A process for the preparation of carbamazepine crystalline form i

Abstract

The application discloses a preparation method of carbamazepine crystal form I and relates to the technical field of drug crystallization. First, a clear and transparent volatile eutectic solvent is formed by using an organic phenolic volatile ligand and carbamazepine crystal form III, then the organic phenolic volatile ligand is removed by heating, and finally, the carbamazepine crystal form I product is obtained. The application only uses a single organic phenolic volatile ligand, can realize rapid removal of the ligand without high-temperature melting, can smoothly convert the crystal form, and has the advantages of simple process route, ingenious design, simple operation, mild conditions and easy industrialization. The obtained carbamazepine crystal form I product is stable in crystal form and high in purity, effectively solves the problems of crystal form conversion, poor product stability and difficult large-scale preparation caused by high temperature in the prior art, and has a good application prospect.

Description

Technical Field

[0001] This invention relates to the field of drug crystallization technology, specifically a method for preparing carbamazepine crystal form I. Background Technology

[0002] Carbamazepine is an antiepileptic and anticonvulsant drug primarily used to treat epilepsy, trigeminal neuralgia, and other neuropathic pain. It can also be used as a mood stabilizer for mania and bipolar disorder. Currently, anhydrous carbamazepine exists in five polymorphs: crystalline form I, crystalline form II, crystalline form III, crystalline form IV, and crystalline form V. Crystalline form III has the most thermodynamically stable structure, while the other polymorphs are metastable and unstable at room temperature, easily transforming into crystalline form III. Crystalline form I has the second highest stability after crystalline form III and higher bioavailability, allowing for faster and more complete absorption into the bloodstream, rapidly reaching effective blood drug concentrations and exerting its therapeutic effect. However, existing methods for preparing carbamazepine crystalline form I require high-temperature melting, making large-scale production difficult. Furthermore, the high-temperature process results in poor stability and low concentrations in the product.

[0003] Therefore, there is an urgent need to develop a process for the mass production of carbamazepine crystal form I without high-temperature melting, so that the product has both high stability and high purity, thereby realizing the industrial-scale production of carbamazepine crystal form I. Summary of the Invention

[0004] To address the above problems, the purpose of this invention is to provide a method for preparing carbamazepine crystal form I.

[0005] To achieve the above objectives, the present invention employs the following technical solution: A method for preparing carbamazepine crystal form I involves first forming a clear and transparent volatile eutectic solvent using an organic phenolic volatile ligand and carbamazepine crystal form III, and then removing the organic phenolic volatile ligand by heating to obtain the carbamazepine crystal form I product.

[0006] A preferred method for preparing carbamazepine crystal form I includes the following steps: ① A volatile organic phenolic ligand and carbamazepine crystal form III are mixed at a molar ratio of 3 to 20:1 and then heated and stirred or ground to form a clear and transparent volatile eutectic solvent. When the molar ratio is less than 3:1, the amount of ligand is insufficient and a stable eutectic solvent cannot be formed. When the molar ratio is greater than 20:1, the amount of ligand is excessive, which will increase the difficulty and time of subsequent volatilization and will not improve the crystal form conversion effect. Therefore, the molar ratio range suitable for this invention is determined.

[0007] ② Heat the mixed solution obtained in step ① at 80~120℃ for 50~70 minutes to volatilize the volatile organic phenolic ligands and obtain an intermediate solid product; ③ Heat the intermediate solid product obtained in step ② at 80~120℃ for 2~5 hours to obtain carbamazepine crystal form I product.

[0008] The heating methods in steps ② and ③ can be existing heating methods, such as vacuum drying or heating plates.

[0009] Preferably, the volatile organic phenolic ligand is phenol, thymol, or carvacrol.

[0010] Preferably, the heating temperature in step ① is 40~50℃.

[0011] Preferably, the ambient humidity during grinding in step ① is 20~70%RH, and the grinding time is 10~15 minutes.

[0012] The preferred ambient humidity and grinding time of this invention are to minimize the absorption of moisture from the air by carbamazepine, thus facilitating solvent removal in subsequent operations.

[0013] Preferably, the volatile organic phenolic ligand is phenol.

[0014] Preferably, the purity of carbamazepine crystal form III is greater than 99%.

[0015] Preferably, the molar ratio of the volatile organic phenolic ligand to carbamazepine crystal form III is 8~12:1.

[0016] Preferably, heating is performed using a heating plate in steps ② and ③, which provides direct and efficient heating.

