JPH1017580A - Production of crystalline l-ascorbic 2-phosphorate sodium salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain crystalline L-ascorbic 2-phosphate which is useful as a stabilized derivative of L-ascorbic acid for cosmetics, medicines, feed and the like by suspending amorphous sodium L ascorbic 2-phosphate in a dispersant. SOLUTION: Amorphous sodium L-ascorbic 2-phosphate is suspended in a dispersant of an organic solvent, for example, an aromatic hydrocarbon, an aliphatic alcohol, an aliphatic ketone or an aliphatic ether, heating is continued at 40-120 deg.C, then, cooled down to room temperature. The suspension is filtered with a centrifugal, separator, the wet precipitate is rinsed with the dispersant and dried in vacuum whereby the objective crystalline sodium L-ascorbic 2-phosphate useful as a stabilized derivative of ascorbic acid for cosmetics, medicines, food additivies, domestic animal feeds and in other various kinds of industrial purposes is readily obtained in high yield.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a crystal of L-ascorbic acid-2-phosphate sodium salt (hereinafter referred to as L-ascorbic acid-2-phosphate).
-Ascorbic acid-2-phosphate sodium salt is abbreviated as APS, and crystals of L-ascorbic acid-2-phosphate sodium salt are abbreviated as crystalline APS). Crystalline APS is useful as a stabilized derivative of L-ascorbic acid, for cosmetics, pharmaceuticals,
It is used for food additives, feed, and various other industrial fields.

[0002]

2. Description of the Related Art L-ascorbic acid (vitamin C) has been known to have various physiological and pharmacological actions.
Above all, it has been used for whitening cosmetics because it has an effect of preventing melanin pigmentation. L-ascorbic acid is
It is a known fact that it is unstable to oxygen and heat, and it can be stabilized against oxygen and heat by phosphorylating the hydroxyl group at the 2-position of this unstable L-ascorbic acid. It is used as a water-soluble vitamin C derivative in the form of a salt of L-ascorbic acid-2-phosphate, especially a sodium salt, that is, APS. Since APS currently on the market is amorphous, it easily absorbs moisture during storage and easily forms powder nodules. A that absorbed moisture
PS causes caking or decreases fluidity,
When blended with other drugs in the form of a powder, variations in quality that hinder practical use are likely to occur. Therefore, a stable crystalline APS with little moisture absorption during storage is desired. Heretofore, crystalline APS and its production method have been scarcely known, and there is only a brief description of crystalline APS and its production method in JP-A-2-131494.

[0003]

In the method of the above-mentioned patent, methanol is added to an aqueous solution containing APS while heating and refluxing at a temperature of 40 to 80 ° C., and after further heating and refluxing for 2 to 10 hours, It is cooled to room temperature overnight to precipitate and obtain crystalline APS. This method is a useful method for producing crystalline APS, but yields 71-85.
% And low. In addition, the aqueous solution containing APS is 40-80.
Since heating is carried out at a temperature of ° C. for a long time, APS is decomposed to lower the yield, and contaminated L-ascorbic acid is decomposed and colored. Furthermore, there is a disadvantage that productivity is low such as continuing heating and refluxing for 2 to 10 hours after completion of addition of methanol and cooling to room temperature overnight.
As described above, the conventional method for producing crystalline APS is not sufficient in terms of simplicity, decomposition, yield, coloring, and the like. The present invention eliminates such disadvantages and eliminates APS without decomposition or coloring.
It is an object of the present invention to provide a method for easily producing a high yield.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies in order to improve the above-mentioned disadvantages. As a result, surprisingly, the present inventors have found that amorphous APS suspended in a dispersion medium such as an organic solvent can be used. The present inventors have found that it changes to crystalline by heating, and that high-purity crystalline APS containing no amorphous material can be obtained easily and in a short time, and the present invention has been achieved. That is, the present invention
A method for producing a crystalline APS, comprising suspending an amorphous APS in a dispersion medium and heating.

