Preparation method of high-purity lactulose

Abstract

The invention belongs to the technical field of lactulose preparation, and particularly relates to a preparation method of high-purity lactulose, which comprises the following steps: preparing lactulose syrup, carrying out nanofiltration purification and concentration, removing boron element by using boron removal resin, removing residual salt by using amphoteric resin, and finally concentrating to obtain a high-purity lactulose concentrated solution. According to the method, the reaction conditions are optimized, the conversion rate of the lactulose is increased, meanwhile, generation of monosaccharide is reduced by controlling the pH value, and the conventional mode that residual salt in the lactulose is removed by alternately using anion exchange resin, cation exchange resin, anion exchange and cation exchange resin is broken through; according to the method, the amphoteric exchange resin is creatively used for removing salt in lactulose at one time, so that the time of a desalting process is greatly shortened, the activation time of the resin is also shortened, purified water required by activation is reduced, the production cost is saved, and the economic benefit is improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of lactulose preparation, and particularly relates to a preparation method of high-purity lactulose. BACKGROUND

[0002] Lactulose concentrate is a water solution of 4-O-beta-D-galactopyranosyl-D-fructofuranose, and the content of lactulose (C12H22O11) should be 631-700 mg / ml. It is a colorless or light yellow to brown yellow clear viscous liquid; odorless, sweet. Lactulose is an important raw material for the pharmaceutical and food industries. It has obvious promoting effect on the growth of bifidobacterium and is widely used in infant food, therapeutic drugs for infantile diarrhea, auxiliary therapeutic drugs for various chronic kidney failure, hepatic encephalopathy, hepatic coma and other liver diseases. In the food industry, lactulose is widely used in beverages, health foods, desserts and the like, as a caries-preventing and low-calorie sweetener to replace sucrose, and has the beneficial effects of regulating intestinal health, improving human immunity and promoting nutrient absorption.

[0003] At present, the chemical synthesis method is the main method for preparing lactulose in industry, which mainly adopts isomerization of lactose under alkaline conditions to prepare lactulose. Lactulose isomerization mainly relies on 1) strong alkaline reagents such as NaOH, KOH, Mg(OH)2 or organic base triethylamine; or 2) weak alkaline reagents such as alkaline magnesium salt, alkali or alkaline earth metal phosphate or sulfite; or 3) adding borate or aluminate as a catalyst under alkaline conditions, and then isomerizing lactose into lactulose in a high-temperature environment. However, the above methods generally have the following disadvantages:

[0004] (1) Low purity of lactulose: the lactulose crude syrup generated in the isomerization reaction contains lactulose, lactose, monosaccharide, pigment, boric acid, hydrochloric acid and other impurities, resulting in low purity of lactulose.

[0005] (2) Many by-products: the isomerization reaction process produces by-products such as pigments and monosaccharides, which affect the quality and purity of the final product.

[0006] (3) Difficult separation and purification: desalination and monosaccharide removal are the main difficulties in the purification of lactulose syrup. The existing desalination technologies such as ion exchange desalination and membrane separation desalination have problems such as large amount of resin, serious sugar adsorption, and the need for a large amount of regenerated acid and alkali, resulting in the production of regenerated acid and alkali and deionized water in the production process, which increases the production cost. Therefore, a new preparation method and post-treatment method are needed to improve the purity and yield of lactulose, simplify the purification process, reduce the production cost, and reduce the impact on the environment.

[0007] The inventors found in the research that the conversion rate of lactulose isomerization is very low, about 30%, without catalyst. After adding boric acid catalyst, the conversion rate of lactulose isomerization is as high as 80% or more, and the conversion rate is significantly improved. With the increase of the amount of boric acid, the conversion rate of lactulose also increases, but too much boric acid brings pressure to the subsequent removal of boron element, and increases the cost of post-treatment. In addition, it is found that the content of tagatose and other monosaccharides increases after the pH value decreases in the post-treatment of lactulose reaction, which affects the quality of lactulose concentrated solution. SUMMARY

[0008] The purpose of the present application is to provide a method for preparing high-purity lactulose with simple method and reasonable design.

[0009] The present application achieves the above-mentioned purpose by the following technical solutions:

[0010] A method for preparing high-purity lactulose, comprising the following contents:

[0011] Preparation of lactulose syrup: food-grade lactose as raw material, boric acid as catalyst, lactose is dissolved in water with a material to water mass ratio of 1:3 to 1:5, boric acid is added, and the mass ratio of boric acid to lactose is 1:8 to 1:10; solid sodium hydroxide is added to adjust the pH value of the syrup to 12 to 13, and the reaction solution is stirred and incubated at 65 to 75℃ for 2 to 3 hours.

