Novel diacerein crystal form and preparation method thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and discloses a novel diacerein crystal form and a preparation method thereof. The X-ray powder diffraction pattern of the novel crystal form shows characteristic diffraction peaks when the angle 2 theta is 5.18 degrees + / -0.2 degrees, 10.42 degrees + / -0.2 degrees, 17.38 degrees + / -0.2 degrees, 21.45 degrees + / -0.2 degrees, 21.86 degrees + / -0.2 degrees, 25.07 degrees + / -0.2 degrees and 27.85 degrees + / -0.2 degrees. Stability tests show that the novel crystal form has excellent stability and solubility, is beneficial to drug absorption and curative effect exertion, and can be applied to preparation of diacerein drugs. The preparation method comprises the following steps: mixing a diacerein crude product with N-methyl pyrrolidone, heating at 90-100 DEG C until the diacerein crude product is completely dissolved, adding acetone or ethanol, and crystallizing to obtain the target new crystal form. The preparation process is simple, convenient and efficient to operate, large-scale production is easy to realize, and a new choice is provided for production and application of diacerein drugs.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a new crystal form of diacerein and its preparation method. Background Technology

[0002] Diacerein (C 19 H 12 Diacerein (4,5-bis(acetyloxy)-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid), as a new generation of disease-modifying antirheumatic drugs (DMARDs), has shown significant therapeutic effects in clinical applications due to its unique pharmacological mechanism of action. It belongs to the anthraquinone class of drugs and is a primary inhibitor of interleukin-1 (IL-1) in osteoarthritis.

[0003]

[0004] Cellular and animal experiments have shown that diacerein has multiple effects, including inducing cartilage regeneration, analgesia, anti-inflammation, and antipyresis, and does not inhibit prostaglandin synthesis, thus avoiding the gastrointestinal side effects that may occur with traditional nonsteroidal anti-inflammatory drugs (NSAIDs). In the treatment of osteoarthritis, diacerein can significantly improve symptoms such as pain and joint dysfunction caused by the disease. It begins to show effects after 2-4 weeks of use, with significant efficacy after 4-6 weeks. If treatment continues for 3 months and then discontinued, the effect can last for at least 1 month (follow-up effect), providing patients with long-term therapeutic benefits.

[0005] However, the polymorphism of diacerein has become a significant issue in the development and production of drugs. Most organic drug crystals are molecular crystals, and different crystal conditions result in different spatial arrangements, a phenomenon known as polymorphism. Different polymorphs of diacerein exhibit significant differences in physical properties such as density, melting point, hardness, appearance, solubility, and dissolution rate, directly impacting the drug's safety, efficacy, and bioavailability.

[0006] Currently, several patents disclose different crystalline forms of bisacerein and their preparation methods. For example, patent EP0636602 discloses a method for synthesizing bisacerein, but does not disclose the crystalline form; patent CN105061208A discloses a crystalline form of bisacerein whose X-ray powder diffraction pattern exhibits specific characteristic absorption peaks; patent CN103058865A also discloses a crystalline form of bisacerein with different diffraction peaks. However, although these studies have provided some understanding of the polymorphism of bisacerein, finding new crystalline forms of bisacerein with good solubility, high bioavailability, stability, and suitability for industrial production remains an urgent problem to be solved.

[0007] Due to its low solubility, diacerein's behavior in the body after oral administration is limited. Low absorption and / or low bioavailability not only affect the therapeutic effect but may also increase the patient's medication burden and the risk of adverse reactions. Therefore, optimizing the crystal form of diacerein to improve its solubility and bioavailability is of great significance for enhancing the drug's therapeutic effect, reducing the risk of adverse reactions, and promoting the industrial production of the drug. Summary of the Invention

[0008] The purpose of this invention is to provide a novel, easily industrially produced, highly soluble, and stable new crystalline form of diacerein, its preparation method, and its application. To address the aforementioned problems, this invention provides a new crystalline form of diacerein, wherein the X-ray powder diffraction pattern of this crystalline form exhibits characteristic absorption peaks at 2θ angles of 5.18±0.2°, 10.42±0.2°, 17.38±0.2°, 21.45±0.2°, 21.86±0.2°, 25.07±0.2°, and 27.85±0.2°. Another objective of this invention is to provide the application of this new crystalline form of diacerein in the preparation of drugs containing diacerein. To achieve the above objectives, this invention provides the following technical solutions: On the one hand, the present invention provides a novel crystalline form of bisacerein, the X-ray powder diffraction pattern of which has characteristic diffraction peaks at 2θ angles of 5.18°±0.2°, 10.42°±0.2°, 17.38°±0.2°, 21.45°±0.2°, 21.86°±0.2°, 25.07°±0.2°, and 27.85°±0.2°.