[0005]

DESCRIPTION OF THE PREFERRED EMBODIMENTS A feature of the present invention is that amorphous APS is suspended in a dispersion medium and heated. On the other hand, amorphous APS is heated as it is without using a dispersion medium. Also,
Amorphous APS does not change to crystalline APS, is colored yellow, and only shows decomposition of APS. For example, the amorphous APS was exposed to a temperature of 60 ° C. for 24 hours in a nitrogen atmosphere, and the change in the crystalline state was followed over time by X-ray diffraction. 24
The APS remained amorphous even after a lapse of time, and after 24 hours, the amorphous APS was colored yellow, and the APS content had decreased to 97% of the initial value. Further, even if the amorphous APS is dissolved in water and heated, and the water is evaporated to dryness, only the amorphous powder is formed, but not the crystalline APS.

On the other hand, an organic solvent is used as a dispersion medium,
When the amorphous APS was suspended in an organic solvent and exposed to a temperature of 60 ° C. for 24 hours, and the change in the crystal state of the APS was followed by X-ray diffraction, it changed to crystalline in 30 minutes. 24
There was no decrease in APS content after time and no coloration was seen. Thus, by suspending in a dispersion medium, a high-quality crystalline APS can be efficiently manufactured in a short time.

The amorphous (amorphous) APS used as the raw material of the present invention is, for example, Ascorbyl PS [trade name,
Manufactured by Showa Denko KK]. These raw materials of amorphous APS may be a mixture with crystalline materials.
The particle diameter of the above-mentioned raw material APS is preferably from 1 to 2000 μm. If the particle size is too large, the time required for heating becomes long, and if it is too small, it is difficult to handle. Therefore, 5 to 500 μm is particularly preferable.

In the present invention, it is important to suspend APS in a dispersion medium. Therefore, any liquid that does not dissolve APS may be used, but suitable ones are mainly organic solvents. The following description is made using an organic solvent as an example. The raw material amorphous APS is suspended in an organic solvent as shown below.
At this time, the slurry concentration of the amorphous APS is 0.1 to 50%.
(Wt / V). If the slurry concentration is high, the viscosity increases and the stirring efficiency becomes poor, and if the slurry concentration is low, the productivity becomes poor. Therefore, 5 to 30% is particularly preferable.

The organic solvent used in the present invention includes aromatic hydrocarbons such as toluene and xylene, aliphatic alcohols,
For example, lower aliphatic alcohols having 4 or less carbon atoms such as methanol, ethanol and isopropyl alcohol, aliphatic ketones such as cyclohexanone and aliphatic ketones having 6 or less carbon atoms such as acetone, and aliphatic ethers such as tetrahydrofuran and 1,1 Examples include cyclic ethers such as 4-dioxane. These solvents can be used alone or in combination. In addition, even if an aliphatic hydrocarbon or a halogenated hydrocarbon is used, there is no essential problem with respect to the conversion of the amorphous APS to the crystalline APS. preferable.
Since the organic solvent is recovered by an operation such as distillation after isolating the crystalline APS, an inexpensive solvent having a low boiling point is preferable. Therefore, methanol and acetone are particularly preferred. Further, water may be contaminated within a range that does not dissolve APS in the organic solvent used in the present invention. Amorphous APS is insoluble in organic solvents, but is very well soluble in water.
The amount of water contaminating in the organic solvent is 40% (wt / V)
The following is preferred.

[0010] The amorphous APS is added to the organic solvent, suspended by stirring and heated. Heating temperature is 40-120 ° C
Is preferred. When the temperature is low, the time required for heating becomes long, and when the temperature is high, the decomposition of APS is promoted.
-100 ° C is particularly preferred. Usually, the time required for heating is 0.3 to 12 hours. If the time is too short, the conversion from amorphous to crystalline is not completed, and if the time is too long, there is no hindrance to the conversion from amorphous to crystalline, but economically because the plant is meaninglessly occupied. Disadvantageous. Therefore, 0.5 to 7 hours is particularly preferable.

After the completion of the heating, the system is cooled to room temperature. After cooling,
There is no particular need for aging. The slurry containing the crystalline APS is isolated using a device such as a centrifuge,
After sufficiently washing with the organic solvent, white crystalline APS can be obtained with high purity and high yield by treatment such as vacuum drying.

