JP3013954B2 - Method for producing crystalline lactulose trihydrate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing crystalline lactulose trihydrate from a lactulose- containing aqueous solution using methanol or ethanol. More specifically, the present invention adjusts the lactulose-containing aqueous solution to a temperature-dependent methanol or ethanol concentration,
The present invention relates to a method for producing crystalline lactulose trihydrate, which comprises producing crystalline lactulose trihydrate in a specific temperature range and separating the crystalline lactulose trihydrate from a solvent.

[0002] In this specification, the crystalline lactulose trihydrate is _{C 12 H 22 O 11 · 3H} 2 O substances having a molecular formula (sometimes hereinafter referred to trihydrate), anhydrous lactulose Lactulose as a conventionally known anhydride (hereinafter sometimes referred to as an anhydride), and the ratio of lactose in water is the percentage (weight) of lactose content to the sum of lactose content and water content of a lactulose-containing aqueous solution. In addition, hereinafter,% is a value by weight, unless otherwise specified.

[0003]

BACKGROUND OF THE INVENTION Lactulose (4-O-.beta.-D-galactopyranosyl-D-fructose) is known as bifidobacterium.
As a growth factor of a microorganism belonging to the genus Bifidobacterium (Bifidobacterium), its effect has been confirmed by many studies, and it is used in a wide range of fields as food or medicine.

[0004] Lactulose is a disaccharide produced by subjecting lactose to Robley-De Bruine rearrangement and is very easily soluble in water, and is usually distributed in syrup form, but is easier to carry and handle than syrup. Therefore, some powdery anhydrides are also commercially available.

[0005] Conventionally, as a method for producing lactulose crystals, for example, a crystallization method using alcohols [Journal of the American Chemical Society,
52, page 2101, 1930], but it is the anhydride that is obtained in this way. In addition, the crystallization method of trihydrate from lactulose aqueous solution [carbohydrate.
Research (Carbohydrate Research), Vol. 226, page 29, 1992] is also known.

[0006]

However, the anhydrous lactulose obtained by the above-mentioned conventional method has low stability under high humidity and has a drawback of absorbing moisture, and has been difficult to handle. On the other hand, the conventional method of producing trihydrate from an aqueous solution is not crystallized unless lactulose in the aqueous solution is maintained at a high concentration, so that the deposition rate of the crystal is slow, and the crystal is easily made fine. There were inconveniences such as difficulty in separating and recovering crystals.

Therefore, the present inventors have studied various processes for producing lactulose trihydrate and the like, and solved various problems in the above-mentioned conventional method, and have high stability under high humidity. The goal is to develop a method for rapidly producing lactulose trihydrate from a relatively low-concentration lactulose aqueous solution without absorbing moisture and maintaining the lactulose concentration in the aqueous solution at a high concentration. As a result of intensive research, they found that methanol and ethanol had different effects on trihydrate crystals even though they were the same alcohol, and these alcohols were added to an aqueous lactulose solution under specific conditions. Lactulose trihydrate was successfully crystallized, and the present invention was completed.

That is, the present invention provides crystalline lactulose trihydrate which is stable without absorbing moisture even when stored at high humidity, is easy to handle, and has a cool feeling at the time of eating and drinking. It is intended to provide a method for rapid production from an aqueous solution.

[0009] The present invention also provides a novel process for producing crystalline lactulose trihydrate which is capable of obtaining a high-purity trihydrate from a relatively low-concentration aqueous lactulose solution without highly purifying the lactulose syrup. It is intended to provide a method.

[0010]

According to a first aspect of the present invention to solve the above-mentioned problems, a lactulose content is 7% of the total solids.
0% (weight) or more, and the total solid content is 60-75%
Lactose aqueous solution having a lactose ratio of 10% (weight) or less in water at a temperature of 0 to 25 ° C and a methanol concentration in a solvent depending on the temperature. M = -1.9T + 67 [where M and T in the above formula represent the methanol concentration (%, volume) and the temperature (° C.) in the solvent, respectively] and are not more than the concentration represented by 10% ( Volume), adding lactulose seeds, stirring to form crystalline lactulose trihydrate, and separating crystalline lactulose trihydrate from the solvent. Manufacturing method.

