WO2015081566A1

WO2015081566A1 - Crystalline forms of trametinib and solvate thereof, preparation method therefor, pharmaceutical composition comprising same and use thereof

Info

Publication number: WO2015081566A1
Application number: PCT/CN2013/088797
Authority: WO
Inventors: 胡晨阳; 盛晓霞; 盛晓红
Original assignee: 杭州普晒医药科技有限公司
Priority date: 2013-12-06
Filing date: 2013-12-06
Publication date: 2015-06-11
Also published as: CN104918937B; CN104918937A

Abstract

The present invention relates to crystalline forms of trametinib and solvate thereof, preparation method therefor, pharmaceutical compositions comprising the crystalline form and use thereof in preparing related medicines. In comparison with the prior art, the crystalline forms of the trametinib and solvate thereof of the present invention has good crystalline state, good crystalline stability, low moisture absorption, improved solubility in water, higher amount of active components, lower solvent toxicity, and is more beneficial to meet the strict requirements for pharmaceutical preparation. The crystalline forms can be prepared at room temperature or low temperature, and is beneficial to industrial production of the products.

Description

Crystal form of trimetinib and its solvate, preparation method thereof, pharmaceutical composition containing same and use thereof

Technical field

The invention relates to the field of medicinal chemical crystallization technology. In particular, it relates to crystalline forms of trimetinib and its solvates and methods for their preparation, and to pharmaceutical compositions and uses of such crystalline forms. Background technique

The chemical name of trimetinib is: N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro-6 ,8-Dimercapto-2,4,7-trioxo-pyrido[4,3-D]pyrimidin-1(2H)-yl]phenyl]acetamide, English name is TRAMETINIB, aka GSK1120212, GSK 212 or JTP 74057, the structure is as follows:

Trimetinib is a novel targeting drug for melanoma cancer developed by GlaxoSmithKline. It is a potent and selective MEK1/MEK2 inhibitor that effectively prevents cancer cell proliferation and induces apoptosis and prolongs patient life. . Phase III clinical trials have shown that the efficacy of trimetinib is significantly better than traditional chemotherapy for the treatment of advanced or positive metastatic melanoma with BRAF V600E/K mutation. In addition, the combination of trimetinib and other anticancer drugs is under further study and the results are very promising. The formulation of trimetinib is an oral coated tablet, and the active ingredient is trimetinib disulfoxide solvate (also known as GSK 1120212B), each tablet containing 0.5 mg, 1 mg or 2 mg of trimetinib. The standard content of disulfoxide is 11.3% (theoretical value) and the low content is about 9.5%. In addition, the trimetini preparation also has an oral liquid dosage form. Its ¹ H-NMR. Although the text of this document describes the disulfoxide solvate, ethanol solvate, etc. of trimetinib, only the -NMR data are disclosed, and no specific description of the preparation methods of these solvates is given. No confirmation of the ratio of the binding of trimetinib to the solvent molecule in its compound is given, nor is there any characterization data for any of its morphologies, such as XRPD, thermal analysis, solubility, stability, and other physicochemical characterization data for the crystalline form. Thus, in essence, this document does not disclose any particular trimetine solvate and its corresponding crystalline form.

Patent document WO2012088033A2 discloses a pharmaceutical composition of trimetinib sulfoxide solvate, a method for the treatment thereof and a method of preparing the composition, but this document also does not disclose any characterization data of the solvate.

The present inventors have found that a certain trimetinib disulfoxide solvate can be prepared according to various conventional methods in the art, and the solvate has the following defects: low solubility in water; dimercaptosulfoxide has a high boiling point and saturation The vapor pressure is low, it is difficult to remove, and the solvent residual amount is large, and it is easy to form an extremely fine particle form.

The present inventors have also found that a certain ethanol solvate can be prepared according to various conventional methods in the art, but the solvate has the following defects: unstable at room temperature, and crystal transformation occurs when left at room temperature for 2 months; It can be found from the XRPD pattern that the ethanol solvate has a low crystallinity.

Therefore, there is still a need to develop trimetinib and its solvates and/or crystal forms with more improved properties to meet the stringent requirements of different pharmaceutical preparations for the active form.

Summary of the invention

In view of the above, the present invention provides crystal forms of trimetinib and its solvates and processes for their preparation, as well as pharmaceutical compositions and uses comprising the crystalline forms.

The novel crystalline form of the invention has one or more improved properties compared to the trimetinib disulfoxide solvate, ethanol solvate prepared according to conventional methods, in particular the new crystalline form has a higher Crystallinity, higher solubility in water, better stability, higher active ingredient content, better flowability and better processability, and the crystal form can be at room temperature or low temperature It is more convenient to prepare, which is more conducive to the industrialization of products.

One of the contents of the present invention is to provide a crystal form E of trimetinib ethanol solvate and a process for the preparation thereof. The trimetine ethanol solvate crystal form E (hereinafter referred to as "crystal form E") is a compound formed by trimetinib and ethanol in a 1:1 molar ratio, and its structural formula is as follows:

.

The trimetini ethoxide solvate crystal form E is characterized in that, using Cu-Κα radiation, the X-ray powder diffraction pattern expressed in terms of 2 角度 angle has a characteristic peak at the following position: 5.4 ± 0.2. , 10.5 ± 0.2. 12.2 ± 0.2. 12.8 ± 0.2. 18.3 ± 0.2. And 21.1 ± 0.2. Further, the X-ray powder diffraction pattern expressed in terms of 2 Θ angle has a characteristic peak at the following position: 5.4 ± 0.2. , 9.2 ± 0.2. , 10.5 ± 0.2. 10.9±0.2°, 12.2±0·2°, 12.8±0·2°, 13.9±0·2°, 16.2±0·2°, 18·3±0·2°, 19.4±0·2 °, 21.1 ± 0.2. And 24.5 ± 0.2. Further, the X-ray powder diffraction pattern expressed in 2Θ angle has characteristic peaks and their relative intensities in the following positions:

Diffraction angle 2Θ relative intensity%

5·4±0·2° 34.1

9·2±0·2° 40.0

10.5 ± 0.2 ° 86.9

10.9士 0.2° 42.4

12.2 ± 0.2 ° 58.7

12.8±0.2° 100.0

13.9 ± 0.2° 49.1

16.2 ± 0.2 ° 38.0

18.3 ± 0.2. 68.7

18.9 ± 0.2. 36.7

19.4 士 0.2° 59.1

20.0 ± 0.2° 50.4

20.8 ± 0.2° 65.3

21.1 ± 0.2. 85.5

21.4 ± 0.2° 37.4

22.1 ± 0.2. 74.6

22.8 ± 0.2 ° 62.2

24.5 ± 0.2° 81.7

25.9 ± 0.2° 51.5

27.9 ± 0.2° 57.1

29.1 ± 0.2 ° 42.3 29.5 ± 0.2 ° 53.2.

Without limitation, a typical example of the Form E has an X-ray powder diffraction (XRPD) pattern as shown in FIG.

The Fourier transform infrared spectroscopy of Form E has characteristic peaks at wave numbers of 693, 777, 812, 1228, 1438, 1548, 1610, 1631, 1676, 2631, 3321 and 3497 cm.

The polarized light microscopy (PLM) pattern of Form E is shown as a fine crystal.

The thermogravimetric analysis (TGA) pattern of Form E showed a weight loss of 6.3% before 200 ° C, which is equivalent to an ethanol molecule.

The differential thermal analysis (DSC) pattern of Form E shows a broad endothermic peak at 100 to 200 °C. The isothermal adsorption curve of Form E showed a weight change of 1.07% in the range of 20% to 80% relative humidity.

The crystal form E was allowed to stand at room temperature and 44% relative humidity for 3 months, and the XRPD detection crystal form was unchanged, and was more stable than the ethanol solvate prepared according to the conventional method (under the same conditions, 2 months of crystal transformation). .

By the XRPD pattern comparison, Form E has a higher crystallinity than the ethanol solvate prepared according to the conventional method.

At room temperature, the Form E was stirred in water for 1 hour and the solubility was 1.31 g/mL, and the stirring time was 0.50 g/mL for 4 hours, which was significantly better than the disulfoxide solvate prepared according to the conventional method (1 hour and 4 hours). The solubility in hours was 0.51 g/mL and 0.35 g/mL, respectively.

The above results indicate that the crystal form E of the present invention has the following beneficial effects:

1 At room temperature, the solubility of Form E in water is significantly better than that of trimetinidil sulfoxide solvate prepared according to the conventional method;

2 Through the room temperature experiment, the crystal form E is more stable than the ethanol solvate prepared according to the conventional method; by the XRPD pattern comparison, the crystal form E has higher crystallinity, has better fluidity and processability;

3 It can be seen from the isothermal adsorption curve that the crystal form E is not easy to absorb moisture;

The above 2 and 3 indicate that the crystal form E of the present invention is better able to counteract the problem of crystal form instability during the preparation of the pharmaceutical preparation and/or storage, and the unworkability of the preparation caused by external factors such as environmental moisture, and is more advantageous. Accurate quantification and subsequent transport and storage in the preparation of unit preparations;

4 Compared to the trimetinidil sulfoxide solvate prepared according to the conventional method, Form E has a higher effective component content, lower solvent toxicity, and is more acceptable in pharmaceutical applications.