It is not clear why the amorphous APS is changed to crystalline by the method of the present invention, but the hydration water in the APS decreases during heating. It is conceivable that the water loss is involved in the crystallization in some way.

The crystalline APS obtained by the present invention has the following physicochemical properties. (1) X-ray diffraction spectrum; CuKα ray, 40 kV, 4
FIG. 1 shows an X-ray diffraction spectrum obtained under the condition of 0 mA. Table 1 shows the surface spacing d (Å) and the comparative strength. For reference, an X-ray diffraction spectrum of amorphous APS is shown in FIG. 2 for comparison. (2) Infrared absorption spectrum; FIG. 3 shows the result measured by the KBr method. The characteristic absorption (wave number) is as follows. 3400 cm ^-1: O-H absorption band 1600 cm ^-1: C = absorption band of O stretching vibration 1000 to 1200 ^-1: absorption band of P-O (3) Solubility: Solubility in soluble (25 ° C. in water 38 % (Wt / V) Insoluble in organic solvent (alcohols, chloroform) (4) Crystal form: fine crystal aggregate of 10 to 500 μm (microscopic observation)

The crystalline APS obtained by the production method of the present invention has low hygroscopicity and excellent stability. For example, it can be used for pharmaceuticals (eg, oral medicines, eye drops, bath agents, etc.), cosmetics (eg, cosmetics) It is used as water, emulsion, cream, pack, etc., food (eg, bread, etc.) and animal feed (eg, shrimp, salmon, hamachi, eel, carp, etc. feed for aquaculture).

[0015]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. Also, hereinafter, the APS obtained in Examples 1 to 7
Showed the same physicochemical properties as the crystalline APS described above. The amorphous APS used in each of Examples and Comparative Examples was manufactured by Showa Denko KK, trade name: Ascorbyl PS, particle size: 1 to 5
0 μm.

Example 1 Amorphous APS was added to 1000 ml of 99% methanol under stirring.
The suspension was adjusted by adding 200 g and heated to 60 ° C. Heating was continued at this temperature for 2 hours and cooled to room temperature. APS was collected by filtration using a centrifugal separator, and the obtained wet body was 99%
Washed thoroughly with methanol. Dried at 40 ° C. under vacuum,
198 g (99% yield) of 100% pure APS was obtained.
X-ray diffraction confirmed that the obtained APS was crystalline.

Example 2 Under stirring, amorphous APS was added to 1000 ml of 99% methanol.
The suspension was adjusted by adding 400 g and heated to 60 ° C. Heating was continued at this temperature for 4 hours and cooled to room temperature. APS was collected by filtration using a centrifugal separator, and the obtained wet body was 99%
Washed thoroughly with methanol. Dried at 40 ° C. under vacuum,
396 g (99% yield) of 100% pure APS was obtained.
X-ray diffraction confirmed that the obtained APS was crystalline.

Example 3 200 g of amorphous APS was added to 1000 ml of a 70% (wt / V) methanol-water / methanol solution with stirring to prepare a suspension, which was heated to 70 ° C. Heating was continued at this temperature for 4 hours and cooled to room temperature. AP using centrifuge
S was collected by filtration, and the obtained wet body was sufficiently washed with the same water-methanol solution as described above. Dry at 40 ° C under vacuum, purity 1
192 g (96% yield) of 00% APS was obtained. X-ray diffraction confirmed that the obtained APS was crystalline.

Example 4 The same water-methanol solution as in Example 3 (1000 m) was stirred.
The suspension was adjusted by adding 50 g of amorphous APS to
Was heated. Heating was continued at this temperature for 2 hours and cooled to room temperature. The APS was collected by filtration using a centrifuge, and the obtained wet body was sufficiently washed with the same water-methanol solution as described above. Drying at 40 ° C. under vacuum yielded 43 g (86% yield) of 100% pure APS. X-ray diffraction confirmed that the obtained APS was crystalline.

Example 5 Under stirring, amorphous APS5 was added to 1000 ml of 99% acetone.
The suspension was adjusted by adding 0 g and heated to 50 ° C. Heating was continued at this temperature for 7 hours and cooled to room temperature. APS was collected by filtration using a centrifugal separator, and the obtained wet body was sufficiently washed with 99% acetone. Dry at 40 ° C under vacuum, purity 1
49 g (98% yield) of 00% APS was obtained. X-ray diffraction confirmed that the obtained APS was crystalline.

