Method and system for purifying carboxymethyl chitosan

Abstract

The invention discloses a method and a system for purifying carboxymethyl chitosan, and belongs to the technical field of chemical processing of biomass materials. The purification method comprises the following steps: providing a carboxymethyl chitosan crude product feed liquid containing carboxymethyl chitosan and a byproduct thereof, mixing the carboxymethyl chitosan crude product feed liquid with water and alcohol, and adjusting the pH value with hydrochloric acid; stirring the pH-adjusted crude product feed liquid, and standing, so that diglycolic acid and salt thereof are dissolved in an upper liquid phase; carrying out solid-liquid separation to obtain a primarily refined carboxymethyl chitosan solid; and repeating the steps for at least one time on the carboxymethyl chitosan solid obtained by primary refining to obtain a high-purity carboxymethyl chitosan solid product. Purified carboxymethyl chitosan can be obtained through the purification method, the purity of the carboxymethyl chitosan product can reach 99.5% or above, and the carboxymethyl chitosan can be used in the medical industry. The method is simple and convenient, the usage amount of alcohol and water can be greatly reduced, and the cost is reduced.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biomass material chemical processing, and particularly relates to a purification method and system of carboxymethyl chitosan. BACKGROUND

[0002] Carboxymethyl chitosan is a water-soluble chitosan derivative, which has a wide application prospect in the fields of medicine, food, cosmetics and environmental protection due to its good biocompatibility, biodegradability and various biological activities. At present, the synthesis of carboxymethyl chitosan mainly adopts the chloroacetic acid method, that is, under alkaline conditions, carboxymethylation reaction occurs between chitosan and chloroacetic acid. However, in addition to the main reaction of carboxymethylation, side reactions also occur in this preparation process, resulting in the generation of a large amount of di-glycolic acid (DGA) and other by-products.

[0003] Di-glycolic acid is a small molecule impurity with certain cytotoxicity, and its presence not only affects the biological safety of carboxymethyl chitosan, but also limits its application in the medical field. Studies have shown that the cytotoxicity of di-glycolic acid poses a threat to the safety of carboxymethyl chitosan. The existing purification methods of carboxymethyl chitosan mainly include organic solvent washing, isoelectric point salt removal and other technologies. Although these methods can reduce the content of di-glycolic acid to a certain extent, they have problems such as low production efficiency, high cost, and the purity of carboxymethyl chitosan cannot meet the medical use level.

[0004] Therefore, how to effectively remove di-glycolic acid from carboxymethyl chitosan products has become a key technical problem in the preparation of medical-grade carboxymethyl chitosan. SUMMARY

[0005] In order to overcome the difficulties in the existing purification process of carboxymethyl chitosan, such as the difficulty in obtaining medical-grade carboxymethyl chitosan and the difficulty in reducing production cost, the present application provides a purification method and system of carboxymethyl chitosan, which can obtain high-purity carboxymethyl chitosan, facilitate its application in medicine, and also reduce production cost.

[0006] The present application provides a purification method of carboxymethyl chitosan, which comprises the following steps:

[0007] A carboxymethyl chitosan crude product solution containing carboxymethyl chitosan and its by-products is provided, mixed with water and alcohol, and then the pH is adjusted with hydrochloric acid; the crude product solution after pH adjustment is stirred and then allowed to stand, so that di-glycolic acid and its salt in it are dissolved in the upper liquid phase; through solid-liquid separation, a preliminarily refined carboxymethyl chitosan solid is obtained;

[0008] The preliminarily refined carboxymethyl chitosan solid is repeated at least once according to the above steps to obtain a high-purity carboxymethyl chitosan solid product.

[0009] In some embodiments, the preparation process of the carboxymethyl chitosan crude liquid includes:

[0010] The carboxymethylation reaction of medical grade chitosan and chloroacetic acid is carried out in an alcohol solvent under alkaline conditions at 60-70°C with stirring for 5-10h.

[0011] The mass of chloroacetic acid is 2-5 times the mass of medical grade chitosan; the mass of alcohol solvent is 10-20 times the mass of medical grade chitosan.

[0012] In some embodiments, the degree of carboxylation of carboxymethyl chitosan in the carboxymethyl chitosan crude liquid is 0.9-1.8.

[0013] In some embodiments, after mixing the carboxymethyl chitosan crude liquid, water and alcohol, the mass proportion of water in the mixed system is 20-30%.

