An S-Flarulaner crystal form and its preparation method

Abstract

The present invention discloses an S - fluralaner crystal form and a preparation method thereof, belonging to the technical field of pharmaceutical chemistry. The X - ray diffraction of the crystal form uses Cu - Kɑ radiation, and the characteristic peaks of the X - ray powder diffraction pattern of the crystal form are represented by 2θ and are located at 8.564° ± 0.1°, 12.811 ± 0.1°, 18.926° ± 0.1°, 20.621° ± 0.1°, 22.685° ± 0.1°, 27.009 ± 0.1°, 27.223° ± 0.1°. By crystallizing using the method of the present invention, the stability of the obtained crystal form and the effect of treating red mites are significantly improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to an S-fluralaner crystal form and a preparation method thereof. Background Art

[0002] Fluralaner is the active substance of the pet drug Bravecto (chewable tablets), and is a new systemic insecticide and acaricide, which was launched in Germany, Spain, Italy, France, the Netherlands and the UK in April 2014. In July 2016, the US FDA approved the application of Merck & Co., Inc. (Fluralaner topical solution) for the treatment of fleas and ticks on cats and dogs, with a validity period of up to 12 weeks after a single administration. At present, the drug component of fluralaner is a mixture of R configuration and S configuration. However, existing research shows that the S form is the effective configuration, as follows:

[0003]

[0004] As a result, the dosage of the main component in the currently marketed fluralaner chewable tablets and drops is relatively large, and the minimum dosage is 40 mg / kg. In order to achieve a safer dosage and reduce toxic and side effects, the Chinese patent application with the patent publication number CN 115677605A discloses an S-configuration fluralaner and a preparation method, and obtains a crystal form of S-configuration fluralaner by a recrystallization method.

[0005] The inventor of the present application reproduced the method of Example 5 in CN 115677605 A to obtain the crystallization of S-configuration fluralaner, and found that there is still room for further improvement in its temperature stability, drug efficacy, etc. Summary of the Invention

[0006] One of the purposes of the present invention is to provide a new S-fluralaner crystal form to solve the above problems.

[0007] In order to achieve the above purpose, the technical solution adopted by the present invention is as follows: an S-fluralaner crystal form, wherein the X-ray diffraction of the crystal form uses Cu-Kɑ radiation, and the characteristic peaks of the X-ray powder diffraction pattern of the crystal form are represented by 2θ and are located at 8.564°±0.1°, 12.811±0.1°, 18.926°±0.1°, 20.621°±0.1°, 22.685°±0.1°, 27.009±0.1°, 27.223°±0.1°.

[0008] As a preferred technical solution: the characteristic peaks are located at 8.564° ± 0.1°, 12.811° ± 0.1°, 17.563° ± 0.1°, 18.225° ± 0.1°, 18.926° ± 0.1°, 20.621° ± 0.1°, 22.685° ± 0.1°, 27.009° ± 0.1°, 27.223° ± 0.1°.

[0009] The second object of the present invention is to provide a method for preparing the above-mentioned S-fluralaner crystal form. The technical solution adopted is that the preparation steps include: dissolving S-fluralaner in isopropanol or ethanol, then heating to dissolve, adding water at room temperature for crystallization, filtering by suction, and drying in vacuum to obtain a white solid; or dissolving S-fluralaner in a mixed solvent of ethylene glycol dimethyl ether / water, then heating to dissolve, crystallizing, filtering by suction, and drying in vacuum to obtain a white solid.

[0010] As a preferred technical solution, the dissolution temperature is the reflux temperature.

[0011] As a preferred technical solution, the volume ratio of the isopropanol or ethanol to water is 1:2.

[0012] As a preferred technical solution, in the mixed solvent of ethylene glycol dimethyl ether / water, the volume ratio of ethylene glycol dimethyl ether to water is 1:2.

[0013] As a preferred technical solution, the crystallization temperature is -10°C to 25°C.

[0014] As a further preferred technical solution, the crystallization temperature is 0 to 10°C.

[0015] Compared with the prior art, the advantages of the present invention are as follows: by using the method of the present invention for crystallization, the stability of the obtained S-fluralaner crystal form and the effect of treating red mites are significantly improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 It is the X-ray powder diffraction pattern of the S-fluralaner crystal form prepared in Example 1 of the present invention;

[0017] Figure 2 It is the DSC curve of the S-fluralaner crystal form prepared in Example 1 of the present invention.

