A preparation method of high-sulfonation degree sodium polystyrene sulfonate

Abstract

The present invention belongs to the field of biomedicine technology, relates to the production of pharmaceutical excipients, and specifically relates to a method for preparing high-sulfonated sodium polystyrene sulfonate. Polystyrene powder is dispersed in chloroform and heated to swell, then a sulfonating agent is added to carry out a sulfonation reaction, and then a dehydrating agent is added to continue the sulfonation reaction. After the sulfonation reaction is completed, washing is carried out, and sodium alkali is added to convert the sulfonic acid group into a sodium sulfonate group, and the sulfonating agent is concentrated sulfuric acid or fuming sulfuric acid, the temperature of the sulfonation reaction is 50°C to the boiling point of chloroform, and the dehydrating agent is one or more of acetic anhydride, chloroacetic anhydride, and cyanuric chloride. The preparation method of the present invention can abandon sulfonating agents such as sulfur trioxide and chlorosulfonic acid that are highly polluting and difficult to purchase, reduce the reaction temperature, and the obtained product has qualified color, no special treatment is required, and the degree of sulfonation is high.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, relates to the production of pharmaceutical excipients, and specifically relates to a preparation method of high-sulfonation sodium polystyrene sulfonate. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Sodium polystyrene sulfonate resin is an excipient for controlled-release preparations. The inventors have found that the sulfonation method of sodium polystyrene sulfonate resin has the following problems: 1. The sulfonation degree is not high, resulting in unqualified product exchange rate of the final product; 2. The strong sulfonating agents used to increase the sulfonation degree: sulfur trioxide, chlorosulfonic acid, etc. are not easy to purchase, and the production process is relatively dangerous; 3. The product color is dark brown, resulting in unqualified product properties. Summary of the invention

[0004] In order to solve the shortcomings of the prior art, the purpose of the present invention is to provide a method for preparing sodium polystyrene sulfonate with a high degree of sulfonation, which can abandon the sulfonating agents such as sulfur trioxide and chlorosulfonic acid that are highly polluting and difficult to purchase, reduce the reaction temperature, and the obtained product has qualified color, does not need to be specially treated, and has a high degree of sulfonation.

[0005] In order to achieve the above object, the technical solution of the present invention is:

[0006] On the one hand, a method for preparing highly sulfonated sodium polystyrene sulfonate comprises dispersing polystyrene powder in chloroform and heating to swell it, then adding a sulfonating agent to carry out a sulfonation reaction, then adding a dehydrating agent to continue the sulfonation reaction, washing after the sulfonation reaction is completed, and adding sodium alkali to convert the sulfonic acid group into a sodium sulfonate group to obtain;

[0007] Wherein, the sulfonating agent is concentrated sulfuric acid or fuming sulfuric acid, the temperature of the sulfonation reaction is 50°C to the boiling point of chloroform, and the dehydrating agent is one or more of acetic anhydride, chloroacetic anhydride, and cyanuric chloride.

[0008] In the conventional preparation method of sodium polystyrene sulfonate as a pharmaceutical excipient, the temperature for sulfonation of polystyrene is generally 80-110°C, so a high boiling point solvent ethylene dichloride (boiling point 83°C) is selected. In special cases, it is necessary to evaporate the solvent and heat the reaction during the reaction. At the same time, the present invention has found that the reaction temperature has a greater impact on the color of the product. When the reaction temperature is 80-110°C, the color of sodium polystyrene sulfonate is darker, brown or even dark brown, and the color is unqualified. It is necessary to add acetone or methanol for soaking and bleaching in the post-process treatment, and the process is cumbersome. First, the present invention selects chloroform as a swelling agent in the reaction process, avoiding a class of solvents such as ethylene dichloride, which has low solvent toxicity and is more secure for pharmaceutical excipients. Secondly, the present invention uses 50°C to the boiling point of chloroform as the temperature of the sulfonation reaction. The method provided by the present invention can react at a lower temperature, and is suitable for selecting low-boiling point, low-toxicity chloroform as a swelling agent, which reduces the difficulty of controlling the residual solvent of the product, and the product is more suitable as a pharmaceutical excipient. However, the reduction in reaction temperature affects the efficiency of the sulfonation reaction, thereby further leading to a reduction in the degree of sulfonation. To this end, the present invention further studies that the sulfonation reaction is not only an electrophilic substitution reaction but also a typical exothermic reaction. The sulfonation reaction is an exothermic reversible reaction. Water is generated during the reaction, resulting in a decrease in the concentration of the sulfonating agent; and the presence of water increases the reverse reaction, ultimately resulting in a low degree of sulfonation of the product. Therefore, the present invention adds a dehydrating agent, the generated water is consumed, the reaction moves to the forward direction, and the degree of sulfonation of the product is increased, so that the reaction can be carried out at a lower temperature to obtain a high degree of sulfonation product.

