Novel capecitabine crystal form M and preparation method thereof

Abstract

The invention relates to the technical field of crystallization, in particular to a capecitabine crystal form M and a preparation method of the crystal form M. The crystal form disclosed by the invention is characterized in that an X-ray powder diffraction pattern has the following characteristic peaks at 2 theta + / -0.2 degrees: 4.82, 5.15, 9.82, 14.99, 17.63, 18.49, 20.13, 25.31, 27.02 and 29.49. Differential scanning calorimetry (DSC) shows that only one endothermic peak exists between 100 DEG C and 180 DEG C, and the top value of the endothermic peak is 124 + / -2 DEG C. Thermal gravimetric analysis (TGA) shows that the crystal form is not solvated and does not contain a crystallization solvent. The invention provides a capecitabine new crystal form M and a preparation method thereof. The crystal form is good in stability and convenient to store and transport; the crystal form is simple in preparation process and easy for industrial production; the solvent system is green and environment-friendly and has no solvent residue risk; the solubility of the crystal form is basically consistent with that of an original crystal form, the medication safety is better guaranteed, and the change cost of a preparation processing technology can be greatly reduced. The properties of the novel crystal form can make up for various defects of the existing crystal form, and the novel crystal form has high economic benefits and social benefits.

Description

Technical Field

[0001] The present invention belongs to the field of crystallization technology, and in particular relates to a new crystal form M of capecitabine and a preparation method thereof. Background Art

[0002] Capecitabine, CAS: 154361-50-9, chemical name 5-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine, is a highly active fluorouracil targeted anti-tumor drug. The drug was originally developed by Hoffmann-La Roche Ltd. in Switzerland, and applied for compound patent CN1094056A in my country in 1994. In 2008, capecitabine was approved by my country for the first-line treatment of advanced gastric cancer.

[0003] The polymorphism of compounds is a cutting-edge topic in the field of food and medicine. Compounds with different crystalline forms often have different physical and chemical properties, such as stability and solubility, which in turn affect the processing of their drug preparations and the bioavailability of the final drug.

[0004] The original research company did not describe the crystal form of the drug. The currently known studies involving the crystal form of capecitabine are as follows: 1. Patent CN103374052A protects a capecitabine crystal form A, which has a simple processing technology and is easy to industrialize. However, according to the description of patent CN117229341A, the stability of the crystal form A is poor, especially the purity decreases significantly under light conditions.

[0005] 2. Patent CN102516338 protects a capecitabine crystal form B. The preparation process of this crystal form uses a large amount of Class II solvents, which are harmful to the human body and have a low residual safety limit. Crystal form control often needs to be achieved in the refining step. As the last step in the processing of raw materials, the safety of its solvent needs to be considered in particular. At the same time, this crystal form also has poor stability.

[0006] 3. Patent CN117229341A protects a capecitabine crystal form I, which has high stability under light conditions, but its solubility and dissolution rate are significantly higher than other existing crystal forms. After being processed into a preparation, its C max It is 1.3 times that of the existing crystal form A. Patents CN101433546 and CN114796147 point out that a sustained-release preparation with a stable blood drug concentration is more conducive to optimizing the therapeutic effect of capecitabine and can significantly improve the safety of medication and patient compliance. The solubility of crystal form I is obviously not conducive to the processing of sustained-release preparations.

[0007] In view of the many shortcomings of the current capecitabine crystal form, it is of great significance to seek a new capecitabine crystal form with a simple preparation process, a green and environmentally friendly solvent system, good process stability, good product stability, and moderate solubility.

[0008] During the research, the inventors discovered a new crystalline form M of capecitabine, which has the following advantages: 1. This crystal form has good stability and is easy to store and transport.

[0009] 2. The crystal preparation process is simple and easy to industrialize.

[0010] 3. The solvent system is green and environmentally friendly, with no risk of solvent residue.

[0011] 4. The solubility of this crystal form is basically the same as that of the original crystal form, which ensures the safety of drug use and can significantly reduce the cost of changing the preparation processing technology.

[0012] The properties of this new crystal form can make up for the various deficiencies of the existing crystal form and have higher economic and social benefits. Summary of the invention

[0013] The present invention provides a capecitabine crystal form M and a method for preparing the crystal form M.