[0014] In some embodiments, the alcohol is an ethanol solution with a mass concentration greater than 95%; the pH adjusted with hydrochloric acid is 7-9.

[0015] In some embodiments, the solid-liquid separation is centrifugal separation, and the preliminary refined carboxymethyl chitosan solid and the separation liquid are obtained respectively.

[0016] After collecting the separation liquid, the pH is adjusted to 3-4 with hydrochloric acid, and then electrodialysis and concentration are performed in sequence to obtain alcohol-water mixed steam and diethylene glycol acid concentrate respectively.

[0017] In some embodiments, the purification method further includes: rectifying the alcohol-water mixed steam to obtain pure alcohol solvent and water respectively.

[0018] In some embodiments, the purification method further includes: vacuum drying the diethylene glycol acid concentrate to obtain diethylene glycol acid solid with a purity greater than 98%.

[0019] The present application provides a system for implementing the purification method of carboxymethyl chitosan, which includes a mixing and adjusting device and a solid-liquid separation device. The mixing and adjusting device is used for mixing carboxymethyl chitosan crude liquid, water and alcohol, and stirring and adjusting treatment. The lower part of the mixing and adjusting device is provided with a liquid outlet, which is connected to the solid-liquid separation device.

[0020] In some embodiments, the mixing and adjusting device is a temperature controllable reaction kettle; the solid-liquid separation device is a filter device or a centrifuge;

[0021] The system further includes an electrodialysis unit and an evaporation and concentration unit connected in series. The electrodialysis unit is connected to the liquid outlet of the solid-liquid separation device.

[0022] Compared with the traditional washing technical idea, in the purification technology provided by the application, the carboxymethyl chitosan crude material liquid is first mixed with water and alcohol, the pH is adjusted with hydrochloric acid, then stirring and standing are carried out, and the preliminary refined carboxymethyl chitosan solid is obtained through solid-liquid separation, and the process is repeated at least once to obtain high-purity carboxymethyl chitosan solid product. In the application, small molecules such as carboxymethyl chitosan and diethylene glycol acid are used, and the different solubility in alcohol-water medium can effectively separate and purify carboxymethyl chitosan by accurately controlling the ratio of water and alcohol; the small molecules such as diethylene glycol acid are repeatedly stirred and extracted for several times, and finally the high-purity (medical grade) carboxymethyl chitosan product is obtained. The carboxymethyl chitosan product obtained by the above purification method has a purity of more than 99.5%, and can be used in the medical industry. The method is simple, and can greatly save the use amount of alcohol and water, and reduce the cost.

[0023] Further, the application can also recycle and purify diethylene glycol acid, and the purity thereof is more than 98%, which can be used as raw material in the field of chemical industry and intermediate; the purity of the recycled and purified ethanol is more than 95%, which can be repeatedly used in the preparation process of carboxymethyl chitosan. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 It is a purification process flow and system device schematic diagram of some embodiments of the application;

[0025] Figure 2 It is a blank spectrum of carboxymethyl chitosan purification detection of embodiment one of the application;

[0026] Figure 3 It is a diethylene glycol acid residual spectrum in carboxymethyl chitosan of embodiment one of the application;

[0027] Figure 4 It is a recovery diethylene glycol acid purity detection result spectrum of embodiment one of the application. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the application will be described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the application, not all the embodiments. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative labor are within the protection scope of the application.

[0029] The application provides a purification method of carboxymethyl chitosan, which comprises the following steps:

[0030] The carboxymethyl chitosan and by-product carboxymethyl chitosan crude liquid are mixed with water and alcohol, and then the pH is adjusted by hydrochloric acid; the crude liquid after pH adjustment is stirred and then left to stand, so that diethylene glycol acid and its salt in the crude liquid are dissolved in the upper liquid phase; through solid-liquid separation, the preliminarily refined carboxymethyl chitosan solid is obtained; the preliminarily refined carboxymethyl chitosan solid is repeated at least once according to the above steps to obtain a high-purity carboxymethyl chitosan solid product.

[0031] The corresponding purification system mainly comprises a mixing adjustment device and a solid-liquid separation device, the mixing adjustment device is used for mixing and stirring adjustment treatment of the carboxymethyl chitosan crude liquid, water and alcohol, and the lower part of the mixing adjustment device is provided with a liquid outlet and is connected with the solid-liquid separation device.

