Preparation process of solvate-free solid lactulose

Abstract

The invention relates to a preparation process of solvate-free solid lactulose. The preparation method comprises the following steps: concentrating and dehydrating a concentrated lactulose solution, heating and dissolving a protonic solvent, cooling, inducing crystallization, carrying out saturated crystallization, filtering, drying, dissolving with pure water, and dehydrating and drying to obtain the solvate-free solid lactulose. The prepared solid lactulose is high in purity, low in organic solvent residue, stable in process and beneficial to industrial large-scale production.

Description

Technical Field

[0001] This invention relates to a method for preparing solid lactulose, specifically to a process for preparing solvent-free solid lactulose. Background Technology

[0002] Lactulose, also known as lactulose or isomerized lactose, is a disaccharide with the chemical name 4-β-D-galactoside-D-fructose. Its structure is as follows:

[0003]

[0004] Lactulose is a synthetic, indigestible lactose isomer. It has beneficial effects on human health and is widely used in the pharmaceutical and food industries. As a medicine, lactulose can be used to prevent and treat chronic constipation, portal venous encephalopathy, and other intestinal or liver diseases. As a food additive, lactulose is used in infant formula and health foods. Furthermore, lactulose is low in calories, has good safety profile, high stability, and does not undergo the Maillard reaction, making it a suitable substitute for sucrose and sweeteners in food.

[0005] Lactulose concentrate is a concentrated aqueous solution containing a mixture of various sugars such as lactulose, lactose, galactose, or fructose. It is obtained from lactose through isomerization reactions using chemical or biological methods. Its purity is relatively low, with a content of only 63%–70%, and a lactose content as high as 5%–10%. However, lactose metabolism requires lactase. If the human body cannot secrete lactase or has insufficient lactase secretion, lactose digestion will be hindered or incomplete, easily causing adverse reactions such as non-infectious diarrhea. Therefore, the high lactose content in existing lactulose concentrates limits their application.

[0006] Lactulose concentration in concentrated solutions is low, and lactulose is highly soluble in water (~76.4% W / W). The concentrated solution has high viscosity, making it impossible to crystallize solid lactulose in aqueous solution. Patent CN118852280A discloses a method for preparing lactulose by adding a hydrophilic organic solvent to a lactulose solution for crystallization; however, in practice, crystallization fails to occur; adding a large amount of organic solvent only yields a small amount of solid, resulting in extremely low yield. Other existing technologies utilize methanol to promote crystallization of high-concentration lactulose solutions, but lactulose readily forms hydrogen bonds with proton solvents, making the organic proton solvent extremely difficult to remove, exceeding the pharmacopoeia's control requirements for residual solvents (the European Pharmacopoeia controls methanol residues to no more than 50 ppm). Summary of the Invention

[0007] The purpose of this invention is to provide a method for preparing solvent-free solid lactulose. This method enables the preparation of high-purity solvent-free solid lactulose, solving the problem of concentrated lactulose solutions. This method has good reproducibility, high yield, and is suitable for large-scale commercial production.

[0008] The technical solution of the present invention is as follows:

[0009] A method for preparing a solvent-free solid lactulose compound includes the following steps:

[0010] 1) Concentration and dehydration: Heat the lactulose solution with a content of 60% to 70% and concentrate it under reduced pressure until the water content is less than 10%;

[0011] 2) Dissolving: Add a hydrophilic solvent to step 1), heat until dissolved and clear, then cool to 35-40°C;

[0012] 3) Induced crystallization: Add lactulose seed crystals to the solution obtained in step 2) to induce crystallization;

[0013] 4) Filtration: Filter and dry to obtain crude solid lactulose;

[0014] 5) Dissolving: Dissolve the solid obtained in step 4) in pure water;

[0015] 6) Dehydration: Vacuum dehydration under reduced pressure or spray drying to form a solid;

[0016] 7) Drying: The solid obtained in step 6) is further dried to obtain the solid lactulose solvent-free compound.

[0017] In some embodiments, the hydrophilic solvent in step 2) is selected from at least one of methanol, ethanol, and isopropanol, with methanol being preferred.

[0018] In some embodiments, the amount of hydrophilic solvent added in step 2) is 1 to 3 times that of the concentrated lactulose solution in step 1), preferably 1.6 times.

