WO2022194160A1 - Solid form of fisogatinib and preparation method therefor - Google Patents

Abstract

The present invention provides a solid form of fisogatinib and a preparation method therefor. In particular, the present invention provides a solid form of a compound as shown in formula I, the solid form comprising a crystalline form I, a crystalline form II, a salt crystal form or an eutectic XM-I, a salt crystal form or an eutectic XM-II, a salt crystal form or an eutectic XM-III, a salt crystal form or an eutectic crystal XM-IV, or a salt crystal form or an eutectic XM-V. Compared with existing fisogatinib compounds, the solid form in the present invention has better stability.

Description

<Solid form of fisotinib and method for producing the same> technical field

The invention relates to the field of medicinal chemistry, in particular to N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl ) amino) tetrahydro-2H-pyran-4-yl) acrylamide crystal form, salt crystal form or co-crystal and preparation method thereof.

Background technique

FGFR4 is an oncogenic driver in patients with locally advanced or metastatic hepatocellular carcinoma (HCC). As a ligand of FGFR4, FGF19 can activate FGFR4, thereby promoting hepatocyte proliferation and regulating intrahepatic bile acid balance. About 30% of HCC patients have abnormal activation of FGF19/FGFR4 signaling pathway. Fisotinib (BLU-554) is an investigational potent and highly selective fibroblast growth factor receptor-4 (FGFR4) inhibitor developed by Blueprint Medicines for the treatment of FGFR4-driven advanced HCC. The drug is not yet on the market, and its phase I clinical trial data show that fisotinib as a single agent has demonstrated clinical efficacy and good tolerability in patients with locally advanced or metastatic hepatocellular carcinoma (HCC) with a history of multiple treatments. The drug can stimulate T cells to infiltrate the tumor microenvironment, suggesting that its combination with an anti-PD-L1 inhibitor may show stronger efficacy in patients with FGFR4-driven advanced HCC.

The chemical name for fisotinib (BLU-554) is N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline) -2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide, the chemical formula is C ₂₄ H ₂₄ Cl ₂ N ₄ O ₄ , the molecular weight is 503.38, and its molecular structure is as follows:

Patent WO2015061572 reports the compound of formula (I). According to the research of the present inventors, the amorphous form of the compound has poor solubility in water, and is less than 1 mg/mL at 50°C. Poor solubility results in slow drug absorption and low bioavailability. Drug co-crystals and salts are effective means to improve drug solubility.

In order to overcome the shortcomings of the prior art, there is an urgent need in the art to carry out research on the salt form or co-crystal of the compound to find a crystal form, salt form or co-crystal with greater solubility that meets the needs of drug development, formulation preparation and industrial production.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a solid form of fisotinib, a compound of formula (I), to meet the needs of drug research and industrial production.

Another object of the present invention is to provide a method for preparing a solid form of fisotinib with high stability.

A first aspect of the present invention provides a solid form of a compound as shown in formula (I),

Wherein, described solid form is selected from following group:

Form I, Form II;

Salt crystal form or co-crystal XM-I of fisotinib and maleic acid;

Salt crystal form or co-crystal XM-II of fisotinib and maleic acid;

Salt crystal form or co-crystal XM-III of fisotinib and sulfuric acid;

The salt crystal form or co-crystal XM-IV of fisotinib with hydrochloric acid; or,

Salt crystal form or co-crystal XM-V of fisotinib and stearic acid.

In another preferred embodiment, the solid form is crystal form I, and the X-ray powder diffraction pattern of the crystal form I includes 3 or more 2θ values selected from the following group: 5.9°±0.2 °, 8.2°±0.2°, 12.0°±0.2°, 20.1°±0.2°, 23.8°±0.2°.

In another preferred embodiment, the solid form is crystal form II, and the X-ray powder diffraction pattern of the crystal form I includes 3 or more 2θ values selected from the following group: 4.2°±0.2 °, 16.7°±0.2°, 20.9°±0.2°, 23.0°±0.2°, 29.7°±0.2°.

Preferably, the crystalline form I has one or more characteristics selected from the group consisting of:

1) The XRPD pattern of the crystal form I comprises 6 or more 2θ values selected from the group consisting of 5.9°±0.2°, 8.2°±0.2°, 10.3°±0.2°, 10.6°±0.2°, 10.9 °±0.2°, 11.7°±0.2°, 12.0°±0.2°, 13.0°±0.2°, 13.9°±0.2°, 16.5°±0.2°, 17.4°±0.2°, 17.8°±0.2°, 18.1°± 0.2°, 19.0°±0.2°, 20.1°±0.2°, 20.6°±0.2°, 21.4°±0.2°, 22.2°±0.2°, 23.1°±0.2°, 23.8°±0.2°, 24.9°±0.2° , 26.6°±0.2°, 27.5°±0.2°, 28.3°±0.2°, 29.1°±0.2°, 31.4°±0.2°.

2) The crystal form I has an XRPD pattern as shown in Figure 1;

3) the crystal form I has a TGA diagram substantially as shown in Figure 2;

4) The crystal form I has a DSC diagram as shown in Figure 3;

5) The crystal form I has a ¹ H NMR spectrum substantially as shown in FIG. 4 .

Preferably, the crystal form II has one or more features selected from the group consisting of:

1) The XRPD pattern of the crystal form II includes 6 or more 2θ values selected from the following group: 4.2°±0.2°, 8.4°±0.2°, 11.6°±0.2°, 12.2°±0.2°, 14.5 °±0.2°, 15.5°±0.2°, 16.7°±0.2°, 20.9°±0.2°, 22.1°±0.2°, 23.0°±0.2°, 25.9°±0.2°, 29.7°±0.2°, 30.5°± 0.2°, 33.7°±0.2°.

2) The crystal form II has an XRPD pattern substantially as shown in Figure 9;

3) The crystal form II has a TGA diagram substantially as shown in Figure 10;

4) The crystal form II has a DSC chart as shown in FIG. 11 ;

5) The crystal form II has a ¹ H NMR spectrum substantially as shown in FIG. 12 .

In another preferred embodiment, the solid form is salt crystal form or co-crystal XM-I. In another preferred embodiment, the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-I comprises the following 2θ values: 3.2°±0.2°; and at least 2 2θ values selected from the following group: 8.7° ±0.2°, 9.8°±0.2°, 11.8°±0.2°, 23.1°±0.2°.

In another preferred embodiment, the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-I further has one or more 2θ values selected from the following group: 5.6°±0.2°, 6.5°± 0.2°, 11.4°±0.2°, 13.1°±0.2°, 15.0°±0.2°.

In another preferred embodiment, the differential scanning calorimetry analysis of the salt crystal form or co-crystal XM-I has an endothermic peak in the range of 200°C to 210°C.

In another preferred embodiment, the salt crystal form or co-crystal XM-I loses about 15 wt% at 150°C-250°C.

In another preferred example, the salt crystal form or co-crystal XM-I has XRPD data substantially as shown in Table 11.

In another preferred embodiment, the salt crystal form or co-crystal XM-I has an XRPD spectrum substantially as shown in FIG. 17 .

In another preferred embodiment, the salt crystal form or co-crystal XM-I has a TGA spectrum substantially as shown in FIG. 18 .

In another preferred embodiment, the salt crystal form or co-crystal XM-I has a DSC spectrum substantially as shown in FIG. 19 .

In another preferred embodiment, the salt crystal form or co-crystal XM-I has a ¹ H NMR spectrum substantially as shown in FIG. 20 .

In another preferred embodiment, the solid form is salt crystal form or co-crystal XM-II. In another preferred embodiment, the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-II includes 3 or more, preferably 4 or more, more preferably 5 , 2θ values selected from the following group: 8.3°±0.2°, 12.5°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 24.6°±0.2°.

In another preferred embodiment, the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-II also has one or more 2θ values selected from the following group: 4.1°±0.2°, 5.9°± 0.2°, 15.9°±0.2°, 19.9°±0.2°, 21.6°±0.2°.

In another preferred embodiment, the differential scanning calorimetry analysis of the salt crystal form or co-crystal XM-II has an endothermic peak in the ranges of 195°C-205°C and 330°C-340°C respectively.

In another preferred embodiment, the salt crystal form or co-crystal XM-II loses about 10% in weight at 100°C-220°C.

In another preferred example, the salt crystal form or co-crystal XM-II has XRPD data substantially as shown in Table 12.

In another preferred embodiment, the salt crystal form or co-crystal XM-II has an XRPD spectrum substantially as shown in FIG. 21 .

In another preferred embodiment, the salt crystal form or co-crystal XM-II has a TGA spectrum substantially as shown in Figure 22.

