A method for preparing a crystalline form a of bemethinib

Abstract

The present application relates to the field of medicine, and more particularly to a preparation method of a crystalline form of bevacizumab, which is prepared by using a combination system of water and an organic solvent such as acetone to obtain the crystalline form A of bevacizumab, the solvents used are more environmentally friendly, the process time is shorter, the production capacity is higher, and the obtained product has high purity and low solvent residue.

Description

Technical Field

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

[0002] Binimetinib is a MEK inhibitor with the chemical name 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide. It can be used to treat and / or prevent proliferative diseases such as cancer in humans or animals.

[0003]

[0004] Bimetinib is known to have extremely low solubility in most standard solvents (i.e., less than 1% at room temperature). Due to this low solubility, crystallization by standard cooling methods is difficult and crystal growth is difficult to control.

[0005] CN109336824A discloses that water, which is generally an antisolvent (solubility <0.01% over a wide temperature range), unexpectedly acts as a solvent for bimmetinib when used in a novel solvent mixture containing ether and optionally decanoic acid, and thus significantly increases the solubility of bimmetinib; more specifically, the addition of water to a solvent mixture of tetrahydrofuran and methanol increases the solubility of bimmetinib by about 50% compared to a solvent mixture of anhydrous methanol and tetrahydrofuran, which further contributes to improving the purity distribution of the final drug substance and yields bimmetinib crystalline form A with reduced viscosity behavior and improved flowability.

[0006] However, the solvents used in the method disclosed in CN109336824A are methanol and tetrahydrofuran, both of which are Class II solvents with relatively low residual limits. This results in the problem of unqualified residual solvents, requiring a complex drying process to control solvent residues. The time required to add purified water dropwise to the solvent mixture of tetrahydrofuran and methanol is approximately 25 hours, the cooling time is approximately 10 hours, and the drying time is approximately 32 hours. The entire process is time-consuming and has low production capacity.

[0007] This shows that there are still some problems in the existing technology, and there is an urgent need to develop new methods for preparing bemettinib crystals. Summary of the Invention

[0008] The purpose of this invention is to provide a new method for preparing bemettinib crystal A, which can avoid the above-mentioned problems, and the prepared bemettinib crystal A has ideal particle size and high purity, with a normal particle size distribution, which meets the requirements for preparation of the formulation and is suitable for large-scale industrial production.

[0009] The first aspect of this invention provides a method for preparing bemettinib crystal form A, comprising the following steps:

[0010] (1) Dissolve the crude benomyl in a mixture of purified water and organic solvent, then filter it. Cool the filtrate to 30-50°C while stirring, add benomyl seed crystal A, and keep it warm and stirred for 0.5-1.5 hours.

[0011] (2) Control the temperature at 35-45℃ and slowly add purified water; then slowly cool down to -10-10℃ and keep warm while stirring for 1-3 hours.

[0012] (3) Filtration: The filter cake is vacuum dried at 40-60℃, preferably 45-55℃, for 4-8 hours to obtain bemettinib crystal A crystalline particles.

[0013] In some embodiments, the organic solvent in step (1) is a ketone, preferably acetone, methylpyrrolidone, butanone and methyl isobutyl ketone, more preferably acetone.

[0014] In some embodiments, the volume ratio of purified water to organic solvent in the mixed solvent of step (1) is about 1:3.5 to 6.5, preferably 1:4 to 6, and more preferably 1:4.5 to 5.5.

[0015] In some embodiments, the mass / volume ratio of crude bemettinib to the mixture of solvent in step (1) and purified water in step (2) is approximately 1:45 to 75, preferably 1:50 to 70, more preferably 1:55 to 66, in g / mL.

[0016] In some embodiments, the dissolution in step (1) is carried out at a temperature of about 40 to 65°C, preferably about 50 to 55°C.

[0017] In some embodiments, the mass / volume ratio of crude bemettinib to purified water in step (2) is approximately 1:20 to 50, preferably 1:25 to 45, more preferably 1:30 to 40, in g / mL.

[0018] In some implementations, the temperature is lowered to about 35-45°C, preferably about 40°C, in step (1).

[0019] In some implementations, the temperature is lowered to about -5 to 5°C, preferably about 0°C, in step (2).

[0020] A second aspect of the present invention provides a bemettinib crystal form A, which is prepared by the method described in the first aspect of the present invention.

