A method for preparing a low-impurity pharmaceutical grade polyvinylpyrrolidone

Abstract

This invention relates to the field of chemical synthesis technology, specifically to a method for preparing low-impurity pharmaceutical-grade polyvinylpyrrolidone. The method involves mixing water, a catalyst, ammonia, and N-vinylpyrrolidone monomer to remove oxygen, heating under nitrogen protection, and then adding hydrogen peroxide to initiate polymerization. During polymerization, ammonia is used to control the pH value, maintaining the temperature until the desired conversion rate is achieved. Excess ammonia is then removed by vacuum extraction, followed by the addition of acidified cation exchange resin to adjust the pH. The mixture is then kept at a constant temperature and stirred to reduce residual monomer to below 10 ppm. Finally, the cation exchange resin is filtered off, and the product is spray-dried to obtain the final product. This invention provides a safe and efficient preparation process, producing a product with low residual monomer, a colorless and transparent appearance, few impurities, and low ash and peroxide content.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a method for preparing low-impurity pharmaceutical-grade polyvinylpyrrolidone. Background Technology

[0002] Polyvinylpyrrolidone (PVP) is a water-soluble polymer with good dispersibility, adhesion, and safety, making it an important pharmaceutical excipient. However, some impurities remaining or generated during the synthesis process pose a potential threat to the activity or safety of the drug. Therefore, the pharmaceutical industry has made detailed regulations on the impurities of PVP, such as requiring residual monomers to be below 10 ppm, ash content below 0.1%, and formic acid below 0.5%. Due to the extremely high requirements for residual monomer content in products, traditional methods for removing residual monomers are time-consuming and labor-intensive, often accompanied by serious side reactions, leading to problems such as yellowing of the product and increased impurities. There is usually a difficult balance to strike when polymerization conditions are mild, but residual monomers cannot be reduced; when polymerization conditions are harsh, serious side reactions occur. To reduce residual monomers to the desired range while avoiding side reactions, researchers have developed several new solutions. These include vacuum extraction for removing residual monomers, as described in Chinese invention patent CN112210026A, "A Post-processing Method for Polyvinylpyrrolidone (PVP) with Low Vinylpyrrolidone (NVP) Content"; adsorption methods for removing residual monomers, as described in Chinese invention patent CN112661890B, "A Preparation Method of Pharmaceutical Low-Impurity Polyvinylpyrrolidone K30"; US patent US4795802, "Removal of vinylpyrrolidone from vinylpyrrolidone polymers"; and US patents US5239053A, "Purification of vinyl lactam polymers," US5830964A, "Vinyl pyrrolidone polymers substantially free of vinyl lactam monomers," and US2002022699A1, "Adding acid to an aqueous solution of...". The process of removing residual N-vinyl compound polymers (NVPs) involves acid hydrolysis. However, NVPs have boiling points exceeding 200°C, resulting in low efficiency under reduced pressure extraction. The extraction conditions described in the aforementioned patent are demanding and inefficient, hindering industrial application. Adsorption methods are generally inefficient, require highly selective adsorbents, involve large quantities, are costly, and can introduce new ions, increasing ash content. NVPs readily hydrolyze in water, a reaction that can occur at room temperature. Acid acts as a catalyst, significantly accelerating the hydrolysis rate. Acid-based residue removal processes are moderate, resulting in high efficiency and a colorless, transparent product.Inorganic acids are generally strong and efficient, but they eventually turn into ash during ablation, leading to an increase in ash content. Furthermore, the potential adverse effects of the salt residues formed by these inorganic acids on downstream applications remain to be studied. Although organic acids decompose during ablation and have a smaller impact on ash content, they are weaker and are often added in higher quantities than inorganic acids. Similarly, the impurities introduced by organic acids also pose potential risks to subsequent applications.

[0003] Therefore, there is an urgent need for a method to prepare pharmaceutical-grade polyvinylpyrrolidone with low impurities to solve the above-mentioned technical problems. Summary of the Invention

[0004] The purpose of this invention is to overcome the difficulty of balancing residual monomer elimination and impurity control in the production process of pharmaceutical-grade PVP, and to provide a method for preparing low-impurity pharmaceutical-grade polyvinylpyrrolidone. This method uses an acidified cation exchange resin to replace conventional small molecule acids to adjust the pH value of the product, and can quickly reduce residual monomers to below 10 ppm without introducing small molecule acid impurities. The process is simple and efficient, and the prepared polyvinylpyrrolidone has the advantages of being pure and colorless.

