Preparation method of febuxostat crystal form C with small particle size

Abstract

The invention relates to a preparation method of a small-particle-size febuxostat crystal form C, and belongs to the field of medicine and pharmacy. The method comprises the following steps: dissolving febuxostat in a low-molecular alcohol or ketone solvent, dissolving, filtering, adding purified water into the obtained filtrate, controlling the feeding speed in the feeding process, cooling the system to 5 DEG C at a constant speed, growing grains for a certain time, finally filtering, leaching a filter cake with purified water, and drying for 5 hours. And the crystal form C product with ideal granularity is directly obtained through crystallization control, so that the use of crushing equipment is avoided, and the cost is reduced. The process is stable, strong in controllability, good in batch stability, low in cost and suitable for industrial production, and the yield can reach 90-95%. Meanwhile, the crystal form obtained by the process is complete, the particle size distribution curve is in normal distribution, and the crystal is easy to disperse and can be directly used for preparation products.

Description

Technical Field

[0001] The invention relates to the technical field of medicines and relates to a method for preparing small-sized febuxostat, in particular to a method for preparing small-sized febuxostat C crystals. Background Art

[0002] Febuxostat, chemical name: 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, English name: 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, its molecular formula is: C 16 H 16 N 2 O 3 S, molecular weight is 316.38, chemical structure formula is

[0003] Febuxostat is a new generation of anti-gout drugs synthesized by Teijin, which shows excellent activity. It is a selective xanthine oxidase / xanthine dehydrogenase inhibitor with good application prospects. The particle size of the API is one of the important factors in the development and control of solid dosage forms. It may have a significant impact on the quality indicators of the final product, such as bioavailability, solubility, uniformity, stability, etc. These effects are more significant in poorly soluble drugs. In addition, the particle size of the API will also affect the manufacturability of the drug, such as fluidity, total mixing uniformity, compressibility, etc., which will ultimately affect the safety and effectiveness of the drug. The particle size needs to be controlled in every step of the production process of solid oral preparations, including mixing, granulation, drying, granulation, drying, coating and tableting. As a poorly soluble drug, the particle size of Febuxostat has a particularly significant effect on the dissolution and absorption of the final solid preparation.

[0004] Patent WO2015 / 063561 discloses the use of air flow milling, fluid grinding or wet grinding to control the particle size within 100 microns. The original research company of Febuxostat, Japan Teijin patent CN1642546A, provides a Febuxostat solid preparation with stable dissolution. In its process description, it is proposed that the solid preparation needs to control the particle size of the raw material drug preferably within the range of 3 to 50 μm. If the particle size is less than 3 μm, the raw material drug is prone to scattering, which is not conducive to operation; if the particle size is greater than 50 μm, the dissolution curve of the preparation will deviate significantly. It can be seen that the particle size of the raw material drug has a significant effect on the dissolution of the Febuxostat solid preparation.

[0005] Patent CN101474175A further refined the effect of the particle size of Febuxostat API on solid preparations. Febuxostat was micronized, and Febuxostat API samples with particle sizes ranging from 1 to 3.5 μm, 3.5 to 10 μm, 10 to 20 μm, 20 to 30 μm, and 30 to 50 μm were collected and processed into solid preparations through wet granulation technology, and then bioequivalence tests were conducted using beagle dogs. The results showed that solid preparations with API particle sizes ranging from 3.5 to 10 μm were bioequivalent, with high bioavailability and good stability, while solid preparations with other particle size ranges were not bioequivalent.

[0006] The above patents involving the particle size of Febuxostat API all control the particle size by mechanical crushing or air flow crushing, which is also the method currently commonly used by domestic and foreign pharmaceutical companies. Due to equipment limitations, it is difficult to obtain products with the desired particle size distribution simply through the crushing process, and the screening process is required to obtain the desired particle size distribution products. However, there are often defects such as poor particle size controllability, poor batch reproducibility, and high energy consumption in the crushing process. Material screening is prone to produce a large amount of waste and dust pollution. If the drug particle size distribution can be controlled through the crystallization process, it can not only improve the control ability of the production process, but also have good batch reproducibility, environmentally friendly process, low energy consumption, and is conducive to industrial production.

