Preparation method of crystalline lactulose

Abstract

The invention belongs to the technical field of food, and particularly relates to a preparation method of crystalline lactulose. The preparation method of the crystalline lactulose comprises the following steps: (1) weighing lactulose powder, dissolving in water, heating and stirring to obtain a lactulose solution; (2) adding a composite regulating agent into the lactulose solution obtained in the step (1), and monitoring the viscosity to obtain a mixed solution; (3) adding lactulose crystal seeds into the mixed solution obtained in the step (2) for induced crystallization; then gradient cooling crystallization is adopted; (4) after crystallization is completed, carrying out heat preservation, separation, washing and drying to obtain a lactulose crystal product, and collecting mother liquor for cyclic utilization; according to the preparation method of the crystalline lactulose, the viscosity of the mother liquor can be reduced, the product purity is high, and the yield is high.

Description

Technical Field

[0001] This invention belongs to the field of food technology, specifically relating to a method for preparing crystalline lactulose. Background Technology

[0002] Lactulose, also known as isolalactose or lactulose, is a synthetic disaccharide that generally does not exist in nature. Its sweetness is approximately 48-70% that of sucrose. Lactulose is obtained from lactose through a chemical or biological isomerization reaction, and is a mixed solution composed of various sugars such as lactulose, lactose, galactose, or fructose. Currently, lactulose solutions contain 60-70 wt% lactulose.

[0003] Industrially, lactulose is mainly prepared by isomerization of lactose under alkaline conditions, but its subsequent crystallization and purification process faces significant technical bottlenecks. Currently, there is no commercially available crystalline lactulose. Firstly, the mother liquor for lactulose crystallization has high viscosity. Due to residual lactose, polysaccharides, pigments, and small amounts of degradation products in the isomerization reaction solution, these impurities significantly increase the viscosity of the lactulose concentrate. After crystallization, solid-liquid separation is difficult, and the crystals easily carry over the mother liquor during centrifugation and filtration. Furthermore, the equipment consumes a lot of energy and has low separation efficiency, severely impacting production continuity. Secondly, the crystals are small and unevenly distributed. The lactulose molecule contains multiple hydroxyl groups, resulting in strong intermolecular hydrogen bonds. During natural crystallization, fine crystals with a diameter of less than 50 μm are easily formed. These fine crystals not only have poor flowability and are prone to agglomeration, but they also clog the filter media, further reducing separation efficiency. At the same time, the purity and stability of the fine crystal product are difficult to meet the requirements of high-end applications. In addition, in traditional processes, alcoholic solvents such as ethanol and isopropanol are often added to reduce the viscosity of the mother liquor or promote crystal growth. However, lactulose easily forms α-type microcrystalline colloids in alcoholic systems. These colloids are difficult to remove by conventional separation methods, resulting in a significant decrease in product yield and an increased risk of solvent residue, which does not meet the safety standards of the food and pharmaceutical industries.

[0004] Therefore, lactulose is troublesome to produce and poses safety hazards due to problems such as high solution saturation concentration (greater than 80%), high viscosity leading to difficulty in crystallization, low product yield, small crystal form, and uneven distribution of crystal mesh size. The production process is complicated, the yield is low, and the cost is high.

[0005] Relevant patent documents were retrieved: For example, US Patent 5480491A, published on April 18, 1994, discloses a method for preparing crystalline lactulose, comprising the following steps: (a) evaporating a portion of water from an aqueous lactulose syrup solution at a temperature of 50°C under continuous stirring. A concentrated lactulose syrup with a sugar concentration of 70-80% is obtained under a pressure of 2660-6650 Pa. The lactulose aqueous syrup has a lactulose content of 50-62%, a lactose content of 3-9%, a galactose content of 3-14%, and other carbohydrate content of 4-7%; (b) the concentrated syrup obtained in step (a) is cooled to 5℃-20℃, and crystalline lactulose trihydrate is added at a total weight of 5%-30% of the lactulose in the lactulose aqueous syrup; (c) the product of step (c) is stirred for 20-120 hours to crystallize the lactulose, which exists in the form of lactulose trihydrate; (d) the crystallized lactulose trihydrate is separated by centrifugation or filtration of the product of step (c), yielding a mother liquor and the separated crystallized lactulose trihydrate; then the lactulose trihydrate is dried at 30℃, and the separated lactulose trihydrate is washed with cold water to obtain crystalline lactulose with a water content of less than 0.5%. However, the yield and purity of the crystalline lactulose of this invention still need to be improved.

