JP6959022B2 - Crystals of protocatechuic acid cation salt and its production method - Google Patents

Description

The present invention relates to crystals of protocatechuic acid (hereinafter referred to as PCA) cation salt, which is useful as, for example, products such as health foods, pharmaceuticals, and crystalline products, raw materials, or intermediates, and a method for producing the same.

PCA is a benzoic acid-related component present in various plant materials such as fruits and vegetables, and since it is a polyphenol like caffeic acid and curcumin, it has an antioxidant effect and lifestyle-related diseases such as arteriosclerosis. It is known to be effective in preventing. In recent years, it has also been reported that it acts suppressively against oral and colon cancer in animal experiments using carcinogens (Non-Patent Documents 1 and 2). Therefore, PCA has been attracting attention in recent years as a product such as a health food, a pharmaceutical product, a crystalline product, a raw material, or an intermediate.

As a crystal of PCA, a plurality of polymorphs of free carboxylic acid (free form) have been known so far (Non-Patent Documents 3 and 4), and commercially, a free form of oblique crystal anhydride is known. Only are on the market. However, free orthorhombic anhydride changes to monohydrate under high humidity conditions, and all free crystals have low solubility in water, making it difficult to manufacture and handle in preparation. be.

Cancer Res., Vol. 53, 3908-3913, 1993 Cancer Res., Vol. 54, 2359-2365, 1994 Proc. R. Soc. Lond. A, Vol. 387, 311-330, 1983 Proc. R. Soc. Lond. A, Vol. 197, 283-294, 1949

An object of the present invention is to provide crystals of a PCA cationic salt which is excellent in solubility and stable under high humidity conditions, and a method for producing the same.

The present invention relates to the following (1) to (26).
(1) Crystals of protocatechuic acid (hereinafter referred to as PCA) cationic salt.
(2) The crystal of (1) above, which is a crystal of PCA sodium salt / anhydrous or a crystal of PCA sodium salt / monohydrate.
(3) In powder X-ray diffraction, the diffraction angles (2θ °) are 8.9 ± 0.2 °, 28.1 ± 0.2 °, 26.5 ± 0.2 °, 25.1 ± 0.1. The crystal according to (2) above, which has peaks at 2 ° and 14.4 ± 0.2 °.
(4) In powder X-ray diffraction, the diffraction angle (2θ °) is 30.5 ± 0.2 °, 31.1 ± 0.2 °, 37.9 ± 0.2 °, 36.4 ± 0. The crystal according to (3) above, which has peaks at 2 ° and 32.3 ± 0.2 °.
(5) In powder X-ray diffraction, the diffraction angle (2θ °) is 33.3 ± 0.2 °, 22.0 ± 0.2 °, 26.9 ± 0.2 °, 23.0 ± 0. The crystal according to (4) above, which has peaks at 2 ° and 40.9 ± 0.2 °.
(6) The crystal of (1) above, which is a crystal of a PCA potassium salt / anhydrous product.
(7) In powder X-ray diffraction, the diffraction angles (2θ °) are 27.3 ± 0.2 °, 21.9 ± 0.2 °, 25.5 ± 0.2 °, 24.4 ± 0. The crystal according to (6) above, which has peaks at 2 ° and 25.3 ± 0.2 °.
(8) In powder X-ray diffraction, the diffraction angles (2θ °) are 11.2 ± 0.2 °, 18.7 ± 0.2 °, 26.9 ± 0.2 °, 32.1 ± 0. The crystal according to (7) above, which has peaks at 2 ° and 15.0 ± 0.2 °.
(9) In powder X-ray diffraction, the diffraction angle (2θ °) is 34.2 ± 0.2 °, 30.2 ± 0.2 °, 27.9 ± 0.2 °, 31.3 ± 0. The crystal according to (8) above, which has peaks at 2 ° and 39.4 ± 0.2 °.
(10) The crystal of (1) above, which is a crystal of a PCA ammonium salt / monohydrate.
(11) In powder X-ray diffraction, the diffraction angles (2θ °) are 12.2 ± 0.2 °, 25.1 ± 0.2 °, 28.2 ± 0.2 °, 17.4 ± 0. The crystal according to (10) above, which has peaks at 2 ° and 23.9 ± 0.2 °.
(12) In powder X-ray diffraction, the diffraction angles (2θ °) are 33.2 ± 0.2 °, 37.9 ± 0.2 °, 24.4 ± 0.2 °, 30.7 ± 0. The crystal according to (11) above, which has peaks at 2 ° and 15.2 ± 0.2 °.
(13) In powder X-ray diffraction, the diffraction angles (2θ °) are 29.5 ± 0.2 °, 28.6 ± 0.2 °, 21.0 ± 0.2 °, 29.1 ± 0. The crystal according to (12) above, which has peaks at 2 ° and 26.4 ± 0.2 °.
(14) The crystal of (1) above, which is a crystal of a PCA calcium salt / monohydrate.
(15) In powder X-ray diffraction, the diffraction angles (2θ °) are 9.3 ± 0.2 °, 16.7 ± 0.2 °, 27.0 ± 0.2 °, 27.7 ± 0. The crystal according to (14) above, which has peaks at 2 ° and 25.5 ± 0.2 °.
(16) In powder X-ray diffraction, the diffraction angles (2θ °) are 15.7 ± 0.2 °, 14.9 ± 0.2 °, 37.6 ± 0.2 °, 21.8 ± 0. The crystal according to (15) above, which has peaks at 2 ° and 38.8 ± 0.2 °.
(17) In powder X-ray diffraction, the diffraction angles (2θ °) are 34.4 ± 0.2 °, 25.3 ± 0.2 °, 50.0 ± 0.2 °, 40.4 ± 0. The crystal according to (16) above, which has peaks at 2 ° and 30.0 ± 0.2 °.
(18) A step of precipitating crystals of PCA cationic salt by dropping or adding an alcohol solution or a nitrile solution to an alcohol solution of PCA in which a cation-containing compound is dissolved, and a step of collecting crystals of PCA cationic salt from the solution. A method for producing crystals of a PCA cationic salt containing.
(19) The production method according to (18) above, wherein the alcohol solution to be dropped or added is a solution selected from the group consisting of alcohols C1 to C6.
(20) The production method according to (18) above, wherein the nitrile solution to be dropped or added is acetonitrile.
(21) Production of PCA cation salt crystals, which comprises a step of precipitating crystals of PCA cation salt by concentrating an aqueous solution of PCA in which a cation-containing compound is dissolved, and a step of collecting crystals of PCA cation salt from the aqueous solution. Method.
(22) The production method according to any one of (18) to (20) above, wherein the cation-containing compound is a sodium-containing compound, and the crystal of the PCA cation salt is a crystal of the PCA sodium salt / anhydrous product. ..
(23) The production method according to (21) above, wherein the cation-containing compound is a sodium-containing compound, and the crystals of the PCA cation salt are crystals of the PCA sodium salt / monohydrate.
(24) The production method according to any one of (18) to (21) above, wherein the cation-containing compound is a potassium-containing compound, and the crystals of the PCA cation salt are crystals of the PCA potassium salt / anhydrate. ..
(25) The production according to any one of (18) to (21) above, wherein the cation-containing compound is an ammonium-containing compound, and the crystal of the PCA cation salt is a crystal of the PCA ammonium salt / monohydrate. Method.
(26) The production method according to (21) above, wherein the cation-containing compound is a calcium-containing compound, and the crystals of the PCA cation salt are crystals of the PCA calcium salt / monohydrate.