[0007] Patent CN1275126A of Haraken Teijin Co., Ltd. discloses a total of 6 crystal forms, including crystal forms A, B, C, D, G and amorphous crystal forms, all of which are obtained by crystallization under specific conditions defined by the temperature and the ratio of methanol to water in the mixed solvent used. Among them, crystal form G is a hydrate crystal form with poor stability and is easily converted into crystal form B; crystal form D is a methanol solvate crystal form, which is not a medicinal crystal form; crystal form B is not stable and is very easy to absorb water and convert into crystal form G; crystal form A is a metastable crystal form in most systems; crystal form C is a stable crystal form in most systems, and there are few reports on the preparation methods of crystal forms A and C with small particle sizes. Summary of the invention

[0008] According to the original patent report, Form C is more stable than Form A, and is not prone to crystal transformation during the preparation of pharmaceutical preparations. It is also easier to maintain stability during storage, and has a higher safety factor for human medication. However, according to the reports of the prior art, there are few preparation methods for Form C, especially the preparation method of Form C with small particles. Therefore, in order to solve the existing problems during the research and development process, the inventors thought of preparing a method for preparing a small-particle Form C that can improve the solubility of the Febuxostat drug while maintaining the stability of the drug. In the process of research and development, the existing technology for preparing cooling systems for other crystal forms was also used, but the final product was either not Form C, or the particle size was too large or too small. After repeated experiments and explorations, the technical invention concept finally obtained is as follows: Step 1: dissolve febuxostat in low molecular weight alcohol or ketone at a liquid-to-solid mass ratio of 8-10:1, continue to stir and dissolve at 45-55°C for 30 minutes, filter, transfer the filtrate to a crystallizer and keep it at 45-55°C for 30-45 minutes; Step 2: Add 4-5 times the mass of febuxostat purified water in the first step to the solution obtained in the first step at a uniform rate for 60-120 min; Step 3: Follow the above step 2 and cool down to 5°C at a rate of 10min / °C, and grow the crystal at this temperature for 10min; Step 4: Filter, wash the filter cake with purified water, and finally dry the product to obtain small-particle Febuxostat Form C.

[0009] The small-particle-size febuxostat crystal form C of the present invention refers to a febuxostat crystal form C having a D90 of less than 15 μm.

[0010] The low molecular alcohol solvent described in the first step of the present invention is one or a mixed solvent of several alcohol solvents selected from methanol, ethanol, isopropanol and n-propanol; The low molecular weight ketone solvent described in the first step of the present invention is one of acetone and butanone.

[0011] The drying conditions of the present invention can be vacuum drying, with a vacuum degree of 0.06-0.1Mpa and a drying temperature of 50-60°C.

[0012] During the research and development process, it was found that the speed of adding purified water in the second step is the key process of the present invention. If the speed is too fast and the addition time is less than 60 minutes, a large number of crystal particles will precipitate, agglomeration will easily occur, and the particle size distribution cannot be effectively controlled; if the addition speed is too slow and the addition time is too long, exceeding 120 minutes, the supersaturation is too low and a product of a sufficiently corresponding particle size cannot be obtained.

[0013] Beneficial effects: The present invention provides a method for preparing small-sized febuxostat C crystals with a D90 of less than 15 μm, and directly obtains a crystal C product with an ideal particle size through crystal control, avoiding the use of crushing equipment and reducing costs. The process is stable, has strong controllability, good batch stability, low cost, and a yield of 90-95%, which is suitable for industrial production. At the same time, the process obtains a complete crystal form, a normal distribution of the particle size distribution curve, is easy to disperse, and can be directly used in preparation products. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 PXRD pattern of Febuxostat C crystals obtained in Example 1; Figure 2 DSC graph of Febuxostat C crystals obtained in Example 1; Figure 3 Particle size distribution diagram of Febuxostat C crystals obtained in Example 1; Figure 4 Particle size distribution diagram of Febuxostat C crystals obtained in Comparative Example 1; Figure 5 Particle size distribution diagram of Febuxostat C crystals obtained in Comparative Example 2. DETAILED DESCRIPTION Example 1