A second invention of the present invention for solving the above-mentioned problems is that the lactulose content is 70% (by weight) or more of the total solids, the total solids content is 60 to 75% (by weight), and lactose is Lactulose aqueous solution having a water ratio of not more than 10% (by weight) was prepared at a temperature of 0 to 25 ° C. and the concentration of ethanol in the solvent was dependent on the temperature. [However, in the above formula, E and T represent the ethanol concentration (%, volume) and the temperature (° C.) in the solvent, respectively] or less, and are adjusted to a range of 10 to 90% (volume). Adding lactulose seeds, stirring to produce crystalline lactulose trihydrate, and separating crystalline lactulose trihydrate from the solvent, the method for producing crystalline lactulose trihydrate. .

Next, the present invention will be described in detail. Lactulose, a starting material of the present invention, can be prepared by a known method (for example,
It may be manufactured according to Japanese Patent No. 874,954 or the like, or may be a commercially available product. Usually, lactulose syrup contains, in addition to water, 45-55% lactulose, 2-8% galactose, 2-5% lactose, and 2-8% other sugars, and The lactulose concentration is 70-90%. This normal lactulose syrup can be used as is without any purification.

[0013] If the lactulose concentration in the solid content is less than 70%, substances other than lactulose are liable to crystallize, making it difficult to separate high-purity trihydrate, which is not desirable. Since lactulose syrup contains lactose with low solubility, it is desirable to eliminate lactose crystals as much as possible to obtain trihydrate. Therefore, the ratio of lactose in lactulose syrup in water is 10
% Or less, and concentrated to a total solid content of 60 to 75%. When the total solid content is less than 60%, lactulose does not become supersaturated, and thus trihydrate is not precipitated, or the yield is low even if precipitated. Conversely, if the total solids concentration exceeds 75%,
The lactulose syrup has a high viscosity and is difficult to handle.

Next, the temperature of the lactulose syrup is adjusted, and methanol or ethanol is added to adjust the methanol or ethanol concentration calculated from the formula I or II.

In the first aspect of the present invention, the temperature of the lactulose syrup is adjusted to 0 to 25 ° C, preferably around 10 ° C. When the temperature of the lactulose syrup exceeds 25 ° C., crystals of trihydrate cannot be obtained, and when it is lower than 0 ° C., dew condensation occurs, making it difficult to separate the crystals. It is important to adjust the temperature of the lactulose syrup to that particular temperature range.

Next, in order to adjust the methanol concentration to be not more than the methanol concentration calculated from the set temperature according to the formula I and not less than 10% (volume), the lactulose.
Add methanol to the syrup. If the methanol concentration is
Either no trihydrate is formed or an anhydride is formed if the concentration exceeds the concentration calculated by Formula I, and if the methanol concentration is less than 10% (by volume), Is slow, and the crystal becomes fine, which is not desirable. Thus, it is important to adjust to the specific concentration conditions calculated by Equation I.

According to a second aspect of the present invention, the first aspect
The temperature of the lactulose syrup is 0 to
The temperature is adjusted to 25 ° C, preferably around 10 ° C. It is important to adjust the temperature of the lactulose syrup to that particular temperature range. Next, ethanol was added, and the concentration of ethanol in the solvent was calculated based on the above-mentioned set temperature.
The concentration is adjusted to be less than the concentration calculated from II and in the range of 10 to 90% (volume). If the ethanol concentration exceeds 90% (by volume), either no trihydrate is formed, the anhydride is crystallized, or a mixture of the trihydrate and the anhydride is crystallized, When the ethanol concentration is less than 10% (volume), the precipitation rate of trihydrate is low, and the crystal becomes fine, which is not desirable. Thus, it is important to adjust to the specific temperature conditions calculated by Equation II.

Next, lactulose is seeded (seeding) at the above-mentioned set temperature, and stirred to precipitate crystals. Lactulose to be seeded is preferably trihydrate. After sufficient crystals are formed, the trihydrate is separated by a known method (eg, centrifugal filtration, decantation, etc.). The separated trihydrate is washed with water to remove impurities. However, since the trihydrate has high solubility, it is desirable to use as little cold water as possible. Since the trihydrate thus obtained is wet with water, it is necessary to remove the water on the surface. Normally, heated air is used for drying such crystals, but heated air cannot be used for drying the trihydrate.

The reason is as follows. Trihydrate has a solubility of about 50% in water at a temperature of 5 ° C., the solubility increasing with increasing temperature. The use of warm air should promote the dissolution of the trihydrate as it absorbs heat when dissolved in water. Melt at elevated temperatures because trihydrate has a melting onset of about 60 ° C. Therefore, drying of the trihydrate must be performed at room temperature. As a method for drying the trihydrate, a known drying method such as a vacuum drying method can be exemplified, and the dried product obtained after drying can be pulverized if necessary.