INDUSTRIAL APPLICABILITY The present invention provides crystals of PCA cationic salts having excellent solubility and more stable under high humidity conditions, and a method for producing the same.

FIG. 1 shows the results of powder X-ray diffraction of the crystals of the PCA sodium salt / anhydrate obtained in Example 1. The vertical axis represents the intensity (cps), and the horizontal axis represents the diffraction angle 2θ (°). FIG. 2 shows the results of infrared spectroscopic (IR) analysis of the crystals of the PCA sodium salt / anhydrate obtained in Example 1. The vertical axis represents the light transmittance (% T), and the horizontal axis represents the wave number (1 / cm). FIG. 3 shows the results of powder X-ray diffraction of the crystals of PCA sodium salt / monohydrate obtained in Example 2. The vertical axis represents the intensity (cps), and the horizontal axis represents the diffraction angle 2θ (°). FIG. 4 shows the results of infrared spectroscopic (IR) analysis of the crystals of PCA sodium salt / monohydrate obtained in Example 2. The vertical axis represents the light transmittance (% T), and the horizontal axis represents the wave number (1 / cm). FIG. 5 shows the results of powder X-ray diffraction of the crystals of the PCA potassium salt / anhydrate obtained in Example 3. The vertical axis represents the intensity (cps), and the horizontal axis represents the diffraction angle 2θ (°). FIG. 6 shows the results of infrared spectroscopic (IR) analysis of the crystals of the PCA potassium salt / anhydrate obtained in Example 3. The vertical axis represents the light transmittance (% T), and the horizontal axis represents the wave number (1 / cm). FIG. 7 shows the results of powder X-ray diffraction of the crystals of the PCA ammonium salt / monohydrate obtained in Example 4. The vertical axis represents the intensity (cps), and the horizontal axis represents the diffraction angle 2θ (°). FIG. 8 shows the results of infrared spectroscopic (IR) analysis of the crystals of PCA ammonium salt / monohydrate obtained in Example 4. The vertical axis represents the light transmittance (% T), and the horizontal axis represents the wave number (1 / cm). FIG. 9 shows the results of powder X-ray diffraction of the crystals of the PCA calcium salt / monohydrate obtained in Example 5. The vertical axis represents the intensity (cps), and the horizontal axis represents the diffraction angle 2θ (°). FIG. 10 shows the results of infrared spectroscopic (IR) analysis of the crystals of PCA calcium salt / monohydrate obtained in Example 5. The vertical axis represents the light transmittance (% T), and the horizontal axis represents the wave number (1 / cm).

1. 1. Crystal of the present invention The crystal of the present invention is a crystal of a PCA cationic salt.
The crystal of the present invention may be a crystal of a salt composed of PCA ions and cations, and the type of cations is not particularly limited. Specifically, for example, PCA ions and sodium ions are contained in a ratio of 1: 1. Salt crystals (hereinafter referred to as PCA sodium salt crystals), salt crystals containing PCA ions and potassium ions at a ratio of 1: 1 (hereinafter referred to as PCA potassium salt crystals), PCA ions and ammonium ions. Crystals of a salt containing 1: 1 (hereinafter referred to as PCA ammonium salt crystals), and crystals of a salt containing PCA ions and calcium ions at a ratio of 2: 1 (hereinafter referred to as PCA calcium salt crystals). .) Can be mentioned.
1-1. Crystals of PCA sodium salt It can be confirmed by analysis using, for example, HPLC that the crystals of PCA sodium salt are crystals of PCA.

Examples of the analysis conditions in the analysis using HPLC include the following conditions.
Column: Column Lcolumn2 ODS φ4.6 × 150mm
Column temperature: 40 ° C
Mobile phase: A solution in which a 20 mol / L phosphoric acid aqueous solution and acetonitrile are mixed at a volume ratio of 4: 1.
Flow velocity: 1.0 mL / min
Detector: UV detector (wavelength 254 nm)
The fact that the crystals are crystals of PCA sodium salt can also be confirmed by analysis by powder X-ray diffraction.

The analysis by powder X-ray diffraction can be performed, for example, by using a powder X-ray diffractometer (XRD) Ultima IV (manufactured by Rigaku), using CuKα as an X-ray source, and following the attached instruction manual.
The crystals of the PCA sodium salt may be anhydrous crystals or hydrated crystals, and preferred examples include anhydrous crystals or monohydrate crystals.

As the crystal of such anhydrous product, specifically, the crystal of _{PCA sodium salt / anhydrous product represented by the composition formula of [C 7} H ₅ O ₄ Na] is used as the crystal of monohydrate. Specifically, crystals of PCA sodium salt / monohydrate represented by the composition formula of _{[C 7} H ₅ O ₄ Na] H _{2 O can be mentioned.}
It can be confirmed that the crystal of the PCA sodium salt is a crystal of the sodium salt by measuring the sodium content contained in the crystal.

The sodium content can be measured using, for example, an atomic absorption spectrophotometer Z-2310 (manufactured by Hitachi High-Technologies Corporation) according to the attached instruction manual.
The sodium content of the crystals of PCA sodium salt varies depending on the number of hydrated water contained in the crystals, but when the crystals of PCA sodium salt are anhydrous crystals, the crystals of PCA sodium salt are crystals of sodium salt. That is, the sodium content in the crystal is usually 13.1 ± 3.0% by weight, preferably 13.1 ± 2.0% by weight, and most preferably 13.1 ± 1.0% by weight. It can be confirmed by. When the crystal of PCA sodium salt is a monohydrate crystal, the fact that the crystal of PCA sodium salt is a crystal of sodium salt means that the sodium content in the crystal is usually 11.8 ± 3.0 weight. %, Preferably 11.8 ± 2.0% by weight, most preferably 11.8 ± 1.0% by weight.

The fact that the crystals of the PCA sodium salt are anhydrous crystals means that the water content in the crystals is usually 1.5% by weight or less, preferably 1.3% by weight, according to the Karl Fischer method or thermogravimetric differential thermal analysis. It can be confirmed by% or less, more preferably 1.0% by weight or less. Further, the fact that the crystal of the PCA sodium salt is a monohydrate crystal means that the water content in the crystal is usually 9.3 ± 3.0% by weight, preferably 9.3 ± 2.0% by weight. , More preferably 9.3 ± 1.0% by weight.

The water content measurement by the Karl Fischer method can be performed using, for example, an automatic water content measuring device AQV-2200 (manufactured by Hiranuma Sangyo Co., Ltd.) according to the attached instruction manual.
Examples of the crystals of the PCA sodium salt include crystals having a peak at the diffraction angle 2θ (°) described in the following (i) in powder X-ray diffraction using CuKα as an X-ray source, and the following (i) A crystal having a peak at the diffraction angle 2θ (°) described in (ii) is preferable, and a crystal having a peak at the diffraction angle 2θ (°) described in (i), (ii) and (iii) below is more preferable. ..
(I) 8.9 ± 0.2 °, 28.1 ± 0.2 °, 26.5 ± 0.2 °, 25.1 ± 0.2 °, and 14.4 ± 0.2 °
(Ii) 30.5 ± 0.2 °, 31.1 ± 0.2 °, 37.9 ± 0.2 °, 36.4 ± 0.2 °, and 32.3 ± 0.2 °
(Iii) 33.3 ± 0.2 °, 22.0 ± 0.2 °, 26.9 ± 0.2 °, 23.0 ± 0.2 °, and 40.9 ± 0.2 °
Specifically, as a crystal of PCA sodium salt, a powder X-ray diffraction pattern using CuKα as an X-ray source is a PCA sodium salt / anhydrous sum defined by the pattern shown in FIG. 1 and the value of the diffraction angle shown in Table 1. When subjected to infrared spectroscopic (IR) analysis, a crystal of a product or a crystal of a PCA sodium salt / anhydrous product showing an infrared absorption spectrum shown in FIG. 2 can be mentioned.

