A method for continuous crystallization of ibuprofen

Abstract

A continuous crystallization production method of ibuprofen, comprising the following steps: placing an aqueous solution of sodium ibuprofen into an electrodialysis device, controlling the temperature at a first temperature, controlling the outlet pH at 7.0-7.5, and obtaining a first crystallization solution; then removing and placing an acid solution, adjusting the pH to 6.0-6.5, controlling the temperature at a second temperature, and obtaining a second crystallization solution; placing the second crystallization solution into the electrodialysis device, and obtaining a third crystallization solution; then removing and continuously placing the acid solution, and obtaining a fourth crystallization solution; filtering and recovering the fourth crystallization solution, and obtaining crystalline ibuprofen after washing. The application uses the obtained sodium ibuprofen as the feed, then obtains the second crystallization solution through the acidification of the electrodialysis and the acidification of the acid solution, then performs the electrodialysis again, and finally adds the acid solution, so that the overall crystallization process is controllable and the nucleation does not burst.

Description

Technical Field

[0001] This application relates to a method for the continuous crystallization production of ibuprofen. Background Technology

[0002] Ibuprofen has good efficacy in anti-inflammatory, antipyretic, and analgesic effects, and has recently received increasing attention, especially for its effectiveness in reducing fever. Currently, there are two main methods for synthesizing ibuprofen: intermittent crystallization and continuous crystallization. The main problem with intermittent crystallization is its low operating efficiency and the need for a large number of seed crystals. Continuous crystallization, on the other hand, often uses a reaction-to-oil process followed by stepwise crystallization. The main challenge is the need for precise stepwise control of pH and temperature. Insufficient adjustment or uniformity of pH or temperature during the process can lead to seed crystal accumulation in the crystallizer, or even problems like explosive nucleation, which are common in intermittent crystallization. Explosive nucleation is a major obstacle affecting the quality of ibuprofen products. Summary of the Invention

[0003] To address the aforementioned problems, this application proposes a method for the continuous crystallization production of ibuprofen, comprising the following steps:

[0004] An aqueous solution of ibuprofen sodium salt was placed into an electrodialysis device, the temperature was controlled at the first temperature, and the outlet pH was controlled at 7.0-7.5 to obtain the first crystallization solution.

[0005] Then, remove it and put it back into the acid solution to adjust the pH to 6.0-6.5, and control the temperature at the second temperature to obtain the second crystallization solution;

[0006] The second crystallization solution is placed into an electrodialysis device, the temperature is controlled at the first temperature, and the outlet pH is controlled at 5.0-5.5 to obtain the third crystallization solution;

[0007] Then, after removing it, continue to put it into acid solution, adjust the pH to below 3.0, and control the temperature at the second temperature to obtain the fourth crystallization solution;

[0008] The fourth crystallization solution was filtered and recovered, and after rinsing, crystalline ibuprofen was obtained. In this application, ibuprofen sodium salt (concentration of approximately 0.06 g / mL) obtained from the reaction was used as feed, and then the second crystallization solution was obtained by electrodialysis acidification and acid solution acidification. Electrodialysis was then performed to obtain raw materials that can be used as nucleation sites for crystallization. Finally, acid solution was added. The overall crystallization process is controllable and will not cause explosive nucleation.

[0009] Preferably, a filter screen with a mesh size of 300 is provided after the second crystallization liquid. By setting a filter screen before the third crystallization, this application can avoid the introduction of crystal components before the third crystallization, ensuring the consistency of crystal seed size and also helping to ensure the crystal quality of ibuprofen.

[0010] Preferably, the electrodialysis device is a bipolar membrane electrodialysis device with a flow rate of 5-10 L / h and a current density of 50-100 mA / cm². 2 .

[0011] Preferably, the first temperature is 70-80℃ and the second temperature is 35-40℃.

[0012] Preferably, the fourth crystallization solution is obtained in the following manner:

[0013] The third crystallization solution is transferred into the crystallizer, and the material in the crystallizer is thoroughly stirred. During stirring, the acid solution is evenly sprayed into the crystallizer and stirred continuously until the pH is adjusted to between 2.5 and 3.0. Then, stirring is continued for 15-30 minutes before recovery.