[0032] The carboxymethyl chitosan with high purity can be obtained by the method, which is beneficial to the application of the carboxymethyl chitosan in medicine, and the production cost is reduced.

[0033] Reference Figure 1 , Figure 1 The purification process and system device of some embodiments of the application are shown in the schematic diagram, wherein 1 is a controllable temperature reaction kettle, 2 is a solid-liquid separation device, 3 is a stainless steel liquid storage tank, 4 is an electrodialyzer, 5 is a vacuum evaporator, 6 is a low-temperature drying machine, 7 is a rectification device, 8 is an ethanol liquid storage tank, 9 is a wastewater treatment device, 10 is a purified water liquid storage tank, and 11 is an electrodialysis concentrated liquid storage tank.

[0034] In the embodiment of the application, the carboxymethyl chitosan crude liquid obtained after reaction is used as the purification raw material, the medical grade chitosan raw material (deacetylation degree > 89%, commercially available) is preferably used in the carboxymethylation reaction under alkaline conditions to obtain the crude carboxymethyl chitosan.

[0035] Specifically, the carboxymethylation reaction process comprises:

[0036] The alkali is added to the alcohol solvent, stirred and dissolved to form an alkali alcohol solution; the alcohol solvent is preferably an ethanol solution with a mass concentration of 95% or more, and the alkali is generally sodium hydroxide or potassium hydroxide. The concentration of the alkali alcohol solution can be 10%-50%, and the pH of the solution system is greater than 13, and more preferably, the concentration of the alkali alcohol solution is 20%-40% and the pH is greater than 13.5.

[0037] The medical-grade chitosan is added to the alkali alcohol solution, and stirring is started to disperse uniformly, wherein the pH of the whole system is controlled to be greater than 13 (the pH needs to be monitored online, and the pH of the whole reaction system is controlled to be greater than 13, and if it is not enough, sodium hydroxide or potassium hydroxide needs to be added), preferably, the chloroacetic acid is added in batches, and the reaction is stirred at a temperature of 60-70 DEG C for 300-600 minutes; in the strong alkaline system, part of the chloroacetic acid reacts with the chitosan to generate a carboxymethyl chitosan crude product, and another part of the chloroacetic acid generates a large amount of diethylene glycol acid and other by-products. As preferred, the mass of the chloroacetic acid is 2-5 times, 2-4 times the mass of the medical-grade chitosan; and the mass of the alcohol solvent is 10-20 times the mass of the medical-grade chitosan.

[0038] The reaction is stopped to obtain a carboxymethyl chitosan crude product solution after the reaction, and the carboxymethyl chitosan obtained has a carboxylation degree of 0.9-1.8, preferably 1.1-1.5, and can be applied in the pharmaceutical industry. The carboxylation degree is the percentage of the total moles of carboxymethyl groups to the total moles of amino sugar units; the carboxylation degree is consistent with the degree of substitution. By optimizing the process parameters, the carboxymethyl chitosan can be accurately controlled in carboxylation degree (0.9-1.5 segmented control) and deacetylation degree (85-95%), and the product quality is stable and reliable.

[0039] After obtaining the carboxymethyl chitosan crude product solution, the embodiment of the present application introduces it into a temperature-controllable reaction kettle 1, and water and alcohol are introduced (which can be introduced into the upper part of the reaction kettle). The reaction kettle 1 is provided with temperature control equipment and stirring equipment, so that the carboxymethyl chitosan crude product solution is uniformly mixed with water and alcohol. The alcohol is an ethanol solution with a mass concentration of greater than 95%; as preferred, the proportion of water in the whole system is strictly controlled to be between 20%-30%. Then, concentrated hydrochloric acid is used to adjust the pH to 7-9, and stirring is performed at room temperature for 2-4 hours, and then the solution is left to stand for 2-4 hours. The concentrated hydrochloric acid is hydrogen chloride with a mass fraction of more than 20%, and the concentration of commercially available concentrated hydrochloric acid is 36%-38%; the room temperature is generally 15-25 DEG C.

[0040] In some embodiments of the present application, by controlling the ratio of the alcohol-water mixed solution (water:alcohol=2:8 to water:alcohol=3:7 in mass ratio), the organic salt, inorganic salt and other impurities in the crude product solution can be effectively removed, and high-purity carboxymethyl chitosan can be obtained. According to the properties of carboxymethyl chitosan, the present application preferably controls the ratio of alcohol to water accurately, which is beneficial to the effective separation of impurities (organic salt, inorganic salt) and carboxymethyl chitosan solids. In the above implementation process, if the proportion of water is too high, a part of the carboxymethyl chitosan material will be dissolved in water, reducing the yield; if the proportion of water is too low, the removal efficiency of small molecule impurities is slow and not clean.