[0005] The specific process is as follows: Water, catalyst, ammonia, and N-vinylpyrrolidone monomer (NVP) are mixed to remove oxygen. After heating under nitrogen protection, hydrogen peroxide is added to initiate polymerization. During this process, ammonia is used to control the pH value and maintain the temperature to polymerize to the required conversion rate. Excess ammonia is then removed by vacuum extraction. Subsequently, acidified ion exchange resin is added to adjust the pH value. The residual monomer is reduced to below 10 ppm by stirring and maintaining the temperature. Finally, the ion exchange resin powder is filtered out to obtain the final product.

[0006] A method for preparing low-impurity pharmaceutical-grade polyvinylpyrrolidone includes the following steps: S1, water, catalyst, ammonia, and N-vinylpyrrolidone monomer are mixed to remove oxygen, heated under nitrogen protection, and hydrogen peroxide is added to initiate polymerization; S2, the pH value is controlled by ammonia water, the temperature is maintained to polymerize to the required conversion rate, and then excess ammonia is removed by vacuum extraction; S3, add acidified ion exchange resin to adjust the pH value, keep warm and stir until the residual mononitrate drops to below 10 ppm; S4, ion exchange resin is removed by filtration, and the product is dried by spray drying to obtain the final product.

[0007] Preferably, in step S1, the catalyst is a polyvalent metal ion; the amount of catalyst used is 0.05-1000 ppm of the total reactant mass.

[0008] More preferably, in step S1, the catalyst is a multivalent metal ion such as iron ion or copper ion; the amount of catalyst used is 1-50 ppm of the total reactant mass.

[0009] Specifically, the amount of catalyst used is measured by the metal ions used.

[0010] Preferably, in step S1, the amount of ammonia water used, based on its active ingredient, accounts for 0.1-1% of the total reactant mass.

[0011] Specifically, the active ingredient in ammonia water refers to the monohydrate of ammonia (NH3) in the ammonia water. H2O).

[0012] Preferably, in step S1, the hydrogen peroxide is added at a temperature of 40-70°C.

[0013] More preferably, in step S1, the hydrogen peroxide is added at a temperature of 50-60°C.

[0014] Preferably, in step S2, the pH value of the ammonia water is controlled to be 6-9.

[0015] More preferably, in step S2, the pH value of the ammonia water is controlled to be 7-8.

[0016] Preferably, in step S2, the polymerization temperature is 50-90℃.

[0017] More preferably, in step S2, the polymerization temperature is 60-80℃.

[0018] Preferably, in step S2, the pre-conversion rate needs to be greater than 99.5%.

[0019] More preferably, in step S2, the pre-conversion rate needs to be greater than 99.9%.

[0020] Preferably, in step S2, the pH value after extraction is lower than 5.5. Extraction and deamination can reduce the pH value of the system, thereby reducing the amount of acidified ion exchange resin used, reducing costs and increasing efficiency, and at the same time improving the odor of the final product.

[0021] Preferably, the acidified ion exchange resin is prepared by activating a cation exchange resin, washing it with alkali, washing it with acid, and then washing it with water.

[0022] Specifically, the preparation process of the acidified ion exchange resin is as follows: Activation: Soak the dry cation exchange resin in 10wt% sodium chloride solution overnight to fully swell. After filtration, wash with 80℃ deionized water by stirring. After filtration, add 5wt% dilute hydrochloric acid and stir for 2 hours. After filtration, wash with deionized water to obtain the activated cation exchange resin. Alkali washing: The activated cation exchange resin is treated with 5wt% sodium hydroxide solution to obtain alkali-washed cation exchange resin; Acid washing: After alkaline washing, the cation exchange resin is treated with 5wt% hydrochloric acid solution to obtain acid-washed cation exchange resin; Water washing: The acid-washed cation exchange resin is washed with pure water and then filtered to obtain acidified ion exchange resin.

[0023] Used acidified ion exchange resins can be washed clean and regenerated with a 5wt% hydrochloric acid solution for continued use.

[0024] Preferably, in step S3, the cation exchange resin is a cross-linked polymer.