As a specific example of the crystals of the PCA sodium salt, a powder X-ray diffraction pattern using CuKα as an X-ray source is defined by the pattern shown in FIG. 3 and the diffraction angle values shown in Table 3. Crystals of monohydrate and crystals of PCA sodium salt / monohydrate showing the infrared absorption spectrum shown in FIG. 4 when subjected to infrared spectroscopic (IR) analysis can also be mentioned.
Infrared spectroscopy (IR) analysis can be performed using, for example, FTIR-8400 (manufactured by Shimadzu Corporation) according to the attached instruction manual.
1-2. Crystals of PCA potassium salt It can be confirmed that the crystals of PCA potassium salt are crystals of PCA, for example, by analysis using HPLC similar to 1-1 above.

It can be confirmed that the crystal is a crystal of PCA potassium salt by the same analysis by powder X-ray diffraction as in 1-1 above.
The crystals of the PCA potassium salt may be an anhydrous crystal or a hydrate crystal, and preferably an anhydrous crystal can be mentioned.
Specific examples of such anhydrate crystals include crystals of a PCA potassium salt / anhydrous salt represented by the composition formula of _{[C 7} H ₅ O _{4 K].}

It can be confirmed that the crystal of the PCA potassium salt is a crystal of the potassium salt by measuring the potassium content contained in the crystal by the same method as in 1-1 above.
The potassium content of the PCA potassium salt crystal varies depending on the number of hydrated water contained in the crystal, but when the PCA potassium salt crystal is an anhydrous crystal, the PCA potassium salt crystal is a potassium salt crystal. That is, the potassium content in the crystal is usually 20.3 ± 3.0% by weight, preferably 20.3 ± 2.0% by weight, and most preferably 20.3 ± 1.0% by weight. It can be confirmed by.

The fact that the crystals of the PCA potassium salt are anhydrous crystals means that the water content in the crystals is usually 1.5% by weight or less, preferably 1.3% by weight, according to the Karl Fischer method or thermogravimetric differential thermal analysis. It can be confirmed by% or less, more preferably 1.0% by weight or less.
The water content can be measured by the Karl Fischer method in the same manner as in 1-1 above.

Examples of the crystals of the PCA potassium salt include crystals having a peak at the diffraction angle 2θ (°) described in the following (iv) in powder X-ray diffraction using CuKα as an X-ray source, and the following (iv) A crystal having a peak at the diffraction angle 2θ (°) described in (v) is preferable, and a crystal having a peak at the diffraction angle 2θ (°) described in (iv), (v) and (vi) below is more preferable. ..
(Iv) 27.3 ± 0.2 ° preferably ± 0.1 °, 21.9 ± 0.2 ° preferably ± 0.1 °, 25.5 ± 0.2 ° preferably ± 0.1 ° , 24.4 ± 0.2 °, preferably ± 0.1 °, and 25.3 ± 0.2 °, preferably ± 0.1 °
(V) 11.2 ± 0.2 ° preferably ± 0.1 °, 18.7 ± 0.2 ° preferably ± 0.1 °, 26.9 ± 0.2 ° preferably ± 0.1 ° , 32.1 ± 0.2 °, preferably ± 0.1 °, and 15.0 ± 0.2 °, preferably ± 0.1 °
(Vi) 34.2 ± 0.2 ° preferably ± 0.1 °, 30.2 ± 0.2 ° preferably ± 0.1 °, 27.9 ± 0.2 ° preferably ± 0.1 ° 3, 31.3 ± 0.2 °, preferably ± 0.1 °, and 39.4 ± 0.2 °, preferably ± 0.1 °
Specifically, as a crystal of PCA potassium salt, a powder X-ray diffraction pattern using CuKα as an X-ray source is a PCA potassium salt / anhydrous sum defined by the pattern shown in FIG. 5 and the diffraction angle value shown in Table 5. When subjected to infrared spectroscopic (IR) analysis, a crystal of a product or a crystal of a PCA potassium salt / anhydrous product showing an infrared absorption spectrum shown in FIG. 6 can be mentioned.

Infrared spectroscopy (IR) analysis can be performed in the same manner as in 1-1 above.
1-3. Crystals of PCA ammonium salt It can be confirmed that the crystals of PCA ammonium salt are crystals of PCA, for example, by analysis using HPLC similar to 1-1 above.
It can be confirmed that the crystal is a crystal of PCA ammonium salt by the same analysis by powder X-ray diffraction as in 1-1 above.

The crystals of the PCA ammonium salt may be an anhydrous crystal or a hydrate crystal, and preferably a hydrate crystal can be mentioned, and more preferably a monohydrate crystal. Crystals can be mentioned.
Specific examples of such monohydrate crystals include crystals of PCA ammonium salt / monohydrate represented by the composition formula of _{[C 7} H ₅ O ₄ NH ₄ ] H _{2 O.} can.

It can be confirmed that the crystal of the PCA ammonium salt is a crystal of the ammonium salt by measuring the ammonium content contained in the crystal.
The ammonium content can be confirmed, for example, by analysis using HPLC.
Examples of the analysis method using HPLC include the phthalaldehyde method, and specific analysis conditions include the following HPLC conditions (post-column method).
Column: YMC-PACK ODS-AQ (150 x 6.0 mm 5 μm)
Column temperature: 40 ° C
Mobile phase: A) 14.7 g trisodium citrate dihydrate, 7.1 g anhydrous sodium sulfate, 15 g SDS, 600 mL n-propanol prepared in 5 L with pure water (pH 3.8), B) 18. 5 g boric acid, 11 g sodium hydroxide, 4.1 mL Brij-35, 0.6 go-phthalaldehyde, 4.6 g N-acetylcysteine prepared in 1 L with pure water Flow velocity: A) 1.2 mL / min, B ) 0.4 mL / min
Detector: Fluorescence detector (excitation wavelength: 355 nm, detection wavelength: 455 nm)
The ammonium content of the PCA ammonium salt crystal varies depending on the number of hydrated water contained in the crystal, but when the PCA ammonium salt crystal is a monohydrate crystal, the PCA ammonium salt crystal is the ammonium salt. Being a crystal means that the ammonium content in the crystal is usually 9.5 ± 3.0% by weight, preferably 9.5 ± 2.0% by weight, and most preferably 9.5 ± 1.0% by weight. It can be confirmed by the presence.

The fact that the crystals of the PCA ammonium salt are monohydrate crystals means that the water content in the crystals is usually 9.5 ± 3.0% by weight, preferably 9.5 ± 3.0% by weight, according to the Karl Fischer method or thermogravimetric differential thermal analysis. It can be confirmed by 9.5 ± 2.0% by weight, most preferably 9.5 ± 1.0% by weight.
The water content can be measured by the Karl Fischer method, for example, in the same manner as in 1-1 above.