[0019] In some implementations, the crystallization temperature in step 3) is 25–50°C, and the crystallization time is 3–4 days, preferably 35–40°C, and the crystallization time is preferably 3 days.

[0020] In some embodiments, the mass of lactulose seed crystals added in step 3) is 0.03 to 0.05 times that of the concentrated lactulose solution in step 1), preferably 0.04 times.

[0021] In some implementations, the drying temperature in steps 4) and 7) is 80°C.

[0022] The lactulose prepared by the method of the present invention can be used in the preparation of drugs for the prevention and / or treatment of chronic constipation, portal venous encephalopathy and other intestinal or liver diseases.

[0023] The application of lactulose prepared by the method of this invention in the preparation of food additives.

[0024] The beneficial effects of this invention are that, by strictly controlling the amount of hydrophilic solvent added, the amount of seed crystals, the crystallization temperature, and the crystallization time, solid lactulose is successfully separated from concentrated lactulose solution; at the same time, by redissolving in water and then removing the hydrophilic solvent under vacuum, the lactulose obtained has high purity, good properties, and meets the control requirements of the pharmacopoeia. Attached Figure Description

[0025] Figure 1 This is the TGA spectrum of the solid lactulose insolvent.

[0026] Figure 2 This is the DSC spectrum of the solvent-free solid lactulose compound;

[0027] Figure 3 This is the HPLC chromatogram of the solvent-free solid lactulose compound; Detailed Implementation

[0028] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.

[0029] Preparation of solvent-free solid lactulose compounds:

[0030] Example 1:

[0031] Take 125.0 g of concentrated lactulose solution (63%–70% concentration, containing approximately 62 g of lactulose) and place it in a rotary evaporator. Dehydrate under vacuum at 65°C in a water bath to remove approximately 20% of the water. Add 200 mL of methanol and heat until completely dissolved. Slowly cool to 35–40°C and add 5.0 g of seed crystals. The crystals do not dissolve. Maintain the temperature at 35–40°C and stir to allow crystallization to occur for 3 days. Filter under nitrogen protection to obtain a white solid. Dry the solid under vacuum at 80°C to constant weight, yielding approximately 43.0 g (69% yield, 0.5% methanol residue).

[0032] Take 35.0g of the above solid and add 35.0ml of pure water. After heating to dissolve, dehydrate the solid in a rotary evaporator under vacuum at 50-65℃ in a water bath until the system becomes viscous and no bubbles are generated. After cooling, the solid becomes granular. The solid is further dried under vacuum at 50-80℃ to constant weight to obtain 33.2g of white solid, with a total yield of 65%.

[0033] The purified lactulose was tested for solvent residue, and the results are shown below:

[0034]

[0035] Chromatographic conditions: Gas chromatography, FID detector

[0036] Column: DB-624 (30m*0.56mm, 3μm)

[0037] Solvent: Water;

[0038] Blank solvent: Accurately measure 2 ml of water into a 20 ml headspace vial, cap it, and seal it.

[0039] Methanol reference solution: Add 20 ml of solvent to a 50 ml volumetric flask, weigh 26.9 mg of methanol, dilute to the mark with water, and mix well; accurately measure 1 ml and place it in a 100 ml volumetric flask, dilute to the mark with water, and mix well. Accurately measure 2 ml into a 20 ml headspace vial, cap, and seal.

[0040] Test solution: Weigh about 200 mg of the test sample and place it in a 20 ml headspace vial. Accurately measure 2 ml of water into the headspace vial, cap it, and seal it.

[0041] Example 2:

[0042] Take 125.0 g of concentrated lactulose solution (63%–70% concentration) in a rotary evaporator and dehydrate it under vacuum at 65°C in a water bath to remove approximately 20% of the water. Add 250 mL of ethanol and heat until completely dissolved. Then, slowly cool to 35–40°C and add 5.0 g of seed crystals. The crystals do not dissolve. Maintain the temperature at 35–40°C and stir to allow crystallization to occur for 3 days. Filter under nitrogen protection to obtain a white solid. Dry the solid under vacuum at 80°C to constant weight, yielding approximately 28.0 g (0.6% ethanol residue).

