JP2018150288A - Crystal of protocatechuic acid cation salt and manufacturing method therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a crystal of PCA (protocatechuic acid) cation salt excellent in dissolubility and stable under a high humidity condition and a manufacturing method therefor.SOLUTION: There is provided a manufacturing method of a crystal of a PCA (protocatechuic acid) cation salt in which the crystal of the PCA cation salt is deposited by dropping or adding an alcohol solution or a nitrile solution to a PCA alcohol solution in which a cation-containing compound is dissolved, or concentrating an aqueous solution of PCA in which the cation-containing compound is dissolved and the crystal of the PCA cation salt is collected from the solution or the aqueous solution. There is provided a crystal of nonhydrate or monohydrate of the PCA cation salt, in which the cation is Na, K, NHor Ca.SELECTED DRAWING: None

Description

  The present invention relates to crystals of protocatechuic acid (hereinafter referred to as PCA) cation salt that are useful as products, raw materials or intermediates such as health foods, pharmaceuticals, and crystal products, 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, lifestyle-related diseases such as arteriosclerosis, etc. It is known that it is effective for prevention. In recent years, it has also been reported that in animal experiments using carcinogens, it works to suppress oral cavity and colon cancer (Non-patent Documents 1 and 2). For this reason, PCA has recently attracted attention as a product, raw material, or intermediate product such as health foods, pharmaceuticals, and crystal products.

  As a crystal of PCA, a plurality of crystal polymorphs of a free carboxylic acid form (free form) have been known so far (Non-patent Documents 3 and 4), and commercially available free orthorhombic anhydrides. Only is in circulation on the market. However, free orthorhombic anhydrides change to monohydrate under high-humidity conditions, and all free crystals have low solubility in water, making them difficult to manufacture and handle in preparations. is there.

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

  The subject of this invention is providing the crystal | crystallization of the PCA cation salt which is excellent in solubility, and stable under high-humidity conditions, and its manufacturing method.

The present invention relates to the following (1) to (26).
(1) Protocatechuic acid (hereinafter referred to as PCA) cationic salt crystals.
(2) The crystal of (1) above, which is a crystal of PCA sodium salt / anhydrate or a crystal of PCA sodium salt / monohydrate.
(3) In powder X-ray diffraction, diffraction angles (2θ °) are 8.9 ± 0.2 °, 28.1 ± 0.2 °, 26.5 ± 0.2 °, 25.1 ± 0. The crystal according to (2) above, having peaks at 2 ° and 14.4 ± 0.2 °.
(4) In powder X-ray diffraction, diffraction angles (2θ °) are 30.5 ± 0.2 °, 31.1 ± 0.2 °, 37.9 ± 0.2 °, 36.4 ± 0. The crystal according to (3) above, having 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, having peaks at 2 ° and 40.9 ± 0.2 °.
(6) The crystal of (1) above, which is a crystal of PCA potassium salt / anhydrate.
(7) In powder X-ray diffraction, 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, having peaks at 2 ° and 25.3 ± 0.2 °.
(8) In powder X-ray diffraction, 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, having 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, having peaks at 2 ° and 39.4 ± 0.2 °.
(10) The crystal of (1) above, which is a crystal of PCA ammonium salt monohydrate.
(11) In powder X-ray diffraction, 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, having peaks at 2 ° and 23.9 ± 0.2 °.
(12) In powder X-ray diffraction, 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, having peaks at 2 ° and 15.2 ± 0.2 °.
(13) In powder X-ray diffraction, 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, having peaks at 2 ° and 26.4 ± 0.2 °.
(14) The crystal of (1) above, which is a crystal of PCA calcium salt monohydrate.
(15) In powder X-ray diffraction, 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, having peaks at 2 ° and 25.5 ± 0.2 °.
(16) In powder X-ray diffraction, diffraction angles (2θ °) are 15.7 ± 0.2 °, 14.9 ± 0.2 °, 37.6 ± 0.2 °, 21.8 ± 0. The crystal according to (15), which has peaks at 2 ° and 38.8 ± 0.2 °.
(17) In powder X-ray diffraction, diffraction angles (2θ °) are 34.4 ± 0.2 °, 25.3 ± 0.2 °, 50.0 ± 0.2 °, 40.4 ± 0. The crystal according to (16), which has peaks at 2 ° and 30.0 ± 0.2 °.
(18) A step of precipitating PCA cation salt crystals by dropping or adding an alcohol solution or a nitrile solution to an alcohol solution of PCA in which the cation-containing compound is dissolved, and a step of collecting PCA cation salt crystals from the solution, A method for producing PCA cation salt crystals comprising:
(19) The production method according to (18), wherein the alcohol solution to be dropped or added is a solution selected from the group consisting of C1 to C6 alcohols.
(20) The production method according to (18), wherein the nitrile solution to be dropped or added is acetonitrile.
(21) Production of PCA cation salt crystals comprising a step of precipitating PCA cation salt crystals by concentrating an aqueous solution of PCA in which the cation-containing compound is dissolved, and a step of collecting PCA cation salt crystals from the aqueous solution. Method.
(22) The production method according to any one of (18) to (20), wherein the cation-containing compound is a sodium-containing compound, and the PCA cation salt crystals are PCA sodium salt / anhydrate crystals. .
(23) The production method according to (21), wherein the cation-containing compound is a sodium-containing compound, and the PCA cation salt crystal is a crystal of PCA sodium salt monohydrate.
(24) The production method according to any one of (18) to (21), wherein the cation-containing compound is a potassium-containing compound, and the crystal of the PCA cation salt is a crystal of a 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 PCA cation salt crystal is a PCA ammonium salt monohydrate crystal. Method.
(26) The production method according to the above (21), wherein the cation-containing compound is a calcium-containing compound, and the crystal of the PCA cation salt is a crystal of PCA calcium salt monohydrate.