In another preferred embodiment, the salt crystal form or co-crystal XM-II has a DSC spectrum substantially as shown in FIG. 23 .

In another preferred embodiment, the salt crystal form or co-crystal XM-II has a 1H NMR spectrum substantially as shown in FIG. 24 .

In another preferred embodiment, the solid form is salt crystal form or co-crystal XM-III.

In another preferred embodiment, the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-III includes 3 or more, preferably 4 or more, more preferably 5 2Θ values selected from the following group: 5.1°±0.2°, 8.1°±0.2°, 10.2°±0.2°, 13.1°±0.2°, 20.4°±0.2°.

In another preferred embodiment, the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-III further has one or more 2θ values selected from the following group: 7.2°±0.2°, 11.7°± 0.2°, 17.6°±0.2°, 21.2°±0.2°, 25.2°±0.2°.

In another preferred embodiment, the salt crystal form or co-crystal XM-III has XRPD data substantially as shown in Table 13.

In another preferred embodiment, the salt crystal form or co-crystal XM-III has an XRPD spectrum substantially as shown in FIG. 25 .

In another preferred embodiment, the salt crystal form or co-crystal XM-III has a TGA spectrum substantially as shown in FIG. 26 .

In another preferred embodiment, the salt crystal form or co-crystal XM-III has a DSC spectrum substantially as shown in FIG. 27 .

In another preferred embodiment, the salt crystal form or co-crystal XM-III has a 1H NMR spectrum substantially as shown in FIG. 28 .

In another preferred embodiment, the solid form is salt crystal form or co-crystal XM-IV.

In another preferred embodiment, the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-IV includes 3 or more, preferably 4 or more, more preferably 5 , 2θ values selected from the following group: 3.6°±0.2°, 5.4°±0.2°, 9.8°±0.2°, 21.8°±0.2°, 25.1°±0.2°.

In another preferred embodiment, the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-IV further has one or more 2θ values selected from the following group: 5.0°±0.2°, 13.2°± 0.2°, 13.8°±0.2°, 17.5°±0.2°, 19.8°±0.2°.

In another preferred example, the salt crystal form or co-crystal XM-IV has XRPD data substantially as shown in Table 14.

In another preferred embodiment, the salt crystal form or co-crystal XM-IV has an XRPD spectrum substantially as shown in FIG. 29 .

In another preferred embodiment, the solid form is salt crystal form or co-crystal XM-V.

In another preferred embodiment, the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-V includes 2θ values selected from the group consisting of: 5.7°±0.2°, and at least 1, preferably 2 One or three 2Θ values selected from the group consisting of: 3.8°±0.2°, 9.5°±0.2°, 24.6°±0.2°.

In another preferred embodiment, the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-V further has one or more 2θ values selected from the following group: 7.6°±0.2°, 13.3°± 0.2°, 23.1°±0.2°.

In another preferred embodiment, the differential scanning calorimetry analysis of the salt crystal form or eutectic XM-V has an endothermic peak in the ranges of 60°C-70°C and 210°C-220°C respectively.

In another preferred embodiment, the salt crystal form or eutectic XM-V loses about 4% weight at 25°C-150°C, and loses about 15% weight at 150°C-250°C.

In another preferred example, the salt crystal form or co-crystal XM-V has XRPD data substantially as shown in Table 15.

In another preferred embodiment, the salt crystal form or co-crystal XM-V has an XRPD spectrum substantially as shown in FIG. 30 .

In another preferred embodiment, the salt crystal form or co-crystal XM-V has a TGA spectrum substantially as shown in FIG. 31 .

In another preferred embodiment, the salt crystal form or co-crystal XM-V has a DSC spectrum substantially as shown in FIG. 32 .

In another preferred embodiment, the X-ray powder diffraction is measured under the condition of CuKα radiation.

A second aspect of the present invention provides a method for preparing a solid form of fisotinib as described in the first aspect of the present invention,

(1) when described solid form is crystal form I and crystal form II, comprise steps:

e) providing a solution of the raw material of the compound of formula (I) in the seventh solvent, adding the eighth solvent to the solution for crystallization, and collecting the precipitated solid to obtain the crystal form;

or,

Including the steps: f) providing a solution of the compound of formula (I) raw material in the seventh solvent, adding the solution to the eighth solvent for crystallization, and collecting the precipitated solid to obtain the crystal form;

or,

It comprises the steps of: g) providing a solution of the compound of formula (I) raw material in the seventh solvent, cooling and crystallizing the solution, and collecting the precipitated solid to obtain the crystal form;

(2) when described solid form is salt crystal form or co-crystal, comprises steps:

(a) in a first solvent, reacting a fisotinib starting material and an acid to obtain a mixture of fisotinib salts or co-crystals; and the acid is selected from the group consisting of maleic acid, concentrated sulfuric acid, hydrochloric acid or stearic acid;

(b) collecting the solid from the mixture to obtain the salt crystal form or co-crystal according to the first aspect of the present invention.

Preferably, the seventh solvent includes an alcohol-based solvent, a ketone-based solvent, an amide-based solvent, an ester-based solvent, an ether-based solvent, a nitrile-based solvent, water, or a combination thereof. in,

The alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, or a combination thereof.

The ketone solvent is selected from the group consisting of acetone, 2-butanone, N-methylpyrrolidone, or a combination thereof.

The amide solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof.

The ester solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, n-propyl acetate, tert-butyl acetate, or a combination thereof.

The ether solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof.

The nitrile solvent is selected from the group consisting of acetonitrile.

Preferably,

The eighth solvent includes hydrocarbons, ethers, water, or a combination thereof.

The hydrocarbon solvent is selected from the group consisting of nitromethane, n-heptane, cyclohexane, methylcyclohexane, toluene, or a combination thereof.

The ester solvent is selected from the group consisting of diethyl ether, methyl tert-butyl ether, petroleum ether, or a combination thereof.

In the step f) or the step g), after collecting the precipitated solid, the solid is processed to obtain the crystal form, wherein the processing includes vacuum drying.

In another preferred embodiment, step (a) further includes a stirring step.

In another preferred embodiment, step (b) includes volatilizing the mixture at room temperature to separate out the solid form of fisotinib.

In another preferred embodiment, step (b) includes rinsing the solid with water or ether after collecting the solid.

In another preferred example, in step (a), the fisotinib raw material is the amorphous form of fisotinib.

In another preferred example, in step (a), the first solvent is selected from the group consisting of alcohol solvents, ketone solvents, aromatic hydrocarbon solvents, water, or a combination thereof.

In another preferred example, in step (a), the first dispersion formed by the fisotinib and the first solvent is a crystal slurry or a suspension.

In another preferred example, in step (a), the alcohol solvent is a C1-C4 alcohol solvent; preferably, the alcohol solvent is selected from methanol, ethanol, isopropanol, n-propanol, or a combination thereof.

In another preferred example, in step (a), the ketone solvent is a C2-C6 ketone solvent; preferably, the ketone solvent is selected from: acetone, 2-butanone, methyl isobutyl ketone, N-methylpyrrolidone, or a combination thereof.

In another preferred example, in step (a), the aromatic hydrocarbon solvent is selected from the group consisting of benzene and toluene.

In another preferred example, in step (a), the volume (mL)/mass (mg) ratio of the first solvent to the fisotinib raw material is 1:(20-40).

In another preferred example, in step (a), the first solvent is selected from the following group: isopropanol/water=2:1～1:4(v/v), acetone/water=2:1～ 1:4(v/v).

In another preferred example, in step (a), the reaction temperature is 16-23°C.

In another preferred embodiment, in step (a), the stirring time is selected from 0.5-6d.

In another preferred example, in step (a), the stirring time is 5d.

In another preferred example, in step (a), the stirring time is 1 d.

In another preferred embodiment, in step (b), the collecting includes filtering.

In another preferred embodiment, in step (b), the rinsing solvent is selected from water or diethyl ether.

In another preferred embodiment, when the solid form is salt crystal form or co-crystal XM-I, step (a) includes:

(i) in a second solvent, react with fisotinib raw material and maleic acid, thereby obtaining the mixture of fisotinib salt or co-crystal;

(ii) stirring the mixture.

In another preferred embodiment, the second solvent is selected from: an alcohol solvent, water or a combination thereof.

In another preferred embodiment, the alcohol solvent is a C1-C4 alcohol solvent; preferably, the alcohol solvent is selected from methanol, ethanol, isopropanol, n-propanol, or a combination thereof.

In another preferred embodiment, the alcoholic solvent is isopropanol.

