An febuxostat crystal form and its preparation method

Abstract

The present invention relates to the technical field of pharmaceutical crystallization, and particularly relates to a febuxostat polymorph S and a preparation method thereof. The polymorph of the present invention does not contain crystal water or other crystallization solvents, and is characterized in that the X-ray powder diffraction pattern has the following characteristic peaks at 2θ±0.2°: 6.78, 7.25, 10.00, 10.97, 11.87, 12.86, 13.51, 14.53, 15.74, 16.24, 16.58, 17.59, 19.06, 19.65. The present invention provides a new febuxostat polymorph with moderate solubility, which is more conducive to formulation processing, has a simple preparation process and is easy to industrialize, and a preparation method thereof.

Description

Technical Field

[0001] The present invention belongs to the technical field of crystallization, and particularly relates to a new crystal form of febuxostat and a preparation method thereof. Background Art

[0002] Febuxostat, with the chemical name 2-[(3-cyano-4-isobutoxyphenyl)]-4-methyl-5-thiazolecarboxylic acid, is a xanthine oxidase inhibitor invented by Teijin of Japan. It can inhibit uric acid production and is used to treat related diseases caused by hyperuricemia.

[0003] Polymorphism of drugs is an important factor affecting drug quality, which has important effects on the physical and chemical properties, bioavailability, dissolution of preparations, etc. The research on the crystal form of the active pharmaceutical ingredient has attracted more and more attention from pharmaceutical workers and has become an indispensable part of drug research and drug quality control. According to their stability, drug polymorphs can be divided into three types: unstable, metastable, and stable crystal forms. Among them, the stable form has the worst solubility but the best chemical stability; the unstable form has good solubility but insufficient chemical stability. Because of these prominent characteristics, these two crystal forms are often not used for the processing and application of preparations. The metastable crystal form is commonly used in the research of preparations because of its relatively high chemical stability and relatively good solubility. Currently, the most commonly used method for identifying and analyzing solid drug crystal forms is X-ray powder diffraction.

[0004] Febuxostat exists in multiple crystal forms, and there are obvious differences in the properties of various crystal forms. The known crystal forms of febuxostat are as follows:

[0005] The patent CN1275126 of the original research company Teijin discloses a total of 6 crystal forms, namely crystal forms A, B, C, D, G and amorphous, all obtained in alcohol or alcohol / water mixed solvents. Among them, crystal form G is a hydrate crystal form with poor stability and is prone to mutual conversion with crystal form B; crystal form D is a methanol solvate crystal form, which is a non-pharmaceutical crystal form; crystal form B has poor stability and is extremely 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.

[0006] Currently, preparations generally mainly use crystal form A and crystal form C. Both crystal form A and crystal form C in this patent are obtained by adding crystal seeds, and the preparation is relatively cumbersome. According to this patent, crystal form A and crystal form C are prepared and made into sustained-release microspheres for dissolution experiments. The results show that the dissolution rate of crystal form A is too fast and the sustained-release control is poor. If used in humans, it is very likely to occur the phenomenon of high C max value, low TC value, and even a risk of toxicity. The release of crystal form C is extremely slow. If used in humans, it may occur C max value, too slow onset time, low TC value, etc., and additional immediate-release pellets need to be added. The properties of these two crystal forms put relatively harsh requirements on the preparation processing, which will undoubtedly increase the difficulty and cost of preparation processing.

[0007] CN101139325 discloses Polymorph I and Polymorph II, among which Polymorph I has relatively high stability. By using the patent solution to prepare Polymorph I and conducting solubility experiments, the results show that the solubility of Polymorph I is not very different from that of Polymorph C. When using this polymorph for pharmaceutical preparation processing, its dissolution is also very similar to that of Polymorph C. The preparation method of Polymorph II is alkali dissolution and acid precipitation under high-temperature conditions. The preparation method is relatively cumbersome and it is difficult to achieve large-scale industrial application. Moreover, the product obtained by this method has relatively low purity compared with other polymorphs. After repeated verification through experiments, its purity is difficult to be satisfactory.

[0008] CN107540630 discloses Polymorph W. This polymorph has good solubility. It can be seen from the examples in this patent that the solubility of Polymorph W at different pH values is much higher than that of Polymorph A. Therefore, the release rate of its preparation must also be higher than that of Polymorph A. If used in the human body, the TC value must also be lower than that of Polymorph A. At the same time, max the higher C value leads to a greater toxicity risk and greater difficulty in processing for pharmaceutical preparations.

[0009] CN1970547 discloses Polymorphs H, I, and J. The crystallization systems of these three polymorphs are all nitrile solvents, which are more harmful to the human body and have a lower safety limit for residual solvents. Polymorph control often needs to be achieved in the refining step. As the last step in the processing of active pharmaceutical ingredients, the solvent safety needs to be considered especially.