[0015] Put 100g of Febuxostat into 800g of acetone, stir and dissolve at 45℃ for 30min, filter while hot, transfer the filtrate into a crystallizer and stir at a constant temperature of 45℃ for 30min. Then, add 400g of purified water (Febuxostat: purified water = 1:4, mass ratio) to the crystallizer at a uniform rate, and the addition time is controlled at 60min. Then, cool the system to 5℃ at a rate of 10min / ℃, and grow the crystals at 5℃ for another 10min. Filter, rinse the filter cake with purified water, and vacuum dry at 70℃ for 5h with a vacuum degree of 0.1Mpa. The PXRD spectrum of the obtained Febuxostat C crystal product is as follows: Figure 1 As shown, the DSC spectrum is Figure 2 As shown, the particle size distribution curve obtained by the Malvern particle size analyzer is a normal single peak. Figure 3 As shown, D90 is 14.242 μm, HPLC purity is 99.97%, and product yield is 95%. Example 2

[0016] Put 100g of Febuxostat into 1000g of ethanol, stir and dissolve at 50℃ for 30min, filter while hot, transfer the filtrate into a crystallizer and stir at 45℃ for 30min. Then add 500g of purified water (Febuxostat: purified water = 1:5, mass ratio) to the crystallizer at a uniform rate, and the addition time is controlled at 80min. Then cool the system to 5℃ at a rate of 10min / ℃, and grow the crystals at 5℃ for another 10min. Filter, rinse the filter cake with purified water, and vacuum dry at 70℃ for 5h with a vacuum degree of 0.1Mpa. The PXRD spectrum of the obtained Febuxostat product is the same as Figure 1 The DSC spectrum is consistent with Figure 2 The particle size distribution curve obtained by the Malvern particle size analyzer was a normal single peak, D90 was 11.734 μm, HPLC purity was 99.96%, and product yield was 97%. Example 3

[0017] Put 100g of Febuxostat into 1000g of butanone, stir and dissolve at 55℃ for 30min, filter while hot, transfer the filtrate into a crystallizer and stir at 45℃ for 30min. Then add 500g of purified water (Febuxostat: purified water = 1:5, mass ratio) to the crystallizer at a uniform rate, and the addition time is controlled at 80min. Then cool the system to 5℃ at a rate of 10min / ℃, and grow the crystals at 5℃ for another 10min. Filter, rinse the filter cake with purified water, and vacuum dry at 70℃ for 5h with a vacuum degree of 0.1Mpa. The PXRD spectrum of the obtained Febuxostat product is the same as Figure 1 The DSC spectrum is consistent with Figure 2 The particle size distribution curve obtained by the Malvern particle size analyzer was a normal single peak, D90 was 13.222 μm, HPLC purity was 99.94%, and the product yield was 98%. Example 4

[0018] Put 100g of Febuxostat into 1000g of methanol, stir and dissolve at 50℃ for 30min, filter while hot, transfer the filtrate into a crystallizer and stir at 45℃ for 30min. Then add 400g of purified water (Febuxostat: purified water = 1:4, mass ratio) to the crystallizer at a uniform rate, and the addition time is controlled at 80min. Then cool the system to 5℃ at a rate of 10min / ℃, and grow the crystals at 5℃ for another 10min. Filter, rinse the filter cake with purified water, and vacuum dry at 70℃ for 5h with a vacuum degree of 0.1Mpa. The PXRD spectrum of the obtained Febuxostat product is the same as Figure 1 The DSC spectrum is consistent with Figure 2 The particle size distribution curve obtained by the Malvern particle size analyzer was a normal single peak, D90 was 12.534 μm, HPLC purity was 99.96%, and the product yield was 96%.