[0025] Preferably, in step S3, the cation exchange resin is a cross-linked polyelectrolyte carrying anionic groups, commonly containing at least one of sulfonate, phosphate, carboxylate, and sulfate groups.

[0026] Specifically, the cation exchange resin is a sulfonic acid type 732 resin, an aminophosphoric acid type D418 resin, a carboxylic acid type D113 resin, etc.

[0027] Preferably, in step S3, the pH value is adjusted to 1.5-4.5 by acidifying the ion exchange resin.

[0028] More preferably, in step S2, the pH value is adjusted to 3-4 using an acidified ion exchange resin.

[0029] Preferably, in step S3, the heat preservation temperature is 0-90℃.

[0030] More preferably, in step S3, the heat preservation temperature is 30-50℃.

[0031] Beneficial effects: The process of this invention is simple, safe and efficient, and produces products with low residue. It overcomes the problem of acid residue in existing acid treatment processes, and at the same time realizes the elimination of residue and control of impurities in the production process of pharmaceutical-grade PVP. It provides a method for preparing low-impurity pharmaceutical-grade polyvinylpyrrolidone. The prepared polyvinylpyrrolidone is pure and colorless, with a colorless and transparent appearance, few impurities, and low ash and peroxide content. Detailed Implementation

[0032] The present invention will be further described below with reference to specific embodiments. The illustrative embodiments and descriptions herein are used to explain the present invention, but are not intended to limit the present invention.

[0033] The resins used in this embodiment are sulfonic acid type 732 resin, aminophosphoric acid type D418 resin, and carboxylic acid type D113 resin. Before first use, the dry resins are soaked overnight in a 10 wt% sodium chloride solution to fully swell. After filtration, they are washed with 80°C deionized water by stirring. After filtration, 5 wt% dilute hydrochloric acid is added and stirred for 2 hours. After filtration, the resins are washed with deionized water. The resins are then treated with 5 wt% sodium hydroxide solution and 5 wt% hydrochloric acid solution respectively. Finally, they are washed with pure water and filtered for later use. The used resins can be regenerated with 5 wt% hydrochloric acid solution after washing.

[0034] Unacidified resin is resin that has undergone alkaline washing following the above treatment method, skipping the 5 wt% hydrochloric acid treatment and directly being washed and filtered with deionized water. Specifically: before first use, the dry resin is soaked overnight in a 10 wt% sodium chloride solution to fully swell, filtered, and then washed with 80℃ deionized water by stirring. After filtration, 5 wt% dilute hydrochloric acid is added and stirred for 2 hours. After filtration, it is washed with deionized water, then treated with a 5 wt% sodium hydroxide solution, and finally washed with pure water and filtered for later use.

[0035] In the following examples and comparative examples, the concentration of ammonia used was 26 wt%; the concentration of hydrogen peroxide used was 35 wt%.

[0036] Example 1 2700g water, 600g NVP, 18ppm iron ions, and 8ml ammonia were mixed to remove oxygen and heated to 50℃. 20g hydrogen peroxide was added to initiate polymerization. When the system began to polymerize and the temperature exceeded 70℃, cooling water was turned on to maintain the reaction at 70±1℃. After 20 minutes, the remaining 700g NVP was added uniformly over half an hour. The reaction continued for 30 minutes, then 10g hydrogen peroxide was added and the pH was adjusted to 7 with ammonia. The reaction was continued at this temperature for 3 hours, followed by vacuum extraction. An equal amount of deionized water was added based on the amount of extracted material to obtain a PVP polymerization solution with a pH of 5.2. A sample was taken for testing, and the residual ions were 950 ppm. 80g of acidified 732 ion exchange resin was added, and the pH of the system was 3.61. The mixture was then kept at 40℃ and stirred for 1 hour. After filtration, the product was spray-dried to obtain a powder sample with a K value of approximately 30.

[0037] Example 2 2700g of water, 500g of NVP, 20ppm of copper ions, and 10ml of ammonia were mixed to remove oxygen and heated to 60℃. 25g of hydrogen peroxide was added to initiate polymerization. When the system began to polymerize and release heat, causing the temperature to exceed 70℃, cooling water was turned on to maintain the reaction at 70±1℃. After 20 minutes, the remaining 800g of NVP was added uniformly over 30 minutes. The reaction was continued at this temperature for 3 hours, followed by vacuum extraction. An equal amount of deionized water was added based on the amount of material extracted to obtain a PVP polymerization solution with a pH of 5.3. A sample was taken and tested to find a residual concentration of 1530ppm. 400g of acidified 732 ion exchange resin was added, resulting in a pH of 3.02. The mixture was then kept at 40℃ and stirred for 1 hour. After filtration, the product was spray-dried to obtain a powder sample with a K value of approximately 30.

