] When the 5-aminolevulinic acid or a salt thereof of the present disclosure is 5-aminolevulinic acid phosphate, it preferably exhibits characteristic peaks at diffraction angles 2θ of 7.9°±0.2, 15.8°±0.2°, 18.9°±0.2°, 20.7°±0.2°, 21.1°±0.2°, 21.4°±0.2°, 22.9°±0.2°, 23.0°±0.2°, 27.8°±0.2°, and 33.2°±0.2° in powder X-ray diffraction.

[0051] The deviation of ±0.2° in the characteristic peak value is a measurement error due to measurement conditions such as the measuring instrument and peak reading conditions, and is preferably ±0.1°, more preferably ±0.01°. Powder X-ray diffraction can be performed according to the method described in the following measurement examples.

[0052] [Example of Powder X-ray Diffraction Measurement] Equipment used: Powder X-ray diffractometer (XRD) Ultima IV (manufactured by Rigaku Corporation) Anode: Cu Wavelength: 1.5418 Å

[0053] The 5-aminolevulinic acid or a salt thereof of the present disclosure preferably has a melting point of 129 to 131°C.

[0054] <Content of 5-aminolevulinic acid or a salt thereof> In the 5-aminolevulinic acid or a salt thereof of the present disclosure, the content of 5-aminolevulinic acid or a salt thereof per solid content is preferably 99.5% by mass or more, and more preferably 99.6% by mass or more, 99.7% by mass or more, 99.8% by mass or more, and 99.9% by mass or more, in that order.

[0055] In the present disclosure, the content and amount of 5-aminolevulinic acid or a salt thereof are calculated by converting 5-aminolevulinic acid (hereinafter also referred to as "free form") or a salt thereof into the equivalent molar amount of 5-aminolevulinic acid phosphate. Note that, in the present disclosure, the "content of 5-aminolevulinic acid or a salt thereof" is synonymous with the "purity of 5-aminolevulinic acid or a salt thereof."

[0056] <Uses> Uses of the 5-aminolevulinic acid or a salt thereof according to the present disclosure include, for example, vitamin B12 production, heme enzyme production, microbial culture, and porphyrin production in the field of microorganisms; infection treatment, sterilization, hemophilus diagnosis, raw material for derivative synthesis, hair removal, rheumatism treatment, cancer treatment, thrombus treatment, intraoperative cancer diagnosis, animal cell culture, heme metabolism research, hair growth, heavy metal poisoning porphyria diagnosis, and anemia prevention in the field of animals, food, or medicine; and plant growth regulation and improvement of salt tolerance in the field of agriculture.

[0057] 2. Method for producing 5-aminolevulinic acid or a salt thereof Hereinafter, the method for producing 5-aminolevulinic acid and a salt thereof according to the present disclosure will be abbreviated as the production method of the present disclosure. The production method of the present disclosure will be described below based on embodiments, but the production method of the present disclosure is not limited thereto. The production methods of the third to sixth embodiments described below are included in the production methods of the present disclosure.

[0058] One embodiment of the production method of the present disclosure described above preferably includes the following steps [1] to [3]. Figures 6 and 7 are flowcharts showing the treatment in one embodiment of the production method of the present disclosure. [1] A step of preparing a solution containing 5-aminolevulinic acid or a salt thereof, and adding water to the solution or concentrating the solution to prepare a crystallization stock solution in which the concentration of 5-aminolevulinic acid or a salt thereof is adjusted to a specific range; [2] A step of adjusting the temperature of the crystallization stock solution obtained in [1]; [3] A step of adding a first organic solvent to the crystallization stock solution obtained in [2] to precipitate 5-aminolevulinic acid or a salt thereof.

[0059] 5-aminolevulinic acid is unstable at temperatures above 30°C and under neutral to basic conditions, and is prone to polymerization to produce 2,5-pyrazinedipropanoic acid (hereinafter, PDPA). In the production method of the present disclosure, high-purity 5-aminolevulinic acid or a salt thereof can be obtained by carrying out crystallization using an organic solvent.

[0060] Each of steps [1] to [3] will be described below. [1] A step of preparing a crystallization stock solution in which the concentration of 5-aminolevulinic acid or a salt thereof is adjusted to a specific range by preparing a solution containing 5-aminolevulinic acid or a salt thereof and adding water to the solution or concentrating the solution. Step [1] is a step of preparing a crystallization stock solution in which the concentration of 5-aminolevulinic acid or a salt thereof is adjusted to a specific range from a solution containing 5-aminolevulinic acid or a salt thereof.

[0061] In the present disclosure, crystallization refers to precipitating the 5-aminolevulinic acid or a salt thereof to be obtained from a crystallization stock solution, and the precipitated powder may be crystalline, amorphous, or a mixture thereof.

[0062] In one embodiment of the production method of the present disclosure, it is preferable that the 5-aminolevulinic acid or a salt thereof is a product derived from fermentation, and that the 5-aminolevulinic acid or a salt thereof is not subjected to chemical synthesis or extraction steps. In one embodiment, the elimination of the chemical synthesis or extraction steps allows the final powder to be mass-produced inexpensively and in an environmentally friendly manner.

[0063] In one aspect of the production method of the present disclosure, step [1] preferably includes steps 0 to 10 shown below. Step 0: A step of separating a culture broth containing a microorganism or a solid content containing a microorganism from the culture broth to recover a culture liquid containing 5-aminolevulinic acid (hereinafter, referred to as solution A). Step 1: A step of treating solution A with a strongly acidic cation exchange resin to separate 5-aminolevulinic acid from impurities and obtain solution B. Step 2: A step of treating solution B with a weakly acidic cation exchange resin to obtain solution C. Step 3: A step of treating solution C with a strongly basic anion exchange resin to obtain solution D. Step 4: A step of adjusting the pH of solution D to obtain solution E. Step 5: A step of concentrating solution E. Step 6: A step of crystallizing the concentrated solution (first crystallization) and then dissolving the obtained powder to obtain solution F. This is an optional step. Step 7: A step of treating solution F with activated carbon to obtain a decolorized solution (solution G). This is an optional step. Eighth step: A step of treating solution G with a chelating resin to obtain solution H. This is an optional step. Ninth step: A step of passing solution H through a microfiltration membrane and an ultrafiltration membrane to obtain a filtrate. This is an optional step. Tenth step: A step of concentrating the filtrate to obtain a concentrate. This is an optional step. Note that process [1] includes both an embodiment in which the solution obtained in steps 0 to 10 (hereinafter referred to as "solution [1]") is used directly, and an embodiment in which the powder obtained after crystallization is further redissolved and utilized in step 11. Steps 0 to 10 will be described below.

[0064] (Step 0) Step 0 is a step in which a culture broth containing microorganisms or a solid content containing microorganisms is separated from the culture broth to recover a culture solution containing 5-aminolevulinic acid (solution A). In step 0, centrifugation, filtering, or the like is used to efficiently separate the culture broth from the microorganisms and solid content. The recovered solution A is a culture solution containing a high concentration of 5-aminolevulinic acid.

[0065] ((Culture Solution)) In this specification, the term "culture solution" includes microorganisms, culture media, etc. The culture solution is obtained by culturing a microorganism capable of producing 5-aminolevulinic acid in a medium containing components necessary for growth. Examples of microorganisms capable of producing 5-aminolevulinic acid (hereinafter also referred to as 5-aminolevulinic acid-producing bacteria) include recombinant microorganisms into which genes necessary for the production of 5-aminolevulinic acid have been introduced.

[0066] Examples of the microorganism include bacteria such as Escherichia coli, Lactobacillus lactis, Corynebacterium glutamicum, Bacillus subtilis, and Pseudomonas putita, and yeasts such as Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Pichia pastoris.

[0067] As a method for genetically modifying the microorganism to produce 5-aminolevulinic acid, the method described in Japanese Patent Application Laid-Open No. 2005-333907 can be mentioned, and fermentative production of 5-aminolevulinic acid can be carried out using a recombinant Corynebacterium glutamicum.

[0068] The medium may contain a carbon source, a nitrogen source, a phosphate source, a sulfur source, other organic components, other inorganic components, etc. The types, combinations, and contents of these components in the medium may be appropriately determined. The medium may further contain amino acids, nucleic acids, vitamins, etc.

[0069] The carbon source is not particularly limited as long as it can be utilized by the transformant, and examples thereof include carbohydrates such as glucose, fructose, sucrose, glycerin, molasses, starch, and starch hydrolysates; organic acids such as gluconic acid, pyruvic acid, lactic acid, and acetic acid; and amino acids such as glycine, glutamic acid, alanine, and aspartic acid.

[0070] Examples of the nitrogen source include various inorganic and organic ammonium salts such as ammonia, ammonium chloride, ammonium sulfate, ammonium phosphate, ammonium nitrate, ammonium carbonate, and ammonium acetate; nitrogen-containing organic substances such as urea, peptone, NZ amine, meat extract, yeast extract, corn steep liquor, casein hydrolysate, fish meal, and digests thereof; and various amino acids such as glycine and glutamic acid.

[0071] Examples of the inorganic component include potassium dihydrogen phosphate, potassium monohydrogen phosphate, magnesium sulfate, magnesium phosphate, sodium chloride, ferrous sulfate, manganese sulfate, zinc sulfate, and calcium carbonate.

[0072] The medium preferably contains glycine, as this improves the productivity of 5-aminolevulinic acid or a salt thereof. The glycine content in the medium is preferably 0.5 to 20% by mass. Glycine may be added to the medium at any time, either at the start of the culture or during the culture, and the required amount may be added all at once or in divided portions.

[0073] In addition, in the production method of the present disclosure, it is not particularly necessary to add 5-aminolevulinic acid, which is generally added to the medium or the like in production methods of 5-aminolevulinic acid using microorganisms, but it may be added as needed.

[0074] Various impurities added to the medium may be removed by a purification step. A solid content containing microorganisms can be separated from the culture solution, and a supernatant containing 5-aminolevulinic acid can be recovered. Methods for separating the solid content containing microorganisms from the culture solution include centrifugation and filtration.

[0075] (Solution A) The composition of Solution A includes, for example, 5-aminolevulinic acid or a salt thereof. The concentration of 5-aminolevulinic acid or a salt thereof in Solution A is not particularly limited, but from the viewpoint of purification efficiency, in one embodiment, it is usually preferably 0.01 g / L or more, more preferably 0.1 g / L or more, even more preferably 1 g / L or more, and most preferably 10 g / L or more, calculated as 5-aminolevulinic acid monophosphate. In another embodiment, the concentration is preferably 0.1 g / L to 100 g / L, more preferably 1 g / L to 70 g / L, and even more preferably 10 g / L to 60 g / L.

[0076] In order to set the concentration of 5-aminolevulinic acid or a salt thereof in Solution A within the above range, the solution containing 5-aminolevulinic acid or a salt thereof may be concentrated, or the solution may be diluted with water or the like. The concentration method may be any common method, such as a heat concentration method or a vacuum concentration method. Solution A is preferably a culture broth derived from fermentation production using a microorganism, or a supernatant obtained by removing solids from the culture broth.

[0077] Solution A may contain impurities. Examples of impurities that may be contained in Solution A include alanine, glycine, and PDPA. The ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof in Solution A, (content of each impurity) / (content of 5-aminolevulinic acid or a salt thereof), is preferably 0.0001 to 1, more preferably 0.0005 to 0.5, even more preferably 0.001 to 0.3, and most preferably 0.002 to 0.1, on a mass basis.

[0078] (First Step) The first step is a step in which solution A obtained in step 0 is treated with a strongly acidic cation exchange resin to obtain solution B. That is, in the first step, solution A is treated with a strongly acidic cation exchange resin to separate 5-aminolevulinic acid from impurities described below.

[0079] More specifically, the first step preferably includes the following steps (1-1) to (1-3): Step (1-1): Passing solution A through a strongly acidic cation exchange resin to remove uncharged neutral impurities and negatively charged impurities that do not bind to the strongly acidic cation exchange resin, Step (1-2): Washing the strongly acidic cation exchange resin with water, Step (1-3): Eluting the acidic compounds including 5-aminolevulinic acid or a salt thereof from the strongly acidic cation exchange resin. Steps (1-1) to (1-3) are described below.

[0080] ((Step (1-1): A step of passing Solution A through a strongly acidic cation exchange resin to remove at least a portion of uncharged neutral impurities and negatively charged impurities that do not bind to the strongly acidic cation exchange resin)) The pH of Solution A to be treated with the strongly acidic cation exchange resin is preferably 1 to 7, more preferably 2 to 5, and most preferably 2.5 to 4.5. The concentration of 5-aminolevulinic acid or a salt thereof in Solution A to be treated with the strongly acidic cation exchange resin is preferably 0.1 g / L to 100 g / L, more preferably 1 g / L to 70 g / L, and even more preferably 10 g / L to 60 g / L, calculated as 5-aminolevulinic acid monophosphate.

[0081] If Solution A does not have a pH or a concentration of 5-aminolevulinic acid or a salt thereof within the above range, Solution A may be pretreated. Examples of pretreatment include adjusting the pH, ultrafiltration of Solution A, dilution with water, concentration, etc.

[0082] The strong acid cation exchange resin is not particularly limited, and examples thereof include a strong acid cation exchange resin having a sulfonic acid group as an exchange group in the strong acid cation exchange resin. Examples of the matrix of the strong acid cation exchange resin include a porous type, a macroporous type, a gel type, a styrene type, and an acrylic type.

[0083] Specific examples of the strong acid cation exchange resin include DOWEX (registered trademark) 88, DOWEX (registered trademark) 88MB, DOWEX (registered trademark) Monosphere (registered trademark) 88, and TG-Gel (also known as XUS40232.01) manufactured by The Dow Chemical Company, and Amberlite (registered trademark) manufactured by DuPont (e.g., FPC16UPS Na, FPC88MB Na, FPC240H, CR3220 Ca, CR1310 Ca,Na, CR1360 Na, CR99K / 350, HPR1100Na, etc.), DOWEX® (e.g., HCR-S / S, HCR-S / S FF, HCR-W2, HGR-NG, Marathon C 10, Monosphere C 350, Monosphere C 400, MARATHON C, Marathon MSC, Marathon 1200, Marathon 1200), Purolite Corporation's C100, C100E, C120E, C100x10, C100x16MBH, C145S, C150, C160, SGC650, Purolite Corporation's Purolite (registered trademark) SST series (e.g., SSTC60, SSTC60H, SSTC80C, etc.), Mitsubishi Chemical Corporation's Diaion (registered trademark) SK series (e.g., SK1B, SK1BH, SK1BL, SK1BLH, SKL10, SKT10 L, SK104, SK110, SKT110, SKT110L, SK110L, SK112, SK112L, SK116, SKT20L, etc.), Mitsubishi Chemical Corporation's Diaion (registered trademark) PK series (e.g., PK208, PK208LH, PK212, PK212L, PK212LH, PK216, PK216L, PK216H, PK216LH, PK220, PK220L, PK228, PK228L, PK228LH, etc.), Mitsubishi Chemical Diaion (registered trademark) RCP series (e.g., RCP145H, RCP160M, etc.) manufactured by Mitsubishi Chemical Corporation, Diaion (registered trademark) HPK25 manufactured by Mitsubishi Chemical Corporation, Diaion (registered trademark) UBK series (e.g., UBK16, UBK14, UBK12, UBK10, UBK10H, UBK10HUP, UBK08, UBK08A, UBK08H, UBK08HUP, UBK04, UBK02, UBKN1U, UBKN) manufactured by Mitsubishi Chemical Corporation 1UMB, UBK522M, UBK530, UBK530J, UBK530K, UBK535, UBK535J, UBK535K, UBK535L, UBK550, UBK555, etc.), Mitsubishi Chemical Corporation's Rewrite JC series (e.g., JC600, JC603, etc.), Lanxess AG's Lewatit (registered trademark) S1668, Lanxess AG's Lewatit (registered trademark) Monoplus series (e.g., S108, S108H, SP112, etc.).

[0084] The strongly acidic cation exchange resin preferably has a sulfonic acid group as an exchange group, and the matrix of the strongly acidic cation exchange resin is more preferably a gel type. Specific examples include MARATHON C, UBK04, and XUS40232.01.

[0085] The ionic type of the exchange group in the strongly acidic cation exchange resin is, for example, H ＋ Type, Na ＋ Type, K ＋ Type, NH ４ ＋ Na ＋ It is preferable that the mold is a mold.

[0086] Neutral contaminants include, for example, carbohydrates such as glucose, fructose, sucrose, molasses, starch, and starch hydrolysates.

[0087] Examples of negatively charged impurities include SO ４ ２－ , Cl － , P.O. ４ ３－ and the like, organic acids such as formic acid, acetic acid, propionic acid, and fatty acids, nucleic acids, amino acids, proteins, and phospholipids.

[0088] In step (1-1), the flow rate when solution A is passed through the ion exchange resin is defined by the space velocity (the volume ratio of the solution passing through the column per hour when the resin volume of the ion exchange resin is taken as 1, hereinafter referred to as "SV").

[0089] As for the flow conditions when treating Solution A with a strongly acidic cation exchange resin, the flow rate is preferably SV 0.1 to 5, more preferably SV 0.2 to 4, and even more preferably SV 0.5 to 2. As for the flow conditions, the temperature is preferably 3 to 50°C, more preferably 8 to 40°C, even more preferably 10 to 40°C, and most preferably 15 to 35°C.

[0090] By this step (1-1), positively charged compounds including 5-aminolevulinic acid in solution A are adsorbed onto the strongly acidic cation exchange resin.

[0091] ((Step (1-2) is a step of eluting at least a portion of the impurities remaining after (1-1) from the strong acid cation exchange resin)) Step (1-2) is a step of eluting neutral impurities and negatively charged impurities remaining on the strong acid cation exchange resin from the strong acid cation exchange resin through which Solution A has been passed in Step (1-1).

[0092] To elute the impurities remaining after step (1-1) from the strongly acidic cation exchange resin, the eluent preferably contains at least one of water, ammonium hydroxide, sodium hydroxide, potassium hydroxide, etc., and more preferably contains water and sodium hydroxide.

[0093] The concentration of the basic substance, such as ammonium hydroxide, sodium hydroxide, or potassium hydroxide, in the eluent is, in order of preference, 0.0000 mol / L or more, 0.0001 mol / L or more, 0.0005 mol / L or more, 0.001 mol / L or more, and 0.005 mol / L or more, and is, in order of preference, 1.0 mol / L or less, 0.7 mol / L or less, 0.5 mol / L or less, 0.1 mol / L, and 0.05 mol / L or less. These upper and lower limits can be combined arbitrarily. In another embodiment, the concentration is preferably 0.0000 to 1.0 mol / L, 0.0001 to 0.7 mol / L, 0.0005 to 0.5 mol / L, 0.001 to 0.1 mol / L, or 0.005 to 0.05 mol / L.

[0094] In another embodiment, from the viewpoint of efficiently removing impurities under mild conditions, a lower concentration of the basic substance is preferable, and the upper limit is not particularly limited, so that the concentration can be 0.005 mol / L or less, preferably 0.001 mol / L or less, more preferably 0.0005 mol / L or less, even more preferably 0.0001 mol / L or less, and most preferably 0.0000 mol / L or less.

[0095] As conditions for washing the strongly acidic cation exchange resin with water, the flow rate is preferably SV 0.1 to 5, more preferably SV 0.2 to 4, and even more preferably SV 0.5 to 2. The temperature is preferably 3 to 50°C, more preferably 8 to 40°C, even more preferably 15 to 40°C, and most preferably 20 to 35°C.

[0096] In the present disclosure, the amount of solution passed through an ion exchange resin is expressed as resin volume (the volume ratio of the solution when the resin volume of the ion exchange resin is taken as 1, hereinafter referred to as "RV").

[0097] The amount of water used for washing in step (1-2) is preferably 0.1 to 20 RV, more preferably 0.5 to 10 RV, even more preferably 1 to 5 RV, and most preferably 2 to 4 RV, relative to the amount of the strongly acidic cation exchange resin in step (1-2) taken as 1.

[0098] In a more preferred embodiment, after passing water, a basic aqueous solution such as ammonium hydroxide, sodium hydroxide, potassium hydroxide or the like is passed through.

[0099] This step (1-2) washes away at least a portion of the impurities remaining in the strongly acidic cation exchange resin after step (1-1). Furthermore, by performing this step (1-2), the contents of alanine, glycine, and PDPA in the finally obtained 5-aminolevulinic acid or a salt thereof tend to be reduced, and the content of 5-aminolevulinic acid or a salt thereof tends to be increased.

[0100] ((Step (1-3): A step of separately eluting a group of compounds containing 5-aminolevulinic acid or a salt thereof and impurities remaining after step (1-2) from the strong acid cation exchange resin)) Step (1-3) is a step of obtaining solution B by eluting 5-aminolevulinic acid or a salt thereof from the strong acid cation exchange resin washed with water in step (1-2).

[0101] In order to separately elute the compounds containing 5-aminolevulinic acid or a salt thereof and the impurities remaining after 1-2) from the strongly acidic cation exchange resin, the eluent preferably contains at least one of water, ammonium hydroxide, sodium hydroxide, potassium hydroxide, etc., and more preferably contains sodium hydroxide.

[0102] The concentration of a basic substance such as ammonium hydroxide, sodium hydroxide, or potassium hydroxide in the eluent is preferably 0.01 mol / L or more, and more preferably 0.05 mol / L or more, 0.1 mol / L or more, and 0.4 mol / L or more, and more preferably 2.0 mol / L or less, 1.5 mol / L or less, 1.0 mol / L, and 0.6 mol / L or less. These upper and lower limits can be combined arbitrarily. In another embodiment, the concentration is preferably 0.01 to 2.0 mol / L, 0.05 to 1.5 mol / L, 0.1 to 1.0 mol / L, or 0.4 to 0.6 mol / L.

[0103] The conditions for eluting 5-aminolevulinic acid or a salt thereof bound to a strongly acidic cation exchange resin are preferably as follows: The eluent is preferably ammonium hydroxide, NaOH, KOH, or the like, more preferably a solution of an eluent such as NaOH. The flow rate is preferably SV 0.1 to 5, more preferably SV 0.2 to 4, and even more preferably SV 0.5 to 2. The temperature is preferably 3 to 50°C, more preferably 8 to 40°C, even more preferably 15 to 40°C, and most preferably 20 to 35°C.

[0104] The amount of the eluent is preferably 0.5 to 20 RV, more preferably 1 to 15 RV, even more preferably 2 to 12 RV, and most preferably 3 to 10 RV.

[0105] Solution B obtained in the first step preferably has a pH of 5 to 12, more preferably a pH of 6 to 10, and even more preferably a pH of 7 to 9. The concentration of 5-aminolevulinic acid or a salt thereof in Solution B, calculated as 5-aminolevulinic acid monophosphate, is preferably 0.1 g / L to 100 g / L, more preferably 1 g / L to 70 g / L, even more preferably 3 g / L to 50 g / L, and most preferably 5 g / L to 20 g / L.

[0106] (Second Step) The second step is a step in which the solution B obtained in the first step is treated with a weakly acidic cation exchange resin to obtain a solution C. The solution B obtained in the first step is purified by removing positively charged impurities, particularly Na ions derived from the eluent. ＋ It contains a lot of and is basic.

[0107] Under basic conditions, compounds containing 5-aminolevulinic acid are not positively charged and pass through without adsorption. Therefore, even under basic conditions, positively charged impurities, particularly inorganic cations such as sodium ions, potassium ions, calcium ions, and magnesium ions, are adsorbed to the weakly acidic cation exchange resin and removed.

[0108] As for the flow conditions when treating Solution B with a weakly acidic cation exchange resin, the flow rate is preferably SV 0.1 to 10, more preferably SV 0.5 to 8, even more preferably SV 3 to 6, and most preferably SV 4 to 5. As for the flow conditions, the temperature is preferably 1 to 50°C, more preferably 5 to 40°C, even more preferably 10 to 35°C, and most preferably 20 to 30°C.