[0009] On the other hand, the present invention also provides a method for preparing the new crystalline form of the bis(acerein), comprising the following steps: Step 1: React aloe-emodin compounds with 2-iodobenzoic acid in N,N-dimethylacetamide at 30-40°C for 4-6 hours, add water to precipitate the solid, and wash and dry to obtain intermediate 1; Step 2: Dissolve intermediate 1 in dimethyl sulfoxide, add sodium dihydrogen phosphate solution and sodium chlorite solution sequentially at 0~5℃, heat to 35℃ and react for 5~6 hours, add water to crystallize and obtain intermediate 2; Step 3: Under inert gas protection, concentrated sulfuric acid is added dropwise to intermediate 2 and acetic anhydride at 5°C, the temperature is raised to 30°C and reacted for 3 hours. After low-temperature hydrolysis, crude diacerein is precipitated. Step 4: Dissolve the crude product in N-methylpyrrolidone, decolorize, add a crystallization solvent, and crystallize to obtain the new crystal form of diacerein.

[0010] Furthermore, in the method, the ratio of the aloe-emodin compound to 2-iodobenzoic acid, by mass, is 1:1.24 to 1:2.59.

[0011] Furthermore, in the method, the aloe-emodin compound in step one is aloe-emodin or aloe-emodin acid.

[0012] Furthermore, in the method, the internal temperature during the water addition and crystallization process in step two does not exceed 40°C.

[0013] Furthermore, in the method, the mass ratio of acetic anhydride to intermediate 2 in step three is 5:1 to 12:1.

[0014] Furthermore, in the method, the crystallization solvent in step four is acetone or ethanol.

[0015] Furthermore, in the method, the crystallization temperature in step four is 5~10℃, and the crystallization time is 1~3 hours.

[0016] Finally, the present invention also provides the application of the new diacerein crystal form prepared by the method in the preparation of drugs containing diacerein.

[0017] Compared with the prior art, the present invention has at least the following advantages or beneficial effects: (1) This invention provides the first preparation of a novel crystalline form of diacerein. X-ray diffraction analysis revealed characteristic absorption peaks at 2θ angles of 5.18±0.2°, 10.42±0.2°, 17.38±0.2°, 21.45±0.2°, 21.86±0.2°, 25.07±0.2°, and 27.85±0.2°, which differ from existing diacerein crystalline forms. This crystalline form exhibits excellent stability. Accelerated stability testing showed that the crystalline structure remained unchanged after 6 months of storage at 40℃±2℃ and 75%±5% humidity. This means that the drug maintains stable physical and chemical properties throughout its shelf life, effectively avoiding the quality degradation caused by crystalline form transformation, and providing reliable assurance for the long-term storage and transportation of the drug.

[0018] (2) The present invention uses a mixture of crude diacerein and N-methylpyrrolidone to be heated to 90-100°C to dissolve, and then acetone or ethanol is added and crystallized to obtain a new crystal form of diacerein. The preparation process is convenient, efficient and suitable for large-scale production. Attached Figure Description

[0019] Figure 1 The diffraction pattern of the new bisacerein crystal form prepared in Example 4.

[0020] Figure 2 The diffraction pattern of the new bisacerein crystal form prepared in Example 5. Detailed Implementation

[0021] The technical solution of the present invention will be described below with reference to the embodiments. However, the present invention is not limited to the following embodiments.

[0022] To enable those skilled in the art to better understand and implement the technical solutions of the present invention, the present invention will be further described below in conjunction with specific embodiments and accompanying drawings. However, the embodiments described are not intended to limit the present invention.

[0023] Unless otherwise specified, the experimental and detection methods described in the following embodiments are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0024] Example 1

[0025] This example describes the preparation of crude diacerein.

[0026] Step 1: N,N-dimethylacetamide (220.0 g), 2-iodobenzoic acid (26.4 g, 94.4 mmol), and aloe-emodin (10.2 g, 37.7 mmol) were added to the reactor and stirred at 35°C for 5 hours. After the reaction was completed by HPLC monitoring, the temperature was lowered to 25°C, and 225 mL of water was added at a uniform rate. The mixture was stirred for 2 hours. The reaction solution was filtered, and the filter cake was washed once with 100 g of ethanol. The filter cake was dried in a forced-air condition at 50°C for 8 hours to obtain 19.2 g of yellowish-brown intermediate 1.