[0012] Nanofiltration purification and concentration: the pH value of the lactulose reaction solution is adjusted to 2 to 3 with concentrated hydrochloric acid, and the insoluble substances and other mechanical impurities are removed by pressure filtration. The obtained filtrate is added to a nanofiltration machine, the operating pressure is 1.5 to 2.5 MPa, and the temperature is 30 to 45℃; the sodium chloride salt and tagatose and other monosaccharides in the lactulose reaction solution are removed by nanofiltration through the nanofiltration membrane of the nanofiltration machine, and the lactulose reaction solution is concentrated.

[0013] Boron removal resin removes boron element: the addition amount of boron removal resin is 20 to 30 grams per liter relative to the volume of nanofiltration liquid, and the obtained nanofiltration concentrated solution is passed through a boron resin column at 20 to 30℃ to obtain a lactulose aqueous solution with a purity of more than 95%.

[0014] Amphiphilic resin removes residual salt: the addition amount of amphiphilic exchange resin is 40 to 50 grams per liter relative to the volume of nanofiltration liquid, and the obtained nanofiltration concentrated solution is passed through an amphiphilic exchange resin column at 20 to 30℃ to obtain a high-purity lactulose aqueous solution.

[0015] The high-purity lactulose aqueous solution is concentrated to 20-30% of the initial volume to prepare a high-purity lactulose concentrated solution.

[0016] Further, the nanofiltration membrane is one of ceramic membrane, sulfonated polysulfone (SPS) and polyamide (PA) with a molecular weight cut-off of 250-400 Da, and the ceramic membrane is preferred.

[0017] Further, the boron-removing resin is specifically polystyrene-based resin (styrene-divinylbenzene copolymer) or macroporous structure chelating resin with specific chelating groups (such as amino, mercapto, imidazole group).

[0018] Further, the amphoteric ion exchange resin includes strong acid-weak base type, weak acid-strong base type and weak acid-weak base type, and can simultaneously exchange cations and anions on the same resin, and has the advantages of showing different ion exchange characteristics in a specific pH range, being suitable for the case of simultaneously removing cations and anions in water, and being effectively used for the separation of electrolytes and non-electrolytes such as desalting of saccharides, separation of glycerol and salt, and separation of caustic soda and salt.

[0019] The application has the following beneficial effects:

[0020] In the application, the isomerization catalyzed by boric acid can make the lactulose content in the lactulose reaction solution reach more than 80%, the nanofiltration desalination rate reach more than 98%, the monosaccharide removal rate reach more than 90%, the lactulose yield reach more than 75%, and the wastewater can be saved by about 40% by using the amphoteric exchange resin compared with the single cation or anion exchange resin activation. The reaction conditions are optimized, the conversion rate of lactulose is improved, the generation of monosaccharides is reduced by controlling the pH value, the conventional method of alternately using anion exchange resin and cation exchange resin is broken through, the amphoteric exchange resin is used to remove the salt in lactulose at one time, the desalination process time is greatly shortened, the resin activation time is also shortened, the purified water required for activation is reduced, the production cost is saved, and the economic benefit is improved. DETAILED DESCRIPTION

[0021] The application will be further described in detail below, and it is necessary to point out here that the following detailed description is only used to further illustrate the application, and cannot be understood as limiting the protection scope of the application. Those skilled in the art can make some non-essential improvements and adjustments to the application according to the above application content.

[0022] Example 1

[0023] A preparation method of high-purity lactulose, specifically comprising the following steps:

[0024] Preparation of lactulose syrup: 10 kg of purified water was added to a 50 L glass reaction kettle, 2 kg of food-grade lactose was added under stirring, 0.3 kg of boric acid was then added, and solid sodium hydroxide was then added to adjust the pH of the syrup to 12. After adjustment, the temperature was raised to 70°C, and the temperature was controlled at 70-75°C for stirring reaction for 3 hours. The reaction was stopped when the content of the starting material was ≤4% as monitored by HPLC.

[0025] Nanofiltration and concentration: when the reaction solution was cooled to room temperature, the pH of the reaction solution was adjusted to 2-3 with dilute hydrochloric acid, and the solution was stirred at room temperature for 0.5 hours. Nanofiltration was performed using a nanofiltration machine using Dow NF-90 nanofiltration membranes (polyamide membranes), an operating pressure of 1.5 MPa, and a temperature of 35°C. Water dialysis was performed until the conductivity of the syrup was 8-10 ms / cm.

[0026] Boron removal resin removes boron elements: at 20-40°C, the nanofiltration solution was passed through a column containing 0.3 kg of D403 boron removal resin to obtain a lactulose aqueous solution with a boron element purity of 95.1% or more.