[0014] The crystal form is characterized in that the X-ray powder diffraction pattern has the following characteristic peaks at 2θ±0.2°: 4.82, 5.15, 9.82, 14.99, 17.63, 18.49, 20.13, 25.31, 27.02, and 29.49.

[0015] More specific powder diffraction characteristics are as follows:

[0016] Differential scanning calorimetry (DSC) analysis showed that it had only one endothermic peak before the decomposition temperature, and the top value of the endothermic peak was 124±2℃.

[0017] Thermogravimetric analysis (TGA) showed that the crystal form did not contain water of crystallization or other crystallization solvents, and its decomposition temperature was 148±2°C.

[0018] Technical solution: The preparation method of capecitabine crystal form M comprises the following steps: The method is obtained by using capecitabine of any crystal form as a raw material through dissolution, filtration, induction of crystallization and crystal growth.

[0019] Step 1: Magnetic treatment of solvent. Stir the solvent in the reactor and apply a magnetic field through a rare earth permanent magnet outside the reactor. The direction of the magnetic field is orthogonal to the direction of the liquid flow field.

[0020] Step 2: Add capecitabine and stir continuously at 35-45°C for about 30 min until it is dissolved or almost dissolved. Filter while hot and keep the mother liquor warm at 35-45°C.

[0021] Step 3: Continue stirring the mother liquor under the action of the magnetic field and cool the system to 20~30℃.

[0022] Step 4: Introduce ultrasonic wave to induce crystallization, the ultrasonic frequency is 20~40 KHz, continue ultrasonic wave after crystals are precipitated, and keep the crystal at constant temperature for 1~2 hours. At this time, the crystal is crystal form M, but the yield is low.

[0023] Step 5: Continue to cool the system to -5~0℃ under the action of the magnetic field, and after growing the crystal at a constant temperature for 2~3 hours at the end of the cooling process, filter.

[0024] More specifically: The magnetic field intensity described in the first step is 0.4~0.6 T, and the magnetic treatment time is 5~8 h.

[0025] The solvent system in the first step is an alcohol solvent.

[0026] The liquid-to-solid ratio of the second step is 3~9:1 The cooling rate in the third step is 3-5°C / h.

[0027] The cooling rate in the fifth step is 2-4 °C / h.

[0028] The key parameters are the strength of the external magnetic field, the magnetization time of the external magnetic field, the ultrasonic frequency and the cooling rate. If the parameters are out of range, other crystal forms may be produced. Beneficial Effects

[0029] The present invention provides a new crystal form M of capecitabine and a method for preparing the crystal form. 1. The crystal form has good stability and is convenient for storage and transportation; 2. The preparation process of this crystal form is simple and easy to industrialize; 3. The solvent system is green and environmentally friendly, and there is no risk of solvent residue; 4. The solubility of this crystal form is basically the same as the original crystal form, and the drug safety is more guaranteed, which can greatly reduce the cost of changing the preparation processing technology. The properties of this new crystal form can make up for the various shortcomings of the existing crystal form and have high economic and social benefits. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 :X-ray powder diffraction (XRD) pattern of Example Form M Figure 2 :Differential scanning calorimetry (DSC) diagram of Example Form M Figure 3 :Thermogravimetric analysis (TGA) of Form M in Example Figure 4: X-ray powder diffraction (XRD) pattern of Form A in Experimental Example 1 DETAILED DESCRIPTION

[0030] Example 1: Preparation of Form M A 0.5 T magnetic field was applied to the outside of the reactor by a rare earth permanent magnet, and then 300 ml of anhydrous ethanol was added to the reactor, and the solvent was stirred so that the flow field direction was orthogonal to the magnetic field direction, and the stirring was continued for 5 h. The temperature of the system was raised to 45 °C, and then 100 g of capecitabine was added thereto. After stirring for 30 min, the filtrate was collected in the reactor and kept at 45 °C, during which the magnetic field was maintained. Then the system was lowered and cooled to 30 °C at a cooling rate of 3 °C / h. After reaching the target temperature, ultrasound was turned on at a frequency of 40 KHz. After crystals were precipitated, ultrasound was continued for 1 h. Then the system was cooled to 0 °C at a cooling rate of 2 °C / h, and the crystals were grown for 2 h at the end of the cooling. The product was obtained after filtration, and was determined to be crystal form M by X-ray powder diffraction.