The trihydrate produced as described above has the following physicochemical properties. (1) having a molecular formula _{C 12 H 22 O 11 · 3H} 2 O molecular formula. (2) Elemental analysis The molar ratio of carbon: hydrogen: oxygen is 12:28:14. (3) Molecular weight The molecular weight measured by the freezing point depression method is 396 daltons. (4) Moisture The water content measured by the Karl Fischer method is 13.6%
(Weight). (5) Melting start point The melting start point measured by the capillary method is 58 to 60 ° C.

(6) Specific Rotation A specific rotation is shown. The specific rotation measured at 20 ° C. of a 1% (weight) aqueous solution at equilibrium is −43.1 ± 0.3 °. (7) Coloring reaction Fehling test Positive ammonia test Positive resorcinol test Positive Ninhydrin test Negative

(8) Qualitative and Quantitative Analysis of Lactulose The method described in the United States Pharmacopeia, Revised 22nd [The United States Pharmopia
macopeia; twenty-second revision), supplement 1,
Page 2138, United States Pharmacopeia Conve
ntion, Inc.), 1990], and a method described in the Japanese Pharmacopoeia Standards for Pharmaceutical Ingredients, supervised by the Ministry of Health and Welfare.
As a result of a test by gas chromatography according to Pharmaceutical Times Co., Ltd., pp. 24 (1986), all showed the same column retention time as the anhydride, and the quantitative values were all 86.4.
%Met.

(9) Different from acidic, basic and neutral Neutral (10) Infrared absorption spectrum As shown in FIG. Fig. 1 is distributed over Nijol,
It is an infrared absorption spectrum measured. The horizontal axis in FIG.
The wave number and the vertical axis indicate the transmittance. 3600-3200cm-1
(ΝOH) and 1200-1000 cm -1 (νCO) show complex absorption of saccharides in general.
A difference is observed in the absorption spectrum in the cm-1 region.

(11) Solubility Easily soluble in water. Soluble in methanol, but an anhydride precipitates out quickly. Insoluble in ethanol, but quickly becomes anhydrous and dissolves. Insoluble in acetone, ethyl ether and benzene. (12) Color tone colorless or white

The trihydrate produced by the method of the present invention is
It is extremely stable in a high temperature environment, does not absorb moisture, is easy to handle, and has a characteristic of exhibiting a unique sweetness accompanied by a cooling sensation because it absorbs heat when dissolved in water. Hydrates have the same uses as anhydrides produced by conventional methods, and are used as pharmaceuticals such as constipation improver, hepatic encephalopathy, hepatic coma, hyperammonemia, etc. As a growth factor, in foods and pharmaceuticals, as a low-calorie sweetener, caries preventive sweetener, as a low-sweetener, etc.
It can be used as it is or as a powder, tablet or the like as it is or by mixing it with other components.

Next, the present invention will be described in detail with reference to test examples.
In the following description, lactulose and water content were quantified by the following method. (1) Lactulose content According to the liquid chromatography method described in the 22nd revised United States Pharmacopoeia described in (8) of the physicochemical properties described above. (2) Moisture content According to the Karl Fischer method.

(Test Example 1) This test was performed to examine the conditions for forming trihydrate in a methanol-water system.

(1) Sample Lactulose and lactose in the total solid content were 73.4% and 4.4%, respectively, and lactulose syrup (sample 1), and 85.6% and 3.1% lactulose. The solid content of the two samples of syrup (Sample 2) (both manufactured by Morinaga Milk Industry Co., Ltd.) was 65.0% and 7%, respectively.
It was adjusted to 5.0%. In addition, the ratio of lactose in these samples in water was 7.6% and 8.5%, respectively.

(2) Test method Methanol (Wako Pure Chemical Industries, purity 9)
9.6%, by volume) to adjust the methanol concentration in the solvent from 10% to 80% every 10%.
Adjusted to 10, 15 and 25 ° C. Next, 0.1 g of trihydrate was seeded, and the mixture was stirred at a predetermined temperature for 7 days. The resulting crystals were centrifuged, washed with cold water, and dried at room temperature of 25 ° C. or less for 15 hours to obtain crystals. Was. The water content of the obtained crystals was measured, and 13.6 ± 0.4% was found to be trihydrate, 1.0%
The following were determined to be anhydrous.