Examples of the crystals of the PCA ammonium salt include crystals having a peak at the diffraction angle 2θ (°) described in the following (vii) in powder X-ray diffraction using CuKα as an X-ray source, and the following (vii) And (viii), a crystal having a peak at a diffraction angle of 2θ (°) is preferable, and a crystal having a peak at a diffraction angle of 2θ (°) described in (vii), (viii) and (ix) below is more preferable. ..
(Vii) 12.2 ± 0.2 ° preferably ± 0.1 °, 25.1 ± 0.2 ° preferably ± 0.1 °, 28.2 ± 0.2 ° preferably ± 0.1 ° , 17.4 ± 0.2 °, preferably ± 0.1 °, and 23.9 ± 0.2 °, preferably ± 0.1 °
(Viii) 33.2 ± 0.2 °, preferably ± 0.1 °, 37.9 ± 0.2 °, preferably ± 0.1 °, 24.4 ± 0.2 °, preferably ± 0.1 ° 3, 30.7 ± 0.2 °, preferably ± 0.1 °, and 15.2 ± 0.2 °, preferably ± 0.1 °
(Ix) 29.5 ± 0.2 °, preferably ± 0.1 °, 28.6 ± 0.2 °, preferably ± 0.1 °, 21.0 ± 0.2 °, preferably ± 0.1 ° , 29.1 ± 0.2 °, preferably ± 0.1 °, and 26.4 ± 0.2 °, preferably ± 0.1 °
Specifically, as a crystal of PCA ammonium salt, a powder X-ray diffraction pattern using CuKα as an X-ray source is defined by the pattern shown in FIG. 7 and the value of the diffraction angle shown in Table 7, PCA ammonium salt and 1 water. Examples include crystals of Japanese products or crystals of PCA ammonium salt / monohydrate showing the infrared absorption spectrum shown in FIG. 8 when subjected to infrared spectroscopic (IR) analysis.

Infrared spectroscopy (IR) analysis can be performed, for example, in the same manner as 1-1 above.
1-4. Crystals of PCA calcium salt It can be confirmed that the crystals of PCA calcium salt are crystals of PCA, for example, by analysis using HPLC similar to 1-1 above.
The fact that the crystals are crystals of PCA calcium salt can also be confirmed by the same analysis by powder X-ray diffraction as in 1-1 above.

The crystals of the PCA calcium salt may be anhydrous crystals or hydrate crystals, and preferably hydrate crystals can be mentioned, and more preferably monohydrate crystals. Crystals can be mentioned.
Specific examples of such monohydrate crystals include crystals of PCA calcium salt / monohydrate represented by the composition formula of _{[C 7} H ₅ O ₄ Ca _1/2 ] H _{2 O.} be able to.

The fact that the crystals of the PCA calcium salt are crystals of the calcium salt can be confirmed by measuring the calcium content contained in the crystals by the same method as in 1-1 above.
The calsim content of the crystals of the PCA calcium salt varies depending on the number of hydrated waters in the crystals, but when the crystals of the PCA calcium salt are monohydrate crystals, the crystals of the PCA calcium salt are of the calcium salt. Being a crystal means that the calcium content in the crystal is usually 10.5 ± 3.0% by weight, preferably 10.5 ± 2.0% by weight, and most preferably 10.5 ± 1.0% by weight. It can be confirmed by the presence.

The fact that the crystals of the PCA calcium salt are monohydrate crystals means that the water content in the crystals is usually 9.4 ± 3.0% by weight, preferably 9.4 ± 3.0% by weight, according to the Karl Fischer method or thermogravimetric differential thermal analysis. It can be confirmed by 9.4 ± 2.0% by weight, most preferably 9.4 ± 1.0% by weight.
The water content can be measured by the Karl Fischer method, for example, in the same manner as in 1-1 above.

Examples of the crystals of the PCA calcium salt include crystals having a peak at the diffraction angle 2θ (°) described in the following (x) in powder X-ray diffraction using CuKα as an X-ray source, and the following (x) A crystal having a peak at the diffraction angle 2θ (°) described in (xi) is preferable, and a crystal having a peak at the diffraction angle 2θ (°) described in (x), (xi) and (xii) below is more preferable. ..
(X) 9.3 ± 0.2 ° preferably ± 0.1 °, 16.7 ± 0.2 ° preferably ± 0.1 °, 27.0 ± 0.2 ° preferably ± 0.1 ° , 27.7 ± 0.2 °, preferably ± 0.1 °, and 25.5 ± 0.2 °, preferably ± 0.1 °
(Xi) 15.7 ± 0.2 ° preferably ± 0.1 °, 14.9 ± 0.2 ° preferably ± 0.1 °, 37.6 ± 0.2 ° preferably ± 0.1 ° , 21.8 ± 0.2 °, preferably ± 0.1 °, and 38.8 ± 0.2 °, preferably ± 0.1 °
(Xii) 34.4 ± 0.2 ° preferably ± 0.1 °, 25.3 ± 0.2 ° preferably ± 0.1 °, 50.0 ± 0.2 ° preferably ± 0.1 ° 4,0.4 ± 0.2 °, preferably ± 0.1 °, and 30.0 ± 0.2 °, preferably ± 0.1 °
Specifically, as a crystal of PCA calcium salt, a powder X-ray diffraction pattern using CuKα as an X-ray source is a PCA calcium salt / 1 water defined by the pattern shown in FIG. 9 and the diffraction angle value shown in Table 9. Crystals of Japanese products or crystals of PCA calcium salt / monohydrate showing the infrared absorption spectrum shown in FIG. 10 when subjected to infrared spectroscopic (IR) analysis can be mentioned.

Infrared spectroscopy (IR) analysis can be performed, for example, in the same manner as 1-1 above.
2. Method for Producing Crystal of the Present Invention The method for producing the crystal of the present invention is the production method according to 2-1 or 2-2 below.
2-1. Method 1 for producing a crystal of the present invention
The method for producing crystals of the present invention is a step of precipitating crystals of PCA cationic salt by dropping or adding an alcohol solution or a nitrile solution to an alcohol solution of PCA in which a cation-containing compound is dissolved, and a step of precipitating crystals of PCA cationic salt from the solution. A method for producing crystals of a PCA cationic salt, which comprises a step of collecting crystals.

The PCA contained in the alcohol solution of the PCA in which the cation-containing compound is dissolved may be produced by any production method such as a fermentation method, an enzyme method, an extraction method from a natural product, or a chemical synthesis method.
When the alcohol solution of PCA in which the cation-containing compound is dissolved contains a solid substance that hinders crystallization, the solid substance can be removed by centrifugation, filtration, a ceramic filter, or the like.

If the alcohol solution of PCA in which the cation-containing compound is dissolved contains water-soluble impurities or salts that hinder crystallization, it is passed through a column filled with an ion exchange resin or the like. Water-soluble impurities and salts can be removed.
If the alcohol solution of PCA in which the cation-containing compound is dissolved contains hydrophobic impurities that hinder crystallization, it is hydrophobic by passing it through a column filled with a synthetic adsorption resin, activated carbon, or the like. Impurities can be removed.

It is desirable to adjust the concentration of PCA in the alcohol solution of PCA in which the cation-containing compound is dissolved to be 40 g / L or more, preferably 50 g / L or more, and more preferably 60 g / L or more.
In order to bring the concentration of the solution to the above concentration, the solution can be concentrated by a general concentration method such as a heat concentration method or a vacuum concentration method.

Specific examples of the cation-containing compound include sodium-containing compounds, potassium-containing compounds, and ammonium-containing compounds.
Examples of the sodium-containing compound include basic compounds such as sodium hydroxide, and neutral salts such as sodium charcoal oxide, sodium sulfate, sodium glass oxide, and sodium chloride. Examples of the neutral salt include sodium carbonate, sodium sulfate, sodium nitrate, and sodium chloride.