[0027] Step 2: Add dimethyl sulfoxide (330g) and intermediate 1 (19.2g, 71.6mmol) to the reactor and stir at 0℃ for 30 minutes. Rapidly add sodium dihydrogen phosphate solution (sodium dihydrogen phosphate dihydrate 49.8g, 0.41mol, 142.1g purified water) at a temperature below 20℃. Add sodium chlorite solution (sodium chlorite 50.4g, 0.56mol, 84.0g purified water) at a temperature of 5℃. After the addition is complete, raise the temperature to 35℃ and continue stirring for 5 hours. After the reaction is complete as monitored by HPLC, lower the temperature to 10℃ and rapidly add 300mL of water, ensuring the internal temperature does not exceed 40℃ during the addition. After the addition is complete, continue stirring for 2 hours. Filter the reaction solution, wash the filter cake once with 100g ethanol, and dry it at 60℃ for 8 hours to obtain 8.1g of yellow intermediate 2.

[0028] Step 3: Acetic anhydride (72.0 g) and intermediate 2 (6.0 g) were added to the reactor, and nitrogen gas was introduced for protection. The mixture was stirred, cooled to 5°C, and 6.8 g of concentrated sulfuric acid was added dropwise. After the addition was complete, the temperature was raised to 30°C, and stirring was continued for 3 hours. After the reaction was completed, purified water (172 mL) at 5°C was added, and the temperature was controlled below 20°C. Stirring was continued for 3 hours. The reaction solution was filtered, and the filter cake was washed and pulped once with 50 mL of water. It was then dried at 60°C for 8 hours to obtain 6.3 g of crude diacerein, labeled as crude diacerein 1#.

[0029] Example 2

[0030] This example describes the preparation of crude diacerein.

[0031] Step 1: N,N-dimethylacetamide (165.0 g), 2-iodobenzoic acid (12.68 g, 45.2 mmol), and aloe-rhein (10.2 g, 37.7 mmol) were added to the reactor and stirred at 35°C for 4 hours. After the reaction was completed by HPLC monitoring, the temperature was lowered to 25°C, and 225 mL of water was added at a uniform rate. The mixture was stirred for 2.5 hours. The reaction solution was filtered, and the filter cake was washed once with 100 g of ethanol. The filter cake was dried in a forced-air condition at 55°C for 7 hours to obtain 19.1 g of yellowish-brown intermediate 1.

[0032] Step 2: Add dimethyl sulfoxide (330g) and intermediate 1 (19.2g, 71.6mmol) to the reactor and stir at 0℃ for 30 minutes. Rapidly add sodium dihydrogen phosphate solution (50.4g anhydrous sodium dihydrogen phosphate, 0.42mol, 28.9g purified water) at a temperature below 20℃. Add sodium chlorite solution (19.3g sodium chlorite, 0.21mol, 104.8g water) at a temperature of 5℃. After the addition is complete, raise the temperature to 35℃ and continue stirring for 5 hours. After the reaction is complete as monitored by HPLC, lower the temperature to 10℃ and rapidly add 300mL of water, ensuring the internal temperature does not exceed 40℃ during the addition. After the addition is complete, continue stirring for 2 hours. Filter the reaction solution, wash the filter cake once with 100g ethanol, and dry it at 60℃ for 8 hours to obtain 8.0g of yellow intermediate 2.

[0033] Step 3: Acetic anhydride (60.0 g) and intermediate 2 (6.0 g) were added to the reactor, and nitrogen gas was introduced for protection. The mixture was stirred, cooled to 0°C, and 6.8 g of concentrated sulfuric acid was added dropwise. After the addition was complete, the temperature was raised to 30°C, and stirring was continued for 3 hours. After the reaction was completed, purified water (172 mL) at 5°C was added, and the temperature was controlled below 20°C. Stirring was continued for 3 hours. The reaction solution was filtered, and the filter cake was washed and pulped once with 50 mL of water. It was then dried at 60°C for 8 hours to obtain 6.15 g of crude diacerein, labeled as crude diacerein 2#.

[0034] Example 3

[0035] This example describes the preparation of crude diacerein.

[0036] Step 1: N,N-dimethylacetamide (220.0 g), 2-iodobenzoic acid (15.8 g, 56.5 mmol), and aloe-rhein (10.2 g, 37.7 mmol) were added to the reactor and stirred at 35°C for 6 hours. After the reaction was completed by HPLC monitoring, the temperature was lowered to 25°C, and 225 mL of water was added at a uniform rate. The mixture was stirred for 3 hours. The reaction solution was filtered, and the filter cake was washed once with 100 g of ethanol. The filter cake was dried in a forced-air condition at 55°C for 7 hours to obtain 19.0 g of yellowish-brown intermediate 1.