The preparation method of the trimetine ethanol solvate crystal form E adopts any one of the following methods: (1) the trimetinib amorphous substance is placed in a sealed container filled with ethanol vapor at room temperature to obtain the crystal form E;

Preferably, the resting time is 1 to 3 days, preferably 1 to 1.5 days;

(2) forming a suspension of trimetinib in an organic solvent, stirring and crystallization at room temperature for 1 to 5 days, and then separating and drying the precipitated crystal to obtain the crystal form E, wherein the organic solvent is selected from the group consisting of a mixed solvent of ethanol and isopropyl acetate in an ethanol or volume ratio of 1:1 to 5:1;

Preferably, the weight to volume ratio of the trimetinib to the organic solvent is 1 to 20 mg: 1 ml, preferably 5-10 mg: 1 ml;

Preferably, in the mixed solvent, B is 1:1~2:1; preferably, the crystallization time is 1~3 days;

(3) adding ethanol to the solution of trimetinib dimethyl sulfoxide, the volume ratio of dimethyl sulfoxide to ethanol is 0.1:1~0.5:1, stirring and crystallization at room temperature for 10-24 hours, then The precipitated crystal is separated and dried to obtain the crystal form E;

Preferably, the amount of trimetinib is 0.5 to 1 times its solubility in dimercaptosulfoxide at room temperature;

Preferably, the volume ratio of the dimercaptosulfoxide to ethanol is from 0.1:1 to 0.2:1;

Preferably, the crystallization time is 10 to 16 hours.

A second aspect of the present invention provides a trimetinib n-propanol solvate and a crystalline form thereof, and a process for the preparation thereof.

The trimetinib n-propanol solvate is a compound formed by trimetinib and n-propanol at a molar ratio of 1:1, and the structural formula is as follows

a crystal of the trimetini n-propanol solvate (hereinafter referred to as "crystal form N") characterized by using Cu-Κα radiation, an X-ray powder diffraction pattern expressed at a 2 Θ angle in the following position Has a characteristic peak: 10·5±0·2. , 12·1±0·2. , 12·8±0·2. , 13·9±0·2. , 18·3±0·2. And 20.9 ± 0.2°; further, the X-ray powder diffraction pattern expressed in terms of 2 角度 angle has characteristic peaks at the following positions: 9.1 ± 0.2 °, 10.5 ± 0.2 °, 12.1 ± 0.2 °, 12.8 ± 0.2 °, 13.9 ± 0.2 °, 18.3 ± 0.2 °, 19.8 ± 0.2 °, 20.6 ± 0. 2. 20.9 士0·2. 21.9 ± 0. 2. 22.6 ± 0.2. And 24.3 士0·2. Further, the X-ray powder diffraction pattern expressed in terms of 2 角度 angle has characteristic peaks and their relative intensities at the following positions:

Diffraction angle 2Θ relative intensity%

9·1±0·2° 16.1

10.5 ± 0.2° 100.0

12.1 ± 0.2 ° 58.2

12.8 ± 0.2 ° 39.2

13.9 ± 0.2° 35.0

18.3 ± 0.2. 38.3

19.2 ± 0.2° 10.1

19.8 ± 0.2 ° 52.0

20.6 ± 0.2° 49.1

20.9 ± 0.2° 86.8

21.9 ± 0.2 ° 57.2

22.6 ± 0.2. 25.8

24.3 ± 0.2 ° 54.4

25.4 ± 0.2° 23.5

27.8 ± 0.2° 30.6

29.2 ± 0.2 ° 32.9

Without limitation, a typical example of the crystalline form has an X-ray powder diffraction (XRPD) pattern as shown in FIG.

The Fourier transform infrared spectrum of the crystalline germanium is 693, 777, 1229, 1350, 1367,

Characteristic peaks at 1438, 1547, 1608, 1632, 1677, 3324, and 3503 cm.

The polarized light microscopy (PLM) pattern of the Form N is shown as a fine crystal.

The thermogravimetric analysis (TGA) pattern of the Form N showed: 8.5% weight loss before 200 ° C, containing about one n-propanol molecule.

The differential thermal analysis (DSC) pattern of the crystalline form N shows a broad endothermic peak at 100 to 200 °C. The isothermal adsorption curve of the Form N showed a weight change of 1.1% in the range of 20% to 80% relative humidity.

The crystal form N was allowed to stand at room temperature and 44% relative humidity for 3 months, and the crystal form was not changed by XRPD. It is more stable than the ethanol solvate prepared under the conventional method (under the same conditions, 2 months of crystal transformation).

By XRPD pattern comparison, Form N has a higher degree of crystallinity than the ethanol solvate prepared according to a conventional method. At room temperature, the Form N was stirred in water for 1 hour and the solubility was ll g/mL, and the stirring time was 1.2 g/mL for 4 hours, which was significantly better than the disulfoxide solvate prepared according to the conventional method (1 hour and 4 hours). The solubility in hours was 0.51 g/mL and 0.35 g/mL, respectively.

The above results indicate that the crystal form N of the present invention has the following beneficial effects:

1 At room temperature, the solubility of Form N in water is significantly better than that of the disulfoxide solvate prepared according to the conventional method;

2 Through the room temperature experiment, the crystal form N is more stable than the ethanol solvate prepared according to the conventional method, and the crystal form N has higher crystallinity by comparison with the XRPD pattern;

3 It can be seen from the isothermal adsorption curve that the crystal form N is not easy to absorb moisture;

The above 2 and 3 indicate that the crystal form N of the present invention is better able to counteract the problem of crystal form instability during the preparation of the pharmaceutical preparation and/or storage, and the unworkability of the preparation caused by external factors of environmental moisture, and is more advantageous for the unit. Accurate quantification and subsequent transport and storage in preparation of the preparation;

4 The crystalline form N has a higher effective component content than the trimetinib disulfoxide solvate prepared according to a conventional method. The preparation method of the trimetinidol n-propanol solvate crystal form N adopts the following method: the trimetinib amorphous substance is placed in n-propanol to form a solid suspension, and the crystal is stirred at room temperature for 3 to 16 After the hour, the precipitated crystals were separated and dried to obtain the crystal form N.

Preferably, the weight-to-volume ratio of the trimetinib amorphous substance to n-propanol is 5 to 40 mg: 1 ml, preferably 5 to 20 mg: 1 ml;

Preferably, the crystallization time is 3 to 8 hours.

A third aspect of the present invention is to provide an anhydride anhydrate of trimetinib and a crystal form thereof, and a process for the preparation thereof. The trimetine anhydrate has the structural formula shown below:

a crystal of the trimetine anhydrate (hereinafter referred to as "crystal form A") characterized in that, using Cu-Κα radiation, an X-ray powder diffraction pattern expressed at a 2 Θ angle has characteristics at the following positions Peaks: 3.8±0.2°, 9.2±0.2°, 14.7±0.2°, 18.5±0.2°, 19.5±0.2°, and 22.1±0.2°; further, The X-ray powder diffraction pattern expressed at an angle of 2 具有 has a characteristic peak at the following position: 3.8 ± 0.2. 9.2 士0.2. 14.7 ± 0.2°, 16.9 ± 0.2°, 18.5 ± 0.2°, 18.8 ± 0.2°, 19.5 ± 0.2°, 20.1 ± 0.2°, 20.5 ± 0.2°, 22.1 ± 0.2. And 23.6 ± 0.2. Further, the X-ray powder diffraction pattern expressed in 2Θ angle has characteristic peaks and their relative intensities at the following positions:

Diffraction angle 2Θ relative intensity%

3.8 ± 0.2° 100

9.2 士 0.2° 59.6

14.7 ± 0.2. 64.6

16.9 ± 0.2 ° 20.5

18.5 ± 0.2. 69.5

18.8 ± 0.2 ° 38.7

19·5±0·2° 83.2

19.8 ± 0.2° 18.3

20.1 ± 0.2° 25.5

20.5 ± 0.2° 66.8

22.1 ± 0.2 ° 88.0

23.6 ± 0.2. 46.3

24.2 ± 0.2. 25.0

24.9 ± 0.2. 20.1

25.3 ± 0.2. 22.8

26.6 ± 0.2. 20.5

27.1 ± 0.2° 17.3

27.9 ± 0.2. 18.7

30.8 ± 0.2° 24.3

32.8 ± 0.2° 17.4

35.9 ± 0.2 ° 19.3.

The Fourier transform infrared spectrum of the Form A has characteristic peaks at wave numbers of 694, 779, 1241, 1302, 1420, 1478, 1550, 1645, 1718, 2363, 2927, 3024 and 3305 cm.

The polarized light microscopy (PLM) pattern of the crystal form A is shown as a very fine crystal.

The thermogravimetric analysis (TGA) spectrum of the crystal form A shows that the weight loss at 30 ° C to 150 ° C is about 0.84%, which is lower than the specific gravity of the hemihydrate water molecule ( 1.44% ), and the crystal is determined by the slow weight loss phenomenon. Type does not contain water or other organic solvents.

The differential thermal analysis (DSC) pattern of Form A shows: a small endothermic peak before 50 ° C (Table The surface solvent peak) has a hot melt peak of 289.5 °C.

The isothermal adsorption curve of Form A showed a weight change of 4.5% in the range of 20% to 80% relative humidity.