[0006] Relevant non-patent literature was retrieved: The thesis, titled "Preparation of Phenylboronic Acid-Based Adsorbents and Their Application in Lactulose Preparation," published by Jiangnan University (2021.001217), organically combines boron affinity chromatography with the significant promoting effect of boric acid on isomerization reactions. By preparing phenylboronic acid adsorbents with high specificity and selectivity for lactulose, its efficiency in lactulose separation and purification was investigated. Furthermore, its application in the targeted and efficient preparation of lactulose was explored, aiming to promote the industrial-scale production of high-purity lactulose. However, the high viscosity of the liquid during the preparation process was unfavorable for lactulose crystallization.

[0007] In solving the above problems or overcoming the above defects, the present invention encountered the following difficulties and obstacles: During the crystallization process of lactulose, the crystals obtained by spontaneous crystallization are small in size, which makes the mother liquor viscous. When alcohol is added during filtration, the mother liquor becomes a colloid, which is even more difficult to separate, resulting in a low yield of lactulose, small crystals, and low purity. Summary of the Invention

[0008] The purpose of this invention is to provide a method for preparing crystalline lactulose, and related technologies, to solve the technical problems of high viscosity and difficult separation of existing lactulose crystallization mother liquor, as well as the removal of impurities and improvement of purity, or combinations thereof.

[0009] Terminology Explanation: Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0010] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0011] The definition of the standard chemical term can be found in the reference "Functional Foods", China Agricultural University Press, 2024.

[0012] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0013] This invention provides a method for preparing crystalline lactulose, comprising the following steps: (1) Weigh out lactulose powder, dissolve it in water, heat and stir to obtain lactulose solution; (2) Add the compound regulator to the lactulose solution obtained in step (1), monitor the viscosity, and obtain a mixed solution; (3) Add lactulose seed crystals to the mixed solution obtained in step (2) to induce crystallization; then use gradient cooling for crystallization; (4) After crystallization, the product is kept warm, separated, washed and dried to obtain lactulose crystals. The mother liquor is collected and recycled. The composite regulator described in step (2) consists of 65%-75% crystal growth promoter and 25%-35% separation agent by mass fraction.

[0014] Preferably, the composite regulator in step (2) consists of 70% crystal growth promoter and 30% separation agent by mass fraction.

[0015] Preferably, the mass concentration of the lactulose solution in step (1) is 78-85%, the heating temperature is 60-65℃, and the stirring speed is 120-180r / min. Other specific values ​​within the above range can be selected to achieve the technical effect of the present invention. For example, the mass concentration of the lactulose solution includes, but is not limited to, 78%, 79%, 80%, 81%, 82%, 83%, 84%, and 85%; the heating temperature includes, but is not limited to, 60℃, 61℃, 62℃, 63℃, 64℃, and 65℃; and the stirring speed includes, but is not limited to, 120r / min, 130r / min, 140r / min, 150r / min, 160r / min, 170r / min, and 180r / min.

[0016] More preferably, the mass concentration of the lactulose solution in step (1) is 80%, the heating temperature is 60°C, and the stirring speed is 150 r / min.

[0017] Preferably, the crystal growth promoter is composed of sodium citrate and sodium pyrophosphate, with a mass ratio of 0.5-1.5:1, and more preferably 1:1.

[0018] Preferably, the separating agent is composed of nano-calcium carbonate and polyethylene glycol, with a mass ratio of 0.5-1.5:1, and more preferably 1:1.

[0019] Preferably, the preparation method of the composite regulator includes the following steps: mixing the crystal growth promoter and the separation agent, followed by ultrasonication, drying, and pulverization to obtain the product.