[0109] Examples of weakly acidic cation exchange resins include those having carboxylic acid groups as exchange groups and whose resin matrix is ​​porous, macroporous, gel, styrene, or acrylic.

[0110] Specific examples of weakly acidic cation exchange resins include Amberlite (registered trademark) manufactured by DuPont (e.g., FPC76J, FPC3500, etc.), Purolite C104, C106, C107E, C115E, Purolite (registered trademark) SSTC104 manufactured by Purolite, Diaion (registered trademark) WK series (e.g., WK10, WK100, WK10S, WK11, WK40, WK60, WK60L, etc.) manufactured by Mitsubishi Chemical Corporation, Diaion (registered trademark) WT01S manufactured by Mitsubishi Chemical Corporation, and Lewatit (registered trademark) CNP80WS manufactured by Lanxess AG.

[0111] The ionic type of the exchange group in the weakly acidic cation exchange resin is not particularly limited, and examples thereof include H＋ Type, Na ＋ Type, K ＋ Type, NH ４ ＋ H ＋ It is preferable that the mold is a mold.

[0112] In the second step, solutions that can be used to pass solution B through the ion exchange resin when treating it with the ion exchange resin include deionized water as well as solution B. Deionized water is used for the purpose of eluting substances that do not adsorb to the ion exchange resin and improving the recovery rate of 5-aminolevulinic acid or a salt thereof.

[0113] (Third Step) The third step is a step in which solution C obtained in the second step is treated with a strongly basic anion exchange resin to obtain solution D. Solution C obtained in the second step is a weakly acidic solution.

[0114] Solution C contains residual compounds similar to 5-aminolevulinic acid and negatively charged impurities. By treating the solution C with a strongly basic anion exchange resin, the negatively charged impurities and colored components are adsorbed, while 5-aminolevulinic acid or a salt thereof is not adsorbed and passes through, thereby removing the negatively charged impurities.

[0115] The flow conditions for treating Solution C with a strongly basic anion exchange resin are a flow rate of preferably SV 0.1 to 10, more preferably SV 0.1 to 5, even more preferably SV 0.5 to 2, and most preferably SV 0.8 to 1.2, and a temperature of preferably 1 to 50°C, more preferably 5 to 40°C, even more preferably 5 to 35°C, and most preferably 12 to 30°C.

[0116] Examples of the strongly basic anion exchange resin include those having either a type I quaternary ammonium having a trimethylammonium group or a triethylammonium group as an exchange group, or a type II quaternary ammonium having a dimethylethanolammonium group, and whose resin matrix is ​​a porous type, macroporous type, gel type, styrene type, or acrylic type.

[0117] Specific examples of the strong basic anion exchange resin include 1x2, 1x4, 1x8, 22, and MSA-2 manufactured by Dow Chemical Company, and Amberlite (registered trademark) manufactured by DuPont (e.g., HPR4700 Cl, HPR4700 OH, FPA400J Cl, IRA404J Cl, FPA420 OH, FPA900UPS Cl, HPR4580 Cl, SCAV4 Cl, FPA410J Cl, IRA411 Cl, FPA22UPS Cl, HPR4780 Cl, IRA400J Cl, IRA402BL Cl, IRA900J Cl, HPR4002 Cl, IRA410J Cl, IRA910CT Cl, HPR4010 Cl, and HPR4100 Cl, HPR9200 Cl, HPR550 Cl, HPR550 OH, etc.), Purolite A400, A600, SGA550, A200, A300, A500, A501P, A502PS, A503, A510, A520E, A850, A860, A870, PFA520E, Purolite (registered trademark) SST series (e.g., SSTA63, SSTA64) manufactured by Purolite, and Mitsubishi Chemical Diaion (registered trademark) P A series (e.g., PA306S, PA308, PA308L, PA312, PA312L, PA312LOH, PA312LTU, PA312LTUMB, PA316, PA316L, PA318L, PA318LOH, PA408, PA412, PA412M, PA418, PA418L, PA418LL, PAF308L, HPA25L, HPA25M, HPA51 2L, HPA716, etc.), Mitsubishi Chemical Corporation's Diaion (registered trademark) NSA100, UMA130J, Mitsubishi Chemical Corporation's Diaion (registered trademark) SA series (e.g., SA10A, SA10AL, SA10ALLP, SA10AOH, SA10AP, SA10DL, SA11A, SA11AL, SA12A, SA12AL, SA12ALL, SA20A, SA20A LL, SA20ALLP, SA20AP, SA20AP2, SAF11AL, SANUPB, SAT10L, SAT20L, etc.), Mitsubishi Chemical Corporation's Diaion (registered trademark) UBA series (e.g., UBA100, UBA100OH, UBA100OHUP, UBA120, UBA120A, UBA120OH, UBA120OHUP, UBA150, UBA200, etc.),Examples include the Relight JA series (e.g., JA100, JA200, JA400, JA420, JA450, etc.) manufactured by Mitsubishi Chemical Corporation, and the Lewatit (registered trademark) Monoplus series (e.g., M500, M800, MP800, M600, MP600, etc.) manufactured by Lanxess AG.

[0118] The ion type of the quaternary ammonium of the exchange group in the strongly basic anion exchange resin is not particularly limited, and examples thereof include hydroxide ions (OH － type), chloride ions (Cl － type), sulfate type (SO ４ ２－ type), phosphate type (PO ４ ３－ type), nitric acid type (NO ３ － and one of the following types of acetic acid ions (CH ３ COO － It is preferable that the hydroxyl group is of the hydroxyl group type.

[0119] In the third step, it is preferable that the recovery conditions for obtaining solution D are such that recovery is initiated and terminated based on a change in Brix. As the rate of change in Brix, a Brix of 0.2% or more after the start of passing solution C can be used as an indicator for the start of recovery, and a Brix of 1.0% or less can be used as an indicator for the end of recovery. In this specification, the indicators at the start of recovery and the end of recovery may be any indicators that can estimate the rate of change in the concentration of 5-aminolevulinic acid, and examples of these include the rate of change in electrical conductivity, the rate of change in pH, and the rate of change in Brix. It is preferable to use the rate of change in Brix as the indicator.

[0120] The pH of Solution D is preferably 0.5 to 10, more preferably 1 to 7, even more preferably 2 to 6, and most preferably 2.5 to 5. The concentration of 5-aminolevulinic acid or a salt thereof in Solution D is preferably 0.1 to 100 g / L, more preferably 1 to 70 g / L, even more preferably 5 to 50 g / L, and most preferably 30 to 45 g / L, calculated as 5-aminolevulinic acid monophosphate.

[0121] In the third step, solutions that can be used to pass solution C through the ion exchange resin when treating it with the ion exchange resin include solution C and deionized water. Deionized water is used for the purpose of eluting substances that do not adsorb to the ion exchange resin and improving the recovery rate of 5-aminolevulinic acid or a salt thereof. In this step, solutions that can be used to pass solution C through the cation exchange resin when treating it with the cation exchange resin are preferably solution C and deionized water.

[0122] (Fourth Step) The fourth step is a step of adjusting the pH of the solution D or the like to obtain a solution E. If the solution D obtained in the third step does not have the aforementioned pH or concentration of 5-aminolevulinic acid or a salt thereof, the fourth step of adjusting the pH of the solution D or the like to obtain a solution E may be included after the third step.

[0123] In the fourth step, examples of the solution used to adjust the pH of solution D include solutions of phosphoric acid, hydrochloric acid, sulfuric acid, acetic acid, and nitric acid.

[0124] Furthermore, if solution E contains impurities that hinder crystallization, the impurities and salts may be removed by filtration or the like by passing the solution through or adding to a column filled with an ion exchange resin, a synthetic adsorption resin, activated carbon, or the like.

[0125] The pH of Solution E is preferably 1 to 7, more preferably 2 to 6, even more preferably 2.5 to 5, and most preferably 2.5 to 3.5. Examples of pH adjusters for adjusting this pH include hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, nitric acid, nitrous acid, acetic acid, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, and ammonia. Phosphoric acid and hydrochloric acid are preferred, and phosphoric acid is most preferred. Two or more of these pH adjusters may be used in combination. The concentration of 5-aminolevulinic acid or a salt thereof in Solution E is preferably 0.1 to 100 g / L, more preferably 1 to 70 g / L, even more preferably 5 to 50 g / L, and most preferably 30 to 45 g / L, calculated as 5-aminolevulinic acid monophosphate.

[0126] (Fifth Step) In the fifth step, Solution E obtained in the fourth step is concentrated by a common concentration method such as a heat concentration method or a vacuum concentration method. The content of 5-aminolevulinic acid or a salt thereof in the concentrate is preferably 10 to 800 g / L, more preferably 50 to 600 g / L, even more preferably 300 to 700 g / L, and most preferably 500 to 650 g / L, calculated as 5-aminolevulinic acid monophosphate.

[0127] (Filtration) Examples of filtration methods include microfiltration of Solution E or the concentrated solution using a membrane with a pore size of 0.2 to 1.2 μm. Specific examples include a method in which Solution E or Solution E is passed through a column filled with an ion exchange resin, a synthetic adsorption resin, activated carbon, or the like, or a solution obtained by adding Solution E is treated with a membrane filter.

[0128] (Sixth Step) The sixth step is an optional step, and in one embodiment, it is a step of crystallizing the concentrated solution (hereinafter also abbreviated as "first crystallization step") and dissolving the obtained powder to obtain solution F. In one embodiment, the first crystallization step preferably includes the following steps (α1) to (α5): (α1) a step of preparing a crystallization stock solution; (α2) a step of adjusting the temperature of the crystallization stock solution obtained in (α1); (α3) a step of adding a first' organic solvent to the crystallization stock solution obtained in (α2) to precipitate 5-aminolevulinic acid or a salt thereof; (α4) a step of adding a second' organic solvent to the crystallization stock solution; and (α5) a step of separating the precipitate. Steps (α1) to (α5) are described below.

[0129] (α1) Preparation of Crystallization Stock Solution For Solution D or Solution E obtained in the above step, an aqueous solution of 5-aminolevulinic acid or a salt thereof can be diluted with water and subjected to a general concentration method such as heating concentration, membrane concentration, or vacuum concentration to obtain a crystallization stock solution containing 5-aminolevulinic acid or a salt thereof. The crystallization stock solution refers to a solution used for crystallizing 5-aminolevulinic acid or a salt thereof.

[0130] The concentration of 5-aminolevulinic acid or a salt thereof in the crystallization stock solution, calculated as 5-aminolevulinic acid monophosphate, is preferably 900 g / L or less, 700 g / L or less, 650 g / L or less, or 600 g / L or less, and preferably 200 g / L or more, 300 g / L or more, 400 g / L or more, or 500 g / L or more. These upper and lower limits can be arbitrarily combined. In another embodiment, the concentration of 5-aminolevulinic acid or a salt thereof in the crystallization stock solution, calculated as 5-aminolevulinic acid phosphate, is preferably 200 to 900 g / L, more preferably 300 to 900 g / L, even more preferably 400 to 900 g / L, and most preferably 500 to 650 g / L. By setting the concentration of 5-aminolevulinic acid or a salt thereof in the crystallization stock solution within the above range, residual organic solvent can be reduced, and product quality can be improved.

[0131] In order to adjust the concentration of 5-aminolevulinic acid or a salt thereof in the aqueous solution in which 5-aminolevulinic acid or a salt thereof is dissolved to the above-mentioned concentration, ion-exchange purified water or the like may be used for dissolution, or the aqueous solution containing 5-aminolevulinic acid or a salt thereof may be concentrated by a general concentration method such as a heat concentration method or a reduced pressure concentration method.

[0132] (α2) Step of Adjusting the Temperature of the Crystallization Stock Solution Obtained in (α1) Step (α2) is a step of adjusting the temperature of the crystallization stock solution obtained in step (α1) to a specific range. The temperature of the crystallization stock solution is preferably 30°C or less, 25°C or less, or 20°C or less, and preferably 5°C or more. These upper and lower limits can be arbitrarily combined. In another embodiment, the temperature of the crystallization stock solution is preferably 5 to 30°C, more preferably 5 to 25°C, even more preferably 5 to 20°C, and most preferably 10 to 20°C. By adjusting the temperature of the crystallization stock solution within the above range, the residual organic solvent can be further reduced and the product quality can be improved. Examples of methods for adjusting the temperature of the crystallization stock solution include a thermostatic bath and a jacketed tank.

[0133] (α3) A step of adding a first' organic solvent to the crystallization stock solution obtained in (α2) to precipitate 5-aminolevulinic acid or a salt thereof. The step (α3) is a step of adding a first' organic solvent to the crystallization stock solution whose temperature has been adjusted in the step (α2) to precipitate 5-aminolevulinic acid or a salt thereof.

[0134] In step (α3), the amount of the first' organic solvent added is preferably 2.0 v / v or less, more preferably 1.0 v / v or less, even more preferably 0.80 v / v or less, and most preferably 0.60 v / v or less, relative to the volume of the crystallization stock solution. The lower limit of the amount of the first' organic solvent added is not particularly limited, but is preferably 0.01 v / v or more, more preferably 0.10 v / v or more, even more preferably 0.20 v / v or more, and most preferably 0.30 v / v or more, relative to the volume of the crystallization stock solution. These upper and lower limits can be arbitrarily combined. In another embodiment, the amount of the first' organic solvent added is 0.01 to 2.0 v / v, 0.10 to 1.0 v / v, 0.20 to 0.80 v / v, or 0.30 to 0.60 v / v, relative to the volume of the crystallization stock solution.

[0135] In the step of adding the first organic solvent, the crystallization temperature is not particularly limited, but is preferably the same temperature as in step (α2). In step (α3), the rate of adding the organic solvent is not particularly limited as long as no solid precipitation occurs due to a local decrease in solubility.

[0136] (First' Organic Solvent) In step (α3), the first' organic solvent is preferably at least one organic solvent selected from the group consisting of methanol, ethanol, acetone, 1-propanol, 2-propanol, ethyl acetate, 1-butanol, 2-butanol, heptane, isopropyl acetate, methyl ethyl ketone, propyl acetate, and tetrahydrofuran. Among these, at least one organic solvent selected from the group consisting of methanol, ethanol, acetone, 1-propanol, and 2-propanol is more preferred, and methanol or ethanol is most preferred. Furthermore, these organic solvents may be used alone or in combination.

[0137] In step (α3), the first' organic solvent may be added as a mixture with an organic solvent, a mixture with water, or a mixture of an organic solvent and water. The concentration of the first' organic solvent in the mixture is preferably 30% by volume or more, more preferably 50% by volume or more, even more preferably 80% by volume or more, and most preferably 100% by volume. These upper and lower limits can be arbitrarily combined. In another embodiment, the concentration of the first' organic solvent in the mixture is preferably 30 to 100% by volume, more preferably 50 to 100% by volume, and even more preferably 80 to 100% by volume.

[0138] In step (α3), seed crystals may be added to the crystallization stock solution before precipitation of 5-aminolevulinic acid or a salt thereof. The timing of adding the seed crystals to the crystallization stock solution is not particularly limited, but from the viewpoint of purification efficiency, the timing may be, for example, preferably within 0 to 12 hours, more preferably within 0 to 8 hours, even more preferably within 0 to 4 hours, and most preferably immediately after completion of the addition of the first organic solvent.

[0139] The amount of the seed crystals to be added to the crystallization stock solution is preferably 0.01 to 5.0% by mass, more preferably 0.01 to 3.0% by mass, even more preferably 0.01 to 0.5% by mass, and most preferably 0.03 to 0.5% by mass, relative to the amount of 5-aminolevulinic acid or a salt thereof in the crystallization stock solution. By setting the amount of seed crystals to be added within this range, the residual organic solvent can be further reduced, and the product quality can be improved.

[0140] After the addition of the seed crystals, the entire crystallization stock solution containing the seed crystals is preferably stirred in a nearly uniform state, and the added seed crystals are preferably aged so as to grow. The aging is carried out mainly for the purpose of growing and enlarging the crystals, but precipitation of new crystals may also occur simultaneously with the growth of the crystals.

[0141] The crystal aging time, measured from the end of the addition of seed crystals, is preferably less than 360 minutes and 240 minutes or less, and is preferably 1 minute or more and 10 minutes or more. These upper and lower limits can be arbitrarily combined. In another embodiment, the crystal aging time, measured from the end of the addition of seed crystals, is preferably 1 to 359 minutes, more preferably 1 to 240 minutes, even more preferably 10 to 359 minutes, and most preferably 10 to 240 minutes. By setting the crystal aging time within the above range, it is possible to further reduce residual organic solvents and improve product quality.

[0142] The temperature at which the seed crystals are added to the crystallization stock solution is not particularly limited as long as the seed crystals do not dissolve, but is preferably 30°C or lower, 25°C or lower, or 20°C or lower, and is preferably 5°C or higher. These upper and lower limits can be arbitrarily combined. In another embodiment, the temperature at which the seed crystals are added to the crystallization stock solution is preferably 5 to 30°C, more preferably 5 to 25°C, and even more preferably 15 to 20°C.

[0143] (α4) Step of adding a second' organic solvent to the crystallization stock solution The first crystallization step preferably includes a step (α4) of adding a second' organic solvent to the crystallization stock solution after adding the seed crystals to the crystallization stock solution in the step (α3). The timing of adding the second' organic solvent to the crystallization stock solution is not particularly limited, but is preferably, for example, immediately after the completion of crystal aging from the viewpoint of purification efficiency.

[0144] The amount of the second' organic solvent added is preferably 3.0 v / v or less, more preferably 2.6 v / v or less, even more preferably 2.4 v / v or less, and most preferably 2.0 v / v or less, relative to the volume of the crystallization stock solution. The amount of the second' organic solvent added is preferably 0.1 v / v or more, relative to the volume of the crystallization stock solution, although there is no particular lower limit. These upper and lower limits can be arbitrarily combined. In another embodiment, the amount of the second' organic solvent added is preferably 0.1 to 3.0 v / v, more preferably 0.1 to 2.7 v / v, even more preferably 0.1 to 2.5 v / v, and most preferably 0.1 to 2.4 v / v, relative to the volume of the crystallization stock solution.

[0145] The total amount of the first' organic solvent and the second' organic solvent added to the crystallization stock solution is preferably 3.0 v / v or less, more preferably 2.5 v / v or less, even more preferably 2.2 v / v or less, and most preferably 2.0 v / v or less, relative to the volume of the crystallization stock solution. The amounts of the first' organic solvent and the second' organic solvent added relative to the volume of the crystallization stock solution are not particularly limited in lower limit, but are preferably 0.1 v / v or more. These upper and lower limits can be arbitrarily combined. In another embodiment, the amounts of the first' organic solvent and the second' organic solvent added relative to the volume of the crystallization stock solution are preferably 0.1 to 4.0 v / v, more preferably 0.1 to 3.5 v / v, even more preferably 0.1 to 3.2 v / v, and most preferably 0.1 to 3.0 v / v.

[0146] In step (α4), the crystallization temperature is not particularly limited, but is preferably the same temperature as in step (α2). The rate at which the second' organic solvent is added to the crystallization stock solution is not particularly limited as long as solid precipitation does not occur due to a local decrease in solubility, but is preferably 5.0 v / v / h or less, 2.0 v / v / h or less, 1.5 v / v / h or less, or 1.0 v / v / h or less relative to the volume of the crystallization stock solution. The rate at which the second' organic solvent is added to the crystallization stock solution is not particularly limited in terms of its lower limit relative to the volume of the crystallization stock solution, but is preferably 0.1 v / v or more, 0.2 v / v or more, 0.3 v / v or more, 0.4 v / v or more, or 0.5 v / v or more. These upper and lower limits can be combined arbitrarily. In another embodiment, the rate at which the second organic solvent is added to the crystallization stock solution is preferably 0.1 to 5.0 v / v / h, more preferably 0.2 to 2.0 v / v / h, even more preferably 0.3 to 1.5 v / v / h, and most preferably 0.5 to 1.3 v / v / h, relative to the volume of the crystallization stock solution.

[0147] In step (α4), the second' organic solvent may be added as a mixture with an organic solvent, a mixture with water, or a mixture of an organic solvent and water. The concentration of the second' organic solvent in the mixture is preferably 30% by volume or more, more preferably 50% by volume or more, even more preferably 80% by volume or more, and most preferably 100% by volume. These upper and lower limits can be arbitrarily combined. In another embodiment, the concentration of the second' organic solvent in the mixture is preferably 30 to 100% by volume, more preferably 50 to 100% by volume, and even more preferably 80 to 100% by volume.

[0148] (α5) Step of Separating Precipitate The first crystallization step preferably further comprises a step of separating the precipitate from the crystallization stock solution. Examples of a method for removing the organic solvent from the precipitate obtained by the above crystallization include a method in which the precipitate is separated from the slurry, washed, and dried.

[0149] (Method of Separating and Washing Precipitate from Slurry) The method of separating and washing the precipitate from the slurry is not particularly limited as long as the precipitate can be separated from the mother liquor (ML), and examples thereof include filtration, pressure filtration, suction filtration, and centrifugation. In the case of centrifugation, washing the precipitate is preferred from the viewpoint of removing impurities. As a method of washing the precipitate, for example, washing can be performed using the organic solvent added during crystallization or an aqueous solution containing an organic solvent.

[0150] The amount of the solution used for the washing is preferably 0.5 to 2 v / w, more preferably 1.0 to 1.9 v / w, and even more preferably 1.2 to 1.8 v / w, in terms of volume ratio to the weight of the precipitate of 5-aminolevulinic acid or a salt thereof.

[0151] (Drying) The drying method is not particularly limited as long as it can remove the organic solvent, does not decompose 5-aminolevulinic acid or a salt thereof, and can maintain the form of the precipitate (crystalline form or amorphous form). For example, reduced pressure drying, fluidized bed drying, ventilation drying, etc. can be applied.

[0152] The separated and dried precipitate is dissolved in ion-exchange purified water or the like to obtain a solution of 5-aminolevulinic acid or a salt thereof (Solution F). The content of 5-aminolevulinic acid or a salt thereof in the solution is preferably 10 to 800 g / L, more preferably 50 to 600 g / L, even more preferably 100 to 500 g / L, and most preferably 300 to 500 g / L, calculated as 5-aminolevulinic acid monophosphate.

[0153] (Seventh Step) The seventh step is an optional step, and in one aspect, is a step of obtaining a decolorized solution (solution G) from solution F using activated carbon. In one aspect, solution G may be obtained by adding activated carbon to decolorize solution E, the concentrated solution, or solution F. Examples of activated carbon include Carborafine (registered trademark) manufactured by Osaka Gas Chemicals Co., Ltd., Strong Shirasagi (hereinafter, Shirasagi is a registered trademark), Purified Shirasagi, Special Shirasagi, Shirasagi A, Shirasagi C, Shirasagi ANOX-1, Shirasagi FAC-10, Shirasagi WP-H, Shirasagi DO-2, Shirasagi DO-5, Granular Shirasagi G2c, Granular Shirasagi WH2c, Granular Shirasagi W2c, Granular Shirasagi WH5c, Granular Shirasagi W5c, Granular Shirasagi LGK-100, Granular Shirasagi LGK-400, Granular Shirasagi KL, Granular Shirasagi LH2c, Spherical Shirasagi X8100H, Spherical Shirasagi XS8100H, Granular Shirasagi G 2x, Granular Shirasagi G5x, Granular Shirasagi S2x, Granular Shirasagi WH2x, Granular Shirasagi X2M, Granular Shirasagi C2c, Granular Shirasagi C2x, Spherical Shirasagi X7000H, spherical white heron X7100H, spherical white heron XS7100H, spherical white heron X7000H-3, spherical white heron Examples of suitable cellulose nanofibers include Spherical Shirasagi LGK-700, Spherical Shirasagi DX7-3, Shirasagi M, Shirasagi P, Granular Shirasagi GM2X, and Seitz AKSJ, as well as Taiko (hereinafter, Taiko is a registered trademark) S, Taiko K, Taiko P, Taiko W, Taiko A, and Taiko Y manufactured by Futamura Chemical Co., Ltd., with Taiko S being preferred.