The Form A was allowed to stand at room temperature and 44% relative humidity for 3 months, and the XRPD detected the crystal form unchanged; the above results indicate that the Form A of the present invention has the following beneficial effects:

1 It can be seen from the placement experiment that Form A is stable at room temperature; this indicates that Form A of the present invention is better able to resist crystal instability in the process of pharmaceutical preparation and/or storage, and is caused by external factors of environmental moisture. The preparation of the preparation is not problematic, and is more conducive to accurate quantification and post-transportation and storage in the preparation of the unit preparation;

2 Compared with the trimetinidil sulfoxide solvate prepared according to the conventional method, the crystalline form A has a higher effective component content and no toxic solvent, and is more acceptable in pharmaceutical applications;

Form 3 can be used to prepare other solvates, such as the preparation of Formmetine Ethanol Solvate Form E of the present invention.

A preparation method of the trimetine anhydrate form A comprises the following steps: forming a solid suspension of the trimmetini amorph in an organic solvent, and stirring and crystallization at room temperature for 1 to 7 days. Then, the precipitated crystals are separated and dried to obtain the crystal form A, and the organic solvent is selected from the group consisting of butanol, ethyl acetate, isopropyl acetate, acetonitrile, toluene or a mixed solvent of two solvents in any ratio thereof; Preferably, the weight ratio of the trimetinib amorphous substance to the organic solvent is 5-20 mg: 1 ml, preferably 5-10 mg: l ml;

Preferably, the crystallization time is 1 to 3 days.

A fourth aspect of the present invention is to provide a trimetinib amorphous form and a process for the preparation thereof.

The trimetinib amorphous substance has the structural formula shown below.

Without limitation, the X-ray powder diffraction (XRPD) pattern of the trimetinib amorphous form is shown in FIG. Differential Thermal Analysis (DSC) of the trimetinib amorphous form Figure 20 shows that an exothermic peak occurs between 150 and 220 ° C and is crystallized.

A preparation method of the trimetinib amorphous substance comprises the following steps:

1) in N-[3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-diindenyl-2,4,7-trioxo-1,2 , a solution of sodium decyl alcohol in tetrahydrofuran in a solution of 3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl]-acetamide in tetrahydrofuran, stirred Carry out the reaction until the reaction is over;

2) adding acetic acid to neutralize;

3) adding water to stir and crystallize, filtering, collecting the filter cake;

4) The filter cake was dissolved in chloroform or dichloromethane, and then concentrated to dryness under reduced pressure to give the crystallite. Yijing type, including trimetine ethanol solvate crystal form E (as a source of trimetinib in the organic solvent solution of trimetini), trimetinib n-propanol solvate crystal form N and trimetinib No crystal type A.

In the process of the present invention, trimetinib tetrahydrofuran solvate and crystal thereof, trimetinib trifluoroethanol solvate and crystal thereof, trimetinib acetone solvate and crystal thereof, and trimetinilide are also prepared. Tert-butyl ether solvate and its crystals.

A preparation method of the trimetinib tetrahydrofuran solvate crystal comprises the steps of: subjecting a solution of trimetinib tetrahydrofuran to natural volatile crystallization, and evaporating the solvent to obtain a crystal of trimetinib tetrahydrofuran solvate.

The preparation method of the trimetinib trifluoroethanol solvate crystal adopts any one of the following methods:

(1) The trimetinib amorphous substance is statically placed in a closed container filled with trifluoroethanol vapor to obtain a crystal of trimetinib trifluoroethanol solvate;

(2) forming a supersaturated solution of trimetinib in trifluoroethanol, adding water under stirring, stirring and crystallization, and then separating and drying the precipitated crystals to obtain a crystal of trimetinib trifluoroethanol solvate; The preparation method of trimetine acetone solvate crystal adopts any one of the following methods:

(1) The trimetinib amorphous form is statically placed in a closed vessel filled with acetone vapor to obtain a crystal of trimetinib acetate;

(2) forming a supersaturated solution of trimetinib in trifluoroethanol, adding acetone under stirring, stirring and crystallization, and then separating and drying the precipitated crystals to obtain crystals of trimetinib acetate;

The preparation method of the trimetinimidyl tert-butyl ether solvate crystal comprises the following steps: In a solution of trimetine in a supersaturated trichloromethane, decyl tert-butyl ether is added with stirring, and the crystals are stirred and then the precipitated crystals are separated and dried to obtain a solvent of trimetinidol tert-butyl ether. Crystals.

The present invention provides a crystal form of trimetinib and its solvate, including its ethanol solvate crystal form

E, n-propanol solvate crystal form N, anhydrate crystal form A, tetrahydrofuran solvate crystal, trifluoroethanol solvate crystal, acetone solvate crystal and mercapto tert-butyl ether solvate crystal, solving the prior art Insufficient crystal form. The crystalline form has one or more advantageous properties such as: higher solubility, less solvent residue, higher purity, more convenient preparation, better thermodynamic stability, good particle morphology , low hygroscopicity, better fluidity, better apparent density, better storage stability, suitable for formulation applications. In particular, the crystal form has a good crystalline state, improved solubility in water, good stability, low moisture absorption, higher active ingredient content, lower solvent toxicity, and is more acceptable in pharmaceutical applications. The preparation method of the related crystal form of trimetinib of the invention, the process tube, the conventional operation, is carried out under the condition of room temperature or low temperature, does not require high-temperature crystallization, and is more favorable for industrialization of the product.

The crystalline form of the present invention is pure, unitary, and substantially free of any other crystalline form. In the present invention, "substantially free" when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Less than 5% by weight of other crystal forms, more than less than 1% by weight of other crystal forms.

In the present invention, "crystal" or "crystal form" means confirmed by the X-ray diffraction pattern characterization shown. Those skilled in the art will appreciate that the experimental error therein depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray diffraction patterns typically vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ±0.2 is usually allowed. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, it will be understood by those skilled in the art that any crystal form having the same or similar characteristic peaks as the map of the present invention is within the scope of the present invention.

The present invention as a trimetine ethanol solvate crystal form E, trimetinib n-propanol solvate crystal form N, trimetinib tetrahydrofuran solvate crystal, trimetinib trifluoroethanol solvate crystal, trimmetine Preparation of starting materials for nicotone solvate crystals and trimetinidol tert-butyl ether solvate crystals

Form A. -6,8-dimercapto-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl Amino]-phenyl]-acetamide is commercially available or can be prepared by the method described in WO2005121142 A1.

As described in the background section, Patent Document WO2005121142 A1, Example 4-149, although the text describes that the ethanol solvate and the dimethyl sulfoxide solvate can be obtained by conventional methods, no confirmation characterization data and specific preparation are disclosed. method. The present inventors have prepared the determined ethanol solvate and dimercapto sulfoxide solvate according to the conventional methods mentioned in the literature, such as the volatile crystallization method, the cooling crystallization method, and the distillation crystallization method, specifically in Comparative Example 1. As embodied in ~5, the inventors herein refer to these specific crystal forms as known crystal forms.

In the above respective preparation methods of the crystal form or amorphous form of trimmetatin and its solvate of the present invention: the "room temperature" means 10-30 °C.

The "anhydrous" means that the sample contains no more than 1.5% by weight or not more than 1.0% by weight of water as measured by TGA.

The "stirring" may be carried out by any conventional stirring method known in the art, for example, stirring, including magnetic stirring, mechanical stirring, and stirring at a speed of 50 to 1800 rpm, preferably 300 to 900 rpm.

The "separation" can be carried out by any conventional separation method known in the art including filtration, centrifugation, and concentration under reduced pressure. The filtration is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa. The specific procedure for centrifugation in the laboratory is: Place the suspension or emulsion sample in a 2 mL centrifuge tube and centrifuge at 6000 rpm until the solids all settle to the bottom of the tube. The specific operation of concentration under reduced pressure is: placing the container containing the solution in a rotary evaporator at a temperature of from room temperature to the boiling point of the solvent (preferably 30 to 50 ° C), less than atmospheric pressure (preferably, the pressure is less than 0.08 MPa). ), at a rotation speed of 10 to 180 rpm (preferably 50 to 100 rpm), the solvent is removed.

The "drying" can be carried out by conventional techniques in the art, such as drying at room temperature, blast drying or reduced pressure drying, in a fume hood, a blast oven or a vacuum oven; the pressure can be reduced or not, preferably the pressure is less than 0.09 MPa. The drying temperature is 20 to 40 ° C, and the drying time is 10 to 72 hours, preferably 10 to 48 hours, more preferably 10 to 24 hours.

The "pore volatilization" means that the reaction flask containing the solution is volatilized and crystallized at room temperature through a single small hole having a diameter of 2 mm.

The "ultrasonic" operation is to place a container containing the solution or suspension in an ultrasonic cleaner and ultrasonically for 1 to 30 minutes at an ultrasonic working power of 20 Khz to 40 Khz. Generally use 40 Khz ultrasonic power super Sound for 5 minutes. Ultrasound has higher energy, which is conducive to the dissolution of the sample, shortens the crystallization time, hinders the agglomeration of the crystal, and changes the habit.

Further, the present invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a pharmaceutically active ingredient selected from the crystalline form or amorphous form of trimetinib and a solvate thereof of the present invention or a crystalline form or amorphous form of trimetinib and a solvate thereof obtained by the preparation method of the present invention, and at least one pharmaceutically acceptable carrier, wherein the crystalline form comprises an ethanol solvate crystal form of trimetinib E, n-propanol solvate Form N, anhydrate Form A, tetrahydrofuran solvate crystals, trifluoroethanol solvate crystals, acetone solvate crystals, and decyl tert-butyl ether solvate crystals. Furthermore, the pharmaceutical composition may further comprise other pharmaceutically acceptable salts, solvates or crystalline forms of trimetinib. Optionally, the pharmaceutical composition may also comprise one or more other pharmaceutically acceptable pharmaceutically active components, such as other compounds having anti-tumor activity.