[0031] Example 2: Preparation of Form M A 0.6 T magnetic field was applied to the outside of the reactor by a rare earth permanent magnet, and then 700 ml of isopropanol was added to the reactor, and the solvent was stirred so that the flow field direction was orthogonal to the magnetic field direction. After continuous stirring for 5 h. The temperature of the system was raised to 40 °C, and then 100 g of capecitabine was added thereto. After stirring for 30 min, the filtrate was collected in the reactor and kept at 40 °C, during which the magnetic field was maintained. Then the system was lowered and cooled to 30 °C at a cooling rate of 4 °C / h. After reaching the target temperature, ultrasound was turned on at a frequency of 40 KHz. After crystals were precipitated, ultrasound was continued for 1 h. Then the system was cooled to 0 °C at a cooling rate of 4 °C / h, and the crystals were grown for 2 h at the end of the cooling. The product was obtained after filtration, and was determined to be crystal form M by X-ray powder diffraction.

[0032] Example 3: Preparation of Form M A 0.6 T magnetic field was applied to the outside of the reactor by a rare earth permanent magnet, and then 900 ml of tert-butyl alcohol was added to the reactor, and the solvent was stirred so that the flow field direction was orthogonal to the magnetic field direction, and the stirring was continued for 6 h. The temperature of the system was raised to 40 °C, and then 100 g of capecitabine was added thereto. After stirring for 30 min, the filtrate was collected in the reactor and kept warm at 40 °C, during which the magnetic field was maintained. Then the system was lowered and cooled to 25 °C at a cooling rate of 3 °C / h. After reaching the target temperature, ultrasound was turned on at a frequency of 30 KHz. After crystals were precipitated, ultrasound was continued for 2 h. Then the system was cooled to -5 °C at a cooling rate of 3 °C / h, and the crystals were grown for 3 h at the end of the cooling. The product was obtained after filtration, and was determined to be crystal form M by X-ray powder diffraction.

[0033] Example 4: Preparation of Form M A 0.4 T magnetic field was applied to the outside of the reactor by a rare earth permanent magnet, and then 400 ml of n-propanol was added to the reactor, and the solvent was stirred so that the flow field direction was orthogonal to the magnetic field direction, and the stirring was continued for 8 h. The temperature of the system was raised to 35 °C, and then 100 g of capecitabine was added thereto. After stirring for 30 min, the filtrate was collected in the reactor and kept at 35 °C, during which the magnetic field was maintained. Then the system was lowered and cooled to 20 °C at a cooling rate of 5 °C / h. After reaching the target temperature, ultrasound was turned on at a frequency of 40 KHz. After crystals were precipitated, ultrasound was continued for 2 h. Then the system was cooled to 0 °C at a cooling rate of 2 °C / h, and the crystals were grown for 3 h at the end of the cooling. The product was obtained after filtration, and was determined to be crystal form M by X-ray powder diffraction.

[0034] Example 5: Preparation of Form M A 0.5 T magnetic field was applied to the outside of the reactor by a rare earth permanent magnet, and then 800 ml of isopropanol was added to the reactor, and the solvent was stirred so that the flow field direction was orthogonal to the magnetic field direction, and the stirring was continued for 7 h. The temperature of the system was raised to 35 °C, and then 100 g of capecitabine was added thereto. After stirring for 30 min, the filtrate was collected in the reactor and kept at 35 °C, during which the magnetic field was maintained. Then the system was lowered and cooled to 30 °C at a cooling rate of 5 °C / h. After reaching the target temperature, ultrasound was turned on at a frequency of 40 KHz. After crystals were precipitated, ultrasound was continued for 1 h. Then the system was cooled to -5 °C at a cooling rate of 4 °C / h, and the crystals were grown for 2 h at the end of the cooling. The product was obtained after filtration, and was determined to be crystal form M by X-ray powder diffraction.