[0020] Preferably, the ultrasound conditions are 280-320W, frequency 15-25 kHz, and ultrasound duration 15-20 minutes. Other specific values ​​within the above range can be selected to achieve the technical effect of the present invention. For example, ultrasound duration includes, but is not limited to, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, and 20 minutes.

[0021] More preferably, the ultrasound conditions are 300W, 20kHz, and ultrasound for 15 minutes.

[0022] Preferably, the drying is freeze drying, which is carried out at -35~-25℃ for 8-15 hours. Other specific values ​​within the above range can be selected, and all can achieve the technical effect of the present invention. For example, the drying time includes but is not limited to 8h, 9h, 10h, 11h, 12h, 13h, 14h, and 15h.

[0023] More preferably, the drying is performed by freeze-drying at -30°C for 10 hours.

[0024] Preferably, the particle size of the pulverized material is 100-200 μm. Other specific values ​​within the above range can be selected to achieve the technical effect of the present invention, including but not limited to 100μm, 110μm, 120μm, 130μm, 140μm, 150μm, 160μm, 170μm, 180μm, 190μm, and 200μm.

[0025] More preferably, the particle size of the pulverized material is 180 μm.

[0026] One of the core reasons for the viscosity of lactulose crystallization mother liquor is the hydrogen bond network formed by intermolecular hydroxyl groups. By using food-grade electrolyte ions to compete for hydrogen bond binding sites of lactulose molecules, the intermolecular hydrogen bond network is disrupted, thereby reducing the viscosity of the mother liquor without affecting the crystallinity of lactulose. Furthermore, sodium citrate and sodium pyrophosphate are electrolytes that do not participate in the crystallization process and can be removed by subsequent washing. They can also be used as crystal growth promoters to increase crystal size and improve crystal regularity. Adding a separation aid can further optimize the system's flowability, reduce the viscosity of the crystallization mother liquor, shorten centrifugation time, and reduce equipment energy consumption.

[0027] Preferably, the amount of the composite regulator added in step (2) is 2.5-3.5% of the mass of the lactulose solution in step (1). Other specific values ​​within the above range can be selected, and all can achieve the technical effect of the present invention, including but not limited to 2.5%, 3%, and 3.5%.

[0028] More preferably, the amount of the compound regulator added in step (2) is 3% of the mass of the lactulose solution in step (1).

[0029] Preferably, in step (2), the temperature is reduced from 60°C to 55°C and the stirring speed is 200 r / min, and the addition of the compound regulator is completed within 2-2.5 h.

[0030] Preferably, the viscosity monitoring in step (2) controls the viscosity to be between 300-400 mPa. s.

[0031] Preferably, the amount of seed crystals added in step (3) is 2.5-3.5% of the mass of lactulose, the particle size of the seed crystals is 150-200 μm, the crystals are grown at a constant temperature for 2-3 hours, and the stirring rate is 80-120 r / min during the process.

[0032] More preferably, the amount of seed crystals added in step (3) is 3.5% of the mass of lactulose, the particle size of the seed crystals is 180 μm, the crystals are grown at a constant temperature for 3 hours, and the stirring rate is 100 r / min during the period.

[0033] Preferably, the lactulose seed crystals mentioned in step (3) are prepared in the company's laboratory. The specific steps are as follows: dissolve and concentrate lactulose to a mass concentration of more than 75%, take 200g and dry it in a vacuum drying oven at 70°C for 3 hours, crush the dried sample to obtain lactulose powder, then take 50g of lactulose solution with a mass concentration of 75% and place it in a measuring cup, add 3% lactulose powder (dry basis) to it, crystallize at 4°C, regardless of the crystal size, separate and filter the crystallization mother liquor, and dry the obtained solid at 40°C for 1 hour to obtain lactulose crystals, which are used as seed crystals for subsequent lactulose crystallization experiments.

[0034] Preferably, the gradient cooling in step (3) adopts a four-stage gradient cooling, specifically: the cooling rate is 0.2℃ / h in the 55-45℃ stage, 0.4℃ / h in the 45-35℃ stage, 0.6℃ / h in the 35-25℃ stage, and 1.0℃ / h in the 25-15℃ stage, with a total crystallization time of 30-36 h.

