Low nanoparticulate sugar alcohol and process for its production

Abstract

The application discloses a kind of low nanoparticle sugar alcohol and its production process, it is related to the technical field of pharmaceutical excipients.The application comprises the following processes: step 1: sugar alcohol is mixed with water, and stirring is dissolved clear;Filtering, ultrafiltration, concentration are sequentially carried out, and pre-purified sugar alcohol is obtained;Step 2: in pre-purified sugar alcohol, methanol is added, cooling, crystallization, centrifugation, drying, and the material is collected, and low nanoparticle sugar alcohol is obtained;The sugar alcohol includes one or more of sucrose, mannitol, trehalose;The solid content of the concentrated is 20~75%.The nanoparticle content in the sugar alcohol prepared by the application is all reduced to 10 5 below per gram, which fully meets the safety standard of less than 10 6 per gram.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical excipients technology, specifically a low-nanoparticle sugar alcohol and its production process. Background Technology

[0002] Protein drugs have become a hot topic in drug development in recent years due to their low side effects, well-defined activity, and high specificity. However, they are physicochemically unstable in aqueous dispersions and often undergo denaturation, loss of activity, or the formation of potential immunogenic products during preparation and storage. Currently, freeze-drying technology is commonly used to prepare solid protein drugs. Sugars are the most widely used non-specific protein stabilizers, protecting protein drugs during freezing, freeze-thaw cycles, and sublimation drying, with the protective effect depending on the type of protein. Disaccharides are the most thoroughly studied and recognized as the best protective agents. A typical example is sucrose (composed of one molecule of glucose and one molecule of fructose), which is chemically stable, mostly amorphous, and can significantly inhibit changes in protein secondary structure, preventing its stretching and aggregation during freeze-drying and storage.

[0003] Literature reported in 2025 that pharmaceutical-grade sugars meeting IPEC quality standards still contain a large amount of nanoparticle impurities (NPIs) composed of dextran (including β-glucan), ash, inorganic metal salts, and aromatic colorants, with an average particle size of 100-200 nm. These impurities originate from the raw materials and are difficult to remove through conventional refining processes. Furthermore, conventional filter cartridges used in existing sugar refining processes suffer from unreasonable pore size distribution and poor selectivity, making it difficult to efficiently remove NPIs in this particle size range. When the NPI concentration exceeds a threshold (10⁻⁶ ppm), the NPI concentration becomes significantly higher. 6 When the concentration of sugar is below a certain threshold (e.g., 1 / g), the stability and shelf life of biological agents such as proteins, monoclonal antibodies, and nucleic acids will be significantly reduced, and the risk of immunogenicity will also increase significantly. Below this threshold, the risk of analytical interference and biomolecular degradation can be significantly reduced, making it an ideal control standard for high-purity pharmaceutical sugar.

[0004] Therefore, providing a low-nanoparticle sugar alcohol and its production process is of practical significance in order to solve the above problems. Summary of the Invention

[0005] The purpose of this invention is to provide a low-nanoparticle sugar alcohol and its production process to solve the problems mentioned in the background art.

[0006] To solve the above-mentioned technical problems, the present invention provides the following technical solution: A process for producing low-nanoparticle sugar alcohols includes the following steps: Step 1: Mix the sugar alcohol with water and stir until dissolved; then filter, ultrafilter, and concentrate to obtain pre-purified sugar alcohol. Step 2: Add methanol to the pre-purified sugar alcohol, cool, crystallize, centrifuge, dry, and collect to obtain low nanoparticle sugar alcohol; The sugar alcohol includes one or more of sucrose, mannitol, and trehalose; the concentrated solids content is 20-75%.

[0007] Ideally, when the sugar alcohol is sucrose, the concentrated solid content is 40-75%. When the sugar alcohol is mannitol, the solid content of the concentrated product is 30-50%. When the sugar alcohol is trehalose, the concentrated solid content is 30-50%.

[0008] Ideally, the mass ratio of the sugar alcohol, water, and methanol is 1:(1~5):(1.1~1.2).