[0009] In summary, in the sulfonation process of the present invention, by adding a dehydrating agent, lowering the reaction temperature, and selecting chloroform as a swelling agent (solvent), the prepared sodium polystyrene sulfonate has a high sulfonation degree and a light color.

[0010] Since the sodium polystyrene sulfonate prepared by the present invention has a higher sulfonation degree and a lighter color, on the other hand, a sodium polystyrene sulfonate is obtained by the above preparation method.

[0011] The third aspect is a use of the above sodium polystyrene sulfonate as a pharmaceutical excipient.

[0012] The beneficial effects of the present invention are:

[0013] In the sulfonation process of preparing sodium polystyrene sulfonate, the present invention reduces the reaction temperature, improves the sulfonation degree (the sulfonation degree is above 95%), has a high yield (above 99.0%), has a light product color, is simple in process, and is more suitable for industrial production. DETAILED DESCRIPTION

[0014] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0015] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and / or combinations thereof.

[0016] In view of the problems that the existing sodium polystyrene sulfonate resin has low sulfonation degree, needs to use strong sulfonating agent, and product color is unqualified during the sulfonation process, the present invention provides a preparation method of sodium polystyrene sulfonate with high sulfonation degree.

[0017] A typical embodiment of the present invention provides a method for preparing sodium polystyrene sulfonate with a high degree of sulfonation, wherein polystyrene powder is dispersed in chloroform and heated to swell, a sulfonating agent is added to carry out a sulfonation reaction, a dehydrating agent is added to continue the sulfonation reaction, washing is performed after the sulfonation reaction is completed, and sodium alkali is added to convert the sulfonic acid group into a sodium sulfonate group, thereby obtaining;

[0018] Wherein, the sulfonating agent is concentrated sulfuric acid or fuming sulfuric acid, the temperature of the sulfonation reaction is 50°C to the boiling point of chloroform, and the dehydrating agent is one or more of acetic anhydride, chloroacetic anhydride, and cyanuric chloride.

[0019] The concentrated sulfuric acid described in the present invention is sulfuric acid with a mass fraction of 96.5-98.5%.

[0020] In the sulfonation process of the present invention, by adding a dehydrating agent, lowering the reaction temperature and selecting chloroform as a swelling agent (solvent), the prepared sodium polystyrene sulfonate has a high sulfonation degree and a light color.

[0021] In some embodiments, the temperature for heating and swelling is 40-50° C. and the swelling time is 30-60 minutes.

[0022] In some embodiments, the sulfonating agent is added dropwise.

[0023] In some embodiments, the sulfonation reaction is carried out by adding the sulfonating agent for 1 to 2 hours, and the sulfonation reaction is carried out by adding the dehydrating agent for 1 to 2 hours.

[0024] In some embodiments, the temperature of the sulfonation reaction is 50-60°C.

[0025] In some embodiments, the mass ratio of the polystyrene powder to the sulfonating agent is 1:2-3.

[0026] In some embodiments, the mass ratio of the polystyrene powder to the dehydrating agent is 1:1-2.

[0027] In some embodiments, after the sulfonation reaction is completed, water or ethanol is added for dilution, and then filtered and then washed with water until neutral.

[0028] The sodium alkali described in the present invention refers to an alkaline compound whose cation is a sodium ion, such as sodium hydroxide, sodium carbonate, etc. In some embodiments, the washed product is added to a sodium alkali solution and soaked for 4 to 7 hours. This method can better convert the sulfonic acid group into a sodium sulfonate group.

[0029] In some embodiments, after the sulfonic acid groups are converted into sodium sulfonate groups, filtration, water washing and drying are sequentially performed at a drying temperature of 70 to 80° C. for 4 to 6 hours.

