Crystal form of dacomitinib monohydrate and preparation method thereof

Abstract

The present invention relates to the field of pharmaceutical chemical technology, and specifically to a crystal form of dacomitinib monohydrate and a preparation method thereof. The crystal form of dacomitinib monohydrate of the present invention has a reflection angle 2θ of an X-ray powder diffraction pattern of the crystal form at 5.9°±0.2°, 9.5°±0.2°, 19.1°±0.2°, 21.9°±0.2°, and 29.1°±0.2°. The crystal form of dacomitinib monohydrate of the present invention and a preparation method thereof have good crystal stability, low operating temperature, high conversion rate, high product purity, easy handling, good fluidity, and are suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical industry, and in particular to a crystal form of dacomitinib monohydrate and a preparation method thereof. Background Art

[0002] Dacomitinib is an oral, selective, adenosine triphosphate (ATP) competitive, irreversible small molecule inhibitor of the human epidermal growth factor receptor (HER, erbB) family receptor tyrosine kinase developed by Pfizer. It exerts anti-tumor effects by inhibiting the tyrosine kinase activity of the EGFR family. Dacomitinib is the world's first drug that has been confirmed to be effective in PFS in a head-to-head comparison with the first-generation EGFR-TKI in patients with advanced NSCLC who have EGFR sensitive mutations.

[0003] Its chemical structure is shown below:

[0004]

[0005] For the drug dacomitinib, the compound patent CN 1972688 B has protected dacomitinib and its pharmaceutically acceptable salts. Different crystal forms of drugs may have different physical and chemical properties, which may affect the effect of the drug in the human body. The polymorphism of drug molecules can be analyzed and determined by means of X-ray powder diffraction, infrared spectrum and thermal analysis.

[0006] The IP.com document [Solid State Characterization of (E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide Monohydrate] (IPCOM000177061D) discloses the preparation method of dacomitinib monohydrate and its solid state characterization data, such as PXRD, NMR, Raman, etc. The dacomitinib monohydrate obtained by the synthesis method in the above document has the following disadvantages: the yield is low at 70-80%; the product is easily degraded in high temperature solution, and the product purity is poor at 99.32%; the handleability and fluidity are poor, which is not conducive to subsequent micro-powder operation; and it needs to be concentrated under reduced pressure, evaporated to remove the solvent and operated at a high temperature, which is not only cumbersome but also energy-intensive. Summary of the invention

[0007] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a crystalline form of dacomitinib monohydrate and a preparation method thereof, which has good crystalline stability, low operating temperature, high conversion rate, high product purity, easy handling, good fluidity, and is suitable for industrial production.

[0008] The crystalline form of dacomitinib monohydrate described in the present invention has characteristic peaks in the reflection angle 2θ of the X-ray powder diffraction pattern at 5.9°±0.2°, 9.5°±0.2°, 19.1°±0.2°, 21.9°±0.2°, and 29.1°±0.2°.

[0009] Preferably, the reflection angle 2θ of the X-ray powder diffraction pattern of the crystalline form is 10.9°±0.2°, 13.0°±0.2°, 13.3°±0.2°, 14.8°±0.2°, 15.0°±0.2°, 17.4°±0.2°, 19.8°±0.2°, 20.4°±0.2°, 21.3°±0.2°, 23.6°±0.2°, 24. There are characteristic peaks at .4°±0.2°, 25.2°±0.2°, 26.5°±0.2°, 27.2°±0.2°, 30.1°±0.2°, 32.1°±0.2°, 33.0°±0.2°, 33.8°±0.2°, 35.5°±0.2°, 37.7°±0.2°, 38.3°±0.2°, and 40.0°±0.2°.

[0010] Preferably, the TGA-DSC spectrum of the crystal form has a weight loss of 3.2-4.2% w / w between about 80-170°C, gradually decomposes after 190°C to form a hydrate crystal form, and undergoes an endothermic transition at about 105-140°C. The product structure corresponding to the TGA-DSC spectrum of the crystal form is shown below:

[0011]

[0012] The method for preparing the crystalline form of dacomitinib monohydrate comprises the following steps:

[0013] (1) dispersing dacomitinib powder in dichloromethane solvent;

[0014] (2) Add purified water at 0-40°C;

[0015] (3) stirring and crystallization;

[0016] (4) filtering and drying to obtain the crystalline form of dacomitinib monohydrate.

[0017] Preferably, in step (1), the mass volume ratio of dacomitinib powder to dichloromethane is 1 g:3 mL to 1 g:50 mL, more preferably 1 g:10 mL.

[0018] Preferably, in step (2), the mass volume ratio of dacomitinib powder to purified water is 1 g:0.04 mL to 1 g:50 mL, more preferably 1 g:5 mL.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] The present invention provides a new crystal form of dacomitinib monohydrate and a preparation method thereof, which has good crystal stability, a high yield of 91% to 96%, a low operating temperature, and a solution stability purity of up to 99.96%, good fluidity and easy micro-powder processing, and no need for reduced pressure concentration, solvent evaporation and other operations, and is more suitable for the needs of industrialized scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is an exemplary PXRD spectrum of the dacomitinib monohydrate Form I obtained in Example 1;

[0022] Figure 2 is an exemplary TGA-DSC spectrum of the dacomitinib monohydrate Form I obtained in Example 1;

[0023] Figure 3 This is an exemplary HPLC spectrum of the dacomitinib monohydrate Form I obtained in Example 1;

[0024] Figure 4 This is the PXRD spectrum of dacomitinib monohydrate Form II obtained in Comparative Example 1. DETAILED DESCRIPTION

[0025] The present invention is further described below with reference to the embodiments.