(3) Test Results The results of this test are as shown in FIG. The vertical axis and horizontal axis of the figure shows the methanol concentration and the crystallization temperature of the respective solvent, ○ and × in the figure, respectively indicate that the trihydrate is obtained and that the resulting such tinged. As is clear from FIG. 2, the methanol concentration in the solvent in which the trihydrate was formed was found to be not less than 10% (volume) and not more than the value indicated by the straight line represented by the formula I. . It should be noted that almost the same results were obtained by changing the lactulose syrup and testing.

(Test Example 2) This test was conducted to examine the conditions for forming trihydrate in an ethanol-water system.

(1) Sample The same sample as in Test Example 1 was used. (2) Test method The same method as in Test Example 1 was used except that ethanol (manufactured by Wako Pure Chemical Industries, Ltd., purity: 99.5%, volume) was used.

(3) Test Results The results of this test are as shown in FIG. The ordinate and abscissa of the figure indicate the ethanol concentration and the crystallization temperature in the solvent, respectively. In the figure, ○, △ and ● indicate that the trihydrate was obtained and that the anhydride was obtained, respectively. And that a mixture of trihydrate and anhydride was obtained. As is clear from FIG. 3, the ethanol concentration in the solvent in which the trihydrate is formed is not less than 10% (volume) and not more than the value indicated by the straight line represented by the formula II and not more than 90% (volume). Turned out to be in the range. It should be noted that almost the same results were obtained by changing the lactulose syrup and testing.

[0034]

EXAMPLES Next, the present invention will be described in more detail by way of examples, but the present invention is not limited to the following examples. Example 1 Lactulose syrup (manufactured by Morinaga Milk Industry Co., Ltd.) having a solid content of 70% (the contents of lactulose and lactose in the total solid content are 73.4% and 4.4%, respectively, and the ratio of lactose in water is 9.3%) ) 10 Kg is cooled to 10 ° C. and the methanol concentration calculated from the formula I is 48% (= −1.9 × 10 + 67)
Methanol (manufactured by Wako Pure Chemical Industries, Ltd.) was added to adjust the volume to 20% (volume), which is less than or equal to 10% or more.
76 l was added, and 12 g of trihydrate was seeded at the same temperature, and kept for 24 hours while stirring to form a trihydrate, which was filtered with a filter-type centrifuge (manufactured by Domestic Centrifuge). The hydrate was separated and washed with cold water to obtain about 1.8 kg of trihydrate. The obtained trihydrate was dried using a vacuum drier (manufactured by Yamato Scientific Co., Ltd.) at 3 mmHg or less and 25 ° C. or less for 24 hours, and pulverized to obtain about 1.6 kg of powdered trihydrate.

The physicochemical properties of the obtained powdery trihydrate were as follows. 1) Moisture Moisture by Karl Fischer method 13.9% Moisture lost on diphosphorus pentoxide at room temperature 0.1% 2) Lactulose quantitative value Quantitative value by the same liquid chromatography method as above 85.9% Room temperature, 5 99.5% of trihydrate in dried product dried on diphosphorus oxide 3) Melting point measured by capillary method 58-60 ° C 4) Specific rotation Rotated product dried on diphosphorus pentoxide at room temperature Of 1% aqueous solution at 20 ° C (at equilibrium) -42.9 °

Example 2 Lactulose syrup (Morinaga) having a solid content of 70% (the contents of lactulose and lactose in the total solid content were 85.6% and 3.1%, respectively, and the ratio of lactose in water was 6.7%) 10 Kg of a dairy company was cooled to 25 ° C., and the methanol concentration calculated from the formula I was 19.5% (= −1.9 × 25 + 6).
7) Add 0.53 l of methanol (manufactured by Wako Pure Chemical Industries, Ltd.) and adjust the seed to 12 g of trihydrate at the same temperature in order to adjust the volume to 15% (volume) which is less than or equal to 10% or more. Crystals were added, and the mixture was kept for 48 hours with stirring to produce trihydrate. The trihydrate was separated by a filter-type centrifuge (manufactured by Kokusai Centrifuge Co., Ltd.) and washed with cold water. 5 Kg of trihydrate was obtained. The obtained trihydrate was dried using a vacuum dryer (manufactured by Yamato Scientific Co., Ltd.) at 3 mmHg or less and 25 ° C. or less for 24 hours, and pulverized to obtain about 2.2 kg of powdered trihydrate.