When a basic compound is used as the sodium-containing compound, the pH is usually 4.0 to 10.0, preferably 4.5 to 9. By adjusting the pH of the alcohol solution of PCA using the basic compound. 5. An alcohol solution of PCA in which a sodium-containing compound, most preferably 5.0 to 9.0, is dissolved can be obtained.
Examples of the potassium-containing compound include basic compounds such as potassium hydroxide, and neutral salts such as potassium charcoal oxide, potassium sulfate, potassium glass oxide, and potassium chloride. Examples of the neutral salt include potassium carbonate, potassium sulfate, potassium nitrate, and potassium chloride.

When a basic compound is used as the potassium-containing compound, the pH is usually 4.0 to 10.0, preferably 4.5 to 9. By adjusting the pH of the alcohol solution of PCA using the basic compound. 5. An alcohol solution of PCA in which a potassium-containing compound, most preferably 5.0 to 9.0, is dissolved can be obtained.
Examples of the ammonium-containing compound include a basic compound such as ammonia, a carbon oxide of ammonia, a sulfated product of ammonia, a glass oxide of ammonia, and a neutral salt such as a chloride of ammonia. Examples of the neutral salt include ammonium carbonate, ammonium sulfate, ammonium nitrate, and ammonium chloride.

When a basic compound is used as the ammonium-containing compound, the pH is usually 4.0 to 10.0, preferably 4.5 to 9. By adjusting the pH of the alcohol solution of PCA using the basic compound. 5. An alcohol solution of PCA in which an ammonium-containing compound, most preferably 5.0 to 9.0, is dissolved can be obtained.
When a sodium-containing compound is used as the cation-containing compound in 2-1 the obtained crystals of the PCA cation salt are crystals of the PCA sodium salt, more specifically, crystals of the PCA sodium salt / anhydrous product.

In 2-1 when a potassium-containing compound is used as the cation-containing compound, the obtained PCA cation salt crystal is a PCA potassium salt crystal, more specifically, a PCA potassium salt / anhydrous crystal.
In 2-1 when an ammonium-containing compound is used as the cation-containing compound, the obtained crystals of the PCA cation salt are crystals of the PCA ammonium salt, more specifically, crystals of the PCA ammonium salt / monohydrate.

The alcohol solution to be added or dropped into the solution is preferably from C1 to C6 alcohols, more preferably from C1 to C3 alcohols, and even more preferably from methanol, ethanol, n-propanol and isopropyl alcohol. Alcohols selected from the above group, more preferably methanol or ethanol, and most preferably ethanol.

The alcohol solution may be a mixture of a plurality of alcohols, or a mixture of an alcohol and another organic solvent or water.
When the alcohol solution is a mixture of alcohol and water, the water content may be 40% by weight or less, preferably 20% by weight or less, more preferably 10% by weight or less, and most preferably 5% by weight or less.

Specific examples of the nitrile solution added or dropped into the solution include acetonitrile.
The nitrile solution may be a mixture with water, in which case the water content is 40% by weight or less, preferably 20% by weight or less, more preferably 10% by weight or less, and most preferably 5% by weight or less. Can be mentioned.

The temperature of the solution in the step of precipitating crystals of PCA cationic salt by adding or dropping an alcohol solution or a nitrile solution to the solution is 0 to 40 ° C, preferably 0 to 30 ° C, more preferably 0. ~ 20 ° C., most preferably 0-10 ° C. can be mentioned.
In the step of precipitating crystals of PCA cationic salt by adding or dropping an alcohol solution or a nitrile solution into the solution, the amount of the alcohol solution or nitrile to be dropped or added is 1 to 30 times the amount of the solution. , Preferably 1 to 20 times equal amount, most preferably 1 to 10 times equal amount.

The time required for the addition or dropping of the alcohol solution or nitrile in the step of precipitating the crystals of the PCA cationic salt by adding or dropping the alcohol solution or the nitrile solution into the solution is 1 to 48 hours, preferably 2 to 2. 24 hours, most preferably 3-12 hours.
In 2-1 immediately before the step of precipitating crystals of the PCA cationic salt by dropping or adding an alcohol solution or a nitrile solution to the alcohol solution of PCA in which the cation-containing compound is dissolved, or immediately before the step of precipitating crystals of the PCA cationic salt, or in the solution, the alcohol solution or nitrile. In the step of precipitating the crystals of the PCA cationic salt by dropping or adding the solution, the seed crystals may be added before the crystals of the PCA cationic salt are precipitated.

As the seed crystal, for example, the crystal of the PCA cation salt obtained in 2-1 can be used.
When a sodium-containing compound is used as the cation-containing compound and a crystal of the PCA sodium salt / anhydrous product is used as the seed crystal, the obtained PCA cation salt crystal is a crystal of the PCA sodium salt / anhydrous product.

When a potassium-containing compound is used as the cation-containing compound and a crystal of a PCA potassium salt / anhydrous product is used as a seed crystal, the obtained PCA cation salt crystal is a crystal of the PCA potassium salt / anhydrous product.
When an ammonium-containing compound is used as the cation-containing compound and a PCA ammonium salt / monohydrate crystal is used as the seed crystal, the obtained PCA cation salt crystal is a PCA ammonium salt / monohydrate crystal.

Seed crystals are added so that the concentration in the aqueous solution is 0.001 to 50 g / L, preferably 0.01 to 10 g / L, and more preferably 0.1 to 5 g / L.
The seed crystal can be added, for example, in the range of 0 to 12 hours, preferably 0 to 8 hours, and most preferably 0 to 4 hours after the start of addition or dropping of the alcohol solution or the nitrile solution. ..

After the crystals of the PCA cationic salt are precipitated by the above method, the precipitated crystals can be aged for 1 to 48 hours, preferably 1 to 24 hours, and most preferably 1 to 12 hours.
Aging the crystals means stopping the step of precipitating the crystals of the PCA cationic salt and growing the crystals.
Growing a crystal means increasing the number of crystals based on the precipitated crystal.

The aging of the crystal is carried out mainly for the purpose of growing the crystal, but the precipitation of a new crystal may occur at the same time as the crystal growth.
Stopping the step of precipitating the crystals of the PCA cationic salt means, for example, suspending the addition or dropping of the alcohol solution or the nitrile solution.
After aging the crystals, the step of precipitating the crystals of the PCA cationic salt may be resumed.

In the step of collecting the crystals of the PCA cationic salt, for example, filtration, pressure filtration, suction filtration, centrifugation and the like can be performed. Further, in order to reduce the adhesion of the mother liquor to the crystals and improve the quality of the crystals, the crystals can be appropriately washed after the crystals are collected.
As the solution used for crystal washing, for example, a solution obtained by mixing one or more kinds selected from the group consisting of water, methanol, ethanol, acetone, n-propanol, and isopropyl alcohol at an arbitrary ratio can be used.

The crystals of the present invention can be obtained by drying the wet crystals thus obtained.
The drying conditions are not particularly limited as long as the crystal form of the PCA cationic salt can be maintained, and vacuum drying, vacuum drying, fluidized bed drying, ventilation drying and the like can be applied.
The drying temperature may be any temperature as long as it can remove the adhering moisture or the solution, but preferably 80 ° C. or lower, more preferably 70 ° C. or lower, and most preferably 60 ° C. or lower.

The drying time may be any range as long as it can remove the adhering water or the solution, but preferably 1 to 60 hours, more preferably 1 to 48 hours.
The purity of the crystals of the PCA cationic salt obtained by the above method may be 95% or more, preferably 96% or more, more preferably 97% or more, and most preferably 97.5% or more.