[0010] For these polymorphs crystallized with toxic solvents to achieve commercial application, it is necessary to conduct scientific and in-depth research and evaluation on the safety limit of solvent residues. Even if the residual solvents can be reduced to meet the range of human safety through post-treatment, there are still problems such as the risk of polymorph transformation during the treatment process and the too high treatment cost.

[0011] Similar to the above situation, there is also Polymorph K disclosed in CN101386605, which is crystallized in a dioxane system; and Polymorph N disclosed in CN101891703, which is prepared in N,N-dimethylformamide or N,N-dimethylacetamide. These solvent systems are highly toxic to the human body and require strict control of residual solvents and are not suitable for the final refining step. If secondary refining is carried out with other systems, it will undoubtedly lead to polymorph change and a decrease in the yield.

[0012] In addition, there are Polymorph Q disclosed in CN101648926, Polymorph P disclosed in CN101824006, and Polymorph M disclosed in CN102276549. According to the X-ray powder diffraction characteristic peaks and spectra described therein, it is considered that these polymorphs are all the same polymorph as Polymorph C in the original research patent and are not new polymorphs.

[0013] The most widely used crystal forms in the current market are the stable crystal form C and the metastable crystal form A. Other crystal forms either have deficiencies or are similar in properties to these two crystal forms, without obvious advantages.

[0014] Through experimental verification, the solubility differences between crystal form A and crystal form C are extremely large, and there are also obvious differences in their dissolution curves after being processed into preparations. The extreme properties of these two crystal forms bring great difficulties in controlling the preparation process. For example, in Patent CN107224431, in order to achieve stable dissolution, it is necessary to separately prepare sustained-release microparticles and immediate-release microparticles, and then mix them in proportion. This undoubtedly greatly increases the difficulty of preparation processing, and also leads to high labor, energy consumption costs, and high production of three wastes in industrial applications, which is contrary to the purpose of green chemistry. There is an urgent need for a crystal form with stability between the two, and the properties of this crystal form will be more conducive to the control of dissolution and release by personnel in the field of preparation processing.

[0015] During the research process of febuxostat, a new crystal form was discovered, which has the following advantages:

[0016] 1. Moderate solubility, which is more conducive to the control of preparation processing;

[0017] 2. Good crystal form stability;

[0018] 3. High purity;

[0019] 4. The solvent system for preparation is a class III solvent with low toxicity;

[0020] 5. The preparation process is simple and easy to industrialize.

[0021] The properties of this new crystal form can make up for the deficiencies of existing crystal forms, especially fill the huge gap between crystal form A and crystal form C, and can significantly reduce the R & D and production difficulties of personnel in the field of febuxostat preparation. Undoubtedly, it will generate high economic, social and environmental benefits. Summary of the Invention

[0022] The present invention provides a febuxostat crystal form S and a preparation method thereof.

[0023] This crystal form does not contain crystal water or other crystal solvents, and is characterized in that the X-ray powder diffraction pattern has the following characteristic peaks at 2θ±0.2°: 6.78, 7.25, 10.00, 10.97, 11.87, 12.86, 13.51, 14.53, 15.74, 16.24, 16.58, 17.59, 19.06, 19.65.

[0024] The more specific powder diffraction characteristics are as follows:

[0025]

[0026] Technical solution of the present invention:

[0027] Preparation method of febuxostat polymorph S, the steps are as follows:

[0028] First step: Dissolve febuxostat in a mixed solvent of a ketone solvent and an alcohol solvent, with a liquid-solid ratio of 6-12:1 (volume-mass ratio); continuously stir at 60-75 °C until dissolved clearly, and then filter.

[0029] Second step: Add purified water in an amount 2-5 times the amount of solid to the system. The addition time is 30-60 min.

[0030] Third step: Keep the temperature constant for crystal cultivation for 60-120 min.

[0031] Fourth step: Cool the system to 5-10 °C, with a cooling rate of 5-10 min / °C, and keep the temperature constant for crystal cultivation for 60-90 min at the end of cooling.

[0032] Fifth step: Filter, wash the filter cake with purified water, and dry the product to obtain febuxostat polymorph S.

[0033] More specifically:

[0034] The alcohol solvent described in the first step of the present invention includes: ethanol, isopropanol; the ketone solvent includes: acetone, methyl ethyl ketone.

[0035] In the mixed solvent described in the first step of the present invention, the ratio of the ketone to the alcohol is 6:4-9:1.

[0036] The yield range of the present invention is 93%-98%, and its HPLC purity can reach more than 99.97%.