[0043] Add the above 28.0g solid to 28.0ml of pure water, heat to dissolve, and then vacuum dehydrate in a rotary evaporator at 50-65℃ in a water bath until the system becomes viscous and no bubbles are generated. After cooling, it becomes a granular solid. The solid is further vacuum dried at 50-80℃ to constant weight to obtain 25.0g of white solid (ethanol residue 0.003%).

[0044] Example 3:

[0045] Take 125.0 g of concentrated lactulose solution (63%–70%) and place it in a rotary evaporator. Dehydrate under vacuum at 65°C in a water bath to remove approximately 20% of the water. Add 250 mL of isopropanol and heat until completely dissolved. Slowly cool to 35–40°C and add 5.0 g of seed crystals. The crystals do not dissolve. Maintain the temperature at 35–40°C and stir to allow crystallization to occur for 4 days. Filter under nitrogen protection to obtain a white solid. Dry the solid under vacuum at 80°C to constant weight, yielding approximately 22.2 g (with 0.6% isopropanol residue).

[0046] 22.2 g of crude solid lactulose obtained in the above examples was added to 22.2 ml of pure water and heated to dissolve. Then, the mixture was dehydrated under reduced pressure in a rotary evaporator at 50-65°C in a water bath until the system became viscous and no bubbles were generated. After cooling, the solid was formed into granular solid. The solid was further dried under reduced pressure at 50-80°C to constant weight to obtain 20.1 g of white solid (isopropanol residue 0.005%).

[0047] Example 4:

[0048] Take 125.0 g of concentrated lactulose solution (63%–70% content) in a rotary evaporator and dehydrate it under vacuum at 65°C in a water bath to remove approximately 20% of the water. Add 200 mL of methanol and heat until completely dissolved. Then, slowly cool to 15–20°C and add 5.0 g of seed crystals. If the crystals do not dissolve, stir at 35–40°C for 3 days to allow crystallization. Filter under nitrogen protection (poor properties, difficult to filter) to obtain a white solid. Dry the solid under vacuum at 80°C to constant weight (the dried product easily forms lumps). The yield is approximately 23.1 g (yield 37%, methanol residue 0.5%).

[0049] Example 5:

[0050] Take 125.0 g of concentrated lactulose solution (63%–70% concentration) in a rotary evaporator and dehydrate it under vacuum at 65°C in a water bath to remove approximately 20% of the water. Add 200 mL of methanol and heat until completely dissolved. Then, slowly cool to 25–30°C and add 5.0 g of seed crystals. If the crystals do not dissolve, stir at 35–40°C for 3 days to allow crystallization. Filter under nitrogen protection to obtain a white solid. Dry the solid under vacuum at 80°C to constant weight (the dried product tends to harden). Approximately 37 g of the product was collected (yield 59%, methanol residue 0.5%).

[0051] Example 6:

[0052] Take 125.0 g of concentrated lactulose solution (63%–70% content) in a rotary evaporator and dehydrate it under vacuum at 65°C in a water bath to remove approximately 20% of the water. Add 200 mL of methanol and heat until completely dissolved. Then, slowly cool to 30–35°C and add 5.0 g of seed crystals. If the crystals do not dissolve, stir at 35–40°C for 3 days to allow crystallization. Filter under nitrogen protection (poor properties, difficult to filter) to obtain a white solid. Dry the solid under vacuum at 80°C to constant weight (the dried product easily forms lumps). The yield is approximately 33.9 g (yield 54%, methanol residue 0.5%).

[0053] Example 7:

[0054] Take 100.0 g of concentrated lactulose solution (63%–70%) in a reaction flask, without removing water, add 800 mL of methanol. No solid precipitates. Stir and crystallize for 7 days at 25–30 °C. Filter under nitrogen protection to obtain a white solid. Dry the solid under vacuum at 80 °C to constant weight, yielding approximately 3.62 g (yield 5.8%, methanol residue 0.5%).

