Dasatinib fumaric acid crystal form and preparation method thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a dasatinib fumaric acid crystal form and a preparation method thereof, and in the dasatinib fumaric acid crystal form provided by the invention, the molar ratio of dasatinib to fumaric acid to methanol is 1: 1: 1. The dasatinib fumaric acid crystal form provided by the invention has relatively good stability and relatively high dissolution rate, and is of great significance for improving the bioavailability of a dasatinib medicine and preparing a preparation.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a crystal form of dasatinib fumarate and a preparation method thereof. BACKGROUND

[0002] Dasatinib, trade name Sprycel, is a tyrosine kinase inhibitor developed by Schering-Plough Corporation. The chemical name is: N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, the molecular formula is C 22 H 26 ClN7O2S, the molecular weight is 488.00600, and the chemical structural formula is as follows:

[0003] Dasatinib is mainly used for treating all stages of chronic myeloid leukemia in adult patients who are resistant to or cannot tolerate treatment programs including imatinib mesylate. It can also be used for treating adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia who are resistant to or cannot tolerate previous treatment drugs.

[0004] Patent WO2005077945 describes five crystal forms of dasatinib, including monohydrate, butanol solvate, ethanol solvate, pure form N-6 and pure form T1H1-7. Patent WO2007035874 discloses the crystalline forms of various salts (such as methanesulfonate, hydrobromide, salicylate, etc.) of dasatinib. Patent WO2009053854 discloses various crystal forms of dasatinib (including isopropanol solvate, isopropanol-dimethyl sulfoxide solvate, methanol solvate, etc.). Patent WO2019209908 discloses the butyl p-hydroxybenzoate co-crystal, propyl p-hydroxybenzoate co-crystal, ethyl vanillin co-crystal, formic acid ethyl ester solvate of dasatinib. Patent WO2018134190 discloses the co-crystals of phenolic compounds of dasatinib and resorcinol, vanillyl alcohol, 4-ethoxyphenol, carvacrol and p-cresol, but there are still problems of poor solubility or poor solubility or poor stability of dasatinib.

[0005] Due to poor solubility of dasatinib, its preparation has low bioavailability, and the absorption rate of the drug depends on the dissolution rate. In view of the pharmaceutical value of dasatinib, although various crystal forms have been reported, there is still an urgent need for a dasatinib compound crystal with excellent physicochemical properties, stable properties and easy industrial production. The present application provides a simple and easy-to-operate method for preparing high-purity dasatinib fumarate crystal form, and provides a product with good chemical stability and solubility, which provides a better basis for the application of dasatinib in drug treatment, so as to more efficiently exert the pharmaceutical value of dasatinib. SUMMARY

[0006] In view of the deficiencies of the prior art, the present application provides a dasatinib fumarate crystal form, which has a simple preparation process, excellent chemical stability and is suitable for various preparations and is more suitable for industrial production.

[0007] The specific technical content of the present application is as follows:

[0008] In a first aspect of the present application, a dasatinib fumarate crystal form is provided, wherein the molar ratio of dasatinib, fumaric acid and methanol in the crystal form is 1:1:1.

[0009] Preferably, the dasatinib fumarate crystal form has characteristic peaks at 5.61±0.2°, 11.40±0.2°, 11.63±0.2°, 14.24±0.2°, 19.05±0.2°, 19.50±0.2°, 22.73±0.2°, 25.97±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0010] Preferably, the dasatinib fumarate crystal form has characteristic peaks at 5.61±0.2°, 5.87±0.2°, 11.02±0.2°, 11.40±0.2°, 11.63±0.2°, 14.24±0.2°, 17.11±0.2°, 19.05±0.2°, 19.50±0.2°, 22.73±0.2°, 24.39±0.2°, 25.97±0.2°, 27.36±0.2°, 30.33±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0011] Preferably, the dasatinib fumarate crystal form has characteristic peaks in the X-ray powder diffraction spectrum shown in Figure 1 .