[0014] Preferably, the filtration and recovery are carried out in the following manner: the fourth crystallization liquid is transferred into a centrifugal filter, the obtained filter material is removed, and then the filter material is rinsed, washed, and dried to obtain crystalline ibuprofen.

[0015] Preferably, the crystallizer includes a cavity, inside which a stirrer is installed. The stirrer is connected to a stirring motor, and the cavity wall has several injection holes for introducing acid. In this application, during the stirring process, the stirrer ensures the uniformity of the internal materials, and the acid is introduced evenly and slowly into the cavity through the injection holes on the cavity wall, thereby avoiding explosive nucleation and ensuring the quality of the crystals.

[0016] Preferably, an acid-containing outer cavity is provided on the outside of the cavity wall, and a plurality of outlet pipes are provided on the acid-containing outer cavity, the outlet pipes being connected to the cavity through injection holes.

[0017] Preferably, an electrically controlled valve is provided on the outlet pipe.

[0018] Preferably, the acid solution is 10 wt% hydrochloric acid.

[0019] This application can bring the following beneficial effects:

[0020] 1. This application uses ibuprofen sodium salt (concentration of about 0.06 g / mL) obtained from the reaction as feed, and then obtains a second crystallization solution by electrodialysis acidification and acid solution acidification. Then, electrodialysis is performed to obtain raw materials that can be used as nucleation material for crystallization. Finally, acid solution is added. The overall crystallization process is controllable and will not burst nucleation.

[0021] 2. By setting a filter screen before the three crystallizations, this application can prevent the introduction of crystal components before the three crystallizations, ensuring the consistency of crystal seed size and also helping to ensure the crystal quality of ibuprofen.

[0022] 3. In the stirring process of this application, the uniformity of the internal materials is ensured by stirring with a stirrer, and the materials are introduced into the cavity evenly and slowly through the injection holes on the cavity wall, thereby avoiding explosive nucleation and ensuring the quality of the crystals. Attached Figure Description

[0023] The accompanying drawings, which are included to provide a further understanding of this application and form part of this application, illustrate exemplary embodiments and are used to explain this application, but do not constitute an undue limitation of this application. In the drawings:

[0024] Figure 1 This is a schematic diagram of the crystallizer. Detailed Implementation

[0025] To clearly illustrate the technical features of this solution, the following detailed description, in conjunction with the accompanying drawings, will be provided.

[0026] Regarding the production method, a method for producing ibuprofen through continuous crystallization includes the following steps:

[0027] S1. Ibuprofen sodium salt aqueous solution (concentration 0.06 g / mL) is placed into the electrodialysis device, the temperature is controlled at 70-80℃, and the outlet pH is controlled at 7.0-7.5 to obtain the first crystallization solution;

[0028] The electrodialysis device is a bipolar membrane electrodialysis device with a flow rate of 5-10 L / h and a current density of 50-100 mA / cm². 2 .

[0029] S2 is then removed and replaced with 10wt% hydrochloric acid to adjust the pH to 6.0-6.5, while maintaining the temperature at 35-40℃ to obtain the second crystallization solution.

[0030] A filter screen with a mesh size of 300 is provided after the second crystallization liquid.

[0031] S3 places the second crystallization solution into the electrodialysis device, controls the temperature at 70-80℃, and controls the outlet pH at 5.0-5.5 to obtain the third crystallization solution;

[0032] S4 was then removed and 10wt% hydrochloric acid was added to adjust the pH to below 3.0. The temperature was controlled at 35-40℃ to obtain the fourth crystallization solution.

[0033] The fourth crystallization solution is obtained as follows:

[0034] The third crystallization solution is transferred into the crystallizer, and the material in the crystallizer is thoroughly stirred. During stirring, the acid solution is evenly sprayed into the crystallizer and stirred continuously until the pH is adjusted to between 2.5 and 3.0. Then, stirring is continued for 15-30 minutes before recovery.

[0035] S5 filters and recovers the fourth crystallization liquid, and after rinsing, obtains crystalline ibuprofen.

[0036] The fourth crystallization solution was transferred into a centrifugal filter, the resulting filter material was removed, and then the filter material was rinsed, washed, and dried to obtain crystalline ibuprofen.