[0154] (Eighth Step) In one embodiment, the eighth step is a step of treating the solution G with a chelating resin to obtain a solution H. In another embodiment, the solution E, the concentrated solution, the solution F, or the decolorizing solution (solution G) may be passed through a chelating resin to obtain a solution H. Examples of the chelating resin include chelating resins having a sulfonic acid group, iminodiacetic acid, aminomethylphosphonic acid, or the like as an exchange group, and having a porous, macroporous, gel, styrene, or acrylic resin matrix.

[0155] Specific examples of chelating resins include C467 manufactured by DuPont, MTS9500 manufactured by Purolite, and Lewatit (registered trademark) CNP80, CNP80WS, MDSTP208, MDSTP260, TP207, TP208, TP209XL, and TP260 manufactured by LANXESS.

[0156] (Step 9) Step 9 is an optional step, and in one embodiment, is a step in which Solution H is passed through a microfiltration membrane or an ultrafiltration membrane to obtain a filtrate. In one embodiment, Solution D, Solution E, or Solution F obtained in the above step may be ultrafiltered by passing it through an ultrafiltration membrane (hereinafter also referred to as "UF membrane") (MWCO = 6000) that can remove substances with a molecular weight of 6000 or more, thereby removing endotoxins, proteins, high molecular weight peptides, toxins, etc. from the decolorized filtrate. Furthermore, microfiltration can be performed using a membrane with a pore size of 0.2 to 1.2 μm before or after this step. Specific examples include a method of treatment with a membrane filter.

[0157] (Step 10) Step 10 is an optional step, and in one embodiment, is a step of concentrating the filtrate obtained in Step 9 to obtain a concentrate. For Solution D, Solution E, Solution F, or Solution G obtained in the above steps, a crystallization stock solution containing 5-aminolevulinic acid or a salt thereof can be obtained by diluting the aqueous solution of 5-aminolevulinic acid or a salt thereof with water and subjecting it to a general concentration method such as heating concentration, membrane concentration, or vacuum concentration.

[0158] The concentration of 5-aminolevulinic acid or a salt thereof in the crystallization stock solution, calculated as 5-aminolevulinic acid monophosphate, is preferably 700 g / L or less, 650 g / L or less, or 600 g / L or less, and is preferably 200 g / L or more, 260 g / L or more, 300 g / L or more, 400 g / L or more, or 500 g / L or more. These upper and lower limits can be arbitrarily combined. In another embodiment, the concentration of 5-aminolevulinic acid or a salt thereof in the crystallization stock solution, calculated as 5-aminolevulinic acid monophosphate, is preferably 200 to 700 g / L, more preferably 260 to 650 g / L, 260 to 600 g / L, 300 to 700 g / L, even more preferably 400 to 700 g / L, and most preferably 500 to 650 g / L. By setting the concentration of 5-aminolevulinic acid or a salt thereof in the crystallization solution within the above range, it is possible to reduce the amount of residual organic solvent and improve the product quality.

[0159] In order to adjust the concentration of 5-aminolevulinic acid or a salt thereof in the aqueous solution in which 5-aminolevulinic acid or a salt thereof is dissolved to the above-mentioned concentration, ion-exchange purified water or the like may be used for dissolution, or the aqueous solution containing 5-aminolevulinic acid or a salt thereof may be concentrated by a general concentration method such as a heat concentration method or a reduced pressure concentration method.

[0160] [2] Step of adjusting the temperature of the crystallization stock solution obtained in [1] Step [2] is a step of adjusting the temperature of the crystallization stock solution obtained in step [1] to a specific range. The temperature of the crystallization stock solution is preferably 30°C or less, 25°C or less, or 20°C or less, and preferably 5°C or more. These upper and lower limits can be arbitrarily combined. In another embodiment, the temperature of the crystallization stock solution is preferably 5 to 30°C, more preferably 5 to 25°C, even more preferably 5 to 20°C, and most preferably 10 to 20°C. By adjusting the temperature of the crystallization stock solution within the above range, the residual organic solvent can be further reduced and the product quality can be improved. Examples of methods for adjusting the temperature of the crystallization stock solution include a thermostatic bath and a jacketed tank.

[0161] [3] A step of adding a first organic solvent to the crystallization stock solution obtained in [2] to precipitate 5-aminolevulinic acid or a salt thereof. The step [3] is a step of adding a first organic solvent to the crystallization stock solution whose temperature has been adjusted in the step [2] to precipitate 5-aminolevulinic acid or a salt thereof.

[0162] In step [3], the amount of the first organic solvent added is 0.55 v / v or less, preferably 0.50 v / v or less, more preferably 0.45 v / v or less, and even more preferably 0.40 v / v or less, relative to the volume of the crystallization stock solution. The lower limit of the amount of the first organic solvent added is not particularly limited, but is 0.01 v / v or more, relative to the volume of the crystallization stock solution. These upper and lower limits can be combined arbitrarily. In another embodiment, the amount of the first organic solvent added is 0.01 to 0.55 v / v, 0.01 to 0.50 v / v, 0.01 to 0.45 v / v, or 0.01 to 0.40 v / v, relative to the volume of the crystallization stock solution.

[0163] In the step of adding the first organic solvent, the crystallization temperature is not particularly limited, but is preferably the same temperature as in step [2]. In step [3], the rate at which the organic solvent is added is not particularly limited as long as no solid precipitation occurs due to a local decrease in solubility.

[0164] (First Organic Solvent) In step [3], the first organic solvent is preferably at least one organic solvent selected from the group consisting of methanol, ethanol, acetone, 1-propanol, 2-propanol, ethyl acetate, 1-butanol, 2-butanol, heptane, isopropyl acetate, methyl ethyl ketone, propyl acetate, and tetrahydrofuran. Among these, at least one organic solvent selected from the group consisting of methanol, ethanol, acetone, 1-propanol, and 2-propanol is more preferred, and ethanol is most preferred. Furthermore, these organic solvents may be used alone or in combination.

[0165] In step [3], the first organic solvent may be added as a mixture with an organic solvent, a mixture with water, or a mixture of an organic solvent and water. The concentration of the first organic solvent in the mixture is preferably 30% by volume or more, more preferably 50% by volume or more, even more preferably 80% by volume or more, and most preferably 100% by volume. These upper and lower limits can be arbitrarily combined. In another embodiment, the concentration of the first organic solvent in the mixture is preferably 30 to 100% by volume, more preferably 50 to 100% by volume, and even more preferably 80 to 100% by volume.

[0166] In step [3], seed crystals may be added to the crystallization stock solution before the precipitation of a precipitate of 5-aminolevulinic acid or a salt thereof. The timing of adding the seed crystals to the crystallization stock solution is not particularly limited, but from the viewpoint of purification efficiency, the timing may be, for example, preferably within 0 to 12 hours, more preferably within 0 to 8 hours, even more preferably within 0 to 4 hours, and most preferably immediately after the completion of the addition of the first organic solvent.

[0167] The amount of the seed crystals to be added to the crystallization stock solution is preferably 0.01 to 5.0% by mass, more preferably 0.01 to 3.0% by mass, even more preferably 0.01 to 0.5% by mass, and most preferably 0.05 to 0.5% by mass, relative to the amount of 5-aminolevulinic acid or a salt thereof in the crystallization stock solution. By setting the amount of seed crystals to be added within this range, the residual organic solvent can be further reduced, and the product quality can be improved.

[0168] After the addition of the seed crystals, the entire crystallization stock solution containing the seed crystals is preferably stirred in a nearly uniform state, and the added seed crystals are preferably aged so as to grow. The aging is carried out mainly for the purpose of growing and enlarging the crystals, but precipitation of new crystals may also occur simultaneously with the growth of the crystals.

[0169] The crystal aging time, measured from the end of the addition of seed crystals, is preferably less than 360 minutes and 240 minutes or less, and is preferably 1 minute or more and 10 minutes or more. These upper and lower limits can be arbitrarily combined. In another embodiment, the crystal aging time, measured from the end of the addition of seed crystals, is preferably 1 to 359 minutes, more preferably 1 to 240 minutes, even more preferably 10 to 359 minutes, and most preferably 10 to 240 minutes. By setting the crystal aging time within the above range, it is possible to further reduce residual organic solvents and improve product quality.

[0170] The temperature at which the seed crystals are added to the crystallization stock solution is not particularly limited as long as the seed crystals do not dissolve, but is preferably 30°C or lower, 25°C or lower, or 20°C or lower, and is preferably 5°C or higher. These upper and lower limits can be arbitrarily combined. In another embodiment, the temperature at which the seed crystals are added to the crystallization stock solution is preferably 5 to 30°C, more preferably 5 to 25°C, and even more preferably 15 to 20°C.

[0171] [4] Step of adding a second organic solvent to the crystallization stock solution The production method of the present disclosure preferably further comprises step [4] of adding a second organic solvent to the crystallization stock solution after adding the seed crystals to the crystallization stock solution in step [3]. The timing of adding the second organic solvent to the crystallization stock solution is not particularly limited, but is preferably, for example, immediately after the completion of crystal aging from the viewpoint of purification efficiency.

[0172] The amount of the second organic solvent added is preferably 3.0 v / v or less, more preferably 2.6 v / v or less, even more preferably 2.4 v / v or less, and most preferably 2.0 v / v or less, relative to the volume of the crystallization stock solution. The amount of the second organic solvent added is not particularly limited to a lower limit relative to the volume of the crystallization stock solution, but is preferably 0.1 v / v or more. These upper and lower limits can be arbitrarily combined. In another embodiment, the amount of the second organic solvent added is preferably 0.1 to 3.0 v / v, more preferably 0.1 to 2.5 v / v, even more preferably 0.1 to 2.2 v / v, and most preferably 0.1 to 2.0 v / v, relative to the volume of the crystallization stock solution.

[0173] The total amount of the first organic solvent and the second organic solvent added to the crystallization stock solution is preferably 3.0 v / v or less, more preferably 2.5 v / v or less, even more preferably 2.2 v / v or less, and most preferably 2.0 v / v or less, relative to the volume of the crystallization stock solution. The lower limit of the amount of the first organic solvent and the second organic solvent added relative to the volume of the crystallization stock solution is not particularly limited, but is preferably 0.1 v / v or more. These upper and lower limits can be arbitrarily combined. In another embodiment, the amount of the first organic solvent and the second organic solvent added relative to the volume of the crystallization stock solution is preferably 0.1 to 3.0 v / v, more preferably 0.1 to 2.5 v / v, even more preferably 0.1 to 2.2 v / v, and most preferably 0.1 to 2.0 v / v.

[0174] In step [4], the crystallization temperature is not particularly limited, but is preferably the same temperature as in step [2]. The rate at which the second organic solvent is added to the crystallization stock solution is not particularly limited as long as solid precipitation does not occur due to a local decrease in solubility, but is preferably 5.0 v / v / h or less, 2.0 v / v / h or less, 1.5 v / v / h or less, or 1.0 v / v / h or less relative to the volume of the crystallization stock solution. The rate at which the second organic solvent is added to the crystallization stock solution is not particularly limited, but is preferably 0.1 v / v or more relative to the volume of the crystallization stock solution. These upper and lower limits can be arbitrarily combined. In another embodiment, the rate at which the second organic solvent is added to the crystallization stock solution is preferably 0.4 to 5.0 v / v / h, more preferably 0.4 to 2.0 v / v / h, even more preferably 0.4 to 1.5 v / v / h, and most preferably 0.4 to 1.0 v / v / h relative to the volume of the crystallization stock solution.

[0175] In step [4], the second organic solvent may be added as a mixture with an organic solvent, a mixture with water, or a mixture of an organic solvent and water. The concentration of the second organic solvent in the mixture is preferably 30% by volume or more, more preferably 50% by volume or more, even more preferably 80% by volume or more, and most preferably 100% by volume. These upper and lower limits can be arbitrarily combined. In another embodiment, the concentration of the second organic solvent in the mixture is preferably 30 to 100% by volume, more preferably 50 to 100% by volume, and even more preferably 80 to 100% by volume.

[0176] [5] Step of Separating Precipitate The production method of the present disclosure preferably further comprises a step of separating the precipitate from the crystallization solution. Examples of a method for removing the organic solvent from the precipitate obtained by the above crystallization include a method in which the precipitate is separated from the slurry, washed, and dried.

[0177] (Method of Separating and Washing Precipitate from Slurry) The method of separating the precipitate from the slurry is not particularly limited as long as the precipitate can be separated from the mother liquor (ML), and examples thereof include filtration, pressure filtration, suction filtration, and centrifugation. In the case of centrifugation, washing the precipitate is preferred from the viewpoint of removing impurities. The precipitate can be washed, for example, using the organic solvent added during crystallization or an aqueous solution containing an organic solvent.

[0178] The amount of the solution used for the washing is preferably 0.5 to 2 v / w, more preferably 0.9 to 1.1 v / w, and even more preferably 0.9 to 1.0 v / w, in terms of volume ratio to the weight of the 5-aminolevulinic acid precipitate.

[0179] (Drying) The drying method is not particularly limited as long as it can remove the organic solvent, does not decompose 5-aminolevulinic acid or a salt thereof, and can maintain the form of the precipitate (crystalline form or amorphous form). For example, reduced pressure drying, fluidized bed drying, ventilation drying, etc. can be applied.

[0180] The drying temperature is not particularly limited as long as it is within a range that allows removal of attached moisture and solvent, but is preferably 50°C or less, more preferably 40°C or less, and most preferably 30°C or less. The drying temperature has no particular lower limit, but is preferably 4°C or higher. These upper and lower limits can be arbitrarily combined. In another embodiment, the drying temperature is preferably 4 to 50°C, more preferably 4 to 40°C, and even more preferably 4 to 30°C. The drying time is not particularly limited as long as it is within a range that allows removal of attached moisture and solvent, but is 48 hours or less, 24 hours or less, 10 hours or less, or 5 hours or less. The lower limit is not particularly limited, but is 1 hour or more. These upper and lower limits can be arbitrarily combined. In another embodiment, the drying time is preferably 1 to 48 hours, more preferably 1 to 24 hours, even more preferably 1 to 10 hours, and most preferably 1 to 5 hours. Furthermore, in the case of reduced pressure drying, the pressure is not particularly limited, but from the viewpoint of purification efficiency, it is preferably 0.1 hPa or more, 1 hPa or more, or 10 hPa or more. The upper limit of the pressure for reduced pressure drying is not particularly limited, but is preferably 150 hPa or less, 100 hPa or less, or 80 hPa or less. These upper and lower limits can be combined arbitrarily. In another embodiment, the pressure for reduced pressure drying is preferably 0.1 to 150 hPa, more preferably 1 to 100 hPa, and even more preferably 10 to 80 hPa.

[0181] [Third to Sixth Embodiments] In a third embodiment of the present disclosure, a solution containing 5-aminolevulinic acid or a salt thereof, glycine, and alanine is dissolved in Na ＋ The method for producing 5-aminolevulinic acid or a salt thereof comprises treating the acid with a strongly acidic cation exchange resin of the type described above.

[0182] A fourth embodiment of the present disclosure is a method for producing 5-aminolevulinic acid or a salt thereof, comprising treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, and alanine with at least one of a phosphoric acid type and an acetate type strong basic anion exchange resin.

[0183] A fifth embodiment of the present disclosure is a method for producing 5-aminolevulinic acid or a salt thereof, comprising the following steps x1) to x3) in any order: x1) treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, and alanine with a strongly acidic cation exchange resin; x2) treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, and alanine with a weakly acidic cation exchange resin; and x3) treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, and alanine with a strongly basic anion exchange resin.

[0184] A sixth embodiment of the present disclosure is a method for producing 5-aminolevulinic acid or a salt thereof, comprising the following steps y1) to y4) in this order: y1) treating solution A containing 5-aminolevulinic acid or a salt thereof, glycine, and alanine with a strongly acidic cation exchange resin to obtain solution B; y2) treating solution B with a weakly acidic cation exchange resin to obtain solution C; y3) treating solution C with a strongly basic anion exchange resin to obtain solution D; and y4) adjusting the pH of solution D to obtain solution E.

[0185] In the third to sixth embodiments, an example of a solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA is Solution A described above in Step 0. The concentration of 5-aminolevulinic acid or a salt thereof in the solution is not particularly limited, but in one aspect, in terms of purification efficiency, it is preferably 0.1 g / L to 100 g / L, more preferably 1 g / L to 70 g / L, and even more preferably 10 g / L to 60 g / L, calculated as 5-aminolevulinic acid monophosphate. The glycine content ratio in the solution, (glycine content) / (5-aminolevulinic acid or a salt thereof content), is preferably 0.0001 to 1, more preferably 0.0005 to 0.5, even more preferably 0.001 to 0.3, and most preferably 0.05 to 0.15, on a mass basis. The alanine content ratio in the solution, (alanine content) / (5-aminolevulinic acid or a salt thereof content), is preferably 0.0001 to 1, more preferably 0.0005 to 0.5, even more preferably 0.001 to 0.3, and most preferably 0.005 to 0.05, on a mass basis. The PDPA content ratio in the solution, (PDPA content) / (5-aminolevulinic acid or a salt thereof content), is preferably 0.0001 to 1, more preferably 0.0005 to 0.5, even more preferably 0.001 to 0.3, and most preferably 0.002 to 0.1, on a mass basis.

[0186] In the third, fifth, and sixth embodiments, the strong acid cation exchange resin is the same as the strong acid cation exchange resin described above in the first step. In the fifth and sixth embodiments, the weak acid cation exchange resin is the same as the weak acid cation exchange resin described above in the second step. In the fourth to sixth embodiments, the strong basic anion exchange resin is the same as the strong basic anion exchange resin described above in the third step.

[0187] An example of x1) in the fifth embodiment is the same as the first step. An example of x2) in the fifth embodiment is the same as the second step. An example of x3) in the fifth embodiment is the same as the third step.

[0188] An example of y1) in the sixth embodiment is the same as the first step. An example of y2) in the sixth embodiment is the same as the second step. An example of y3) in the sixth embodiment is the same as the third step. An example of y4) in the sixth embodiment is the same as the fourth step.

[0189] In y1) of the sixth embodiment, the recovery conditions for obtaining solution B are preferably initiated by a change in Brix value and terminated by a change in pH. In this specification, the Brix value is a measure of the mass percentage of soluble solids in a liquid, primarily 5-aminolevulinic acid or its salts, and refers to the number of grams of 5-aminolevulinic acid or its salts contained in 100 grams of liquid. The Brix value is usually expressed in degrees (°Brix), but it can also be expressed as a mass percentage (% by mass). For example, a Brix value of 10°Brix (or 10% by mass) means that the liquid contains 10% by mass of 5-aminolevulinic acid or its salts. The measurement method involves measuring the refractive index of the liquid using a refractometer, and then calculating the Brix value based on this. When using the refractometer, it is calibrated with a standard solution, a sample solution is dropped onto the prism surface, and the refractive index is read, with temperature correction performed as necessary.

[0190] As used herein, "initiated by a change in Brix value" refers to initiating the recovery process when a certain change occurs in the Brix value under the recovery conditions for obtaining a solution. Specifically, this refers to an operation in which the recovery of a solution is initiated when the sugar content (Brix value) of the liquid begins to change as the process progresses. Furthermore, "terminated by a change in pH" refers to terminating the recovery process when the pH value reaches a certain range under the recovery conditions for obtaining a solution. Specifically, this refers to an operation in which the solution recovery process is stopped when the pH value of the liquid reaches a target range or a specific condition during the recovery process. By combining the Brix value and pH changes, more accurate recovery conditions can be set and the process can be optimized.

[0191] Specifically, in y1), the Brix value and pH of the solution are measured, and collection of solution B is started when the Brix value reaches preferably 2.0 to 6.0 mass %, more preferably 4.0 to 6.0 mass %, and collection of solution B is terminated when the pH reaches preferably 11.0 to 13.0, more preferably 12.0 to 13.0, thereby enabling efficient separation of solution B.

[0192] After the preparation of solution B in the sixth embodiment is completed, in the next step y2), solution B is further treated with a weakly acidic cation exchange resin. This is to further remove impurities remaining in solution B and improve the purity of 5-aminolevulinic acid. The weakly acidic cation exchange resin has exchange sites different from those of the strongly acidic resin, and therefore exhibits different adsorption and separation properties for impurities.

[0193] In y2), the recovery conditions for obtaining the solution C are preferably such that the recovery is initiated and terminated based on a change in Brix. Specifically, the recovery of the solution C is initiated when the Brix value of the solution preferably reaches 2.0% by mass, and the recovery of the solution C is terminated when 4.5±1.5 RV of ion-exchanged water has been passed through the weakly acidic cation exchange resin from the time when the Brix value of the solution C preferably reaches 1.0% by mass. This enables effective removal of impurities.

[0194] Next, in y3), solution C is treated with a strongly basic anion exchange resin. This removes anionic impurities from solution C and adjusts the ionic equilibrium of 5-aminolevulinic acid or a salt thereof. Strongly basic anion exchange resins have high selectivity and can efficiently remove even trace amounts of remaining impurities.

[0195] In y3), the recovery conditions for obtaining the solution D are preferably such that the recovery is initiated and terminated based on a change in Brix. Specifically, the recovery of the solution D is initiated when the Brix value of the solution preferably reaches 0.2% by mass, and the recovery of the solution D is terminated when 1.25±0.625 RV of ion-exchanged water has been passed through the strongly basic anion exchange resin from the time when the Brix value of the solution preferably reaches 1.0% by mass. This enables effective removal of anionic impurities.

[0196] Finally, in y4), the pH of solution D is adjusted to obtain solution E. At this stage, the pH is preferably adjusted to within a specific range (preferably 2.5 to 3.5) to provide appropriate storage conditions for 5-aminolevulinic acid or a salt thereof. This final adjustment ensures product stability and maintains consistency in product quality.

[0197] [Seventh embodiment] The method for producing 5-aminolevulinic acid or a salt thereof, comprising the following steps [1]' to [3]' in the above [1]. Before steps [2] to [5], a step similar to (step 6) in the second embodiment may be carried out.