Pharmaceutically acceptable carriers in the pharmaceutical compositions include, but are not limited to, binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxy Ethyl cellulose, polyethylene glycol, copolyvidone, etc.; diluents, such as starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, tricalcium phosphate, mannitol, Sorbitol, sugar, etc.; disintegrating agents, such as starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; Lubricants, such as stearic acid, magnesium stearate, stearic acid, sodium benzoate, sodium acetate, etc.; glidants, such as colloidal silica; etc.; complex forming agents, such as various grades of cyclodextrin Fine and resin; release rate controlling agent such as hydroxypropyl cellulose, hydroxydecyl cellulose, hydroxypropyl decyl cellulose, ethyl cellulose, decyl cellulose, decyl methacrylate, wax, and the like. Other pharmaceutically acceptable carriers that may be used include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, stabilizers, buffers, antioxidants, and the like.

The pharmaceutical composition may be in the form of a tablet (including a plain tablet, a film coated tablet, a sugar coated tablet, an enteric coated tablet, etc.), a pill, a powder, a granule, a capsule, a syrup, an emulsion, a suspension, an injection. , solutions, suppositories, tinctures, tinctures, aerosols, eye drops, lyophilizates, and the like. The route of administration includes systemic administration or topical administration, oral administration or parenteral administration, preferably oral administration which enables good absorption of the drug and long-term maintenance of blood concentration. In the preparation of a pharmaceutical composition, the crystalline form or amorphous form of trimetinib and its solvate of the invention is admixed with one or more pharmaceutically acceptable carriers, optionally with one or more The other pharmaceutically active ingredients are mixed. The solid preparation can be prepared by a process such as direct mixing, granulation, or the like. Further, the present invention provides the use of a crystalline form or an amorphous form of trimetinib and a solvate thereof of the present invention for the preparation of a medicament for treating and/or preventing a hyperproliferative disease, the crystal form comprising Qumei Ethanol solvate crystal form 替, n-propanol solvate crystal form 无水, anhydrate form Α, tetrahydrofuran solvate crystal, trifluoroethanol solvate crystal, acetone solvate crystal and decyl tert-butyl ether solvent Crystalline, the hyperproliferative disease, may involve, for example, a tumor, specifically a brain tumor (a glioma with malignant astroglioma and oligodendroglioma, etc.), esophagus Cancer, stomach cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, primary and metastatic squamous cell carcinoma, etc.), kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin Cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, extragonadal tumor, testicular tumor, uterine tumor (cervical cancer, endometrial cancer) ), head and neck cancer (maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, intraoral cancer, etc.), multiple myeloma, malignant lymphoma (reticulocyte sarcoma, lymphosarcoma, Hodgkin's disease, etc.), polycythemia vera, Leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), verrucous gland, renal pelviccancer, ureteral tumor, bladder tumor, biliary cancer, cholangiocarcinoma, chorionic epithelial cancer, melanin Tumor cancer, pediatric tumor (Ewing family sarcoma, Wilms sarcoma, rhabdomyosarcoma, angiosarcoma, embryonic testicular cancer, neuroblastoma, retinoblastoma, hepatic blastoma, nephroblastoma, etc.); It is preferably applied to brain tumors (astroglioma with malignant astroglioma and oligodendroglioma), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, Lung cancer (non-small cell lung cancer, small cell lung cancer, primary and metastatic squamous cell carcinoma, etc.), kidney cancer, milk Cancer, ovarian cancer, prostate cancer, skin cancer, melanoma cancer, neuroblastoma, sarcoma and the like; and more preferably applied to colon, pancreas, kidney, lung, breast, melanoma cancer.

Furthermore, the crystalline form or amorphous form of trimetinib and its solvates of the present invention may be involved in the treatment of chronic pain, in particular neuropathic pain, sudden pain, chronic alcoholism, vitamin deficiency, uremia and symptoms. Pain associated with hypogonadism. In addition, it may involve neutrophil-mediated diseases or symptoms, specifically ischemia-reperfusion injury, chronic pulmonary obstruction, acute respiratory disease syndrome, bloated fibrosis, sudden pulmonary fibrosis, sepsis , endotoxemia, emphysema and asbestosis lungs. In addition, transplant rejection can be involved. In addition, arthritis may be involved, specifically rheumatoid arthritis and osteoarthritis. In addition, asthma can be involved. In addition, it may involve viral diseases, specifically herpesvirus HSV-1 infection, human cytomegalovirus HCMV infection, human immunodeficiency virus HIV infection. Further, diseases caused by cartilage degeneration or damage may be involved, specifically osteoarthritis, rheumatoid arthritis, isolated osteochondritis, and diseases requiring cartilage formation. Further, the present invention provides a method of treating and/or preventing a hyperproliferative disease, comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of one or more of the trimetine forms of the present invention. Or a pharmaceutical composition of the invention having an amorphous form; the crystalline form comprising an ethanol solvate crystal form E of trimetinib, a n-propanol solvate crystal form N, an anhydrate form A, a tetrahydrofuran solvate crystal, a trifluoroethanol solvate crystal, an acetone solvate crystal, and a decyl tert-butyl ether solvate crystal; the hyperproliferative disease selected from the group consisting of brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, lung cancer , kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, melanoma, neuroblastoma or sarcoma, preferably colon cancer, pancreatic cancer, kidney cancer, lung cancer, breast cancer or melanoma cancer; said patient is Refers to mammals including humans; adult doses are 0.01 mg to 1 g, and oral or injectables are administered once to several times a day. DRAWINGS

Figure 1 XRPD pattern of crystal form E of trimetinib ethanol solvate of the present invention

Figure 2 PLM map of crystal form E of trimetine ethanol solvate of the present invention

Figure 3 TGA spectrum of crystal form E of trimetine ethanol solvate of the present invention

Figure 4 DSC spectrum of crystal form E of trimetini ethoxide solvate of the present invention

Figure 5 IR spectrum of crystal form E of trimetine ethanol solvate of the present invention

Figure 6 isotherm adsorption curve of crystal form E of trimetini ethoxide solvate of the present invention

Figure 7 XRPD pattern of the crystal form N of trimetine n-propanol solvate of the present invention

Figure 8 PLM pattern of the crystal form N of trimetine n-propanol solvate of the present invention

Figure 9 TGA spectrum of the crystal form N of trimetine n-propanol solvate of the present invention

Figure 10 is a DSC pattern of the crystal form N of trimetinidol n-propanol solvate of the present invention

Figure 11 IR spectrum of the crystal form N of trimetine n-propanol solvate of the present invention

Figure 12 isotherm adsorption curve of crystal form N of trimetinidol n-propanol solvate of the present invention

Figure 13 XRPD pattern of crystal form A of trimetini hydrate of the present invention

Figure 14 PLM map of the crystal form A of trimetini hydrate of the present invention

Figure 15 TGA spectrum of crystal form A of trimetini hydrate of the present invention

Figure 16 DSC spectrum of crystal form A of trimetini hydrate of the present invention

Figure 17 IR spectrum of the crystal form A of trimetini hydrate of the present invention

Figure 18 isotherm adsorption curve of crystal form A of trimetine anhydrate in the present invention Figure 19 XRPD pattern of the trimetinib amorphous form of the present invention

Figure 20 DSC spectrum of the trimetinib amorphous form of the present invention

Figure 21 DSC spectrum of trimetinib disulfoxide solvate prepared according to conventional methods

detailed description

The invention is further defined by the following examples which describe in detail the crystalline form of the invention and its preparation and use. It will be apparent to those skilled in the art that many changes in the materials and methods can be practiced without departing from the scope of the invention.

Testing equipment and methods:

The XRD powder diffraction (XRPD) instrument used was a Bruker D8 Advance Diffractometer equipped with a Θ-2Θ goniometer, a Mo monochromator, and a Lynxeye detector. The acquisition software is Diffrac Plus XRPD Commander and the analysis software is MDI Jade 5.0. The instrument is calibrated with the standard (usually corundum) supplied with the instrument before use. Detection method: The sample is placed on a non-reflecting plate, tested at room temperature, using a Ka X-ray with a copper target wavelength of 1.54 nm, scanning at 40 kV and 40 mA operating conditions, 2 Θ scanning angle range 3~40°, step 0.02° long and 0.2 second/step. Samples were not ground prior to testing unless otherwise stated.

The polarized light microscope (PLM) image was taken from an XP-500E polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on the glass slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover glass, and then place the sample on the stage of the XP-500E polarized light microscope, select the appropriate magnification Multiply observe the morphology of the sample and take a picture.

The differential thermal analysis (DSC) data was taken from the TA Instruments Q200 MDSC, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually, samples of 1~10 mg are placed in an uncoated (unless otherwise specified) aluminum crucible, and the sample is raised from room temperature to a temperature of 10 °C/min under the protection of 40 mL/min dry N ₂ . At 310 ° C, the TA software records the change in heat during the temperature rise of the sample. In the present application, the melting point is reported as the starting temperature.

Thermogravimetric analysis (TGA) data is taken from TA Instruments Q500 TGA, instrument control software is Thermal Advantage, and analysis software is Universal Analysis. Normally 5 to 15 mg of sample is placed in platinum crucible, using segmented high-resolution detection. The sample was raised from room temperature to 400 ° C under the protection of 40 mL/min dry N ₂ at a heating rate of 10 ° C/min, while the TA software recorded the change in weight of the sample during the temperature increase.