[0037] The amount of water added and the water addition rate are key process parameters. The water addition rate has an important influence on regulating the crystallization kinetics. If the water addition rate exceeds the range, the controllability of the crystal form will be poor. Beneficial effects

[0038] The present invention provides a febuxostat polymorph S and a preparation method of this crystal form. This crystal form has stable physical and chemical properties; moderate solubility, which is more conducive to the control of formulation processing; the crystallization preparation process is simple and easy to industrialize; the solvent systems used are all Class III solvents, with low cost and low toxicity; the obtained febuxostat product has high purity. Description of the drawings

[0039] Figure 1 X-ray powder diffraction pattern of polymorph S Embodiments

[0040] Example 1 Preparation of polymorph S

[0041] Add 10 g of febuxostat and a mixed solution of 90 ml of methyl ethyl ketone and isopropyl alcohol into a crystallizer. The ratio of methyl ethyl ketone to isopropyl alcohol in the mixed solution is 7:3. Continuously stir and dissolve at 70 °C, then filter out mechanical impurities and keep the temperature. Add purified water to the system, control the addition time to 60 min, and add a total of 40 ml. Then keep the temperature constant for crystal cultivation for 75 min. Cool the system to 5 °C at a cooling rate of 5 min / °C, and continue crystal cultivation for 90 min at the end of cooling. Filter, wash the filter cake with purified water, and dry to obtain. The febuxostat obtained in this example is determined to be crystal form S by X-ray powder diffraction, with an HPLC purity of 99.98% and an overall yield of 96%.

[0042] Example 2 Preparation of Crystal Form S

[0043] Add 10 g of febuxostat and a mixed solution of 120 ml of acetone and isopropyl alcohol into a crystallizer. The ratio of acetone to isopropyl alcohol in the mixed solution is 6:4. Continuously stir and dissolve at 60 °C, then filter out mechanical impurities and keep the temperature. Add purified water to the system, control the addition time to 40 min, and add a total of 30 ml. Then keep the temperature constant for crystal cultivation for 90 min. Cool the system to 5 °C at a cooling rate of 10 min / °C, and continue crystal cultivation for 80 min at the end of cooling. Filter, wash the filter cake with purified water, and dry to obtain. The febuxostat obtained in this example is determined to be crystal form S by X-ray powder diffraction, with an HPLC purity of 99.97% and an overall yield of 93%.

[0044] Example 3 Preparation of Crystal Form S

[0045] Add 10 g of febuxostat and a mixed solution of 100 ml of acetone and ethanol into a crystallizer. The ratio of acetone to ethanol in the mixed solution is 5:5. Continuously stir and dissolve at 60 °C, then filter out mechanical impurities and keep the temperature. Add purified water to the system, control the addition time to 30 min, and add a total of 20 ml. Then keep the temperature constant for crystal cultivation for 120 min. Cool the system to 5 °C at a cooling rate of 6 min / °C, and continue crystal cultivation for 60 min at the end of cooling. Filter, wash the filter cake with purified water, and dry to obtain. The febuxostat obtained in this example is determined to be crystal form S by X-ray powder diffraction, with an HPLC purity of 99.97% and an overall yield of 95%.

[0046] Example 4 Preparation of Crystal Form S

[0047] Add 10 g of febuxostat and 60 ml of a mixed solution of methyl ethyl ketone and ethanol into a crystallizer. The ratio of methyl ethyl ketone to ethanol in the mixed solution is 9:1. Stir and dissolve continuously at 75 °C, then filter out mechanical impurities and keep the temperature. Add purified water to the system, control the addition time to 30 min, and add a total of 30 ml. Then carry out isothermal crystal cultivation for 100 min. Cool the system to 10 °C at a cooling rate of 8 min / °C, and continue crystal cultivation for 80 min at the end of cooling. Filter, wash the filter cake with purified water, and dry to obtain the product. The febuxostat obtained in this example is determined to be crystal form S by X-ray powder diffraction, with an HPLC purity of 99.97% and an overall yield of 98%.

[0048] Example 5 Preparation of Crystal Form S

[0049] Add 100 g of febuxostat and 800 ml of a mixed solution of acetone and isopropanol into a crystallizer. The ratio of acetone to isopropanol in the mixed solution is 7:3. Stir and dissolve continuously at 65 °C, then filter out mechanical impurities and keep the temperature. Add purified water to the system, control the addition time to 60 min, and add a total of 500 ml. Then carry out isothermal crystal cultivation for 60 min. Cool the system to 10 °C at a cooling rate of 10 min / °C, and continue crystal cultivation for 60 min at the end of cooling. Filter, wash the filter cake with purified water, and dry to obtain the product. The febuxostat obtained in this example is determined to be crystal form S by X-ray powder diffraction, with an HPLC purity of 99.98% and an overall yield of 95%.