[0198] As explained above, this specification discloses the following configurations. 1. 5-aminolevulinic acid or a salt thereof that satisfies at least one of the following (A1) and (A2) based on the peak area determined by HPLC analysis: (A1) The ratio of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (1), is 0.0007 or less. (A2) The sum of the ratios of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (2), is 0.0016 or less. Ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof = Peak area of ​​each impurity quantifiable by HPLC / Peak area of ​​5-aminolevulinic acid or a salt thereof...formula (1) Sum of the ratios of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof = Σ (Peak area of ​​each impurity quantifiable by HPLC / Peak area of ​​5-aminolevulinic acid or a salt thereof)...formula (2) 2. 5-aminolevulinic acid or a salt thereof that satisfies the following (B1) and (B2): (B1) The transmittance of light at a wavelength of 430 nm is 98.8% or more. (B2) The transmittance of light at a wavelength of 430 nm measured by a severe stability test under the following conditions is 92.0% or more. Conditions for the severe stability test: The 5-aminolevulinic acid or a salt thereof is stored at a temperature of 70°C ± 2°C for 2 days, and then the transmittance of light at a wavelength of 430 nm is measured with a spectrophotometer. 3. 5-aminolevulinic acid or a salt thereof according to 1 or 2 above, wherein the content of residual organic solvent contained in the 5-aminolevulinic acid or a salt thereof is 1000 ppm or less. 4. 5-aminolevulinic acid or a salt thereof according to any one of 1 to 3 above, wherein the content of arsenic contained in the 5-aminolevulinic acid or a salt thereof is less than 0.3 ppm. 5. 5-aminolevulinic acid or a salt thereof according to any one of 1 to 4 above, wherein the 5-aminolevulinic acid or a salt thereof is 5-aminolevulinic acid phosphate. 6. A method for producing 5-aminolevulinic acid or a salt thereof, comprising the following steps [1] to [3]: [1] a step of preparing a solution containing 5-aminolevulinic acid or a salt thereof, and adding water to the solution or concentrating the solution to prepare a crystallization stock solution having a concentration of 200 to 700 g / L in terms of 5-aminolevulinic acid monophosphate.[2] A step of adjusting the temperature of the crystallization stock solution obtained in [1] above to 5 to 25°C. [3] A step of adding a first organic solvent to the crystallization stock solution obtained in [2] above to precipitate 5-aminolevulinic acid or a salt thereof. 7. The method according to 6 above, wherein the 5-aminolevulinic acid or a salt thereof satisfies at least one of the following (A1) and (A2) based on the peak area determined by HPLC analysis: (A1) The ratio of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (1), is 0.0007 or less. (A2) The total ratio of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (2), is 0.0016 or less. Ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof=peak area of ​​each impurity quantifiable by HPLC / peak area of ​​5-aminolevulinic acid or a salt thereof...Equation (1) Sum of the ratios of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof=Σ(peak area of ​​each impurity quantifiable by HPLC / peak area of ​​5-aminolevulinic acid or a salt thereof)...Equation (2) 8. The method according to 6 above, which satisfies the following (B1) and (B2): (B1) The transmittance of light at a wavelength of 430 nm is 98.8% or more. (B2) The transmittance of light at a wavelength of 430 nm measured by a severe stability test under the following conditions is 92.0% or more. Conditions for the severe stability test: The 5-aminolevulinic acid or a salt thereof is stored at a temperature of 70°C ± 2°C for 2 days, and then the transmittance of light at a wavelength of 430 nm is measured using a spectrophotometer. 9. 9. The method according to any one of 6 to 8 above, wherein the content of residual organic solvent contained in the 5-aminolevulinic acid or salt thereof is 1000 ppm or less. 10. The method according to any one of 6 to 9 above, wherein the content of arsenic contained in the 5-aminolevulinic acid or salt thereof is less than 0.3 ppm. 11. The method according to any one of 6 to 10 above, wherein the 5-aminolevulinic acid or salt thereof is 5-aminolevulinic acid phosphate. 12. The method according to any one of 6 to 11 above, in [3] above, further comprising adding seed crystals to the crystallization stock solution so that the content is 0.01 to 5.0 mass %.13. The method according to item 12 above, wherein, in item [3], the method further comprises adding the seed crystals to the crystallization stock solution and then stirring for less than 360 minutes to mature the crystals. 14. The method according to any one of items 6 to 13 above, wherein, in item [3], the amount of the first organic solvent added is 0.50 v / v or less relative to the volume of the crystallization stock solution. 15. The method according to any one of items 12 to 14 above, wherein, in item [3], the method further comprises a step of adding a second organic solvent to the crystallization stock solution after adding the seed crystals. 16. The method according to item 15 above, wherein the addition rate of the second organic solvent is 0.4 to 5.0 v / v / h relative to the volume of the crystallization stock solution. 17. The method according to item 15 or 16 above, wherein the total amount of the first organic solvent and the second organic solvent added is 2 v / v or less relative to the volume of the crystallization stock solution. 18. The method according to any one of items 6 to 17, comprising separating and drying the precipitate obtained in item [3] to obtain a powder, wherein the content of residual organic solvent in the powder is 1000 ppm or less. 19. The method according to any one of items 6 to 18, wherein the first organic solvent in item [3] is at least one selected from methanol, ethanol, isopropanol, normal propanol, acetone, and acetonitrile. 20. The method according to any one of items 15 to 19, wherein the second organic solvent in item [3] is at least one selected from methanol, ethanol, isopropanol, normal propanol, acetone, and acetonitrile. 21. The method according to item 19 or 20, wherein the first organic solvent in item [3] is ethanol. 22. The method according to item 20 or 21, wherein the second organic solvent in item [3] is ethanol. 23. A solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA is dissolved in Na. ＋24. A method for producing 5-aminolevulinic acid or a salt thereof, comprising treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with at least one of a phosphoric acid-type and an acetate-type strongly basic anion exchange resin. 25. A method for producing 5-aminolevulinic acid or a salt thereof, comprising the following x1) to x3) in any order: x1) treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with a strongly acidic cation exchange resin. x2) treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with a weakly acidic cation exchange resin. x3) treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with a strongly basic anion exchange resin. 26. A method for producing 5-aminolevulinic acid or a salt thereof, comprising the following y1) to y4) in this order: y1) treating solution A containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with a strongly acidic cation exchange resin to obtain solution B. y2) treating solution B with a weakly acidic cation exchange resin to obtain solution C. y3) treating solution C with a strongly basic anion exchange resin to obtain solution D. y4) adjusting the pH of solution D to obtain solution E. 27. The method according to any one of 23 to 26 above, wherein the strongly acidic cation exchange resin is a polystyrene-based resin having sulfonic acid groups as functional groups and is in the Na+ ion type. 28. The method according to any one of 24 to 27 above, wherein the strongly basic anion exchange resin is a polystyrene-based resin having dimethylethanolammonium groups as functional groups and is in at least one of the acetate type and the phosphate type. 29. 30. The method according to any one of 26 to 28, wherein in y1), the recovery conditions for obtaining solution B are initiated by a change in Brix and terminated by a change in pH. 31. The method according to any one of 26 to 29, wherein in y2), the recovery conditions for obtaining solution C are initiated by a change in Brix and terminated by a change in Brix.31. The method according to any one of 26 to 30 above, wherein in y3), the recovery conditions for obtaining solution D are initiated and terminated by a change in Brix. 32. The 5-aminolevulinic acid or a salt thereof according to any one of 1 to 5 above, wherein the 5-aminolevulinic acid or a salt thereof is in a powder state. 33. A method for producing 5-aminolevulinic acid or a salt thereof, comprising the following steps [1]' to [3]' when preparing a solution containing 5-aminolevulinic acid or a salt thereof in [1] above: [1]' A step of preparing a solution containing 5-aminolevulinic acid or a salt thereof, and adding water to the solution or concentrating the solution to prepare a crystallization stock solution having a concentration of 200 to 900 g / L calculated as 5-aminolevulinic acid monophosphate. [2]' A step of raising the temperature of the crystallization stock solution obtained in [1]' above to 25°C. [3] 'A step of adding a first organic solvent to the crystallization stock solution obtained in [2]' above to precipitate 5-aminolevulinic acid or a salt thereof. 34. The method according to 33 above, wherein the 5-aminolevulinic acid or a salt thereof satisfies at least one of the following (A1) and (A2) based on peak areas determined by HPLC analysis: (A1) The ratio of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (1), is 0.0007 or less. (A2) The total ratio of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (2), is 0.0016 or less. Ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof=peak area of ​​each impurity quantifiable by HPLC / peak area of ​​5-aminolevulinic acid or a salt thereof...formula (1) Sum of the ratios of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof=Σ(peak area of ​​each impurity quantifiable by HPLC / peak area of ​​5-aminolevulinic acid or a salt thereof)...formula (2) 35. The method according to 33 above, which satisfies the following (B1) and (B2): (B1) The transmittance of light at a wavelength of 430 nm is 98.8% or more. (B2) The transmittance of light at a wavelength of 430 nm measured by a severe stability test under the following conditions is 92.0% or more.Conditions for severe stability test: After storing the 5-aminolevulinic acid or a salt thereof at a temperature of 70°C ± 2°C for 2 days, the transmittance of light at a wavelength of 430 nm is measured with a spectrophotometer. 36. The method according to any one of 33 to 35 above, wherein the content of residual organic solvent contained in the 5-aminolevulinic acid or a salt thereof is 1000 ppm or less. 37. The method according to any one of 33 to 36 above, wherein the content of arsenic contained in the 5-aminolevulinic acid or a salt thereof is less than 0.3 ppm. 38. The method according to 33 above, wherein the 5-aminolevulinic acid or a salt thereof is 5-aminolevulinic acid phosphate. 39. The method according to any one of 33 to 38 above, in [3]' above, further comprising adding seed crystals to the crystallization stock solution so that the content is 0.01 to 5.0 mass%. 40. The method according to the above item 39, wherein in the above item [3]', the method comprises adding the seed crystals to the crystallization stock solution and then stirring for less than 360 minutes to mature the crystals. 41. The method according to any one of the above items 33 to 40, wherein in the above item [3]', the amount of the first' organic solvent added is 2.0 v / v or less relative to the volume of the crystallization stock solution. 42. The method according to any one of the above items 39 to 41, wherein in the above item [3]', the method comprises a step of further adding a second' organic solvent to the crystallization stock solution after adding the seed crystals. 43. The method according to the above item 42, wherein the addition rate of the second' organic solvent is 0.1 to 5.0 v / v / h relative to the volume of the crystallization stock solution. 44. The method according to the above item 42 or 43, wherein the total amount of the first' organic solvent and the second' organic solvent added is 3.0 v / v or less relative to the volume of the crystallization stock solution. 45. The method according to any one of the above items 33 to 44, comprising separating and drying the precipitate obtained in the above item [3]' to obtain a powder, wherein the content of residual organic solvent in the powder is 1000 ppm or less. 46. The method according to any one of the above items 33 to 45, wherein the first' organic solvent in the above item [3]' is at least one selected from methanol, ethanol, isopropanol, normal propanol, acetone, and acetonitrile. 47. The method according to any one of the above items 33 to 46, wherein the second' organic solvent in the above item [3]' is at least one selected from methanol, ethanol, isopropanol, normal propanol, acetone, and acetonitrile.48. The method according to 46 or 47 above, wherein the first organic solvent in [3]' above is methanol or ethanol. 49. The method according to 47 or 48 above, wherein the second organic solvent in [3]' above is methanol or ethanol.

[0199] Hereinafter, the present disclosure will be described using examples, but the present disclosure is not limited to these examples. Unless otherwise specified, % indicates % by mass, and ppm indicates ppm by mass.

[0200] [Procedures of Various Analytical Methods] [Gas Chromatography (GC)] Measurement of Ethanol Concentration <Analysis Example 1: Measurement of Ethanol Concentration in 5-Aminolevulinic Acid Phosphate Powder> Ethanol standard solutions of 0.008 g / L, 0.016 g / L, 0.040 g / L, 0.080 g / L, and 0.160 g / L and a sample solution with a 5-aminolevulinic acid monophosphate concentration of 50 g / L were prepared with ion-exchange purified water, and analysis was performed under the following conditions. The ethanol peak (retention time: 1.6 minutes) was detected, and ethanol was quantified using a five-point calibration curve method from the peak area value of the standard sample.

[0201] GC analysis conditions: Instrument used: GC-2014 (Shimadzu Corporation) Hydrogen generator: HE-260 (Shimadzu Corporation) Autosampler: AOC-20s (Shimadzu Corporation) Separation column: DB-WAX (30 m x 0.530 mm x 1.0 μm, Agilent) Carrier gas: Helium Carrier gas flow rate: 25.0 mL / min Sample introduction amount: 1.0 μL Column temperature: 35.0°C Vaporization chamber temperature: 200°C Detector temperature: 230.0°C Detector: Hydrogen flame ionization detector (FID)

[0202] (Calculation of Ethanol Concentration in 5-Aminolevulinic Acid Phosphate Powder) The residual ethanol value of 5-aminolevulinic acid phosphate powder was calculated based on the calibration curve Y=AX+B obtained from the 0.008 to 0.160 g / L ethanol standard solutions.

[0203] The X-axis represents the concentration of the ethanol standard solution, the Y-axis represents the peak area value detected from each ethanol standard solution, and the slope of the calibration curve calculated is A, the intercept is B, the peak area value of ethanol in the sample solution is C, and the weighed value of 5-aminolevulinic acid phosphate powder is W. １ (g), and the volume of the 5-aminolevulinic acid hydrochloride solution is L １ (L) The concentration of ethanol in the sample solution was calculated using the following formula (I).

[0204] Ethanol content (ppm) = (C - B) / A / W １ ×L １ × 1000000... Formula (I)

[0205] [Liquid Chromatography (HPLC)] Potency The following procedure is hereinafter also referred to as "potency analytical HPLC." <Analysis Example 1: Measurement of 5-aminolevulinic acid phosphate concentration> 5-aminolevulinic acid hydrochloride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was dissolved in distilled water to prepare a 0.1 g / L 5-aminolevulinic acid phosphate standard solution. A sample solution was also prepared with distilled water so that the concentration of 5-aminolevulinic acid phosphate was 0.1 g / L. Analysis was performed under the following conditions. The 5-aminolevulinic acid phosphate peak (retention time: 22 minutes) was detected, and 5-aminolevulinic acid phosphate was quantified using a single-point calibration curve method from the peak area of ​​the standard. Similarly, the glycine peak (retention time: 9 minutes) and alanine peak (retention time: 13 minutes), which may be contained as impurities in the sample solution, were detected, and glycine and alanine were quantified using a single-point calibration curve method from the peak area of ​​the standard.

[0206] (Analytical Conditions for 5-Aminolevulinic Acid Phosphate) 5-Aminolevulinic acid phosphate, glycine, and alanine were analyzed using HPLC with a fluorescence detector under the following conditions: Separation column: YMC Triart-C18, 3 μm, 3.0 × 150 nm, manufactured by YMC Mobile phase: A 70% by volume aqueous solution of potassium hydrogen phosphate (3.325 g) and sodium lauryl sulfate (1.45 g) dissolved in 3.5 L of ion-exchange purified water, adjusted to pH 2.5 with phosphoric acid, to which MeOH was added to make a 30% by volume aqueous solution. Mobile phase flow rate: 0.5 mL / min. Reaction solution: An aqueous solution prepared by dissolving boric acid (54.0 g), sodium hydroxide (32.4 g), and Briji-35 (22%, 4.1 mL) in 2.7 L of ion-exchange purified water, and then dissolving o-phthalaldehyde (0.6 g) and N-acetylcysteine ​​(4.6 g). Reaction solution flow rate: 0.2 mL / min. Sample introduction amount: 5 μL. Column temperature: 40°C. Detector: Fluorescence detector (excitation wavelength: 360 nm, fluorescence wavelength: 440 nm).

[0207] (Calculation of the concentration of 5-aminolevulinic acid phosphate) The weighed value of 5-aminolevulinic acid hydrochloride standard (for biochemistry, standard content 98.0%+, Fujifilm Wako Pure Chemical Industries, Ltd.) was calculated by W ２ The volume of the 5-aminolevulinic acid hydrochloride solution in ion-exchange purified water as the solvent is L ２ The purity of 5-aminolevulinic acid hydrochloride was defined as P, the peak area value of the 5-aminolevulinic acid hydrochloride solution was defined as D, and the peak area value of 5-aminolevulinic acid phosphate in the sample solution was defined as E. The concentration of 5-aminolevulinic acid phosphate in the sample solution was calculated using the following formula (II).

[0208] The salt form of 5-aminolevulinic acid was corrected by setting the molecular weight of 5-aminolevulinic acid phosphate to 229.125 g / mol and the molecular weight of 5-aminolevulinic acid hydrochloride to 167.59 g / mol.

[0209] 5-aminolevulinic acid phosphate concentration in the sample solution (g / L) = W ２ / L ２× P × 229.125 ÷ 167.59 × (E / D) Formula (II) (Calculation of Glycine Concentration) The weighed value of a glycine standard (special grade reagent, standard content 99.0%+, Fujifilm Wako Pure Chemical Industries, Ltd.) was calculated by W Ｇｌｙ The volume of the glycine solution in ion-exchange purified water is L Ｇｌｙ , the peak area value of the glycine solution is D Ｇｌｙ , the peak area value of glycine in the sample solution is E Ｇｌｙ The concentration of glycine in the sample solution was calculated using the following formula (XXXa).

[0210] Glycine concentration in sample solution (g / L) = W Ｇｌｙ / L Ｇｌｙ × (E Ｇｌｙ / D Ｇｌｙ ) Formula (XXXa) (Calculation of alanine concentration) The weighed value of an alanine standard (special grade reagent, standard content 99.0%+, Fujifilm Wako Pure Chemical Industries, Ltd.) was calculated by W Ａｌａ The volume of the alanine solution in ion-exchange purified water as the solvent is L Ａｌａ , the peak area value of the alanine solution is D Ａｌａ , the peak area value of alanine in the sample solution is E Ａｌａ The concentration of alanine in the sample solution was calculated using the following formula (XXXb).

[0211] Alanine concentration in sample solution (g / L) = W Ａｌａ / L Ａｌａ × (E Ａｌａ / D Ａｌａ )...Formula (XXXb)

[0212] [Liquid Chromatography (HPLC)] PDPA <Analysis Example 1: Measurement of PDPA Content in 5-aminolevulinic acid phosphate powder> A commercially available 5-aminolevulinic acid phosphate product and a sample solution were diluted with 0.05 mol / L of aqueous HCl solution so that the concentration of 5-aminolevulinic acid phosphate became 1 g / L, and analysis was performed under the following conditions to detect a PDPA peak (retention time: 9 minutes), and the content of impurities was quantified from the peak area value by a single-point calibration curve method.

[0213] (Analysis Conditions for 5-Aminolevulinic Acid Phosphate) Analysis of 5-aminolevulinic acid phosphate was carried out using HPLC equipped with an ultraviolet-visible absorbance detector under the following conditions. Separation column: Inertsil ODS-3V (5 μm, 4.6 × 150 mm, GL-Science) Mobile phase A: 6.0 g of sodium 1-heptanesulfonate was dissolved in 5 L of ion-exchange purified water, and the pH was adjusted to 2.0 with phosphoric acid (85.0%, special reagent grade, Fujifilm Wako Pure Chemical Industries, Ltd.) Mobile phase B: acetonitrile (isocratic grade for liquid chromatography, Supelco) Mobile phase flow rate: 1.0 mL / min Sample introduction amount: 20 μL Column temperature: 25°C Detector: ultraviolet absorption detector (SPD-40, Shimadzu Corporation) Detection wavelength: 210 nm Operation was performed with the mobile phase gradient shown in Table 1X.

[0214]

[0215] Quantitation limit: Based on the PDPA peak area determined by HPLC analysis, the quantitation limit of PDPA was determined to be 10 ppm relative to the liquid volume.

[0216] (Calculation of PDPA Content in 5-Aminolevulinic Acid Phosphate) A PDPA reagent (NIPPON RIKA CO., LTD.) was dissolved in 0.05 M HCl to prepare a PDPA standard solution with a PDPA concentration of 0.01 g / L.

[0217] The area value of PDPA in each sample solution detected by HPLC was defined as A1, and the area value of a PDPA standard solution having a PDPA concentration of 0.01 g / L was defined as A2, and the PDPA concentration (g / L) in each sample solution was quantified using the following formula (X1).

[0218] PDPA concentration (g / L) = A1 / A2 x 0.01...Formula (X1)

[0219] (Calculation of PDPA concentration relative to 5-aminolevulinic acid phosphate concentration)

[0220] The concentration (g / L) of 5-aminolevulinic acid phosphate in each sample solution quantified according to the procedure shown in Analysis Example 1 above was designated as A3, and the concentration (g / L) of PDPA in each sample solution quantified according to the procedure shown in the above (Analytical conditions for 5-aminolevulinic acid phosphate) was designated as A4. The relative concentration of PDPA to the concentration of 5-aminolevulinic acid phosphate in each sample solution was calculated using the following formula (X2):

[0221] PDPA relative concentration (ppm) = A4 / A3 × 1000000 ... formula (X2)

[0222] [Liquid Chromatography (HPLC)] Impurities <Analysis Example 1: Measurement of impurity content in 5-aminolevulinic acid phosphate powder> A commercially available 5-aminolevulinic acid phosphate product and a sample solution were diluted with a mobile phase (0.1% trifluoroacetic acid / 15% acetonitrile) so that the concentration of 5-aminolevulinic acid phosphate would be 5 g / L, and analysis was performed under the following conditions. The peak of 5-aminolevulinic acid phosphate (retention time: 3 minutes) was detected, and each sample solution was diluted 100-fold to prepare a standard solution, and the impurity content was quantified from the peak area value of 5-aminolevulinic acid phosphate in the standard solution by a single-point calibration curve method.

[0223] (Analysis Conditions for 5-Aminolevulinic Acid Phosphate) Analysis of 5-aminolevulinic acid phosphate was carried out using HPLC equipped with an ultraviolet-visible absorbance detector under the following conditions. Separation column: InertSustain C18 (UP) (5 μm, 4.6 × 250 mm, GL-Science) Mobile phase: 0.1% trifluoroacetic acid / 15% acetonitrile Mobile phase flow rate: 1.0 mL / min Sample introduction amount: 50 μL Column temperature: 30°C Detector: Ultraviolet absorption detector (SPD-20A, Shimadzu Corporation) Detection wavelength: 216 nm Quantitation limit: Based on the peak area obtained by HPLC analysis, the ratio of the content of impurities to the content of 5-aminolevulinic acid or a salt thereof was 0.0005 Detection limit: Based on the peak area obtained by HPLC analysis, the ratio of the content of impurities to the content of 5-aminolevulinic acid or a salt thereof was 0.0002 Peaks below the detection limit (0.0002) were not considered to be impurities and are not listed in the table of analysis results for impurity content.

[0224] (Calculation of the Content of Impurities in 5-Aminolevulinic Acid Phosphate) The peak area of ​​5-aminolevulinic acid phosphate in the standard solution of each sample was designated as F, and the peak area of ​​each impurity quantifiable by HPLC in the sample solution was designated as G. The content ratio of each impurity quantifiable by HPLC in the sample solution was calculated using the following formula (III):

[0225] Ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof=peak area of ​​each impurity quantifiable by HPLC in a sample solution / (peak area of ​​5-aminolevulinic acid or a salt thereof in a standard solution)=G / F...Equation (III)

[0226] The total number of impurities detected in a sample was defined as N, and the total ratio I of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof was calculated by the following formula (IV): In the following formula (IV), H is the ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof.

[0227]

[0228] [Analysis of the Content of 5-Aminolevulinic Acid Phosphate or Its Salt by Potentiometric Titration] 0.3 g of potassium hydrogen phthalate that had been dried at 105°C for 4 hours was weighed into a 100 mL glass beaker. 50 mL of acetic acid was then added together with a stir bar, and the mixture was stirred to dissolve the potassium hydrogen phthalate. 50 mL of acetic acid alone with the stir bar was used as a factor blank.

[0229] 0.22 g of 5-aminolevulinic acid phosphate powder was weighed into a 100 mL glass beaker. 5 mL of formic acid was added with a stirrer bar and stirred to dissolve the 5-aminolevulinic acid phosphate powder. 50 mL of acetic acid was then added and stirred again. A blank was prepared by adding 50 mL of acetic acid to 5 mL of formic acid alone.

[0230] For the potentiometric titration, an automatic potentiometric titrator (AT-710, Kyoto Electronics Manufacturing Co., Ltd.) and a main control unit (MCU-710, Kyoto Electronics Manufacturing Co., Ltd.) were used to perform potentiometric titration on Factor Blank, potassium hydrogen phthalate, Blank, and 5-aminolevulinic acid phosphate powder samples.

[0231] The titrant was a 0.1M perchloric acid-acetic acid solution, and the sample was stirred during titration. The titration amount of FactorBlank was D ＦａｃｔｏｒＢｌａｎｋ , the titration amount of potassium hydrogen phthalate is D Ｆａｃｔｏｒ , the weighed value of potassium hydrogen phthalate is W Ｆａｃｔｏｒ The molar mass of potassium hydrogen phthalate was 204.23 g / mol, the concentration of the titrant 0.1 mol / L perchloric acid acetic acid solution was 0.1 mol / L, and the Factor value f was calculated by the following formula (V).