[0017] The present invention has the following advantages over the prior art: This invention discloses a method for preparing carbamazepine crystal form I, employing a volatile eutectic solvent method. Carbamazepine crystal form III is mixed with a volatile organic phenolic ligand under heating, stirring, or grinding conditions. Subsequently, the volatile organic phenolic ligand is volatilized at 80–120°C to obtain a stable carbamazepine crystal form I product. This invention uses only a single volatile organic phenolic ligand, achieving rapid ligand removal without high-temperature melting, and enabling smooth crystal form conversion. The process route is simple, ingeniously designed, easy to operate, and operates under mild conditions, making it easy to scale up industrially. The resulting carbamazepine crystal form I product exhibits stable crystal form and high purity, effectively solving problems in existing technologies such as crystal form transformation due to high temperatures, poor product stability, and difficulty in large-scale preparation, demonstrating promising application prospects. Attached Figure Description

[0018] Figure 1 Scanning electron microscope image of the intermediate solid product; Figure 2XRD patterns of intermediate solid product, final product carbamazepine crystal form I, comparative example 1 product, comparative example 2 product and comparative example 3 product; Figure 3 Thermogravimetric diagram of intermediate solid product; Figure 4 The differential scanning calorimetry (DSC) curve for the intermediate solid product is shown. Figure 5 Scanning electron microscope image of carbamazepine crystal form I, the final product; Figure 6 Thermogravimetric analysis of the final product, carbamazepine crystal form I; Figure 7 Differential scanning thermal analysis diagram of the final product, carbamazepine crystal form I; Figure 8 Scanning electron microscope images of Comparative Example 1, Comparative Example 2, and Comparative Example 3; Figure 9 Thermogravimetric analysis of product 2 (Comparative Example 2); Figure 10 This is a differential scanning thermal analysis (DSC) graph of the product in Comparative Example 2. Detailed Implementation

[0019] The purpose of this invention is to provide a method for preparing carbamazepine crystal form I. The invention will be further described below with reference to specific embodiments.

[0020] In this embodiment of the invention, the purity of carbamazepine crystal form III is greater than 99%. The higher the purity of the raw material, the higher the purity of the final product. Example

[0021] A method for preparing carbamazepine crystal form I includes the following steps: ① Using phenol as a volatile ligand, phenol and carbamazepine crystal form III are mixed in proportion and pretreated to form a clear and transparent volatile eutectic solvent. ②The mixed solution obtained in step ① is heated at T1℃ for t1 minutes to volatilize the phenol and obtain an intermediate solid product; ③ The intermediate solid product obtained in step ② is heated at T2℃ for t2 hours to obtain carbamazepine crystal form I product.

[0022] The parameters in Example 1 were adjusted according to Table 1 to obtain the following example.

[0023] Table 1. Preparation parameters of carbamazepine crystal form I with phenol as the volatile ligand. Phenol / g Carbamazepine Crystal Form III / g Preprocessing T1 t1 T2 t2 Example 1-1 28.2 23.6 Heating and stirring at 40℃ 80 70 80 5 Examples 1-2 75.3 23.6 Heating and stirring at 50°C 100 55 105 2.5 Examples 1-3 84.7 23.6 Heating and stirring at 45℃ 110 65 110 3.5 Examples 1-4 112.9 23.6 Grind for 10 minutes at 20% RH humidity. 85 70 95 4.5 Examples 1-5 169.3 23.6 Grind for 15 minutes at 70% RH humidity. 95 60 100 4 Examples 1-6 188.2 23.6 Grind for 12 minutes at 40% RH humidity. 120 55 120 3 Example 2 A method for preparing carbamazepine crystal form I includes the following steps: ① Using thymol as a volatile ligand, thymol and carbamazepine crystal form III are mixed in proportion and pretreated to form a clear and transparent volatile eutectic solvent. ② Heat the mixed solution obtained in step ① at T1℃ for t1 minutes to volatilize thymol and obtain an intermediate solid product; ③ The intermediate solid product obtained in step ② is heated at T2℃ for t2 hours to obtain carbamazepine crystal form I product.

[0024] The parameters in Example 2 were adjusted according to Table 2 to obtain the following example.