[0021] Beneficial effects:

[0022] 1) This invention prepares crystalline particles of compound A by changing the type of organic solvent used for dissolution, and the resulting product has the same crystal habit and release as the original research.

[0023] 2) The solvent used in the method of this invention is a Class III solvent, which is more environmentally friendly;

[0024] 3) The present invention has short addition time for purified water, short cooling time, and short drying time, resulting in a shorter overall process time, higher production capacity, and cost savings;

[0025] 4) The product obtained by the method of the present invention has ideal particle size, high purity and low solvent residue, and the particle size is normally distributed, which meets the requirements of formulation and is very suitable for large-scale industrial production. Attached Figure Description

[0026] Figure 1 The image shows the XRPD spectrum of crystal form A obtained in Example 1.

[0027] Figure 2 The image shown is a scanning electron microscope (SEM) image of crystal form A prepared in Example 1.

[0028] Figure 3 The particle size distribution diagram is shown for crystal form A prepared in Example 1.

[0029] Figure 4 The image shows the TGA-DSC image of crystal form A obtained in Example 1. Detailed Implementation

[0030] The present invention will be described in detail below with reference to examples, but this does not imply any adverse limitation on the invention. The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.

[0031] It should be noted that, in this document, all numerical values ​​or ranges are assumed to be constrained by the term "about". Here, "about" or "approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, the error depending in part on how the value was measured or determined. In some embodiments, "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In some embodiments, "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range.

[0032] Instruments and analytical methods:

[0033] 1. X-ray powder diffraction (XRPD)

[0034] Solid samples were analyzed using an X-ray powder diffractometer (X'Pert PRO). An appropriate amount of fine powder was placed in the groove of the sample holder and pressed into a flat and dense plane using a glass slide. The XRPD measurement parameters are shown in Table 1.

[0035] Table 1 XRPD Test Parameters

[0036]

[0037]

[0038] 2. Thermogravimetric-Differential Scanning Calorimetry (TGA-DSC)

[0039] Thermogravimetric-differential scanning calorimetry (TGC) analysis of solids was performed using a Mettler Toledo simultaneous thermal analyzer. A suitable amount of the sample was placed in a crucible using a small spoon, ensuring even distribution, and weighed. The sample was heated according to the parameters listed in Table 2, and the data were analyzed using STARE.

[0040] Table 2. Parameters of TGA-DSC Analysis Method

[0041]

[0042] 3. Thermal scanning electron microscope (SEM)

[0043] Take the test sample, spread it evenly on conductive tape, and observe it under an electron microscope. Analyze the sample according to the parameters listed in Table 3.

[0044] Table 3 Parameters of Thermal Scanning Electron Microscopy Analysis Method

[0045]

[0046] 4. Particle size distribution

[0047] Particle size and particle size distribution analysis of the solid was performed using a Malvern Panaco laser scattering particle size analyzer. Take this product, add 5 mL of a heptane solution of lecithin (1→100), mix well, and use this as the test suspension. Analyze the sample according to the parameters listed in Table 4.

[0048] Table 4 Parameters of Laser Scattering Particle Size Distribution Analysis Method

[0049]

[0050] Example 1: Preparation of Bemetrinib Crystal Form A Crystals

[0051] First, 21 ml of acetone was added to 4 ml of purified water to prepare an acetone / purified water solution. Stirring was started, and then 1.0 g of crude bemettinib was added. The solution was stirred and dissolved at 50–55 °C. After filtration, the solution was washed with a mixture of 0.6 ml of acetone and 0.4 ml of purified water. Crystallization A seeds were added at 35–45 °C, and the solution was kept at this temperature and stirred for 0.5–1.5 h. The temperature was maintained at 35–45 °C, and 35 ml of purified water was slowly added. The solution was cooled to -5–5 °C and stirred for 1–3 h. The filter cake was obtained and dried under vacuum at 50±5 °C for 4 h to yield 0.904 g of bemettinib crystallization A particles, with a yield of 90.4% and a purity of 99.59%.

[0052] The XRPD results of the product are as follows Figure 1 As shown; Scanning electron microscopy results are as follows Figure 2 As shown; the median volume diameter is DV(50) = 16.357 μm, as Figure 3 As shown; TGA-DSC results are as follows Figure 4 As shown.