[0026] Example 1

[0027] Add 1000mL of dichloromethane to a 2L four-necked round-bottom reaction flask, control the temperature at 22±2°C, add 100.00g of dacomitinib anhydrous, stir mechanically to disperse evenly, then drop 500mL of purified water, complete the addition, stir and crystallize for 1 hour. Filter and dry. Collect the material to obtain 96.52g of white solid, which is the crystalline form I of dacomitinib monohydrate, with a yield of 93.0%. HPLC purity is 99.96%.

[0028] The PXRD, TGA-DSC and HPLC of the crystalline form I of dacomitinib monohydrate obtained in this example are as follows: Figure 1 , Figure 2 and Figure 3 shown.

[0029] Example 2

[0030] Add 15L of dichloromethane to a 30L double glass reactor, control the temperature at 5-10°C, add 1.50kg of dacomitinib anhydrous, stir mechanically to disperse evenly, then drop 7.5L of purified water, stir and crystallize for 2 hours after the addition is complete. Filter and dry. Collect the material to obtain 1.49kg of white solid, which is the crystal form I of dacomitinib monohydrate, with a yield of 95.7%. HPLC purity is 99.96%.

[0031] Example 3

[0032] Add 3L of dichloromethane to a 5L four-necked round-bottomed reaction flask, control the temperature at 30-35°C, add 300.00g of dacomitinib anhydrous, stir mechanically to disperse evenly, then drop 1.5L of purified water, stir and crystallize for 1 hour after the addition is complete. Filter and dry. Collect the material to obtain 286.60g of white solid, which is the crystal form I of dacomitinib monohydrate, with a yield of 92.0%. HPLC purity is 99.97%.

[0033] Example 4

[0034] Add 60L of dichloromethane to a 100L double glass reactor, control the temperature at 15-20°C, add 6.00kg of dacomitinib anhydrous, stir mechanically to disperse evenly, then drop 30L of purified water, stir and crystallize for 2 hours after the addition is complete. Filter and dry. Collect 5.86kg of white solid, which is crystalline form I of dacomitinib monohydrate, with a yield of 94.1%. HPLC purity is 99.96%.

[0035] Example 5

[0036] Add 1000mL of dichloromethane to a 2L four-necked round-bottomed reaction flask, heat to reflux, add 100.00g of dacomitinib anhydrous, stir mechanically to disperse evenly, then drop 500mL of purified water, add dropwise, stir under reflux for 1 hour to crystallize. Filter and dry. Collect the material to obtain 95.01g of white solid, which is the crystal form I of dacomitinib monohydrate, with a yield of 91.5%. HPLC purity is 99.98%.

[0037] Comparative Example 1

[0038] Refer to the preparation method in the literature (IPCOM000177061D).

[0039] 1500 mL of 2-methyltetrahydrofuran, 500 mL of purified water, and 100.00 g of dacomitinib anhydrous were added to a 2L four-necked round-bottomed reaction flask, refluxed until completely dissolved, concentrated to 1 / 2 volume, cooled to 5°C for crystal growth, filtered, and dried. 81.00 g of white solid was obtained, which was crystalline form II of dacomitinib monohydrate, with a yield of 78.0%. HPLC purity was 99.32%.

[0040] The PXRD pattern of the crystalline form II of dacomitinib monohydrate obtained in this example is as follows: Figure 4 .

[0041] Stability test:

[0042] The samples of dacomitinib monohydrate crystal forms I and II prepared in Example 1 and Comparative Example 1 were spread on a surface dish, placed in a high temperature test box and a high humidity test box, respectively, and appropriate amounts of samples were taken out at 10 days and 30 hours to detect their purity.

[0043] The purity data are shown in Table 1 below:

[0044] Table 1 Experimental research data on factors affecting dacomitinib monohydrate form I

[0045]

[0046]

[0047] It can be seen from the data in Table 1 that the monohydrate crystal form I of dacomitinib described in the present invention has good stability under high temperature and high humidity, which is basically equivalent to the original crystal form II.

Claims

1. A method for preparing a crystalline form of dacomitinib monohydrate, characterized in that: Here are the steps: Add 15 L of dichloromethane to a 30 L double glass reactor, control the temperature at 5-10 ° C, add 1.50 kg of dacomitinib anhydrous, stir mechanically to disperse evenly, then drop 7.5 L of purified water, stir and crystallize for 2 hours, filter, dry, and collect 1.49 kg of white solid, which is dacomitinib monohydrate Form I, with a yield of 95.7% and a HPLC purity of 99.96%; The reflection angle 2θ of the X-ray powder diffraction pattern of the crystal form has characteristic peaks at 5.9°±0.2°, 9.5°±0.2°, 19.1°±0.2°, 21.9°±0.2°, and 29.1°±0.2°; The reflection angle 2θ of the X-ray powder diffraction pattern of the crystalline form is 10.9°±0.2°, 13.0°±0.2°, 13.3°±0.2°, 14.8°±0.2°, 15.0°±0.2°, 17.4°±0.2°, 19.8°±0.2°, 20.4°±0.2°, 21.3°±0.2°, 23.6°±0.2°, 24.4 There are characteristic peaks at 25.4°±0.2°, 25.2°±0.2°, 26.5°±0.2°, 27.2°±0.2°, 30.1°±0.2°, 32.1°±0.2°, 33.0°±0.2°, 33.8°±0.2°, 35.5°±0.2°, 37.7°±0.2°, 38.3°±0.2°, and 40.0°±0.2°.

2. The method for preparing the crystalline form of dacomitinib monohydrate according to claim 1, characterized in that: The TGA-DSC spectrum of the crystal form shows a weight loss of 3.2-4.2% w / w between 80-170°C, and gradually decomposes after 190°C to form a hydrate crystal form; an endothermic transition occurs at 105-140°C.

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