[0050] Example 6 Stability Test

[0051] Select the crystal form S sample obtained in Example 5 for accelerated experimental research.

[0052] The experimental conditions are 40 °C ± 2.0 °C and 75% RH ± 5% RH.

[0053]

[0054] Control Example 1: Preparation of Crystal Form A

[0055] Add 10 g of febuxostat and 114 ml of methanol into a crystallizer. Stir and dissolve continuously at 65 °C, filter out mechanical impurities while it is hot and keep the temperature. Disperse 0.02 g of febuxostat crystal form A as crystal seeds in 114 ml of purified water. Slowly drip the purified water suspension into the methanol solution, and control the dripping time to 1 h. Then cool the system to 35 °C, filter, and dry to obtain crystal form A, with an HPLC purity of 99.31%.

[0056] Control Example 2 Preparation of Crystal Form C

[0057] Put 10 g of febuxostat, 100 ml of a mixed solution of methanol and water into a crystallizer. The ratio of methanol to water in the mixed solution is 7:3. Stir and dissolve continuously at 65 °C, then filter out mechanical impurities and keep warm. Add 0.02 g of febuxostat polymorph C as a seed crystal to the solution, cool the solution system to crystallize, filter, and dry to obtain polymorph C, with an HPLC purity of 99.45%.

[0058] Control 3: Preparation of Polymorph I

[0059] Put 1.7 g of febuxostat and 30 ml of ethyl acetate into a crystallizer, reflux and dissolve, filter, stir and cool to room temperature, crystalize for 2 h, filter, and dry to obtain polymorph I, with an HPLC purity of 99.40%.

[0060] Control Example 4: Preparation of Polymorph II

[0061] Put 4 g of febuxostat, 16 ml of 1 mol / L sodium hydroxide solution, and 80 ml of ethanol into a crystallizer and mix. Heat to 40 °C to dissolve, then cool to 20 °C and keep warm. Adjust the pH to 2 with 19 ml of 1 mol / L hydrochloric acid solution, stir for 30 min, filter, and dry to obtain polymorph II, with an HPLC purity of 92.63%.

[0062] Test Example 1: Solubility Experiment

[0063] Conduct a comparative study on the solubility of various polymorphs.

[0064]

[0065] Test Example 2: Comparison of Dissolution of Sustained Release Preparations

[0066] Weigh 40 mg of the active pharmaceutical ingredient, use low-viscosity hydroxypropyl methylcellulose (E30) as a binder; use lactose, microcrystalline cellulose, and magnesium stearate as other excipients; use hydroxypropyl methylcellulose, polyethylene glycol 4000, and titanium dioxide for film coating. Obtain the required sustained release preparation product by using the ordinary tablet preparation process.

[0067] According to the Chinese Pharmacopoeia 2020, use the paddle method, 75 r / min, and measure the release degrees of the sustained release preparations of four polymorphs S, A, C, and I in a pH 6.8 medium. The results are as follows:

[0068]

[0069] Combined with Test Example 1 and Test Example 2, it can be seen that when the preparation processing technology is the same, the crystal form solubility can significantly affect the dissolution of the preparation. The solubility of crystal form A is relatively high and the dissolution is relatively fast, making it difficult to achieve the expected sustained release; the solubility of crystal form C is relatively low and the release is too slow. However, for the febuxostat crystal form S described in the present invention, the solubility is moderate and the dissolution rate is moderate, which can significantly reduce the R & D and processing difficulties of the preparation.

Claims

1. A febuxostat polymorph S, which does not contain water of crystallization or other crystallization solvents, characterized in that The X-ray powder diffraction pattern has characteristic peaks at 2θ ± 0.2°, as shown in Figure 1.

2. The preparation method of febuxostat polymorph S according to claim 1, characterized in that, It includes the following steps: The first step: Dissolve febuxostat in a mixed solvent of a ketone solvent and an alcohol solvent, continuously stir at 60-75 °C until it is clear, filter, the ratio of the ketone to the alcohol is 1.5-9:1, the alcohol solvent includes ethanol and isopropanol; the ketone solvent includes acetone and butanone, and the volume-mass ratio of the mixed solvent to febuxostat is 6-12:1; The second step: Add 2-5 times the amount of purified water of febuxostat to the system, and the addition time is 30-60 min; The third step: Carry out constant-temperature crystal cultivation, and the constant-temperature crystal cultivation time is 60-120 min; The fourth step: Cool the system to 5-10 °C, and carry out constant-temperature crystal cultivation at the end of the cooling, the cooling rate is 5-10 min / °C, and carry out constant-temperature crystal cultivation for 60-90 min at the end of the cooling; The fifth step: Filter, wash the filter cake with purified water, and dry the product to obtain febuxostat polymorph S.

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