In another preferred example, the second solvent is selected from the following group: isopropanol: water=2:1˜1:2 (v/v).

In another preferred example, the second solvent is isopropanol:water=1:1 (v/v).

In another preferred embodiment, in step (ii), the stirring is performed at room temperature.

In another preferred embodiment, in step (ii), stirring is performed for 5 days.

In another preferred embodiment, the volume (mL)/mass (mg) ratio of the second solvent to the fisotinib raw material is 1:(10-20).

In another preferred example, the mass ratio of the maleic acid to the fisotinib raw material is 1:(1-10).

In another preferred example, when the solid form is salt crystal form or co-crystal XM-II, step (a) includes:

(i) in a third solvent, react with fisotinib raw material and maleic acid, thereby obtaining the mixture of fisotinib salt or co-crystal;

(ii) stirring the mixture.

In another preferred embodiment, the third solvent is selected from the group consisting of ketone solvents, water or a combination thereof.

In another preferred embodiment, the ketone solvent is acetone.

In another preferred example, the third solvent is selected from the group consisting of: acetone:water=1:(2-10)(v/v).

In another preferred example, the third solvent is acetone:water=1:4 (v/v).

In another preferred example, when the solid form is salt crystal form or co-crystal XM-III, step (a) includes:

(i) in the fourth solvent, react with fisotinib raw material and concentrated sulfuric acid, thereby obtain the mixture of fisotinib salt or co-crystal;

(ii) stirring the mixture.

In another preferred embodiment, the fourth solvent is selected from the group consisting of alcohol solvents, water, or a combination thereof.

In another preferred embodiment, the alcohol solvent is a C1-C4 alcohol solvent; preferably, the alcohol solvent is selected from methanol, ethanol, isopropanol, n-propanol, or a combination thereof.

In another preferred embodiment, the alcoholic solvent is isopropanol.

In another preferred example, the fourth solvent is selected from the following group: isopropanol:water=2:1˜1:2 (v/v).

In another preferred example, the fourth solvent is isopropanol:water=1:1 (v/v).

In another preferred example, the volume (mL)/mass (mg) ratio of the fourth solvent to the fisotinib raw material is 1:(10-20).

In another preferred embodiment, when the solid form is salt crystal form or co-crystal XM-IV, step (a) includes:

(i) in the fifth solvent, react with fisotinib raw material and hydrochloric acid, thereby obtain the mixture of fisotinib salt or co-crystal;

(ii) stirring the mixture.

In another preferred embodiment, the fifth solvent is selected from the group consisting of aromatic hydrocarbon solvents.

In another preferred example, the fifth solvent is toluene.

In another preferred embodiment, the volume (mL)/mass (mg) ratio of the fifth solvent to the fisotinib raw material is 1:(20-40).

In another preferred embodiment, when the solid form is salt crystal form or co-crystal XM-V, step (a) includes:

(i) in a sixth solvent, react with fisotinib starting material and stearic acid, thereby obtaining a mixture of fisotinib salts or co-crystals.

In another preferred embodiment, the sixth solvent is selected from the group consisting of aromatic hydrocarbon solvents.

In another preferred embodiment, the sixth solvent is toluene.

In another preferred embodiment, the volume (mL)/mass (mg) ratio of the sixth solvent to the fisotinib raw material is 1:(20-40).

In another preferred example, the mass ratio of the stearic acid and fisotinib raw material is 1:(1-5).

In another preferred embodiment, the rinsing solvent is diethyl ether.

A third aspect of the present invention provides a pharmaceutical composition comprising (a) the solid form of fisotinib as the active ingredient in the first aspect of the present invention; and (b) pharmaceutically acceptable accepted vector.

In another preferred embodiment, the dosage form of the pharmaceutical composition or preparation is selected from the group consisting of powder, capsule, granule, tablet, pill or injection.

In another preferred embodiment, the pharmaceutical composition is used to treat patients with FGFR4-driven locally advanced or metastatic hepatocellular carcinoma (HCC).

The fourth aspect of the present invention provides a use of the pharmaceutical composition according to the third aspect to prepare a medicament for treating patients with FGFR4-driven locally advanced or metastatic hepatocellular carcinoma (HCC).

The fifth aspect of the present invention provides the use of the solid form according to the first aspect, the use comprising: 1) preparing a compound of formula (I) or a salt thereof; 2) preparing a compound for the treatment of FGFR4-driven locally advanced or Drugs for patients with metastatic hepatocellular carcinoma (HCC).

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.

Description of drawings

Fig. 1 is the XRPD pattern of the crystal form I of the present invention.

Figure 2 is a TGA diagram of the crystal form I of the present invention.

Figure 3 is the DSC chart of the crystal form I of the present invention.

Figure 4 is the 1H NMR spectrum of the crystal form I of the present invention.

Fig. 5 is the XRPD comparison chart of the crystal form I of the present invention placed at 25°C/60%RH and 40°C/75%RH for one month (from bottom to top in the figure are before placing and placing at 25°C/60%RH, Figure after one month at 40°C/75% RH).

Figure 6 is a DVS diagram of the crystal form I of the present invention.

7 is the XRPD pattern of the crystal form I of the present invention before and after the DVS test (the bottom picture is the XRPD pattern of the sample before the DVS test, and the top picture is the XRPD pattern of the sample after the DVS test).

8 is the XRPD pattern of the crystal form I of the present invention before and after grinding (the lower picture is the XRPD pattern of the sample before grinding, and the upper picture is the XRPD pattern of the sample after grinding).

Figure 9 is an XRPD pattern of the crystal form II of the present invention.

Figure 10 is a TGA diagram of the crystal form II of the present invention.

Figure 11 is a DSC chart of the crystal form II of the present invention.

Figure 12 is the 1H NMR spectrum of the crystal form II of the present invention.

Figure 13 is the XRPD comparison chart of the crystal form II of the present invention placed at 25°C/60%RH and 40°C/75%RH for one month (from bottom to top in the figure are before placing and placing at 25°C/60%RH, Figure after one month at 40°C/75% RH).

Figure 14 is a DVS diagram of the crystal form II of the present invention.

Figure 15 is the XRPD pattern of the crystal form II of the present invention before and after the DVS test (the bottom picture is the XRPD pattern of the sample before the DVS test, and the top picture is the XRPD pattern of the sample after the DVS test)

16 is the XRPD pattern of the crystal form II of the present invention before and after grinding (the bottom picture is the XRPD pattern of the sample before grinding, and the top picture is the XRPD pattern of the sample after grinding).

Figure 17 is the XRPD pattern of salt crystal form or co-crystal XM-I of the present invention;

Figure 18 is a TGA diagram of the salt crystal form or co-crystal XM-I of the present invention;

Figure 19 is the DSC chart of the salt crystal form or co-crystal XM-I of the present invention;

Figure 20 is the ¹ H NMR spectrum of the salt crystal form or co-crystal XM-I of the present invention;

Figure 21 is the XRPD pattern of the salt crystal form or co-crystal XM-II of the present invention;

Figure 22 is a TGA diagram of the salt crystal form or co-crystal XM-II of the present invention;

Figure 23 is the DSC chart of the salt crystal form or co-crystal XM-II of the present invention;

Figure 24 is the ¹ H NMR spectrum of the salt crystal form or co-crystal XM-II of the present invention;

Figure 25 is the XRPD pattern of the salt crystal form or co-crystal XM-III of the present invention;

Figure 26 is a TGA diagram of the salt crystal form or co-crystal XM-III of the present invention;

Figure 27 is the DSC chart of the salt crystal form or co-crystal XM-III of the present invention;

Figure 28 is the ¹ H NMR spectrum of the salt crystal form or co-crystal XM-III of the present invention;

Figure 29 is the XRPD pattern of salt crystal form or co-crystal XM-IV of the present invention;

Figure 30 is the XRPD pattern of salt crystal form or co-crystal XM-V of the present invention;

Figure 31 is a TGA diagram of the salt crystal form or co-crystal XM-V of the present invention;

Figure 32 is a DSC chart of the salt crystal form or co-crystal XM-V of the present invention.

Detailed ways

After long-term and in-depth research, the inventors provided a crystal form I and crystal form II of the compound of formula (I) fisotinib, as well as salt crystal form or co-crystal-salt crystal form or co-crystal XM-I , XM-II, XM-III, XM-IV and XM-V. The 7 solid forms of fisotinib have at least the following aspects: stability, solubility, hygroscopicity, tableting stability, mechanical stability, fluidity, process developability, formulation development, purification, and powder processing performance. advantage on the one hand. Based on the above findings, the inventors have completed the present invention.

the term

Herein, unless otherwise specified, each abbreviation has the conventional meaning understood by those skilled in the art.