[0035] Comparative Example 1: No external magnetic field Add 300 ml of anhydrous ethanol to the reactor, stir the solvent, heat the system to 45 °C, then add 100 g of capecitabine, stir for 30 minutes, filter, collect the filtrate in the reactor, and keep it at 45 °C. Then lower and cool the system to 30 °C at a cooling rate of 3 °C / h. After reaching the target temperature, turn on ultrasound at a frequency of 40 KHz. After crystals precipitate, continue ultrasound for 1 h. Then continue to cool the system to 0 °C at a cooling rate of 2 °C / h, and grow crystals for 2 h at the end of the cooling. The product is obtained after filtration, and is determined to be Form A by X-ray powder diffraction.

[0036] Control Example 2: Crystallization without ultrasonic induction A 0.5 T magnetic field was applied to the outside of the reactor by a rare earth permanent magnet, and then 300 ml of anhydrous ethanol was added to the reactor, and the solvent was stirred so that the flow field direction was orthogonal to the magnetic field direction, and the stirring was continued for 5 h. The temperature of the system was raised to 45 °C, and then 100 g of capecitabine was added thereto, and the mixture was filtered after stirring for 30 min. The filtrate was collected in the reactor and kept at 45 °C, during which the magnetic field was maintained. Then the system was lowered and cooled to 20 °C at a cooling rate of 3 °C / h. After reaching the target temperature, the crystallization was continued by stirring, and after crystals were precipitated, the crystals were grown for 2 h, and then the system was continued to be cooled to 0 °C at a cooling rate of 2 °C / h, and the crystals were grown for 2 h at the end of the cooling, and the product was obtained after filtration, which was determined to be Form A by X-ray powder diffraction.

[0037] Comparative Example 3: Cooling rate exceeds the range A 0.5 T magnetic field was applied to the outside of the reactor by a rare earth permanent magnet, and then 300 ml of anhydrous ethanol was added to the reactor, and the solvent was stirred so that the flow field direction was orthogonal to the magnetic field direction. After continuous stirring for 5 h. The temperature of the system was raised to 45 °C, and then 100 g of capecitabine was added thereto. After stirring for 30 min, the filtrate was collected in the reactor and kept warm at 45 °C, during which the magnetic field was maintained. Then the system was lowered and cooled to 30 °C at a cooling rate of 20 °C / h. After reaching the target temperature, ultrasound was turned on at a frequency of 40 KHz. After crystals were precipitated, ultrasound was continued for 1 h. Then the system was cooled to 0 °C at a cooling rate of 20 °C / h, and the crystals were grown for 2 h at the end of the cooling. The product was obtained after filtration, and was determined to be form A by X-ray powder diffraction, and the characteristic peak of the extremely small form M was visible.

[0038] It can be seen from the above control examples that magnetic treatment, ultrasound and cooling rate are all key parameters. When the experimental conditions exceed the range, other crystal forms or mixed crystals of other crystal forms and crystal form M are likely to be produced.

[0039] Experimental Example 1: Preparation of Form A Form A was prepared by referring to the method provided in patent CN103374052, and the sample was confirmed by XRD to be consistent with Form A in the patent.

[0040] Experimental Example 2: Preparation of Form I The crystal form I was prepared by referring to the method provided in patent CN117229341, and the sample was confirmed by XRD to be consistent with the crystal form I in the patent.

[0041] Test Example 3: Stability Study Referring to the 9001 API Stability Test Guidelines of the Chinese Pharmacopoeia 2020 Edition, the most severe influencing factor experimental method was selected to evaluate the stability of the capecitabine crystal form M obtained in the embodiment of the present invention, and compared with the crystal form A and crystal form I. The results are as follows: A. High temperature test: Place at 50℃±2.0℃ for 30 days, and take samples on the 0th, 5th, 10th and 30th days.

[0042]

[0043] B. High humidity test: Place in a constant temperature and humidity chamber at 25°C and 90%±5% for 30 days. Take samples for testing on the 0th, 5th, 10th and 30th days. The results are as follows:

[0044] C. Lighting experiment: 4500Lx±500lx for 30 days, samples were taken on the 5th and 10th days, and samples were taken on the 0th, 5th, 10th and 30th days for testing. The results are as follows:

[0045] The test results show that: The capecitabine crystal form M prepared by the method of the present invention has high stability in an environment of 50°C.

[0046] The wet stability of the capecitabine crystal form M prepared by the method of the present invention is much higher than that of the original product.