[0012] Preferably, the dasatinib fumarate crystal form has a DSC-TGA spectrum as shown in Figure 2 , and an endothermic melting peak appears at 167.92℃ and 196.41℃, respectively.

[0013] Preferably, the crystallographic parameters of the dasatinib fumarate crystal form are: monoclinic system, space group P21 / n; cell parameters are: a = 18.4067(3), b = 9.37900(10), c = 18.7942(3), α = 90°, β = 108.135(2), γ = 90°, z = 58, cell volume V = 3083.39(8) Å3.

[0014] In a second aspect of the present application, a preparation method of the dasatinib fumarate crystal form is provided, which specifically comprises the following steps: Dasatinib and fumaric acid are added into a mixed solvent of methanol and organic solvent A for dissolution, and ultrasonic heating and stirring are performed until the solid is completely dissolved, then crystallization is performed by standing, and the dasatinib fumarate crystal is obtained by filtration and drying.

[0015] Preferably, the molar ratio of the dasatinib to the fumaric acid in the raw material is 1:1-1.5.

[0016] Further preferably, the molar ratio of the dasatinib to the fumaric acid in the raw material is 1:1.2.

[0017] Preferably, the organic solvent A is selected from one or more of ethanol, acetone, acetonitrile, isopropanol and trifluoroethanol.

[0018] Preferably, in the mixed solvent, the volume ratio of methanol to the organic solvent A is 1:0-1.5.

[0019] Preferably, the mass-volume ratio of the dasatinib to the mixed solvent is 1:0.15-0.3, wherein the mass is in mg and the volume is in mL.

[0020] Preferably, the heating temperature is 40-65°C, and further preferably 55°C.

[0021] Preferably, the crystallization temperature is 0-30°C, and further preferably 15-25°C.

[0022] Preferably, the crystallization time is 8-36h.

[0023] Preferably, the drying temperature is 55°C, and the drying time is 8-16h.

[0024] In the preparation method provided in the present application, the dasatinib crude material is commercially available dasatinib or dasatinib prepared according to the method of the prior art.

[0025] The dasatinib fumarate crystal form provided in the present application is used as an active ingredient for preparing a drug for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.

[0026] In a third aspect, the present application provides a pharmaceutical composition comprising the dasatinib fumarate crystal form and a pharmaceutically acceptable additional component.

[0027] Preferably, the pharmaceutical composition is prepared by using standard and conventional techniques to combine the compound of the present application with a pharmaceutically acceptable solid or liquid carrier, and optionally with pharmaceutically acceptable adjuvants and excipients to form a useful dosage form.

[0028] Preferably, the useful dosage form of the pharmaceutical composition is selected from one of a spray, a tablet, a capsule, a powder injection, a liquid injection, a lyophilized powder injection, or other pharmaceutically useful dosage forms.

[0029] Confirmation of crystal structure

[0030] The dasatinib fumarate crystal form of the present application is subjected to X-ray single crystal diffraction test analysis. The X-ray single crystal diffraction instrument and test conditions involved in the present application are as follows: Rigaku XtaLAB Synergy X-ray single crystal diffraction instrument; light source copper target, temperature 293 K, voltage 50 kv, current 1 mA, data is collected in ω scanning mode and is corrected. Lp The structure is solved by direct method, all non-hydrogen atoms are found by difference Fourier method, all hydrogen atoms on carbon and nitrogen are obtained by theoretical hydrogenation, and the structure is refined by least square method.

[0031] The crystallographic data obtained by testing and analyzing the dasatinib fumarate crystal form prepared in the present application are shown in Table 1: the crystallographic parameters are monoclinic crystal system, space group P21 / n; the cell parameters are: a = 18.4067(3), b = 9.37900(10), c = 18.7942(3), α = 90°, β = 108.135(2), γ = 90°, z = 58, cell volume V = 3083.39(8) Å3.