[0037] Step 2: Add dimethyl sulfoxide (330g) and intermediate 1 (19.2g, 71.6mmol) to the reactor and stir at 0℃ for 30 minutes. Rapidly add sodium dihydrogen phosphate solution (50.4g anhydrous sodium dihydrogen phosphate, 0.42mol, 28.9g purified water) at a temperature below 20℃. Add sodium chlorite solution (19.3g sodium chlorite, 0.21mol, 104.8g water) at a temperature of 5℃. After the addition is complete, raise the temperature to 35℃ and continue stirring for 5 hours. After the reaction is complete as monitored by HPLC, lower the temperature to 10℃ and rapidly add 300mL of water, ensuring the internal temperature does not exceed 40℃ during the addition. After the addition is complete, continue stirring for 2 hours. Filter the reaction solution, wash the filter cake once with 100g ethanol, and dry it at 60℃ for 8 hours to obtain 7.9g of yellow intermediate 2.

[0038] Step 3: Acetic anhydride (30.0 g) and intermediate 2 (6.0 g) were added to the reactor, and nitrogen gas was introduced for protection. The mixture was stirred, cooled to 0°C, and 6.8 g of concentrated sulfuric acid was added dropwise. After the addition was complete, the temperature was raised to 30°C, and stirring was continued for 3 hours. After the reaction was completed, purified water (172 mL) at 3°C ​​was added, and the temperature was controlled below 20°C. Stirring was continued for 3 hours. The reaction solution was filtered, and the filter cake was washed and pulped once with 50 mL of water. It was then dried at 60°C for 8 hours to obtain 6.1 g of crude diacerein, labeled as crude diacerein 3#.

[0039] Example 4

[0040] This embodiment describes the preparation of a new crystal form of diacerein.

[0041] The crude diacerein products prepared in Examples 1, 2, and 3 were mixed evenly and labeled as crude diacerein mixture for further purification.

[0042] N-methylpyrrolidone (30 ml) and 6.0 g of crude diacerein were added to a reactor and heated to 90 °C to dissolve. Activated carbon was added for decolorization, and the mixture was stirred for 0.5 h. The mixture was then filtered while hot, and acetone (30 ml) was added and stirred under reflux for 0.5 h. The mixture was then slowly cooled to 5 °C and stirred for another 2 h. The mixture was filtered, and the filter cake was washed and pulped once with 50 ml of ethanol. The cake was then vacuum dried at 65 °C for 12 h to obtain 5.4 g of the new crystalline form of diacerein, with a yield of 90% and a purity of 99.5%.

[0043] The newly synthesized bis(acerein) crystal form was scanned using a D8 Advance X powder diffractometer to obtain the corresponding spectra, as shown in the figure below. Figure 1As shown, the 2θ angle in the diffraction pattern exhibits characteristic absorption peaks at 5.18±0.2°, 10.42±0.2°, 17.38±0.2°, 21.45±0.2°, 21.86±0.2°, 25.07±0.2°, and 27.85±0.2°. The novel bis(acerein) crystal form prepared in this embodiment is designated as No. 1 bis(acerein) crystal form.

[0044] Example 5

[0045] This embodiment describes the preparation of a new crystal form of diacerein.

[0046] The crude diacerein products prepared in Examples 1, 2, and 3 were mixed evenly and labeled as crude diacerein mixture for further purification.

[0047] N-methylpyrrolidone (40 ml) and crude diacerein (10.0 g) were added to the reactor and heated to 100 °C to dissolve. Activated carbon was added for decolorization, and the mixture was stirred for 1 h. The mixture was filtered while hot, and then ethanol (40 ml) was added and stirred under reflux for 0.5 h. The mixture was slowly cooled to 10 °C and stirred for another 2 h. The mixture was then filtered, and the filter cake was washed and pulped once with 60 ml of ethanol each time. The pulp was dried under vacuum at 65 °C to obtain 9.2 g of the new crystalline form of diacerein, with a yield of 92% and a purity of 99.6%.

[0048] The newly synthesized bis(acerein) crystal form was scanned using a D8 Advance X powder diffractometer to obtain the corresponding spectra, as shown in the figure below. Figure 2 As shown, the 2θ angle in the diffraction pattern exhibits characteristic absorption peaks at 5.18±0.2°, 10.42±0.2°, 17.38±0.2°, 21.45±0.2°, 21.86±0.2°, 25.07±0.2°, and 27.85±0.2°. The novel bis(acerein) crystal form prepared in this embodiment is designated as No. 2 bis(acerein) crystal form.