Example 6 Amorphous APS2 was added to 1000 ml of 99% toluene under stirring.
The suspension was adjusted by adding 00 g and heated to 100 ° C. Heating was continued at this temperature for 1 hour and cooled to room temperature. APS was collected by filtration using a centrifugal separator, and the obtained wet body was 99%
It was thoroughly washed with acetone. It was dried at 55 ° C. under vacuum to obtain 195 g (yield 98%) of 100% pure APS. X
The obtained APS was confirmed to be crystalline by line diffraction.

Example 7 Under stirring, 200 g of amorphous APS was added to 1000 ml of 99% 1,4-dioxane to prepare a suspension, which was heated to 90 ° C. Heating was continued at this temperature for 1 hour and cooled to room temperature. APS was collected by filtration using a centrifugal separator, and the obtained wet body was sufficiently washed with 99% acetone. After drying at 50 ° C. under vacuum, 195 g of 100% pure APS (98% yield)
Obtained. X-ray diffraction confirmed that the obtained APS was crystalline.

Comparative Example 1 The same water-methanol solution of 1000 m as in Example 3 was stirred under stirring.
200 g of amorphous APS was added to 1 to prepare a suspension, and stirring was continued for 24 hours at room temperature (20 ° C.). The APS was collected by filtration using a centrifuge, and the obtained wet body was sufficiently washed with the same water-methanol solution as described above. It is dried at 40 ° C. under vacuum, and 192 g of APS having a purity of 100% (96% yield).
Obtained. X-ray diffraction confirmed that the obtained APS remained amorphous.

Comparative Example 2 Amorphous APS2 was added to 1000 ml of 99% toluene under stirring.
The suspension was adjusted by adding 00 g, and stirring was continued for 24 hours at room temperature. APS was collected by filtration using a centrifugal separator, and the obtained wet body was sufficiently washed with 99% toluene. Under vacuum, 5
After drying at 5 ° C., 196 g (yield 98%) of 100% pure APS was obtained. X-ray diffraction confirmed that the obtained APS was amorphous.

[0025]

[Table 1]

[0026]

According to the production method of the present invention, crystalline L-ascorbic acid-2-phosphate sodium salt can be produced simply and in high yield. The crystalline L-ascorbic acid-2-phosphate sodium salt obtained by the production method of the present invention is used for cosmetics, feed, medicine, food additives and the like.

[Brief description of the drawings]

FIG. 1 shows crystalline L-ascorbic acid obtained by the present invention.
2 is an X-ray diffraction spectrum (CuKα ray, 40 kV, 40 mA) of 2-phosphate sodium salt. In the figure, the vertical axis represents the diffraction intensity (unit: count / second), and the horizontal axis represents the diffraction angle (unit: 2θ (°)).

FIG. 2 shows an X-ray diffraction spectrum of an amorphous sodium salt of L-ascorbic acid-2-phosphate (CuKα ray,
0 kV, 40 mA). In the figure, the vertical axis represents the diffraction intensity (unit: count / second), and the horizontal axis represents the diffraction angle (unit: 2θ).
(°)).

FIG. 3 shows crystalline L-ascorbic acid obtained in the present invention.
It is an infrared absorption spectrum of 2-phosphate sodium salt.

Claims (5)

[Claims] An amorphous L-ascorbic acid in a dispersion medium.
A method for producing crystalline sodium salt of L-ascorbic acid-2-phosphate, comprising suspending 2-phosphate sodium salt and heating. 2. The method according to claim 1, wherein the dispersion medium is an organic solvent. 3. The method according to claim 2, wherein the organic solvent is at least one selected from aromatic hydrocarbons, aliphatic alcohols, aliphatic ketones and aliphatic ethers. 4. The method according to claim 3, wherein the aliphatic alcohol is methanol and the aliphatic ketone is acetone. 5. The method according to claim 1, wherein the heating temperature is 40 to 120 ° C.