[0032] The ORTEP diagram of the dasatinib fumarate crystal form of the present application shows that the crystal is composed of one molecule of dasatinib, one molecule of fumaric acid and one molecule of methanol. Figure 3

[0033] Table 1 Main crystallographic data of dasatinib fumarate crystal form

[0034] ​The X-ray powder diffraction tester and test conditions in the test of the dasatinib fumarate crystal form of the application are as follows: X-ray powder diffraction tester: PANalytical Emprem; Cu-Ka; sample table: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage: 45 kv, current: 40 mA; divergence slit: 1 / 4; anti-scattering slit: 1; soller slit: 0.04 rad; step length: 0.5 s; scanning range: 3-50°.

[0035] According to the crystallographic data, the characteristic peaks in the X-ray powder diffraction (X-ray powder diffraction (Cu-Ka) are shown in the following table 1 and table 2. Figure 1

[0036] Table 2: Main PXRD peaks of dasatinib fumarate crystal form

[0037] The TGA / DSC thermal analysis tester and test conditions in the application are as follows: TGA / DSC thermal analyzer: METTLER TOLEDO TGA / DSC3+; dynamic temperature section: 30-350℃; heating rate: 10℃ / min; program section gas: N2; gas flow: 50 mL / min; crucible: aluminum crucible 40ul.

[0038] The TGA / DSC test results of the dasatinib fumarate crystal prepared by the method of the application are shown in the following table 3 and table 4. Figure 2 As shown in the table, the DSC detection results appear an endothermic melting peak at 167.92℃ and 196.41℃, respectively.

[0039] Compared with the prior art, the technical effects obtained by the application are as follows: the preparation of the dasatinib fumarate crystal form provided by the application has good chemical stability and high dissolution rate, the preparation method provided by the application has good reproducibility and simple operation, and the dissolution rate of the crystal form prepared according to the method is higher than that of the existing conventional crystal. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 : X-ray powder diffraction pattern of dasatinib fumarate crystal form.

[0041] Figure 2 : DSC-TGA graph of dasatinib fumarate crystal form.

[0042] Figure 3 : ORTEP graph of dasatinib fumarate crystal form.

[0043] Figure 4 : Packing graph of dasatinib fumarate crystal form. DETAILED DESCRIPTION

[0044] ​The application is further illustrated by the following examples, it should be understood that the examples of the application are only used to illustrate the application, but not limit the application, so, the simple improvement of the application under the premise of the method of the application is within the scope of the application.

[0045] Example 1

[0046] 24.6 mg of dasatinib and 7.1 mg of fumaric acid were added to 5 ml of methanol, ultrasonic heating to 55°C, stirring to dissolve, filtering, standing at 20°C to crystallize, filtering and drying to get dasatinib fumaric acid crystal form. The yield was 97.99%, and the purity was 99.97%.

[0047] Example 2

[0048] 24.6 mg of dasatinib and 8.9 mg of fumaric acid were added to 2.5 ml of methanol and 1.3 ml of acetone, ultrasonic heating to 40°C, stirring to dissolve, filtering, standing at 15°C to crystallize, filtering and drying to get dasatinib fumaric acid crystal form. The yield was 97.38%, and the purity was 99.94%.

[0049] Example 3

[0050] 24.6 mg of dasatinib and 5.9 mg of fumaric acid were added to 3 ml of methanol and 4.5 ml of acetonitrile, ultrasonic heating to 65°C, stirring to dissolve, filtering, standing at 30°C to crystallize, filtering and drying to get dasatinib fumaric acid crystal form. The yield was 97.83%, and the purity was 99.96%.

[0051] Example 4

[0052] 24.6 mg of dasatinib and 7.1 mg of fumaric acid were added to 2.2 ml of methanol and 5 ml of isopropyl alcohol, ultrasonic heating to 55°C, stirring to dissolve, filtering, standing at 0°C to crystallize, filtering and drying to get dasatinib fumaric acid crystal form. The yield was 95.67%, and the purity was 99.92%.

[0053] The crystal forms of dasatinib fumaric acid obtained in the above examples were the same, and their stability and dissolution were studied.