[0019] Comparative Example 1: Add purified water quickly, add in 30 minutes Put 100g of Febuxostat into 800g of acetone, stir and dissolve at 45℃ for 30min, filter while hot, transfer the filtrate into a crystallizer and stir at a constant temperature of 45℃ for 30min. Then, add 400g of purified water (Febuxostat: purified water = 1:4, mass ratio) to the crystallizer at a uniform rate, and the addition time is controlled at 30min. Then, cool the system to 5℃ at a rate of 10min / ℃, and grow the crystals at 5℃ for another 10min. Filter, rinse the filter cake with purified water, and vacuum dry at 70℃ for 5h with a vacuum degree of 0.1Mpa. The PXRD spectrum of the obtained Febuxostat C crystal product is as follows: Figure 1 The DSC spectrum is consistent with Figure 2 The particle size distribution curve obtained by the Malvern particle size analyzer is a normal single peak. Figure 4 As shown, D90 is 56.873 μm, HPLC purity is 99.90%, and product yield is 94%.

[0020] The conditions of this comparative example are consistent with those of Example 1, with the only difference being that the time for adding purified water exceeds the aforementioned key process parameter range. The particle size distribution of the product has a tail, which is caused by the addition of purified water too quickly, excessive supersaturation, and out-of-control of the process, spontaneous precipitation of smaller crystals, and crystal agglomeration, which leads to larger particle size. It can be seen from this comparative example that the addition speed of purified water exceeds the aforementioned key process parameter range, which will cause the product D90 to become larger and the particle size distribution to have a tail.

[0021] Comparative Example 2: Adding purified water for 150 minutes Put 100g of Febuxostat into 1000g of ethanol, stir and dissolve at 50℃ for 30min, filter while hot, transfer the filtrate into a crystallizer and stir at a constant temperature of 45℃ for 30min. Then add 500g of purified water (Febuxostat: purified water = 1:5, mass ratio) to the crystallizer at a uniform rate, and the addition time is controlled at 150min. Then cool the system to 5℃ at a rate of 10min / ℃, and grow the crystals at 5℃ for another 10min. Filter, rinse the filter cake with purified water, and vacuum dry at 70℃ for 5h with a vacuum degree of 0.1Mpa. The PXRD spectrum of the obtained Febuxostat C crystal product is as follows: Figure 1 The DSC spectrum is consistent with Figure 2 The particle size distribution curve obtained by the Malvern particle size analyzer is a normal single peak. Figure 5 As shown, D90 is 65.460 μm, HPLC purity is 99.91%, and product yield is 95%.

[0022] The conditions of this comparative example are consistent with those of Example 2, the only difference being that the time for adding purified water exceeds the aforementioned key process parameter range. The particle size of the product is normally distributed, with a large number of particles in a large particle size range. The reason is that the water purification time is too long, the supersaturation is too low, and the crystals are mainly growing. From this comparative example, it can be seen that the addition speed of purified water exceeds the range of the aforementioned key process parameters, which will cause the overall particle size to become larger and cannot meet the downstream product requirements.

Claims

1. A method for preparing small-particle febuxostat crystal form C, characterized in that: Step 1: dissolve febuxostat in low molecular weight alcohol or ketone at a liquid-to-solid mass ratio of 8-10:1, continue to stir and dissolve at 45-55°C for 30 minutes, filter, transfer the filtrate to a crystallizer and keep it at 45-55°C for 30-45 minutes; Step 2: Add 4-5 times the mass of febuxostat purified water in the first step to the solution obtained in the first step at a uniform rate for 60-120 min; Step 3: Follow the above step 2 and cool down to 5°C at a rate of 10min / °C, and grow the crystal at this temperature for 10min; Step 4: Filter, wash the filter cake with purified water, and finally dry the product to obtain small-particle Febuxostat Form C.

2. The preparation method according to claim 1, characterized in that The small-particle size febuxostat crystal form C refers to febuxostat crystal form C with D90 less than 15 μm.

3. The preparation method according to claim 1, characterized in that The low molecular alcohol solvent described in the first step is one of methanol, ethanol, isopropanol, and n-propanol, or a mixed solvent of several alcohol solvents.

4. The preparation method according to claim 1, characterized in that The low molecular weight ketone solvent in the first step is one of acetone and butanone.

5. The preparation method according to claim 1, characterized in that The drying conditions may be vacuum drying, with a vacuum degree of 0.06-0.1Mpa and a drying temperature of 50-60°C.

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