The purity of the crystals of the PCA cation salt can be confirmed, for example, by analysis using HPLC similar to 1-1 above.
As the crystals of the PCA cation salt that can be produced by the above production method, specifically, a powder X-ray diffraction pattern using CuKα as an X-ray source is a pattern shown in FIG. 1 and a diffraction angle shown in Table 1. Crystals of PCA sodium salt / hydrate specified by the value of, the pattern shown in FIG. 5 and the crystal of PCA potassium salt / hydrate specified by the value of the diffraction angle shown in Table 5, and the pattern shown in FIG. And the crystals of the PCA ammonium salt / monohydrate defined by the values of the diffraction angles shown in Table 7 can be mentioned.

As the crystals of the PCA cation salt that can be produced by the above production method, the PCA sodium salt / anhydrous product showing the infrared absorption spectrum shown in FIG. 2 when subjected to infrared spectroscopy (IR) analysis. Examples thereof include crystals, crystals of PCA potassium salt / anhydride showing an infrared absorption spectrum shown in FIG. 6, and crystals of PCA ammonium salt / monohydrate showing an infrared absorption spectrum shown in FIG. 8.
2-2. Method 2 for producing a crystal of the present invention
As a method for producing crystals of the present invention, in addition to the method of 2-1 above, a step of precipitating crystals of PCA cation salt by concentrating an aqueous solution of PCA in which a cation-containing compound is dissolved, and a step of precipitating crystals of a PCA cation salt from the aqueous solution, and a PCA cation from the aqueous solution. Examples thereof include a method for producing crystals of PCA cationic salt, which comprises a step of collecting salt crystals.

The PCA contained in the aqueous solution of the PCA in which the cation-containing compound is dissolved may be produced by any production method such as a fermentation method, an enzyme method, an extraction method from a natural product, or a chemical synthesis method.
When the aqueous solution of PCA in which the cation-containing compound is dissolved contains a solid substance that hinders crystallization, the aqueous solution of PCA in which the cation-containing compound is dissolved contains water-soluble impurities and salts that hinder crystallization. If this is the case, or if the aqueous solution of PCA in which the cation-containing compound is dissolved contains hydrophobic impurities that hinder crystallization, the same treatment as in 2-1 above can be performed.

It is desirable to adjust the concentration of PCA in the aqueous solution of PCA in which the cation-containing compound is dissolved to be 30 g / L or more, preferably 40 g / L or more, and more preferably 50 g / L or more.
Specific examples of the cation-containing compound include sodium-containing compounds, potassium-containing compounds, ammonium-containing compounds, and calcium-containing compounds.

As the sodium-containing compound, the potassium-containing compound, and the ammonium compound, the same compounds as in 2-1 can be used.
Examples of the calcium-containing compound include a basic compound such as calcium hydroxide, or a neutral salt such as a carbon oxide of calcium, a sulfated product of calcium, a glass oxide of calcium or a chloride of calcium. Examples of the neutral salt include calcium carbonate, calcium sulfate, calcium nitrate, and calcium chloride.

When each basic compound is used as the cation-containing compound, the pH is usually 4.0 to 10.0, preferably 4.5 to 9 by adjusting the pH of the aqueous solution of PCA using the basic compound. An aqueous solution of PCA in which the cation-containing compound, which is 5.5, most preferably 5.0 to 9.0, is dissolved can be obtained.
When a sodium-containing compound is used as the cation-containing compound in 2-2, the obtained crystals of the PCA cation salt are crystals of the PCA sodium salt, more specifically, crystals of the PCA sodium salt / monohydrate.

In 2-2, when a potassium-containing compound is used as the cation-containing compound, the obtained PCA cation salt crystal is a PCA potassium salt crystal, and more specifically, a PCA potassium salt / anhydrous crystal.
When an ammonium-containing compound is used as the cation-containing compound in 2-2, the obtained crystals of the PCA cation salt are crystals of the PCA ammonium salt, more specifically, crystals of the PCA ammonium salt / monohydrate.

When a calcium-containing compound is used as the cation-containing compound in 2-2, the obtained crystals of the PCA cation salt are crystals of the PCA calcium salt, more specifically, crystals of the PCA calcium salt / monohydrate.
In the step of precipitating the crystals of the PCA cationic salt by concentrating the aqueous solution, a general concentration method such as a vacuum concentration method or a heat concentration method can be used.

When the aqueous solution is concentrated under reduced pressure, the temperature of the aqueous solution may be 40 to 80 ° C, preferably 40 to 70 ° C, and most preferably 40 to 60 ° C.
When the aqueous solution is concentrated under reduced pressure, the time required for concentration varies depending on the concentration of PCA in the aqueous solution and the temperature of the aqueous solution, but it may be any time as long as the crystals of the PCA cationic salt are precipitated in the aqueous solution. A person skilled in the art can appropriately set the setting in the range of, for example, 1 to 24 hours, preferably 2 to 18 hours, and most preferably 3 to 12 hours.

When the aqueous solution is heated and concentrated, the temperature of the aqueous solution may be 40 to 80 ° C, preferably 50 to 70 ° C.
When the aqueous solution is heated and concentrated, the time required for concentration varies depending on the concentration of PCA in the aqueous solution and the temperature of the aqueous solution, but it may be any time as long as the crystals of the PCA cationic salt are precipitated in the aqueous solution. A person skilled in the art can appropriately set the temperature in the range of, for example, 1 to 24 hours, preferably 2 to 18 hours, and most preferably 3 to 12 hours.

In 2-2, immediately before the step of precipitating the crystals of the PCA cation salt by concentrating the aqueous solution of PCA in which the cation-containing compound is dissolved, or the step of precipitating the crystals of the PCA cation salt by concentrating the solution. In, seed crystals may be added before the crystals of the PCA cationic salt are precipitated.
As the seed crystal, for example, the crystal of the PCA cation salt obtained in 2-2 can be used.

When a sodium-containing compound is used as the cation-containing compound and a PCA sodium salt / monohydrate crystal is used as the seed crystal, the obtained PCA cation salt crystal is a PCA sodium salt / monohydrate crystal.
When a potassium-containing compound is used as the cation-containing compound and a crystal of PCA potassium salt / anhydrous is used as the seed crystal, the obtained PCA cation salt crystal is a crystal of PCA potassium salt / anhydrous.

When an ammonium-containing compound is used as the cation-containing compound and a PCA ammonium salt / monohydrate crystal is used as the seed crystal, the obtained PCA cation salt crystal is a PCA ammonium salt / monohydrate crystal.
When a calcium-containing compound is used as the cation-containing compound and a PCA calcium salt / monohydrate crystal is used as the seed crystal, the obtained PCA cation salt crystal is a PCA calcium salt / monohydrate crystal.

Seed crystals are added so that the concentration in the aqueous solution is 0.001 to 50 g / L, preferably 0.01 to 10 g / L, and more preferably 0.1 to 5 g / L.
The seed crystal can be added, for example, 0 to 12 hours after the start of concentration of the aqueous solution of PCA in which the cation-containing compound is dissolved, preferably 0 to 8 hours, and most preferably 0 to 4 hours.

After the crystals of the PCA cationic salt are precipitated by the above method, the precipitated crystals can be aged for 1 to 48 hours, preferably 1 to 24 hours, and most preferably 1 to 12 hours.
Aging the crystals means stopping the step of precipitating the crystals of the PCA cationic salt and growing the crystals.
The crystal growth and aging are the same as in 2-1 above.