[0041] The embodiment of the present application can introduce the static layered feed liquid into a solid-liquid separation device 2 (or a sedimentation separation device) through the bottom outlet of the reaction kettle 1, which is preferably a conventional filtration device or a centrifuge; preferably after centrifugal separation (using a medium or high speed centrifuge, rotation speed ≥5000 rpm, centrifugation for 30-60 min, and stopping centrifugation), the preliminarily refined carboxymethyl chitosan solid and the separated liquid are obtained respectively.

[0042] In some embodiments, the preliminarily refined carboxymethyl chitosan solid is repeated for 2 times according to the above steps, and a high-purity carboxymethyl chitosan solid product with a purity of >99.5% is obtained; and the separated liquid is collected for recycling, purification, and reuse. The embodiment of the present application purifies the carboxymethyl chitosan by accurately controlling the ratio of water and alcohol, so that the carboxymethyl chitosan and organic and inorganic impurities, especially the small molecules of diethylene glycol acid, can be effectively separated, and the purity of the obtained carboxymethyl chitosan can be increased to more than 99.5%, which is a high-purity medical-grade carboxymethyl chitosan, which is beneficial to be applied in medicine and other aspects, and reduces the production cost.

[0043] Further, the embodiment of the present application also recovers and purifies alcohol and water, etc. by concentration, so that the waste diethylene glycol acid and ethanol can be purified and recycled, which can increase the income, avoid environmental pollution and resource waste, and has more important industrial application value. The operation process of the recycling and purification specifically includes:

[0044] The obtained separated liquid can be collected in a stainless steel liquid storage tank 3 through the bottom outlet of the solid-liquid separation device 2, and the pH is adjusted by using concentrated hydrochloric acid; then the electrodialysis is performed by using an electrodialyzer 4 to remove a large amount of inorganic salts, and the evaporation is performed by connecting an evaporator to obtain alcohol and water mixed steam and diethylene glycol acid concentrated liquid respectively;

[0045] The alcohol and water mixed steam generated by evaporation is subjected to conventional rectification to obtain pure alcohol solvent and water respectively; the recycled alcohol solvent is stored and reused to reduce environmental pollution and save cost.

[0046] The process conditions of the electrodialysis can include: using a homogeneous ion exchange membrane resistant to organic solvents (ethanol); the current density is 15-25 mA / cm 2 ; the flow rate of the desalination chamber and the concentration chamber is controlled at 3-5 cm / s to ensure turbulent flow, while the pressure difference between the two chambers is ≤0.05 MPa to prevent membrane deformation; the circulating liquid temperature is controlled at 25-35℃; the operation mode is continuous circulation, that is, the feed liquid circulates in the desalination chamber; the conductivity of the diluted liquid is monitored in real time. When the conductivity of the diluted liquid is less than 100 μS / cm, the electrodialysis is stopped.

[0047] Preferably, the diethylene glycol acid concentrated liquid is vacuum dried to obtain high-purity diethylene glycol acid solid.

[0048] The preferred embodiment of the present application prepares a purified carboxymethyl chitosan solid product, and purifies and recovers a large amount of diglycolic acid and reaction solvent, and the purification system of the method further comprises: a series connection of an electrodialysis unit and an evaporation and concentration unit, etc.

[0049] The evaporation and concentration unit comprises a reduced-pressure evaporator 5 and a low-temperature dryer 6. Alcohol-water mixed steam is generated in the upper part and then enters a rectification device 7 for rectification. The alcohol solvent in the upper part is recovered and can enter an ethanol storage tank 8 for repeated use in the preparation and purification process of carboxymethyl chitosan. The relatively pure water recovered at the bottom enters a waste water treatment device 9 and then enters a purified water storage tank 10. The desalination liquid generated by the electrodialysis device 4 enters the reduced-pressure evaporator 5, and the concentrated sodium chloride liquid generated enters an electrodialysis concentrated liquid storage tank 11. According to the embodiment of the present application, the solvent recovery realizes the recycling of ethanol, greatly reduces the consumption of organic solvents and the discharge of waste water, and reduces environmental pollution.