  The present invention provides a crystal of a PCA cation salt that is excellent in solubility and more stable under high humidity conditions, and a method for producing the same.

FIG. 1 shows the result of powder X-ray diffraction of the crystals of PCA sodium salt / anhydrate obtained in Example 1. The vertical axis represents intensity (cps), and the horizontal axis represents diffraction angle 2θ (°). FIG. 2 shows the result of infrared spectroscopic (IR) analysis of the PCA sodium salt / anhydrate crystal 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 result of the powder X-ray diffraction of the PCA sodium salt monohydrate crystal obtained in Example 2. The vertical axis represents intensity (cps), and the horizontal axis represents diffraction angle 2θ (°). FIG. 4 shows the result of infrared spectroscopic (IR) analysis of the crystal 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 result of powder X-ray diffraction of the crystals of PCA potassium salt / anhydrate obtained in Example 3. The vertical axis represents intensity (cps), and the horizontal axis represents diffraction angle 2θ (°). FIG. 6 shows the result of infrared spectroscopic (IR) analysis of the crystal of 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 result of powder X-ray diffraction of the crystal of PCA ammonium salt monohydrate obtained in Example 4. The vertical axis represents intensity (cps), and the horizontal axis represents diffraction angle 2θ (°). FIG. 8 shows the result of infrared spectroscopic (IR) analysis of the crystal 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 result of powder X-ray diffraction of the crystal of PCA calcium salt monohydrate obtained in Example 5. The vertical axis represents intensity (cps), and the horizontal axis represents diffraction angle 2θ (°). FIG. 10 shows the result of infrared spectroscopic (IR) analysis of the crystal 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. Crystal of the Present Invention The crystal of the present invention is a crystal of PCA cation salt.
The crystal of the present invention may be a salt crystal composed of PCA ions and cations, and the type of cation is not particularly limited. For example, specifically, it contains PCA ions and sodium ions in a ratio of 1: 1. Salt crystals (hereinafter referred to as PCA sodium salt crystals), salt crystals containing PCA ions and potassium ions in a ratio of 1: 1 (hereinafter referred to as PCA potassium salt crystals), PCA ions and ammonium ions. Of the salt containing PCA ions and calcium ions in a ratio of 1: 1 (hereinafter referred to as PCA calcium salt crystals). .).
1-1. Crystal of PCA sodium salt It can be confirmed, for example, by analysis using HPLC that the crystal of PCA sodium salt is a crystal 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: 20 mol / L phosphoric acid aqueous solution and acetonitrile mixed at a volume ratio of 4: 1
Flow rate: 1.0 mL / min
Detector: UV detector (wavelength 254 nm)
Whether the crystal is a PCA sodium salt crystal can also be confirmed by analysis by powder X-ray diffraction.

Analysis by powder X-ray diffraction can be performed, for example, using a powder X-ray diffractometer (XRD) Ultimate IV (manufactured by Rigaku Corporation), using CuKα as an X-ray source, and according to the attached instruction manual.
The PCA sodium salt crystal may be an anhydrate crystal or a hydrate crystal, preferably an anhydrate crystal or a monohydrate crystal.

As such an anhydrous crystal, specifically, a PCA sodium salt / anhydrate crystal represented by a composition formula of [C ₇ H ₅ O ₄ Na] is a monohydrate crystal. Specifically, a crystal of PCA sodium salt monohydrate represented by a composition formula of [C ₇ H ₅ O ₄ Na] H ₂ O can be given.
It can confirm that the crystal | crystallization of a PCA sodium salt is a crystal | crystallization of a sodium salt by measuring the sodium content contained in the said crystal | crystallization.

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

  The crystal of PCA sodium salt is an anhydrate crystal because the water content in the crystal is usually 1.5% by weight or less, preferably 1.3% by Karl Fischer method or thermogravimetric differential thermal analysis. % Or less, more preferably 1.0% by weight or less. The crystal of PCA sodium salt is a monohydrate crystal, which 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, it can be confirmed by 9.3 ± 1.0% by weight.