[0232] f = 1000 x W Ｆａｃｔｏｒ / {204.23 × 0.1 × (D Ｆａｃｔｏｒ -D ＦａｃｔｏｒＢｌａｎｋ )}...Formula (V)

[0233] The titer of Blank is D Ｂｌａｎｋ , the titer of 5-aminolevulinic acid phosphate powder is D Ｓａｍｐｌｅ , Factor value is f, and the weighed value of 5-aminolevulinic acid phosphate powder is W Ｓａｍｐｌｅ The molar mass of the 5-aminolevulinic acid phosphate powder was 229.1 g / mol, and the concentration of the titrant, a 0.1 mol / L perchloric acid acetic acid solution, was 0.1 mol / L. The content of 5-aminolevulinic acid phosphate in the 5-aminolevulinic acid phosphate powder was calculated by the following formula (VI).

[0234] Content of 5-aminolevulinic acid phosphate (%) = {(D Ｓａｍｐｌｅ -D Ｂｌａｎｋ )×229.1×0.1×f×100} / {W Ｓａｍｐｌｅ ×1000}...Formula (VI)

[0235] [Transmittance of light at a wavelength of 430 nm] Procedure for measuring color: 1 g of 5-aminolevulinic acid phosphate was precisely weighed out, and a sample solution was prepared with ion-exchange purified water to a concentration of 100 g / L (C = 10), and filtered with a syringe filter (Merck Millipore, MillEX-LH, PTFE membrane, pore diameter: 0.45 μm). The filtered sample was poured into a quartz cell, and the absorbance at a wavelength of 430 nm was measured using a double-beam spectrophotometer (Hitachi, U-3900H). Ion-exchange purified water was used as a reference for the spectrophotometer.

[0236] (Calculation of concentration from weighed value of 5-aminolevulinic acid phosphate powder) The weighed value of 5-aminolevulinic acid phosphate powder was calculated as W ３ (approximately 1 g), and the volume of the 5-aminolevulinic acid hydrochloride solution was adjusted to L ３ The concentration of 5-aminolevulinic acid phosphate, C (g / L), was calculated by the following formula (i).

[0237] C=W ３ / L ３ × 1000... Formula (i)

[0238] (Calculation of absorbance of light at a wavelength of 430 nm from 5-aminolevulinic acid phosphate powder) The concentration of 5-aminolevulinic acid phosphate is C, the absorbance is Abs, and the absorbance of Blank (ion-exchange purified water) is Abs Ｂｌａｎｋ The concentration of 5-aminolevulinic acid phosphate in the sample solution was calculated using the following formula (ii).

[0239] Abs １００ｇ／Ｌ = Abs / C × 100... formula (ii)

[0240] (Calculation of light transmittance at a wavelength of 430 nm from the absorbance of 5-aminolevulinic acid phosphate powder) The concentration of 5-aminolevulinic acid phosphate is C, the absorbance is Abs, and the absorbance of Blank (ion-exchange purified water) is Abs Ｂｌａｎｋ The concentration of 5-aminolevulinic acid phosphate in the sample solution was calculated using the following formula (iii).

[0241]

[0242] [Inductively Coupled Plasma Mass Spectrometry (ICP-MS)] Arsenic <Analysis Example 1: Measurement of Residual Metal Concentration in 5-aminolevulinic Acid Phosphate Solution> The concentration of each metal element in a 5-aminolevulinic acid phosphate solution was quantified from a calibration curve prepared from the intensity of each metal element in the 5-aminolevulinic acid phosphate solution and a metal element standard solution. The residual metal concentration analysis for one sample was performed three times (n=3), and the concentration of each metal element in each sample was quantified and the average value was calculated.

[0243] ICP-MS analysis conditions: Instrument used: Agilent 7900 (Agilent Technologies) Autosampler: G8410A (Agilent Technologies) Quantitation limit: The content of each residual metal concentration is 0.25 ppm based on the concentration of 5-aminolevulinic acid phosphate determined by HPLC analysis.

[0244] Description of standard material: General-purpose mixed standard solution (XSTC-13B) (manufactured by Spex Cetiprep) containing 10 mg / L of arsenic (As).

[0245] (Calculation of Residual Metal Concentration in 5-Aminolevulinic Acid Phosphate Solution) The residual metal concentration in the 5-aminolevulinic acid phosphate solution was calculated from the calibration curve obtained from the metal standard solution and the ICP-MS intensity of each metal element detected from the 5-aminolevulinic acid phosphate solution.

[0246] Intensity for ICP-MS in this disclosure is counts per second (counts per second).

[0247] Preparation of Diluted Solution 66 mL of nitric acid and 10 mL of hydrochloric acid were added to 500 mL of ion-exchanged purified water, and ion-exchanged purified water was added to make 1000 mL to prepare a diluted solution.

[0248] Preparation of Metal Standard Solutions (Calibration Curve Solutions for Ag / Al / As, etc.) Calibration Curve Solution 1 (BLANK): Diluted solution only (As concentration: 0 μg / mL) Calibration Curve Solution 2: Measure 0.5 mL of the general-purpose mixed standard solution and add 9.5 mL of dilution solution to make 10 mL (As concentration: 500 μg / L) Calibration Curve Solution 3: Measure 0.25 mL of the general-purpose mixed standard solution and add 9.75 mL of dilution solution to make 10 mL (As concentration: 250 μg / L) Calibration Curve Solution 4: Measure 0.1 mL of the general-purpose mixed standard solution and add 9.9 mL of dilution solution to make 10 mL (As concentration: 100 μg / L) Calibration Curve Solution 5: Measure 1.0 mL of the calibration curve solution 4 and add 9.0 mL of dilution solution to make 10 mL. (As concentration: 10 μg / L) Calibration solution 6: 0.5 mL of calibration solution 4 was measured and 9.5 mL of diluent was added to make 10 mL (As concentration: 5 μg / L).

[0249] Preparation of sample solution 3.0 mL of the 5-aminolevulinic acid phosphate solution was taken, and 0.21 mL of nitric acid and 5.79 mL of diluent were added to make 9 mL of sample solution.

[0250] Calibration curve solutions with metal concentrations of 0, 5.0, 10, 100.0, 250.0, and 500.0 μg / L were measured by ICP-MS to create a calibration curve Y=AX+B.

[0251] The sample solution was measured using ICP-MS, and the intensity Ix1 (arb. unit) of each metal in the sample solution was used as Yx1 on the calibration curve, and the measured concentration Xx1 (ppb) of the same metal element was calculated. The concentration Inx1 of each metal element in the blank was also measured in the same way, and the concentration of each metal element in the blank (noise intensity, ppb) was calculated from the intensity. The calculated concentrations of each metal element for n=3 samples were averaged.

[0252] The concentration of each metal element was calculated using the following formula (X): In formula (X), f is the concentration of each element (1 μg / mL) when the general-purpose mixed standard solution is diluted 10 times.

[0253] 1 Metal element concentration Cmetx1 (ng / mL) = [Measured concentration Xx1 (ppb) × f - Concentration in sample blank Inx1 (ppb)] × [Amount of sample solution adjusted for ICP-MS (9 mL) / Original sample amount (3 mL)] ... Formula (X)

[0254] The concentration (ppm) of each metal element relative to the concentration of 5-aminolevulinic acid phosphate in the sample was calculated using the calculated concentration of one element Cmetx1 (ng / mL) and the concentration of 5-aminolevulinic acid phosphate Calv (g / L) in the 5-aminolevulinic acid phosphate salt solution according to formula (X2).

[0255] 1 Metal element concentration Cmet1 (ng / mL) / Calv (g / L)...Formula (X2)

[0256] Test Example 1: Production of powder with a high content of 5-aminolevulinic acid phosphate Preparation Example 1 Preparation Example 1 is an example. [1] Preparation process of crystallization stock solution (Step 0) 5-aminolevulinic acid was produced by fermentation using recombinant Corynebacterium glutamicum according to the method disclosed in Japanese Patent Application Laid-Open No. 2005-333907, and then sulfuric acid was added to adjust the pH to 2.88 to inactivate the 5-aminolevulinic acid-producing bacteria, thereby obtaining 60.0 L of a culture solution containing 45.4 g / L of 5-aminolevulinic acid.

[0257] Crossflow filter (0.1 μm filter, membrane area 0.35 m ２ The inactivated bacterial cells (biomass) were separated from the culture medium using a filter (manufactured by PALL) to obtain 150.1 L of a solution containing 17.3 g / L of 5-aminolevulinic acid (referred to as solution A).

[0258] In Preparation Example 1, the prepared solution A was subjected to the following first, second and third steps of ion exchange chromatography.

[0259] (First step) In the first step, Na ＋ Solution A was passed through and adsorbed onto UBK04 (24.935 L, DIAION™, manufactured by Mitsubishi Chemical Corporation), a type of strongly acidic cation exchange resin, at 25° C. or lower and an SV of 0.682 RV / h. Subsequently, the UBK04 was washed with 37.4 L of purified ion-exchange water.

[0260] 0.5±0.1 mol / L NaOH was passed through UBK04 to elute the adsorbed components. While measuring the Brix and pH at the UBK04 outlet during elution, the UBK04 permeate (referred to as Solution B) was passed through WK40L in the second step when the Brix reached 5.0±1.0%. Thereafter, when the pH at the UBK04 outlet reached 12.0, passing through WK40L was stopped.

[0261] (Second step) Next, H ＋ 3.74 L of WK40L [DIAION (trademark) manufactured by Mitsubishi Chemical Corporation], a weakly acidic cation exchange resin of the type, was used, and the solution B was passed through WK40 under the condition of SV 4.545 RV / h.

[0262] While measuring the Brix at the outlet of the WK40 resin tower, the liquid passing through the WK40 resin tower was collected when the Brix reached 2.0%. When solution B was depleted, the liquid was flushed with ion-exchanged purified water, and when the Brix reached 1.0% again and the cumulative amount of liquid passing through the tower reached 16.3 L, the liquid passing through the WK40 resin tower was collected and designated solution C.

[0263] (Third Step) Furthermore, using 5.44 L of acetate-type strongly basic anion exchange resin PA412 [DIAION (trademark), manufactured by Mitsubishi Chemical Corporation], the above solution C adjusted to 12±3°C was passed through a PA412 resin tower under the condition of SV 1.042 RV / h. While measuring the Brix at the outlet of the PA412 resin tower, collection of the PA412 passed liquid was started when the Brix reached 0.2 mass%.

[0264] When solution C was exhausted, the solution was washed with ion-exchanged purified water, and when the Brix again reached 1.0% and the cumulative amount of liquid passing through the column reached 6.6 L, 59.0 L of the PA412 passing liquid was recovered into a container with an internal stirring while being cooled to 13°C, and this solution was named solution D. During recovery, solution D was cooled to 13.0°C.

[0265] (Fourth step) While adjusting the temperature of Solution D to 25°C or less, add phosphoric acid (H ３ P.O. ４, 75% by mass) was added to adjust the pH to 2.5 to 3.0, and 5-aminolevulinic acid was converted into 5-aminolevulinic acid phosphate (this was designated Solution E). Solution D after the pH adjustment was concentrated at 40°C or lower, and 3.48 L of a concentrate containing 627.7 g / L of 5-aminolevulinic acid was recovered and designated as a concentrate (crystallization stock solution).

[0266] The above crystallization stock solution was introduced into a crystallization tank, and the temperature of the crystallization stock solution was adjusted to 17°C. Primary methanol (MeOH) was added to the crystallization tank at a rate of 0.8 v / v / h in an amount of 0.6 v / v relative to the volume of the crystallization stock solution, and the crystallization stock solution and the primary MeOH were mixed by stirring. While adjusting the solution temperature to 17°C, 0.33 g of seed crystals was added, and the mixture was aged for 2 hours with stirring. As the seed crystals, 5-aminolevulinic acid phosphate powder having the powder X-ray diffraction spectrum pattern obtained in Example 1 of Japanese Patent No. 4989153 (Patent Document 4) was used.

[0267] After the concentration was completed, 2.4 v / v MeOH was added at a rate of 0.8 v / v / h relative to the volume of the crystallization stock solution, and the crystallization stock solution and the second MeOH were mixed by stirring. While controlling the solution temperature at 17±3°C, stirring was continued for 2 hours from the end of the second MeOH addition to obtain a slurry of 5-aminolevulinic acid phosphate crystals.

[0268] The crystal slurry was centrifuged to filter out the 5-aminolevulinic acid crystals, which were then washed at room temperature with 100% MeOH in an amount of 1.0 v / w based on the weight of the wet crystals to obtain 1952.5 g of wet crystals.

[0269] Comparative Example 1-1 Comparative Study of Example 1 of Japanese Patent No. 4989153 (Patent Document 4) 4.67 g of 5-aminolevulinic acid hydrochloride (27.92 mmol, content 100.14%, Hamari Chemical Industry Co., Ltd.) and 3.576 g (31.33 mmol) of 85% by mass phosphoric acid were dissolved in 14 g of distilled water, and 2.970 g (29.35 mmol) of triethylamine was added dropwise to the solution while stirring at 0 to 5°C.

[0270] After the dropwise addition was completed, the mixture was stirred at room temperature for 30 minutes, and then 14.75 g of ethanol was added. In this state, 1.01 mg of 5-aminolevulinic acid phosphate crystals (obtained in Example 3 described below) was added, and gentle stirring was continued, whereupon colorless, transparent crystals began to slowly precipitate.

[0271] After stirring for approximately 30 minutes, an additional 59.07 g of ethanol was added, and stirring was continued for 2 hours to completely precipitate crystals. The crystals were collected by suction filtration (three sheets of 5C, φ55 mm, ADVANTEC filter paper) and dried under reduced pressure at room temperature for 16 hours. 5.015 g of 5-aminolevulinic acid phosphate powder was obtained.

[0272] Comparative Example 1-2 Comparative Study of Example 2 in JP 2007-238577 A 40 g (239 mmol, content 100.14%, Hamari Chemical Industry Co., Ltd.) of 5-aminolevulinic acid hydrochloride and 18 mL (263 mmol) of 85% phosphoric acid were dissolved in 120 mL of purified water, and 25.4 g (251 mmol) of triethylamine was added dropwise to the solution while stirring in an ice bath.

[0273] After the dropwise addition was completed, the mixture was stirred at room temperature for 10 minutes, and then 1.6 L of ethanol was added and stirred. The precipitate was collected by suction filtration (filter paper: 5C, φ55 mm, ADVANTEC *3 sheets) and dried under reduced pressure at room temperature for 16 hours. 50.62 g (224 mmol) of 5-aminolevulinic acid phosphate powder was obtained.

[0274] [Comparative Examples 1-3] <Comparative study with Example 1 of Japanese Patent No. 5845203 (Patent Document 5)> A strongly acidic cation exchange resin (UBK08, manufactured by Nippon Rensui Co., Ltd.) was packed into a 20 mL column. The cation exchange resin was used after passing 1 N hydrochloric acid (4 RV) through it to convert it from sodium ion form to hydrogen ion form. The flow rate was 0.0115 L / h, and SV was 0.568 RV / h.

[0275] A solution of 4 g of 5-aminolevulinic acid hydrochloride (content 100.14%, Hamari Pharmaceutical Co., Ltd.) dissolved in 200 mL of ion-exchanged purified water was passed through the column, followed by ion-exchanged purified water (2 RV). Next, 0.5 N aqueous ammonia (8 RV) was slowly passed through the column, and 92 mL of eluate was obtained while cooling in a thermostatic bath at 6°C.

[0276] A system in which 13.8 mL of 15% aqueous phosphoric acid solution was added to the beaker for collecting the eluate is designated Comparative Example 1-3a. A system in which 12.8 mL of 15% aqueous phosphoric acid solution was added is designated Comparative Example 1-3b. The 15% aqueous phosphoric acid solution was stirred with a magnetic stirrer while the system was left on standby, and the eluate was collected.

[0277] After passing activated carbon (SG280P, 0.0035 g, 0.07% relative to 5-aminolevulinic acid phosphate) through the solution, the solution was concentrated to a volume of 9 mL (Comparative Example 1-3a) or 8 mL (Comparative Example 1-3b) using an evaporator.

[0278] While cooling in a thermostatic bath at 6° C., 16 mL of ethanol was added to the concentrated solution, which was then vigorously stirred with a stirrer and allowed to stand overnight at 4° C. The precipitated solid was collected by suction filtration using Omnipore (registered trademark) Membrane Filters (0.45 μm JH, Millipore) and washed with 100 mL of ethanol.

[0279] The obtained solid was dried under reduced pressure at room temperature for 24 hours to obtain 5.6179 g (Comparative Example 1-3a) or 6.6169 g (Comparative Example 1-3b) of 5-aminolevulinic acid phosphate powder.

[0280] <Analysis of Residual Ethanol in Powders Obtained in Comparative Studies> The results of measuring the residual ethanol in the powders obtained in Comparative Examples 1-1 to 1-3 are shown in Table 1A.

[0281]

[0282] As shown in Table 1A, residual ethanol exceeding 1000 ppm was detected in all samples.

[0283] <Analysis of impurities in powders obtained in comparative examples> The impurity contents in the powders obtained in comparative examples 1-1 to 1-3 were determined by HPLC analysis based on the above formula (III). The results are shown in Table 1B.

[0284] In Table 1B, the numerical values ​​represent the "ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate." In Table 1B, RT stands for Retention time, and ND stands for Not Detected.

[0285]

[0286] As shown in Table 1B, one or more impurities were detected in all samples, with the ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof exceeding 0.0005. Furthermore, in some samples, the total ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof exceeded 0.0015.

[0287] <Analysis of impurities in powders used as raw materials in comparative examples> The impurity contents in the 5-aminolevulinic acid phosphate powders used as raw materials in comparative examples 1-1 to 1-3 were determined by HPLC analysis based on the above formula (III). The results are shown in Table 1C.

[0288] In Table 1C, the numerical values ​​represent the "ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate." In Table 1C, RT stands for Retention time, and ND stands for Not Detected.

[0289]

[0290] As shown in Table 1C, the number of impurities detected in the 5-aminolevulinic acid phosphate powder used as the raw material in Comparative Examples 1-1 to 1-3 and the total ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof (0.0064) were clearly lower than those in Comparative Examples 1-1 to 1-3.

[0291] The majority of impurities detected in the powders of Comparative Examples 1-1 to 1-3 are presumed to have been produced by contamination from chemicals added during the production process of 5-aminolevulinic acid crystals, or by denaturation of 5-aminolevulinic acid due to heat load in a reduced-pressure heating concentration process, etc. Therefore, the production method of the present disclosure can be said to be useful because it removes impurities as much as possible from powders containing 5-aminolevulinic acid or a salt thereof.

[0292] Example 1-1 <Study on the amount of first organic solvent and the amount of second organic solvent> [1] Preparation of crystallization stock solution 5-aminolevulinic acid phosphate powder obtained under the same conditions as in Preparation Example 1 above was dissolved in ion-exchange purified water to prepare 15.0 L of a 333 g / L solution of 5-aminolevulinic acid phosphate.

[0293] The concentration of the 5-aminolevulinic acid phosphate solution was measured by titer analysis HPLC. ＋ Using 6.0 L of a chelating resin Lewatit (registered trademark) TP260 (manufactured by LANXESS), the 5-aminolevulinic acid phosphate solution was passed through TP260, and when the Brix reached 1.0 mass %, the resin column passing liquid was collected.

[0294] Thereafter, when the 5-aminolevulinic acid phosphate solution was exhausted, the solution was washed with deproteinized ion-exchange purified water, and when the Brix value again reached 1.0 mass%, the collection of the resin tower effluent was terminated. Molecules with a molecular weight of 6,000 or more, such as proteins, which may be contained in the collected resin tower effluent were removed using an ultrafiltration membrane.

[0295] The ultrafiltration permeate was introduced into a recovery flask, and the recovery flask containing the ultrafiltration permeate was heated in a thermostatic bath controlled at 60° C., while being concentrated for 10 hours in an evaporator with an internal pressure of 65 hPa. The concentration of 5-aminolevulinic acid phosphate after concentration was 500 g / L, and this solution is hereinafter referred to as a crystallization stock solution.

[0296] [2] The crystallization stock solution obtained in [1] was introduced into a crystallization tank for adjusting the temperature of the crystallization stock solution, and the temperature of the crystallization stock solution was adjusted to 20°C.

[0297] [3] In the crystallization step of adding a first organic solvent to the crystallization stock solution obtained in [2] to precipitate 5-aminolevulinic acid or a salt thereof, ethanol (EtOH), a poor solvent for 5-aminolevulinic acid phosphate, was added to the crystallization stock solution in a primary (first organic solvent) and secondary (second organic solvent) portions. The total amount of ethanol (EtOH) added from the primary to secondary portions was 2.0 v / v relative to the volume of the crystallization stock solution. The primary EtOH was added to the crystallization tank in amounts of 0.4, 0.6, 0.8, and 1.0 v / v relative to the volume of the crystallization stock solution, and the crystallization stock solution and the primary EtOH were mixed by stirring.

[0298] 0.07 mass % of 5-aminolevulinic acid phosphate powder (seed crystals) relative to the volume of the crystallization stock solution at the time of completion of concentration (before the addition of the primary EtOH) was added to a mixed solution of the crystallization stock solution and the primary EtOH, and the mixture was stirred while controlling the temperature of the crystallization stock solution at 20°C, and aged for 10 minutes with stirring.

[0299] [4] Step of adding a second organic solvent to the crystallization stock solution: Secondary EtOH was added at a rate of 0.5 v / v / h in an amount of (2.0 - amount of primary EtOH added) v / v relative to the volume of the crystallization stock solution at the time of completion of concentration, and the mixture and secondary EtOH were mixed by stirring. Stirring was continued for 2 hours after completion of the addition of secondary EtOH, and 5-aminolevulinic acid phosphate was crystallized from the mixture. This solution is hereinafter referred to as crystallization slurry.

[0300] [5] Step of separating crystals The wet crystals of 5-aminolevulinic acid phosphate in the crystallization slurry were separated from the mother liquor by centrifugation, and then EtOH was added to the wet crystals of 5-aminolevulinic acid phosphate in the centrifuge to wash the wet crystals of 5-aminolevulinic acid phosphate, and the wet crystals of 5-aminolevulinic acid phosphate were recovered in an eggplant flask.

[0301] The wet crystals of 5-aminolevulinic acid phosphate were placed in a tray dryer (AVO-310V, AS ONE). The internal temperature of the tray dryer was set to 30°C, and the inside of the tray dryer was evacuated until the pressure gauge attached to the tray dryer reached -0.1 MPa or less, and the wet crystals of 5-aminolevulinic acid phosphate were dried. The residual solvent content in the 5-aminolevulinic acid phosphate powder was analyzed by gas chromatography (GC). The results are shown in Table 1 and Figure 1.

[0302]

[0303] As shown in Table 1 and FIG. 1, when the primary EtOH addition amount was 0.4 v / v, the residual EtOH in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0304] [Example 1-2] <Investigation of Crystallization Temperature> A crystallization stock solution of 5-aminolevulinic acid phosphate was prepared in the same manner as in [Example 1-1] up to the concentration stage, and 5-aminolevulinic acid phosphate powder was prepared by adjusting the solution temperature during crystallization (crystallization temperature) to 5, 10, 15, 25, or 30°C, and the residual solvent level in the 5-aminolevulinic acid phosphate powder was analyzed by gas chromatography.

[0305] Since the seed crystals dissolved at crystallization temperatures of 25° C. and 30° C., the amount of primary EtOH added was changed to 0.4 v / v at 5 to 20° C., 0.5 v / v at 25° C., and 0.7 v / v at 30° C. The results are shown in Table 2 and Figure 2.

[0306]

[0307] As shown in Table 2 and FIG. 2, by carrying out crystallization under conditions where the crystallization temperature was 15 to 25° C., the residual EtOH in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0308] [Example 1-3] <Study on Secondary EtOH Addition Rate> A crystallization stock solution of 5-aminolevulinic acid phosphate was prepared using the same procedures as in [Example 1-1] up to the concentration stage, and 5-aminolevulinic acid phosphate powder was prepared by changing the secondary EtOH addition rate during crystallization to 0.1, 0.3, 0.5, 0.7, or 1.0 v / v / h, and the residual solvent level in the 5-aminolevulinic acid phosphate powder was analyzed by gas chromatography. The results are shown in Table 3 and FIG. 3.