[0030] Another embodiment of the present invention provides sodium polystyrene sulfonate obtained by the above preparation method.

[0031] A third embodiment of the present invention provides a use of the above sodium polystyrene sulfonate as a pharmaceutical excipient.

[0032] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0033] Example 1: Preparation of sodium polystyrene sulfonate by conventional method

[0034] Put 10.0g polystyrene into a 100mL reaction bottle, add 25mL dichloroethane, and heat to 55℃ for swelling for 30 minutes. Add 19.0g 98% concentrated sulfuric acid dropwise, and heat to 80℃ for reaction for 3h. After the reaction is completed, cool down and dilute with 20mL of water, filter, and wash with water until neutral. Soak in 8% sodium hydroxide solution for 6 hours. Filter, wash with water until neutral, and dry at 80℃ for 5 hours to obtain 16.3g brown powder sodium polystyrene sulfonate, with a yield of 82.3%. Sodium content: 8.9%.

[0035] Example 2: Preparation of sodium polystyrene sulfonate by conventional method

[0036] Put 10.0g polystyrene into a 100mL reaction bottle, add 25mL dichloroethane, heat to 55℃ and swell for 30 minutes. Add 19.0g 98% concentrated sulfuric acid dropwise, heat to 105℃ and react for 3h after dropping, during which the solvent is evaporated under reduced pressure. After the reaction is completed, add 20mL of water to dilute after cooling, filter, and wash with water until neutral. Add 8% sodium hydroxide solution and soak for 6 hours. Filter, wash with water until neutral, and dry at 80℃ for 5 hours to obtain 18.5g of brown powder sodium polystyrene sulfonate, with a yield of 93.4%. Sodium content: 9.4%.

[0037] Example 3: Preparation of sodium polystyrene sulfonate by conventional method

[0038] Put 10.0g polystyrene into a 100mL reaction bottle, add 25mL dichloroethane, heat to 55℃ and swell for 30 minutes. Add 30.0g 20% ​​fuming sulfuric acid dropwise, heat to 105℃ and react for 3h, during which the solvent is evaporated under reduced pressure. After the reaction is completed, cool down and dilute with 20mL of water, filter, and wash with water until neutral. Soak in 8% sodium hydroxide solution for 6 hours. Filter, wash with water until neutral, and dry at 80℃ for 5 hours to obtain 19.1g dark brown powder sodium polystyrene sulfonate, yield: 96.5%. Sodium content: 10.8%.

[0039] Example 4: Preparation of sodium polystyrene sulfonate by the method of the present invention

[0040] Put 10.0g polystyrene into a 100mL reaction bottle, add 25mL chloroform, heat to 45℃ and swell for 30 minutes. Add 19.0g 98% concentrated sulfuric acid dropwise, heat to 55℃ and react for 2h. Add 10.0g acetic anhydride and react, cool down and dilute with 20mL ethanol, filter, and wash with water until neutral. Soak in 8% sodium hydroxide solution for 6 hours. Filter, wash with water until neutral, and dry at 80℃ for 5 hours to obtain 19.6g light brown powder sodium polystyrene sulfonate, yield: 99.0%. Sodium content: 10.6%.

[0041] Example 5: Preparation of sodium polystyrene sulfonate by the method of the present invention

[0042] Put 10.0g polystyrene into a 100mL reaction bottle, add 25mL chloroform, and heat to 45℃ to swell for 30 minutes. Add 19.0g 98% concentrated sulfuric acid, and heat to 55℃ for 2h. Add 14.0g chloroacetic anhydride and keep warm for 2 hours. After the reaction, cool down and dilute with 20mL ethanol, filter, and wash with water until neutral. Soak in 8% sodium hydroxide solution for 6 hours. Filter, wash with water until neutral, and dry at 80℃ for 5 hours to obtain 19.7g light brown powder sodium polystyrene sulfonate, yield: 99.5%. Sodium content: 10.9%.

[0043] Example 6: Preparation of Sodium Polystyrene Sulfonate by the Method of the Present Invention

[0044] Put 10.0g polystyrene into a 100mL reaction bottle, add 25mL chloroform, heat to 45℃ and swell for 30 minutes. Add 30.0g 20% ​​fuming sulfuric acid dropwise, heat to 55℃ and react for 2h. Add 14.0g chloroacetic anhydride and keep warm for 2 hours. After the reaction is completed, cool down and dilute with 20mL ethanol, filter, and wash with water until neutral. Soak in 8% sodium hydroxide solution for 6 hours. Filter, wash with water until neutral, and dry at 80℃ for 5 hours to obtain 19.8g brown powder sodium polystyrene sulfonate, yield: 100.0%. Sodium content: 10.8%.