Stopping the step of precipitating the crystals of the PCA cationic salt means, for example, interrupting the concentration step in the case of precipitating the crystals of the PCA cationic salt by concentrating the aqueous solution under reduced pressure.
After aging the crystals, the step of precipitating the crystals of the PCA cationic salt may be resumed.
After precipitating the crystals of the PCA cation salt by the above method, the crystals of the PCA cation salt can be collected by the same step as in the above 2-1.

The purity of the crystals of the PCA cationic salt obtained by the above method may be 95% or more, preferably 96% or more, more preferably 97% or more, and most preferably 97.5% or more.
The purity of the crystals of the PCA cation salt can be confirmed, for example, by analysis using HPLC similar to 1-1 above.

As the crystals of the PCA cation salt that can be produced by the above production method, specifically, a powder X-ray diffraction pattern using CuKα as an X-ray source is a pattern shown in FIG. 3 and a diffraction angle shown in Table 3. Crystals of PCA sodium salt / monohydrate specified by the value of, and crystals of PCA calcium salt / monohydrate specified by the values of the pattern shown in FIG. 9 and the diffraction angle shown in Table 9 can be mentioned. can.

As the crystals of the PCA cation salt that can be produced by the above production method, the PCA sodium salt / monohydrate showing the infrared absorption spectrum shown in FIG. 4 when subjected to infrared spectroscopy (IR) analysis. Crystals of PCA calcium salt / monohydrate showing the infrared absorption spectrum shown in FIG. 10 can be mentioned.

Examples are shown below, but the present invention is not limited to the following examples.

Acquisition of Crystals of PCA Sodium Salt / Anhydrous A PCA reagent (manufactured by Wako Pure Chemical Industries, Ltd., anhydrous crystals) was dissolved in ethanol to make a total volume of 100 mL. The solution was filtered using a membrane filter (CP045AN, manufactured by Advantech Toyo Co., Ltd.) to obtain a filtrate. 130 mL of a 1 mol / L sodium hydroxide aqueous solution was added to the filtrate. 230 mL of the obtained aqueous solution was subjected to the next step.

The aqueous solution was cooled in a constant temperature bath set at 5 ° C., and 600 mL of ethanol was slowly added thereto over 5 hours to cause crystals to crystallize. After the ethanol injection was completed, the crystals were separated and vacuum dried at 40 ° C. for 16 hours to obtain 15.9 g of crystals.
From the results of powder X-ray diffraction of the obtained crystals, Table 1 shows the diffraction angles of the peaks _{having a relative intensity ratio (I / I 0) of 10 or more.} In the table, "2θ" indicates the diffraction angle (2θ °), and "relative intensity" indicates the relative intensity ratio (I / I ₀ ).

As a result of measuring the sodium content of the crystal by the atomic absorption method, it was 13.1% by weight, which was in agreement with the theoretical value (13.1% by weight) of the monosodium salt / anhydrate. Moreover, as a result of measuring the amount of water contained in the crystal by the Karl Fischer method, it was 0.1% by weight. From the above, it was found that the crystal was a crystal of PCA sodium salt / anhydrate.
Table 2 shows various physical characteristics of the crystal. The melting point was measured using Melting Point M-565 (manufactured by BUCHI) under the conditions of 170 ° C. to 270 ° C. and 2 ° C./min according to the instruction manual.

Acquisition of crystals of PCA sodium salt / monohydrate 13 mL of a 10 mol / L sodium hydroxide aqueous solution was diluted with pure water to make a total volume of 150 mL. To the obtained aqueous solution, 20 g of a PCA reagent (manufactured by Wako Pure Chemical Industries, Ltd., anhydrous crystal) was added and dissolved. The aqueous solution was filtered using a membrane filter (CP045AN, manufactured by Advantech Toyo Co., Ltd.), and the entire amount of the obtained aqueous solution was subjected to the next step.

The aqueous solution was concentrated under reduced pressure to a concentration of 280 g / L for 3 hours under the conditions of 55 ° C. and 10 mbar, and crystals were crystallized. After cooling the aqueous solution to 5 ° C., the crystals were separated and further vacuum dried at 40 ° C. for 16 hours to obtain 11.6 g of crystals.
Based on the results of powder X-ray diffraction of the obtained crystals, Table 3 shows the diffraction angles of the peaks _{having a relative intensity ratio (I / I 0) of 10 or more.} In the table, "2θ" indicates the diffraction angle (2θ °), and "relative intensity" indicates the relative intensity ratio (I / I ₀ ).

As a result of measuring the sodium content of the crystal by the atomic absorption method, it was 11.1% by weight, which was almost the same as the theoretical value (11.8% by weight) of 1 sodium salt / monohydrate. Moreover, as a result of measuring the amount of water contained in the crystal by the Karl Fischer method, it was 9.4% by weight. From the above, it was found that the crystals were crystals of PCA sodium salt / monohydrate.
Table 4 shows various physical characteristics of the crystal. The melting point was measured using Melting Point M-565 (manufactured by BUCHI) under the conditions of 170 ° C. to 270 ° C. and 2 ° C./min according to the instruction manual.

Acquisition of Crystals of PCA Potassium Salt / Anhydrous Salt 20 g of PCA reagent (manufactured by Wako Pure Chemical Industries, Ltd., anhydrous crystals) was dissolved in ethanol to make a total volume of 100 mL. The solution was filtered using a membrane filter (CP045AN, manufactured by Advantech Toyo Co., Ltd.) to obtain a filtrate. 130 mL of a 1 mol / L potassium hydroxide aqueous solution was added to the filtrate. 230 mL of the obtained aqueous solution was subjected to the next step.

The aqueous solution was cooled in a constant temperature bath set at 5 ° C., and 600 mL of ethanol was slowly added thereto over 5 hours to cause crystals to crystallize. After the completion of charging, the crystals were separated and further vacuum dried at 40 ° C. for 16 hours to obtain 17.7 g of crystals.
Based on the results of powder X-ray diffraction of the obtained crystals, Table 5 shows the diffraction angles of the peaks _{having a relative intensity ratio (I / I 0) of 10 or more.} In the table, "2θ" indicates the diffraction angle (2θ °), and "relative intensity" indicates the relative intensity ratio (I / I ₀ ).

As a result of measuring the potassium content of the crystal by the atomic absorption method, it was 20.3% by weight, which was in agreement with the theoretical value (20.3% by weight) of the 1-potassium salt / anhydrous product. Moreover, as a result of measuring the amount of water contained in the crystal by the Karl Fischer method, it was 0.1% by weight. From the above, it was found that the crystal was a crystal of a PCA potassium salt / anhydrous product.
Table 6 shows various physical characteristics of the crystals obtained in Example 3. The melting point was measured using Melting Point M-565 (manufactured by BUCHI) under the conditions of 170 ° C. to 270 ° C. and 2 ° C./min according to the instruction manual.

Acquisition of Crystals of PCA Ammonium Salt / Monohydrate 20 g of PCA reagent (manufactured by Wako Pure Chemical Industries, Ltd., anhydrous crystal) was dissolved in a 1: 1 mixed solvent of ethanol and water to make a total volume of 200 mL. The solution was filtered using a membrane filter (CP045AN, manufactured by Advantech Toyo Co., Ltd.) to obtain a filtrate. 130 mL of a 1 mol / L aqueous ammonia solution was added to the filtrate. 330 mL of the obtained aqueous solution was subjected to the next step.