The isothermal adsorption curve data was taken from the TA Instruments Q5000 TGA, and the instrument control software was Thermal Advantage, the analysis software is Universal Analysis. A sample of 1 to 10 mg is usually placed in a platinum crucible, and the TA software records the change in weight of the sample during a change in relative humidity from 0% to 80% to 0%. Depending on the specifics of the sample, different adsorption and desorption steps are also applied to the sample. The isothermal adsorption curve can be obtained by the analysis software.

Nuclear magnetic resonance spectroscopy (1H NMR) data was taken from Bruker Ascend Tm 500. Usually full-frequency excitation is used, with a spectral width of 30 PPM, single pulse, 30. Angle excitation, scanning 16 times, digital orthogonal detection, temperature control 298 K.

Infrared spectroscopy (IR) data was taken from Bruker Tensor 27, and instrument control software and data analysis software were OPUS. The ATR device is usually used to collect the infrared absorption spectrum in the range of όΟΟ-^ΟΟαη- ¹ . The scanning time of the sample and the blank background is 16 seconds. The resolution of the instrument A cm-high performance liquid chromatography (HPLC) data is collected from Waters. 2695/2487, Instrument Control Software and Analysis Software is Empower. Using C18 column, 150 mm * 4.6 mm, column temperature 25 ° C, wavelength 254 nm, flow rate 1.0 ml / min, injection volume 5 L, running time 25 min. Mobile phase A is water with 0.05% TFA and mobile phase B is acetonitrile. The gradient is as follows:

The various reagents used in the examples are commercially available unless otherwise specified.

The examples were operated at room temperature unless otherwise noted.

Example 1

Under a nitrogen atmosphere, 15.7 g of a 28% sodium sterol sterol solution was added to 366 mL of N-[3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8 -dimercapto-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl] -Acetylamine (45.7 g) in tetrahydrofuran was stirred at room temperature for 4 hours. Add 5.6 mL of acetic acid, stir at room temperature for half an hour, keep 70 ° C in the oil bath, add 366 mL of water while stirring, stir for 1 hour, cool to room temperature, filter, filter cake dissolved in 200 mL chloroform, concentrated at 40 ° C under reduced pressure To the dry, 42.3 g of trimetinib amorphous form was obtained.

Nuclear Magnetic Data: ^ NMR (CDC1 ₃ , 500 MHz): 0.79-0.82 (m, 2H), 1.13-1.15 (m, 2H) _: 1.44 (s, 3H), 2.17 (s, 3H), 2.73-2.77 (m, 1H), 3.22 (s, 3H), 6.72 (t, 1H, J = 8.0 Hz), 7.03 (d, 1H, J = 8.0 Hz), 7.30-7.40 (m, 2H), 7.46-7.49 (m, 1H), 7.52-7.56 (m, 2H), 7.70 (s, 1H), 11.31 (s, 1H).

The X-ray powder diffraction pattern XRPD of the trimetinib amorphous form is shown in Fig. 19.

The DSC spectrum of the trimetini amorph is shown in Figure 20.

Example 2 1.57 g of a 28% sodium decyl alcohol decyl alcohol solution was added to 40 mL of N-[3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)- under a nitrogen atmosphere. 6,8-dimercapto-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino] A solution of phenyl]-acetamide (5.0 g) in tetrahydrofuran was stirred at room temperature for 4 hours. Add 0.56 mL of acetic acid, stir at room temperature for half an hour, add 40 mL of water, stir for 1 hour, filter, filter cake is dissolved in 20 mL of dichlorosilane, concentrated to dryness under reduced pressure at 40 ° C to obtain 4.1 g of trimetinib amorphous Things.

Comparative Example 1 Preparation of Ethanol Solvent by Conventional Method (Volatilization Crystallization)

At room temperature, 10.0 mg of trimetinib amorphous substance was added, 15.0 mL of ethanol was added, and 40 Khz was ultrasonicated for 5 minutes to obtain a solution, and the pores were volatilized and crystallized to obtain an ethanol solvate prepared according to a conventional method.

Its X-ray powder diffraction pattern at 2 Θ angle is 5.0 ± 0.2. , 11.0 ± 0.2. , 13.7 ± 0.2. , 17.1 ± 0.2. , 19.8 ± 0.2. And 24.3 ± 0.2. There are characteristic peaks.

Comparative Example 2 Preparation of Ethanol Solvent by Conventional Method (Cooling Crystallization Method)

At room temperature, take 20.0 mg of trimetinib amorphous substance, add lO.O mL of ethanol, heat to 75 ° C to dissolve, 15 ° C per hour to room temperature, crystallize, filter, filter cake 30 ° C vacuum drying 16 In an hour, an ethanol solvate prepared according to a conventional method was obtained.

Comparative Example 3 Preparation of Ethanol Solvent by Conventional Method (Evaporation Crystallization)

At room temperature, 20.0 mg of trimetinib amorphous substance was added, and 10 mL of ethanol was added thereto, and the mixture was heated to 50 ° C for distillation crystallization, and the solvent was distilled to dry to obtain an ethanol solvate prepared according to a conventional method.

The samples prepared in Comparative Examples 2 to 3 had the same or similar XRPD (not shown) as Comparative Example 1. It is stated that the samples of Comparative Example 2 to 3 and the sample of Comparative Example 1 are the same substance.

Comparative Example 4 Preparation of dimethyl sulfoxide solvate by conventional method (cooling crystallization method)

At room temperature, 500.0 mg of trimetinib amorphous substance was added, 2.5 mL of dimercaptosulfoxide was added, and the mixture was heated to 80 ° C to dissolve. After 2 hours, the solid was precipitated, stirred for 3 hours, cooled to room temperature and stirred overnight. After filtration, the filter cake was dried under vacuum at 30 ° C for 16 hours to obtain a dimethyl sulfoxide solvate prepared according to a conventional method.

Its X-ray powder diffraction pattern at 2 Θ angle is 7.5 ± 0.2. 11.1±0.2. , 18.1 ± 0.2. , 19.6 ± 0.2. 20.7 ± 0.2. And 22.8 ± 0.2. There are characteristic peaks.

The DSC spectrum is shown in Fig. 21. It has an endothermic peak at 160 to 190 ° C and a melting point of 183.8 ° C.

The solubility of the disulfoxide solvate prepared according to the conventional method at room temperature in water for 1 hour and 4 hours was 0.51 g/mL and 0.35 g/mL, respectively.

Comparative Example 5 Preparation of dimethyl sulfoxide solvate by conventional method (evaporation crystallization method)

At room temperature, take 20.0 mg of trimetinib amorphous, add lO.O mL of dimercaptosulfoxide, and heat up to

The mixture was subjected to distillation under reduced pressure at 80 ° C, and the solvent was distilled to dryness to obtain a dimercapto sulfoxide solvent prepared according to a conventional method.

The sample prepared in Comparative Example 5 had the same or similar XRPD graphic and DSC graphic (not shown) as Comparative Example 4. The sample of Comparative Example 5 and the sample of Comparative Example 4 are the same substance.

Example 3

At room temperature, 100.0 mg of trimetinib amorphous substance was added, 10.0 mL of ethyl acetate was added, and 40 Khz was sonicated for 5 minutes to obtain a suspension, which was stirred at room temperature for 3 days, centrifuged at 30 ° C for 16 hours under vacuum to obtain Qumei. Tinidine anhydrate Form A. The yield was 92.4 mg; the yield was 92.4%.

Nuclear Magnetic Data: ^ NMR (CDC1 ₃ , 500 MHz): 0.79-0.82 (m, 2H), 1.13-1.15 (m, 2H) _: 1.44 (s, 3H), 2.17 (s, 3H), 2.73-2.77 (m , 1H), 3.22 (s, 3H), 6.72 (t, 1H, J = 8.0 Hz), 7.03 (d, 1H, J = 8.0 Hz), 7.30-7.40 (m, 2H), 7.46-7.49 (m, 1H), 7.52-7.56 (m, 2H), 7.70 (s, 1H), 11.31 (s, 1H).

The X-ray powder diffraction pattern XRPD is shown in Figure 13.

The PLM graphics are shown in Figure 14.

The TGA map is shown in Figure 15.

The DSC spectrum is shown in Figure 16.

The IR spectrum is shown in Figure 17.

The isothermal adsorption curve is shown in Figure 18.

The above test results show that: Formemidine anhydrate form A is very stable at room temperature, will adsorb a small amount of surface water, and does not contain organic solvents.

Example 4

Take 50.0 mg of trimetinib amorphous substance, add 100.0 mL of acetonitrile, sonicate for 40 minutes at 40 Khz to obtain a suspension, stir at room temperature for 7 days, centrifuge at 30 ° C for 20 hours under vacuum to obtain trimetinib. Water crystal form eight. The yield was 42.5 mg; the yield was 85.0%.

Example 5 Take 50.0 mg of trimetinib amorphous substance, add 2.5 mL of a mixed solvent of butanol and terpene 1:1, sonicate at 40 Khz for 5 minutes, stir at room temperature for 1 day, centrifuge at 30 ° C and vacuum dry 18 In hours, the crystal form A of trimetine anhydrate was obtained. The yield was 45.6 mg; the yield was 91.2%.

The samples prepared in Examples 4 to 5 had the same or similar XRPD patterns, PLM patterns, TGA patterns, DSC patterns, and IR patterns (not shown) as in Example 3. The samples of Examples 4 to 5 and the samples of Example 3 were the same.