[0050] The concentrated liquid in the reduced-pressure evaporator is dried by low-temperature vacuum drying, and the process includes: a drying temperature of 40-50℃, a vacuum degree of ≤2.67 kPa, and a drying time of 36-48h, to obtain a high-purity diglycolic acid solid raw material, the purity of which can be above 98%, and which can be used in the fields of chemical industry and intermediates. In the above steps, the evaporator, the vacuum dryer and the rectification device are provided with a temperature control system.

[0051] The embodiment of the present application recovers and purifies diglycolic acid and alcohol for reuse, protects the environment and reduces production costs. Some embodiments separately obtain a carboxymethyl chitosan solid product with a purity of above 99.5%, diglycolic acid with a purity of above 98%, and alcohol solvent with a purity of above 95%. According to the embodiment of the present application, the alcohol-water ratio and the step-by-step precipitation technology are controlled to realize efficient recovery of diglycolic acid, the purity of which is above 98%, greatly reducing the residual amount of diglycolic acid in the carboxymethyl chitosan product to below 1000μg / g, meeting the medical standard requirements of YY / T 0953-2020. The process flow of the present application is simple, the equipment investment is small, the operation is convenient, and it is suitable for large-scale industrial production, greatly reducing the production cost.

[0052] In the traditional process, when the solvent is washed and precipitated, for example, 40Kg of carboxymethyl chitosan is washed and precipitated with anhydrous ethanol, the alcohol concentration of the upper clear liquid is increased to 95, and about 2 tons of anhydrous ethanol are required; when the isoelectric point is precipitated, 400-500kg of anhydrous ethanol is required. According to the purification method of the embodiment of the present application, only 50-100kg of 95% ethanol is consumed, and a carboxymethyl chitosan (medical grade) with higher purity is obtained. The required ethanol does not need to be anhydrous ethanol, and compared with the isoelectric point precipitation process, the amount of ethanol used is reduced by at least 80%, greatly reducing the amount of ethanol used.

[0053] Secondly, the impurities such as organic and inorganic, alcohol solvent in the traditional process are not recycled, which increases the production cost and environmental pollution. According to the purification method of the embodiment of the present application, a large amount of diethylene glycol acid is produced, which can be recycled and purified for repeated use, thereby greatly reducing the production cost and reducing environmental pollution. The diethylene glycol acid in the embodiment of the present application is converted from harmful waste into valuable products, which can be used as chemical raw materials, pharmaceutical intermediates and the like, thereby realizing comprehensive utilization of resources.

[0054] In order to better understand the technical content of the present application, the following specific embodiments are provided to further illustrate the present application.

[0055] Example 1:

[0056] Method for purifying carboxymethyl chitosan with higher purity and recycling and purifying diethylene glycol acid and alcohol:

[0057] (1) After 40 kg of carboxymethyl chitosan crude product with a carboxymethyl substitution degree of 1.3 is added with 400 kg of 95% ethanol and 75 kg of purified water, stirring is started, concentrated hydrochloric acid is used to adjust the pH, the pH of the system is controlled to be 7-9, stirring is carried out at room temperature for 3 h, and standing is carried out for 2 h. The upper liquid is removed by using a medium-speed centrifuge (rotating speed 5000 rpm) for 60 min to obtain preliminarily refined carboxymethyl chitosan solid; the upper liquid is collected and waits for the next step.

[0058] After the preliminarily refined carboxymethyl chitosan solid is added with 400 kg of 95% ethanol and 75 kg of purified water, stirring is carried out at room temperature for 3 h, standing is carried out for 2 h, the upper liquid is removed by centrifugation to obtain further refined carboxymethyl chitosan, and the upper liquid is collected and waits for the next step. The carboxymethyl chitosan solid product with a purity of 99.6% can be obtained by repeating twice.

[0059] (2) The collected liquid separation liquid is adjusted to pH 3.5-4.0 by using concentrated hydrochloric acid, and then a large amount of inorganic salt is removed by using an electrodialysis device. The process includes: using an organic solvent (ethanol) resistant homogeneous ion exchange membrane; the current density is 15-25 mA / cm 2 ; the flow rate of the desalination chamber and the concentration chamber is controlled to be 3-5 cm / s, while the pressure difference between the two chambers is kept ≤0.05 MPa; the circulating liquid temperature is controlled to be 25-35℃; the operation mode is continuous circulation; the conductivity of the diluting liquid is monitored in real time. When the conductivity of the diluting liquid is less than 100 μS / cm, the electrodialysis is stopped.