[0009] Ideally, the cooling temperature is 10~30℃; the crystallization time is 2~10 hours; and the drying temperature is 50~70℃ for 5~10 hours.

[0010] In a more optimized manner, in step 1, the base membrane material used for filtration and ultrafiltration includes one or two of polyethersulfone and regenerated cellulose; The filter element has a pore size of 45~55μm; The pore size of the ultrafiltration filter element is 4~6kD.

[0011] In a more optimized manner, the base membrane material of the filter element is a modified polyethersulfone membrane. The modification process is as follows: after swelling the polyethersulfone base membrane, a modification liquid is coated on it, and it is heat-treated at 60~80℃ for 15~30 minutes, then immersed in water, washed with water, and dried to obtain the modified polyethersulfone membrane.

[0012] The swelling process of the polyethersulfone-based membrane is as follows: the polyethersulfone-based membrane is immersed in N,N-dimethylacetamide for 10 minutes to swell, then removed and drained; when the base membrane material of the filter element is a regenerated cellulose membrane, the regenerated cellulose base membrane is immersed in a 4-6% sodium hydroxide solution for 5-10 minutes to activate, then removed and washed with water until neutral.

[0013] In a more optimized manner, the raw materials of the modified liquid, by weight, are: 8-12 parts styrene-maleic anhydride copolymer, 5-10 parts sulfonated polyethersulfone, 3-4 parts sulfonated dextran microspheres, 2-4 parts polyethyleneimine, 20-30 parts polyethersulfone resin, 5-8 parts pore-forming agent, and 2-4 parts dispersant.

[0014] In a more optimized manner, the preparation method of the sulfonated polyether sulfone is as follows: under a nitrogen atmosphere, polyether sulfone and chlorosulfonic acid in a mass ratio of (8~12):(10~12) are added sequentially to dichloromethane, stirred, cooled, filtered, washed and dried to obtain sulfonated polyether sulfone.

[0015] In a more optimized manner, the preparation method of the sulfonated dextran microspheres is as follows: Step 1: Dextran and 1,4-butanediol diglycidyl ether in a mass ratio of (8~10):(0.8~1) are added sequentially to a sodium hydroxide solution, stirred for 30~60 minutes, vacuum dispersed and stirred for 18~24 hours, filtered, washed and dried to obtain dextran microspheres; Step 2: Add the dextran microspheres and sulfur trioxide-pyridine complex in a mass ratio of (8~12):(4~6) to formamide in sequence. Stir for 5~8 hours under ice bath conditions, add methanol to precipitate, filter, wash with water until neutral, and dry to obtain sulfonated dextran microspheres.

[0016] A process for producing low-nano-particle sugar alcohols.

[0017] Compared with the prior art, the beneficial effects achieved by the present invention are: This invention modifies the base membrane material of the filter element, thereby optimizing the pore size distribution and retention selectivity of the filter element at the material level, effectively retaining NPI in the feed liquid, improving the crystallization behavior of sugar alcohols, and increasing the yield of sugar alcohols.

[0018] Sulfonated polyethersulfone and sulfonated dextran microspheres are added to the filter base membrane for synergistic retention. Sulfonated polyethersulfone, as a functional modifier, has negatively charged and highly hydrophilic sulfonic acid groups on its surface, effectively reducing non-specific adsorption of sugar alcohol molecules and improving sugar alcohol yield. A dense cross-linked network forms a more precise secondary sieve layer on the base membrane surface, effectively reducing the level of NPI in the sugar alcohol feed solution, thereby increasing the upper limit of the concentrateable solids content, raising the initial concentration of sugar alcohol crystallization, and promoting crystal growth during the sugar alcohol crystallization process, thus further improving the sugar alcohol yield. Simultaneously, sulfonated dextran microspheres, as a functional filler, have sulfonic acid and hydroxyl groups on their surface that further enhance the overall hydrophilicity of the filter membrane. Their microsphere structure introduces secondary channels, effectively optimizing the pore size distribution. Furthermore, their polysaccharide backbone is structurally similar to the dextran impurities in NPI, enabling specific recognition through intermolecular forces such as hydrogen bonds, thus assisting in the interception of polysaccharide NPI. The two work synergistically to form dense negatively charged adsorption sites between sulfonated polyethersulfone and sulfonated dextran microspheres, enabling electrostatic capture of metal cations and inorganic metal salt ions in the feed solution. At the same time, sulfonated dextran microspheres undergo hydrogen bond recognition with polysaccharide NPIs, effectively forming a multi-mechanism adsorption system that achieves efficient retention of different types of NPIs. Attached Figure Description