The moisture content measurement by the Karl Fischer method can be performed, for example, using an automatic moisture measuring apparatus AQV-2200 (manufactured by Hiranuma Sangyo Co., Ltd.) according to the attached instruction manual.
Examples of the PCA sodium salt crystal include a crystal having a peak at a diffraction angle 2θ (°) described in (i) below in powder X-ray diffraction using CuKα as an X-ray source. And a crystal having a peak at a diffraction angle 2θ (°) described in (ii) is preferable, and a crystal having a peak at a 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 PCA sodium salt crystal, a powder X-ray diffraction pattern using CuKα as an X-ray source has a pattern shown in FIG. In the case of a product crystal or an infrared spectroscopic (IR) analysis, a PCA sodium salt / anhydrate crystal showing an infrared absorption spectrum shown in FIG. 2 can be exemplified.

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

Whether the crystal is a PCA potassium salt crystal can also be confirmed by analysis by powder X-ray diffraction similar to 1-1.
The PCA potassium salt crystal may be an anhydrous crystal or a hydrate crystal, and preferably an anhydrous crystal.
Specific examples of such anhydrous crystals include PCA potassium salt / anhydride crystals represented by a composition formula of [C ₇ H ₅ O ₄ K].

It can confirm that the crystal | crystallization of a PCA potassium salt is a crystal | crystallization of potassium salt by measuring the potassium content contained in the said crystal | crystallization by the method similar to said 1-1.
The potassium content of PCA potassium salt crystals varies depending on the number of hydrated water contained in the crystals, but when the PCA potassium salt crystals are anhydrous crystals, the PCA potassium salt crystals are potassium salt crystals. This means that the potassium content in the crystal is usually 20.3 ± 3.0% by weight, preferably 20.3 ± 2.0% by weight, most preferably 20.3 ± 1.0% by weight. This can be confirmed.

The crystal of PCA potassium salt is an anhydrate crystal because, according to Karl Fischer method or thermogravimetric differential thermal analysis, the water content in the crystal is usually 1.5% by weight or less, preferably 1.3% by weight. % Or less, more preferably 1.0% by weight or less.
The water content measurement by the Karl Fischer method can be performed by the same method as in 1-1.

Examples of the crystal of PCA potassium salt include a crystal having a peak at a diffraction angle 2θ (°) described in (iv) below in powder X-ray diffraction using CuKα as an X-ray source. And 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) 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 ° 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 / anhydride defined by the pattern shown in FIG. 5 and the diffraction angle values shown in Table 5. In the case of a product crystal or an infrared spectroscopic (IR) analysis, a PCA potassium salt / anhydrate crystal showing an infrared absorption spectrum shown in FIG. 6 can be exemplified.

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

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

Whether the PCA ammonium salt crystals are ammonium salt crystals can be confirmed by measuring the ammonium content contained in the crystals.
The ammonium content can be confirmed, for example, by analysis using HPLC.
Examples of the analytical method using HPLC include the phthalaldehyde method, and specific analytical conditions include, for example, the following HPLC conditions (post-column method).
Column: YMC-PACK ODS-AQ (150 × 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 g o-phthalaldehyde, 4.6 g N-acetylcysteine prepared in 1 L with pure water Flow rate: A) 1.2 mL / min, B ) 0.4mL / min
Detector: Fluorescence detector (excitation wavelength: 355 nm, detection wavelength: 455 nm)
The ammonium content of the crystal of PCA ammonium salt varies depending on the number of hydrated water contained in the crystal. When the crystal of PCA ammonium salt is a monohydrate crystal, the crystal of PCA ammonium salt is The fact that it is crystalline means that the ammonium content in the crystal is usually 9.5 ± 3.0% by weight, preferably 9.5 ± 2.0% by weight, most preferably 9.5 ± 1.0% by weight. It can be confirmed by being.

The crystal of PCA ammonium salt is a monohydrate crystal because the water content in the crystal is usually 9.5 ± 3.0% by weight, preferably by 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 measurement by the Karl Fischer method can be performed, for example, by the same method as in 1-1.

Examples of the crystal of PCA ammonium salt include a crystal having a peak at a diffraction angle 2θ (°) described in (vii) below in powder X-ray diffraction using CuKα as an X-ray source. And a crystal having a peak at a diffraction angle 2θ (°) described in (viii) is preferable, and a crystal having a peak at a diffraction angle 2θ (°) described in (vii), (viii) and (ix) 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 ° 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 the PCA ammonium salt crystal, a powder X-ray diffraction pattern using CuKα as an X-ray source is defined by the pattern shown in FIG. 7 and the diffraction angle values shown in Table 7. In the case of a hydrate crystal or an infrared spectroscopic (IR) analysis, a PCA ammonium salt monohydrate crystal showing an infrared absorption spectrum shown in FIG. 8 can be exemplified.