As used herein, unless otherwise specified, the term "starting material for the compound of formula (I)" refers to the amorphous (form) and/or various crystalline forms of the compound of formula (I), including the various crystalline and amorphous forms mentioned herein , the crystalline form or amorphous form mentioned in various documents or patents, published or unpublished.

As used herein, unless otherwise specified, the method of adding the solvent or solution is direct pouring or uniform addition, and the like.

As used herein, the term "room temperature" generally refers to 4-30°C, preferably 20±5°C.

As used herein, the manner of "slow addition" includes, but is not limited to, dropwise addition, slow addition along the container wall, and the like.

As used herein, the solid form of the compound represented by the formula (I) includes the solid form of the compound represented by the formula (I) or its salt, preferably a crystalline form, preferably including the crystalline form of the compound represented by the formula (I), the formula (I) ), the salt crystal form or co-crystal formed by the compound represented by ) and an acid, wherein the acid is preferably maleic acid, sulfuric acid, hydrochloric acid or stearic acid.

Fisotinib crystalline form, fisotinib salt crystalline form or co-crystal

As used herein, "crystalline forms of the present invention" refer to Form I and Form II, salt forms or co-crystal XM-I, salt form or co-crystal XM-II, salt form as described herein Or co-crystal XM-III, salt form or co-crystal XM-IV and salt form or co-crystal XM-V. Among them, the salt crystal form or co-crystal XM-I and XM-II are the crystal form or co-crystal formed by fisotinib and maleic acid, and the salt crystal form or co-crystal XM-III is the crystal form formed by fisotinib and sulfuric acid. Form or co-crystal, salt crystal form or co-crystal XM-IV is the crystal form or co-crystal formed by fisotinib and hydrochloric acid; salt crystal form or co-crystal XM-V is the crystal form or co-crystal formed by fisotinib and stearic acid Eutectic.

Wherein, the salt crystal form or co-crystal XM-I is the crystal form or co-crystal formed by fisotinib and maleic acid, and its XRPD pattern includes 3 or more (preferably 6 or more) selected from 2θ values of the next group: 3.2°±0.2°, 5.6°±0.2°, 6.5°±0.2°, 8.7°±0.2°, 9.8°±0.2°, 11.4°±0.2°, 11.8°±0.2°, 13.1° ±0.2°, 14.3°±0.2°, 15.0°±0.2°, 20.0°±0.2°, 20.6°±0.2°, 23.1°±0.2°.

In a preferred embodiment, the salt crystal form or co-crystal XM-I has an XRPD pattern substantially as shown in FIG. 17 .

In another preferred embodiment, the salt crystal form or co-crystal XM-I has a TGA diagram substantially as shown in FIG. 18 .

In another preferred embodiment, the salt crystal form or co-crystal XM-I has a DSC pattern substantially as shown in FIG. 19 .

In another preferred embodiment, the salt crystal form or co-crystal XM-I has a 1H NMR spectrum substantially as shown in FIG. 20 .

The salt crystal form or co-crystal XM-II is the crystal form or co-crystal formed by fisotinib and maleic acid, and its XRPD diagram includes 3 or more (preferably 6 or more) selections. 2θ values from the next group: 4.1°±0.2°, 5.9°±0.2°, 8.3°±0.2°, 12.5°±0.2°, 14.2°±0.2°, 15.9°±0.2°, 16.7°±0.2°, 17.5 °±0.2°, 18.0°±0.2°, 19.9°±0.2°, 21.6°±0.2°, 22.7°±0.2°, 24.6°±0.2°, 25.0°±0.2°, 26.1°±0.2°, 27.7°± 0.2°, 29.7°±0.2°.

In a preferred embodiment, the salt crystal form or co-crystal XM-II has an XRPD pattern substantially as shown in Figure 21;

In another preferred embodiment, the salt crystal form or co-crystal XM-II has a TGA diagram substantially as shown in FIG. 22 ;

In another preferred embodiment, the salt crystal form or co-crystal XM-II has a DSC chart substantially as shown in Figure 23;

In another preferred embodiment, the salt crystal form or co-crystal XM-II has a 1H NMR spectrum substantially as shown in FIG. 24 .

Salt crystal form or co-crystal XM-III is a crystal form or co-crystal formed by fisotinib and sulfuric acid, and its XRPD pattern includes 6 or more 2θ values selected from the following group: 5.1°±0.2°, 7.2° ±0.2°, 8.1°±0.2°, 10.2°±0.2°, 11.7°±0.2°, 13.1°±0.2°, 15.0°±0.2°, 16.2°±0.2°, 17.6°±0.2°, 19.5°±0.2 °, 20.4°±0.2°, 21.2°±0.2°, 25.2°±0.2°, 26.3°±0.2°;

Under a preferred embodiment, the salt crystal form or co-crystal XM-III has an XRPD pattern substantially as shown in Figure 25;

In another preferred embodiment, the salt crystal form or co-crystal XM-III has a TGA diagram substantially as shown in Figure 26;

In another preferred embodiment, the salt crystal form or co-crystal XM-III has a DSC chart substantially as shown in Figure 27;

In another preferred embodiment, the salt crystal form or co-crystal XM-III has a ¹ H NMR spectrum substantially as shown in FIG. 28 .

Salt crystal form or co-crystal XM-IV is the crystal form or co-crystal formed by fisotinib and hydrochloric acid, and its XRPD pattern includes 6 or more 2θ values selected from the following group: 3.6°±0.2°, 5.0° ±0.2°, 5.4°±0.2°, 9.8°±0.2°, 13.2°±0.2°, 13.8°±0.2°, 16.4°±0.2°, 17.5°±0.2°, 18.6°±0.2°, 19.8°±0.2 °, 20.8°±0.2°, 21.8°±0.2°, 24.1°±0.2°, 25.1°±0.2°, 26.4°±0.2°.

In a preferred embodiment, the salt crystal form or co-crystal XM-IV has an XRPD pattern substantially as shown in FIG. 29 .

Salt crystal form or co-crystal XM-V is a crystal form or co-crystal formed by fisotinib and stearic acid, and its XRPD pattern includes 6 or more 2θ values selected from the following group: 3.8°±0.2°, 5.7 °±0.2°, 7.6°±0.2°, 9.5°±0.2°, 13.3°±0.2°, 23.1°±0.2°, 24.6°±0.2°;

In another preferred embodiment, the salt crystal form or co-crystal XM-V has an XRPD pattern substantially as shown in Figure 30;

In another preferred embodiment, the salt crystal form or co-crystal XM-V has a TGA diagram substantially as shown in FIG. 31 ;

In another preferred embodiment, the salt crystal form or co-crystal XM-V has a DSC pattern substantially as shown in FIG. 32 .

Pharmaceutical composition containing crystalline form of fisotinib

Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a solid form of fisotinib as described in the present invention, and optionally, one or more pharmaceutically acceptable carriers, excipients Excipients, adjuvants, excipients and/or diluents. The auxiliary materials are, for example, odorants, flavoring agents, sweeteners, and the like.

The pharmaceutical composition provided by the present invention preferably contains 1-99% by weight of active ingredients, and the preferred ratio is that the compound of formula I as an active ingredient accounts for 65wt% to 99wt% of the total weight, and the rest is pharmaceutically acceptable carrier, diluent or solution or saline solution.

The compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or diluents Neutralize in suitable sterile equipment for injection or instillation.

Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit measurement of the formulation contains 1 mg-700 mg of the compound of general formula I, preferably, the unit measurement of the formulation contains 25 mg-300 mg of the compound of general formula I.

The compounds and pharmaceutical compositions of the present invention can be used clinically in mammals, including humans and animals, by oral, nasal, dermal, pulmonary, or gastrointestinal routes of administration. Most preferred is oral administration. The most preferred daily dose is 50-1400 mg/kg body weight in a single dose, or 25-700 mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dose for an individual will depend on the specific treatment. It is common to start with a small dose and gradually increase the dose until the most suitable dose is found.

The pharmaceutical composition of the present invention can be used for the treatment of patients with FGFR4-driven locally advanced or metastatic hepatocellular carcinoma (HCC), and when used for treatment, the solid form of the present invention or the fexotite prepared from the solid form of the present invention Ni (amorphous) can be administered alone or in combination with other pharmaceutically acceptable compounds.

In the present invention, unless otherwise specified, the drying method is a conventional drying method in the field. For example, drying in the embodiments of the present invention refers to vacuum drying or normal pressure drying in a conventional drying oven. Generally, drying is performed for 0.1 to 50h or 1 to 30h.