[0019] Figure 1 This is a production process diagram for the low nanoparticle sugar alcohol of this invention.

[0020] Figure 2 This is a detection image of nanoparticles in the low-nanoparticle sugar alcohol prepared in Example 4 of the present invention.

[0021] Figure 3 This is a detection image of nanoparticles in the low-nanoparticle sugar alcohol prepared in Example 9 of the present invention.

[0022] Figure 4 This is a detection image of nanoparticles in the low-nanoparticle sugar alcohol prepared in Example 14 of the present invention. Detailed Implementation

[0023] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] In the following embodiments, the parts are by weight; it should be noted that there are no special restrictions on the manufacturers of the raw materials involved in this invention, and they include, exemplarily, the following: polyethersulfone (CAS: 25667-42-9), chlorosulfonic acid (CAS: 7790-94-5), dextran (molecular weight 60000), 1,4-butanediol diglycidyl ether (CAS: 2425-79-8), formamide (CAS: 75-12-7), sulfur trioxide-pyridine complex (CAS: 26412-87-3), and polyethersulfone resin (model Ultrason E). 6020P), polyethylene glycol-400 (CAS: 25852-47-5), N,N-dimethylacetamide (CAS: 127-19-5), styrene-maleic anhydride copolymer (CAS: 9011-13-6), Tween-80 (CAS: 9005-65-6), polyethyleneimine (molecular weight 25000), sucrose (CAS: 57-50-1), mannitol (CAS: 69-65-8), trehalose (CAS: 99-20-7).

[0025] Pre-preparation: Preparation of sulfonated polyethersulfone: Under a nitrogen atmosphere, 10 parts of polyethersulfone and 12 parts of chlorosulfonic acid were added sequentially to 100 parts of dichloromethane, stirred until homogeneous, cooled to 35°C, filtered, washed and dried to obtain sulfonated polyethersulfone.

[0026] II. Preparation of sulfonated dextran microspheres: Step 1: Add 9 parts of dextran and 0.9 parts of 1,4-butanediol diglycidyl ether to 95 parts of 15wt% sodium hydroxide solution, stir for 45 minutes, vacuum disperse and stir for 20 hours, filter, wash and dry to obtain dextran microspheres; Step 2: Add 10 parts of dextran microspheres and 5 parts of sulfur trioxide-pyridine complex to 80 parts of formamide in sequence, stir for 6.5 hours under ice bath conditions, add methanol to precipitate, filter, wash with water until neutral, and dry to obtain sulfonated dextran microspheres.

[0027] III. Preparation of modified solution: Dissolve 25 parts of polyethersulfone resin, 8 parts of sulfonated polyethersulfone, and 6.5 parts of pore-forming agent (polyethylene glycol-400) in N,N-dimethylacetamide and stir at 60°C for 4 hours; add 10 parts of styrene-maleic anhydride copolymer and continue stirring at 60°C for 24 hours; cool to room temperature, add 3 parts of dispersant (Tween-80), then add 3.5 parts of sulfonated dextran microspheres and ultrasonically disperse for 30 minutes; finally, slowly add 3 parts of a 10wt% N,N-dimethylacetamide solution of polyethyleneimine, stir at room temperature for 1 hour, and degas under vacuum for 30 minutes to obtain the modified solution.

[0028] Example 1: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve sucrose and water in a 1:1 mass ratio by stirring, then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 40% to obtain pre-purified sugar alcohol; Step 2: Add methanol to the pre-purified sugar alcohol, cool to 30°C, crystallize for 4 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to sucrose is 1.2:1.