Infrared spectroscopy (IR) analysis can be performed, for example, by the same method as in 1-1.
1-4. Crystal of PCA Calcium Salt It can be confirmed, for example, by analysis using the same HPLC as 1-1 above that the crystal of PCA calcium salt is a crystal of PCA.
Whether the crystal is a PCA calcium salt crystal can also be confirmed by analysis by powder X-ray diffraction similar to 1-1.

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

It can be confirmed that the PCA calcium salt crystal is a calcium salt crystal by measuring the calcium content contained in the crystal by the same method as in 1-1.
The calcium content of the PCA calcium salt crystal varies depending on the number of hydrated water contained in the crystal, but when the PCA calcium salt crystal is a monohydrate crystal, the PCA calcium salt crystal is a calcium salt crystal. The fact that it is 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 being.

The crystal of PCA calcium salt is a monohydrate crystal by the Karl Fischer method or thermogravimetric differential thermal analysis. The water content in the crystal is usually 9.4 ± 3.0% by weight, preferably It can be confirmed by 9.4 ± 2.0% by weight, most preferably 9.4 ± 1.0% by weight.
The water content measurement by the Karl Fischer method can be performed, for example, by the same method as in 1-1.

Examples of the crystal of PCA calcium salt include a crystal having a peak at a diffraction angle 2θ (°) described in (x) below in powder X-ray diffraction using CuKα as an X-ray source. And a crystal having a peak at a diffraction angle 2θ (°) described in (xi) is preferable, and a crystal having a peak at a diffraction angle 2θ (°) described in (x), (xi) and (xii) 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 ° 40.4 ± 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 defined by the pattern shown in FIG. 9 and the diffraction angle values shown in Table 9. In the case of a Japanese-style crystal or an infrared spectroscopic (IR) analysis, a PCA calcium salt monohydrate crystal showing an infrared absorption spectrum shown in FIG. 10 can be exemplified.

Infrared spectroscopy (IR) analysis can be performed, for example, by the same method as in 1-1.
2. The manufacturing method of the crystal | crystallization of this invention The manufacturing method of the crystal | crystallization of this invention is a manufacturing method as described in the following 2-1 or 2-2.
2-1. Production method 1 of the crystal of the present invention
The method for producing a crystal of the present invention comprises a step of precipitating a crystal of a PCA cation 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. A method of producing a crystal of a PCA cation salt, comprising a step of collecting the crystal.

The PCA contained in the PCA alcohol solution in which the cation-containing compound is dissolved may be produced by any production method such as a fermentation method, an enzymatic method, a natural product extraction method, or a chemical synthesis method.
If the alcohol solution of PCA in which the cation-containing compound is dissolved contains a solid matter that hinders crystallization, the solid matter can be removed using 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, the solution is passed through a column packed with an ion exchange resin or the like. Water-soluble impurities and salts can be removed.
In addition, if the PCA alcohol solution in which the cation-containing compound is dissolved contains hydrophobic impurities that hinder crystallization, it can be removed by passing through a column filled with synthetic adsorption resin or activated carbon. The impurities can be removed.

It is desirable that the concentration of PCA in the alcohol solution of PCA in which the cation-containing compound is dissolved is 40 g / L or more, preferably 50 g / L or more, more preferably 60 g / L or more.
In order to adjust the concentration of the solution to the above-mentioned 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 a basic compound such as sodium hydroxide, or a neutral salt such as sodium carbonate, sodium sulfate, sodium nitrate, or sodium chloride. Examples of neutral salts include sodium carbonate, sodium sulfate, sodium nitrate, or sodium chloride.

When using a basic compound as a sodium containing compound, pH is 4.0-10.0 normally by adjusting the pH of the alcohol solution of PCA using the said basic compound, Preferably 4.5-9. 5, Most preferably, an alcohol solution of PCA in which a sodium-containing compound of 5.0 to 9.0 is dissolved can be obtained.
Examples of the potassium-containing compound include a basic compound such as potassium hydroxide, or a neutral salt such as potassium carbonate, potassium sulfate, potassium nitrate, or potassium chloride. Examples of the neutral salt include potassium carbonate, potassium sulfate, potassium nitrate, and potassium chloride.

When using a basic compound as a potassium containing compound, pH is 4.0-10.0 normally by adjusting the pH of the alcohol solution of PCA using the said basic compound, Preferably 4.5-9. 5, Most preferably, an alcohol solution of PCA in which a potassium-containing compound of 5.0 to 9.0 is dissolved can be obtained.
Examples of the ammonium-containing compound include a basic compound such as ammonia, or a neutral salt such as ammonia carbonate, ammonia sulfate, ammonia nitrate, or ammonia chloride. Examples of the neutral salt include ammonium carbonate, ammonium sulfate, ammonium nitrate, and ammonium chloride.