[0035] Preferably, the heat preservation in step (4) is to keep warm at 10-20℃ for 0.5-1.5h. Other specific values ​​within the above range can be selected, and all can achieve the technical effect of the present invention. For example, the heat preservation time includes but is not limited to 0.5h, 1h, and 1.5h.

[0036] Preferably, the separation in step (4) is performed using a horizontal spiral centrifuge with a centrifuge speed of 3000-5000 r / min. Other specific values ​​within the above range can be selected to achieve the technical effect of the present invention, including but not limited to 3000 r / min, 4000 r / min, and 5000 r / min.

[0037] More preferably, the centrifuge speed is 4000 r / min.

[0038] Preferably, the washing in step (4) involves washing with deionized water 1-2 times.

[0039] The beneficial effects of this invention are as follows: 1. Significantly reduces mother liquor viscosity: The separation aid in the composite regulator further optimizes the system's flowability, reducing the viscosity of the crystallization mother liquor, shortening centrifugation time, and reducing equipment energy consumption; 2. Regulating crystal growth: By improving the crystal surface energy through the crystal growth promoter in the composite regulator, combined with gradient cooling and directional seed induction, the particle size of lactulose crystals increases, the crystal regularity is improved, the filtration rate is increased, and the product flowability is significantly improved; 3. Complete avoidance of colloid formation: No alcohol-based solvents are used throughout the process. Through the synergistic effect of composite regulators and process parameters, the formation of lactulose microcrystalline colloids is avoided, resulting in a product purity of ≥98.0%. 4. Strong process stability: The preparation process of the composite regulator is simple, and it can be added directly without complicated pretreatment. It is compatible with existing industrial production lines and is easy to promote on a large scale. Detailed Implementation

[0040] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention. Those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and these should also fall within the scope of protection claimed by the present invention. The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0041] The lactulose seed crystals used in this invention were prepared in the company's laboratory. The specific steps are as follows: lactulose was dissolved and concentrated to a mass concentration of over 75%. 200g of the solution was placed in a vacuum drying oven and dried at 70°C for 3 hours. The dried sample was then pulverized to obtain lactulose powder. 50g of a 75% lactulose solution was placed in a measuring cup, and 3% of the lactulose powder (dry basis) was added to it. The solution was crystallized at 4°C, regardless of crystal size. The mother liquor was separated and filtered, and the resulting solid was dried at 40°C for 1 hour to obtain lactulose crystals, which were used as seed crystals for subsequent lactulose crystallization experiments.

[0042] The nano-calcium carbonate used in this invention has CAS number 471-34-1; the nano-silicon dioxide used has CAS number 60676-86-0, both of which were purchased from Shanghai Maclean Biochemical Technology Co., Ltd.

[0043] Basic Example 1: A method for preparing a composite regulator Based on the total mass fraction of the composite regulator, 70% of the crystal growth promoter (sodium citrate and sodium pyrophosphate in a mass ratio of 1:1) and 30% of the separation aid (nano-calcium carbonate and polyethylene glycol in a mass ratio of 1:1) were mixed and ultrasonically dispersed for 20 min (power 300 W, frequency 20 kHz). Then, the mixture was freeze-dried at -30℃ for 10 h and pulverized to a particle size of 100-200 μm to obtain a powdered composite regulator, which was then sealed and stored.

[0044] Basic Comparison Example 1 Based on the total mass fraction of the composite regulator, 50% of crystal growth promoter (sodium citrate and sodium pyrophosphate in a mass ratio of 1:1) and 50% of separation aid (nano-calcium carbonate and polyethylene glycol in a mass ratio of 1:1) were mixed and ultrasonically dispersed for 20 min (power 300 W, frequency 20 kHz). Then, the mixture was freeze-dried at -30℃ for 10 h and pulverized to a particle size of 100-200 μm to obtain a powdered composite regulator, which was then sealed and stored.

[0045] Basic Comparative Example 2 The difference from Basic Example 1 is that sodium citrate is replaced with anhydrous disodium hydrogen phosphate, and everything else is the same as Basic Example 1.