[0049] Example 6

[0050] This example tests the solubility of a new crystalline form of diacerein.

[0051] Using the novel crystalline form of diacerein #1 prepared in Example 4 and the novel crystalline form of diacerein #2 prepared in Example 5, along with commercially available diacerein 1 and diacerein 2, as samples, the solubility of different crystalline forms of diacerein in different solvents was tested. The test results are shown in the table.

[0052] Table 1. Solubility of different crystal forms of diacerein

[0053] As shown in Table 1, the new crystalline compound of diacerein provided by the present invention improves the solubility of diacerein in water and tetrahydrofuran compared with commercially available diacerein 1 and diacerein 2, while the solubility in other solvents is not significantly different from that of commercially available samples.

[0054] Example 7

[0055] This example demonstrates the stability testing of a novel crystalline form of diacerein. The accelerated stability of the mixed sample was tested using the novel crystalline form 1 of diacerein prepared in Example 4 and the novel crystalline form 2 of diacerein prepared in Example 5. The test results are shown in Table 2. The accelerated stability of commercially available sample 1 was tested as a control, and the results are shown in Table 3.

[0056] Table 2. Accelerated stability test results of the new crystalline form of bis(acerein) prepared in this invention.

[0057] Table 3. Accelerated stability test results of commercially available diacerein sample 1

[0058] As shown in Tables 2 and 3, the accelerated stability results of the new crystalline form of diacerein provided by this invention are compared with those of diacerein (different crystalline forms) in the prior art. All key quality attributes are more stable and show no significant changes. Moreover, the impurity E content of the new crystalline form of diacerein is about 0.1% lower than that of commercially available samples.

[0059] As described above, the basic principles, main features, and advantages of the present invention have been well described. The above embodiments and specifications are merely descriptions of preferred embodiments of the present invention, and the present invention is not limited to the above embodiments. Various changes and improvements made to the technical solutions of the present invention by those skilled in the art without departing from the spirit and scope of the present invention should fall within the protection scope defined by the present invention.

Claims

1. A novel crystalline form of diacerein, characterized in that, The X-ray powder diffraction pattern of this crystal form has characteristic diffraction peaks at 2θ angles of 5.18°±0.2°, 10.42°±0.2°, 17.38°±0.2°, 21.45°±0.2°, 21.86°±0.2°, 25.07°±0.2°, and 27.85°±0.2°.

2. A method for preparing the new crystalline form of bis(acerein) according to claim 1, characterized in that, Includes the following steps: Step 1: React aloe-emodin compounds with 2-iodobenzoic acid in N,N-dimethylacetamide at 30-40°C for 4-6 hours, add water to precipitate the solid, and wash and dry to obtain intermediate 1; Step 2: Dissolve intermediate 1 in dimethyl sulfoxide, add sodium dihydrogen phosphate solution and sodium chlorite solution sequentially at 0~5℃, heat to 35℃ and react for 5~6 hours, add water to crystallize and obtain intermediate 2; Step 3: Under inert gas protection, concentrated sulfuric acid is added dropwise to intermediate 2 and acetic anhydride at 5°C, the temperature is raised to 30°C and reacted for 3 hours. After low-temperature hydrolysis, crude diacerein is precipitated. Step 4: Dissolve the crude product in N-methylpyrrolidone, decolorize, add a crystallization solvent, and crystallize to obtain the final product. The new crystalline form of diacerein as described in claim 1.

3. The method according to claim 2, characterized in that, The ratio of the aloe-emodin compounds to 2-iodobenzoic acid, by mass, is 1:1.24 to 1:2.

59.

4. The method according to claim 3, characterized in that, The aloe-emodin compounds mentioned in step one are aloe-emodin or aloe-emodin acid.

5. The method according to claim 2, characterized in that, In step two, the internal temperature during the water addition and crystallization process does not exceed 40°C.

6. The method according to claim 2, characterized in that, In step three, the mass ratio of acetic anhydride to intermediate 2 is 5:1 to 12:

1.

7. The method according to claim 2, characterized in that, The crystallization solvent in step four is acetone or ethanol.

8. The method according to claim 2, characterized in that, In step four, the crystallization temperature is 5~10℃ and the crystallization time is 1~3 hours.

9. The use of the new diacerein crystal form prepared by the method according to claims 2-8 in the preparation of drugs containing diacerein.

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