Example 6

Take 10.0 mg of trimetinib amorphous substance, add 1.0 mL of ethanol, sonicate for 40 minutes at 40 Khz to obtain a suspension, stir at room temperature for 3 days, centrifuge at 30 ° C for 16 hours under vacuum to obtain trimetinib ethanol solvate. Form 5 The yield was 9.2 mg; the yield was 85.6%.

Nuclear Magnetic Data: ^ NMR (CDC1 ₃ , 500 MHz) 0.79-0.82 (m, 2H), 1.13-1.15 (m, 2H), 1.17 (t, 3H, J = 7.0 Hz), 1.44 (s, 3H), 2.17 (s, 3H), 2.73-2.77 (m, 1H), 3.22 (s, 3H), 3.65 (d, 2H, J = 7.0 Hz), 6.72 (t, 1H, J = 8.0 Hz), 7.03 (d, 1H, J = 8.0 Hz), 7.30-7.40 (m, 2H), 7.46-7.49 (m, 1H), 7.52-7.56 (m, 2H), 7.70 (s, 1H), 11.31 (s, 1H).

X-ray powder diffraction pattern XRPD is shown in Figure 1.

The PLM graphics are shown in Figure 2.

The TGA map is shown in Figure 3.

The DSC spectrum is shown in Figure 4.

The IR spectrum is shown in Figure 5.

The isothermal adsorption curve is shown in Figure 6.

The solubility of trimetine ethanol solvate Form E at room temperature in water for 1 hour and 4 hours was 1.31 g/mL and 0.50 g/mL, respectively.

The above test results show that: the solubility of the trimetine ethanol solvate crystal form E in water at room temperature is significantly better than the disulfoxide solvate prepared according to the conventional method, which is very stable at room temperature, is not easy to absorb moisture, and the solvent is more acceptable. , crystal form stability.

Example 7

Take 10.0 mg of trimetine anhydrate Form A, add 2.0 mL of 1:1 ethanol/isopropyl acetate solution, sonicate for 40 minutes at 40 Khz, stir at room temperature for 1 day, centrifuge, 30 Drying in vacuo at °C for 16 hours gave the crystal form E of trimetine ethanol solvate. The yield was 9.4 mg; the yield was about 87.5%. Example 8

Take 20.0 mg of trimetinib amorphous substance, add 1.0 mL volume ratio of 5:1 ethanol/isopropyl acetate solution, sonicate for 40 minutes at 40 Khz, stir at room temperature for 5 days, centrifuge, vacuum at 30 °C After drying for 16 hours, the crystal form E of trimetinib ethanol solvate was obtained. The yield was 17.8 mg; the yield was about 82.8%.

Example 9

Take 10.0 mg of trimetine anhydrate crystal form A, add 10 mL of ethanol/acetic acid isopropyl ester solution in a volume ratio of 2:1, stir at room temperature for 5 days, centrifuge, and vacuum dry at 30 ° C for 16 hours to obtain Qumei. Tinifol solvate Form E. The yield was 8.8 mg; the yield was 81.9%.

Example 10

50.0 mg of the trimetinib amorphous substance prepared in Example 1 was placed in an open reaction flask, 10 mL of ethanol was added, and the open reaction flask was placed in a sealed glass bottle filled with ethanol vapor, and allowed to stand at room temperature. After 3 days, the crystal form E of trimetine ethanol solvate was obtained. The yield was 54.0 mg; the yield was about 100.0%. Example 11

Take 15.0 mg of trimetine anhydrate crystal form A, add 0.5 mL of dimethyl sulfoxide, sonicate for 40 minutes at 40 Khz to obtain a yellow solution, slowly add 2.5 mL of ethanol, stir and crystallize at room temperature for 16 hours, centrifuge, 30 Drying under vacuum at °C for 16 hours gave the crystal form E of trimetine ethanol solvate. The yield was 13.5 mg; the yield was 83.7%.

Example 12

Take 10.0 mg of trimetinib amorphous substance, add 1 mL of dimethyl sulfoxide, sonicate for 40 minutes at 40 Khz to obtain a yellow solution, slowly add 2 mL of ethanol, stir and crystallize at 10 ° C for 24 hours, centrifuge, 30 ° C Vacuum drying for 16 hours gave the crystal form E of trimetinib ethanol solvate. The yield was 8.9 mg; the yield was 82.8%.

Example 13

Take 10.0 mg of trimetine anhydrate crystal form A, add 0.5 mL of dimethyl sulfoxide, sonicate for 40 minutes at 40 Khz to obtain a yellow solution, slowly add 5 mL of ethanol, stir and crystallize at 10 ° C for 10 hours, centrifuge It was dried under vacuum at 30 ° C for 16 hours to obtain crystal form E of trimetine ethanol solvate. The yield was 9.4 mg; the yield was 87.5%.

The samples prepared in Examples 7 to 13 had the same or similar XRPD patterns, PLM patterns, TGA patterns, DSC patterns, and IR patterns (not shown) as in Example 6. The samples of Examples 7 to 13 and the samples of Example 6 are the same. The preparation of the crystal form E of trimetinib ethanol solvate in Examples 6 to 13 was significantly different from the conventional method of preparing the ethanol solvate in Comparative Examples 1 to 3, for example, using 40 Khz sonication or longer. Stirring time or co-crystallization with a mixed solvent containing ethanol or the like.

Example 14

10.0 mg of the trimetinib amorphous substance prepared in Example 1 was added, 2.0 mL of n-propanol was added, and 40 Khz was sonicated for 5 minutes to obtain a suspension, stirred at room temperature for 3 hours, centrifuged, and vacuum dried at 30 ° C for 16 hours to obtain a koji. Metinib n-propanol solvate crystal form N. The yield was 8.7 mg; the yield was 79.2%.

Nuclear Magnetic Data: NMR (CDC1 ₃ , 500 MHz) 0.79-0.82 (m, 2H), 0.89 (t, 3H, J = 7.0 Hz), 1.13-1.15 (m, 2H), 1.42-1.62 (m, 2H), 1.44 (s, 3H), 2.17 (s, 3H), 2.73-2.77 (m, 1H), 3.22 (s, 3H), 3.52-3.56 (m, 2H), 6.72 (t, 1H, J = 8.0 Hz) , 7.03 (d, 1H, J = 8.0 Hz), 7.30-7.40 (m, 2H), 7.46-7.49 (m, 1H), 7.52-7.56 (m, 2H), 7.70 (s, 1H), 11.31 (s , 1H).

X-ray powder diffraction pattern XRPD is shown in Figure 7.

The PLM graphics are shown in Figure 8.

The TGA map is shown in Figure 9.

The DSC spectrum is shown in Figure 10.

The IR spectrum is shown in Figure 11.

The isothermal adsorption curve is shown in Figure 12.

At room temperature, the n-propanol solvate crystal form N had a solubility of 1.1 g/mL in water for 1 hour and a solubility of 1.2 g/mL at 4 hours.

The above test results show that: the solubility of trimetinidol n-propanol solvate Form N in water at room temperature is significantly better than the disulfoxide solvate prepared according to the conventional method, which is very stable at room temperature, is not easy to absorb moisture, and contains more solvent. Accepted, crystal form stability.

Example 15

Take 20.0 mg of trimetinib amorphous substance, add 1 mL of n-propanol, sonicate for 40 minutes at 40 Khz, stir at room temperature for 8 hours, centrifuge, and vacuum dry at 30 ° C for 16 hours to obtain trimetinib. Alcohol solvate crystal form N. The yield was 18.2 mg; the yield was 82.8%.

Example 16

Take 40.0 mg of trimetinib amorphous substance, add 1 mL of n-propanol, sonicate for 40 minutes at 40 Khz, stir at room temperature for 16 hours, centrifuge, and vacuum dry at 30 ° C for 16 hours to obtain trimetinib. Alcohol solvate crystal form N. The yield was 30.8 mg; the yield was 70.1%. The samples prepared in Examples 15 to 16 had the same or similar XRPD patterns, PLM patterns, TGA patterns, DSC patterns, and IR patterns (not shown) as in Example 14. The samples of Examples 15 to 16 and the samples of Example 14 are the same.

Example 17

10 mg of trimetinib amorphous substance was added, 5 mL of tetrahydrofuran was added, and 40 Khz was sonicated for 5 minutes to obtain a solution, which was filtered, and the pores were volatilized at room temperature, and the solvent was evaporated to dryness to obtain crystals of trimetinib tetrahydrofuran solvate. The yield was 9.2 mg; the yield was 82.3%.

Example 18

The ometinidin amorphous material prepared in Example 1 was placed in a sealed glass bottle filled with trifluoroethanol vapor, and allowed to stand at room temperature for 1 day to obtain a crystal of trimetinib trifluoroethanol solvate. The yield was 11.6 mg; the yield was about 100.0%.

Example 19

Take 30.0 mg of trimetinib amorphous substance, add 3 mL of trifluoroethanol, sonicate for 40 minutes at 40 Khz to obtain a saturated solution, and quickly filter. The filtrate is slowly added to 30 mL of water while stirring at room temperature, and a white solid is precipitated and stirred for 1 hour. After centrifugation, vacuum drying at 30 ° C for 16 hours gave crystals of trimetinib trifluoroethanol solvate. The yield was 18.5 mg; the yield was 53.0%.