330 mL of the aqueous solution was cooled in a constant temperature bath set at 5 ° C., and 600 mL of ethanol was slowly added thereto over 5 hours to crystallize crystals. After the completion of charging, the crystals were separated and further vacuum dried at 40 ° C. for 16 hours to obtain 12.4 g of crystals.
From the results of powder X-ray diffraction of the obtained crystals, Table 7 shows the diffraction angles of the peaks _{having a relative intensity ratio (I / I 0) of 10 or more.} In the table, "2θ" indicates the diffraction angle (2θ °), and "relative intensity" indicates the relative intensity ratio (I / I ₀ ).

As a result of measuring the ammonium content of the crystal by HPLC, it was 9.6% by weight, which was almost the same as the theoretical value (9.5% by weight) of the 1-ammonium salt / anhydrate. Moreover, as a result of measuring the amount of water contained in the crystal by the Karl Fischer method, it was 9.6% by weight. From the above, it was found that the crystal was a crystal of PCA ammonium salt / monohydrate.
Table 8 shows various physical characteristics of the crystals obtained in Example 4. The melting point was measured using Melting Point M-565 (manufactured by BUCHI) under the conditions of 170 ° C. to 270 ° C. and 2 ° C./min according to the instruction manual.

Acquisition of Crystals of PCA Calcium Salt / Monohydrate 1.25 g of calcium hydroxide and 5 g of PCA reagent (manufactured by Wako Pure Chemical Industries, Ltd., anhydrous Japanese crystal) were dissolved in 100 mL of pure water. The solution was filtered using a membrane filter (CP045AN, manufactured by Advantech Toyo Co., Ltd.), and the entire amount of the obtained aqueous solution was subjected to the next step.

The aqueous solution was concentrated under reduced pressure to a concentration of 400 g / L for 3 hours under the conditions of 55 ° C. and 10 mbar, and crystals were crystallized. After cooling the solution to 5 ° C., the crystals were separated and further vacuum dried at 40 ° C. for 16 hours to obtain 4.6 g of crystals.
Based on the results of powder X-ray diffraction of the obtained crystals, Table 9 shows the diffraction angles of the peaks _{having a relative intensity ratio (I / I 0) of 10 or more.} In the table, "2θ" indicates the diffraction angle (2θ °), and "relative intensity" indicates the relative intensity ratio (I / I ₀ ).

As a result of measuring the calcium content of the crystal by the atomic absorption method, it was 10.4% by weight, which was in agreement with the theoretical value (10.5% by weight) of 1 calcium salt / monohydrate. Moreover, as a result of measuring the amount of water contained in the crystal by the Karl Fischer method, it was 9.2% by weight. From the above, it was found that the crystals were crystals of PCA calcium salt / monohydrate.
Table 10 shows various physical characteristics of the crystals obtained in Example 5. The melting point was measured using Melting Point M-565 (manufactured by BUCHI) under the conditions of 170 ° C. to 270 ° C. and 2 ° C./min according to the instruction manual.

Measurement of Solubility The crystals of the cationic salt of each PCA obtained in Examples 2, 3, 4 and 5 are dissolved in water at room temperature until saturated solubility is reached, and the crystals are contained after stirring and holding for a sufficient time. No supernatant was collected and the PCA concentration was measured using HPLC. The measurement results are shown in Table 11.

* Free anhydrous crystals purchased from Wako Junyaku Kogyo

As shown in Table 11, the obtained PCA sodium salt / monohydrate crystal, PCA potassium salt / incompatibility crystal, PCA ammonium salt / monohydrate crystal, and PCA calcium salt / monohydrate crystal. The crystal of was significantly improved in solubility in water as compared with the existing free crystal.

Hygroscopicity of PCA cation salt crystals Obtained PCA sodium salt / monohydrate crystals, PCA potassium salt / incompatibility crystals, PCA ammonium salt / monohydrate crystals, and PCA calcium salt / monohydrate The hygroscopicity of the product was compared with each amorphous product under the following conditions. Amorphous was obtained by freeze-drying an aqueous solution in which crystals of each PCA cationic salt were dissolved at −40 ° C. or lower.
Equipment used: Moisture absorption / desorption device IGA SORP Made by Heiden Sample amount: Approximately 30 to 100 mg
Sample room temperature: 25 ° C
Relative humidity condition: Moisture absorption condition RH 0% to 90% (10% STEP)
STEP Transition time: Maximum 120 minutes, minimum 30 minutes Table 12 shows the results of measuring the weight change rate at that time by increasing the external humidity of the sample under the above conditions. The weight of the sample at 0% external humidity was set to 100%.

As a result, the obtained crystals of PCA sodium salt / monohydrate, crystals of PCA potassium salt / incompatibility, crystals of PCA ammonium salt / monohydrate, and crystals of PCA calcium salt / monohydrate were obtained. It was found that each of them has lower hygroscopicity and excellent storage stability as compared with amorphous.

INDUSTRIAL APPLICABILITY The present invention provides, for example, crystals of PCA cationic salts that are useful as products such as health foods, pharmaceuticals, and crystalline products, raw materials, intermediates, and the like, and methods for producing the same.

Claims (9)

In powder X-ray diffraction, the diffraction angles (2θ °) are 8.9 ± 0.2 °, 28.1 ± 0.2 °, 26.5 ± 0.2 °, 25.1 ± 0.2 °, And crystals of protocatechuic acid (hereinafter referred to as PCA) monosodium salt / anhydrous or PCA monosodium salt / monohydrate having a peak at 14.4 ± 0.2 °. In powder X-ray diffraction, the diffraction angle (2θ °) is 30.5 ± 0.2 °, 31.1 ± 0.2 °, 37.9 ± 0.2 °, 36.4 ± 0.2 °, And the crystal according to claim 1 , which has a peak at 32.3 ± 0.2 °. In powder X-ray diffraction, the diffraction angle (2θ °) is 33.3 ± 0.2 °, 22.0 ± 0.2 °, 26.9 ± 0.2 °, 23.0 ± 0.2 °, And the crystal according to claim 2 , which has a peak at 40.9 ± 0.2 °. In powder X-ray diffraction, the diffraction angles (2θ °) are 27.3 ± 0.2 °, 21.9 ± 0.2 °, 25.5 ± 0.2 °, 24.4 ± 0.2 °, And crystals of PCA monopotassium salt / anhydrate having a peak at 25.3 ± 0.2 °. In powder X-ray diffraction, the diffraction angles (2θ °) are 11.2 ± 0.2 °, 18.7 ± 0.2 °, 26.9 ± 0.2 °, 32.1 ± 0.2 °, And the crystal according to claim 4 , which has a peak at 15.0 ± 0.2 °. In powder X-ray diffraction, the diffraction angle (2θ °) is 34.2 ± 0.2 °, 30.2 ± 0.2 °, 27.9 ± 0.2 °, 31.3 ± 0.2 °, And the crystal according to claim 5 , which has a peak at 39.4 ± 0.2 °. In powder X-ray diffraction, the diffraction angles (2θ °) are 12.2 ± 0.2 °, 25.1 ± 0.2 °, 28.2 ± 0.2 °, 17.4 ± 0.2 °, And crystals of PCA monoammonium salt monohydrate with peaks at 23.9 ± 0.2 °. In powder X-ray diffraction, the diffraction angles (2θ °) are 33.2 ± 0.2 °, 37.9 ± 0.2 °, 24.4 ± 0.2 °, 30.7 ± 0.2 °, And the crystal according to claim 7 , which has a peak at 15.2 ± 0.2 °. In powder X-ray diffraction, the diffraction angles (2θ °) are 29.5 ± 0.2 °, 28.6 ± 0.2 °, 21.0 ± 0.2 °, 29.1 ± 0.2 °, And the crystal according to claim 8 , which has a peak at 26.4 ± 0.2 °.

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