[0038] Example 3 2700g water, 600g NVP, 18ppm iron ions, and 8ml ammonia were mixed to remove oxygen and heated to 50℃. 20g hydrogen peroxide was added to initiate polymerization. When the system began to polymerize and release heat, causing the temperature to exceed 70℃, cooling water was turned on to maintain the reaction at 70±1℃. After 20 minutes, the remaining 700g NVP was added uniformly over half an hour. The reaction continued for 30 minutes, then 10g hydrogen peroxide was added, and the pH was adjusted to 7 with ammonia. The reaction was maintained at this temperature for another 3 hours, followed by vacuum extraction. An equal amount of deionized water was added based on the amount of material extracted, resulting in a PVP polymerization solution with a pH of 4.9. A sample was taken for testing, and the residual ions were 1050 ppm. 800g of acidified D113 ion exchange resin was added, resulting in a pH of 3.96. The mixture was then kept at 50℃ and stirred for 2 hours. After filtration, the product was spray-dried to obtain a powder sample with a K value of approximately 30.

[0039] Example 4 2700g water, 600g NVP, 18ppm iron ions, and 8ml ammonia were mixed to remove oxygen and heated to 50℃. 20g hydrogen peroxide was added to initiate polymerization. When the system began to polymerize and release heat, causing the temperature to exceed 70℃, cooling water was turned on to maintain the reaction at 70±1℃. After 20 minutes, the remaining 700g NVP was added uniformly over half an hour. The reaction continued for 30 minutes, then 10g hydrogen peroxide was added, and the pH was adjusted to 7 with ammonia. The reaction was maintained at this temperature for another 3 hours, followed by vacuum extraction. An equal amount of deionized water was added based on the amount of material extracted to obtain a PVP polymerization solution with a pH of 5.0. A sample was taken for testing, and the residual ions were 900 ppm. 400g of acidified D418 ion exchange resin was added, resulting in a pH of 3.75. The mixture was then kept at 40℃ and stirred for 2 hours. After filtration, the product was spray-dried to obtain a powder sample with a K value of approximately 30.

[0040] Comparative Example 1 2700g water, 600g NVP, 18ppm iron ions, and 8ml ammonia were mixed to remove oxygen and heated to 50℃. 20g hydrogen peroxide was added to initiate polymerization. When the system began to polymerize and release heat, causing the temperature to exceed 70℃, cooling water was turned on to maintain the reaction at 70±1℃. After 20 minutes, the remaining 700g NVP was added uniformly over half an hour. The reaction continued for 30 minutes, then 10g hydrogen peroxide was added, and the pH was adjusted to 7 with ammonia. The reaction was continued at this temperature for 3 hours, followed by vacuum extraction. An equal amount of deionized water was added based on the amount of extracted material to obtain a PVP polymerization solution with a pH of 5.0. A sample was taken for testing, and the residual ions were 1120 ppm. 80g of untreated 732 ion exchange resin was added, resulting in a pH of 6.1. The mixture was then kept at 40℃ and stirred for 1 hour. After filtration, the product was spray-dried to obtain a powder sample with a K value of approximately 30.

[0041] Comparative Example 2 2700g water, 600g NVP, 18ppm iron ions, and 8ml ammonia were mixed to remove oxygen and heated to 50℃. 20g hydrogen peroxide was added to initiate polymerization. When the system began to polymerize and the temperature exceeded 70℃, cooling water was turned on to maintain the reaction at 70±1℃. After 20 minutes, the remaining 700g NVP was added uniformly over half an hour. The reaction continued for 30 minutes, then 10g hydrogen peroxide was added and the pH was adjusted to 7 with ammonia. The reaction was continued at this temperature for 3 hours, followed by vacuum extraction. An equal amount of deionized water was added based on the amount of material extracted to obtain a PVP polymerization solution with a pH of 5.1. A sample was taken for testing, and the residual ions were 1040 ppm. Dilute sulfuric acid was added to adjust the pH to 3.5, and the mixture was stirred at 40℃ for 1 hour. After filtration, the product was spray-dried to obtain a powder sample with a K value of approximately 30.