[0025] Table 2. Preparation parameters of carbamazepine crystal form I with thymol as volatile ligand. thymol / g Carbamazepine Crystal Form III / g Preprocessing T1 t1 T2 t2 Example 2-1 45.1 23.6 Heating and stirring at 40℃ 80 70 80 5 Example 2-2 90.1 23.6 Heating and stirring at 50°C 100 55 105 2.5 Example 2-3 120.2 23.6 Heating and stirring at 45℃ 120 50 120 2 Examples 2-4 150.2 23.6 Grind for 10 minutes at 20% RH humidity. 80 70 95 4.5 Examples 2-5 210.3 23.6 Grind for 15 minutes at 70% RH humidity. 95 60 100 4 Examples 2-6 300.4 23.6 Grind for 14 minutes at 30% RH humidity. 120 50 120 3 Example 3 A method for preparing carbamazepine crystal form I includes the following steps: ① Using carvacrol as a volatile ligand, carvacrol and carbamazepine crystal form III are mixed in proportion and pretreated to form a clear and transparent volatile eutectic solvent. ② Heat the mixed solution obtained in step ① at T1℃ for t1 minutes to volatilize carvacrol and obtain an intermediate solid product; ③ The intermediate solid product obtained in step ② is heated at T2℃ for t2 hours to obtain carbamazepine crystal form I product.

[0026] The parameters in Example 3 were adjusted according to Table 3 to obtain the following example.

[0027] Table 3. Preparation parameters of carbamazepine crystal form I with carvacrol as the volatile ligand. carvacrol / g Carbamazepine Crystal Form III / g Preprocessing T1 t1 T2 t2 Example 3-1 45.1 23.6 Heating and stirring at 40℃ 80 70 80 5 Example 3-2 75.1 23.6 Heating and stirring at 50°C 100 55 105 2.5 Example 3-3 135.2 23.6 Heating and stirring at 45℃ 120 50 120 2 Examples 3-4 180.2 23.6 Grind for 10 minutes at 20% RH humidity. 80 70 95 4.5 Examples 3-5 240.3 23.6 Grind for 15 minutes at 70% RH humidity. 95 60 100 4 Examples 3-6 300.4 23.6 Grind for 12 minutes at 50% RH humidity. 120 50 120 3 Example 4 A method for preparing carbamazepine crystal form I includes the following steps: ① Phenol and carbamazepine crystal form III were mixed at a molar ratio of 1:10 and ground to form a clear and transparent volatile eutectic solvent; the grinding environment was 35%RH and the grinding time was 12 minutes. ②Heat the mixed solution obtained in step ① on a heating plate at 100°C for 60 minutes to volatilize the phenol and obtain an intermediate solid product; ③ The intermediate solid product obtained in step ② is heated on a heating plate at 100°C for 4 hours to obtain carbamazepine crystal form I product.

[0028] The intermediate solid products in the above embodiments are shown in the scanning electron microscope as follows: Figure 1 As shown, the XRD detection pattern is as follows: Figure 2 As shown, the thermogravimetric diagram is as follows Figure 3As shown, the differential scanning thermal analysis diagram is as follows: Figure 4 As shown; the scanning electron microscope image of the final product, carbamazepine crystal form I, is shown below. Figure 5 As shown, its XRD pattern is as follows. Figure 2 As shown, the thermogravimetric diagram is as follows Figure 6 As shown, the differential scanning thermal analysis diagram is as follows: Figure 7 As shown, the intermediate solid product is a stacked blocky structure, while the final product is a needle-like crystal. The XRD diffraction peaks of the intermediate solid product are at 12.52°, 12.86°, 19.30°, 21.08°, and 25.58°, while the XRD diffraction peaks of the final product are at 9.48°, 12.36°, 13.20°, 14.06°, and 19.90°. The crystal forms of the intermediate solid product and the final product, carbamazepine crystal form I, are inconsistent. A comparison of the thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) plots shows that the intermediate solid product exhibits a weight loss peak near 120°C, while carbamazepine crystal form I is more stable. Crystal form I begins to melt and decompose at around 191°C, further illustrating that the two are different crystal forms.

[0029] The liquid chromatography method for determining carbamazepine content is as follows: Test solution: Accurately weigh approximately 50 mg of the sample and place it in a 50 mL volumetric flask. Add 25 mL of methanol, shake to dissolve, and dilute to the mark with water. Mix well. Accurately measure 5 mL of the solution and place it in a 25 mL volumetric flask. Dilute to the mark with a methanol-water solution (1:1 volume ratio) and mix well. Reference solution: Accurately weigh approximately 50 mg of carbamazepine reference standard and place it in a 50 mL volumetric flask. Add 25 mL of methanol, shake to dissolve, and dilute to the mark with water. Mix well. Accurately measure 5 mL of the reference standard and place it in a 25 mL volumetric flask. Dilute to the mark with a methanol-water solution (1:1 volume ratio) and mix well. The determination conditions for high performance liquid chromatography (Agilent 1260) were as follows: C18 column (4.6 mm × 250.0 mm, 5.0 μm), mobile phase was methanol:water = 60:40 (volume ratio), column temperature was set at 35 °C, flow rate was 1.0 mL / min, detection wavelength was 240 nm, and injection volume was 10 μL.