[0060] The concentrated liquid in the evaporator is subjected to low-temperature vacuum drying (drying temperature 40-50℃, vacuum degree ≤2.67 kPa, drying time 48h) to obtain diethylene glycol acid solid with a purity of 98.2%, and 8kg of diethylene glycol acid recovery solid.

[0061] The concentrated liquid in the evaporator is subjected to low-temperature vacuum drying (drying temperature 40-50℃, vacuum degree ≤2.67 kPa, drying time 48h) to obtain diethylene glycol acid solid with a purity of 98.2%, and 8kg of diethylene glycol acid recovery solid.

[0062] The total amount of 95% concentration ethanol used in the above purification process is 1200kg, and the amount of purified water is 225kg. 1100kg of 95% concentration ethanol is recovered, and 8kg of diethylene glycol acid with a purity of 98.2% is recovered. Compared with the prior art (isoelectric point precipitation, anhydrous ethanol washing) for purifying 40kg of carboxymethyl chitosan, 2 tons of water and 450kg of anhydrous ethanol are required. In comparison, the present application greatly saves the amount of ethanol and water, reduces environmental pollution, and more importantly, recovers high-purity diethylene glycol acid, turning waste into treasure; obtains medical-grade carboxymethyl chitosan, and reduces production cost.

[0063] Product detection: The residual amount of diethylene glycol acid in the carboxymethyl chitosan product is detected by high performance liquid chromatography, which is 100μg / g, lower than the standard requirement of 1000μg / g in YY / T 0953-2020; the carboxylation degree of carboxymethyl chitosan is 1.3, and the deacetylation degree is 90%, which meets the medical standard requirements.

[0064] Figure 2 The blank spectrum of the residual amount of diethylene glycol acid in the carboxymethyl chitosan product is shown in the figure. Figure 3 The residual spectrum of diethylene glycol acid in carboxymethyl chitosan is shown in the figure. Figure 4 The purity detection result spectrum of the recovered diethylene glycol acid is shown in the figure.

[0065] The present application is suitable for various production enterprises of carboxymethyl chitosan prepared by using chitosan raw material and adopting chloroacetic acid method, and is particularly suitable for high-standard enterprises that need to produce medical-grade carboxymethyl chitosan. The recovered diethylene glycol acid product can be used as a chemical raw material, a pharmaceutical intermediate, etc., and has a wide market application prospect.

[0066] Example two:

[0067] The method for purifying carboxymethyl chitosan with higher purity and recovering and purifying diethylene glycol acid and alcohol by regulating the ratio of water to ethanol (comparative analysis):

[0068] The same crude product, equipment and basic operation as in Example 1 are used, only the ratio of water to ethanol in the mixed solvent is changed, and five parallel experimental groups are set up:

[0069] Group A: 95% concentration of ethanol (400 kg), purified water (18 kg), water / ethanol = 10%;

[0070] Group B: 95% concentration of ethanol (400 kg), purified water (56 kg), water / ethanol = 20%;

[0071] Group C: 95% concentration of ethanol (400 kg), purified water (94 kg), water / ethanol = 30%;

[0072] Group D: 95% concentration of ethanol (400 kg), purified water (132 kg), water / ethanol = 40%;

[0073] Group E: 95% concentration of ethanol (400 kg), purified water (170 kg), water / ethanol = 50%.

[0074] Results and analysis:

[0075] Table 1 Comparison of purification and recovery results of Example 2

[0076]

[0077] The same crude product, equipment and basic operation as in Example 1 are used, only the ratio of water to ethanol in the mixed solvent is changed, and five parallel experimental groups are set up: when the water / ethanol is less than 20%, the diethylene glycol acid impurities are not fully dissolved, the residual amount of diethylene glycol acid in the carboxymethyl chitosan product is higher than the requirement of 1000 μg / g in YY / T 0953-2020 standard, the carboxymethyl chitosan product does not meet the medical industry standard, and the product is unqualified; when the water / ethanol is higher than 30%, the solubility of the carboxymethyl chitosan product is too large, resulting in a significant decrease in product yield. When the water / ethanol is between 20-30%, the best balance between impurity removal rate and product yield is achieved.