[0045] Example 7: Preparation of Sodium Polystyrene Sulfonate by the Method of the Present Invention

[0046] Put 10.0g polystyrene into a 100mL reaction bottle, add 25mL chloroform, heat to 45℃ and swell for 30 minutes. Add 19.0g 98% concentrated sulfuric acid, heat to 55℃ and react for 2h. Add 18.0g cyanuric chloride and keep warm for 1 hour. After the reaction, cool down and dilute with 20mL ethanol, filter, and wash with water until neutral. Soak in 8% sodium hydroxide solution for 6 hours. Filter, wash with water until neutral, and dry at 80℃ for 5 hours to obtain 19.8g brown-yellow powder sodium polystyrene sulfonate, yield: 100.0%. Sodium content: 10.7%.

[0047] Schedule:

[0048]

[0049]

[0050] Note: According to the national drug standard (WS1-XG-023-2021), the sodium (Na) content of the product should be 9.4% to 11.0% based on the dry product. The potassium exchange capacity per 1g of the product should be 110 to 135mg.

[0051] As can be seen from the table above, the sulfonation degree of the sample obtained without adding a dehydrating agent in Example 1 is not high, resulting in an unqualified potassium exchange amount in the final product; the temperature increase reaction without adding a dehydrating agent in Examples 2-3 easily leads to a darker product color, resulting in unqualified properties. In Examples 4-7, under the condition of adding a dehydrating agent, the potassium exchange amount of the product obtained by the low-temperature reaction is qualified, and the product color is lighter.

[0052] In summary, the method of the present invention can react at a relatively low temperature to produce a product with a high degree of sulfonation, and the obtained product has a qualified sodium content and potassium exchange amount, a qualified product color, and is suitable for use as a pharmaceutical excipient. The process is suitable for industrialized scale-up production.

[0053] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing high-sulfonation degree sodium polystyrene sulfonate, characterized in that: The polystyrene powder is dispersed in chloroform and heated to swell, and then a sulfonating agent is added to carry out a sulfonation reaction, and then a dehydrating agent is added to continue the sulfonation reaction. After the sulfonation reaction is completed, the polystyrene powder is washed, and sodium alkali is added to convert the sulfonic acid group into a sodium sulfonate group to obtain the polystyrene powder; Wherein, the sulfonating agent is concentrated sulfuric acid or fuming sulfuric acid, the sulfonating agent is added dropwise, the temperature of the sulfonation reaction is 50°C to 60°C, and the dehydrating agent is one or more of acetic anhydride, chloroacetic anhydride, and cyanuric chloride; The mass ratio of polystyrene powder to sulfonating agent is 1:2~3; the mass ratio of polystyrene powder to dehydrating agent is 1:1~2; The time for the sulfonation reaction by adding the sulfonating agent is 1 to 2 hours, and the time for the sulfonation reaction by adding the dehydrating agent is 1 to 2 hours.

2. The method for preparing high-sulfonation degree sodium polystyrene sulfonate according to claim 1, characterized in that: The temperature for heating and swelling is 40~50 ℃.

3. The method for preparing high-sulfonation degree sodium polystyrene sulfonate according to claim 1, characterized in that: After the sulfonation reaction is completed, water or ethanol is added for dilution, and then filtered and then washed with water.

4. The method for preparing high-sulfonation degree sodium polystyrene sulfonate according to claim 1, characterized in that: The washed product is added to a sodium alkali solution and soaked for 4 to 7 hours.

5. The method for preparing high-sulfonation degree sodium polystyrene sulfonate as claimed in claim 1, characterized in that: After the sulfonic acid group is converted into a sodium sulfonate group, filtering, washing with water and drying are performed in sequence.

6. A sodium polystyrene sulfonate, characterized in that: Obtained by the preparation method according to any one of claims 1 to 5.

7. Use of the sodium polystyrene sulfonate according to claim 6 as a pharmaceutical excipient.

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