[0027] Ampholytic resin removes residual salt: at 20-40°C, the boron-removed lactulose aqueous solution was passed through a column containing 0.5 kg of an ampholytic exchange resin, Dowex XFS-43274, to obtain a lactulose aqueous solution with a purity of 96.4%. The solution was concentrated to 20-30% of the initial volume to obtain a high-purity lactulose concentrated solution.

[0028] Example 2

[0029] A method for preparing high-purity lactulose, specifically comprising the following steps:

[0030] Preparation of lactulose syrup: 10 kg of purified water was added to a 50 L glass reaction kettle, 2 kg of food-grade lactose was added under stirring, 0.3 kg of boric acid was then added, and solid sodium hydroxide was then added to adjust the pH of the syrup to 12. After adjustment, the temperature was raised to 70°C, and the temperature was controlled at 70-75°C for stirring reaction for 3 hours. The reaction was stopped when the content of the starting material was ≤4.5% as monitored by HPLC.

[0031] Nanofiltration and concentration: when the reaction solution was cooled to room temperature, the pH of the reaction solution was adjusted to 2-3 with dilute hydrochloric acid, and the solution was stirred at room temperature for 0.5 hours. Nanofiltration was performed using a nanofiltration machine using Dow NF-270 nanofiltration membranes, an operating pressure of 1.5 MPa, and a temperature of 35°C. Water dialysis was performed until the conductivity of the syrup was 8-10 ms / cm.

[0032] Boron removal resin removes boron elements: at 20-40°C, the nanofiltration solution was passed through a column containing 0.25 kg of Dowex HCR-S boron removal resin to obtain a lactulose aqueous solution with a boron element purity of 95.5% or more.

[0033] Removal of residual salts by amphoteric resin: The above boron-removed lactulose aqueous solution was passed through a 0.5 kg D304 amphoteric exchange resin column, type CB-Dual 100, at 20-40°C to obtain a 95.8% pure lactulose aqueous solution, which was concentrated to 20-30% of the initial volume to obtain a high-purity lactulose concentrated solution.

[0034] The above-described embodiments only express several implementation manners of the present application, which are described in a more specific and detailed manner, but should not be understood as a limitation on the patent scope of the present application. It should be noted that, for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present application, which all belong to the protection scope of the present application.

Claims

1. A method for preparing high-purity lactulose, characterized in that: The steps include: Step (1), using food-grade lactose as raw material and boric acid as catalyst, dissolving lactose in water at a material-water mass ratio of 1:3 to 1:5, adding boric acid, and the mass ratio of boric acid to lactose is 1:8 to 1:10; Step (2), adding solid sodium hydroxide to adjust the pH value of the syrup to 12 to 13, and stirring the reaction solution at 65 to 75° C. for 2 to 3 hours; Step (3), adjusting the pH value of the lactulose reaction solution to 2 to 3 with dilute hydrochloric acid, and filtering to remove insoluble impurities; Step (4), the obtained filtrate is nanofiltered at an operating pressure of 1.5 MPa to 2.5 MPa and a temperature of 30 to 45° C., and the sodium chloride salt and tagatose monosaccharide in the lactulose reaction solution are removed by nanofiltration, and the lactulose reaction solution is concentrated; Step (5), passing the obtained nanofiltrate concentrate through a boron removal resin column, wherein the amount of the boron removal resin added is 20 to 30 g / L relative to the volume of the nanofiltrate, and performing the boron removal treatment at 20 to 30° C.; Step (6), passing the obtained boron-removed lactulose aqueous solution through an amphoteric exchange resin column, wherein the amount of the amphoteric exchange resin added is 40 to 50 g / L relative to the volume of the nanofiltrate, and performing a desalting treatment at 20 to 30° C. to obtain a high-purity lactulose aqueous solution; Step (7), concentrating the high-purity lactulose aqueous solution to prepare a high-purity lactulose concentrated solution.

2. The method for preparing high-purity lactulose according to claim 1, wherein: The molecular weight cut-off of the nanofiltration membrane of the nanofiltration machine is between 250-400 Da, and the nanofiltration membrane is one of a ceramic membrane, a sulfonated polysulfone or a polyamide.

3. The method for preparing high-purity lactulose according to claim 1, wherein: The boron removal resin in step (5) is a polystyrene-based resin or a macroporous chelating resin having a specific chelating group.

4. The method for preparing high-purity lactulose according to claim 1, wherein: The amphoteric exchange resin in step (5) includes strong acid-weak base type, weak acid-strong base type and weak acid-weak base type, and can simultaneously exchange cations and anions on the same resin.

5. The method for preparing high-purity lactulose according to claim 1, wherein: In the step (7), the high-purity lactulose aqueous solution is concentrated to a high-purity lactulose concentrated solution of 20-30% of the initial volume.