[0078] The industrial application of the method is not only limited to the production of medical grade carboxymethyl chitosan production enterprises, but also can be applied to other chemical processes that need to handle similar by-products. By adjusting the process parameters appropriately, the present application can adapt to different scale, different requirements of industrial production environment, has wide applicability and good popularization value. In addition, the diethylene glycol acid product recovered by the present application can be used in various fields: as an organic synthesis intermediate in the chemical industry; as a pharmaceutical preparation auxiliary in the pharmaceutical industry, which further improves the economic value and market competitiveness of the present application.

[0079] In summary, by optimizing the purification process of carboxymethyl chitosan, the present application introduces the recovery and purification steps of diethylene glycol acid, which not only solves the problem of product safety, but also realizes the comprehensive utilization of resources, conforms to the concept of green chemistry and sustainable development, and has significant economic, environmental and social benefits.

[0080] The principles and implementation modes of the present application are described by applying specific examples in this paper, and the above examples are only used to help understand the method of the present application and its core idea. The above description is only the preferred embodiment of the present application, and it should be pointed out that due to the limitation of language expression, there are infinite specific structures, and for ordinary skilled persons in the technical field, some improvements, refinements or changes can be made without departing from the principles of the present application, and the above technical features can be combined in an appropriate way; these improvements, refinements, changes or combinations, or the direct application of the inventive concept and technical scheme to other occasions without improvement, should be regarded as the protection scope of the present application.

Claims

1. A method for purifying carboxymethyl chitosan, characterized in that, Includes the following steps: A crude carboxymethyl chitosan solution containing carboxymethyl chitosan and its byproducts is provided. After mixing with water and alcohol, the pH is adjusted with hydrochloric acid. The pH-adjusted crude solution is stirred and allowed to stand to dissolve the diethylene glycol acid and its salt in the upper liquid phase. Preliminary purified carboxymethyl chitosan solid was obtained through solid-liquid separation; The carboxymethyl chitosan solid obtained from the preliminary purification was repeated at least once to obtain a high-purity carboxymethyl chitosan solid product.

2. The purification method according to claim 1, characterized in that, The preparation process of the crude carboxymethyl chitosan solution includes: Medical-grade chitosan and chloroacetic acid are carboxymethylated in an alcohol solvent under alkaline conditions at 60-70°C with stirring for 5-10 hours to obtain the product. The mass of the chloroacetic acid is 2-5 times the mass of the medical-grade chitosan; the mass of the alcohol solvent is 10-20 times the mass of the medical-grade chitosan.

3. The purification method according to claim 2, characterized in that, The degree of carboxylation of the carboxylmethyl chitosan in the crude carboxyl chitosan solution is 0.9-1.

8.

4. The purification method according to any one of claims 1-3, characterized in that, After the crude carboxymethyl chitosan solution, water, and alcohol are mixed, the mass ratio of water in the mixed system is 20-30%.

5. The purification method according to claim 4, characterized in that, The alcohol is an ethanol solution with a mass concentration greater than 95%; the pH adjusted with hydrochloric acid is 7-9.

6. The purification method according to any one of claims 1-3, characterized in that, The solid-liquid separation is performed by centrifugation, yielding preliminarily purified carboxymethyl chitosan solid and a separation liquid, respectively. The separated liquid was collected and the pH was adjusted to 3-4 with hydrochloric acid. Then, electrodialysis and concentration were performed sequentially to obtain alcohol-water mixed vapor and diethylene glycol acid concentrate, respectively.

7. The purification method according to claim 6, characterized in that, Also includes: The alcohol-water mixture was distilled to obtain pure alcohol solvent and water, respectively.

8. The purification method according to claim 6, characterized in that, Also includes: The diethylene glycol concentrate was vacuum dried to obtain diethylene glycol solid with a purity greater than 98%.

9. A system for implementing the purification method of carboxymethyl chitosan according to any one of claims 1-5, characterized in that, It includes a mixing and regulating device and a solid-liquid separation device. The mixing and regulating device is used for mixing carboxymethyl chitosan crude product liquid, water and alcohol, as well as stirring and regulating the process. The mixing and regulating device has a liquid outlet at the bottom, which is connected to the solid-liquid separation device.

10. The system according to claim 9, characterized in that, The mixing and regulating device is a temperature-controlled reaction vessel; the solid-liquid separation device is a filtration device or a centrifuge. The system also includes an electrodialysis unit and an evaporation concentration unit connected in series, wherein the electrodialysis unit is connected to the liquid outlet of the solid-liquid separation device.

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