Pharmaceutical compositions and methods of administration

Since the solid form of the present invention or fisotinib (amorphous) prepared from the solid form of the present invention has excellent therapeutic and preventive effects on cancer or tumor (such as metastatic hepatocellular carcinoma), the present invention Solid form or fisotinib (amorphous) prepared from the solid form of the present invention and a pharmaceutical combination containing the solid form of the present invention or fisotinib (amorphous) prepared from the solid form of the present invention as the main active ingredient The drug can be used to treat and/or prevent cancer or tumors such as metastatic hepatocellular carcinoma. Therefore, the solid form of the present invention or the filsotinib (amorphous form) prepared from the solid form of the present invention can be used to prepare the treatment or prevention of cancer or tumor (such as metastatic hepatocellular carcinoma), and the drug can be prepared by methods commonly used in the art. be made of.

The pharmaceutical composition of the present invention comprises the solid form of the present invention or fisotinib (amorphous) prepared from the solid form of the present invention within a safe and effective amount, and a pharmaceutically acceptable excipient or carrier.

Wherein, the "safe and effective amount" refers to the amount of the compound (or solid form or amorphous form) sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the crystal form/dose of the present invention, more preferably, 10-200 mg of the crystal form/dose of the present invention. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween)

), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.

Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

In addition to the active ingredient, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms of the polymorphs of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.

The solid forms of the present invention or fisotinib (amorphous) prepared from the solid forms of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

When a pharmaceutical composition is used, a safe and effective amount of the solid form of the present invention or fisotinib (amorphous) prepared from the solid form of the present invention is suitable for a mammal (eg, a human) in need of treatment, wherein the dosage at the time of administration For a pharmaceutically effective dose, for a person with a body weight of 60 kg, the daily dose is usually 1-2000 mg, preferably 20-500 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.

The main advantages of the present invention are:

(1) The crystal form stability and mechanical stability of the present invention are good. The crystal form of the present invention has good crystal form stability, can reduce the risk of changing the dissolution rate and bioavailability due to the change of the crystal form of the drug, is beneficial to the crystal form control in the crystallization and preparation process, and is also beneficial to Production and storage of products. The crystal form of Form I and Form II did not change before and after grinding, indicating that their mechanical stability is good, which can reduce the risk of crystal transformation caused by crushing the API during the preparation process.

(2) The crystal form of the present invention has low hygroscopicity. Under the condition of 40%RH～80%RH, the weight gain of crystal form I and crystal form II is 0.7% and 2.2%, respectively, and has low hygroscopicity. Therefore, the crystal form of the present invention does not have strict requirements on packaging and storage conditions, and does not require special drying conditions in the preparation process, which simplifies the preparation and post-treatment processes of the medicine, is beneficial to industrial production, and significantly reduces the production, transportation and storage of medicines. the cost of.

(3) The solvent used in the preparation process of the crystal form of the present invention can be selected as a low-toxic or non-toxic solvent, and the preparation method is a conventional, industrially-produced crystallization method, and the particle size, crystal habit can be controlled by controlling the process parameters. And crystal form, etc., and then obtain stable and high-quality products.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Methods and materials for preferred embodiments described herein are provided for illustrative purposes only.

General Methods and Reagents

The solvents used in the present invention are all analytically pure, and the water content is about 0.1%. The compounds of formula (I) used as raw materials in the examples were all purchased. All test methods of the present invention are general methods, and the test parameters are as follows:

XRPD pattern determination method:

X-ray powder diffractometer: Bruker D2 Phaser X-ray powder diffractometer; radiation source Cu

Generator kv: 30kv; Generator mA: 10mA; initial 2θ: 2.000°, scanning range: 2.0000-35.000°, scanning step size 0.02°, scanning speed 0.1s/step.

TGA chart determination method:

Thermogravimetric analysis (TGA) instrument: TGA55 of TA company in the United States; heating rate: 10° C./min; nitrogen flow rate: 40 mL/min.

DSC chart determination method:

Differential scanning calorimetry (DSC) instrument: TA Q2000 type from TA company in the United States; heating rate: 10°C/min, nitrogen flow rate: 50mL/min.

Hydrogen nuclear magnetic resonance data ( ¹ H NMR) were obtained from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. 2 mg of the sample was weighed, dissolved in 0.6 mL of deuterated dimethyl sulfoxide, filtered, and the filtrate was added to a NMR tube for testing.

DVS chart determination method:

Dynamic Moisture Sorption (DVS) Instrument: TA Q5000 SA from TA Company, USA; Temperature: 25℃; Nitrogen Flow Rate: 50mL/min; Mass Change per Unit Time: 0.002%/min; Relative Humidity Range: 0%RH～90% RH.

In the present invention, unless otherwise specified, the drying method is a conventional drying method in the field. For example, drying in the embodiments of the present invention refers to vacuum drying or normal pressure drying in a conventional drying oven. Generally, drying is performed for 0.1 to 50h or 1 to 30h.

The solid forms of the present invention or fisotinib (amorphous) prepared from the solid forms of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

Example 1: Preparation of Form I

Weigh 50 mg of the compound of formula (I) and dissolve it in 1 mL of 2-butanone, filter, slowly add 3 mL of petroleum ether to the filtrate, stir at 25 ° C for 16 h, a solid is precipitated, and the obtained solid is the compound of formula (I) crystal form I . The obtained solid is tested by XRPD, and its X-ray powder diffraction data is shown in Table 1, its X-ray powder diffraction data is shown in Table 1, and its XRPD pattern is shown in Figure 1; the obtained solid is tested by TGA, Its spectrum is shown in Figure 2; the obtained solid is tested by DSC, and its spectrum is shown in Figure 3; the obtained solid is tested by ¹ H NMR, and its spectrum is shown in Figure 4, and nuclear magnetic data: ¹ H NMR ( 400MHz, DMSO-d ₆ )δ9.18(s, 1H), 8.01(d, J=7.1Hz, 1H), 7.69(s, 1H), 7.55-7.47(m, 2H), 7.01(s, 2H) ,6.25(dd,J＝17.1,10.2Hz,1H),6.06(dd,J＝17.1,2.1Hz,1H),5.55(dd,J＝10.2,2.1Hz,1H),4.34(s,2H), 3.97(s,6H),3.85(d,J=11.6Hz,2H),3.65(d,J=10.4Hz,1H),3.55(t,J=8.9Hz,1H),1.98(dd,J=12.9 , 8.5Hz, 1H), 1.69 (d, J=11.0Hz, 1H).

Table 1

2θ(°)	Relative Strength(%)
5.9	42.2
8.2	46.1
10.3	6.9
10.6	8.8
10.9	6.6
11.7	19.1
12.0	100.0
13.0	9.6
13.9	14.7
16.5	16.1
17.4	10.0
17.8	17.6
18.1	43.9
19.0	8.8
20.1	77.5
20.6	15.0
21.4	15.1
22.2	37.6
23.1	17.3
23.8	68.9
24.9	10.7
26.6	11.7
27.5	5.4
28.3	4.7
29.1	6.5
31.4	7.0

Example 2: Preparation of Form I

Weigh 50 mg of the compound of formula (I) and dissolve it in 1 mL of acetonitrile, filter, slowly add 15 mL of diethyl ether to the filtrate, stir at 25 ° C for 16 h, a solid is precipitated, the obtained solid is the compound of formula (I) crystal form I, and the obtained solid is Form I of the compound of formula (I). The obtained solid was tested by XRPD, and its X-ray powder diffraction data are shown in Table 2.

Table 2

2θ(°)	Relative Strength(%)
6.0	29.0
8.3	36.4
10.6	5.2
12.0	100.0

13.0	3.7
13.9	4.9
16.5	14.4
20.1	8.6
20.6	10.0
21.4	12.3
22.1	9.9
22.3	11.8
23.9	5.1
24.9	8.3

Example 3: Preparation of Form I

15 mg of the compound of formula (I) was weighed and dissolved in 0.2 mL of ethanol/n-heptane (1:4, v/v) at 40 °C, filtered, and the filtrate was stirred at 5 °C for 16 h, a solid was precipitated, and the obtained solid It is the crystalline form I of the compound of formula (I). The obtained solid was tested by XRPD, and its X-ray powder diffraction data are shown in Table 3.

table 3

2θ(°)	Relative Strength(%)
5.9	93.7
8.1	36.9
10.3	32.8
11.8	100.0
13.1	8.4
13.9	21.6
16.3	21.5
17.6	15.5
18.1	27.3
20.0	24.0
20.7	20.0
22.0	55.3
23.9	12.2
26.7	11.1
27.3	6.5

Example 4: Preparation of Form I

20 mg of the compound of formula (I) was weighed and dissolved in 0.4 mL of diethylene glycol dimethyl ether, filtered, and the filtrate was slowly dropped into 4 mL of isopropyl ether at 17°C, stirred for 16 h, and the obtained solid was the compound of formula (I) Form I. The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data are shown in Table 4.