[0054] Comparative Example 1

[0055] Dasatinib N-6 form (5.00 g, 10.25 mmol) and carvacrol (12.5 mL, 81.55 mmol) were added to a round-bottom flask, heated at 50°C overnight. The solid was filtered, washed with a heptane / methyl tert-butyl ether mixture and dried under vacuum (room temperature) to obtain a co-crystal of dasatinib and carvacrol as a white solid, with a yield of 88.23% and a product purity of 98.54%.

[0056] Comparative Example 2

[0057] In a 30 L reaction flask, 1.68 kg of dasatinib crude, 8.4 L of DMF was added, heated to dissolve, filtered, concentrated to precipitate a large amount of solid, 16.8 L of ethanol was added, stirred at reflux for 1 h, cooled to room temperature, filtered, and the filter cake was washed with ethanol. In a 30 L reaction flask, the above filter cake, 16.8 L of ethanol, 1.68 L of DMF was added, heated to reflux for 1 h with stirring, cooled to room temperature, filtered, and the filter cake was washed with ethanol, heated to reflux for 1 h with 16.8 L of ethanol, cooled to room temperature, filtered, and dried at 105 °C under reduced pressure for 12 h to obtain white crystals, with a yield of 95.12% and a product purity of 99.85%.

[0058] Comparative Example 3

[0059] 50 mg of dasatinib and 18 mg of ethyl vanillin were added to 5 mL of methanol, heated to 55 °C to obtain a clear solution. The clear solution was placed in a vacuum oven at 50 °C for solvent evaporation to obtain Form II co-crystal of dasatinib and ethyl vanillin, with a yield of 81.92% and a product purity of 99.90%.

[0060] Comparative Example 4

[0061] 72 mg of dasatinib was added to 9 mL of methanol, heated to 55 °C with ultrasonic at 35 kHz, and stirred until completely dissolved; cooled to 22 °C, and controlled temperature crystallization for 18 h, filtered, and dried at 40 °C under vacuum to obtain dasatinib methanol solvate, with a yield of 97.02% and a product purity of 99.97%.

[0062] Comparative Example 5

[0063] 1.000 g (2.05 mmol) of dasatinib base, 0.367 g (2.05 mmol) of cyclamic acid, and 20 cm 3 Acetone aqueous solution (water to acetone ratio of 10:1) was weighed into the instrument, stirred for 4 days. The precipitated crystals were filtered, washed with a small amount of cold ethanol and tert-butyl methyl ether, and dried under vacuum at a temperature of 45 °C and 11 mbar for 24 h to obtain dasatinib cyclamic acid (1:1) salt Form II. Yield 94.7%, product purity 99.65%.

[0064] Comparative Example 6

[0065] 1.0 g of dasatinib base and 20 cm 3Methanol was weighed into the apparatus, and the mixture was heated to a temperature of 70°C with vigorous stirring. The mixture was stirred at this temperature for 5 minutes. With stirring, 0.390 g of p-toluenesulfonic acid monohydrate was added to the reaction mixture by stopping heating. The mixture was stirred at room temperature for 20 hours, and precipitation occurred. The precipitated crystals were filtered and dried slowly to obtain the methanol solvate of dasatinib p-toluenesulfonic acid (1:1) salt. The yield was 81.5%, and the purity of the product was 89.65%.

[0066] Stability test

[0067] The specific stability test method refers to the guidance method for stability test in the fourth part of the Chinese Pharmacopoeia 2020 edition. The purity is detected by HPLC method, and the specific test results are shown in Table 3.

[0068] Table 3 Stability test of dasatinib crystal form under light, high temperature and high humidity conditions

[0069] The stability test results show that the dasatinib fumarate crystal form prepared by the application has good stability. It is found that Examples 1-4 have similar stability test results.

[0070] Accelerated test

[0071] The crystal forms obtained by Examples 1 and Comparative Examples 1-6 of the application were subjected to accelerated test using the marketing package, and were placed in a constant temperature and humidity incubator at 40±2°C; RH 75±5% for 24 months. Samples were taken at the end of 3, 6, 12 and 24 months for inspection, and compared with the results at 0 months. The results are shown in Table 4.