Example 20

The omethatinib prepared in Example 1 was amorphous, placed in a sealed glass vial filled with acetone vapor, and allowed to stand at room temperature for 3 days to obtain a crystal of trimetinib acetate. The yield was 10.9 mg; the yield was about 100.0%.

Example 21

Take 30.0 mg of trimetinib amorphous substance, add 1 mL of trifluoroethanol, sonicate for 40 minutes at 40 Khz to obtain a saturated solution, and quickly filter. The filtrate is slowly added with 5 mL of acetone while stirring at room temperature, and stirred for 5 days to precipitate a white solid. After centrifugation, vacuum drying at 30 ° C for 16 hours gave crystals of trimetinib acetal solvate. The yield was 9.7 mg; the yield was 29.5%.

Example 22

Take 30.0 mg of trimetinib amorphous substance, add 1 mL of trichloromethane, sonicate for 40 minutes at 40 Khz to obtain a saturated solution, and quickly filter. The filtrate is slowly added with 10 mL of decyl tert-butyl ether at room temperature. After stirring at ° C for 1 day, a white solid was precipitated, centrifuged, and dried under vacuum at 30 ° C for 16 hours to obtain crystals of the trimetinimidyl tert-butyl ether solvate. The yield was 8.0 mg; the yield was 23.3%. Each of 5.0 mg of the trimetinidil sulfoxide solvate prepared according to the conventional method, the trimetinib ethanol solvate crystal form E prepared by the present invention, and the trimetinib n-propanol solvate prepared by the present invention were respectively taken. Form N, 5 mg sample per 100 mL of water was stirred at 25 ° C, and the solubility test was performed by HPLC for 1 hour and 4 hours. The solubility results are shown in Table 1 in g/mL.

Table 1 Solubility Test Results Crystal Form 1 hour 4 hours Dimethyl sulfoxide solvate 0.51 0.35 prepared according to a conventional method Ethanol solvate crystal form E 1.31 0.50 of the present invention n-propanol solvate crystal form N 1.14 1.17 of the present invention The solubility test results of 1 show that: the crystal form E of trimetinib ethanol solvate of the invention and the crystal form N of trimetinib n-propanol solvate of the invention have a solubility in water at room temperature which is significantly better than that prepared according to a conventional method. Trimetrepine disulfoxide solvate.

Example 24

Tablet embodiments of trimetine ethanol solvate Form E. See Table 2 for the amount of each component.

Table 2 Tablet Formulation of Trimetirin Ethanol Solvate Form E

Trimetrinol Ethanol Solvate Form E 0.54 1.07 2.15 Sodium lauryl sulfate 0.017 0.034 0.068 Colloidal silica 0.01 0.02 0.04 Mannitol 95.47 101.51 106.95 Microcrystalline cellulose 36.25 38.75 41.25 Hydroxypropyl cellulose 7.25 7.75 8.25 Crosslinking Carboxymethyl cellulose sodium 4.35 4.65 4.95 Magnesium stearate 1.09 1.16 1.24 Coating material Opadry YS-1-14762-A 0 0 4.95 Coating material Opadry YS-1-12525-A 4.35 0 0 Coating material Opadry OY- S-28876 0 4.65 0 Tablet Weight 149.33 159.59 169.85 Procedure:

1) The amount of trimetine ethanol solvate crystal form E and mannitol is equal in the three-dimensional mixer The addition method is uniformly mixed, and sodium lauryl sulfate, colloidal silica, microcrystalline cellulose, hydroxypropylcellulose and croscarmellose sodium are added and sieved.

2) The magnesium stearate is sieved and mixed with the mixture in step 1.

3) The mixture in step 2 is pressed into a tablet core of each dose on a rotary tablet press. A total of 1000 tablets were pressed. 4) The film core is continuously coated with an aqueous solution of the coating material until an increase of about 3% of the target weight is achieved. Among them, Opadry YS-1-14762-A (pink) for 0.5 mg dose core film, Opadry YS-1-12525-A (yellow) for 1 mg dose core film, Opadry OY-S- 28876 (white) For 2 mg dose core film.

Example 25

Tablet embodiments of trimetinib n-propanol solvate Form N. See Table 3 for the amount of each component.

Table 3 Tablet formulations of trimetinib n-propanol solvate crystal form N

Trimetrein n-propanol solvate crystal form N 0.55 1.10 2.20

Sodium lauryl sulfate 0.017 0.034 0.068 Colloidal silica 0.01 0.02 0.04

Mannitol 95.47 101.51 106.95 Microcrystalline cellulose 36.25 38.75 41.25 Hydroxypropyl cellulose 7.25 7.75 8.25 Cross-linked carboxymethyl cellulose Sodium 4.35 4.65 4.95

Magnesium stearate 1.09 1.16 1.24 Coating material Opadry YS-1-14762-A 0 0 4.95 Coating material Opadry YS-1-12525-A 4.35 0 0 Coating material Opadry OY-S-28876 0 4.65 0

Tablet weight 149.34 159.62 169.90 The same procedure as in Example 24. Example 26

Tablet embodiments of trimetine anhydrate Form A. The amount of each component is shown in Table 4. Table 4 Tablet formulation of trimetine anhydrate crystal form A

Dosage (mg/tablet) 0.5 1 2 trimetine anhydrate crystal form A 0.5 1 2 sodium lauryl sulfate 0.017 0.034 0.068 colloidal silica 0.01 0.02 0.04 mannitol 95.47 101.51 106.95 microcrystalline cellulose 36.25 38.75 41.25 hydroxypropionin cellulose 7.25 7.75 8.25 croscarmellose sodium 4.35 4.65 4.95 Magnesium stearate 1.09 1.16 1.24 Coating material Opadry YS-1-14762-A 0 0 4.95 Coating material Opadry YS-1-12525-A 4.35 0 0 Coating material Opadry OY-S-28876 0 4.65 0 Tablet weight 149.29 159.52 169.70 The procedure is the same as in Example 24. Those skilled in the art will appreciate that many modifications or variations can be made in the present invention. Such modifications and variations are also intended to be included within the scope of the appended claims.

Claims

Rights request

1. The structural form of trimetine ethanol solvate crystal form E as shown below,

It is characterized in that, using Cu-Κα radiation, the X-ray powder diffraction pattern expressed at a 2 Θ angle has a characteristic peak at the following position: 5.4 ± 0.2. , 10.5 ± 0.2. 12.2 ± 0.2. 12.8 ± 0.2. , 18.3 ± 0.2. And 21.1 士0·2 ^ο .

2. The trimetine ethanol solvate crystal form according to claim 1, wherein the X-ray powder diffraction pattern represented by the angle of 2 具有 has a characteristic peak at 5.4 ± 0.2. , 9.2 ± 0.2. , 10·5±0·2 ^ο , 10.9士0·2 ^ο , 12.2士0·2 ^ο , 12·8±0·2 ^ο , 13.9士0·2 ^ο , 16.2士0·2 ^ο , 18·3士0·2 ^ο , 19.4 ± 0.2°, 21.1 ± 0.2° and 24.5 ± 0.2°.

3. The trimetine ethanol solvate crystal form according to claim 2, wherein the X-ray powder diffraction pattern represented by the angle of 2 具有 has characteristic peaks and relative intensities at the following positions:

Diffraction angle 2Θ relative intensity%

5.4 ± 0.2° 34.1

9.2 士 0.2° 40.0

10.5 ± 0.2. 86.9

10.9 ± 0.2. 42.4

12.2±0.2° 58.7

12.8 ± 0.2. 100.0

13.9 ± 0.2. 49.1

16.2±0.2° 38.0

18.3±0.2° 68.7

18.9 ± 0.2 ° 36.7

19.4 ± 0.2. 59.1

20.0 ± 0.2. 50.4

20.8 ± 0.2. 65.3

21.1 ± 0.2. 85.5

21.4 ± 0.2° 37.4

22·1±0·2° 74.6

22.8±0.2° 62.2

24.5±0.2° 81.7

25·9±0·2° 51.5

27.9 ± 0.2 ° 57.1

29.1±0.2° 42.3

29.5 ± 0.2 ° 53.2

The trimetine ethanol solvate crystal form according to any one of claims 1 to 3, wherein the Fourier transform infrared spectrum of the crystalline form is 693, 777, 812, 1228 Characteristic peaks at 1438, 1548, 1610, 1631, 1676, 2631, 3321, and 3497 cm.

The method for producing crystal form E of trimetinib ethanol solvate according to any one of claims 1 to 4, wherein the preparation method comprises any one of the following methods:

(1) The trimetinib amorphous form is placed in a closed container filled with ethanol vapor at room temperature to obtain the crystal form E of the trimetinib ethanol solvate;

Preferably, the rest time is 1 to 3 days, preferably 1 to 1.5 days;

(2) Forming a suspension of trimetinib in an organic solvent, stirring and crystallization at room temperature for 1 to 5 days, and then separating and drying the precipitated crystal to obtain the crystal form E of the trimetinib ethanol solvate. Wherein the organic solvent is selected from the group consisting of ethanol or a mixed solvent of ethanol and isopropyl acetate in a volume ratio of 1:1 to 5:1;

Preferably, the weight to volume ratio of the trimetinib to the organic solvent is from 1 to 20 mg: 1 ml, preferably from 5 to 10 mg: 1 ml;

Preferably, the volume ratio of ethanol to isopropyl acetate in the mixed solvent is 1:1~2:1;

Preferably, the crystallization time is 1 to 3 days;

(3) adding ethanol to the solution of trimetinib dimethyl sulfoxide, the volume ratio of dimethyl sulfoxide to ethanol is 0.1:1~0.5:1, stirring and crystallization at room temperature for 10-24 hours, then The precipitated crystal is separated and dried to obtain the crystal form E of the trimetinib ethanol solvate;

Preferably, the amount of the trimetinib is 0.5 to 1 times the solubility in the dimercaptosulfoxide at room temperature; preferably, the volume ratio of the dimercaptosulfoxide to the ethanol is preferably 0.1:1~ 0.2:1;

Preferably, the crystallization time is 10 to 16 hours.