[0053] Example 2: Preparation of Bemetrinib Crystal Form A Crystals

[0054] First, 25 ml of acetone was added to 5 ml of purified water to prepare an acetone / purified water solution. Stirring was started, and then 1.0 g of crude bemettinib was added. The solution was stirred and dissolved at 50–55 °C. After filtration, the solution was washed with a mixture of 0.8 ml of acetone and 0.2 ml of purified water. Crystallization A seeds were added at 35–45 °C, and the solution was kept at this temperature and stirred for 0.5–1.5 h. The temperature was maintained at 35–45 °C, and 30 ml of purified water was slowly added. The solution was cooled to -5–5 °C and stirred for 1–3 h. The filter cake was obtained and dried under vacuum at 50±5 °C for 4 h to yield 0.905 g of bemettinib crystallization A particles, with a yield of 90.5% and a purity of 99.63%.

[0055] Example 3: Preparation of Bemetrinib Crystal Form A Crystals

[0056] First, 23.88 kg of acetone was added to 5.74 kg of purified water to prepare an acetone / purified water solution. Stirring was started, and then 1.44 kg of crude bemettinib was added. The solution was dissolved by stirring at 50–55 °C, filtered, and washed with a mixed solvent of 0.90 kg of acetone and 0.58 kg of purified water. Seed crystals of crystal form A were added at 35–45 °C, and the mixture was kept at this temperature and stirred for 0.5–1.5 h. The temperature was controlled at 35–45 °C, and 50.40 kg of purified water was slowly added. The temperature was lowered to -5–5 °C, and the mixture was kept at this temperature and stirred for 1–3 h. The filter cake was obtained and dried under vacuum at 50±5 °C for 4 hours to obtain 1.30 g of bemettinib crystal form A crystalline particles, with a yield of 90.3% and a purity of 99.81%.

[0057] Comparative Example 1: Preparation of Bemetrinib Crystal Form A in the Prior Art

[0058] 0.5 g of crude bemettinib was added to 4.5 ml of methanol, 4.5 ml of tetrahydrofuran, and 3.75 ml of purified water. Stirring was started, and the mixture was heated to 53–56 °C to dissolve. The temperature was then lowered to 47–48 °C, and 9.75 ml of purified water was slowly added dropwise over approximately 25 hours. After the addition of purified water was complete, the temperature was lowered to 0–5 °C after approximately 10 hours. The mixture was kept at this temperature and stirred for 2 hours. The resulting filter cake was filtered and dried under vacuum at 50 ± 5 °C for 4 hours to obtain 0.376 g of bemettinib crystals (type A), with a yield of 75.2% and a purity of 98.99%.

Claims

1. A method for preparing bemettinib crystal form A, comprising the following steps: (1) Dissolve the crude benomyl in a mixture of purified water and organic solvent, then filter it. Cool the filtrate to 30-50°C while stirring, add benomyl seed crystal A, and keep it warm and stirred for 0.5-1.5 hours. (2) Control the temperature at 35-45℃ and slowly add purified water; then slowly cool down to -10-10℃ and keep warm while stirring for 1-3 hours. (3) Filtration: The filter cake is vacuum dried at 40-60℃, preferably 45-55℃, for 4-8 hours to obtain bemettinib crystal A crystalline particles.

2. The method according to claim 1, wherein the organic solvent in step (1) is a ketone, preferably acetone, methylpyrrolidone, butanone and methyl isobutyl ketone, more preferably acetone.

3. According to the method of claim 1 or 2, the volume ratio of purified water to organic solvent in the mixed solvent of step (1) is about 1:3.5 to 6.5, preferably 1:4 to 6, and more preferably 1:4.5 to 5.

5.

4. According to any one of claims 1 to 3, the mass / volume ratio of the crude bemettinib to the mixed solvent in step (1) and the purified water in step (2) is about 1:45 to 75, preferably 1:50 to 70, more preferably 1:55 to 66, in g / mL.

5. The method according to any one of claims 1 to 4, wherein the dissolution in step (1) is carried out at a temperature of about 40 to 65°C, preferably 50 to 55°C.

6. In the method according to any one of claims 1 to 5, in step (2), the mass / volume ratio of crude bemettinib to purified water is about 1:20 to 50, preferably 1:25 to 45, more preferably 1:30 to 40, in g / mL.

7. The method according to any one of claims 1 to 6, wherein in step (1), the temperature is lowered to about 35 to 45°C, preferably about 40°C.

8. In the method according to any one of claims 1 to 7, the temperature is lowered to about -5 to 5°C, preferably about 0°C, in step (2).

9. A bemettinib crystal form A obtained by the method according to any one of claims 1 to 8.

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