[0037] For crystallizers, such as Figure 1 As shown, the crystallizer includes a cavity 1, inside which a stirrer 2 is installed. The stirrer 2 is connected to a stirring motor 3. Several injection holes 4 for introducing acid are provided on the cavity wall of the cavity 1. An acid-containing outer cavity 7 is provided on the outer side of the cavity wall, and several outlet pipes 5 are provided on the acid-containing outer cavity 7. The outlet pipes 5 are connected to the cavity 1 through the injection holes 4. An electrically controlled valve 6 is installed on the outlet pipes 5. In use, the acid in the acid-containing outer cavity is supplied and pressurized, and then the introduction and closure of the acid inside the crystallizer are controlled by opening and closing the electrically controlled valves.

[0038] This application illustrates the advantages of using the method described in this application through the following embodiments and comparative examples:

[0039] Example 1:

[0040] S101 Ibuprofen sodium salt aqueous solution (concentration 0.06 g / mL) is placed into the electrodialysis device, the temperature is controlled at 70℃, and the outlet pH is controlled at 7.0-7.5 to obtain the first crystallization solution;

[0041] The electrodialysis device is a bipolar membrane electrodialysis device with a flow rate of 5 L / h and a current density of 50 mA / cm². 2 .

[0042] S102 is then removed and replaced with 10wt% hydrochloric acid to adjust the pH to 6.0-6.5. The temperature is controlled at 35℃ to obtain the second crystallization solution.

[0043] A filter screen with a mesh size of 300 is provided after the second crystallization liquid.

[0044] S103 The second crystallization solution is placed into the electrodialysis device, the temperature is controlled at 70℃, and the outlet pH is controlled at 5.0-5.5 to obtain the third crystallization solution;

[0045] S104 was then removed and 10wt% hydrochloric acid was added to adjust the pH to below 3.0. The temperature was controlled at 35℃ to obtain the fourth crystallization solution.

[0046] The fourth crystallization solution is obtained as follows:

[0047] The third crystallization solution is transferred into the crystallizer, and the material in the crystallizer is thoroughly stirred. During stirring, the acid solution is evenly sprayed into the crystallizer and stirred continuously until the pH is adjusted to between 2.5 and 3.0. Then, stirring is continued for 15 minutes before recovery.

[0048] S105 filters and recovers the fourth crystallization liquid, and after rinsing, obtains crystalline ibuprofen.

[0049] The fourth crystallization solution was transferred into a centrifugal filter, the resulting filter material was removed, and then the filter material was rinsed, washed, and dried to obtain crystalline ibuprofen.

[0050] The average particle size of the crystalline ibuprofen was 175 μm, with a purity of 99.9% and a yield of 99.4% based on ibuprofen sodium salt.

[0051] Example 2:

[0052] S201 Ibuprofen sodium salt aqueous solution (concentration 0.06 g / mL) is placed into the electrodialysis device, the temperature is controlled at 80℃, and the outlet pH is controlled at 7.0-7.5 to obtain the first crystallization solution;

[0053] The electrodialysis device is a bipolar membrane electrodialysis device with a flow rate of 10 L / h and a current density of 100 mA / cm². 2 .

[0054] S202 is then removed and replaced with 10wt% hydrochloric acid to adjust the pH to 6.0-6.5. The temperature is controlled at 40℃ to obtain the second crystallization solution.

[0055] A filter screen with a mesh size of 300 is provided after the second crystallization liquid.

[0056] S203 The second crystallization solution is put into the electrodialysis device, the temperature is controlled at 80℃, and the outlet pH is controlled at 5.0-5.5 to obtain the third crystallization solution;

[0057] After removing S204, add 10wt% hydrochloric acid to adjust the pH to below 3.0 and control the temperature at 35-40℃ to obtain the fourth crystallization solution.

[0058] The fourth crystallization solution is obtained as follows:

[0059] The third crystallization solution is transferred into the crystallizer, and the material in the crystallizer is thoroughly stirred. During stirring, the acid solution is evenly sprayed into the crystallizer and stirred continuously until the pH is adjusted to between 2.5 and 3.0. Then, stirring is continued for 30 minutes before recovery.

[0060] S205 filters and recovers the fourth crystallization liquid, and after rinsing, obtains crystalline ibuprofen.