The physicochemical properties of the obtained powdery trihydrate were as follows. 1) Moisture 13.7% moisture by Karl Fischer method Room temperature, moisture lost on diphosphorus pentoxide 0.3% 2) Quantitative value of lactulose Quantitative value by the same liquid chromatography method as above 86.0% Room temperature, 5% 99.8% of trihydrate in dried product dried over diphosphorus oxide 3) Melting start point Measured by the same method as in Example 1 58-60 ° C 4) Specific rotation At room temperature, on diphosphorus pentoxide 1% aqueous solution of the dried product dried at 20 ° C (at equilibrium) -42.8 °

Example 3 Lactulose syrup having a solids content of 70% (the contents of lactulose and lactose in the total solids were 73.4% and 4.4%, respectively, and the ratio of lactose in water was 9.3%) (Morinaga) 10 kg was cooled to 5 ° C., and the ethanol concentration calculated from the formula II was 96.5% (= −1.3 × 5 + 10).
3) Add 3.0 l of ethanol (manufactured by Wako Pure Chemical Industries, Ltd.) to adjust the volume to 50.0% (volume) of not more than 90% (volume) and not more than 10%, and At the same temperature, 12 g of trihydrate was added as a seed crystal, and kept for 48 hours with stirring to form a trihydrate. The trihydrate was separated by a filter-type centrifuge (manufactured by Kokusan Centrifuge). Then, the resultant was washed with cold water to obtain about 1.7 kg of trihydrate. The obtained trihydrate was dried using a vacuum drier (manufactured by Yamato Scientific Co., Ltd.) at 3 mmHg or less and 25 ° C. or less for 24 hours, and pulverized to obtain about 1.5 kg of powdered trihydrate.

The physicochemical properties of the obtained powdered trihydrate were as follows. 1) Moisture Moisture by Karl Fischer method 13.8% Moisture lost on diphosphorus pentoxide at room temperature 0.1% 2) Lactulose quantitative value Quantitative value by the same liquid chromatographic method as above 86.1% Room temperature, 5 99.8% of trihydrate in dried product dried over diphosphorus oxide 3) Melting start point Measured by the same method as in Example 1 58-60 ° C 4) Specific rotation At room temperature, on diphosphorus pentoxide 1% aqueous solution of the dried product dried at 20 ° C (at equilibrium) -42.9 °

Example 4 Lactulose syrup (Morinaga) having a solid content of 65% (the contents of lactulose and lactose in the total solid content were 73.4% and 4.4%, respectively, and the ratio of lactose in water was 7.6%) 10 kg was cooled to 10 ° C., and the ethanol concentration calculated from the formula II was 90.0% (= −1.3 × 10 +).
103) or less and 90% (capacity) or less and 10%
To adjust to the above range of 20.0% (volume), 0.881 of ethanol (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and 12 g of trihydrate was seeded at the same temperature, followed by stirring. While holding for 48 hours to form a trihydrate, separating the trihydrate by a filter-type centrifuge (manufactured by Kokusai Centrifuge Co., Ltd.), washing with cold water, and adding about 1.5 kg of trihydrate. I got The obtained trihydrate was dried with a vacuum dryer (manufactured by Yamato Scientific Co., Ltd.) by 3 mm
It was dried at a temperature of not more than Hg and not more than 25 ° C. for 24 hours and pulverized to obtain about 1.3 kg of powder trihydrate.

The physicochemical properties of the obtained powdered trihydrate were as follows. 1) Moisture Moisture by Karl Fischer method 13.9% Moisture lost on diphosphorus pentoxide at room temperature 0.2% 2) Quantitative value of lactulose Quantitative value by the same liquid chromatography method as described above 86.2% Room temperature, 5 Trihydrate in dried product dried over diphosphorus oxide 100.0% 3) Melting start point Measured value by the same method as in Example 1 58-60 ° C 4) Specific rotation At room temperature, on diphosphorus pentoxide 1% aqueous solution of the dried product dried at 20 ° C (at equilibrium) -43.0 °