[0018] Figure 3 It is the chiral spectrum of the racemic fluralaner compound provided by the synthesis chamber of the present invention.

[0019] Figure 4 It is the chiral spectrum of the chiral S-fluralaner compound provided by the synthesis chamber of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention will be further described below in conjunction with the accompanying drawings.

[0021] Example 1:

[0022] A method for preparing S-fluralaner crystal form B, comprising the following steps:

[0023] S-fluralaner (10 g) is dissolved in ethylene glycol dimethyl ether / water (150 ml, V / V = 1:2), then heated to reflux for dissolution. After completion, it is stirred at room temperature for crystallization, cooled to 9 °C and filtered by suction to obtain 8.5 g of solid, with an HPLC purity of 99.4%.

[0024] The applicant conducted a large number of experiments and compared different crystallization solvents, including but not limited to DMF, DMSO, isopropanol, ethanol, methanol, petroleum ether, ethyl acetate, ethylene glycol dimethyl ether, water, etc., including the types of organic solvents and the ratio of organic solvents to water, and also compared different crystallization temperatures, including but not limited to -10 °C, 0 °C, 25 °C, 9 °C. Finally, the above crystallization conditions were selected, and the obtained crystal form has better stability and efficacy in treating red mites.

[0025] The X-ray powder diffraction pattern of S-fluralaner crystal form B prepared by the above method was measured by X-ray powder diffraction method for its crystal plane spacing d, Bragg 2θ angle and relative intensity I (expressed as a percentage relative to the strongest ray) as Figure 1 shown, and its characteristic diffraction data are shown in Table 1:

[0026] Table 1: Diffraction data of crystal B prepared in Example 1

[0027]

[0028]

[0029] The DSC data of this crystal form shows an endothermic peak at 107.46 °C, as Figure 2 shown.

[0030] Example 2

[0031] A method for preparing S-fluralaner crystal form B, comprising the following steps:

[0032] S-fluralaner (10 g) is dissolved in ethylene glycol dimethyl ether (50 ml), then heated to reflux for dissolution, the heating is turned off, and 100 ml of water is slowly added dropwise. After completion, it is stirred at room temperature of 25 °C for crystallization to obtain 8 g of white solid, with a purity of 99.71%.

[0033] Example 3

[0034] A method for preparing S-fluralaner crystal form B, comprising the following steps:

[0035] S-Fluralaner (10 g) was dissolved in ethylene glycol dimethyl ether (50 ml), then the temperature was raised to reflux for dissolution. Heating was turned off, and 100 ml of water was slowly added dropwise. After completion, the mixture was stirred at room temperature for crystallization, cooled to 9 °C, and filtered by suction to obtain 8.6 g of white solid with a purity of 99.69%. Compared with Example 2, in this example, the temperature was cooled to 9 °C and filtered by suction, and the yield was higher.

[0036] Accelerated stability test

[0037] The crystalline forms prepared in Example 1 and Example 3 were subjected to accelerated stability tests together with the crystalline form obtained in Example 5 of CN 115677605 A (abbreviated as the comparative example). Experimental conditions: temperature: 40 °C, humidity: 70%; Table 2: Accelerated stability test results of crystalline form B of the present invention and crystalline form A of the literature (CN 112724095 A). Note: The best ee value synthesized by the method of patent CN 112724095 A is 94.5%. The raw materials used in Examples 1 and 3 of the present invention were provided by the Madixin Biopharmaceutical Synthesis Laboratory, and the ee value was 98.02%. The spectra are as Figure 3 、 Figure 4 shown.

[0038] Crystal form 1 month 3 months 6 months Example 1 99.71% (ee98.02%) 99.68% (ee98.02%) 99.66% (ee98.01%) Example 3 99.69% (ee98.02%) 99.69% (ee98.01%) 99.66% (ee97.99%) Comparative example 99.54% (ee98.02%) 99.32% (ee97.97%) 99.11% (ee97.88%)

[0039] Pharmacodynamic test

[0040] The crystalline forms prepared in Example 1 and Example 3 and the crystalline form obtained in Example 5 of CN 115677605 A (abbreviated as the comparative example) were used for the treatment of red mites. The specific test method was as follows:

[0041] The crystalline forms prepared in Example 1 and Example 3 and the crystalline form of the comparative example were respectively mixed with an appropriate amount of solvent DMSO, added with Tween and tocopherol, stirred and dispersed into a uniform and clear solution, and water was added to maintain clarity. The drinking water was used for the treatment of red mites in chickens.

