A method for producing a clathrate pharmaceutical
By employing multiple crystallization and stirring control methods, the problem of ibuprofen concentration fluctuations in the human body was solved, achieving stability in drug release and improving crystal quality, while simplifying the production process.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANDONG XINHUA PHARMA CO LTD
- Filing Date
- 2023-07-10
- Publication Date
- 2026-04-17
AI Technical Summary
The concentration of ibuprofen in the human body fluctuates greatly, resulting in unstable efficacy and potential harm to the human body. Existing sustained-release methods prolong the synthesis process and increase costs.
A solution of ibuprofen sodium salt pre-added with cyclodextrin was used. The pH value and temperature were controlled by electrodialysis acidification and acid solution acidification. Multiple crystallizations were carried out. A filter screen and a stirrer were set up to ensure the uniformity and quality of the crystals.
This method achieves good uniformity of ibuprofen inclusion complexes, avoids explosive nucleation, ensures crystal quality and drug release stability, and reduces synthesis steps and costs.
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Figure CN116688154B_ABST
Abstract
Description
Technical Field
[0001] This application relates to a method for producing an inclusion compound pharmaceutical product. Background Technology
[0002] Ibuprofen has good efficacy in anti-inflammatory, antipyretic, and analgesic effects, and has recently received increasing attention due to its effectiveness in reducing fever. However, since ibuprofen is an immediate-acting antipyretic, its effectiveness generally lasts for several hours. Furthermore, considering the large fluctuations in ibuprofen concentration in the body, it can easily cause harm. Several patents have been developed to improve ibuprofen to achieve a sustained-release effect. CN108992422A describes a synthesis method primarily using β-cyclodextrin and mannitol as excipients. Since this method requires the prior preparation of ibuprofen before synthesizing the product, it undoubtedly prolongs the overall synthesis process and increases the overall cost. Summary of the Invention
[0003] To address the aforementioned problems, this application proposes a method for producing an inclusion compound drug, comprising the following steps:
[0004] Cyclodextrin was added to an aqueous solution of ibuprofen sodium salt at the saturated concentration of cyclodextrin at the first temperature, and then 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, ibuprofen inclusion complex was obtained. This application uses pre-added cyclodextrin, and uses cyclodextrin and the ibuprofen sodium salt obtained from the reaction (concentration approximately 0.06 g / mL) as feed. Then, a second crystallization solution is obtained through electrodialysis acidification and acid treatment. Electrodialysis is then performed to obtain a raw material that can be used as a nucleation site for crystallization. Finally, acid is added for final crystallization. The overall inclusion process is controllable, with good uniformity and no explosive nucleation.
[0009] Preferably, a filter screen with a mesh size of 100 is provided after the second crystallization liquid. By providing a filter screen before the third crystallization, this application can avoid introducing crystal components before the third crystallization, ensuring the consistency of crystal seed size and also helping to ensure the crystal quality of the ibuprofen inclusion complex.
[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 50-55℃.
[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 ibuprofen inclusion complex.
[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 cyclodextrin pre-added, and uses cyclodextrin and ibuprofen sodium salt (concentration of about 0.06 g / mL) obtained from the reaction as feed. Then, the second crystallization solution is obtained by electrodialysis acidification and acid solution acidification. Then, electrodialysis is performed to obtain raw materials that can be used as crystal nucleation. Finally, acid solution is added for final crystallization. The overall inclusion process is controllable, with good uniformity and no explosive nucleation.
[0021] 2. By setting a filter screen before the three crystallizations, this application can avoid introducing crystal components before the three crystallizations, ensuring the consistency of crystal seed size and also helping to ensure the crystal quality of ibuprofen inclusion complex.
[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 of this application 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 manufacturing method, a method for manufacturing an inclusion compound drug includes the following steps:
[0027] S1. Ibuprofen sodium salt aqueous solution is added with cyclodextrin at the saturation concentration of cyclodextrin at 70-80℃, and then placed into an 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. The temperature is controlled at 50-55℃ to obtain the second crystallization solution.
[0030] A filter screen with a mesh size of 100 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 50-55℃ 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 ibuprofen inclusion complex.
[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 ibuprofen inclusion complex.
[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 Add cyclodextrin to ibuprofen sodium salt aqueous solution (concentration 0.06 g / mL) according to the saturation concentration of cyclodextrin at 70℃, and then put it into an 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 100 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 ibuprofen inclusion complex.
[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 ibuprofen inclusion complex.
[0050] The average particle size of the ibuprofen inclusion complex was 336 μm, and the yield based on ibuprofen sodium salt was 87.4%. Release efficiency was tested using in vitro release assays: the cumulative drug release was 38% at 5 hours, 69% at 10 hours, 85% at 15 hours, 93% at 20 hours, and 93% at 24 hours.