[0309]

[0310] As shown in Table 3 and FIG. 3, by performing crystallization under conditions where the secondary EtOH addition rate was 0.5 v / v / h or more, the residual EtOH in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0311] [Example 1-4] <Study 1 on Crystallization Temperature When the Concentration of the Crystallization Stock Solution is 600 g / L> A crystallization stock solution of 5-aminolevulinic acid phosphate was prepared using the same procedures as in [Example 1-1] up to the concentration stage, and the concentration of the crystallization stock solution was increased from 500 g / L to 600 g / L, and the crystallization temperature was set to 10, 20, or 30°C to prepare a 5-aminolevulinic acid phosphate powder. The residual solvent level in the 5-aminolevulinic acid phosphate powder was analyzed by gas chromatography.

[0312] When the concentration of the crystallization stock solution is 600 g / L and the crystallization temperature is 30° C., the seed crystals do not dissolve if the primary EtOH addition amount is 0.3 v / v, so the primary EtOH addition amount was set to 0.3 v / v even at 10° C. and 20° C. The results are shown in Table 4.

[0313]

[0314] As shown in Table 4, when the crystallization temperature was 10°C or 20°C, the residual EtOH in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0315] [Example 1-5] <Study 2 on Crystallization Temperature When the Concentration of the Crystallization Stock Solution is 600 g / L> A crystallization stock solution of 5-aminolevulinic acid phosphate was prepared using the same procedures as in [Example 1-1] up to the concentration stage, and a 5-aminolevulinic acid phosphate powder was prepared by adjusting the concentration of the crystallization stock solution to 600 g / L and setting the crystallization temperatures to 5°C and 25°C, and the residual solvent level in the 5-aminolevulinic acid phosphate powder was analyzed by gas chromatography.

[0316] It was confirmed that the seed crystals did not dissolve under conditions where the primary EtOH addition rate was 0.1 v / v or more at 25° C., and therefore the primary EtOH addition rate was set to 0.1 v / v even at 5° C. The results are shown in Table 5.

[0317]

[0318] As shown in Table 5, under both conditions of crystallization at a crystallization temperature of 5°C and 25°C, the residual EtOH in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0319] Example 1-6 Study on Crystallization Temperature When the Concentration of the Crystallization Stock Solution is 650 g / L A crystallization stock solution of 5-aminolevulinic acid phosphate was prepared using the same procedures as in Example 1-1 up to the concentration stage, and a 5-aminolevulinic acid phosphate powder was prepared by adjusting the concentration of the crystallization stock solution to 650 g / L and setting the crystallization temperatures to 5° C. and 25° C. The residual solvent level in the 5-aminolevulinic acid phosphate powder was analyzed by gas chromatography. The results are shown in Table 6.

[0320]

[0321] As shown in Table 6, when the crystallization temperature was set at 5° C., the residual EtOH in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0322] [Example 1-7] <Study on the amount of seed crystals added> A crystallization stock solution of 5-aminolevulinic acid phosphate was prepared in the same manner as in [Example 1-1] up to the concentration stage, and 0, 0.07, 0.21, or 0.5 mass% of seed crystals were added during crystallization to prepare 5-aminolevulinic acid phosphate powder, and the residual solvent level in the 5-aminolevulinic acid phosphate powder was analyzed by gas chromatography. The results are shown in Table 7.

[0323]

[0324] As shown in Table 7, even without the addition of seed crystals, the residual EtOH in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0325] Example 2-1: Examination of the concentration of the crystallization stock solution when the concentration of the crystallization stock solution after decolorization with activated carbon was set to 535, 560, or 585 g / L. [1] Preparation of crystallization stock solution: 5-aminolevulinic acid phosphate powder was prepared using the same method as in Preparation Example 1. The 5-aminolevulinic acid phosphate powder was dissolved in ion-exchange purified water to prepare two 9.985 L sets of 5-aminolevulinic acid phosphate solutions with a concentration of approximately 380 g / L. The concentration of the 5-aminolevulinic acid phosphate solutions was measured using a titer analytical HPLC.

[0326] Two sets of 137 g of activated carbon (Taiko S) were added, and the solution was decolorized for 3 hours while maintaining the temperature at 15°C. Thereafter, the activated carbon was removed from the 5-aminolevulinic acid phosphate solution, and the decolorized filtrate was collected and mixed to form one set. ＋ 9.0 L of a chelate resin Lewatit (registered trademark) TP260 (manufactured by LANXESS) of the type was used. While measuring the Brix at the outlet of the resin tower, the decolorized filtrate was passed through TP260, and when the Brix reached 1.0 mass %, the resin tower passing liquid was collected.

[0327] Thereafter, when the 5-aminolevulinic acid phosphate solution was exhausted, the solution was washed with ion-exchange purified water, and when the Brix again reached 1.0 mass%, collection of the resin tower filtrate was terminated. Molecules with a molecular weight of 6,000 or more, such as proteins, which may be contained in the collected resin tower filtrate were removed using an ultrafiltration membrane to obtain the ultrafiltration filtrate.

[0328] The ultrafiltration permeate was introduced into a recovery flask, and while the recovery flask containing the ultrafiltration permeate was heated in a thermostatic bath controlled at 65°C, the solution was concentrated for 18 hours in an evaporator with an internal pressure of 70 hPa. Through concentration, the concentrations of 5-aminolevulinic acid phosphate were adjusted to 330 mL for 535 g / L, 316 mL for 560 g / L, or 302 mL for 585 g / L, respectively. Hereinafter, these solutions are referred to as the crystallization stock solution.

[0329] [2] The crystallization stock solution obtained in [1] was introduced into a crystallization tank for adjusting the temperature of the crystallization stock solution, and the temperature of the crystallization stock solution was adjusted to 15°C.

[0330] [3] A step of adding a first organic solvent to the crystallization stock solution obtained in [2] to precipitate 5-aminolevulinic acid or a salt thereof. Primary EtOH was added to the crystallization tank at a volume of 0.3 v / v relative to the volume of the crystallization stock solution, and the crystallization stock solution and the primary EtOH were mixed by stirring. 0.125 g of 5-aminolevulinic acid phosphate crystal powder was added to the crystallization stock solution as seed crystals, and the crystallization stock solution was aged for 10 minutes with stirring while controlling the temperature of the crystallization stock solution at 15°C.

[0331] [4] Step of adding a second organic solvent to the crystallization stock solution: EtOH was added at a rate of 0.7 v / v / h in an amount of 1.7 v / v relative to the volume of the crystallization stock solution at the time of completion of concentration (before the addition of the first EtOH), and the crystallization stock solution and the second EtOH were mixed by stirring. Stirring was continued for 2 hours after the completion of the addition of the second EtOH, and 5-aminolevulinic acid phosphate was crystallized from the mixed solution to obtain a crystal slurry.

[0332] [5] Step of separating crystals The crystal slurry was centrifuged to separate the wet crystals of 5-aminolevulinic acid phosphate into solid and liquid, and then 100% EtOH was added to the wet crystals of 5-aminolevulinic acid phosphate in an amount of 1.0 v / w relative to the weight of the wet crystals to wash the wet crystals of 5-aminolevulinic acid phosphate in the centrifuge, and the wet crystals of 5-aminolevulinic acid phosphate were recovered in an eggplant flask.

[0333] The recovery flask containing the wet crystals of 5-aminolevulinic acid phosphate was heated in a thermostatic bath controlled at 30°C, while the wet crystals of 5-aminolevulinic acid phosphate were dried at room temperature for 5 hours in an evaporator with an internal pressure of 53 hPa. The residual solvent content in the 5-aminolevulinic acid phosphate powder was analyzed by gas chromatography. The results are shown in Table 8.

[0334]

[0335] As shown in Table 8, when crystallization was carried out at a concentration of 535 to 585 g / L of the crystallization stock solution in terms of 5-aminolevulinic acid monophosphate, the residual EtOH in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0336] The impurity contents of the 5-aminolevulinic acid phosphate powder prepared in Example 2-1 were determined by HPLC analysis based on the above formula (III). The results are shown in Table 9.

[0337] In Table 9, the numerical values ​​represent the "ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate." In Table 9, RT stands for Retention time, and ND stands for Not Detected.

[0338]

[0339] As shown in Table 9, at any concentration of the crystallization stock solution, the ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate mixed in the 5-aminolevulinic acid phosphate powder was 0.0005 or less, and the total ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate was 0.0015 or less. On the other hand, impurities whose content ratio of each impurity to the content of 5-aminolevulinic acid phosphate exceeded 0.0005 were detected in products on the market.

[0340] Example 2-2: Examination of Crystallization Temperature When the Concentration of the Crystallization Stock Solution After Decolorization with Activated Carbon Was 535 or 585 g / L A crystallization stock solution of 5-aminolevulinic acid phosphate was prepared in the same manner as in Example 2-1 before concentration and after centrifugation, and 5-aminolevulinic acid phosphate powder was prepared by setting the crystallization temperature at 5, 15, or 25° C. The residual solvent level in the 5-aminolevulinic acid phosphate powder was analyzed by gas chromatography. The results are shown in Table 10.

[0341]

[0342] As shown in Table 10, under all conditions, the residual EtOH value in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0343] The impurity contents in the 5-aminolevulinic acid phosphate powder prepared in Example 2-2 were determined by HPLC analysis based on the above formula (III). The results are shown in Table 11.

[0344] In Table 11, the numerical values ​​represent the "ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate." In Table 11, RT stands for Retention time, and ND stands for Not Detected.

[0345]

[0346] As shown in Table 11, under the condition that the crystallization temperature was 15°C or higher, at both crystallization solution concentrations of 535 and 585 g / L calculated as 5-aminolevulinic acid monophosphate, no impurities were detected in the 5-aminolevulinic acid phosphate powder such that the ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate exceeded 0.0005, and the total ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate was 0.0015 or less.

[0347] When the crystallization temperature was 5°C, at a concentration of both crystallization stock solutions of 535 g / L calculated as 5-aminolevulinic acid monophosphate, the ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate mixed into the 5-aminolevulinic acid phosphate powder was 0.0005 or less, and the total ratio of the content of each impurity to the content of 5-aminolevulinic acid was 0.0015 or less. On the other hand, impurities whose ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate exceeded 0.0005 were detected in products distributed on the market.

[0348] Example 2-3: Examination of the secondary EtOH addition rate when the concentration of the crystallization stock solution after decolorization with activated carbon was 560 g / L. A crystallization stock solution of 5-aminolevulinic acid phosphate was prepared using the same procedures as in Example 2-1 before concentration and after centrifugation, and 5-aminolevulinic acid phosphate powder was prepared by changing the secondary EtOH addition rate during crystallization to 0.4, 0.7, or 1.0 v / v / h, and the residual solvent level in the 5-aminolevulinic acid phosphate powder was analyzed by gas chromatography. The results are shown in Table 12.

[0349]

[0350] As shown in Table 12, under all conditions, the residual EtOH value in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0351] Example 2-4: Examination of Crystallization Concentration When the Concentration of the Crystallization Stock Solution After Decolorization with Activated Carbon Was 520 g / L or 560 g / L A crystallization stock solution of 5-aminolevulinic acid phosphate was prepared in the same manner as in Example 2-1 before concentration and after centrifugation, and 5-aminolevulinic acid phosphate powder was prepared by crystallization at a concentration of 520 g / L or 600 g / L calculated as 5-aminolevulinic acid monophosphate. The residual solvent content of the 5-aminolevulinic acid phosphate powder was analyzed by gas chromatography. The results are shown in Table 13.

[0352]

[0353] As shown in Table 13, under all conditions, the residual EtOH value in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0354] The impurity contents of the 5-aminolevulinic acid phosphate powder prepared in Example 2-4 were determined by HPLC analysis based on the above formula (III). The results are shown in Table 14.

[0355] In Table 14, the numerical values ​​represent the "ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate." In Table 14, RT stands for Retention time, and ND stands for Not Detected.

[0356]

[0357] As shown in Table 14, at any concentration of the crystallization stock solution, the ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate mixed in the 5-aminolevulinic acid phosphate powder was 0.0005 or less, and the total ratio of the content of each impurity to the content of 5-aminolevulinic acid was 0.0015 or less. On the other hand, impurities whose ratio of the content of each impurity to the content of 5-aminolevulinic acid exceeded 0.0005 were detected in products on the market.

[0358] Example 2-5: Study on the amount of primary EtOH added when the concentration of the crystallization stock solution after decolorization with activated carbon was 560 g / L. A crystallization stock solution of 5-aminolevulinic acid phosphate was prepared using the same procedures as in Example 2-1 before concentration and after centrifugation, and the amount of primary EtOH added was increased from 0.3 v / v to 0.35 v / v to prepare 5-aminolevulinic acid phosphate powder. The residual solvent level in the 5-aminolevulinic acid phosphate powder was analyzed by gas chromatography. The results are shown in Table 15.

[0359]

[0360] As shown in Table 15, under all conditions, the residual EtOH value in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0361] Example 2-6: Study on Aging Time After Addition of Seed Crystals When the Concentration of the Crystallization Stock Solution After Decolorization with Activated Carbon Was 560 g / L A crystallization stock solution of 5-aminolevulinic acid phosphate was prepared in the same manner as in Example 2-1 before concentration and after centrifugation, and 5-aminolevulinic acid phosphate powder was prepared by adjusting the aging time from the addition of seed crystals to 10, 120, 180, 240, or 360 minutes, and the residual solvent level in the 5-aminolevulinic acid phosphate powder was analyzed by gas chromatography. The results are shown in Table 16 and FIG. 4.

[0362]

[0363] As shown in Table 16 and Figure 4, the residual EtOH value in the 5-aminolevulinic acid phosphate powder increased with an increase in the aging time from the addition of seed crystals. When the aging time was 240 minutes or less, the residual EtOH value in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0364] [Analysis of Impurities in Company A Product 2 and Company B Product 2] [Reference Test Example 1-1] The contents of impurities in Company A Product 2 and Company B Product 2 were determined by HPLC analysis based on the above formula (III). The results are shown in Table 17.

[0365] In Table 17, the numerical values ​​represent the "ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate." In Table 17, RT stands for Retention time, and ND stands for Not Detected.

[0366]

[0367] As shown in Table 17, impurities were detected in all commercially available products, with the ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate exceeding 0.0005.

[0368] [Example 3] [1] Preparation of Crystallization Stock Solution 5-aminolevulinic acid phosphate powder was prepared by the same method as in Preparation Example 1. The 5-aminolevulinic acid phosphate powder was dissolved in ion-exchange purified water to prepare 2220 mL of a 5-aminolevulinic acid phosphate solution having a concentration of 441.3 g / L in terms of 5-aminolevulinic acid monophosphate. The concentration of the 5-aminolevulinic acid phosphate solution was measured by titer analytical HPLC.

[0369] 10 g of activated carbon (Taiko S) was added, and the solution was decolorized for 30 minutes while adjusting the temperature at 15°C. Thereafter, the activated carbon was removed from the 5-aminolevulinic acid phosphate solution, and the decolorized filtrate was recovered. ＋ 1.0 L of a chelate resin Lewatit (registered trademark) TP260 (manufactured by LANXESS) was used. The decolorized filtrate was passed through TP260 at room temperature and SV4.5RV / h while measuring the Brix at the outlet of the resin tower. When the Brix reached 1.0% by mass, the TP260-permeated liquid was collected.

[0370] When the decolorized filtrate was exhausted, water pumping with ion-exchange purified water was started, and when the Brix again reached 1.0 mass%, collection of the resin tower filtrate was stopped. Molecules with a molecular weight of 6,000 or more, such as proteins, which may be contained in the collected resin tower filtrate were removed using an ultrafiltration membrane to obtain the ultrafiltration filtrate.

[0371] The ultrafiltration permeate was introduced into a recovery flask, and while the recovery flask containing the ultrafiltration permeate was heated in a thermostatic bath controlled at 60°C, it was concentrated for 21.6 hours using an evaporator with an internal pressure of 65 hPa. Through concentration, 1500 mL containing a 5-aminolevulinic acid phosphate concentration of 560 g / L (amount of 5-aminolevulinic acid phosphate obtained was 856.8 g) was prepared, and this solution was divided into four 375 mL portions (containing 563.2 g / L of 5-aminolevulinic acid phosphate). These solutions are hereinafter referred to as crystallization stock solutions 1 to 4.

[0372] [2] A step of adjusting the temperature of the crystallization stock solution obtained in [1]. Four crystallization stock solutions 1 to 4 were introduced into a crystallization tank, and the temperature of the crystallization stock solution was adjusted to 15°C.

[0373] [3] A step of adding a first organic solvent to the crystallization stock solution obtained in [2] to precipitate 5-aminolevulinic acid or a salt thereof. Primary EtOH was added to the crystallization tank at a rate of 0.7 v / h (v / h) relative to the volume of the crystallization stock solution, and the crystallization stock solution and the primary EtOH were mixed by stirring. 0.1252 g (0.06% by mass) of 5-aminolevulinic acid phosphate powder was added as seed crystals to the crystallization stock solution, and the crystallization stock solution was aged for 10 minutes with stirring while controlling the temperature at 15°C. 5-aminolevulinic acid phosphate powder having the powder X-ray diffraction spectrum pattern obtained in Example 1 of Japanese Patent No. 4989153 (Patent Document 4) was used as the seed crystals.

[0374] [4] Step of adding a second organic solvent to the crystallization stock solution: EtOH was added at a rate of 0.7 v / v / h in an amount of 1.7 v / v relative to the volume of the crystallization stock solution at the time of completion of concentration (before the addition of the first EtOH), and the crystallization stock solution and the second EtOH were mixed by stirring. Stirring was continued for 2 hours after the completion of the addition of the second EtOH, and 5-aminolevulinic acid phosphate was crystallized from the mixed solution to obtain a crystal slurry.

[0375] [5] Step of separating crystals The crystal slurry was centrifuged to separate the 5-aminolevulinic acid crystals into solid and liquid. The wet crystals were then washed at room temperature with 100% EtOH in an amount of 1.0 v / w relative to the weight of the wet crystals to obtain wet crystals.

[0376] [6] Crystal Separation Step The obtained wet crystals were placed in individual portions in recovery flasks, and while heating in a thermostatic bath controlled at 30°C, the wet crystals of 5-aminolevulinic acid phosphate crystals were dried at room temperature for 5 hours in an evaporator with an internal pressure of 53 hPa. All four portions of the dried crystals were condensed to obtain 658.02 g of 5-aminolevulinic acid phosphate powder, and the residual solvent content of the powder was analyzed by gas chromatography. The results are shown in Table 2A.

[0377]

[0378] As shown in Table 2A, the residual EtOH in the 5-aminolevulinic acid phosphate powder was less than 1000 ppm.

[0379] The impurity contents in the 5-aminolevulinic acid phosphate powder obtained in Example 3 were determined by HPLC analysis based on the above formula (III). The results are shown in Table 2B.

[0380] The values ​​shown in Table 2B are the "ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate." In Table 2B, RT stands for Retention time, and ND stands for Not Detected.

[0381]

[0382] As shown in Table 2B, at any concentration of the crystallization stock solution, the ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate mixed in the 5-aminolevulinic acid phosphate powder was 0.0005 or less, and the total ratio of the content of each impurity to the content of 5-aminolevulinic acid was 0.0015 or less.

[0383] On the other hand, impurities were detected in the marketed product, with the ratio of the content of each impurity to the content of 5-aminolevulinic acid phosphate exceeding 0.0005.

[0384] The 5-aminolevulinic acid phosphate powder obtained in Example 3 was subjected to a severe stability test, and the color before and after the test was evaluated. The results are shown in Table 2C.

[0385]

[0386] As shown in Table 2C, Example 3 and all of the commercially available products showed a decrease in light transmittance at a wavelength of 430 nm, which indicates yellow in the severe stability test. However, Example 3 had a lower light transmittance at a wavelength of 430 nm than the commercially available products.

[0387] [Analysis of the Content of 5-Aminolevulinic Acid or Its Salt in Various Examples] The content of 5-aminolevulinic acid phosphate in Example 3 and Comparative Examples 1-1 to 1-3 was measured by potentiometric titration. The results are shown in Table 3A.

[0388]

[0389] As shown in Table 3A, the content of 5-aminolevulinic acid phosphate in Example 3 was 100.1%, whereas the contents of 5-aminolevulinic acid phosphate in Comparative Examples 1-1 to 1-3 were 100.4% to 120.9%.

[0390] In principle, potentiometric titration reacts to impurities other than 5-aminolevulinic acid phosphate. In Example 3, the total ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof was detected by HPLC at only 0.0000 (below the detection limit), and therefore, from the two measurements by potentiometric titration and HPLC, it is believed that the content of 5-aminolevulinic acid phosphate is nearly 100%.

[0391] On the other hand, it is clear from HPLC analysis that the samples of Comparative Examples 1-1 to 1-3 contain large amounts of impurities. Even Comparative Example 1-2, which has a moisture content of 100.4%, contains impurities such that the total ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof by HPLC is 0.0017. Therefore, the content of 100.4% should be considered to be the result of some impurities being detected in addition to 5-aminolevulinic acid.

[0392] Furthermore, potentiometric titration cannot detect impurities that can be detected by HPLC (ultraviolet absorption spectroscopy) with a ratio of the content of each impurity being less than 0.02. To more accurately indicate purity, it is necessary to refer to HPLC in addition to potentiometric titration, and impurities with a ratio of the content of each impurity of 0.0005 or more were confirmed in all lots of products on the market.

[0393] From the above, it can be said that Example 3, which showed a content of almost 100% by two measurements, potentiometric titration and HPLC, is superior in terms of the content of 5-aminolevulinic acid phosphate compared to both the commercially available product and the comparative product of another company's patent.

[0394] Table 3B shows the PDPA content in each step of Example 3. The culture broth contained 39.2 g of PDPA, but the amount of PDPA was reduced to 0.021 g by the time the crystals obtained in the crystallization (first crystallization) were dried to a dry powder. Large amounts of PDPA were removed in steps (1-1) and (1-2) where UBK04 was used, indicating that PDPA can be removed from the 5-aminolevulinic acid phosphate fermentation broth by using a strongly acidic cation exchange resin.

[0395]

[0396] [6] The 5-aminolevulinic acid phosphate powder obtained in the crystal separation step was subjected to powder X-ray diffraction measurement, and the results are shown in Table 3C and FIG. 5. In the table, "2θ" indicates the diffraction angle (2θ°), and "relative intensity" indicates the relative intensity ratio (I / I0). Relative intensity ratios of 5 or more are indicated. The 5-aminolevulinic acid phosphate powder was confirmed to be a crystalline powder.

[0397]

[0398] The residual metal concentrations in Company C Product 1, a commercially available 5-aminolevulinic acid phosphate powder, and Example 3 were measured using ICP-MS, and the results are shown in Table 3D. The units are parts per million (ppm) relative to the 5-aminolevulinic acid phosphate concentration. LOQ in Table 3D is the limit of quantification.

[0399]

[0400] As shown in Table 3D, the As content of Company C's Product 1, a commercially available 5-aminolevulinic acid phosphate powder, was 0.3 ppm, whereas the As content of the 5-aminolevulinic acid phosphate powder prepared by the procedure shown in Example 3 was 0.25 ppm or less.

[0401] [Preparation Example 2: Preparation of 5-aminolevulinic acid culture solution] 5-aminolevulinic acid was produced by fermentation using recombinant Corynebacterium glutamicum according to the method disclosed in Japanese Patent Application Laid-Open No. 2005-333907, and then sulfuric acid was added to adjust the pH to 3.0±0.2. Subsequently, the culture solution was maintained at 20±10°C for 5 hours or more to inactivate the 5-aminolevulinic acid-producing bacteria, and 57.3 kL of culture solution containing 41.0 g / L of 5-aminolevulinic acid was obtained.

[0402] The inactivated cells were separated from the culture medium using a cross-flow filter (0.1 μm filter) to obtain 71.0 kL of solution A (supernatant) containing 15.2 g / L of 5-aminolevulinic acid phosphate.