[0042] The test was carried out in a breeding chicken house of a poultry company. It was administered once at a dose of 0.2 mg / kg. Before administration, there were many red mites. After administration, the fecal conveyor belt was covered with shed mites. The corrugated board was placed in a 100 ml EP tube and fixed in the chicken cage for mite collection;

[0043] In Example 1 of the present invention, the weights of mites in the traps after 1 day of administration of the crystal form were 1.312 g, 0.683 g, and 0.811 g; after 4 days of administration, the weights of mites in the traps were 0.119 g, 0.107 g, and 0.183 g; after 7 days of administration, the weights of mites in the traps were 0.004 g, 0.006 g, and 0.002 g. Evaluating by the mite reduction rate is more objective and accurate. The mite reduction rate (%) = (the number of live mites before the test - the number of live mites after the test) / the number of live mites before the test * 100. The lowest mite reduction rate after 4 days of administration was 98.7%, and the highest was 99.8%. After a single administration, the mite reduction rate reached 99.2%. When the second administration was given 4 days later, the mite reduction rate was 100%, achieving the effect of complete killing.

[0044] In Example 3 of the present invention, the weights of mites in the traps after 1 day of administration of the crystal form were 1.317 g, 0.679 g, and 0.821 g; after 4 days of administration, the weights of mites in the traps were 0.121 g, 0.101 g, and 0.187 g; after 7 days of administration, the weights of mites in the traps were 0.003 g, 0.007 g, and 0.003 g. Evaluating by the mite reduction rate is more objective and accurate. The mite reduction rate (%) = (the number of live mites before the test - the number of live mites after the test) / the number of live mites before the test * 100. The lowest mite reduction rate after 4 days of administration was 98.6%, and the highest was 99.7%. After a single administration, the mite reduction rate reached 99.3%. When the second administration was given 4 days later, the mite reduction rate was 100%, achieving the effect of complete killing.

[0045] In the comparative example, the weights of mites in the traps after 1 day of administration were 0.987 g, 0.883 g, and 0.871 g; after 2 days of administration, the weights of mites in the traps were 0.457 g, 0.446 g, and 0.466 g; after 4 days of administration, the weights of mites in the traps were 0.234 g, 0.369 g, and 0.322 g. The lowest mite reduction rate after 4 days of administration was 78.1%, and the highest was 82.6%. After a single administration, the mite reduction rate was 70%. When the second administration was given 4 days later, the mite reduction rate was 90%.

[0046] From the above tests, it can be seen that the crystal form obtained in Example 1 of the present invention has a significantly better effect on treating red mites than the crystal form of the comparative example.

[0047] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims

1. An S-fluralaner crystal form, characterized in that: For the X-ray diffraction of the crystal form, Cu-Kɑ radiation is used, and the characteristic peaks of the X-ray powder diffraction pattern of the crystal form are located at 8.564°±0.1°, 12.811±0.1°, 18.926°±0.1°, 20.621°±0.1°, 22.685°±0.1°, 27.009±0.1°, 27.223°±0.1° in terms of 2θ.

2. The S-fluralaner crystal form according to claim 1, characterized in that: The characteristic peaks are located at 8.564 °±0.1°, 12.811°±0.1°, 17.563°±0.1°, 18.225°±0.1°, 18.926°±0.1°, 20.621°±0.1°, 22.685°±0.1°, 27.009°±0.1°, 27.223°±0.1° in terms of 2θ.

3. A method for preparing the S-fluralaner crystal form according to claim 1 or 2, characterized in that the preparation steps include: dissolving S-fluralaner in a mixed solvent of ethylene glycol dimethyl ether / water, then heating to dissolve, crystallizing, filtering by suction, and drying under vacuum to obtain a white solid.

4. The preparation method according to claim 3, characterized in that the dissolution temperature is the reflux temperature.

5. The preparation method according to claim 3, characterized in that in the mixed solvent of ethylene glycol dimethyl ether / water, the volume ratio of ethylene glycol dimethyl ether to water is 1:

2.

6. The preparation method according to claim 3, characterized in that the crystallization temperature is -10°C to 25°C.

7. The preparation method according to claim 6, characterized in that the crystallization temperature is 0 to 10°C.

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