[0046] Basic Comparison Example 3 The difference from Basic Example 1 is that sodium pyrophosphate is replaced with potassium pyrophosphate, and everything else is the same as Basic Example 1.

[0047] Basic Comparison Example 4 The difference from Basic Example 1 is that nano-calcium carbonate is replaced with nano-silica, and the rest is the same as Basic Example 1.

[0048] Basic Comparison Example 5 The difference from Basic Example 1 is that polyethylene glycol is replaced with polyglycerol, and everything else is the same as Basic Example 1.

[0049] Example 1: A method for preparing crystalline lactulose Specifically as follows: (1) Prepare 100 g of a lactulose solution with a lactulose content of 80 wt%; heat and stir at 60℃ with a stirring speed of 150 r / min until all lactulose is dissolved to obtain a lactulose solution; (2) Add 3 g of the composite regulator prepared in Example 1 (3% by mass) to the lactulose solution, stir at 200 r / min, and reduce the temperature from 60℃ to 55℃ over 2.5 h, during which time the composite regulator is completely added. Monitor the viscosity of the mother liquor in real time and control the viscosity to drop to 300 mPa. s(25℃); (3) Add 3.0% of the lactulose solution system seed crystals (particle size 150-200 μm) to the lactulose solution, 3 g, stir at 100 r / min, and keep at a constant temperature for 3 h; then carry out a four-stage gradient cooling. In the first stage, the temperature is reduced from 55℃ to 45℃ at a cooling rate of 0.2℃ / h. In the second stage, the temperature is reduced from 45℃ to 35℃ at a cooling rate of 0.4℃ / h. In the third stage, the temperature is reduced from 35℃ to 25℃ at a cooling rate of 0.6℃ / h. In the fourth stage, the temperature is reduced from 25℃ to 15℃ at a cooling rate of 1.0℃ / h. The total crystallization time is 33 h. The gradient cooling process is carried out gently to achieve the purpose of slow and uniform crystal growth. (5) After crystallization, the liquid was kept at 15°C for 1 h and separated by a horizontal spiral centrifuge (4000 r / min). The mother liquor was collected and recycled. The crystals collected after centrifugation were washed twice with deionized water, then centrifuged to dehydrate and dried to obtain 76g of lactulose crystals.

[0050] Example 2: A method for preparing crystalline lactulose Specifically as follows: (1) Prepare 100 g of a lactulose solution with a lactulose content of 78 wt%; heat and stir at 65℃ with a stirring speed of 150 r / min until all lactulose is dissolved to obtain a lactulose solution; (2) Add 3.5g of the composite regulator prepared in Example 1 (3.5% by mass) to the lactulose solution, stir at 200 r / min, and reduce the temperature from 60℃ to 55℃ over 2.5 h, during which time the composite regulator is completely added. Monitor the viscosity of the mother liquor in real time and control the viscosity to drop to 300 mPa. s(25℃); (3) Add 3 g of lactulose seed crystals (particle size 150-200 μm) at a mass of 3.0% to the lactulose solution, stir at a rate of 100 r / min, and maintain the temperature for 3 h to grow crystals. (4) Then, a four-stage gradient cooling process is carried out. In the first stage, the temperature is reduced from 55℃ to 45℃ at a cooling rate of 0.2℃ / h. In the second stage, the temperature is reduced from 45℃ to 35℃ at a cooling rate of 0.4℃ / h. In the third stage, the temperature is reduced from 35℃ to 25℃ at a cooling rate of 0.6℃ / h. In the fourth stage, the temperature is reduced from 25℃ to 15℃ at a cooling rate of 1.0℃ / h. The total crystallization time is 36 h. The gradient cooling process is carried out gently to achieve the purpose of slow and uniform crystal growth. (5) After crystallization, the liquid was kept at 15°C for 1 h and separated by a horizontal spiral centrifuge (4000 r / min). The mother liquor was collected and recycled. The collected crystals were washed twice with deionized water, then centrifuged, dehydrated and dried to obtain 70 g of lactulose crystals.