[0403] Solution A prepared in Preparation Example 2 was used in the following Comparative Examples 2 and 3. Comparative Example 2: Preparation of 5-aminolevulinic acid phosphate powder obtained using only a strongly acidic cation exchange resin

[0404] Na ＋ A column was packed with 0.108 L of UBK04 [DIAION™, manufactured by Mitsubishi Chemical Corporation], a type of strongly acidic cation exchange resin, and 0.6633 L of Solution A (5-aminolevulinic acid concentration after dispensing: 15.1 g / L) was passed through and adsorbed onto the UBK04 at around room temperature and an SV of 0.682 RV / h. Subsequently, the UBK04 was washed with 0.162 L of purified ion-exchange water.

[0405] Next, 0.5±0.1 mol / L NaOH was passed through the UBK04 to elute the adsorbed components. The Brix and pH at the outlet of the UBK04 were measured during elution, and the UBK04 eluate (Solution B) was collected from the time the Brix reached 5.0±1.0 mass% until the pH reached 12.0. During collection, Solution D was cooled to 13.0°C.

[0406] The UBK04 eluate was heated to 25°C and then dissolved in phosphoric acid (H ３ P.O. ４, 75%) was added to adjust the pH to 2.74, converting 5-aminolevulinic acid into 5-aminolevulinic acid phosphate. The pH-adjusted solution was concentrated at 40°C, and 0.018 L of a concentrate containing 364.4 g / L of 5-aminolevulinic acid in terms of 5-aminolevulinic acid monophosphate was recovered.

[0407] To the concentrate, 0.084 g (1.2% by mass) of activated carbon (SW-50, Taiko) was added, and the solution was decolorized for 180 min while controlling the solution temperature to a target of 15.0°C. The concentrate was suction filtered using 0.084 g of filter aid (BC200, Arbocel) to remove the activated carbon. The 5-aminolevulinic acid phosphate remaining in the suction filter bottle was recovered with ion-exchange purified water, yielding 0.529 L of decolorized filtrate (Solution G).

[0408] The decolorized filtrate was concentrated at 40° C. or less, and 0.0147 L of the concentrate containing 389.9 g / L of 5-aminolevulinic acid calculated as 5-aminolevulinic acid monophosphate was recovered as a crystallization stock solution.

[0409] Primary EtOH (purity 99.5%) was added to the crystallization tank at a rate of 0.8124 v / v / h in an amount of 0.3 v / v relative to the volume of the crystallization stock solution, and the crystallization stock solution and primary EtOH were mixed by stirring. 0.00503 g (0.07% by mass) of 5-aminolevulinic acid phosphate crystal powder was added to the crystallization stock solution as seed crystals, and the crystallization stock solution was aged for 10 minutes with stirring while controlling the temperature at 15°C.

[0410] EtOH was added at a rate of 0.8124 v / v / h in an amount of 1.7 v / v relative to the volume of the crystallization stock solution at the time of completion of concentration (before the addition of the first EtOH), and the crystallization stock solution and the second EtOH (purity 99.5%) were mixed by stirring. Stirring was continued for 19 hours after the completion of the addition of the second EtOH, and 5-aminolevulinic acid phosphate was crystallized from the mixed solution to obtain a crystal slurry.

[0411] 11.44 g of 5-aminolevulinic acid phosphate wet crystals were recovered by suction filtration (four sheets of 5C ADVANTEC filter paper), and 11.44 mL of EtOH (purity 99.5%) was poured into the recovered solution all at once and stirred for about 1 minute to wash the 5-aminolevulinic acid phosphate wet crystals.

[0412] The 5-aminolevulinic acid phosphate wet crystals were dried under reduced pressure for 5 hours in an evaporator with an internal pressure of 53 hPa, and 10.14 g of 5-aminolevulinic acid phosphate powder was recovered. Table 3E shows the contents of 5-aminolevulinic acid (as phosphate), Gly, Ala, and PDPA in the process solution and the dried powder of the crystallization (first crystallization) in Comparative Example 2. The ALVP, Gly, and Ala contained in the eluate (solution B) were quantified by HPLC for titer analysis. The PDPA content was quantified by HPLC for PDPA content analysis.

[0413]

[0414] As shown in Table 3E, both Gly and Ala were removed by the time the UBK04 eluate was obtained. As for PDPA, as in Table 3B, PDPA contained in Solution A was removed by the time the UBK04 eluate (Solution B) of UBK04 was obtained. In other words, Gly, Ala, and PDPA contained in the 5-aminolevulinic acid culture solution can be removed by the strongly acidic cation exchange resin.

[0415] Comparative Example 3: Production of 5-aminolevulinic acid phosphate powder obtained using only a strongly acidic cation exchange resin and a strongly basic anion exchange resin

[0416] Na ＋ Using 0.108 L of UBK04 [DIAION (trademark) manufactured by Mitsubishi Chemical Corporation], a type of strongly acidic cation exchange resin, 0.6897 L of Solution A (the 5-aminolevulinic acid concentration after dispensing was 14.5 g / L in terms of 5-aminolevulinic acid monophosphate) was passed through and adsorbed onto the UBK04 under conditions of 25°C or lower and SV of 0.682 RV / h.

[0417] 0.5±0.1 mol / L NaOH was passed through UBK04 to elute the adsorbed components. The Brix and pH at the outlet of UBK04 were measured during the elution, and the UBK04 eluate (eluate B) was collected from the time when the Brix reached 5.0±1.0 mass% until the pH reached 12.0.

[0418] UBK04 filtrate is CH ３ COO ―Using 0.024 L of PA412 (DIAION™, manufactured by Mitsubishi Chemical Corporation), a strongly basic anion exchange resin of the type UBK04, the permeate adjusted to 12±3°C was passed through a PA412 resin tower at an SV of 1.042 RV / h. While measuring the Brix at the outlet of the PA412 resin tower, collection of the PA412 permeate (Solution D) began when the Brix reached 0.2% by mass. During collection, Solution D was cooled to 13.0°C.

[0419] When the UBK04 permeate (solution B) was exhausted, the mixture was washed with ion-exchange purified water until the Brix reached 0.0% by mass, and the PA412 permeate (solution D) was collected.

[0420] While controlling the temperature to 25°C or less, ３ P.O. ４ , 75%) was added to adjust the pH to 2.65 to convert 5-aminolevulinic acid into 5-aminolevulinic acid phosphate. After adjusting the pH, the solution was concentrated at 40°C or lower, and a volume of 0.0106 L (384 g / L in terms of 5-aminolevulinic acid monophosphate) of concentrated solution was recovered.

[0421] To the concentrate, 0.0489 g of activated carbon (SW-50, Taiko) was added, and the solution was decolorized for 180 minutes while maintaining a target temperature of 15.0°C. The concentrate was subjected to suction filtration using 0.0489 g of filter aid (BC200, Arbocel) to remove the activated carbon. The 5-aminolevulinic acid phosphate remaining in the suction filter bottle was recovered with ion-exchange purified water, yielding 0.560 L of decolorized filtrate (Solution G).

[0422] The decolorized filtrate was concentrated to 0.0073 L at 40° C. or lower so that the concentration of 5-aminolevulinic acid phosphate became 500 g / L, and this was used as a crystallization stock solution.

[0423] A primary EtOH solution was added to the crystallization tank at a rate of 0.7 v / v / h in an amount of 0.3 v / v relative to the volume of the stock solution, and the crystallization stock solution and the primary EtOH were mixed by stirring. 0.00258 g (0.07% by mass) of 5-aminolevulinic acid phosphate crystal powder was added as seed crystals to the crystallization stock solution, and the crystallization stock solution was aged for 10 minutes with stirring while controlling the temperature at 15°C.

[0424] EtOH was added at a rate of 0.7 v / v / h in an amount of 1.7 v / v relative to the volume of the crystallization stock solution at the time of completion of concentration (before the addition of the first EtOH), and the crystallization stock solution and the second EtOH were mixed by stirring. Stirring was continued for 15 hours after the completion of the addition of the second EtOH, and 5-aminolevulinic acid phosphate was crystallized from the mixed solution to obtain a crystal slurry.

[0425] 7.44 g of 5-aminolevulinic acid phosphate wet crystals were collected by suction filtration (four sheets of 5C ADVANTEC filter paper), and 7.44 mL of ethanol was poured into the collected solution all at once and stirred for about 1 minute to wash the 5-aminolevulinic acid phosphate wet crystals.

[0426] The 5-aminolevulinic acid phosphate wet crystals were dried under reduced pressure for 5 hours in an evaporator with an internal pressure of 53 hPa, and 6.89 g of 5-aminolevulinic acid phosphate powder was recovered.

[0427] The dissolution state of the 5-aminolevulinic acid phosphate powders obtained in Comparative Examples 2 and 3 was analyzed, and the results are shown in Table 19A.

[0428]

[0429] As shown in Table 19A, when impurities were removed from a 5-aminolevulinic acid solution produced by fermentation using a strong acidic cation exchange resin, a weak acidic cation exchange resin, and a strong basic anion exchange resin, the resulting 5-aminolevulinic acid phosphate powder had a transmittance of 99.8% at a wavelength of 430 nm. On the other hand, when only a strong acidic cation exchange resin was used, the transmittance was 0.0%, and when a strong acidic cation exchange resin and a strong basic anion exchange resin were used, the transmittance was 6.1%.

[0430] From the above, it was demonstrated that the removal of impurities using a combination of a strong acidic cation exchange resin, a weak acidic cation exchange resin, and a strong basic anion exchange resin is more effective in decolorizing a 5-aminolevulinic acid solution produced by fermentation than using only ion exchange resins 1 and 2.

[0431] The residual solvent levels in the 5-aminolevulinic acid phosphate powders obtained in Comparative Examples 2 and 3 were analyzed by gas chromatography (GC). The results are shown in Table 19B.

[0432]

[0433] As shown in Table 19B, when impurities were removed from a 5-aminolevulinic acid solution produced by fermentation using a strong acid cation exchange resin, a weak acid cation exchange resin, and a strong basic anion exchange resin, the residual EtOH in the resulting 5-aminolevulinic acid phosphate powder was 498 ppm. On the other hand, when only a strong acid cation exchange resin was used, the residual EtOH was 20,108 ppm, and when a strong acid cation exchange resin and a strong basic anion exchange resin were used, the residual EtOH was 15,649 ppm.

[0434] From the above, it was demonstrated that a production method using a combination of a strong acidic cation exchange resin, a weak acidic cation exchange resin, and a strong basic anion exchange resin is useful for reducing the residual solvent concentration in 5-aminolevulinic acid phosphate powder, compared to the use of only one or two types of ion exchange resins.

[0435] Preparation Example 3: Preparation of 5-aminolevulinic acid culture broth 5-aminolevulinic acid was produced by fermentation using recombinant Corynebacterium glutamicum according to the method disclosed in Japanese Patent Application Laid-Open No. 2005-333907, and then sulfuric acid was added to adjust the pH to 3.0±0.2. The culture broth was then maintained at 20±10°C for 5 hours or more to inactivate the 5-aminolevulinic acid-producing bacteria, yielding 2.38 L of a culture broth containing 50.5 g / L of 5-aminolevulinic acid.

[0436] The culture medium prepared in Preparation Example 3 was used in the following Reference Examples 1-1 and 1-2.

[0437] [Reference example 1-1: H ＋ Amino acid removal efficiency in 5-aminolevulinic acid solution when using a strongly acidic cation exchange resin of the type

[0438] H ＋ 1.6 L of MARATHON C [DOWEX (trademark) manufactured by DuPont], a type of strongly acidic cation exchange resin, was used, and the MARATHON C was heated to 35°C. 2.38 L of culture solution (5-aminolevulinic acid concentration: 50.5 g / L in terms of phosphate) was passed through and adsorbed under conditions of SV0.9 RV / h. Subsequently, the MARATHON C was washed with ion-exchange purified water.

[0439] 0.5±0.1 mol / L NaOH was passed through the MARATHON C to elute the adsorbed components. The Brix and pH at the outlet of the MARATHON C were measured during the elution, and the MARATHON C eluate was collected from the time when the Brix reached 1.0 mass% until the pH reached 12.0.

[0440] H ＋ 0.3 L of WK40L (DIAION™, manufactured by Mitsubishi Chemical Corporation), a weakly acidic cation exchange resin of the type, was used, and the solution B was passed through WK40L under the condition of SV 4.545 RV / h.

[0441] While measuring the Brix at the outlet of the WK40L resin tower, the Brix increased to 0.1% by mass, and the WK40L resin tower permeate (solution C) was collected. When the MARATHON C permeate (solution B) was exhausted, the solution was flushed with ion-exchanged purified water, and the WK40L tower permeate (solution C) was collected until the Brix decreased to 1.0% by mass.

[0442] CH ３ COO ― Using 380 mL of a strong basic anion exchange resin PA412 [DIAION™, manufactured by Mitsubishi Chemical Corporation], 2.49 L of the WK40L resin column permeate (solution C) was passed through a PA412 resin column at room temperature under conditions of SV 1.0 RV / h. While measuring the Brix at the outlet of the PA412 resin column, collection of the PA412 permeate (solution D) began when the Brix reached 0.2 mass%.

[0443] When the WK40L resin column permeate (Solution C) was depleted, the column was washed with ion-exchanged purified water until the Brix reached 1.0% by mass, and the PA412 permeate (Solution D) was recovered. The pH of Solution D was 4.96.

[0444] 30.0 mL of phosphoric acid (H ３ P.O. ４ , 75%) was added to adjust the pH to 2.77 to convert 5-aminolevulinic acid to 5-aminolevulinic acid phosphate, thereby obtaining 2.63 L of a PA412 permeate (solution E) containing 30.5 g / L of 5-aminolevulinic acid phosphate.

[0445] [Reference Example 1-2: Na ＋ Amino acid removal efficiency in 5-aminolevulinic acid solution when using a strongly acidic cation exchange resin of the type

[0446] Na ＋ 1.5 L of MARATHON C [DOWEX (trademark) manufactured by DuPont], a type of strongly acidic cation exchange resin, was used, and the MARATHON C was heated to 35°C. 2.38 L of culture solution (5-aminolevulinic acid concentration: 50.5 g / L) was passed through and adsorbed under conditions of SV0.9 RV / h. Subsequently, the MARATHON C was washed with ion-exchange purified water.

[0447] 0.5±0.1 mol / L NaOH was passed through the MARATHON C to elute the adsorbed components. The Brix and pH at the outlet of the MARATHON C were measured during the elution, and the MARATHON C eluate (solution B) was collected from the time when the Brix reached 1.0±1.0 mass% until the pH reached 12.0.

[0448] The ALVP, Gly and Ala contained in the culture medium used as the raw material in Comparative Example 3 and Reference Example 1-1, and in the MARATHON C eluate (solution B) were quantified by titer analytical HPLC.

[0449] H ＋ 0.3 L of WK40L (DIAION™, manufactured by Mitsubishi Chemical Corporation), a weakly acidic cation exchange resin of the type, was used, and the solution B was passed through WK40L at an SV of 4.5 RV / h.

[0450] While measuring the Brix at the outlet of the WK40L resin tower, the Brix increased to 0.1% by mass, and the liquid passing through the WK40L resin tower (solution C) was collected. When the liquid passing through the MARATHON C was exhausted, the liquid was flushed with ion-exchanged purified water, and the liquid passing through the WK40L tower (solution C) was collected until the Brix decreased to 1.0% by mass.

[0451] CH ３ COO ―380 mL of a strong basic anion exchange resin PA412 [DIAION (trademark), manufactured by Mitsubishi Chemical Corporation] was used, and 2.18 L of the WK40L resin column permeate (solution C) was passed through the PA412 resin column at an SV of 1.0 RV / h. While measuring the Brix at the outlet of the PA412 resin column, collection of the PA412 permeate (solution D) began when the Brix reached 0.2% by mass.

[0452] When the PA412 permeate was exhausted, the column was washed with ion-exchange purified water until the Brix reached 1.0% by mass, and the PA412 permeate (solution D) was recovered. The pH of solution D was 5.07.

[0453] 28.0 mL of phosphoric acid (H ３ P.O. ４ , 75%) was added to adjust the pH to 2.73 to convert 5-aminolevulinic acid to 5-aminolevulinic acid phosphate, thereby obtaining 2.33 L of a PA412 permeate (solution E) containing 31.8 g / L of 5-aminolevulinic acid phosphate.

[0454] Tables 20 and 21 are H ＋ Type and Na ＋ 1 shows the degree of removal of Gly and Ala when using a strongly acidic cation exchange resin of the type.

[0455]

[0456]

[0457] As shown in Table 21, the strongly acidic cation exchange resin was ＋ In the case of the H type, most of the Gly and Ala contained in the culture medium were removed from WK40L (solution C). On the other hand, as shown in Table 20, when the strongly acidic cation exchange resin was H type, most of the Gly and Ala contained in the culture medium were removed from WK40L (solution C). ＋ In the case of the α-type, Ala remains in WK40L (solution C), and Na ＋ Although the removal efficiency was not as high as that of the type, effectiveness was observed against ALVP and Gly.

[0458] From the above, Na ＋ It was confirmed that the use of this type of strongly acidic cation exchange resin allows for more efficient removal of Gly and Ala, which are impurities present during the fermentation process.

[0459] The state of the solution of the pH-adjusted PA412 permeate (Solution E) obtained in Reference Examples 1-1 and 1-2 was analyzed. The results are shown in Table 22.

[0460]

[0461] As shown in Table 22, H ＋ Compared with the case of using a strongly acidic cation exchange resin of the Na type, ＋ Using a strongly acidic cation exchange resin of the type, and then CH ３ COO ― When the solution was passed through a strongly basic anion exchange resin of the type PA412, the pH of the solution passed through (solution E) was significantly improved. ＋ When the strongly acidic cation exchange resin of the type was used, the transmittance of the pH-adjusted PA412 effluent (solution E) at a wavelength of 430 nm was 66.2%. ＋ When a strongly acidic cation exchange resin of this type was used, the yield was 53.3%.

[0462] From the above, we can see that the strongly acidic cation exchange resin is ＋ By using this type, ＋ As a result, it was shown that the color remaining in the solution that passed through the subsequent strong basic anion exchange resin (solution E) could be reduced.

[0463] Preparation Example 4: Preparation of 5-aminolevulinic acid culture solution 5-aminolevulinic acid was produced by fermentation using recombinant Corynebacterium glutamicum according to the method disclosed in Japanese Patent Application Laid-Open No. 2005-333907, and then sulfuric acid was added to adjust the pH to 3.0±0.2. Subsequently, the culture solution was maintained at 20±10°C for 5 hours or more to inactivate the 5-aminolevulinic acid-producing bacteria, and 15.5 L of a culture solution (Solution A) containing 31.0 g / L of 5-aminolevulinic acid in terms of phosphate was obtained.

[0464] H ＋6.9 L of MARATHON C [DOWEX (trademark) manufactured by DuPont], a type of strongly acidic cation exchange resin, was used, and the MARATHON C was heated to 35°C. 15.5 L of culture solution (5-aminolevulinic acid concentration: 31.0 g / L in terms of phosphate) was passed through and adsorbed under conditions of SV0.9 RV / h. Subsequently, the MARATHON C was washed with ion-exchange purified water.

[0465] 0.5 mol / L NaOH was passed through the MARATHON C to elute the adsorbed components. The Brix and pH at the outlet of the MARATHON C were measured during the elution, and the eluate (eluate B) of MARATHON C was collected from the time when the Brix reached 2.5% by mass until the pH reached 12.7.

[0466] H ＋ 1.4 L of WK40L (DIAION™, manufactured by Mitsubishi Chemical Corporation), a weakly acidic cation exchange resin of the type, was used, and the solution B was passed through WK40L at an SV of 4.5 RV / h.

[0467] While measuring the Brix at the outlet of the WK40L resin tower, the WK40L resin tower permeate was collected when the Brix increased to 0.1% by mass. When the MARATHON C permeate (solution B) was exhausted, the WK40L resin tower permeate (solution C) was collected by water pumping with ion-exchange purified water until the Brix decreased to 0.8% by mass.

[0468] The WK40L column effluent (Solution C) prepared in Preparation Example 4 was used in the following Reference Examples 2-1, 2-2, and 2-3.

[0469] [Reference Example 2-1: Cl ― Efficiency of removing residual amino acids from 5-aminolevulinic acid solution when using a strongly basic anion exchange resin of the Cl type ― Using 440 mL of a strong basic anion exchange resin PA412 [DIAION™, manufactured by Mitsubishi Chemical Corporation], 2.3 L of the WK40L resin column permeate (solution C) was passed through a PA412 resin column at an SV of 1.0 RV / h. While measuring the Brix at the outlet of the PA412 resin column, collection of the PA412 permeate (solution D) began when the Brix reached 0.2% by mass.

[0470] When the WK40L resin column permeate (solution C) was exhausted, the column was washed with ion-exchanged purified water until the Brix reached 1.0 mass%, and 2.24 L of PA412 permeate (solution D) containing 31.2 g / L of 5-aminolevulinic acid in terms of phosphate was recovered.

[0471] 25 mL of phosphoric acid (H ３ P.O. ４ , 75%) was added to adjust the pH to 2.09, converting 5-aminolevulinic acid into 5-aminolevulinic acid phosphate (solution E). Concentration was carried out under reduced pressure, and 0.436 L of a concentrate containing 160 g / L of 5-aminolevulinic acid phosphate was recovered and used as the concentrate. During the concentration, the 5-aminolevulinic acid phosphate solution was heated to 53°C for a total of 12 hours.

[0472] The concentrate was filtered through a membrane filter (Omnipore, Merck) with a pore size of 0.45 μm.

[0473] The solution was concentrated under reduced pressure, and 0.090 L of the concentrate containing an estimated 786 g / L of 5-aminolevulinic acid phosphate was collected and used as a crystallization stock solution. During the concentration, the 5-aminolevulinic acid phosphate solution was heated to 40°C for a total of 19 hours.

[0474] The crystallization stock solution was introduced into a crystallization tank, and the temperature of the crystallization stock solution was adjusted to 17±3° C. 0.02 g (0.03% by mass) of seed crystals was added, and the solution was aged for 2 hours with stirring.

[0475] Methanol (MeOH) was added to the crystallization tank at a rate of 0.8 v / v / h in an amount of 3.0 v / v relative to the volume of the crystallization stock solution, and the crystallization stock solution and MeOH were mixed by stirring. After aging with stirring for 2 hours, a slurry of 5-aminolevulinic acid phosphate crystals was obtained.

[0476] The crystal slurry was centrifuged to filter out the 5-aminolevulinic acid crystals. The mother liquor of the slurry was called ML, and 0.3 L of this was recovered. 100% MeOH (100 v / w % relative to the weight of the wet crystals) was added to the 5-aminolevulinic acid wet crystals at room temperature and stirred for about 1 minute to wash the wet crystals. The crystal slurry was centrifuged again to obtain 40.5 g of washed 5-aminolevulinic acid wet crystals.

[0477] The wet crystals of 5-aminolevulinic acid phosphate were collected in a recovery flask. While the recovery flask containing the wet crystals of 5-aminolevulinic acid phosphate was heated in a thermostatic bath controlled at 27±3°C, the wet crystals of 5-aminolevulinic acid phosphate were dried for 15±10 hours in an evaporator with the internal pressure set to full vacuum.

[0478] [Reference Example 2-2: CH ３ COO ― Efficiency of Amino Acid Removal from 5-Aminolevulinic Acid Solution Using a Strongly Basic Anion Exchange Resin of CH Type ３ COO ― Using 440 mL of a strong basic anion exchange resin PA412 [DIAION™, manufactured by Mitsubishi Chemical Corporation], 2.3 L of the WK40L resin column permeate (solution C) was passed through a PA412 resin column at an SV of 1.0 RV / h. While measuring the Brix at the outlet of the PA412 resin column, collection of the PA412 permeate (solution D) began when the Brix reached 1.0 mass%.