[0055] Example 8:

[0056] Take 125.0 g of concentrated lactulose solution (63%–70% concentration) in a rotary evaporator and dehydrate it under vacuum at 65°C in a water bath to remove approximately 10% of the water. Add 200 mL of methanol and heat until completely dissolved. Then, slowly cool to 35–40°C and add 5.0 g of seed crystals. The crystals do not dissolve. Maintain the temperature at 35–40°C and stir to allow crystallization to occur for 3 days. Filter under nitrogen protection to obtain a white solid. Dry the solid under vacuum at 80°C to constant weight, yielding approximately 14.5 g (yield 23%, methanol residue 0.4%).

[0057] Example 9:

[0058] Take 125.0 g of concentrated lactulose solution (63%–70% concentration) in a rotary evaporator and dehydrate it under vacuum at 65°C in a water bath to remove approximately 20% of the water. Add 300 mL of methanol and heat until completely dissolved. Then, slowly cool to 35–40°C and add 5.0 g of seed crystals. The crystals do not dissolve. Maintain the temperature at 35–40°C and stir to allow crystallization to occur for 3 days. Filter under nitrogen protection to obtain a white solid. Dry the solid under vacuum at 80°C to constant weight, yielding approximately 29.8 g (yield 47%, methanol residue 0.6%).

[0059] Comparative Example 1

[0060] The crude solid lactulose obtained in Example 1 (with 0.5% methanol residue) was dried at 80°C, 90°C, and 100°C under forced air and reduced pressure for 72 hours. During the drying process, the product gradually turned yellow at temperatures ≥90°C. After drying, the methanol residue was detected according to the residual solvent detection method described in Example 1. The methanol residue was 0.1% to 0.3%, which still exceeded the pharmacopoeia control requirements. The organic protic solvent could not be removed by drying.

[0061] Comparative Example 2

[0062] The procedure was performed according to patent CN118852280A: 100g of ethanol (or methanol) was added to 100g of concentrated lactulose solution (in a dissolved state, with no product precipitation), and the mixture was heated to 65°C. 1g of solid lactulose seed crystals were then added to the system, and the mixture was kept at 55°C with stirring for 4 hours (the seed crystals dissolved, with no product precipitation). 600g of ethanol (or methanol) was then added dropwise, controlled to be completed within 7 hours. After the addition was complete, the mixture was kept at 55°C to allow crystallization (with no product precipitation). The temperature was then lowered to 0-5°C and kept at this temperature for 5 days, during which no solid precipitation occurred.

Claims

1. A method for preparing a solvent-free solid lactulose compound, comprising the following steps: 1) Concentration and dehydration: Heat the lactulose solution with a content of 60% to 70% and concentrate it under reduced pressure until the water content is less than 10%; 2) Dissolving: Add a hydrophilic solvent to step 1), heat until dissolved and clear, then cool to 35-40°C; 3) Induced crystallization: Add lactulose seed crystals to the solution obtained in step 2) to induce crystallization; 4) Filtration: Filter and dry to obtain crude solid lactulose; 5) Dissolving: Dissolve the solid obtained in step 4) in pure water; 6) Dehydration: Vacuum dehydration under reduced pressure or spray drying to form a solid; 7) Drying: The solid obtained in step 6) is further dried to obtain the solid lactulose solvent-free compound.

2. The preparation method according to claim 1, characterized in that, In step 2), the hydrophilic solvent is selected from at least one of methanol, ethanol, and isopropanol, preferably methanol.

3. The preparation method according to claim 1, characterized in that, The amount of hydrophilic solvent added in step 2) is 1 to 3 times that of the concentrated lactulose solution in step 1), preferably 1.6 times.

4. The preparation method according to claim 1, characterized in that, In step 3), the crystallization temperature is 25-50℃, the crystallization time is 3-4 days, preferably 35-40℃, and the crystallization time is preferably 3 days.

5. The preparation method according to claim 1, characterized in that, In step 3), the mass of lactulose seed crystals added is 0.03 to 0.05 times that of the concentrated lactulose solution in step 1), preferably 0.04 times.

6. The preparation method according to claim 1, characterized in that, The drying temperature in steps 4) and 7) is 80°C.

7. The use of lactulose prepared by the method according to claim 1 in the preparation of drugs for the prevention and / or treatment of chronic constipation, portal venous encephalopathy and other intestinal or liver diseases.

8. The application of lactulose prepared by the method according to claim 1 in the preparation of food additives.

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