When using a basic compound as an ammonium containing compound, pH is 4.0-10.0 normally by adjusting the pH of the alcohol solution of PCA using the said basic compound, Preferably it is 4.5-9. 5, Most preferably, an alcohol solution of PCA in which an ammonium-containing compound of 5.0 to 9.0 is dissolved can be obtained.
In 2-1, when a sodium-containing compound is used as the cation-containing compound, the PCA cation salt crystal obtained is a PCA sodium salt crystal, more specifically a PCA sodium salt / anhydrate crystal.

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

  The alcohol solution to be added or dropped into the solution is preferably a C1 to C6 alcohol, more preferably a C1 to C3 alcohol, still more preferably from methanol, ethanol, n-propanol and isopropyl alcohol. More preferably, alcohols selected from the group consisting of methanol or ethanol, and most preferably ethanol can be mentioned.

The alcohol solution may be a mixture of a plurality of alcohols, or a mixture of alcohol and another organic solvent or water.
When the alcohol solution is a mixture of alcohol and water, the water content can 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 to be added or dropped into the solution include acetonitrile.
The nitrile solution may be a mixture with water, in which case the water content is not more than 40% by weight, preferably not more than 20% by weight, more preferably not more than 10% by weight, most preferably not more than 5% by weight. Can be mentioned.

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

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

As a seed crystal, the crystal | crystallization of the PCA cation salt acquired by 2-1, for example can be used.
When a sodium-containing compound is used as the cation-containing compound and a crystal of PCA sodium salt / anhydride is used as a seed crystal, the obtained crystal of PCA cation salt is a crystal of PCA sodium salt / anhydrate.

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

The seed crystal is added so that the concentration in the aqueous solution is 0.001 to 50 g / L, preferably 0.01 to 10 g / L, 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 dropwise addition of the alcohol solution or nitrile solution. .

After the PCA cation salt crystals 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 crystal means stopping the step of precipitating the PCA cation salt crystal and growing the crystal.
Growing a crystal means increasing the crystal based on the precipitated crystal.

Crystal ripening is performed mainly for the purpose of growing a crystal, but a new crystal may be precipitated simultaneously with the growth of the crystal.
Stopping the step of precipitating PCA cation salt crystals means, for example, stopping the addition or dropping of an alcohol solution or a nitrile solution.
After aging the crystals, the step of precipitating PCA cation salt crystals may be resumed.

In the step of collecting PCA cation salt crystals, for example, filtration, pressure filtration, suction filtration, centrifugation and the like can be performed. Furthermore, in order to reduce the adhesion of the mother liquor to the crystal and improve the quality of the crystal, the crystal can be washed as appropriate after collecting the crystal.
As a solution used for crystal washing, for example, a solution in which one or more kinds selected from the group consisting of water, methanol, ethanol, acetone, n-propanol, and isopropyl alcohol are mixed 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 PCA cation salt crystal form 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 as long as it can remove the attached moisture or solution, but preferably 80 ° C. or less, more preferably 70 ° C. or less, and most preferably 60 ° C. or less.

The drying time may be any as long as the attached moisture or solution can be removed, but preferably 1 to 60 hours, more preferably 1 to 48 hours.
The purity of the PCA cation salt crystals obtained by the above method can be 95% or more, preferably 96% or more, more preferably 97% or more, and most preferably 97.5% or more.

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

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

PCA contained in an aqueous solution of PCA in which a cation-containing compound is dissolved may be produced by any production method such as a fermentation method, an enzymatic method, a natural product extraction method, or a chemical synthesis method.
When the aqueous solution of PCA in which the cation-containing compound is dissolved contains a solid matter 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 the aqueous solution of PCA in which the cation-containing compound is dissolved contains a hydrophobic impurity that hinders crystallization, the same treatment as in 2-1 can be performed.

It is desirable that the concentration of PCA in the aqueous PCA solution in which the cation-containing compound is dissolved is 30 g / L or higher, preferably 40 g / L or higher, more preferably 50 g / L or higher.
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 those described above can be used.
Examples of the calcium-containing compound include a basic compound such as calcium hydroxide, or a neutral salt such as calcium carbonate, calcium sulfate, calcium nitrate, or calcium chloride. Examples of neutral salts include calcium carbonate, calcium sulfate, calcium nitrate, or 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 PCA solution using the basic compound. .5, and most preferably, an aqueous solution of PCA in which a cation-containing compound of 5.0 to 9.0 is dissolved can be obtained.
In 2-2, when a sodium-containing compound is used as the cation-containing compound, the resulting PCA cation salt crystal is a PCA sodium salt crystal, more specifically, a PCA sodium salt monohydrate crystal.