[0042] Comparative Example 3 2700g water, 600g NVP, 18ppm iron ions, and 8ml ammonia were mixed to remove oxygen, and the mixture was heated to 50℃. 20g hydrogen peroxide was added to initiate polymerization. Once the system began to polymerize exothermically and the temperature exceeded 70℃, cooling water was turned on to maintain the reaction at 70±1℃. After 20 minutes, the remaining 700g NVP was added uniformly over half an hour, and the reaction continued for 30 minutes. Then, 10g hydrogen peroxide was added, and the pH was adjusted to 7 with ammonia. The reaction was continued at this temperature, with 4g hydrogen peroxide added every 2 hours, and the pH maintained between 6.5 and 7 with ammonia until the residual NVP was below 10ppm. The resulting PVP solution was spray-dried to obtain a sample with a K value of approximately 30.

[0043] The samples prepared in the examples and comparative examples were tested, and the test results of each example and comparative example are shown in Table 1.

[0044] Table 1

[0045] Compared with conventional preparation methods, the product synthesized by the present invention has a lower color, lower impurity and ash content. Compared with existing adsorption technologies, the present invention has a higher residue removal efficiency with the same amount of resin, and a significant reduction in ash content compared with existing acid residue removal processes.

[0046] The embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments.

[0047] The technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made in accordance with the technical solutions of the present invention fall within the protection scope of the present invention.

Claims

1. A method for preparing low-impurity pharmaceutical-grade polyvinylpyrrolidone, characterized in that, Includes the following steps: S1, water, catalyst, ammonia, and N-vinylpyrrolidone monomer are mixed to remove oxygen, heated under nitrogen protection, and hydrogen peroxide is added to initiate polymerization; S2, the pH value is controlled by ammonia water, the temperature is maintained to polymerize to the required conversion rate, and then excess ammonia is removed by vacuum extraction; S3, add acidified ion exchange resin to adjust the pH value, keep warm and stir until the residual mononitrate drops to below 10 ppm; S4, ion exchange resin is removed by filtration, and the product is dried by spray drying to obtain the final product.

2. The method for preparing low-impurity pharmaceutical-grade polyvinylpyrrolidone according to claim 1, characterized in that: In step S1, the catalyst is a polyvalent metal ion; the amount of catalyst used is 0.05-1000 ppm of the total reactant mass.

3. The method for preparing low-impurity pharmaceutical-grade polyvinylpyrrolidone according to claim 1, characterized in that: In step S1, the amount of ammonia water used, based on its active ingredient, accounts for 0.1-1% of the total reactant mass.

4. The method for preparing low-impurity pharmaceutical-grade polyvinylpyrrolidone according to claim 1, characterized in that: In step S1, the hydrogen peroxide is added at a temperature of 40-70℃.

5. The method for preparing low-impurity pharmaceutical-grade polyvinylpyrrolidone according to claim 1, characterized in that: In step S2, the pH value of the ammonia water is controlled to be 6-9.

6. The method for preparing low-impurity pharmaceutical-grade polyvinylpyrrolidone according to claim 1, characterized in that: In step S2, the polymerization temperature is 50-90℃.

7. The method for preparing low-impurity pharmaceutical-grade polyvinylpyrrolidone according to claim 1, characterized in that: In step S2, the pre-conversion rate must be greater than 99.5%.

8. The method for preparing low-impurity pharmaceutical-grade polyvinylpyrrolidone according to claim 1, characterized in that: In step S3, the acidified ion exchange resin is prepared by activating, alkali washing, acid washing and then water washing of cation exchange resin.

9. The method for preparing a low-impurity pharmaceutical-grade polyvinylpyrrolidone according to claim 8, characterized in that: In step S3, the cation exchange resin is a cross-linked polymer containing at least one of sulfonate, phosphate, carboxylate, and sulfate groups.

10. The method for preparing a low-impurity pharmaceutical-grade polyvinylpyrrolidone according to claim 1, characterized in that: In step S3, the pH value is adjusted to 1.5-4.5 using an acidified ion exchange resin; in step S3, the heat preservation temperature is 0-90℃.

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