[0029] Example 2: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve sucrose and water in a 1:1 mass ratio by stirring, then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 50% to obtain pre-purified sugar alcohol; Step 2: Add methanol to the pre-purified sugar alcohol, cool to 30°C, crystallize for 4 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to sucrose is 1.2:1.

[0030] Example 3: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve sucrose and water in a 1:1 mass ratio by stirring, then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 65% to obtain a pre-purified sugar alcohol; Step 2: Add methanol to the pre-purified sugar alcohol, cool to 20°C, crystallize for 7 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to sucrose is 1.2:1.

[0031] Example 4: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve sucrose and water in a 1:1 mass ratio by stirring, then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 75% to obtain pre-purified sugar alcohol; Step 2: Add methanol to the pre-purified sugar alcohol, cool to 20°C, crystallize for 7 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to sucrose is 1.2:1.

[0032] Example 5: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve sucrose and water in a 1:1 mass ratio by stirring, then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 75% to obtain pre-purified sugar alcohol; Step 2: Add methanol to the pre-purified sugar alcohol, cool to 20°C, crystallize for 7 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to sucrose is 1.1:1.

[0033] Example 6: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve mannitol and water in a mass ratio of 1:5 by stirring, and then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 30% to obtain a pre-purified sugar alcohol. Step 2: Add methanol to the pre-purified sugar alcohol, cool to 30°C, crystallize for 4 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to mannitol is 1.2:1.

[0034] Example 7: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve mannitol and water in a mass ratio of 1:5 by stirring, and then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 40% to obtain a pre-purified sugar alcohol. Step 2: Add methanol to the pre-purified sugar alcohol, cool to 35°C, crystallize for 4 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to mannitol is 1.2:1.

[0035] Example 8: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve mannitol and water in a mass ratio of 1:5 by stirring, and then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 40% to obtain a pre-purified sugar alcohol. Step 2: Add methanol to the pre-purified sugar alcohol, cool to 20°C, crystallize for 7 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to mannitol is 1.2:1.

[0036] Example 9: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve mannitol and water in a mass ratio of 1:5 by stirring, and then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 50% to obtain a pre-purified sugar alcohol. Step 2: Add methanol to the pre-purified sugar alcohol, cool to 20°C, crystallize for 7 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to mannitol is 1.2:1.

[0037] Example 10: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve mannitol and water in a mass ratio of 1:5 by stirring, and then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 50% to obtain a pre-purified sugar alcohol. Step 2: Add methanol to the pre-purified sugar alcohol, cool to 20°C, crystallize for 7 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to mannitol is 1.1:1.

[0038] Example 11: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve trehalose and water in a mass ratio of 1:2 by stirring, and then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 30% to obtain a pre-purified sugar alcohol; Step 2: Add methanol to the pre-purified sugar alcohol, cool to 30°C, crystallize for 4 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to trehalose is 1.2:1.

[0039] Example 12: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve trehalose and water in a mass ratio of 1:2 by stirring, and then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 35% to obtain a pre-purified sugar alcohol; Step 2: Add methanol to the pre-purified sugar alcohol, cool to 30°C, crystallize for 4 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to trehalose is 1.2:1.

[0040] Example 13: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve trehalose and water in a mass ratio of 1:2 by stirring, and then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 40% to obtain a pre-purified sugar alcohol; Step 2: Add methanol to the pre-purified sugar alcohol, cool to 20°C, crystallize for 7 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to trehalose is 1.2:1.

[0041] Example 14: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve trehalose and water in a mass ratio of 1:2 by stirring, and then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 50% to obtain a pre-purified sugar alcohol; Step 2: Add methanol to the pre-purified sugar alcohol, cool to 20°C, crystallize for 7 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to trehalose is 1.2:1.