[0030] In the embodiments of the present invention, when the purity of the raw material carbamazepine crystal form III is greater than 99.0%, the purity of the obtained carbamazepine crystal form I product is greater than 99.0%, and can reach a maximum of 99.9%.

[0031] Comparative Example 1 A method for preparing carbamazepine includes the following steps: taking 100g of carbamazepine crystal form III (purity 99.2%) solid, vacuum drying at 170℃ for 3h to obtain carbamazepine, and XRD detection results as shown below. Figure 2 As shown, the product is carbamazepine crystal form I. The product was observed under a scanning electron microscope, and the results are as follows. Figure 8As shown in Comparative Example 1, the product was needle-like crystals. The difference between this comparative example and the present invention is the absence of ligands forming a eutectic solvent and the different heating conditions. Only under vacuum and high-temperature conditions above 170°C could carbamazepine crystal form III be transformed into carbamazepine crystal form I, and the resulting crystals showed a carbamazepine content of 97.5% as determined by high-performance liquid chromatography.

[0032] Comparative Example 2 A method for preparing carbamazepine includes the following steps: 100g of carbamazepine crystal form III (purity 99.2%) solid is ground to obtain carbamazepine. The XRD results are as follows: Figure 2 As shown, XRD patterns at 10.1°, 14.2°, 17.1°, and 21.9° indicate that the product is carbamazepine crystal form III. Thermogravimetric analysis and differential scanning calorimetry were performed on the product, and the results are as follows. Figure 9 and Figure 10 As shown, this further confirms that it is crystal form III. The product was observed under a scanning electron microscope, and the results are as follows... Figure 8 As shown in Comparative Example 2, the product is a granular crystal. This comparative example illustrates that simply grinding carbamazepine crystal form III solid does not transform it into crystal form I.

[0033] Comparative Example 3 A method for preparing carbamazepine includes the following steps: placing 100g of carbamazepine crystal form III solid on a 150℃ heating plate and allowing it to stand for 6 hours; characterizing the obtained product. The product is observed under a scanning electron microscope, and the results are as follows. Figure 8 As shown in Comparative Example 3, the product is a granular crystal. The XRD results are as follows: Figure 2 As shown, XRD diffraction peaks at 10.1°, 14.2°, 17.1°, and 21.9° indicate that the product is carbamazepine crystal form III. It can be seen that no ligands involved in forming a eutectic solvent are present, but a hot plate drying process (temperature below 170°C) is still performed, and the final product is carbamazepine crystal form III.

Claims

1. A method for preparing carbamazepine crystal form I, characterized in that: First, a clear and transparent volatile eutectic solvent is formed using volatile organic phenol ligands and carbamazepine crystal form III. Then, the volatile organic phenol ligands are removed by heating to obtain carbamazepine crystal form I product.

2. The method for preparing carbamazepine crystal form I according to claim 1, characterized in that: Includes the following steps: ① Mix organic phenolic volatile ligands and carbamazepine crystal form III at a molar ratio of 3~20:1, and then heat and stir or grind to form a clear and transparent volatile eutectic solvent; ② Heat the mixed solution obtained in step ① at 80~120℃ for 50~70 minutes to volatilize the volatile organic phenolic ligands and obtain an intermediate solid product; ③ Heat the intermediate solid product obtained in step ② at 80~120℃ for 2~5 hours to obtain carbamazepine crystal form I product.

3. The method for preparing carbamazepine crystal I according to claim 2, characterized in that: The volatile ligands of the organic phenols are phenol, thymol, or carvacrol.

4. The method for preparing carbamazepine crystal I according to claim 2, characterized in that: The heating temperature in step ① is 40~50℃.

5. The method for preparing carbamazepine crystal I according to claim 2, characterized in that: In step ①, the ambient humidity for grinding is 20~70%RH, and the grinding time is 10~15 minutes.

6. The method for preparing carbamazepine crystal I according to claim 3, characterized in that: The volatile ligand of the organic phenol is phenol.

7. The method for preparing carbamazepine crystal I according to claim 2, characterized in that: The purity of carbamazepine crystal form III is greater than 99%.

8. The method for preparing carbamazepine crystal I according to claim 2, characterized in that: The molar ratio of volatile organic phenolic ligands to carbamazepine crystal form III is 8~12:

1.

9. The method for preparing carbamazepine crystal I according to claim 2, characterized in that: Heating is performed using a heating plate in steps ② and ③.

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