[0051] Example 3: A method for preparing crystalline lactulose Specifically as follows: (1) Prepare 100 g of lactulose solution with a lactulose content of 85 wt%; heat and stir at 60℃ with a stirring speed of 150 r / min until all lactulose is dissolved to obtain lactulose solution; (2) Add 2.5g of the composite regulator prepared in Example 1 (2.5% by mass) to the lactulose solution, stir at 200 r / min, and reduce the temperature from 60℃ to 55℃ within 2 h, during which time the composite regulator is completely added. Monitor the viscosity of the mother liquor in real time and control the viscosity to drop to 300 mPa. s(25℃); (3) Induced crystallization: Add 3g of lactulose seed crystals (particle size 150-200 μm) at a mass of 3.0% to the lactulose solution, stir at a rate of 100 r / min, and maintain constant temperature for crystal growth for 3h; then carry out a four-stage gradient cooling. In the first stage, the temperature is reduced from 55℃ to 45℃ at a cooling rate of 0.2℃ / h; in the second stage, the temperature is reduced from 45℃ to 35℃ at a cooling rate of 0.4℃ / h; in the third stage, the temperature is reduced from 35℃ to 25℃ at a cooling rate of 0.6℃ / h; and in the fourth stage, the temperature is reduced from 25℃ to 15℃ at a cooling rate of 1.0℃ / h. The total crystallization time is 33h. The gradient cooling process is carried out gently to achieve the purpose of slow and uniform crystal growth. (5) After crystallization, the liquid was kept at 15°C for 1 h and separated by a horizontal spiral centrifuge (4000 r / min). The mother liquor was collected and recycled. The collected crystals were washed twice with deionized water, then centrifuged, dehydrated and dried to obtain 77 g of lactulose crystals.

[0052] Comparative Example 1 The difference from Example 1 is that the composite regulator prepared by the basic comparative example 1 was used, and the rest was the same as in Example 1, resulting in 58.2g of lactulose crystal product.

[0053] Comparative Example 2 The difference from Example 1 is that the composite regulator prepared by the basic comparative example 2 was used, while the rest was the same as in Example 1, resulting in 65.2g of lactulose crystal product.

[0054] Comparative Example 3 The difference from Example 1 is that the composite regulator prepared by the basic comparative example 3 was used, while the rest was the same as in Example 1, resulting in 66.3g of lactulose crystal product.

[0055] Comparative Example 4 The difference from Example 1 is that the composite regulator prepared by the basic comparative example 4 was used, while the rest was the same as in Example 1, resulting in 60.4g of lactulose crystal product.

[0056] Comparative Example 5 The difference from Example 1 is that the composite regulator prepared by the basic comparative example 5 was used, while the rest was the same as in Example 1, and 63.2g of lactulose crystals were obtained.

[0057] Comparative Example 6 The difference from Example 1 is that the amount of compound additive added in step (2) is 4% of the mass of the lactulose solution, i.e., 4g. The rest is the same as in Example 1, and 55.3g of lactulose crystal product is obtained.

[0058] Comparative Example 7 The difference from Example 1 is that the amount of compound additive added in step (2) is 2% of the mass of the lactulose solution, i.e., 2g. The rest is the same as in Example 1, and 47.6g of lactulose crystal product is obtained.

[0059] Comparative Example 8 The difference from Example 1 is that in step (4), the temperature is not kept at 15°C for 1 hour, but the rest is the same as in Example 1, and 58.7g of lactulose crystal product is obtained.

[0060] Detection example The yield and lactulose purity of Examples 1-3 and Comparative Examples 1-8 were tested. The specific operating method is as follows: The formula for calculating the yield is: % Lactulose content detection: Dissolve lactulose crystals to a mass concentration of 4%-5%, and detect by high performance liquid chromatography (HPLC). Chromatographic conditions and system suitability tests were performed using an amino column packed with fully porous silica gel, with acetonitrile-phosphate buffer (82:18) as the mobile phase, and a differential refractive index detector. For the phosphate buffer, weigh 1.15 g of anhydrous sodium dihydrogen phosphate, dissolve in water, and dilute to 1000 mL.