In 2-2, when a potassium-containing compound is used as the cation-containing compound, the resulting PCA cation salt crystal is a PCA potassium salt crystal, more specifically, a PCA potassium salt / anhydrate crystal.
In 2-2, when an ammonium-containing compound is used as the cation-containing compound, the obtained PCA cation salt crystal is a PCA ammonium salt crystal, more specifically, a PCA ammonium salt monohydrate crystal.

In 2-2, when a calcium-containing compound is used as the cation-containing compound, the obtained PCA cation salt crystal is a PCA calcium salt crystal, more specifically, a PCA calcium salt monohydrate crystal.
In the step of precipitating PCA cation salt crystals 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.
The time required for concentration in the case of concentrating the aqueous solution under reduced pressure 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 crystals of the PCA cation salt are precipitated in the aqueous solution. A person skilled in the art can appropriately set the time in the range of, for example, 1 to 24 hours, preferably 2 to 18 hours, and most preferably 3 to 12 hours.

The temperature of the aqueous solution when the aqueous solution is concentrated by heating can be 40 to 80 ° C, preferably 50 to 70 ° C.
The time required for concentration in the case of concentrating the aqueous solution by heating varies depending on the concentration of PCA in the aqueous solution and the temperature of the aqueous solution, and may be any time as long as crystals of the PCA cation salt are precipitated in the aqueous solution. A person skilled in the art can appropriately set the time 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 PCA cation salt crystals by concentrating an aqueous solution of PCA in which the cation-containing compound is dissolved, or the step of precipitating PCA cation salt crystals by concentrating the solution In this case, seed crystals may be added before the PCA cation salt crystals are precipitated.
As a seed crystal, the crystal | crystallization of the PCA cation salt acquired by 2-2 can be used, for example.

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

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

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

After the PCA cation salt crystals 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 crystal means stopping the step of precipitating the PCA cation salt crystal and growing the crystal.
Crystal growth and aging are the same as in 2-1.

Stopping the step of precipitating PCA cation salt crystals means, for example, that the concentration step is interrupted when PCA cation salt crystals are precipitated by concentrating the aqueous solution under reduced pressure.
After aging the crystals, the step of precipitating PCA cation salt crystals may be resumed.
After the PCA cation salt crystals are precipitated by the above method, the PCA cation salt crystals can be collected by the same process as in 2-1.

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

  As the PCA cation salt crystal that can be produced by the above production method, specifically, a powder X-ray diffraction pattern using CuKα as an X-ray source has a pattern shown in FIG. 3 and a diffraction angle shown in Table 3. PCA sodium salt monohydrate crystals defined by the values of PCA and PCA calcium salt monohydrate crystals defined by the diffraction angle values shown in FIG. it can.

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

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

Acquisition of PCA Sodium Salt / Anhydrous Crystal 20 g of PCA reagent (anhydrous crystal manufactured by Wako Pure Chemical Industries, Ltd.) 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. To the filtrate, 130 mL of a 1 mol / L aqueous sodium hydroxide solution was added. 230 mL of the obtained aqueous solution was used for the next step.

The aqueous solution was cooled in a thermostatic bath set at 5 ° C., and 600 mL of ethanol was slowly added thereto over 5 hours to crystallize crystals. After completion of the addition of ethanol, the crystals were separated and vacuum dried at 40 ° C. for 16 hours to obtain 15.9 g of crystals.
Table 1 shows the diffraction angle of the peak having a relative intensity ratio (I / I ₀ ) of 10 or more based on the result of powder X-ray diffraction of the obtained crystal. In the table, “2θ” indicates a diffraction angle (2θ °), and “relative intensity” indicates a 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 consistent with the theoretical value (13.1% by weight) of monosodium salt / anhydride. The water content in the crystals was measured by the Karl Fischer method and found to be 0.1% by weight. From the above, it was found that the crystals were PCA sodium salt / anhydrate crystals.
Various physical properties of the crystal are shown in Table 2. 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 PCA sodium salt monohydrate crystals 13 mL of a 10 mol / L aqueous sodium hydroxide solution was diluted with pure water to make a total volume of 150 mL. To the resulting aqueous solution, 20 g of PCA reagent (Wako Pure Chemical Industries, Ltd., anhydrous crystals) was added and dissolved. The aqueous solution was filtered using a membrane filter (CP045AN, manufactured by Advantech Toyo Co., Ltd.), and the total amount of the obtained aqueous solution was subjected to the next step.