6. The structural formula is as follows: the trimetine n-propanol solvate crystal form N,

It is characterized in that, using Cu-Κα radiation, the X-ray powder diffraction pattern expressed at a 2 Θ angle has a characteristic peak at the following position: 10.5 ± 0.2. 12.1 ± 0.2. 12.8 ± 0.2. , 13.9 ± 0.2. , 18.3 ± 0.2. And 20.9 士0·2 ^ο .

The trimetine n-propanol solvate crystal form according to claim 6, wherein the X-ray powder diffraction pattern represented by the angle of 2 具有 has a characteristic peak at the following position: 9.1 ± 0.2. , 10.5 ± 0.2. 12.1士0·2 ^ο , 12.8士0·2 ^ο , 13.9士0·2 ^ο , 18.3士0·2 ^ο , 19.8士0·2 ^ο , 20.6士0·2 ^ο , 20.9士0·2 ^ο , 21.9 ± 0.2 °, 22.6 ± 0.2 ° and 24.3 ± 0.2 °.

The trimetine n-propanol solvate crystal form according to claim 7, wherein the X-ray powder diffraction pattern represented by the angle of 2 具有 has characteristic peaks and relative intensities at the following positions:

Diffraction angle 2Θ relative intensity%

9·1±0·2° 16.1

10.5 ± 0.2° 100.0

12.1 ± 0.2 ° 58.2

12.8 ± 0.2 ° 39.2

13.9 ± 0.2° 35.0

18.3 ± 0.2. 38.3

19.2 ± 0.2° 10.1

19.8 ± 0.2 ° 52.0

20.6 ± 0.2° 49.1

20.9 ± 0.2° 86.8

21.9 ± 0.2 ° 57.2

22.6 ± 0.2. 25.8

24.3 ± 0.2 ° 54.4

25.4 ± 0.2° 23.5

27.8 ± 0.2° 30.6

29.2 ± 0.2 ° 32.9.

The trimetine n-propanol solvate crystal form according to any one of claims 6 to 8, wherein the Fourier transform infrared spectrum of the crystalline form is 693, 777, and 1229 Characteristic peaks at 1350, 1367, 1438, 1547, 1608, 1632, 1677, 3324, and 3503 cm. The process for preparing a morphine n-propanol solvate crystal form N according to any one of claims 6 to 9, wherein the preparation method comprises: placing a trimetinib amorphous substance in n-propanol to form a solid The suspension is stirred and crystallized at room temperature for 3 to 16 hours, and then the precipitated crystals are separated and dried to obtain the crystal form N of trimetinib n-propanol solvate;

Preferably, the weight-to-volume ratio of the trimetinib amorphous substance to n-propanol is 5 to 40 mg: 1 ml, preferably 5-20 mg: 1 ml;

Preferably, the crystallization time is 3 to 8 hours.

11,

It is characterized in that, using Cu-Κα radiation, the X-ray powder diffraction pattern expressed at a 2 Θ angle has a characteristic peak at the following position: 3·8±0·2. , 9·2±0·2. , 14·7±0·2. , 18·5±0·2. , 19·5±0·2. And 22·1±0·2 ^ο .

12. The trimetini anhydride anhydrate form according to claim 11, wherein the X-ray powder diffraction pattern represented by the angle of 2 turns has a characteristic peak at the following position: 3.8 ± 0.2. , 9.2 ± 0.2. , 14.7 ± 0.2. , 16·9±0·2°, 18·5±0·2°, 18·8±0·2°, 19·5±0·2°, 20·1±0·2°, 20·5± 0·2°, 22·1±0·2 ^ο and 23·6±0·2 ^ο .

13. The trimetine anhydrate crystalline form according to claim 12, wherein the X-ray powder diffraction pattern represented by the angle of 2 turns has characteristic peaks and relative intensities at the following positions:

Diffraction angle 2Θ relative intensity%

3.8±0.2° 100

9.2±0.2° 59.6

14.7±0.2° 64.6

16.9±0.2° 20.5

18.5±0.2° 69.5

18.8±0.2° 38.7

19·5±0·2° 83.2

19.8±0.2° 18.3

20·1±0·2° 25.5

20·5±0·2° 66.8

22.1 ± 0.2 88.0

23.6 ± 0.2 46.3

24.2 ± 0.2 25.0

24·9±0·2 20.1

25·3±0·2 22.8

26.6 ± 0.2 20.5

27·1±0·2 17.3

27.9 ± 0.2 18.7

30.8 ± 0.2 24.3

32.8 ± 0.2 17.4

35·9±0·2 19.3

The crystal form of the trimetine anhydrate form according to any one of claims 11 to 13, wherein the Fourier transform infrared spectrum of the crystalline form is 694, 779, 1241, 1302 Characteristic peaks at 1420, 1478, 1550, 1645, 1718, 2363, 2927, 3024, and 3305 cm.

15. A process for the preparation of crystal form A of trimetinib anhydride according to any one of claims 11 to 14, wherein the preparation method comprises: forming a solid suspension of trimetinib amorphous form in an organic solvent. The solution is stirred and crystallized at room temperature for 1 to 7 days, and then the precipitated crystals are separated and dried to obtain the crystal form A of trimetinib anhydride, which is selected from the group consisting of butanol, ethyl acetate and acetic acid. a mixed solvent of isopropyl ester, acetonitrile, toluene or a solvent thereof in any ratio;

Preferably, the weight-to-volume ratio of the trimetinib amorphous substance to the organic solvent is 5-20 mg: 1 ml, preferably 5-10 mg: l ml;

Preferably, the crystallization time is 1 to 3 days.

16,

The amorphous form of trimetinib according to claim 16, which has an X-ray powder diffraction pattern as shown in FIG.

18. A method of preparing a trimetinib amorphous form according to any of claims 16-17, the method comprising the steps of: 1) in N-[3-[3-cyclopropyl-l-(2-fluoro-4-iodophenyl)-6,8-diindenyl-2,4,7-trioxo-1,2 , a solution of sodium decyl citrate in tetrahydrofuran solution of 3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl]-acetamide, stirred under stirring Carry out the reaction until the reaction is over;

2) adding acetic acid to neutralize;

3) adding water to stir and crystallize, filtering, collecting the filter cake;

4) The filter cake was dissolved in chloroform or dichloromethane, and then concentrated to dryness under reduced pressure to give the crystals of the trimetinib.

A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a pharmaceutically active ingredient selected from the group consisting of the trimetine ethanol solvate crystal form E according to any one of claims 1 to 4, in claims 6-9 Any one of the trimetini n-propanol solvate crystal form N, the trimetini alfate crystal form A according to any one of claims 11 to 14, and any one of claims 16-17 a smeltinidin n-propanol solvate crystal obtained by the preparation method according to the preparation method according to claim 10, wherein the trimetini aldehyde solvate crystal form E obtained by the preparation method according to claim 5 Form N, the trimetiniline anhydrate form A obtained according to the preparation method of claim 15, or the trimetinib amorphous form obtained according to the preparation method of claim 18, and at least one pharmaceutically acceptable a.

The trimetine ethanol solvate crystal form E according to any one of claims 1 to 4, the trimetini n-propanol solvate crystal form N according to any one of claims 6 to 9, and the claims The crystal form A of trimetine anhydrate of any one of 11 to 14, the amorphine of trimetinib according to any one of claims 16 to 17, and the preparation method according to the preparation method of claim 5. Forminidin ethanol solvate crystal form E, trimetinib n-propanol solvate crystal form N obtained according to the preparation method of claim 10, and trimetinib anhydrate obtained by the preparation method according to claim 15. The use of Form A or the trimetinib amorphous form obtained by the preparation method according to claim 18 for the treatment and/or prevention of a drug for a hyperproliferative disease; the hyperproliferative disease selected from the group consisting of a brain tumor and an esophageal cancer , gastric cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, melanoma cancer, neuroblastoma or sarcoma, preferably colon cancer, pancreatic cancer, Kidney cancer, lung cancer, milk Cancer or melanoma cancer.

21. A method of treating and/or preventing a hyperproliferative disorder, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of one or more selected from any one of claims 1-4 The morphemin ethanol solvate crystal form E, the trimetinib n-propanol solvate crystal form N according to any one of claims 6 to 9, and the method according to any one of claims 11 to Formmetinilide anhydrate amorphous form A, trimetinib amorphous form according to any one of claims 16-17, and trimetinib ethanol solvate crystal form E obtained according to the preparation method of claim 5. The trimetinib obtained by the preparation method according to claim 10 a propanol solvate crystal form N, a trimetinib anhydride anhydrate form A obtained according to the preparation method of claim 15, a trimetinib amorphous form obtained according to the preparation method of claim 18 or claim 19 The pharmaceutical composition; the hyperproliferative disease selected from the group consisting of brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colon cancer, rectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer , melanoma, neuroblastoma or sarcoma, preferably colon cancer, pancreatic cancer, kidney cancer, lung cancer, breast cancer or melanoma cancer.