[0051] Example 2:
[0052] S201 Add cyclodextrin to ibuprofen sodium salt aqueous solution (concentration 0.06 g / mL) according to the saturation concentration of cyclodextrin at 80℃, and then put it into an 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 100 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 50-55℃ 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 ibuprofen inclusion complex.
[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 ibuprofen inclusion complex.
[0062] The average particle size of the ibuprofen inclusion complex was 297 μm, and the yield based on ibuprofen sodium salt was 90.1%. Release efficiency was tested using in vitro release assays: the cumulative drug release was 35% at 5 hours, 64% at 10 hours, 81% at 15 hours, 92% at 20 hours, and 92% at 24 hours.
[0063] Comparative Example 1:
[0064] S301 adds cyclodextrin to an ibuprofen sodium salt aqueous solution (concentration 0.06 g / mL) according to the saturation concentration of cyclodextrin at 35°C, and then puts it into an electrodialysis device. The temperature is controlled at 35°C 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 100 is provided after the second crystallization liquid.
[0068] S303 introduces the second crystallization solution into an electrodialysis device, controls the temperature at 35℃, and controls the outlet pH 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 ibuprofen inclusion complex.
[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 ibuprofen inclusion complex.
[0074] The average particle size of the ibuprofen inclusion complex was 451 μm, and the yield based on ibuprofen sodium salt was 78.5%. Release efficiency was tested using in vitro release assays: the cumulative drug release was 42% at 5 hours, 83% at 10 hours, 90% at 15 hours, 92% at 20 hours, and 92% at 24 hours.
[0075] Comparative Example 2:
[0076] S401 adds cyclodextrin to an ibuprofen sodium salt aqueous solution (concentration 0.06 g / mL) according to the saturation concentration of cyclodextrin at 70℃, and then puts it into an electrodialysis device, with the temperature controlled at 70℃ and the outlet pH controlled 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 100 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 ibuprofen inclusion complex.
[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 ibuprofen inclusion complex.
[0085] The average particle size of the ibuprofen inclusion complex was 674 μm, and the yield based on ibuprofen sodium salt was 75.4%. Release efficiency was tested using in vitro release assays: the cumulative drug release was 40% at 5 hours, 75% at 10 hours, 89% at 15 hours, 91% at 20 hours, and 91% at 24 hours.
[0086] Comparative Example 3:
[0087] S501 adds cyclodextrin to an ibuprofen sodium salt aqueous solution (concentration 0.06 g / mL) according to the saturation concentration of cyclodextrin at 70℃, then adds 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;
[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 100 is provided after the second crystallization liquid.
[0090] S503 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;
[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 ibuprofen inclusion complex.
[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 ibuprofen inclusion complex.
[0096] The average particle size of the ibuprofen inclusion complex was 855 μm, and the yield based on ibuprofen sodium salt was 73.8%. Release efficiency was tested using in vitro release assays: the cumulative drug release was 45% at 5 hours, 87% at 10 hours, 92% at 15 hours, 92% at 20 hours, and 92% at 24 hours.
[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 method for producing an inclusion compound drug, characterized in that: Includes the following steps: Cyclodextrin was added to an aqueous solution of ibuprofen sodium salt at the saturated concentration of cyclodextrin at the first temperature, and then 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. 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; 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; 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; The fourth crystallization liquid was filtered and recovered, and after rinsing, ibuprofen inclusion complex was obtained; 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 ; The first temperature is 70-80℃, and the second temperature is 50-55℃.
2. The method for producing an inclusion compound drug according to claim 1, characterized in that: A filter screen with a mesh size of 100 is provided after the second crystallization liquid.
3. The method for producing an inclusion compound drug according to claim 1, characterized in that: The fourth crystallization solution is obtained as follows: 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.
4. The method for producing an inclusion compound drug according to claim 3, characterized in that: The filtration and recovery are carried out as follows: 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 ibuprofen inclusion complex.
5. The method for producing an inclusion complex pharmaceutical product according to claim 3, characterized in that: The crystallizer includes a cavity, inside which a stirrer is installed. The stirrer is connected to a stirring motor, and several injection holes for introducing acid solution are provided on the cavity wall.
6. The method for producing an inclusion compound drug according to claim 5, characterized in that: An acid-containing outer cavity is provided on the outside of the cavity wall, and several outlet pipes are provided on the acid-containing outer cavity. The outlet pipes are connected to the cavity through injection holes.
7. The method for producing an inclusion compound drug according to claim 6, characterized in that: An electrically controlled valve is installed on the outlet pipe.
8. The method for producing an inclusion compound drug according to claim 1, characterized in that: The acid solution is 10wt% hydrochloric acid.
Citation Information
Patent Citations
Method for preparing ibuprofen slow-release micro-capsule
CN108992422A
In-situ preparation method for starch-ibuprofen clathrate compound of V-type crystal structure
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