[0047] The capecitabine crystal form M prepared by the method of the present invention can significantly slow down the photodegradation rate.

[0048] Compared with the existing crystal forms, the capecitabine crystal form M prepared by the method of the present invention has obvious advantages in stability.

[0049] Test Example 4: Solubility Study According to the Chinese Pharmacopoeia method, the solubility of Form M and existing Form A and Form I were investigated in different media. The results are as follows:

[0050] The solubility test results show that the crystal form M of the present invention has a low solubility and is suitable for the processing of sustained-release preparations. On the other hand, its solubility is comparable to that of the original crystal form A, and the drug safety is more guaranteed, which can greatly reduce the cost of changing the preparation processing technology.

[0051] The test case results show that A. Capecitabine crystal form M has good stability and is easy to store and transport, overcoming the defect of the original crystal form A that is unstable under light.

[0052] B. The solubility of capecitabine crystal form M is basically the same as that of the original crystal form A, which ensures the safety of medication and can significantly reduce the cost of changing the preparation processing technology.

[0053] The method for preparing the capecitabine crystal form M disclosed and proposed in the present invention can be realized by those skilled in the art by referring to the content of this article and appropriately changing the raw materials, process parameters and other links. The method and product of the present invention have been described through preferred embodiments, and relevant technical personnel can obviously modify or appropriately change and combine the method and product described herein without departing from the content, spirit and scope of the present invention to realize the technology of the present invention. It should be particularly pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the scope and content of the present invention.

Claims

1. A new crystalline form M of capecitabine, characterized in that: a. The crystal form is characterized by having the following characteristic peaks 4.82, 5.15, 9.82, 14.99, 17.63, 18.49, 20.13, 25.31, 27.02, 29.49 in the X-ray powder diffraction pattern at 2θ±0.2°. b. Differential scanning calorimetry (DSC) shows that it has only one endothermic peak before the decomposition temperature, and its endothermic peak top value is 124±2°C. c. Thermogravimetric analysis (TGA) shows that the crystal form is unsolvated, does not contain a crystallization solvent, and its decomposition temperature is 148±2°C.

2. The capecitabine crystalline form M according to claim 1, characterized in that It has an X-ray powder diffraction (XRD) pattern as shown in FIG1 .

3. The capecitabine crystalline form M according to claim 1, characterized in that It has a differential scanning calorimetry (DSC) graph as shown in FIG2 .

4. The method for preparing the capecitabine crystal form M according to claim 1, characterized in that: The following steps are involved: Using any crystalline form of capecitabine as the raw material, it is obtained after dissolution, filtration, induced crystallization, and crystal growth. Step 1: Magnetic treatment of the solvent. Stir the solvent in the reactor, and apply a magnetic field through a rare earth permanent magnet outside the reactor. The direction of the magnetic field is orthogonal to the direction of the liquid flow field. Step 2: Add capecitabine and stir continuously at 35~45℃ for about 30 min until it is dissolved or basically dissolved. Filter while hot, and keep the mother liquor at 35~45℃. Step 3: Continue stirring the mother liquor under the action of the magnetic field, and cool the system to 20~30℃. Step 4: Introduce ultrasonic induced crystallization, the ultrasonic frequency is 20~40 KHz, continue ultrasonication after crystals are precipitated, and keep the crystal at a constant temperature for 1~2 h. At this time, the crystal is crystal form M, but the yield is low. Step 5: Continue to cool the system to -5~0℃ under the action of the magnetic field, and keep the crystal at a constant temperature for 2~3 h at the end of the cooling, and filter.

5. The method for preparing capecitabine crystal form M according to claim 5, characterized in that The solvent system in the first step is an alcohol solvent. The magnetic field strength is 0.4-0.6 T, and the magnetic treatment time is 5-8 h.

6. The method for preparing capecitabine crystalline form M according to claim 5, characterized in that The liquid-to-solid ratio of the second step feed is 3~9:

1.

7. The method for preparing capecitabine crystalline form M according to claim 5, characterized in that The cooling rate in the third step is 3-5°C / h.

8. The method for preparing capecitabine crystalline form M according to claim 5, characterized in that The cooling rate in the fifth step is 2-4 °C / h.

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