[0479] When the WK40L resin column permeate (solution C) was exhausted, the column was washed with ion-exchanged purified water until the Brix reached 1.0 mass%, and 2.280 L of PA412 permeate (solution D) containing 31.1 g / L of 5-aminolevulinic acid in terms of phosphate was recovered.

[0480] 25.4 mL of phosphoric acid (H ３ P.O. ４ , 75%) was added to adjust the pH to 2.74 to convert 5-aminolevulinic acid into 5-aminolevulinic acid phosphate (solution E). Concentration was carried out at 53°C or lower, and 0.443 L of a concentrate containing 160 g / L of 5-aminolevulinic acid phosphate was collected and used as the concentrate. During the concentration, the 5-aminolevulinic acid phosphate solution was heated to 53°C for a total of 12 hours.

[0481] The concentrate was filtered through a membrane filter (Omnipore, Merck) with a pore size of 0.45 μm.

[0482] Concentration was carried out at 40°C or lower, and 0.091 L of a concentrate containing 779 g / L of 5-aminolevulinic acid phosphate was recovered and used as a crystallization stock solution. During the concentration, the 5-aminolevulinic acid phosphate solution was heated to 40°C for a total of 19 hours.

[0483] The crystallization stock solution was introduced into a crystallization tank, and the temperature of the crystallization stock solution was adjusted to 17±3° C. 0.02 g (0.03% by mass) of seed crystals was added, and the solution was aged for 2 hours with stirring.

[0484] Methanol (MeOH) was added to the crystallization tank at a rate of 0.8 v / v / h in an amount of 3.0 v / v relative to the volume of the crystallization stock solution, and the crystallization stock solution and MeOH were mixed by stirring. After aging with stirring for 2 hours, a slurry of 5-aminolevulinic acid phosphate crystals was obtained.

[0485] The crystal slurry was centrifuged to filter out the 5-aminolevulinic acid crystals. The mother liquor of the slurry was called ML, and 0.3 L of this was recovered. 100% MeOH (100 v / w % based on the weight of the wet crystals) was added to the 5-aminolevulinic acid wet crystals at room temperature and stirred for about 1 minute to wash the wet crystals. The crystal slurry was centrifuged again to obtain 56.5 g of washed 5-aminolevulinic acid wet crystals.

[0486] The wet crystals of 5-aminolevulinic acid phosphate were collected in a recovery flask. While the recovery flask containing the wet crystals of 5-aminolevulinic acid phosphate was heated in a thermostatic bath controlled at 27±3°C, the wet crystals of 5-aminolevulinic acid phosphate were dried for 15±10 hours in an evaporator with the internal pressure set to full vacuum.

[0487] [Reference Example 2-3: PO ４ ３― Efficiency of removing residual amino acids from 5-aminolevulinic acid solution when using a strongly basic anion exchange resin of the type PO ４ ３― 440 mL of a strong basic anion exchange resin PA412 [DIAION™, manufactured by Mitsubishi Chemical Corporation] was used, and 2.3 L of the WK40L resin column permeate was passed through the PA412 resin column at an SV of 1.0 RV / h. While measuring the Brix at the outlet of the PA412 resin column, collection of the PA412 permeate began when the Brix reached 0.2% by mass.

[0488] When the PA412 permeate was exhausted, the column was washed with ion-exchanged purified water until the Brix reached 1.0% by mass, and 2.240 L of the PA412 permeate containing 32.9 g / L of 5-aminolevulinic acid calculated as phosphate was recovered.

[0489] 15.5 mL of phosphoric acid (H ３ P.O. ４ , 75%) was added to adjust the pH to 2.75, and 5-aminolevulinic acid was converted to 5-aminolevulinic acid phosphate. Concentration was carried out at 53°C or lower, and 0.460 L of a concentrate containing 160 g / L of 5-aminolevulinic acid phosphate was collected and used as the concentrate. During the concentration, the 5-aminolevulinic acid phosphate solution was heated to 53°C for a total of 12 hours.

[0490] The concentrate was filtered through a membrane filter (Omnipore, Merck) with a pore size of 0.45 μm.

[0491] Concentration was carried out at 40°C or lower, and 0.095 L of the concentrate containing an estimated 746 g / L of 5-aminolevulinic acid phosphate was recovered and used as a crystallization stock solution. During the concentration, the 5-aminolevulinic acid phosphate solution was heated to 40°C for a total of 19 hours.

[0492] The crystallization stock solution was introduced into a crystallization tank, and the temperature of the crystallization stock solution was adjusted to 17±3° C. 0.02 g (0.03% by mass) of seed crystals was added, and the solution was aged for 2 hours with stirring.

[0493] Methanol (MeOH) was added to the crystallization tank at a rate of 0.8 v / v / h in an amount of 3.0 v / v relative to the volume of the crystallization stock solution, and the crystallization stock solution and MeOH were mixed by stirring. After aging with stirring for 2 hours, a slurry of 5-aminolevulinic acid phosphate crystals was obtained.

[0494] The crystal slurry was centrifuged to filter out the 5-aminolevulinic acid crystals. The mother liquor of the slurry was called ML, and 0.3 L of this was recovered. 100% MeOH (100 v / w % based on the weight of the wet crystals) was added to the 5-aminolevulinic acid wet crystals at room temperature and stirred for about 1 minute to wash the wet crystals. The crystal slurry was centrifuged again to obtain 58.4 g of washed 5-aminolevulinic acid wet crystals.

[0495] The wet crystals of 5-aminolevulinic acid phosphate were collected in a recovery flask. While the recovery flask containing the wet crystals of 5-aminolevulinic acid phosphate was heated in a thermostatic bath controlled at 27±3°C, the wet crystals of 5-aminolevulinic acid phosphate were dried for 15±10 hours in an evaporator with the internal pressure set to full vacuum.

[0496] The state of the solution of the PA412 permeate obtained in Reference Examples 2-1 to 2-3, and adjusted to pH 2.75, was analyzed. The results are shown in Table 23.

[0497]

[0498] As shown in Table 23, the ionic form of PA412 is CH ３ COO ― When the ion type of PA412 was Cl, the transmittance of the PA412-passed solution (solution E) at a wavelength of 430 nm was 33.5%. ― When the ionic form of PA412 was PO, the transmittance of the PA412-passed solution (solution E) at a wavelength of 430 nm was 33.5%. ４ ３― In this case, the transmittance of the PA412-passed solution (solution E) at a wavelength of 430 nm was 3.9%.

[0499] From the above, the ion type of the strong basic anion exchange resin is CH ３ COO ― By doing so, Cl ― It was shown that the color remaining in the liquid passing through the strong basic anion exchange resin (solution E) can be reduced compared to the strong basic anion exchange resin of Example 1.

[0500] The amount of 5-aminolevulinic acid phosphate dissolved in the ML obtained in Reference Examples 2-1 to 2-3 was measured by titer analytical HPLC. The results are shown in Table 24.

[0501]

[0502] As shown in Table 24, the ionic form of PA412 is CH ３ COO ― In this case, the amount of 5-aminolevulinic acid phosphate dissolved in ML was 7.1 g, and the ionic form of PA412 was PO ４― On the other hand, when the ionic form of PA412 was Cl, the weight was 6.3 g. ― In this case, the amount of 5-aminolevulinic acid phosphate dissolved in the ML was 35.9 g.

[0503] From the above, the ion type of the strong basic anion exchange resin is CH ３ COO ― or P.O. ４ － By doing so, Cl ― It was shown that the dissolution of 5-aminolevulinic acid phosphate in ML can be reduced and the yield can be improved compared to the strongly basic anion exchange resin of ML.

[0504] Preparation Example 5: Preparation of 5-aminolevulinic acid fermentation broth 5-aminolevulinic acid was produced by fermentation using recombinant Corynebacterium glutamicum according to the method disclosed in Japanese Patent Application Laid-Open No. 2005-333907, and then sulfuric acid was added to adjust the pH to 3.0±0.2. The culture broth was then maintained at 20±10°C for 5 hours or more to inactivate the 5-aminolevulinic acid-producing bacteria, yielding 39.0 L of a culture broth containing 47.4 / L of 5-aminolevulinic acid.

[0505] The inactivated cells were separated from the fermentation broth using a cross-flow filter (0.1 μm filter) to obtain 16.7 L of solution A (supernatant) containing 18.7 g / L of 5-aminolevulinic acid phosphate.

[0506] Solution A prepared in Preparation Example 4 was used in Example 4 below. [Example 4: Preparation of 5-aminolevulinic acid phosphate crystals by one-time crystallization method]

[0507] Na ＋ 16.7 L of Solution A was passed through and adsorbed onto 4.940 L of XUS40232.01 [Dowex (trademark), manufactured by DuPont], a type of strongly acidic cation exchange resin, at an SV of 0.68 RV / h relative to XUS40232.01.

[0508] 0.6 mol / L NaOH was passed through XUS40232.01 to elute the adsorbed components. The Brix and pH at the outlet of XUS40232.01 were measured during elution, and the XUS40232.01 eluate (eluate B) was collected from the time when the Brix reached 5.0 mass% or more until the pH reached 12.0 or more.

[0509] H ＋ 0.41 L of WK40L [DIAION (trademark), manufactured by Mitsubishi Chemical Corporation], a weakly acidic cation exchange resin of the type, was used, and the XUS40232.01 eluate (eluate B) was passed through WK40L at an SV of 8.23 ​​RV / h.

[0510] While measuring the Brix at the outlet of the WK40L resin tower, the WK40L resin tower permeate (eluate C) was collected when the Brix rose to 2.0% by mass. When the XUS40232.01 eluate (eluate B) was depleted, water pumping with ion-exchanged purified water was started. The WK40L permeate (eluate C) was collected from the point when the Brix fell to 1.0% by mass or less until 1.85 L (4.5 times the resin volume) of ion-exchanged purified water was used to pump the water. The WK40L tower permeate (eluate C) was cooled to 12.0°C during collection.

[0511] CH ３ COO ― 1.30 L of a strong basic anion exchange resin PA412M [DIAION™, manufactured by Mitsubishi Chemical Corporation] of the WK40L type was used, and when 5.94 L of the WK40L resin column permeate (eluate C) had accumulated, the liquid was passed through the PA412M resin column under conditions of 12°C and SV0.80 RV / h. While measuring the Brix at the outlet of the PA412M resin column, collection of the PA412M permeate (eluate D) began when the Brix reached 0.2 mass%.

[0512] When the WK40L resin column permeate (eluate C) was exhausted, the solution was washed with ion-exchange purified water until the Brix reached 1.0% by mass, and the PA412M permeate (solution D) was recovered. The PA412M permeate (solution D) was cooled to 12.0°C during recovery. During the cooling and recovery, solution D was appropriately diluted with phosphoric acid (H ３ P.O. ４ , 75%) was added to adjust the pH to the range of 3.00±0.25.

[0513] After recovering all of the solution D, ３ P.O. ４ , 75%) was added from time to time to adjust the pH to 2.75±0.25, converting 5-aminolevulinic acid to 5-aminolevulinic acid phosphate, and 6.63 L of a pH-adjusted PA412M permeate (Solution E) containing 37.7 g / L of 5-aminolevulinic acid phosphate was obtained. The total amount of phosphoric acid added dropwise was 90.0 mL.

[0514] After adjusting the pH at 45° C. or less, the PA412M effluent (solution E) was concentrated, and 0.351 L of the concentrate containing 492.7 g / L of 5-aminolevulinic acid (as phosphate) was recovered as the primary concentrate.

[0515] To the primary concentrate, 17.20 g (10% by mass) of activated carbon (SW-50, Taiko) was added, and the solution was decolorized for 180 min while controlling the solution temperature to a target of 15.0°C. The concentrate was suction filtered using 1.72 g of filter aid (BC200, Arbocel) to remove the activated carbon. The 5-aminolevulinic acid phosphate remaining in the suction filter bottle was recovered with ion-exchange purified water, yielding 0.923 L of decolorized filtrate (Solution G).

[0516] 0.176 L of H+-type chelating resin Lewatit (registered trademark) TP260 (manufactured by LANXESS) was used. The solution was passed through TP260 at an SV of 4.5 RV / h. While measuring the Brix at the resin tower outlet, the decolorized filtrate was passed through TP260, and when the Brix reached 1.0% by mass, the resin tower-passed liquid (solution H) was collected.

[0517] Thereafter, when the 5-aminolevulinic acid phosphate solution was depleted, the solution was washed with ion-exchange purified water, and collection of the resin tower permeate was terminated when the Brix again reached 1.0% by mass. Molecules with a molecular weight of 6,000 or more, such as proteins, which may be contained in the collected resin tower permeate were removed using an ultrafiltration membrane to obtain the ultrafiltration permeate. The volume of the ultrafiltration permeate was 1.462 L, and it contained 106.6 g / L of 5-aminolevulinic acid (phosphate equivalent).

[0518] Impurities in the ultrafiltration permeate were removed using a filter (0 μm pore size: 0.2 μm).

[0519] The ultrafiltration filtrate was concentrated at 40° C. or less, and 0.255 L of a concentrate containing 603 g / L of 5-aminolevulinic acid (as phosphate) was recovered as a secondary concentrate.

[0520] While the temperature of the secondary concentrate was controlled at 15°C, 0.3 v / v of primary EtOH (purity 99.5%) relative to the volume of the secondary concentrate was added to the crystallization tank at a rate of 0.7 v / v / h, and the crystallization stock solution and primary EtOH were mixed by stirring. 0.090 g (0.059 mass%) of 5-aminolevulinic acid phosphate crystal powder was added as seed crystals to the crystallization stock solution, which was then stirred and aged for 10 minutes.

[0521] EtOH was added at a rate of 0.7 v / v / h in an amount of 1.7 v / v relative to the volume of the crystallization stock solution at the time of completion of concentration (before the addition of the first EtOH), and the crystallization stock solution and the second EtOH (purity 99.5%) were mixed by stirring. Stirring was continued for 2 hours after the completion of the addition of the second EtOH, and 5-aminolevulinic acid phosphate was crystallized from the mixed solution to obtain a crystal slurry.

[0522] The wet crystals of 5-aminolevulinic acid phosphate in the crystal slurry were subjected to solid-liquid separation by centrifugation, and then 140 mL (100% by mass) of 100% EtOH was added relative to the weight of the wet crystals to wash the wet crystals of 5-aminolevulinic acid phosphate. After solid-liquid separation again by centrifugation, the wet crystals of 5-aminolevulinic acid phosphate were recovered in an eggplant flask.

[0523] The recovery flask containing the wet crystals of 5-aminolevulinic acid phosphate was heated in a thermostatic bath controlled at 30°C, while being attached to an evaporator with an internal pressure of 53 hPa, and the wet crystals of 5-aminolevulinic acid phosphate were dried for 1 hour while rotating at a very low speed of 5 to 10 rpm.

[0524] The residual solvent in the 5-aminolevulinic acid phosphate crystals prepared in Example 4 was analyzed by gas chromatography. The results of the residual solvent analysis are shown in Table 25.

[0525]

[0526] As shown in Table 25, even when 5-aminolevulinic acid phosphate was produced by the one-time crystallization process, the residual ethanol in the 5-aminolevulinic acid phosphate crystals was less than 1000 ppm. Therefore, it was demonstrated that the one-time crystallization process does not adversely affect the residual ethanol in the 5-aminolevulinic acid phosphate crystals.

[0527] The impurity concentrations in the 5-aminolevulinic acid phosphate crystals prepared in Example 4 were analyzed by HPLC. The impurity analysis results are shown in Table 26.

[0528]

[0529] As shown in Table 26, when 5-aminolevulinic acid phosphate was produced by the one-step crystallization process, no impurity peaks exceeding the detection limit (area value 0.0002) were detected, as in the two-step crystallization process in Example 3. Therefore, it was demonstrated that impurities can be reduced by using the crystallization process of the present invention, regardless of the number of crystallizations.

[0530] As shown in Table 26, when 5-aminolevulinic acid phosphate was produced by a process in which steps 6 to 10 were omitted, no impurity peaks exceeding the detection limit (area value 0.0002) were detected in the 5-aminolevulinic acid phosphate crystals, as in the case of producing 5-aminolevulinic acid phosphate crystals by a process in which steps 6 to 10 were not omitted (Example 3). This indicates that omission of steps 6 to 10 does not adversely affect the impurity concentrations in the 5-aminolevulinic acid phosphate crystals.

[0531] Although the present invention has been described in detail with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention. This application is based on a Japanese patent application (Patent Application No. 2024-144553) filed on August 26, 2024, the entirety of which is incorporated by reference. All references cited herein are incorporated in their entirety.

Claims

1. 5-aminolevulinic acid or a salt thereof that satisfies at least one of the following (A1) and (A2) based on peak areas determined by HPLC analysis: (A1) The ratio of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (1), is 0.0007 or less. (A2) The sum of the ratios of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (2), is 0.0016 or less. Ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof = Peak area of ​​each impurity quantifiable by HPLC / Peak area of ​​5-aminolevulinic acid or a salt thereof...formula (1) Sum of the ratios of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof = Σ(Peak area of ​​each impurity quantifiable by HPLC / Peak area of ​​5-aminolevulinic acid or a salt thereof)...formula (2) 2. 5-aminolevulinic acid or a salt thereof that satisfies the following (B1) and (B2): (B1) The transmittance of light at a wavelength of 430 nm is 98.8% or more. (B2) The transmittance of light at a wavelength of 430 nm measured by a severe stability test under the following conditions is 92.0% or more. Conditions for the severe stability test: After storing the 5-aminolevulinic acid or a salt thereof at a temperature of 70°C ± 2°C for two days, the transmittance of light at a wavelength of 430 nm is measured using a spectrophotometer.

3. 5-aminolevulinic acid or a salt thereof according to claim 1 or 2, wherein the content of residual organic solvent contained in the 5-aminolevulinic acid or a salt thereof is 1000 ppm or less.

4. 5-aminolevulinic acid or a salt thereof according to claim 1 or 2, wherein the arsenic content of the 5-aminolevulinic acid or a salt thereof is less than 0.3 ppm.

5. The 5-aminolevulinic acid or a salt thereof according to claim 1 or 2, wherein the 5-aminolevulinic acid or a salt thereof is 5-aminolevulinic acid phosphate.

6. A method for producing 5-aminolevulinic acid or a salt thereof, comprising the following steps [1] to [3]: [1] a step of preparing a solution containing 5-aminolevulinic acid or a salt thereof, and adding water to the solution or concentrating the solution to prepare a crystallization stock solution having a concentration of 200 to 700 g / L calculated as 5-aminolevulinic acid monophosphate; [2] a step of adjusting the temperature of the crystallization stock solution obtained in [1] to 5 to 25°C; and [3] a step of adding a first organic solvent to the crystallization stock solution obtained in [2] to precipitate 5-aminolevulinic acid or a salt thereof.

7. The method according to claim 6, wherein the 5-aminolevulinic acid or a salt thereof satisfies at least one of the following (A1) and (A2) based on peak areas determined by HPLC analysis: (A1) The ratio of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (1), is 0.0007 or less. (A2) The sum of the ratios of the content of each impurity to the content of the 5-aminolevulinic acid or a salt thereof, as represented by the following formula (2), is 0.0016 or less. Ratio of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof = Peak area of ​​each impurity quantifiable by HPLC / Peak area of ​​5-aminolevulinic acid or a salt thereof...formula (1) Sum of the ratios of the content of each impurity to the content of 5-aminolevulinic acid or a salt thereof = Σ(Peak area of ​​each impurity quantifiable by HPLC / Peak area of ​​5-aminolevulinic acid or a salt thereof)...formula (2) 8. The method according to claim 6, which satisfies the following (B1) and (B2): (B1) The transmittance of light at a wavelength of 430 nm is 98.8% or more. (B2) The transmittance of light at a wavelength of 430 nm measured by a severe stability test under the following conditions is 92.0% or more. Conditions for the severe stability test: After storing the 5-aminolevulinic acid or a salt thereof at a temperature of 70°C ± 2°C for two days, the transmittance of light at a wavelength of 430 nm is measured using a spectrophotometer.

9. The method according to claim 6, wherein the content of residual organic solvent contained in the 5-aminolevulinic acid or a salt thereof is 1000 ppm or less.

10. The method according to claim 6, wherein the arsenic content of the 5-aminolevulinic acid or a salt thereof is less than 0.3 ppm.

11. The method according to claim 6, wherein the 5-aminolevulinic acid or a salt thereof is 5-aminolevulinic acid phosphate.

12. The method according to claim 6, further comprising adding seed crystals to the crystallization solution in an amount of 0.01 to 5.0% by mass in the above [3].

13. The method according to claim 12, wherein the seed crystals are added to the crystallization solution and then stirred for less than 360 minutes to mature the crystals.

14. The method according to claim 6, wherein in [3], the amount of the first organic solvent added is 0.50 v / v or less relative to the volume of the crystallization stock solution.

15. The method according to claim 12, wherein the method according to [3] further comprises a step of adding a second organic solvent to the crystallization stock solution after adding the seed crystals.

16. The method according to claim 15, wherein the rate of addition of the second organic solvent is 0.4 to 5.0 v / v / h relative to the volume of the crystallization stock solution.

17. The method according to claim 15, wherein the total amount of the first organic solvent and the second organic solvent added is 2 v / v or less relative to the volume of the crystallization stock solution.

18. The method according to claim 6, which comprises separating and drying the precipitate obtained in [3] to obtain a powder, wherein the content of residual organic solvent in the powder is 1000 ppm or less.

19. The method according to any one of claims 6 to 18, wherein the first organic solvent in [3] is at least one selected from methanol, ethanol, isopropanol, normal propanol, acetone, and acetonitrile.

20. The method according to any one of claims 15 to 18, wherein the second organic solvent in [3] is at least one selected from methanol, ethanol, isopropanol, normal propanol, acetone, and acetonitrile.

21. The method according to claim 19, wherein the first organic solvent in [3] is ethanol.

22. The method according to claim 20, wherein the second organic solvent in [3] is ethanol.

23. A solution containing 5-aminolevulinic acid or its salt, glycine, alanine, and PDPA is dissolved in Na ＋ A method for producing 5-aminolevulinic acid or a salt thereof, comprising treating the acid with a strongly acidic cation exchange resin of the type 24. A method for producing 5-aminolevulinic acid or a salt thereof, comprising treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with at least one of a phosphoric acid type and an acetate type strong basic anion exchange resin.

25. A method for producing 5-aminolevulinic acid or a salt thereof, comprising the following steps x1) to x3) in any order: x1) treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with a strongly acidic cation exchange resin; x2) treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with a weakly acidic cation exchange resin; and x3) treating a solution containing 5-aminolevulinic acid or a salt thereof, glycine, alanine, and PDPA with a strongly basic anion exchange resin.

26. A method for producing 5-aminolevulinic acid or a salt thereof, comprising the following y1) to y4) in this order: y1) Treating solution A containing 5-aminolevulinic acid or a salt thereof, glycine, alanine and PDPA with a strongly acidic cation exchange resin to obtain solution B. y2) treating said solution B with a weakly acidic cation exchange resin to obtain solution C; y3) treating the solution C with a strong base anion exchange resin to obtain a solution D; and y4) adjusting the pH of the solution D to obtain a solution E.

27. The strongly acidic cation exchange resin is a polystyrene resin having a sulfonic acid group as a functional group, and the ion type is Na ＋ 27. The method of any one of claims 23, 25 and 26, wherein the 28. The method according to any one of claims 24 to 26, wherein the strongly basic anion exchange resin is a polystyrene-based resin having dimethylethanolammonium groups as functional groups, and the ionic form is at least one of acetate and phosphate.

29. The method according to claim 26, wherein in y1), the recovery conditions for obtaining solution B are initiated by a change in Brix and terminated by a change in pH.

30. The method according to claim 26, wherein in y2), the recovery conditions for obtaining solution C are initiated and terminated by a change in Brix.

31. The method according to claim 26, wherein in y3), the recovery conditions for obtaining solution D are initiated and terminated by a change in Brix.

Images