[0061] The fourth crystallization solution was transferred into a centrifugal filter, the resulting filter material was removed, and then the filter material was rinsed, washed, and dried to obtain crystalline ibuprofen.

[0062] The average particle size of the crystalline ibuprofen was 188 μm, with a purity of 99.9% and a yield of 99.7% based on ibuprofen sodium salt.

[0063] Comparative Example 1:

[0064] S301: Ibuprofen sodium salt aqueous solution (concentration 0.06 g / mL) is placed into the electrodialysis device, the temperature is controlled at 35℃, and the outlet pH is controlled at 7.0-7.5 to obtain the first crystallization solution;

[0065] The electrodialysis device is a bipolar membrane electrodialysis device with a flow rate of 5 L / h and a current density of 50 mA / cm². 2 .

[0066] S302 is then removed and replaced with 10wt% hydrochloric acid to adjust the pH to 6.0-6.5. The temperature is controlled at 35℃ to obtain the second crystallization solution.

[0067] A filter screen with a mesh size of 300 is provided after the second crystallization liquid.

[0068] S103 The second crystallization solution is placed into the electrodialysis device, the temperature is controlled at 35℃, and the outlet pH is controlled at 5.0-5.5 to obtain the third crystallization solution;

[0069] S304 was then removed and 10 wt% hydrochloric acid was added to adjust the pH to below 3.0. The temperature was controlled at 35°C to obtain the fourth crystallization solution.

[0070] The fourth crystallization solution is obtained as follows:

[0071] The third crystallization solution is transferred into the crystallizer, and the material in the crystallizer is thoroughly stirred. During stirring, the acid solution is evenly sprayed into the crystallizer and stirred continuously until the pH is adjusted to between 2.5 and 3.0. Then, stirring is continued for 15 minutes before recovery.

[0072] S305 filters and recovers the fourth crystallization liquid, and after rinsing, obtains crystalline ibuprofen.

[0073] The fourth crystallization solution was transferred into a centrifugal filter, the resulting filter material was removed, and then the filter material was rinsed, washed, and dried to obtain crystalline ibuprofen.

[0074] The average particle size of the crystalline ibuprofen was 351 μm, with a purity of 99.9% and a yield of 97.7% based on ibuprofen sodium salt.

[0075] Comparative Example 2:

[0076] S401 adds ibuprofen sodium salt aqueous solution (concentration 0.06 g / mL) to 10 wt% hydrochloric acid, controls the temperature at 70℃, and controls the outlet pH at 7.0-7.5 to obtain the first crystallization solution;

[0077] S402 was then removed and replaced with 10wt% hydrochloric acid to adjust the pH to 6.0-6.5. The temperature was controlled at 35℃ to obtain the second crystallization solution.

[0078] A filter screen with a mesh size of 300 is provided after the second crystallization liquid.

[0079] S403 adds the second crystallization solution to 10wt% hydrochloric acid, controls the temperature at 70℃, and controls the outlet pH at 5.0-5.5 to obtain the third crystallization solution;

[0080] After removing S404, 10wt% hydrochloric acid was added to adjust the pH to below 3.0 and the temperature was controlled at 35℃ to obtain the fourth crystallization solution.

[0081] The fourth crystallization solution is obtained as follows:

[0082] The third crystallization solution is transferred into the crystallizer, and the material in the crystallizer is thoroughly stirred. During stirring, the acid solution is evenly sprayed into the crystallizer and stirred continuously until the pH is adjusted to between 2.5 and 3.0. Then, stirring is continued for 15 minutes before recovery.

[0083] S405 filters and recovers the fourth crystallization liquid, and after rinsing, obtains crystalline ibuprofen.

[0084] The fourth crystallization solution was transferred into a centrifugal filter, the resulting filter material was removed, and then the filter material was rinsed, washed, and dried to obtain crystalline ibuprofen.

[0085] The average particle size of the crystalline ibuprofen was 515 μm, with a purity of 99.9% and a yield of 93.1% based on ibuprofen sodium salt.