The aqueous solution was concentrated under reduced pressure at 55 ° C. and 10 mbar for 3 hours until the concentration reached 280 g / L, and crystals were crystallized. After cooling the aqueous solution to 5 ° C., the crystals were separated and further dried in vacuo at 40 ° C. for 16 hours to obtain 11.6 g of crystals.
Table 3 shows the diffraction angle of the peak having a relative intensity ratio (I / I ₀ ) of 10 or more based on the result of powder X-ray diffraction of the obtained crystal. In the table, “2θ” indicates a diffraction angle (2θ °), and “relative intensity” indicates a 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 almost coincided with the theoretical value (11.8% by weight) of the monosodium salt monohydrate. Further, the amount of water contained in the crystal was measured by the Karl Fischer method, and as a result, it was 9.4% by weight. From the above, it was found that the crystals were PCA sodium salt monohydrate crystals.
Table 4 shows various physical properties 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 PCA Potassium Salt / Anhydrous Crystal 20 g of PCA reagent (anhydrous crystal manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in ethanol to 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. To the filtrate, 130 mL of 1 mol / L potassium hydroxide aqueous solution was added. 230 mL of the obtained aqueous solution was used for the next step.

The aqueous solution was cooled in a thermostatic bath set at 5 ° C., and 600 mL of ethanol was slowly added thereto over 5 hours to crystallize crystals. After completion of the addition, the crystals were separated and further vacuum dried at 40 ° C. for 16 hours to obtain 17.7 g of crystals.
Table 5 shows the diffraction angle of the peak having a relative intensity ratio (I / I ₀ ) of 10 or more based on the result of powder X-ray diffraction of the obtained crystal. In the table, “2θ” indicates a diffraction angle (2θ °), and “relative intensity” indicates a 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 monopotassium salt / anhydrate. The water content in the crystals was measured by the Karl Fischer method and found to be 0.1% by weight. From the above, it was found that the crystal was a PCA potassium salt / anhydrate crystal.
Table 6 shows various physical properties 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 PCA ammonium salt monohydrate crystals 20 g of PCA reagent (Wako Pure Chemical Industries, Ltd., anhydrous crystals) 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. To the filtrate, 130 mL of a 1 mol / L aqueous ammonia solution was added. 330 mL of the obtained aqueous solution was used for the next step.

330 mL of the aqueous solution was cooled in a thermostatic bath set to 5 ° C., and 600 mL of ethanol was slowly added thereto over 5 hours to crystallize crystals. After completion of the addition, the crystals were separated and further vacuum dried at 40 ° C. for 16 hours to obtain 12.4 g of crystals.
Table 7 shows the diffraction angle of the peak having a relative intensity ratio (I / I ₀ ) of 10 or more based on the result of powder X-ray diffraction of the obtained crystal. In the table, “2θ” indicates a diffraction angle (2θ °), and “relative intensity” indicates a 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 almost coincided with the theoretical value (9.5% by weight) of monoammonium salt / anhydride. The water content in the crystals was measured by the Karl Fischer method and found to be 9.6% by weight. From the above, it was found that the crystals were PCA ammonium salt monohydrate crystals.
Table 8 shows various physical properties 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 PCA calcium salt monohydrate crystals 1.25 g of calcium hydroxide and 5 g of PCA reagent (Wako Pure Chemical Industries, Ltd., anhydrous crystals) 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 total amount of the obtained aqueous solution was subjected to the next step.

The aqueous solution was concentrated under reduced pressure at 55 ° C. under 10 mbar for 3 hours until a concentration of 400 g / L was reached to crystallize crystals. 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.
Table 9 shows the diffraction angle of the peak having a relative intensity ratio (I / I ₀ ) of 10 or more based on the result of powder X-ray diffraction of the obtained crystal. In the table, “2θ” indicates a diffraction angle (2θ °), and “relative intensity” indicates a 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 consistent with the theoretical value (10.5% by weight) of 1 calcium salt · monohydrate. The water content in the crystals was measured by the Karl Fischer method and found to be 9.2% by weight. From the above, it was found that the crystal was a PCA calcium salt monohydrate crystal.
Table 10 shows various physical properties 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 Crystals of the cation salts of each PCA obtained in Examples 2, 3, 4 and 5 were dissolved in water at room temperature until saturation solubility was reached, and after stirring and holding for a sufficient time, crystals were contained. A non-supernatant was collected and the PCA concentration was measured using HPLC. Table 11 shows the measurement results.

* Free anhydrous crystals purchased from Wako Pure Chemical Industries

As shown in Table 11, obtained PCA sodium salt monohydrate crystals, PCA potassium salt / unhydrated crystals, PCA ammonium salt monohydrate crystals, and PCA calcium salt monohydrate Compared with the existing free crystal, the crystal of this material has greatly improved solubility in water.

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

  As a result, the obtained PCA sodium salt monohydrate crystals, PCA potassium salt / unmatched crystals, PCA ammonium salt monohydrate crystals, and PCA calcium salt monohydrate crystals are: It was found that each had lower hygroscopicity than amorphous and excellent storage stability.

  According to the present invention, for example, crystals of PCA cation salts that are useful as products, raw materials, intermediates, and the like such as health foods, pharmaceuticals, and crystalline products, and methods for producing the same are provided.