Table 4

2θ(°)	Relative Strength(%)
6.0	40.7

8.3	36.0
10.6	7.7
12.1	100.0
13.1	8.5
14.1	22.9
16.6	17.1
17.5	13.6
18.2	70.3
20.2	94.6
21.4	14.1
22.3	53.4
23.2	28.9
23.9	81.0
24.9	8.1
26.8	14.7

Example 5: Preparation of Form I

Weigh 15 mg of the compound of formula (I) and dissolve it in 0.2 mL of ethyl acetate/tert-butyl acetate (1:1, v/v) at 40 °C, filter, and place the filtrate at 5 °C and stir for 16 h. The obtained solid is Form I of the compound of formula (I). The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data are shown in Table 5.

table 5

2θ(°)	Relative Strength(%)
5.9	33.7
8.2	19.2
10.5	5.6
11.9	100.0
13.0	4.3
13.9	5.7
16.5	12.6
20.0	16.3
21.3	19.3
22.1	7.7
22.3	14.5
23.8	12.5
24.8	7.8
26.7	19.9
27.5	5.5

Example 6: Preparation of Form II

Weigh 50 mg of the compound of formula (I) and dissolve it in 0.5 mL of N-methylpyrrolidone, filter, add 4 mL of water to the filtrate, and stir at 20 ° C for 2 h, a solid is precipitated, and the obtained solid is the compound of formula (I) crystal form II . The obtained solid was tested by XRPD, and its X-ray powder diffraction data was shown in Table 6, and its XRPD pattern was shown in Figure 9; The weight loss is about 0.8%; the obtained solid is tested by DSC, and its spectrum is shown in Figure 11; the obtained solid is tested by ¹ H NMR, and its spectrum is shown in Figure 12, nuclear magnetic data: ¹ H NMR (400MHz, DMSO) δ9.18(s,1H),8.01(d,J=7.6Hz,1H),7.69(s,1H),7.56–7.47(m,2H),6.99(d,J=10.0Hz,2H),6.25 (dd,J=17.1,10.1Hz,1H),6.06(dd,J=17.1,2.1Hz,1H),5.55(dd,J=10.1,2.1Hz,1H),4.34(s,2H),3.97( s, 6H), 3.89–3.81 (m, 2H), 3.65 (d, J=10.0Hz, 1H), 3.54 (t, J=8.8Hz, 1H), 2.05–1.90 (m, 1H), 1.69 (d , J=10.3Hz, 1H).

Table 6

2θ(°)	Relative Strength(%)
4.2	100.0
8.4	3.0
11.6	6.1
12.2	5.4
14.5	7.1
15.5	3.0
16.7	83.5
20.9	82.9
22.1	6.8
23.0	10.7
25.9	4.4
29.7	10.9
30.5	3.6
33.7	5.6

Example 7: Preparation of Form II

30 mg of the compound of formula (I) was weighed and dissolved in 0.4 mL of pyridine/water (1:1, v/v) at 40 °C, filtered, and the filtrate was stirred at 5 °C for 16 h, a solid was precipitated, and the obtained solid was of formula ( I) Compound form II. The obtained solid was subjected to XRPD test, and its X-ray powder diffraction data are shown in Table 7.

Table 7

2θ(°)	Relative Strength(%)
4.0	100.0
8.2	2.8
11.8	4.6
14.6	5.2
15.7	2.6
16.6	25.5

20.9	31.2
22.0	5.9
22.8	2.7

test case

Test Example 1 Crystal Form Stability

The crystal form I and the crystal form II prepared by the present invention were placed openly for 30 days under different conditions respectively, XRPD detection was performed on the crystal forms before and after placement, and the XRPD patterns of the crystal forms before and after placement were compared. The specific placement conditions and the results after placement are shown in Table 8. By comparing the XRPD patterns before and after placing in each figure, it can be seen that the crystal form I and crystal form II provided by the present invention do not change the crystal form when placed in the open for 30 days under the conditions of 25°C/60%RH and 40°C/75%RH , indicating that the crystal form of the present invention has good stability under different temperature/humidity.

Table 8

Test Example 2: Mechanical Stability

50 mg of crystal form I and crystal form II were weighed and ground in a mortar for 10 min, respectively, and the ground solids were subjected to XRPD test. By comparing the XRPD patterns before and after grinding in each figure, it can be seen that the crystal form I and crystal form II provided by the present invention do not change the crystal form before and after grinding, indicating that the crystal form I and crystal form II provided by the present invention have good mechanical stability. .

Table 9

Test Example 3: Humidity

About 20 mg of crystal form I and crystal form II were weighed respectively, and their hygroscopicity was tested by dynamic moisture absorption instrument (DVS). The DVS diagrams of Form I and Form II are shown in Figure 6 and Figure 14, respectively. In addition, the XRPD test was performed on the solid before and after the DVS test, and the XRPD patterns of the crystal form I and the crystal form II before and after the test are shown in Fig. 7 and Fig. 15, respectively. The overall test results are shown in Table 10.

It can be seen from the DVS test results that the crystal forms I and II provided by the present invention have low hygroscopicity; from the XRPD results, it can be seen that the crystal forms of the crystal forms I and II do not change before and after the DVS test. It can be seen that the crystal form I and the crystal form II of the present invention have the ability to withstand high humidity environment.

Table 10

Example 8: Preparation of salt crystal form or co-crystal XM-I

In 0.2 mL of isopropanol/water (1:1, v/v) solution, 6.7 mg of fisotinib, a compound of formula (I), was added, and stirred uniformly. Then, a maleic acid solution (2.0 mg maleic acid dissolved in 0.2 mL of isopropanol/water (1:1, v/v)) was slowly added dropwise, stirred at 20° C. for 5 days, filtered, and the solid was collected and used Rinse with 1 mL of water, and the obtained solid is the salt crystal form or co-crystal XM-I of formula (I) fisotinib combined with maleic acid.

The obtained salt crystal form or co-crystal XM-I was tested by XRPD, and the results were shown in Figure 17, and the spectrum data were shown in Table 11; the obtained solid was tested by TGA, and its spectrum was shown in Figure 18; the obtained solid was tested by DSC , its spectrum is shown in Figure 19; the obtained solid is tested by ¹ H NMR, and its spectrum is shown in Figure 20, nuclear magnetic data: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.19(s,1H) ,8.02(d,J＝8.8Hz,1H),7.69(s,1H),7.57–7.48(m,2H),7.03(d,J＝17.8Hz,2H),6.25(s,2H),6.06( dd,J＝17.1,2.2Hz,1H),5.55(dd,J＝10.1,2.1Hz,1H),4.33(s,2H),3.97(s,6H),3.85(d,J＝11.7Hz,2H ), 3.65 (d, J=12.8Hz, 1H), 3.55–3.53 (m, 1H), 1.98 (d, J=6.0Hz, 1H), 1.69 (d, J=12.8Hz, 1H).

Table 11 XRPD spectrum of fisotinib salt crystal form or co-crystal XM-I

2θ(°)	Relative Strength(%)
3.2	100.0
5.6	1.3
6.5	1.2
8.7	9.7
9.8	4.1
11.4	1.9
11.8	2.9

13.1	1.5
14.3	0.6
15.0	1.1
20.0	0.7
20.6	0.3
23.1	2.0

Example 9: Preparation of salt crystal form or co-crystal XM-II

In 0.2 mL of acetone/water (1:4, v/v) solution, 7.5 mg of fisotinib, a compound of formula (I), was added, and the mixture was stirred uniformly. Then, a maleic acid solution (2.7 mg maleic acid was dissolved in 0.2 mL of isoacetone/water (1:4, v/v) solution) was slowly added dropwise, stirred at 20°C for 5 days, filtered, and the solid was collected with Rinse with 1 mL of water, and the obtained solid is the salt crystal form or co-crystal XM-II of formula (I) fisotinib combined with maleic acid.