[0042] Example 15: A production process for low-nanoparticle sugar alcohol, comprising the following steps: Step 1: Dissolve trehalose and water in a mass ratio of 1:2 by stirring, and then filter through a 50μm filter cartridge (the filter base membrane is a polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 50% to obtain a pre-purified sugar alcohol; Step 2: Add methanol to the pre-purified sugar alcohol, cool to 20°C, crystallize for 7 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to trehalose is 1.1:1.

[0043] Example 16: Further, based on Example 4, filtration is performed using a filter cartridge made of modified polyethersulfone membrane, including the following steps: I. Preparation of modified polyethersulfone membrane: Step 1: Immerse the polyethersulfone base membrane in N,N-dimethylacetamide to swell for 10 minutes, remove and drain to obtain the swollen base membrane; Step 2: Coat the modified liquid onto the swollen base film, heat treat at 70℃ for 20 minutes, then immerse in a deionized hydrogel bath for 24 hours to cure, wash with water, and dry to obtain the modified polyethersulfone film. II. Preparation of low-nanoparticle sugar alcohols: Step 1: Dissolve sucrose and water in a 1:1 mass ratio by stirring, then filter through a 50μm filter cartridge (the filter base membrane is a modified polyethersulfone membrane); then ultrafilter through a 5kD filter cartridge (the ultrafiltration base membrane is a polyethersulfone membrane), collect the filtrate, and concentrate it to a solid content of 75% to obtain pre-purified sugar alcohol; Step 2: Add methanol to the pre-purified sugar alcohol, cool to 20°C, crystallize for 7 hours, centrifuge, dry at 60°C for 8 hours, collect the material, and obtain low nanoparticle sugar alcohol; In this embodiment, the mass ratio of methanol to sucrose is 1.2:1.

[0044] Comparative Example 1: Based on Example 16, the composition of the modified liquid was adjusted, and a modified polyethersulfone membrane was prepared without the addition of sulfonated polyethersulfone; the rest remained the same as in Example 16.

[0045] Comparative Example 2: Based on Example 16, the composition of the modified liquid was adjusted, and sulfonated dextran was not added to prepare a modified polyethersulfone membrane; the rest remained the same as in Example 16.

[0046] Comparative Example 3: Based on Example 16, the composition of the modified liquid was adjusted, and dextran microspheres were used to replace sulfonated dextran to prepare a modified polyethersulfone membrane; the rest remained the same as in Example 16.

[0047] Comparative Example 4: Based on Example 16, a modified polyethersulfone membrane was prepared without swelling treatment of the polyethersulfone-based membrane; the rest remained the same as in Example 16.

[0048] Performance testing: The low-nanoparticle sugar alcohols prepared in Examples 1-16 and Comparative Examples 1-4 were analyzed for nanoparticle detection using a nanoparticle tracking analyzer; the yields of the low-nanoparticle sugar alcohols prepared in Examples 1-16 and Comparative Examples 1-4 were also tested, and the data are shown in the table below:

[0049] Conclusion: The data in the table above show that the sugar alcohols obtained in Examples 4, 9, and 14 have good yields. Furthermore, the sugar alcohol yield obtained by filtration using a modified polyethersulfone membrane in Example 16 is further improved. In Comparative Example 1, the absence of sulfonated polyethersulfone in the modified solution of the modified polyethersulfone membrane leads to decreased hydrophilicity and negative charge density, thereby reducing separation efficiency and sugar alcohol yield. In Comparative Example 2, the absence of sulfonated dextran microspheres in the modified solution of the modified polyethersulfone membrane results in the loss of its specific ability to recognize polysaccharide NPIs, thus reducing the sugar alcohol yield. In Comparative Example 3, the use of dextran microspheres in the modified solution of the modified polyethersulfone membrane reduces the negative charge density, and the physical adsorption between the polyethersulfone membrane and the modified solution may cause blockage within the polyethersulfone membrane pores, thereby reducing separation efficiency and sugar alcohol yield. In Comparative Example 4, the polyethersulfone membrane is not swollen; under pressure, the polyethersulfone membrane structure is incomplete, resulting in decreased filtration performance, thus reducing separation efficiency and sugar alcohol yield. Furthermore, through… Figures 2-4 It can be seen that after the nanoparticle removal process, the nanoparticle content in sucrose, mannitol, and trehalose was reduced to 10%. 5 Below 10 per gram, fully meets the requirement of less than 10 6 Safety standard per gram.