Claims (26)

Protocatechuic acid (hereinafter referred to as PCA) cation salt crystals. The crystal according to claim 1, which is a crystal of PCA sodium salt · anhydrate or a crystal of PCA sodium salt · monohydrate. In powder X-ray diffraction, diffraction angles (2θ °) are 8.9 ± 0.2 °, 28.1 ± 0.2 °, 26.5 ± 0.2 °, 25.1 ± 0.2 °, And a crystal according to claim 2 having a peak at 14.4 ± 0.2 °. In powder X-ray diffraction, diffraction angles (2θ °) are 30.5 ± 0.2 °, 31.1 ± 0.2 °, 37.9 ± 0.2 °, 36.4 ± 0.2 °, And the crystal of claim 3 having 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 of claim 4 having a peak at 40.9 ± 0.2 °. The crystal of claim 1, which is a crystal of PCA potassium salt / anhydrate. In powder X-ray diffraction, diffraction angles (2θ °) are 27.3 ± 0.2 °, 21.9 ± 0.2 °, 25.5 ± 0.2 °, 24.4 ± 0.2 °, And the crystal of claim 6 having a peak at 25.3 ± 0.2 °. In powder X-ray diffraction, diffraction angles (2θ °) are 11.2 ± 0.2 °, 18.7 ± 0.2 °, 26.9 ± 0.2 °, 32.1 ± 0.2 °, And the crystal of claim 7 having 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 of claim 8 having a peak at 39.4 ± 0.2 °. The crystal of claim 1, which is a crystal of PCA ammonium salt monohydrate. In powder X-ray diffraction, diffraction angles (2θ °) are 12.2 ± 0.2 °, 25.1 ± 0.2 °, 28.2 ± 0.2 °, 17.4 ± 0.2 °, And the crystal of claim 10 having a peak at 23.9 ± 0.2 °. In powder X-ray diffraction, diffraction angles (2θ °) are 33.2 ± 0.2 °, 37.9 ± 0.2 °, 24.4 ± 0.2 °, 30.7 ± 0.2 °, And the crystal of claim 11 having a peak at 15.2 ± 0.2 °. In powder X-ray diffraction, diffraction angles (2θ °) are 29.5 ± 0.2 °, 28.6 ± 0.2 °, 21.0 ± 0.2 °, 29.1 ± 0.2 °, And the crystal of claim 12 having a peak at 26.4 ± 0.2 °. The crystal of claim 1, which is a crystal of PCA calcium salt monohydrate. In powder X-ray diffraction, diffraction angles (2θ °) are 9.3 ± 0.2 °, 16.7 ± 0.2 °, 27.0 ± 0.2 °, 27.7 ± 0.2 °, And crystals having a peak at 25.5 ± 0.2 °. In powder X-ray diffraction, diffraction angles (2θ °) are 15.7 ± 0.2 °, 14.9 ± 0.2 °, 37.6 ± 0.2 °, 21.8 ± 0.2 °, And crystals having peaks at 38.8 ± 0.2 °. In powder X-ray diffraction, diffraction angles (2θ °) are 34.4 ± 0.2 °, 25.3 ± 0.2 °, 50.0 ± 0.2 °, 40.4 ± 0.2 °, And the crystal of claim 16 having a peak at 30.0 ± 0.2 °. PCA including a step of dropping a PCA cation salt crystal by dropping or adding an alcohol solution or a nitrile solution to a PCA alcohol solution in which a cation-containing compound is dissolved, and a step of collecting a PCA cation salt crystal from the solution A method for producing a crystal of a cationic salt. The production method according to claim 18, wherein the alcohol solution to be dropped or added is a solution selected from the group consisting of C1 to C6 alcohols. The manufacturing method of Claim 18 whose nitrile solution dripped or added is acetonitrile. A method for producing PCA cation salt crystals, comprising: concentrating an aqueous solution of PCA in which a cation-containing compound is dissolved to precipitate PCA cation salt crystals; and collecting PCA cation salt crystals from the aqueous solution. The production method according to any one of claims 18 to 20, wherein the cation-containing compound is a sodium-containing compound, and the crystal of the PCA cation salt is a crystal of PCA sodium salt / anhydrate. The production method according to claim 21, wherein the cation-containing compound is a sodium-containing compound, and the crystal of the PCA cation salt is a crystal of PCA sodium salt monohydrate. The production method according to any one of claims 18 to 21, wherein the cation-containing compound is a potassium-containing compound, and the crystal of the PCA cation salt is a crystal of a PCA potassium salt / anhydrate. The production method according to any one of claims 18 to 21, wherein the cation-containing compound is an ammonium-containing compound, and the crystal of the PCA cation salt is a crystal of PCA ammonium salt monohydrate. The production method according to claim 21, wherein the cation-containing compound is a calcium-containing compound, and the crystal of the PCA cation salt is a crystal of PCA calcium salt monohydrate.