[0061] The yield and lactulose purity results are shown in Table 1.

[0062] Table 1

[0063] The data in Table 1 show that, compared to Example 1, Comparative Example 1 demonstrates that reducing the proportion of crystal growth promoter and increasing the proportion of separation agent leads to uneven crystal growth and inconsistent particle size, resulting in a lower yield. The high separation agent content also reduces product purity. Comparative Examples 2-5 show that sodium citrate, sodium pyrophosphate, nano-calcium carbonate, and polyethylene glycol are the optimal composite regulators. This combination most effectively satisfies the purposes of promoting crystal growth and aiding separation, resulting in uniform crystal growth, increased centrifugation rate, and thus improved yield and purity. Comparative Examples 6 and 7 show that excessive addition of the composite regulator leads to uneven crystal shape and size, affecting the yield; too little results in small crystal growth and no significant improvement in mother liquor viscosity. Comparative Example 8 demonstrates that maintaining a certain temperature during centrifugation can effectively reduce mother liquor viscosity and improve centrifugal separation efficiency.

[0064] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing crystalline lactulose, characterized in that, Includes the following steps: (1) Weigh out lactulose powder, dissolve it in water, heat and stir to obtain lactulose solution; (2) Add the compound regulator to the lactulose solution obtained in step (1), monitor the viscosity, and obtain a mixed solution; (3) Add lactulose seed crystals to the mixed solution obtained in step (2) to induce crystallization; then use gradient cooling for crystallization; (4) After crystallization, the product is kept warm, separated, washed and dried to obtain lactulose crystals. The mother liquor is collected and recycled. The composite regulator, by mass fraction, consists of 65%-75% crystal growth promoter and 25%-35% separation aid.

2. The preparation method according to claim 1, characterized in that, The mass concentration of the lactulose solution in step (1) is 78-85%, the heating temperature is 60-65℃, and the stirring speed is 120-180r / min.

3. The preparation method according to claim 1, characterized in that, The crystal growth promoter is composed of sodium citrate and sodium pyrophosphate, with a mass ratio of 0.5-1.5:

1.

4. The preparation method according to claim 1, characterized in that, The separation aid is composed of nano-calcium carbonate and polyethylene glycol, with a mass ratio of 0.5-1.5:

1.

5. The preparation method according to claim 1, characterized in that, The preparation method of the composite regulator includes the following steps: mixing the crystal growth promoter and the separation agent, followed by ultrasonication, drying, and pulverization.

6. The preparation method according to claim 5, characterized in that, The ultrasonic conditions are as follows: ultrasonication for 15-20 minutes at 280-320W and 15-25 kHz; the drying is freeze-drying at -35~-25℃ for 8-15 hours; the particle size of the pulverized material is 100-200 μm.

7. The preparation method according to claim 1, characterized in that, The amount of the compound regulator added in step (2) is 2.5-3.5% of the mass of the lactulose solution in step (1).

8. The preparation method according to claim 1, characterized in that, In step (2), the temperature is reduced from 60℃ to 55℃ and the stirring speed is 200 r / min, and the addition of the compound regulator is completed within 2-2.5 h; in step (2), the viscosity is monitored to control the viscosity at 300-400 mPa. s.

9. The preparation method according to claim 1, characterized in that, The amount of seed crystals added in step (3) is 2.5-3.5% of the mass of lactulose, the particle size of the seed crystals is 150-200 μm, the crystals are grown at a constant temperature for 2-3 hours, and the stirring rate is 80-120 r / min during the process; the gradient cooling in step (3) adopts a four-stage gradient cooling method, specifically: the cooling rate is 0.2℃ / h in the 55-45℃ stage, 0.4℃ / h in the 45-35℃ stage, 0.6℃ / h in the 35-25℃ stage, and 1.0℃ / h in the 25-15℃ stage, with a total crystallization time of 30-36 hours.

10. The preparation method according to claim 1, characterized in that, The heat preservation in step (4) is to keep the temperature at 10-20℃ for 0.5-1.5h.

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