[0050] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

Claims

1. A production process for low-nanoparticle sugar alcohols, characterized in that: Includes the following steps: Step 1: Mix the sugar alcohol with water and stir until dissolved; then filter, ultrafilter, and concentrate to obtain pre-purified sugar alcohol. Step 2: Add methanol to the pre-purified sugar alcohol, cool, crystallize, centrifuge, dry, and collect to obtain low nanoparticle sugar alcohol; The sugar alcohol includes one or more of sucrose, mannitol, and trehalose; the concentrated solids content is 20-75%.

2. The production process of a low-nanoparticle sugar alcohol according to claim 1, characterized in that: When the sugar alcohol is sucrose, the solid content of the concentrated product is 40-75%. When the sugar alcohol is mannitol, the solid content of the concentrated product is 30-50%. When the sugar alcohol is trehalose, the concentrated solid content is 30-50%.

3. The production process of a low-nanoparticle sugar alcohol according to claim 1, characterized in that: The mass ratio of the sugar alcohol, water and methanol is 1:(1~5):(1.1~1.2).

4. The production process of a low-nanoparticle sugar alcohol according to claim 1, characterized in that: The cooling temperature is 10~30℃; the crystallization time is 2~10 hours; the drying temperature is 50~70℃ and the time is 5~10 hours.

5. The production process of a low-nanoparticle sugar alcohol according to claim 1, characterized in that: In step 1, the base membrane material used for filtration and ultrafiltration includes one or two of polyethersulfone and regenerated cellulose; The filter element has a pore size of 45~55μm; The pore size of the ultrafiltration filter element is 4~6kD.

6. The production process of a low-nanoparticle sugar alcohol according to claim 5, characterized in that: The base membrane material of the filter element is a modified polyethersulfone membrane. The modification process is as follows: after the polyethersulfone base membrane is swollen, a modification liquid is coated on it, and it is heat-treated at 60~80℃ for 15~30 minutes. Then it is immersed in water, washed with water, and dried to obtain the modified polyethersulfone membrane.

7. The production process of a low-nanoparticle sugar alcohol according to claim 6, characterized in that: The raw materials of the modified liquid, by weight, are: 8-12 parts styrene-maleic anhydride copolymer, 5-10 parts sulfonated polyethersulfone, 3-4 parts sulfonated dextran microspheres, 2-4 parts polyethyleneimine, 20-30 parts polyethersulfone resin, 5-8 parts pore-forming agent, and 2-4 parts dispersant.

8. The production process of a low-nanoparticle sugar alcohol according to claim 7, characterized in that: The preparation method of the sulfonated polyether sulfone is as follows: under a nitrogen atmosphere, polyether sulfone and chlorosulfonic acid in a mass ratio of (8~12):(10~12) are added to dichloromethane in sequence, stirred, cooled, filtered, washed and dried to obtain sulfonated polyether sulfone.

9. The production process of a low-nanoparticle sugar alcohol according to claim 7, characterized in that: The preparation method of the sulfonated dextran microspheres is as follows: Step 1: Dextran and 1,4-butanediol diglycidyl ether in a mass ratio of (8~10):(0.8~1) are added to sodium hydroxide solution in sequence, stirred for 30~60 minutes, vacuum dispersed and stirred for 18~24 hours, filtered, washed and dried to obtain dextran microspheres; Step 2: Add the dextran microspheres and sulfur trioxide-pyridine complex in a mass ratio of (8~12):(4~6) to formamide in sequence. Stir for 5~8 hours under ice bath conditions, add methanol to precipitate, filter, wash with water until neutral, and dry to obtain sulfonated dextran microspheres.

10. The low nanoparticle sugar alcohol prepared by the production process of the low nanoparticle sugar alcohol according to any one of claims 1 to 9.

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