The obtained solid is tested by XRPD, and the result is shown in Figure 21, and the spectrum data is shown in Table 12; the obtained solid is tested by TGA, and its spectrum is shown in Figure 22; the obtained solid is tested by DSC, and its spectrum is shown in Figure 23. The obtained solid was tested by ¹ H NMR, and its spectrum is shown in Figure 24. Nuclear magnetic data: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.18(s, 1H), 8.01(d, J=7.7 Hz, 1H), 7.69(s, 1H), 7.53(d, J=9.2Hz, 2H), 7.01(s, 2H), 6.30–6.19(m, 3H), 6.06(dd, J=17.1, 2.1Hz) ,1H),5.55(dd,J＝10.1,2.2Hz,1H),4.33(s,2H),3.97(s,6H),3.85(d,J＝10.4Hz,2H),3.65(d,J＝ 12.6Hz, 1H), 3.55–3.53 (m, 1H), 1.99–1.96 (m, 1H), 1.69 (d, J=15.3Hz, 1H).

Table 12 XRPD spectrum of fisotinib salt crystal form or co-crystal XM-II

2θ(°)	Relative Strength(%)
4.1	27.4
5.9	53.9
8.3	91.5
12.5	69.4
14.2	24.3
15.9	53.0
16.7	24.6
17.5	54.0
18.0	54.3
19.9	33.6
21.6	34.8
22.7	28.4
24.6	100.0

25.0	27.2
26.1	32.4
27.7	28.6
29.7	32.7

Example 10: Preparation of salt crystal form or co-crystal XM-III

Weigh 37.5 mg of the compound of formula (I) fisotinib into 2 mL of IPA/water (1:1, v/v) solution, and shake evenly. The fisotinib solution was then mixed with sulfuric acid solution (1 mL concentrated sulfuric acid (95%-98%) in 1.5 mL IPA/water (1:1, v/v)). At 17°C, it was stirred for 5 days. The solid was collected, rinsed with 1 mL of water, and the obtained solid was the salt crystal form of the compound of formula (I) fexotinib combined with sulfuric acid or the co-crystal XM-III.

The obtained solid was tested by XRPD, and the results were shown in Figure 25, and the spectrum data were shown in Table 13; the obtained solid was tested by TGA, and its spectrum was shown in Figure 26; the obtained solid was tested by DSC, and its spectrum was shown in Figure 27. The obtained solid was tested by ¹ H NMR, and its spectrum is shown in Figure 28. Nuclear magnetic data: ¹ H NMR (400MHz, DMSO-d ₆ )δ9.18(s, 1H), 8.00(d, J=3.0 Hz, 1H), 7.69 (s, 1H), 7.56–7.50 (m, 2H), 7.10–6.94 (m, 2H), 6.25 (dd, J=15.5, 11.3Hz, 1H), 6.06 (d, J= 18.6Hz, 1H), 5.55(d, J=10.1Hz, 1H), 4.35(s, 2H), 3.97(s, 6H), 3.85(d, J=10.9Hz, 2H), 3.65(d, J= 10.9Hz, 1H), 3.51 (d, J=3.2Hz, 1H), 2.03–2.01 (m, 1H), 1.69 (d, J=9.4Hz, 1H).

Table 13 XRPD spectrum of fisotinib salt crystal form or co-crystal XM-III

2θ(°)	Relative Strength(%)
5.1	54.0
7.2	13.8
8.1	21.4
10.2	100.0
11.7	5.4
13.1	25.9
15.0	4.1
16.2	4.6
17.6	6.8
19.5	5.1
20.4	20.6
21.2	12.0
25.2	6.5

26.3

9.3

Example 11: Preparation of salt crystal form or co-crystal XM-IV

In 0.2 mL of toluene, 7.4 mg of fisotinib, the compound of formula (I), was added, and the mixture was stirred uniformly. Then, the fisotinib solution was mixed with hydrochloric acid solution (2 μL of hydrochloric acid in 0.2 mL of toluene). At 18°C, stirred for 24h. The solid was collected, rinsed with 1 mL of water, and the obtained solid was the salt crystal form or co-crystal XM-IV of the compound of formula (I) combined with hydrochloric acid.

The obtained solid was tested by XRPD, the results are shown in Figure 29, and the spectrum data are shown in Table 14.

Table 14 XRPD spectrum of fisotinib salt crystal form or co-crystal XM-IV

2θ(°)	Relative Strength(%)
3.6	100.0
5.0	67.0
5.4	73.3
9.8	96.0
13.2	48.1
13.8	52.7
16.4	37.2
17.5	40.6
18.6	35.0
19.8	47.6
20.8	41.0
21.8	99.9
24.1	65.4
25.1	73.9
26.4	51.4

Example 12: Preparation of salt crystal form or co-crystal XM-V

In 0.2 mL of toluene, 7.2 mg of fisotinib, the compound of formula (I), was added, and the mixture was stirred uniformly. Then, stearic acid solution (4.9 mg of stearic acid dissolved in 0.2 mL of toluene) was slowly added dropwise, and the mixture was stirred at 18° C. for 24 h. After the solution was clarified, the clarified solution was placed in an environment of 18°C to quickly volatilize, and solids were precipitated. The solid was collected, rinsed with 1 mL of ether, and the obtained solid was a salt crystal form or co-crystal XM-V of the compound of formula (I) combined with stearic acid.

The obtained solid was tested by XRPD, and the results were shown in Figure 30, and the spectrum data were shown in Table 15; the obtained solid was tested by TGA, and its spectrum was shown in Figure 31; the obtained solid was tested by DSC, and its spectrum was shown in Figure 32. Show.

Table 15 XRPD spectrum of fisotinib salt crystal form or co-crystal XM-V

2θ(°)	Relative Strength(%)
3.8	32.3
5.7	100.0
7.6	14.2
9.5	34.6
13.3	5.8
23.1	11.1
24.6	29.8

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (12)

1. A solid form of a compound of formula (I), characterized in that,

   

   The solid form is selected from the group consisting of:

   Form I, Form II;

   Salt crystal form or co-crystal XM-I of fisotinib and maleic acid;

   Salt crystal form or co-crystal XM-II of fisotinib and maleic acid;

   Salt crystal form or co-crystal XM-III of fisotinib and sulfuric acid;

   The salt crystal form or co-crystal XM-IV of fisotinib with hydrochloric acid; or,

   Salt crystal form or co-crystal XM-V of fisotinib and stearic acid.
2. The solid form of claim 1, wherein:

   The solid form is crystal form I, and the X-ray powder diffraction pattern of the crystal form I comprises 3 or more 2θ values selected from the following group: 5.9°±0.2°, 8.2°±0.2° , 12.0°±0.2°, 20.1°±0.2°, 23.8°±0.2°;

   The solid form is crystal form II, and the X-ray powder diffraction pattern of the crystal form I includes 3 or more 2θ values selected from the group consisting of 4.2°±0.2°, 16.7°±0.2° , 20.9°±0.2°, 23.0°±0.2°, 29.7°±0.2°;

   The solid form is a salt crystal form or co-crystal XM-I, and the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-I comprises the following 2θ values: 3.2°±0.2°; and at least 2 2θ values selected from the group consisting of 8.7°±0.2°, 9.8°±0.2°, 11.8°±0.2°, 23.1°±0.2°;

   The solid form is a salt crystal form or co-crystal XM-II, and the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-II comprises 3 or more 2θ values selected from the group consisting of: 8.3°±0.2°, 12.5°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 24.6°±0.2°;

   The solid form is a salt crystal form or co-crystal XM-III, and the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-III comprises 3 or more 2θ values selected from the group consisting of: 5.1°±0.2°, 8.1°±0.2°, 10.2°±0.2°, 13.1°±0.2°, 20.4°±0.2°;

   The solid form is a salt crystal form or co-crystal XM-IV, and the X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-IV comprises 3 or more 2θ values selected from the group consisting of: 3.6°±0.2°, 5.4°±0.2°, 9.8°±0.2°, 21.8°±0.2°, 25.1°±0.2°;

   The solid form is a salt form or co-crystal XM-V, and the X-ray powder diffraction pattern of the salt form or co-crystal XM-V comprises a 2θ value selected from the group consisting of 5.7°±0.2°, and at least one 2Θ value selected from the group consisting of: 3.8°±0.2°, 9.5°±0.2°, 24.6°±0.2°.
3. The solid form of claim 1, wherein the solid form is Form I, and the Form I further has one or more features selected from the group consisting of:

   1) The XRPD pattern of the crystal form I comprises 6 or more 2θ values selected from the group consisting of 5.9°±0.2°, 8.2°±0.2°, 10.3°±0.2°, 10.6°±0.2°, 10.9 °±0.2°, 11.7°±0.2°, 12.0°±0.2°, 13.0°±0.2°, 13.9°±0.2°, 16.5°±0.2°, 17.4°±0.2°, 17.8°±0.2°, 18.1°± 0.2°, 19.0°±0.2°, 20.1°±0.2°, 20.6°±0.2°, 21.4°±0.2°, 22.2°±0.2°, 23.1°±0.2°, 23.8°±0.2°, 24.9°±0.2° , 26.6°±0.2°, 27.5°±0.2°, 28.3°±0.2°, 29.1°±0.2°, 31.4°±0.2°;