[0072] Table 4 Accelerated test results

[0073] Comparative Examples 1-6 are existing crystal forms. The new crystal of the application has no obvious increase in impurities under accelerated experimental conditions for 24 months, the crystal form does not change, and the stability is good, which is suitable for long-term storage and application in preparation.

[0074] Dissolution test

[0075] The dissolution of the dasatinib crystal form obtained in Example 1 and Comparative Examples 1-6 was determined according to the following method. 1000 mL of acetate buffer (pH 4.0+0.05%) containing 1% Triton X-100 was used as the dissolution medium, the rotation speed was 60 rpm, the operation was performed according to the law, the temperature was 37°C, 10 mL was taken at 10 min, 20 min, 30 min and 45 min, filtered, and the filtrate was used as the test solution, and the same amount of fresh dissolution medium at the same temperature was added; another appropriate amount of dasatinib reference substance was dissolved and diluted to prepare a 0.05 mg / mL solution as the reference solution, 5 μl was accurately taken and injected into the chromatograph, and the chromatogram was recorded, and the dissolution amount was calculated by peak area according to the external standard method.

[0076] Table 5 Dissolution (%)

[0077] Comparative Examples 1-6 are existing crystal forms, and the highest dissolution of the existing crystal form at 10 min is 88.71%, and the cumulative dissolution of the dasatinib single crystal of the present application at 10 min is more than 90%, which is obviously superior to the existing crystal form.

Claims

1. A dasatinib fumarate crystal form, characterized in that, It is formed by combining dasatinib, fumaric acid, and methanol in a molar ratio of 1:1:

1.

2. The dasatinib fumarate crystal form as described in claim 1, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, shows characteristic peaks at 5.61±0.2°, 11.40±0.2°, 11.63±0.2°, 14.24±0.2°, 19.05±0.2°, 19.50±0.2°, 22.73±0.2°, and 25.97±0.2°.

3. The dasatinib-fumarate crystal form as described in claim 1, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, shows characteristic peaks at 5.61±0.2°, 5.87±0.2°, 11.02±0.2°, 11.40±0.2°, 11.63±0.2°, 14.24±0.2°, 17.11±0.2°, 19.05±0.2°, 19.50±0.2°, 22.73±0.2°, 24.39±0.2°, 25.97±0.2°, 27.36±0.2°, and 30.33±0.2°.

4. The dasatinib fumarate crystal form as described in claim 1, characterized in that, The crystallographic parameters are: monoclinic crystal system, space group P21 / n; cell parameters are: a = 18.4067(3), b = 9.37900(10), c = 18.7942(3), α = 90°, β = 108.135(2), γ = 90°, z = 58, cell volume V = 3083.39(8) Å3.

5. The dasatinib fumarate crystal form as described in claim 1, characterized in that, Its characteristic peaks conform to the X-ray powder diffraction pattern shown in Figure 1.

6. A method for preparing the dasatinib fumarate crystal form as described in any one of claims 1-5, characterized in that, The specific preparation method includes: adding dasatinib and fumaric acid to a mixed solvent of methanol and organic solvent A to dissolve them, ultrasonically heating and stirring until the solid is completely dissolved, allowing it to stand to crystallize, filtering and drying to obtain dasatinib fumaric acid crystals.

7. The preparation method according to claim 6, characterized in that, The molar ratio of dasatinib to fumaric acid is 1:1-1.5, preferably 1:1-1.2; the volume ratio of methanol to organic solvent A is 1:0-1.5; and the mass-volume ratio of dasatinib to the mixed solvent is 1:0.15-0.3, wherein the mass is expressed in mg and the volume in mL.

8. The preparation method according to claim 6, characterized in that, The organic solvent A is selected from one or more of ethanol, acetone, acetonitrile, isopropanol and trifluoroethanol.

9. The preparation method according to claim 6, characterized in that, The heating temperature is 40-65℃, and the crystallization temperature is 0-30℃.

10. A pharmaceutical composition, characterized in that, The composition comprises the dasatinib fumarate crystal form as described in any one of claims 1-5 and other pharmaceutically acceptable ingredients.

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