[0086] Comparative Example 3:

[0087] S501 adds ibuprofen sodium salt aqueous solution (concentration 0.06 g / mL) to 10 wt% hydrochloric acid, controls the temperature at 35℃, and controls the outlet pH at 7.0-7.5 to obtain the first crystallization solution;

[0088] S502 is then removed and 10wt% hydrochloric acid is added to adjust the pH to 6.0-6.5. The temperature is controlled at 35℃ to obtain the second crystallization solution.

[0089] A filter screen with a mesh size of 300 is provided after the second crystallization liquid.

[0090] S503 adds the second crystallization solution to 10wt% hydrochloric acid, controls the temperature at 35℃, and controls the outlet pH at 5.0-5.5 to obtain the third crystallization solution;

[0091] After removing S504, 10wt% hydrochloric acid was added to adjust the pH to below 3.0 and the temperature was controlled at 35℃ to obtain the fourth crystallization solution.

[0092] The fourth crystallization solution is obtained as follows:

[0093] The third crystallization solution is transferred into the crystallizer, and the material in the crystallizer is thoroughly stirred. During stirring, the acid solution is evenly sprayed into the crystallizer and stirred continuously until the pH is adjusted to between 2.5 and 3.0. Then, stirring is continued for 15 minutes before recovery.

[0094] S505 filters and recovers the fourth crystallization liquid, and after rinsing, obtains crystalline ibuprofen.

[0095] The fourth crystallization solution was transferred into a centrifugal filter, the resulting filter material was removed, and then the filter material was rinsed, washed, and dried to obtain crystalline ibuprofen.

[0096] The average particle size of the crystalline ibuprofen was 422 μm, with a purity of 99.9% and a yield of 96.8% based on ibuprofen sodium salt.

[0097] The above are merely embodiments of this application and are not intended to limit the scope of this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the scope of the claims of this application.

Claims

1. A process for the continuous crystallization of ibuprofen, characterized in that: It comprises the following steps: Put the sodium ibuprofen aqueous solution into an electrodialysis device, control the temperature at a first temperature, control the outlet pH at 7.0-7.5, and obtain a first crystallization liquid; Then remove it and put it into an acid solution, adjust the pH to 6.0-6.5, control the temperature at a second temperature, and obtain a second crystallization liquid; Put the second crystallization liquid into the electrodialysis device, control the temperature at the first temperature, and control the outlet pH at 5.0-5.5 to obtain a third crystallization liquid; Then remove it and continue to put it into an acid solution, adjust the pH to below 3.0, control the temperature at the second temperature, and obtain a fourth crystallization liquid; Filter and recover the fourth crystallization liquid, and obtain crystalline ibuprofen after washing; The fourth crystallization liquid is obtained as follows: Put the third crystallization liquid into a crystallizer, fully stir the material in the crystallizer, spray the acid solution uniformly into the crystallizer during stirring, and continuously fully stir until the pH is adjusted to 2.5-3.0, then continue to stir for 15-30 min, and then recover; The crystallizer comprises a cavity, a stirrer is arranged in the cavity, the stirrer is connected with a stirring motor, and a plurality of injection holes for introducing the acid solution are arranged on the cavity wall of the cavity; A filter screen is arranged after the second crystallization liquid, and the mesh number of the filter screen is 300.

2. The process for continuous crystallization of ibuprofen according to claim 1, characterized in that: The electrodialysis device is a bipolar membrane electrodialysis device, the flow rate is 5-10 L / h, and the current density is 50-100 mA / cm 2 .

3. The method for continuous crystallization of ibuprofen according to claim 1, characterized in that: The first temperature is 70-80℃, and the second temperature is 35-40℃.

4. The method for continuous crystallization of ibuprofen according to claim 1, characterized in that: The filtering and recovering are performed as follows: move the fourth crystallization liquid into a centrifugal filter, remove the obtained filtrate, then wash and dry the filtrate to obtain crystalline ibuprofen.

5. The method of claim 1, wherein the method is characterized by: An acid solution containing outer cavity is arranged outside the cavity wall, a plurality of outlet pipelines are arranged on the acid solution containing outer cavity, and the outlet pipelines are connected with the cavity through the injection holes.

6. The process for continuous crystallization of ibuprofen according to claim 5, characterized in that: An electric control valve is arranged on the outlet pipeline.

7. The method of claim 1, wherein the method is characterized by: The acid solution is 10wt% hydrochloric acid.

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