   2) The crystal form I has an XRPD pattern as shown in Figure 1;

   3) the crystal form I has a TGA diagram substantially as shown in Figure 2;

   4) The crystal form I has a DSC diagram as shown in Figure 3;

   5) The crystal form I has a ¹ H NMR spectrum substantially as shown in FIG. 4 .
4. The solid form of claim 1, wherein the solid form is Form II, and the Form II further has one or more features selected from the group consisting of:

   1) The XRPD pattern of the crystal form II includes 6 or more 2θ values selected from the following group: 4.2°±0.2°, 8.4°±0.2°, 11.6°±0.2°, 12.2°±0.2°, 14.5 °±0.2°, 15.5°±0.2°, 16.7°±0.2°, 20.9°±0.2°, 22.1°±0.2°, 23.0°±0.2°, 25.9°±0.2°, 29.7°±0.2°, 30.5°± 0.2°, 33.7°±0.2°;

   2) The crystal form II has an XRPD pattern substantially as shown in Figure 9;

   3) The crystal form II has a TGA diagram substantially as shown in Figure 10;

   4) The crystal form II has a DSC chart as shown in FIG. 11 ;

   5) The crystal form II has a ¹ H NMR spectrum substantially as shown in FIG. 12 .
5. The solid form of claim 1, wherein the solid form is a salt crystal form or co-crystal XM-I, and the salt crystal form or co-crystal XM-I further has one or more of the following feature:

   (1) The X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-I further has one or more 2θ values selected from the group consisting of 5.6°±0.2°, 6.5°±0.2°, 11.4 °±0.2°, 13.1°±0.2°, 15.0°±0.2°;

   (2) The differential scanning calorimetry analysis of the salt crystal form or co-crystal XM-I has an endothermic peak in the range of 200°C to 210°C.
6. The solid form of claim 1, wherein the solid form is a salt crystal form or co-crystal XM-II, and the salt crystal form or co-crystal XM-II further has one or more of the following feature:

   (1) The X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-II has one or more 2θ values selected from the following group: 4.1°±0.2°, 5.9°±0.2°, 15.9° ±0.2°, 19.9°±0.2°, 21.6°±0.2°;

   (2) The differential scanning calorimetry analysis of the salt crystal form or co-crystal XM-II has an endothermic peak in the ranges of 195°C-205°C and 330°C-340°C respectively.
7. The solid form of claim 1, wherein the solid form is a salt crystal form or co-crystal XM-III, and the salt crystal form or co-crystal XM-III further has the following characteristics:

   (1) The X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-III has one or more 2θ values selected from the following group: 7.2°±0.2°, 11.7°±0.2°, 17.6° ±0.2°, 21.2°±0.2°, 25.2°±0.2°.
8. The solid form of claim 1, wherein the solid form is a salt crystal form or co-crystal XM-IV, and the salt crystal form or co-crystal XM-IV further has the following characteristics:

   (1) The X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-IV has one or more 2θ values selected from the following group: 5.0°±0.2°, 13.2°±0.2°, 13.8° ±0.2°, 17.5°±0.2°, 19.8°±0.2°.
9. The solid form of claim 1, wherein the solid form is a salt crystal form or co-crystal XM-V, and the salt crystal form or co-crystal XM-V further has one or more of the following feature:

   (1) The X-ray powder diffraction pattern of the salt crystal form or co-crystal XM-V has one or more 2θ values selected from the following group: 3.8°±0.2°, 5.7°±0.2°, 7.6° ±0.2°, 9.5°±0.2°, 24.6°±0.2°;

   (2) The differential scanning calorimetry analysis of the salt crystal form or eutectic XM-V has an endothermic peak in the ranges of 60°C-70°C and 210°C-220°C respectively.
10. The solid form of claim 1, wherein:

    (i) The solid form is a salt crystal form or co-crystal XM-I, and the salt crystal form or co-crystal XM-I also has one or more of the following characteristics:

    (1) The salt crystal form or co-crystal XM-I has XRPD data substantially as shown in Table 11;

    (2) the salt crystal form or co-crystal XM-I has an XRPD spectrum substantially as shown in Figure 17; and/or

    (3) the salt crystal form or co-crystal XM-I has a TGA spectrum substantially as shown in FIG. 18; and/or

    (4) the salt crystal form or co-crystal XM-I has a DSC spectrum substantially as shown in FIG. 19 ; and/or

    (5) The salt crystal form or co-crystal XM-I has a ¹ H NMR spectrum as shown in FIG. 20 ;

    or,

    (ii) the solid form is a salt crystal form or co-crystal XM-II, and the salt crystal form or co-crystal XM-II also has one or more of the following characteristics:

    (1) The salt crystal form or co-crystal XM-II has XRPD data substantially as shown in Table 12;

    (2) the salt crystal form or co-crystal XM-II has an XRPD spectrum substantially as shown in Figure 21; and/or

    (3) the salt crystal form or co-crystal XM-II has a TGA spectrum substantially as shown in FIG. 22; and/or

    (4) the salt crystal form or co-crystal XM-II has a DSC spectrum substantially as shown in Figure 23; and/or

    (5) The salt crystal form or co-crystal XM-II has a ¹ H NMR spectrum substantially as shown in FIG. 24 ;

    or,

    (iii) The solid form is a salt crystal form or co-crystal XM-III, and the salt crystal form or co-crystal XM-III also has one or more of the following characteristics:

    (1) The salt crystal form or co-crystal XM-III has XRPD data substantially as shown in Table 13;

    (2) the salt crystal form or co-crystal XM-III has an XRPD spectrum substantially as shown in Figure 25; and/or

    (3) the salt crystal form or co-crystal XM-III has a TGA spectrum substantially as shown in Figure 26; and/or

    (4) the salt crystal form or co-crystal XM-III has a DSC spectrum substantially as shown in Figure 27; and/or

    (5) The salt crystal form or co-crystal XM-III has a ¹ H NMR spectrum as shown in FIG. 28 ;

    or,

    (iv) the solid form is a salt crystal form or co-crystal XM-IV, and the salt crystal form or co-crystal XM-IV also has one or more of the following characteristics:

    (1) The salt crystal form or co-crystal XM-IV has XRPD data substantially as shown in Table 14;

    (2) The salt crystal form or co-crystal XM-IV has an XRPD spectrum substantially as shown in Figure 29;

    or,

    (v) the solid form is a salt crystal form or co-crystal XM-V, and the salt crystal form or co-crystal XM-V further has one or more of the following characteristics:

    (1) The salt crystal form or co-crystal XM-II has XRPD data substantially as shown in Table 15;

    (2) the salt crystal form or co-crystal XM-V has an XRPD spectrum substantially as shown in Figure 30; and/or

    (3) the salt crystal form or co-crystal XM-V has a TGA spectrum substantially as shown in Figure 31; and/or

    (4) The salt crystal form or co-crystal XM-V has a DSC spectrum substantially as shown in FIG. 32 .
11. A method for preparing fisotinib solid form as claimed in claim 1, characterized in that,

    (1) when described solid form is crystal form I and crystal form II, comprise steps:

    e) providing a solution of the raw material of the compound of formula (I) in the seventh solvent, adding the eighth solvent to the solution for crystallization, and collecting the precipitated solid to obtain the crystal form;

    or,

    It comprises the steps of: f) providing a solution of the raw material of the compound of formula (I) in the seventh solvent, adding the solution to the eighth solvent for crystallization, and collecting the precipitated solid to obtain the crystal form;

    or,

    It comprises the steps of: g) providing a solution of the raw material of the compound of formula (I) in the seventh solvent, cooling and crystallizing the solution, and collecting the precipitated solid to obtain the crystal form;

    (2) when described solid form is salt crystal form or co-crystal, comprises steps:

    (a) in a first solvent, reacting a fisotinib starting material and an acid to obtain a mixture of fisotinib salts or co-crystals; and the acid is selected from the group consisting of maleic acid, concentrated sulfuric acid, hydrochloric acid and stearic acid;

    (b) collecting the solid from the mixture to obtain the salt crystal form or co-crystal of claim 1 .
12. A pharmaceutical composition, characterized in that: (a) the active ingredient is the solid form of fisotinib as claimed in claim 1; and (b) a pharmaceutically acceptable carrier.

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