Example 5 Lactulose syrup having a solid content of 75% (the content of lactulose and lactose in the total solid content was 85.6% and 3.1%, respectively, and the ratio of lactose in water was 8.5%) (Morinaga) 10 kg was cooled to 5 ° C., and the ethanol concentration calculated from the formula II was 96.5% (= −1.3 × 5 + 10).
3) Add 10.3 liters of ethanol (manufactured by Wako Pure Chemical Industries, Ltd.) to adjust the volume to 80.0% (volume), which is not more than 90% (volume) but not more than 90% (volume), At the same temperature, 12 g of trihydrate was seeded, and 48
The trihydrate was generated by holding for a time, and the trihydrate was separated by a filter-type centrifuge (manufactured by Domestic Centrifuge) and washed with cold water to obtain about 2.8 kg of trihydrate. Was. The obtained trihydrate was dried at 3 mmHg using a vacuum dryer (manufactured by Yamato Scientific Co., Ltd.).
Thereafter, the powder was dried at 25 ° C. or lower for 24 hours and pulverized to obtain about 2.5 kg of powder trihydrate.

The physicochemical properties of the obtained powdery trihydrate were as follows. 1) Moisture 13.8% water by Karl Fischer method Room temperature, water lost on diphosphorus pentoxide 0.2% 0.2% 2) Lactulose quantitative value Quantitative value by the same liquid chromatographic method as above 86.2% room temperature, 5 Trihydrate in dried product dried over diphosphorus oxide 100.0% 3) Melting start point Measured value by the same method as in Example 1 58-60 ° C 4) Specific rotation At room temperature, on diphosphorus pentoxide 1% aqueous solution of the dried product dried at 20 ° C (at equilibrium) -42.9 °

[0044]

The effects of the present invention are as follows. That is, the present invention provides a lactulose aqueous solution, the concentration of methanol and ethanol in the solvent is adjusted to specific conditions depending on the specific temperature, to produce crystalline lactulose trihydrate, and from the solvent, the crystalline lactulose trihydrate The present invention relates to a method for rapidly producing the trihydrate, characterized in that the trihydrate is separated, and the trihydrate obtained by the method of the present invention is extremely stable in a high-humidity environment. It does not absorb moisture and is easy to handle.
Further, the trihydrate obtained by the method of the present invention absorbs heat when dissolved in water, and thus exhibits a unique sweetness accompanied by a cooling sensation.

Further, the method of the present invention comprises the use of lactulose
Since there is no need to purify the syrup, the manufacturing process is extremely simple. Further, the method of the present invention can rapidly precipitate crystals, rapidly obtain crystals from a relatively low-concentration aqueous lactulose solution, and obtain high-purity trihydrate.

[Brief description of the drawings]

FIG. 1 is an infrared absorption spectrum of trihydrate.

FIG. 2 shows the relationship between the crystallization temperature of trihydrate and the methanol concentration.

FIG. 3 shows the relationship between the crystallization temperature of trihydrate and the ethanol concentration.

Continued on the front page (72) Inventor Satoshi Nakano 1-10-5 Seiyano, Matsumoto City, Nagano Prefecture City 2D, City Koshiishi (72) Inventor Itsuko Suzawa 6-10-5, Ogami, Ayase City, Kanagawa Prefecture Waco Reelegance Sagami No. 2-301 (58) Field surveyed (Int. Cl. ⁷ , DB name) C07H 3/04 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A lactulose content of 70% of the total solids
(Weight) or more, a lactulose aqueous solution having a total solid content of 60 to 75% (weight) and a ratio of lactose in water of 10% (weight) or less, at a temperature of 0 to 25 ° C and in a solvent. The methanol concentration is represented by the following equation M = -1.9T + 67 [where M and T represent the methanol concentration (%, volume) and the temperature (° C.) in the solvent, respectively] depending on the temperature. The concentration is adjusted to not more than 10% (volume) but not less than 10% (volume), lactulose seed crystals are added, and the mixture is stirred to produce crystalline lactulose trihydrate, and the crystalline lactulose trihydrate is separated from the solvent. For producing crystalline lactulose trihydrate. 2. Lactulose content of 70% of total solids
(Weight) or more, a lactulose aqueous solution having a total solid content of 60 to 75% (weight) and a ratio of lactose in water of 10% (weight) or less, at a temperature of 0 to 25 ° C and in a solvent. The ethanol concentration is represented by the following equation E = -1.3T + 103 depending on the temperature, where E and T represent the ethanol concentration (%, volume) and the temperature (° C.) in the solvent, respectively. Adjusting the concentration to below 10% to 90% (volume), adding lactulose seeds and stirring to produce crystalline lactulose trihydrate and separating crystalline lactulose trihydrate from the solvent A method for producing crystalline lactulose trihydrate, comprising: