Crystal form of brutinib as well as preparation method and application of crystal form

Abstract

The invention relates to a crystal form of brutinib as well as a preparation method and application thereof, and belongs to the technical field of crystals. The invention provides a crystal form 1 of brutinib. The chemical formula of the brutinib is as shown in the formula (I). In an X-ray powder diffraction pattern of the crystal form 1, characteristic peaks exist when the 2theta value is 4.5 + / -0.2 degrees, 8.5 + / -0.2 degrees, 11.4 + / -0.2 degrees, 15.2 + / -0.2 degrees, 18.4 + / -0.2 degrees and 24.6 + / -0.2 degrees. The crystal form 1 of brutinib provided by the invention has the advantages of high solubility, good fluidity, high purity, relatively high stability, simple preparation process, good processability, excellent dissolution performance, high bioavailability and the like, is suitable for industrial production and preparation processing, and has a relatively good application prospect.

Description

Technical Field

[0001] This invention relates to the field of crystal technology, and in particular to a crystal form of brigatinib, its preparation method, and its application. Background Technology

[0002] Brigatinib is a potent third-generation ALK (anaplastic lymphoma kinase) inhibitor used to treat non-small cell lung cancer (NSCLC) and other diseases. It is a multi-target tyrosine kinase inhibitor and can be used in patients who are intolerant to crizotinib. Its structural formula is: .

[0003] The original patent CN107108559A discloses multiple crystal forms of brigatinib, including crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form G, crystal form H, crystal form J, crystal form K, and crystal form L. Among them, crystal forms A and B are amorphous, while crystal forms C and D are hydrated crystal forms. Crystal forms B, C, and D are unstable and can transform into each other under different humidity conditions. Only crystal form A is relatively stable, but the poor solubility of crystal form A can affect drug absorption.

[0004] Existing technology WO2018077187A1 also discloses hydrate crystal forms CS1 and CS2 of brigatinib. Crystal form CS1 is obtained by evaporating a brigatinib solution at 35°C or 50°C or by crystallizing at a low temperature of -20°C; crystal form CS2 is obtained by evaporating the solution system at 50°C for several days or by allowing CS1 to undergo crystal transformation under specific humidity conditions for a long time. However, the preparation conditions of crystal forms CS1 and CS2 are difficult to achieve for industrial production, making it difficult to scale up the preparation of these crystal forms.

[0005] Existing technology CN113943323A also discloses crystal forms LX-1, LX-2, and LX-3. The preparation methods for these three crystal forms all involve dissolving brigatinib at a high temperature of 70°C in a methanol system, then cooling to a lower temperature of -10°C to -20°C, and adding two other unsuitable solvents. In this preparation method, methanol has a boiling point of 64.7°C, making it difficult to reach 70°C, potentially requiring pressurized operation. Furthermore, the lower limit of the low temperature range of -10°C to -20°C is low, necessitating the use of cryogenic equipment. In other words, the preparation of these three crystal forms places high demands on the crystallization equipment. Summary of the Invention

[0006] This invention aims to solve at least one of the problems of defects or difficulties in the preparation of brigatinib crystal forms in the prior art. Therefore, one objective of this invention is to provide a crystal form of brigatinib that exhibits high solubility, good flowability, high purity, and high stability, while also possessing advantages such as simple preparation process, good processability, excellent dissolution performance, and high bioavailability. This makes it suitable for industrial production and formulation processing, and has promising application prospects.

[0007] The second objective of this invention is to provide a method for preparing the crystal form of the above-mentioned brigatinib.

[0008] A third objective of this invention is to provide a pharmaceutical composition.

[0009] The fourth objective of this invention is to provide an application of the crystal form of the above-mentioned brigatinib.

[0010] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A first aspect of the present invention provides a crystal form 1 of brigatinib, the chemical formula of which is shown in formula (I): Formula (I); The X-ray powder diffraction pattern of crystal form 1 shows characteristic peaks at 2theta values ​​of 4.5±0.2°, 8.5±0.2°, 11.4±0.2°, 15.2±0.2°, 18.4±0.2°, and 24.6±0.2°.

[0011] According to the first aspect of the present invention, the crystal form 1 of brigatinib has at least the following beneficial effects: The crystal form 1 of brigatinib provided by this invention has high solubility, good flowability, high purity and high stability, as well as good processability, making it suitable for industrial production and formulation processing, and exhibiting good drug-like properties.

[0012] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form 1 also has a characteristic peak at at least one of the following 2theta values: 9.9±0.2°, 16.8±0.2°, 17.4±0.2°, 19.6±0.2°, and 22.7±0.2°.

[0013] In some embodiments of the present invention, the X-ray powder diffraction pattern of the crystal form 1 also has a characteristic peak at at least one of the following 2theta values: 13.4±0.2°, 14.9±0.2°, 18.8±0.2°, 23.1±0.2°, and 28.1±0.2°.

[0014] In some embodiments of the present invention, the crystal form 1 has substantially the following characteristics: Figure 2 The X-ray powder diffraction pattern shown.

[0015] In some embodiments of the present invention, the crystal form 1 is a hydrate.

[0016] In some embodiments of the present invention, the differential scanning calorimeter of the crystal form 1 has an endothermic peak at 50~99°C, an endothermic peak at 100~129°C, an exothermic peak at 130~180°C, and an endothermic peak at 190~240°C.

[0017] In some embodiments of the present invention, in the infrared detection pattern of crystal form 1, at a frequency of 3400~3500 cm⁻¹ -1 2900~3000cm -1 2750~2850cm -1 1450~1550cm -1 1280~1350cm -1 1200~1250cm -1 1160~1200cm -1 1142~1155cm -1 1120~1140cm -1 765~800cm -1 740~760cm -1 At least one of them has a characteristic peak.

[0018] In some embodiments of the present invention, the crystal form 1 experiences a 3-6% mass loss when heated from 30°C to 104°C.

[0019] In some embodiments of the present invention, the crystal form 1 experiences a 3-6% mass loss when heated from 104°C to 170°C.

[0020] In some embodiments of the present invention, the crystal form 1 experiences a mass loss of 6-12% when heated from 30°C to 170°C.

[0021] The second aspect of the present invention provides a method for preparing crystal form 1 as described in the first aspect of the present invention, comprising the following steps: dissolving brigatinib in a mixed solvent containing a first solvent and a second solvent, and performing crystallization to obtain crystal form 1; the first solvent includes methanol; the second solvent includes a haloalkane solvent, an aromatic hydrocarbon solvent, or a combination thereof; the volume ratio of the first solvent to the second solvent is 1:(0.01~5).

[0022] The method for preparing brigatinib crystal form 1 according to the second aspect of the present invention has at least the following beneficial effects: This invention uses a specific solvent combination to prepare a specific brigatinib crystal form 1. The preparation process is simple, and the resulting crystal form 1 has a uniform morphology and stable performance. This preparation method has the advantage of industrial production.

[0023] In some embodiments of the present invention, the first solvent is selected from methanol.

[0024] In some embodiments of the present invention, the haloalkane solvent is selected from C1-C5 haloalkane solvents.

[0025] In some embodiments of the present invention, the aromatic hydrocarbon solvent is selected from C6 to C20 aromatic hydrocarbon solvents.

[0026] In some embodiments of the present invention, the crystallization temperature is -30~30°C.

[0027] In some embodiments of the present invention, the crystallization is carried out under anti-solvent conditions.

[0028] In some embodiments of the present invention, the antisolvent includes ether solvents, ester solvents, or combinations thereof.

[0029] A third aspect of the present invention provides a pharmaceutical composition comprising crystal form 1 as described in the first aspect of the present invention.

[0030] The pharmaceutical composition according to the third aspect of the present invention has at least the following beneficial effects: In some embodiments of the present invention, the pharmaceutical composition further includes at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable solvent, or a pharmaceutically acceptable excipient.

[0031] The pharmaceutical composition provided by this invention has excellent dissolution properties, high bioavailability, good stability, and good therapeutic effects.

[0032] A fourth aspect of the invention provides the use of crystal form 1 as described in the first aspect of the invention in the preparation of a medicament for treating non-small cell lung cancer.

[0033] According to the application described in the fourth aspect of the present invention, at least the following beneficial effects are achieved: The crystal form 1 provided by this invention has the advantages of high solubility, high dissolution rate, high bioavailability and good stability, and has good application prospects in the preparation of drugs for the treatment of non-small cell lung cancer. Attached Figure Description

[0034] Figure 1 The X-ray powder diffraction pattern is for the original crystal form A.

[0035] Figure 2 The X-ray powder diffraction pattern is shown for crystal form 1 obtained in Example 1 of this invention.

[0036] Figure 3 This is the thermogravimetric analysis spectrum of crystal form 1 obtained in Example 1 of the present invention.

[0037] Figure 4 This is the differential scanning calorimeter of crystal form 1 obtained in Example 1 of the present invention.

[0038] Figure 5 The infrared detection spectrum of crystal form 1 obtained in Example 1 of this invention.

[0039] Figure 6 The image shows the infrared detection spectrum of the original crystal form A.

[0040] Figure 7 The images are scanning electron microscope (SEM) images of crystal form 1 obtained in Example 5 of this invention and the purchased original crystal form A.

[0041] Figure 8 The X-ray powder diffraction patterns are those of the original crystal form A and crystal form 1 and their formulation tablets.

[0042] Figure 9 This is a comparison chart of the cumulative dissolution of crystal form 1 tablets and the original crystal form A tablets. Detailed Implementation

[0043] The embodiments of the present invention are described in detail below. These embodiments are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. The term "comprising" and other equivalent descriptive methods used in the specification and claims of this application are intended to cover a non-exclusive inclusion, which includes both the contents explicitly described in the specification and claims and steps or units that are not described in the specification and claims but are inherent in the product, method, or structure.

[0044] In this invention, "crystal form" refers to a crystal structure whose differences can be distinguished by X-ray powder diffraction (XRD) patterns. Those skilled in the art will understand that experimental errors are influenced by instrument conditions, sample preparation, sample purity, and measurement conditions. In particular, it is known to those skilled in the art that the relative intensity of XRD patterns can also vary with experimental conditions; therefore, the order of diffraction peaks and their relative intensities cannot be considered decisive factors in distinguishing crystal form differences. In fact, the relative intensity of diffraction peaks in an XRD pattern is related to preferred orientation. Furthermore, due to the influence of experimental factors such as sample height, an overall shift in peak angles may occur. A certain degree of shift is generally allowed, with the same peak position potentially differing by ±0.2°. Therefore, identical crystal form XRD patterns are not necessarily absolutely identical; the same peak position can differ by ±0.2°, and peak intensities are allowed to have some variability. Any crystal form with peaks identical or similar to the characteristic peaks in its pattern falls within the scope of this invention.

[0045] A first aspect of the present invention provides a crystal form 1 of brigatinib, the chemical formula of which is shown in formula (I): Formula (I); In the X-ray powder diffraction pattern of crystal form 1, characteristic peaks are observed at 2theta values ​​of 4.5±0.2°, 8.5±0.2°, 11.4±0.2°, 15.2±0.2°, 18.4±0.2°, and 24.6±0.2°.

[0046] The crystal form 1 of brigatinib provided in this embodiment of the invention has high solubility, good flowability, high purity and high stability, as well as good processability, making it suitable for industrial production and formulation processing, and exhibiting good drug-like properties.

[0047] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form 1 also shows a characteristic peak at at least one of the following 2theta values: 9.9±0.2°, 16.8±0.2°, 17.4±0.2°, 19.6±0.2°, and 22.7±0.2°; in some specific embodiments of the present invention, the X-ray powder diffraction pattern of crystal form 1 also shows characteristic peaks at at least two of the following 2theta values: 9.9±0.2°, 16.8±0.2°, 17.4±0.2°, 19.6±0.2°, and 22.7±0.2°; in some examples of the present invention, the X-ray powder diffraction pattern of crystal form 1 also shows characteristic peaks at at least one of the following 2theta values: 9.9±0.2°, 16.8±0.2°, 17.4±0.2°, 19.6±0.2°, and 22.7±0.2°; Characteristic peaks are present at least three of the following values: 6.8±0.2°, 17.4±0.2°, 19.6±0.2°, and 22.7±0.2°. In some specific examples of the present invention, characteristic peaks are also present at least four of the following values: 2theta: 9.9±0.2°, 16.8±0.2°, 17.4±0.2°, 19.6±0.2°, and 22.7±0.2°. In some more specific examples of the present invention, characteristic peaks are also present at the following values: 2theta: 9.9±0.2°, 16.8±0.2°, 17.4±0.2°, 19.6±0.2°, and 22.7±0.2°.

[0048] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form 1 also has a characteristic peak at at least one of the following 2theta values: 13.4±0.2°, 14.9±0.2°, 18.8±0.2°, 23.1±0.2°, and 28.1±0.2°; in some specific embodiments of the present invention, the X-ray powder diffraction pattern of crystal form 1 also has characteristic peaks at at least two of the following 2theta values: 13.4±0.2°, 14.9±0.2°, 18.8±0.2°, 23.1±0.2°, and 28.1±0.2°; in some examples of the present invention, the X-ray powder diffraction pattern of crystal form 1 also has characteristic peaks at at least one of the following 2theta values: 13.4±0.2°, 14.9±0.2°, 18.8±0.2°, 23.1±0.2°, and 28.1±0.2°; Characteristic peaks are present at least three of the following values: 4.9±0.2°, 18.8±0.2°, 23.1±0.2°, and 28.1±0.2°. In some specific examples of the present invention, characteristic peaks are also present at least four of the following values: 2theta values: 13.4±0.2°, 14.9±0.2°, 18.8±0.2°, 23.1±0.2°, and 28.1±0.2°. In some more specific examples of the present invention, characteristic peaks are also present at the following values: 2theta values: 13.4±0.2°, 14.9±0.2°, 18.8±0.2°, 23.1±0.2°, and 28.1±0.2°.

[0049] In some embodiments of the present invention, the X-ray powder diffraction pattern of crystal form 1 has the 2theta values ​​and their relative intensities shown in the table below:

[0050] In other embodiments of the present invention, the X-ray powder diffraction pattern of crystal form 1 has the 2theta values ​​and their relative intensities shown in the table below:

[0051] In some embodiments of the present invention, crystal form 1 has substantially the following characteristics: Figure 2 The X-ray powder diffraction pattern shown.

[0052] In some embodiments of the present invention, crystal form 1 is a hydrate; in some specific embodiments of the present invention, crystal form 1 is at least one of a monohydrate, dihydrate, trihydrate, tetrahydrate, or pentahydrate; in some examples of the present invention, crystal form 1 is a trihydrate.

[0053] In some embodiments of the present invention, the differential scanning calorimeter of crystal form 1 has endothermic peak values ​​at 85.31±5℃, 115.74±5℃, and 216.08±5℃, and an exothermic peak value at 152.21±5℃; in some specific embodiments of the present invention, the differential scanning calorimeter of crystal form 1 has endothermic peak values ​​at 85.31±3℃, 115.74±3℃, and 216.08±3℃, and an exothermic peak value at 152.21±3℃.

[0054] In some embodiments of the present invention, crystal form 1 has substantially the following characteristics: Figure 4 The differential scanning calorimeter shown is a differential scanning calorimeter.

[0055] In some embodiments of the present invention, in the infrared detection pattern of crystal form 1, at a frequency of 3400~3500 cm⁻¹ -1 2900~3000cm -1 2750~2850cm -1 1450~1550cm -1 1280~1350cm -1 1200~1250cm -1 1160~1200cm -1 1142~1155cm -1 1120~1140cm -1 765~800cm -1 740~760cm -1 At least one of the components has a characteristic peak; in some specific embodiments of the present invention, in the infrared detection image of crystal form 1, at a frequency of 3400~3500 cm⁻¹, a characteristic peak is observed. -1 2900~3000cm -1 2750~2850cm -1 1450~1550cm -1 1280~1350cm -1 1200~1250cm -1 1160~1200cm -1 1142~1155cm -1 1120~1140cm -1 765~800cm -1 740~760cm -1 At least four characteristic peaks are present in the infrared detection pattern of crystal form 1; in some examples of the present invention, the characteristic peaks are present at frequencies of 3400~3500 cm⁻¹. -1 2900~3000cm -1 2750~2850cm -1 1450~1550cm-1 1280~1350cm -1 1200~1250cm -1 1160~1200cm -1 1142~1155cm -1 1120~1140cm -1 765~800cm -1 740~760cm -1 At least eight characteristic peaks are present in the infrared detection image of crystal form 1; in some specific examples of the present invention, the characteristic peaks are present at frequencies of 3400~3500 cm⁻¹. -1 2900~3000cm -1 2750~2850cm -1 1450~1550cm -1 1280~1350cm -1 1200~1250cm -1 1160~1200cm -1 1142~1155cm -1 1120~1140cm -1 765~800cm -1 740~760cm -1 Characteristic peaks are present at all locations.

[0056] In some embodiments of the present invention, crystal form 1 has substantially the following characteristics: Figure 5 The infrared detection spectrum shown.

[0057] In some embodiments of the present invention, crystal form 1 experiences a mass loss of 3-6% when heated from 30°C to 104°C; in some specific embodiments of the present invention, crystal form 1 experiences a mass loss of 3.5-5.5% when heated from 30°C to 104°C; in some examples of the present invention, crystal form 1 experiences a mass loss of 4-5% when heated from 30°C to 104°C; for example, the mass loss of crystal form 1 when heated from 30°C to 104°C can be any value of 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, or 5%, or a range of any two, such as 4.4-4.9%.

[0058] In some embodiments of the present invention, crystal form 1 experiences a mass loss of 3-6% when heated from 104°C to 170°C; in some specific embodiments of the present invention, crystal form 1 experiences a mass loss of 3.2-5.2% when heated from 104°C to 170°C; in some examples of the present invention, crystal form 1 experiences a mass loss of 3.5-4.5% when heated from 104°C to 170°C; for example, the mass loss of crystal form 1 when heated from 104°C to 170°C can be any value or a range formed by any two of 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, and 4.5%, such as 3.7-4.3%.

[0059] In some embodiments of the present invention, crystal form 1 experiences a mass loss of 6-12% when heated from 30°C to 170°C; in some specific embodiments of the present invention, crystal form 1 experiences a mass loss of 6.7-10.7% when heated from 30°C to 104°C; in some examples of the present invention, crystal form 1 experiences a mass loss of 7.5-9.5% when heated from 30°C to 104°C; for example, the mass loss of crystal form 1 when heated from 30°C to 104°C can be any value of 7.5%, 7.8%, 8%, 8.2%, 8.5%, 8.6%, 8.8%, 9%, 9.2%, 9.5%, or a range of any two, such as 8-9%.

[0060] In some embodiments of the present invention, crystal form 1 has substantially the following characteristics: Figure 3 The thermogravimetric analysis spectrum is shown.

[0061] The second aspect of the present invention provides a method for preparing crystal form 1 of brigatinib according to the first aspect of the present invention, comprising the following steps: dissolving brigatinib in a mixed solvent containing a first solvent and a second solvent, and crystallizing to obtain crystal form 1; the first solvent includes methanol; the second solvent includes a haloalkane solvent, an aromatic hydrocarbon solvent, or a combination thereof; the volume ratio of the first solvent and the second solvent is 1:(0.01~5).

[0062] The embodiments of the present invention employ a specific solvent combination to obtain a specific brigatinib crystal form 1. The preparation process is simple, and the resulting crystal form 1 has the advantages of uniform morphology and stable performance. This preparation method has the advantage of industrial production.

[0063] In some embodiments of the present invention, the first solvent is selected from methanol.

[0064] In some embodiments of the present invention, the second solvent includes a haloalkane solvent or an aromatic hydrocarbon solvent; in some specific embodiments of the present invention, the second solvent is selected from haloalkane solvents or aromatic hydrocarbon solvents.

[0065] In some embodiments of the present invention, the haloalkane solvent includes at least one of monohaloalkane, dihaloalkane, or trihaloalkane; in some specific embodiments of the present invention, the haloalkane solvent is selected from dihaloalkane.

[0066] In some embodiments of the present invention, the haloalkane solvent includes at least one of chloroalkane, bromoalkane, or iodoalkane; in some specific embodiments of the present invention, the haloalkane solvent is selected from chloroalkane.

[0067] In some embodiments of the present invention, the haloalkane solvent is selected from C1-C5 haloalkane solvents; in some specific embodiments of the present invention, the haloalkane solvent includes at least one of halomethane, haloethane, or halopropane; in some examples of the present invention, the haloalkane solvent is selected from halomethane.

[0068] In some embodiments of the present invention, the haloalkane solvent includes at least one of chloromethane, dichloromethane, trichloromethane, bromomethane, dibromomethane, tribromomethane, iodomethane, diiodomethane, or triiodomethane; in some specific embodiments of the present invention, the haloalkane solvent includes at least one of chloromethane, dichloromethane, or trichloromethane; in some examples of the present invention, the haloalkane solvent is selected from dichloromethane.

[0069] In some embodiments of the present invention, the aromatic hydrocarbon solvent is selected from C6 to C20 aromatic hydrocarbon solvents; in some specific embodiments of the present invention, the aromatic hydrocarbon solvent is selected from C6 to C12 aromatic hydrocarbon solvents.

[0070] In some embodiments of the present invention, the aromatic hydrocarbon solvent includes at least one of benzene, toluene, ethylbenzene, xylene, trimethylbenzene, naphthalene, or styrene; in some specific embodiments of the present invention, the aromatic hydrocarbon solvent includes at least one of benzene, toluene, xylene, or trimethylbenzene; in some examples of the present invention, the aromatic hydrocarbon solvent is selected from toluene.

[0071] In some embodiments of the present invention, the volume ratio of the first solvent and the second solvent is 1:(0.05~3); in some specific embodiments of the present invention, the volume ratio of the first solvent and the second solvent is 1:(0.08~2.5); in some embodiments of the present invention, the volume ratio of the first solvent and the second solvent is 1:(0.1~2); for example, the volume ratio of the first solvent and the second solvent can be any value or a range formed by any two of 1:0.1, 1:0.2, 1:0.25, 1:0.3, 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, such as 1:(0.1~0.5).

[0072] In some embodiments of the present invention, the ratio of brigatinib to the mixed solvent is 1 g: (1~50) mL; in some specific embodiments of the present invention, the ratio of brigatinib to the mixed solvent is 1 g: (3~40) mL; in some examples of the present invention, the ratio of brigatinib to the mixed solvent is 1 g: (5~30) mL; for example, the ratio of brigatinib to the mixed solvent can be any value or a range formed by any two of the following: 1 g: 5 mL, 1 g: 8 mL, 1 g: 10 mL, 1 g: 12 mL, 1 g: 15 mL, 1 g: 20 mL, 1 g: 25 mL, 1 g: 30 mL, such as 1 g: (5~15) mL.

[0073] In some embodiments of the present invention, the crystallization temperature is -30~30℃; in some specific embodiments of the present invention, the crystallization temperature is -20~25℃; in some embodiments of the present invention, the crystallization temperature is -5~25℃; for example, the crystallization temperature can be any value or a range formed by any two of -5℃, -2℃, 0℃, 2℃, 5℃, 8℃, 10℃, 12℃, 15℃, 20℃, and 25℃, such as -5~15℃ or 0~25℃.

[0074] The crystal form 1 of the present invention can crystallize at temperatures of 0°C and above, such as 0~25°C. The conditions are mild and controllable, the preparation process is simple, and it has the advantage of industrial production.

[0075] In some embodiments of the present invention, the crystallization time is 1 to 40 hours; in some specific embodiments of the present invention, the crystallization time is 2 to 30 hours; in some examples of the present invention, the crystallization time is 3 to 20 hours; for example, it can be any value of 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 15 hours, 18 hours, 20 hours or a range formed by any two of them, such as 3 to 15 hours.

[0076] In some embodiments of the present invention, crystallization is also carried out under anti-solvent conditions.

[0077] Adding an antisolvent during crystallization can effectively improve the yield of crystal form 1.

[0078] In some embodiments of the present invention, the antisolvent includes ether solvents, ester solvents, or combinations thereof; in some specific embodiments of the present invention, the antisolvent is selected from ether solvents or ester solvents.

[0079] In some embodiments of the present invention, the ether solvent is selected from C1-C10 ether solvents; in some specific embodiments of the present invention, the ether solvent includes at least one of methyl ether, diethyl ether, propyl ether, isopropyl ether, methyl propyl ether, methyl n-butyl ether, butyl ether, pentyl ether, isopentyl ether, hexyl ether, ethyl butyl ether, or methyl tert-butyl ether; in some specific embodiments of the present invention, the ether solvent includes at least one of methyl propyl ether, methyl n-butyl ether, ethyl butyl ether, or methyl tert-butyl ether; in some examples of the present invention, the ether solvent is selected from methyl tert-butyl ether.

[0080] In some embodiments of the present invention, the ester solvent is selected from C1-C10 ester solvents; in some specific embodiments of the present invention, the ester solvent includes at least one of methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, or isobutyl propionate; in some examples of the present invention, the ester solvent includes at least one of methyl acetate, ethyl acetate, propyl acetate, or isopropyl acetate; in some specific examples of the present invention, the ester solvent is selected from ethyl acetate or isopropyl acetate.

[0081] In some embodiments of the present invention, the volume ratio of the mixed solvent to the antisolvent is 1:(0.3~3); in some specific embodiments of the present invention, the volume ratio of the mixed solvent to the antisolvent is 1:(0.4~2.5); in some examples of the present invention, the volume ratio of the mixed solvent to the antisolvent is 1:(0.5~2); for example, the volume ratio of the mixed solvent to the antisolvent can be any value of 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2 or a range of any two, such as 1:(0.8~1.5).

[0082] In some embodiments of the present invention, brigatinib is first dissolved in a mixed solvent, and after solid precipitation, an antisolvent is added; in some specific embodiments of the present invention, brigatinib is first dissolved in a mixed solvent at a controlled temperature of -30 to 30°C, and after solid precipitation, an antisolvent is added, and the temperature is controlled at -30 to 10°C; in some examples of the present invention, brigatinib is first dissolved in a mixed solvent at a controlled temperature of -20 to 20°C, and after solid precipitation, an antisolvent is added, and the temperature is controlled at -20 to 5°C; in some examples of the present invention, brigatinib is first dissolved in a mixed solvent at a controlled temperature of -10 to 15°C, and after solid precipitation, an antisolvent is added, and the temperature is controlled at -10 to 5°C.

[0083] In some embodiments of the present invention, the step of drying the precipitated crystals after crystallization is included; in some specific embodiments of the present invention, the drying temperature is 20~50°C; for example, the drying temperature can be any value of 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C or a range of any two, such as 25~40°C.

[0084] A third aspect of the present invention provides a pharmaceutical composition comprising crystal form 1 of the first aspect of the present invention.

[0085] The pharmaceutical compositions provided in the embodiments of the present invention have high bioavailability, good stability, and good therapeutic effects.

[0086] In some embodiments of the present invention, the mass content of crystal form 1 in the pharmaceutical composition is 0.001 to 100%; for example, the mass content of crystal form 1 in the pharmaceutical composition may be any value or a range formed by any two of 0.01%, 0.1%, 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, such as 0.01 to 20% or 1 to 30%.

[0087] In some embodiments of the present invention, the pharmaceutical composition further includes at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable solvent, or a pharmaceutically acceptable excipient.

[0088] The pharmaceutical compositions disclosed in the embodiments of this invention may take any pharmaceutical form that a person skilled in the art would consider suitable. Non-limiting examples of suitable pharmaceutical forms include solid, semi-solid, liquid, and lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols.

[0089] The tablets disclosed in the embodiments of this invention may be uncoated or coated using known techniques to delay disintegration and adsorption in the gastrointestinal tract, thereby providing sustained action over a longer period of time. For example, time-retarding materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient can be mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient can be mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0090] The pharmaceutical compositions disclosed in this invention also include anhydrous pharmaceutical compositions and dosage forms containing at least one active ingredient. Water can promote the degradation of some compounds. For example, water (e.g., about 5%) from the pharmaceutical industry can be added as a way to simulate long-term storage to determine characteristics of the formulation over time, such as shelf life or stability. Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions. For example, lactose-containing pharmaceutical compositions and dosage forms can be prepared as anhydrous and / or intended for storage if they are exposed to significant amounts of moisture and / or humidity during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored such that their anhydrous properties are maintained. Therefore, anhydrous pharmaceutical compositions can be packaged using known materials to prevent exposure to water, allowing them to be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, airtight sealing foil, plastics, etc., unit-dose containers, blister packs, and strip packs.

[0091] In embodiments of the present invention, the active ingredient and pharmaceutical carrier can be combined in a close mixture according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms, depending on the preparation method required for administration. During the preparation of pharmaceutical compositions for oral dosage forms, any common pharmaceutical medium can be used as a carrier, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., in the case of oral liquid formulations (such as suspensions, solutions, and elixirs) or aerosols; or in some embodiments where lactose is not used, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants can be used in oral solid dosage forms. In some embodiments, the mixture can be blended with lactose, sucrose, starch powder, cellulose esters of alkanonic acids, alkyl cellulose esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol for subsequent formulation. For example, in the case of solid oral dosage forms, suitable carriers include powders, capsules, and tablets. In some embodiments, tablets may be coated using standard aqueous or non-aqueous techniques.

[0092] Non-limiting examples of adhesives suitable for the pharmaceutical compositions and dosage forms disclosed in the embodiments of the present invention include, but are not limited to, corn starch, potato starch and other starches, gelatin, natural and synthetic gums (such as gum arabic, sodium alginate, alginic acid, other alginates, powdered astragalus gum, guar gum), cellulose and its derivatives (such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose and mixtures thereof.

[0093] Non-limiting examples of fillers applicable to the pharmaceutical compositions and dosage forms disclosed in the embodiments of the present invention include, but are not limited to, talc, calcium carbonate (such as granules or powders), microcrystalline cellulose, powdered cellulose, dextran, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0094] Disintegrants can be used in the pharmaceutical compositions and dosage forms disclosed in the embodiments of the present invention to provide tablets that disintegrate upon exposure to an aqueous environment. Too much disintegrant can result in tablets that disintegrate in the bottle. Too little may be insufficient to cause disintegration and may therefore alter the rate and extent of release of the active ingredient from the dosage form. Therefore, a sufficient amount of disintegrant (i.e., neither too little nor too much to adversely alter the release of the active ingredient) can be used to prepare the pharmaceutical compositions and dosage forms disclosed herein. The amount of disintegrant can vary based on the type of formulation and the method of administration, and may be readily discernible to those skilled in the art. For example, in some embodiments, at least one disintegrant may be used in amounts from about 0.5 to about 15% of the total weight. In some embodiments, at least one disintegrant may be used in the pharmaceutical composition in amounts from about 1 to about 5% of the total weight. The disintegrants that may be used include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, croscarmellose, polacolin potassium, sodium hydroxyacetic acid starch, potato or cassava starch, other starches, pregelatinized starch, other starches, clay, other alginate, other cellulose, gums and mixtures thereof.

[0095] Lubricants that can be used in the pharmaceutical compositions and dosage forms disclosed in the embodiments of this invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl lauryl ester, agar, syloid silica gel, coagulated aerosols of synthetic silica, and mixtures thereof. The lubricant may optionally be added in an amount less than about 1% by weight of the total pharmaceutical composition.

[0096] In some embodiments of the present invention, the pharmaceutical composition further includes at least one adjuvant selected from preservatives, wetting agents, emulsifiers, dispersants, lubricants, antioxidants, antibacterial agents, antifungal agents (such as parabens, chlorobutanol, phenolic sorbic acid, etc.), isotonic agents (such as sugars, sodium chloride, etc.), and reagents capable of delaying adsorption (such as aluminum monostearate, gelatin, etc.).

[0097] A fourth aspect of the present invention provides the use of crystal form 1 as described in the first aspect of the present invention in the preparation of a medicament for treating non-small cell lung cancer.

[0098] The crystal form 1 provided in this embodiment of the invention has the advantages of high solubility, high dissolution rate, good fluidity, high bioavailability and good stability, and has good application prospects in the preparation of drugs for the treatment of non-small cell lung cancer.

[0099] The following detailed description of the present invention is provided through specific embodiments. It should also be understood that the following embodiments are only for further illustration and should not be construed as limiting the scope of protection of the present invention. Non-essential improvements and adjustments made by those skilled in the art based on the principles described herein are all within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make selections within a suitable range based on the description herein, and are not intended to be limited to the specific data in the examples below.

[0100] Experimental methods in the following examples that do not specify specific conditions were performed according to conventional methods and conditions, or according to the product instructions. The reagents and methods used in the embodiments of this invention are all conventional reagents and methods in the art. Those skilled in the art should understand that, unless otherwise specified, temperature is expressed in degrees Celsius (°C) in the following text, and the operating temperature is at room temperature, which refers to 10~30°C, more specifically 20~25°C.

[0101] The brigatinib material used in this invention was purchased from Bidex Pharmaceuticals and was identified as crystal form A reported in the original patent CN107108559A (its X-ray powder diffraction pattern is shown in...). Figure 1 (The original crystal form A used in this invention was used directly without any processing. Unless otherwise specified, all materials used in this invention were purchased from external sources as described above.)

[0102] Experimental methods 1. X-ray powder diffraction (XRPD). XRPD data for the example samples were measured using a Malvern Panaco Empyrean 3 with the following parameters: X-ray reflection parameters: Cu kα; K-Alpha1 (Å) 1.54060; K-Alpha2 (Å) 1.54443; voltage and current: 45 kV, 40 mA; scanning range: 3–45 degrees.

[0103] 2. Thermogravimetric Analysis / Differential Scanning Calorimeter (TGA / DSC). The TGA / DSC data for the example samples were measured using a Mettler TGA / DSC1 simultaneous thermal analyzer. The detection parameters were as follows: temperature range (°C): 30~300; heating rate (°C / min): 10; protective gas: nitrogen; protector flow rate (mL / min): 40.

[0104] 3. Karl Fischer method (KF). Moisture data in the examples were determined according to Method 1 of the Chinese Pharmacopoeia 2020 edition, 0832, using a Karl Fischer moisture analyzer 915 from Metrohm, Switzerland. Karl Fischer reagents were readily available from conventional commercial sources.

[0105] 4. High-performance liquid chromatography (HPLC) analysis method. The solubility and dissolution curves involved in the embodiments of this invention were detected by high-performance liquid chromatography (HPLC). Data were collected from an Agilent 1260, and the detector used was an Agilent DAD. Specific chromatographic conditions and methods are as follows: Column: Waters XBridge Rp18, 5 mm, 4.6 × 250 mm; Mobile phase A: 0.1 wt% trifluoroacetic acid solution; Mobile phase B: acetonitrile-methanol-trifluoroacetic acid (volume ratio 1000:5:1); Gradient elution program:

[0106] 5. Preparation of biological media solutions. FaSSGF (simulated fasting gastric fluid): Weigh 3.68g of FaSSGF blank buffer and 6mg of FaSSGF / FaSSIF / FeSSIF powder, dissolve in 96mL of water, and mix well. FaSSIF (simulated fasting intestinal fluid): Weigh 4.16g of FaSSIF blank buffer and 224mg of FaSSGF / FaSSIF / FeSSIF powder, dissolve in 96mL of water, and mix well.

[0107] 6. Preparation of dissolution medium solution. 50 mmol / L potassium dihydrogen phosphate solution (pH 7.2): Weigh 6.80 g of potassium dihydrogen phosphate and 1.39 g of sodium hydroxide, add 1000 mL of water, dissolve completely, and measure the pH value to be approximately 7.2.

[0108] 7. Purity Detection Method. The purity of the samples involved in this embodiment of the invention was detected by high-performance liquid chromatography (HPLC). Data were obtained from an Agilent 1260, and the detector used was an Agilent VWD. Specific chromatographic conditions and methods are as follows: Column: Waters XTerra RP18, 5 μm, 4.6 × 250 mm; Mobile phase A: 0.05 mol / L ammonium bicarbonate solution (7.9 g of ammonium bicarbonate was dissolved in 2000 mL of water, and the pH was adjusted to 9.40 ± 0.05 with ammonia); Mobile phase B: methanol-acetonitrile (volume ratio 92:8); Flow rate: 1.0 mL / min; Column temperature: 35℃; Injection volume: 10 mL; Detection wavelength: 295 nm; Gradient elution program:

[0109] Example 1 The specific steps for preparing brigatinib crystal form 1 are as follows: Weigh 1g of brigatinib, add 7.2mL of a mixed solvent of methanol / dichloromethane = 5 / 1 (volume ratio), cool to 10~15℃ and stir until solid precipitates, add 6mL of methyl tert-butyl ether, stir for 3h, cool to 0℃ and stir for 3h, filter, and dry the filter cake overnight at 40℃.

[0110] Upon testing, the dried filter cake was found to be crystal form 1 as described in this invention. The X-ray powder diffraction (XRPD) pattern of crystal form 1 obtained in Example 1 is shown below. Figure 2 As shown in Table 1, the specific X-ray powder diffraction data are as follows.

[0111] The thermogravimetric analysis (TGA) spectrum of crystal form 1 obtained in Example 1 is as follows: Figure 3 As shown, during thermogravimetric analysis, heating to 103.9℃ resulted in a weight loss of approximately 4.6%, and further heating to 166.8℃ resulted in a further weight loss of approximately 4.0%. The differential scanning calorimetry (DSC) spectrum of crystal form 1 obtained in Example 1 is shown below. Figure 4 As shown, when differential scanning calorimetry is performed, the first endothermic peak appears when heated to 70.8℃, the second endothermic peak appears when heated to 101.3℃, the first exothermic peak appears when heated to 130.8℃, and the third endothermic peak appears when heated to 203.7℃.

[0112] The infrared spectrum of crystal form 1 obtained in Example 1 is as follows: Figure 5 As shown, the infrared detection spectrum of the original crystal form A is as follows: Figure 6 As shown. It can be seen that crystal form 1 obtained in Example 1 has the following properties at 3427, 2939, 2800, 1508, 1311, 1236, 1163, 1149, 1134, 775, and 758 cm⁻¹. -1Peaks were observed at various locations. When the water content of crystal form 1 was determined, the KF value was 8.65%, which is approximately trihydrate.

[0113] Table 1. X-ray powder diffraction data of crystal form 1 in Example 1

[0114] Example 2 The specific steps for preparing brigatinib crystal form 1 are as follows: Weigh 3g of brigatinib, add 39.6mL of a mixed solvent of methanol / dichloromethane = 10 / 1 (volume ratio), cool to 15℃, add crystal seed of crystal form 1, stir until solid precipitates, cool to 0~5℃ and stir overnight, filter, dry the filter cake at 40℃ overnight, and the sample is detected to be crystal form 1.

[0115] Example 3 The specific steps for preparing brigatinib crystal form 1 are as follows: Weigh 1g of brigatinib, add 15mL of a mixed solvent of methanol / dichloromethane = 2 / 1 (volume ratio), cool to -20℃ and stir, add 20mL of methyl tert-butyl ether dropwise, keep warm at -20℃ and stir for 4h, filter, and dry the filter cake at 40℃ overnight. The sample was detected as crystal form 1.

[0116] Example 4 The specific steps for preparing brigatinib crystal form 1 are as follows: Weigh 1g of brigatinib, add 7.2mL of a mixed solvent of methanol / dichloromethane = 5 / 1 (volume ratio), cool to 10~15℃ and stir until solid precipitates, add 6mL of ethyl acetate dropwise, stir for 3h, cool to 0℃ and stir for 3h, filter, dry the filter cake at 40℃ overnight, and the crystal form of the sample is crystal form 1.

[0117] Example 5 The specific steps for preparing brigatinib crystal form 1 are as follows: Weigh 20g of brigatinib and add 140mL of a mixed solvent of methanol / dichloromethane = 5 / 1 (volume ratio). Cool to 10~15℃ and stir until solid precipitates. Add 120mL of methyl tert-butyl ether and stir for 3h. Cool to 0℃ and stir overnight. Filter and dry the filter cake at 40℃ overnight. 17.2g of the material was collected, with a yield of 86.2%. The sample was detected as crystal form 1. The detection data are shown in Table 2.

[0118] Table 2. X-ray powder diffraction data of crystal form 1 in Example 5

[0119] Example 6 The specific steps for preparing brigatinib crystal form 1 are as follows: Weigh 4g of brigatinib and add 25mL of a mixed solvent of methanol / toluene (4 / 1, volume ratio). Dissolve the brigatinib at room temperature by stirring. Cool the solution to 10-15℃ and add crystal form 1 seed crystals. Stir for 2 hours, then add 20mL of methyl tert-butyl ether. Cool the solution to 0℃ and stir overnight. Filter the solution, wash the filter cake with methyl tert-butyl ether, and dry it overnight at 40℃ using a forced-air drying method. Collect 3.3g of the product, yielding 82.5%. The solid was identified as crystal form 1.

[0120] Example 7 The specific steps for preparing brigatinib crystal form 1 are as follows: Weigh 120g of brigatinib and add 720mL of a mixed solvent of methanol / toluene (5 / 1, volume ratio). Dissolve the brigatinib by stirring at 32℃. Cool the solution to 10-15℃ and add crystal form 1 seed crystals. Stir for 2 hours, then add 600mL of methyl tert-butyl ether. Cool the solution to 0℃ and stir overnight. Filter the solution, wash the filter cake with methyl tert-butyl ether, and dry it overnight at 40℃. 108.2g of the product was collected, with a yield of 90.2%. The solid was identified as crystal form 1.

[0121] Example 8 The specific steps for preparing crystal form 1 and original crystal form A from crude brigatinib are as follows: The preparation of compound 5 (crude brigatinib) in Example 122 of patent CN102105150A was repeated to obtain 1.2 g of crude brigatinib. 500 mg of crude brigatinib was purified using the method of Example 7 of this invention, and the resulting solid was identified as crystal form 1. Another 500 mg of crude brigatinib was taken and 1.5 mL of a mixed solvent of dichloromethane / ethanol = 1 / 1 (volume ratio) was added. The mixture was heated until dissolved, cooled to room temperature, and 7.5 mL of ethyl acetate was added dropwise. After the addition was complete, the mixture was stirred for 1 hour, filtered, and the filter cake was dried overnight at 40°C. The collected material was then subjected to crystal form testing, and the result was identified as the original crystal form A.

[0122] According to Example 8, if ethanol is used instead of methanol as the first solvent during crystallization, the resulting brigatinib is the original crystal form A. It can be seen that the specific solvent combination is required to obtain the specific brigatinib crystal form 1 in the embodiments of the present invention.

[0123] The brigatinib crystal forms obtained in Examples 1-8 were tested as follows: (I) Morphology, purification comparison and flowability study a. Morphological study The crystal morphology of crystal form 1 obtained in Example 5 and the purchased original crystal form A were observed under a scanning electron microscope. The scanning electron microscope images of crystal form 1 obtained in Example 5 and the purchased original crystal form A are shown below. Figure 7 As shown, (a) is the original crystal form A, and (b) is crystal form 1; see Table 3 for a detailed comparison.

[0124] Table 3. Comparison of crystal morphology between crystal form 1 obtained in Example 5 and the purchased original crystal form A

[0125] from Figure 7 As shown in Table 3, crystal form A has an uneven morphology and small particle size, making it unsuitable for separation in the crystallization process. Compared with crystal form A, crystal form 1 has a larger particle size. Larger particles are less affected by electrostatic adsorption and are easier to separate during the crystallization process. This also avoids uneven mixing in the formulation process, making the drug quality more controllable. At the same time, crystals with uniform morphology and large particle size can effectively avoid inclusion problems during crystallization, which is more conducive to purification.

[0126] b. Comparison of impurity removal effects between crystal form 1 and original A crystal Impurity control is a crucial part of drug quality research. The content and types of impurities are closely related to drug quality. ICH has issued the Q3 series of guidelines for impurity research, which sets strict limits and requirements for various types of impurities.

[0127] The crude brigatinib obtained in Example 8, crystal form 1, and original crystal form A were subjected to purity testing using the same method. Impurities with peak areas greater than or equal to 0.05% were counted, and the statistical results are shown in Table 4.

[0128] Table 4 Comparison of purity results of crude brigatinib and different crystal forms in Example 8

[0129] As shown in Table 4, the purity of crude brigatinib was 98.65%. After preparation into crystal form 1, the purity increased to 99.55%, an increase of 0.9%. However, after preparation into the original crystal form A, the purity only increased to 99.02%, an increase of 0.37%. The purity improvement of crystal form 1 was 243% of that of the original crystal form A. Furthermore, after preparation into crystal form 1, the number of impurity peaks greater than or equal to 0.05% decreased from 10 to 3, while after preparation into crystal form A, there were still 6 impurity peaks greater than or equal to 0.05%.

[0130] c. Liquidity assessment The loose density and tap density of crystal form 1 and the purchased original crystal A from Example 7 were measured. The specific operation was as follows: 30g of brigatinib was weighed and placed in a graduated cylinder, and the material surface was gently tapped to make it horizontal. The scale was read and the loose density was calculated. The number of vibrations of the tap density meter was set to 500. After the vibration was completed, the scale was read and the tap density was calculated. The loose density and tap density data of crystal form 1 and original crystal form A are shown in Table 5.

[0131] In the formulation process, compressibility and Hausner ratio are commonly used to evaluate the flowability of powders or intermediate particles. r ρ represents the tap density, ρ0 represents the loose density, and the compressibility is calculated using the formula c = (ρ0 / ρ0) / ρ0. r-ρ0) / ρ r The Hausner ratio is calculated using the formula HR = ρr / ρ0. The compressibility of crystal form 1 is 9.8%, and the Hausner ratio is 1.11; the compressibility of the original crystal form A is 22.9%, and the Hausner ratio is 1.30. The "Guidelines for Powder Flowability Testing" published by the Pharmacopoeia Commission in 2022 and the "Pharmaceutics" published by China Medical Science and Technology Press both mention the same evaluation rules regarding the relationship between compressibility, Hausner ratio, and flowability, as shown in Table 6. As can be seen from the evaluation criteria in Table 6, crystal form 1 has excellent flowability, significantly better than the original crystal form A. Since the active pharmaceutical ingredient (API) accounts for as much as 20% of the marketed brigatinib tablets, the powder properties of this high proportion have a significant impact on the formulation process. The flowability of the original crystal form A and the new crystal form 1 differs by several grades. Improving the flowability of the original crystal form through excipient ratios and process adjustments is very difficult. The new crystal form 1 is far more suitable for direct powder compression processing than the original crystal form A.

[0132] Table 5. Results of loose density, tap density, compressibility, and Hauss-Nabi for different crystal forms.

[0133] Table 6. Liquidity Evaluation Criteria Based on Compressibility and Hausner Ratio

[0134] (II) Study on Crystal Form Stability a. Solution stability studies 10 mg of the original crystal A and 10 mg of crystal form 1 from Example 5 were weighed and placed in a methanol / dichloromethane / methyl tert-butyl ether = 5 / 1 / 5 (volume ratio) system and stirred at 0°C for 72 h. After filtration, the filter cake was dried by forced air at 40°C and identified as crystal form 1.

[0135] The mixture of the original crystal form A and crystal form 1 will transform into crystal form 1, indicating that crystal form 1 will not transform under this condition, while the original crystal form A will transform, and crystal form 1 is more stable.

[0136] b. Study on the tolerance of crystal form to formulation process Weigh 1.45g of crystal form 1 from Example 5, 2.73g of lactose monohydrate, 1.93g of microcrystalline cellulose, 0.58g of sodium carboxymethyl starch, 0.07g of magnesium stearate, and 0.48g of colloidal silica, mix them evenly, and place them in a mold to directly press them into tablets to obtain crystal form 1 tablets. The crystal form is then tested. The same operation is performed to obtain the original crystal form A tablets, and the crystal form is then tested.

[0137] X-ray powder diffraction patterns of original crystal form A and crystal form 1 and their formulation tablets are shown below. Figure 8It can be seen that the crystal form of the active pharmaceutical ingredient in the crystal form 1 tablet remains unchanged, and its stability is comparable to that of the original crystal form A. Furthermore, the tablets obtained by crystal form 1 according to the original formulation ratio do not undergo crystal transformation, indicating that crystal form 1 has good stability, can withstand the influence of the formulation process, and has good drug-like properties.

[0138] c. Solid-state stability studies of crystal form 1 active pharmaceutical ingredient and tablets A suitable amount of the active pharmaceutical ingredient (API) of crystal form 1 from Example 5 and its formulation tablets were placed in a constant temperature and humidity chamber at 25°C and 60%RH, and samples were taken at the beginning, 10 days, and 30 days for crystal form and related substance detection; a suitable amount of API of crystal form 1 and its formulation tablets were placed in a 4500Lux / UV 85μw / cm² chamber. 2 Under the light, samples were taken at the beginning, 10 days and 30 days later for crystal form and related substance testing.

[0139] The results showed that neither the active pharmaceutical ingredient (API) of crystal form 1 nor its tablets underwent crystal transformation after 10 days or 30 days, and the purity of related substances was above 99%, which meets the stability requirements for drug development.

[0140] (III) Solubility Study a. Solubility of FaSSGF and FaSSIF Approximately 30 mg of each of the crystal form 1 and the original crystal form A samples from Example 6 were weighed into 5 mL centrifuge tubes. 1 mL of simulated fasting gastric fluid (FaSSGF) and simulated fasting intestinal fluid (FaSSIF) were added respectively to obtain sample suspensions. The suspensions were then rapidly placed in a shaker (37°C, 150 rpm). After 5 minutes, the samples were observed. Appropriate amounts of sample or medium were added to obtain a new suspension. Samples were taken at 1 h and 24 h, and centrifuged at 9000 rpm for 3 minutes. The supernatant was collected, appropriately diluted, and then subjected to high-performance liquid chromatography (HPLC) for analysis. The sample concentration was calculated using the external standard method.

[0141] Table 7. Solubility data of FaSSGF and FaSSIF for crystal form 1 and original crystal form A in Example 6.

[0142] The test results are shown in Table 7. The data in the table show that the solubility of crystal form 1 in both FaSSGF and FaSSIF of Example 6 is better than that of the original crystal form A. In the prior art, the solubility of crystal form CS2 in FaSSIF in Chinese invention patent CN110036003A is only 43% higher than that of the original crystal form A; the solubility of crystal form LX-3 in FaSSIF in Chinese invention patent CN113943323A is less than twice that of the original crystal form A. However, the solubility of crystal form 1 in FaSSIF of this invention is more than three times higher than that of crystal form A. By comparing the differences in solubility between each crystal form and the original crystal form A, it is indirectly shown that the solubility of crystal form 1 in FaSSIF is higher than that of crystal forms CS2 and LX-3, producing an unexpected effect. Brigatinib is an oncology drug, and patients usually need to take multiple medications. The increased solubility in FaSSIF eliminates the need for patients to avoid using antacids, which will help improve drug bioavailability.

[0143] Since the methods provided in CN110036003A and CN113943323A could not successfully prepare the crystal forms CS2 and LX-3 described therein, meaning the crystal forms in the prior art could not be reproduced, it is impossible to directly compare the effects of crystal form 1 in this invention with those of crystal forms CS2 and LX-3 in the prior art. However, based on the above comparison with the original crystal form A, the solubility of crystal form 1 obtained by this invention in FaSSIF is higher than that of crystal forms CS2 and LX-3, producing an unexpected effect.

[0144] Furthermore, the preparation of crystal form CS1 in Chinese invention patent CN110036003A requires specific humidity, while the preparation of CS2 requires solvent evaporation for several days, which is time-consuming and the ambient temperature and humidity are uncontrollable. The preparation of crystal forms LX-1, LX-2, and LX-3 in Chinese invention patent CN113943323A all require dissolving brigatinib raw material in methanol at 70°C at high temperature. However, this system generally makes it difficult to heat methanol (boiling point 64.7°C) to 70°C, and LX-3 requires further preparation at an extremely low temperature of -20°C. In contrast, as shown in Examples 1-6 of this invention, the preparation method of this crystal form is simple, the conditions are mild and controllable, the temperature range of the entire crystallization process can be controlled within 0-25°C (as in Examples 1-2 and Examples 4-5), and it can be prepared at room temperature with lower equipment requirements. Furthermore, none of the existing methods for preparing brigatinib crystal forms have achieved 100-gram scale-up preparation, while this crystal form has achieved 100-gram scale-up preparation with a yield of over 90% (Example 7). Crystal form 1 of the present invention has significant advantages for industrial production.

[0145] b. Water solubility Equal amounts of crystal form 1 and original crystal form A from Example 6 were placed in pure water, and the concentrations of crystal form 1 and original crystal form A in the pure water were tested at different times. The results are shown in Table 8.

[0146] Table 8. Water solubility data of crystal form 1 and original crystal form A in Example 6

[0147] As can be seen from Table 8, the crystal form 1 obtained in Example 6 of the present invention has a higher solubility in pure water than the original crystal form A, especially at 0.5h, the solubility of crystal form 1 in pure water is more than 10 times higher than that of the original crystal form A.

[0148] (iv) Dissolution study Crystal form 1 tablets (using crystal form 1 from Example 5) and original crystal form A tablets were prepared according to the method in Test (II) b. Crystal form 1 tablets and original crystal form A tablets were then placed in a dissolution apparatus and measured sequentially. Dissolution test conditions are shown in Table 9, and dissolution data results are shown in Table 10. A comparison of the cumulative dissolution amounts of crystal form 1 tablets and original crystal form A tablets is shown in the figure below. Figure 9 As shown.

[0149] Table 9 Dissolution Test Conditions

[0150] Table 10 Dissolution data of crystal form 1 tablets and original crystal form A tablets

[0151] from Figure 9 As shown in Table 10, the cumulative dissolution of the two tablets was studied according to the pharmacopoeia method. The cumulative dissolution data showed that the cumulative dissolution of crystal form 1 tablets at each sampling point was higher than that of the original crystal form A tablets. At 5 minutes, the cumulative dissolution of crystal form 1 tablets was more than 70% higher than that of the original crystal form A tablets. At 30 minutes, the cumulative dissolution of the two tablets nearly reached equilibrium, but the cumulative dissolution of crystal form 1 tablets at equilibrium was about 21% higher than that of the original crystal form A tablets, producing an unexpected effect. Using the same formulation as the original crystal form A, the dissolution rate and equilibrium dissolution of crystal form 1 were both higher than those of the original crystal form A, indicating that crystal form 1 helps improve the bioavailability of brigatinib.

[0152] As can be seen from the above, compared with the prior art, crystal form 1 of the present invention has better solubility and dissolution rate, especially in FaSSIF (artificial intestinal fluid under fasting conditions), where the solubility of crystal form 1 is 3 times higher than that of the original crystal form A, and the dissolution rate is 70% higher. Since brigatinib is an oncology drug, patients usually need to take multiple medications. The improved solubility in FaSSIF eliminates the need for patients to avoid using antacids, which will help improve drug bioavailability and thus enhance drug efficacy. Furthermore, crystal form 1 provided by the present invention has good stability, high solubility, good flowability, simple production and preparation conditions, and is easy to scale up. The crystal form 1 obtained by crystallization of the crude product has higher purity than that obtained by crystal form A, with a 243% increase in impurity removal efficiency. Therefore, the discovery of crystal form 1 provides a better option for the development of drug formulations.

[0153] In summary, the brigatinib crystal form 1 provided by this invention has high solubility, good flowability, high purity and high stability. It also has the advantages of simple preparation process, good processability, excellent dissolution performance and high bioavailability, making it suitable for industrial production and formulation processing, and has good application prospects.

Claims

1. A crystal form 1 of brigatinib, the chemical formula of which is shown in formula (I): Formula (I); Its features are, The X-ray powder diffraction pattern of crystal form 1 shows characteristic peaks at 2theta values ​​of 4.5±0.2°, 8.5±0.2°, 11.4±0.2°, 15.2±0.2°, 18.4±0.2°, and 24.6±0.2°.

2. The crystal form 1 according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form 1 also shows a characteristic peak at at least one of the following 2theta values: 9.9±0.2°, 16.8±0.2°, 17.4±0.2°, 19.6±0.2°, and 22.7±0.2°. And / or, in the X-ray powder diffraction pattern of the crystal form 1, there is a characteristic peak at at least one of the following 2theta values: 13.4±0.2°, 14.9±0.2°, 18.8±0.2°, 23.1±0.2°, and 28.1±0.2°.

3. The crystal form 1 according to claim 1, characterized in that, The crystal form 1 has an X-ray powder diffraction pattern that is substantially as shown in Figure 2.

4. The crystal form 1 according to claim 1, characterized in that, Crystal form 1 is a hydrate.

5. The crystal form 1 according to claim 1, characterized in that, In the differential scanning calorimetry (DSC) of crystal form 1, there are endothermic peaks at 85.31±5℃, 115.74±5℃, and 216.08±5℃, and an exothermic peak at 152.21±5℃. And / or, in the infrared detection pattern of crystal form 1, at a frequency of 3400~3500 cm⁻¹ -1 2900~3000cm -1 2750~2850cm -1 1450~1550cm -1 1280~1350cm -1 1200~1250cm -1 1160~1200cm -1 1142~1155cm -1 1120~1140cm -1 765~800cm -1 740~760cm -1 At least one of them has a characteristic peak; And / or, the crystal form 1 experiences a 3-6% mass loss when heated from 30°C to 104°C; And / or, the crystal form 1 experiences a 3-6% mass loss when heated from 104°C to 170°C; And / or, the crystal form 1 experiences a mass loss of 6-12% when heated from 30°C to 170°C.

6. A method for preparing crystal form 1 as described in any one of claims 1 to 5, characterized in that, The process includes the following steps: dissolving brigatinib in a mixed solvent containing a first solvent and a second solvent, and crystallizing to obtain the crystal form 1; the first solvent includes methanol; the second solvent includes a haloalkane solvent, an aromatic hydrocarbon solvent, or a combination thereof; the volume ratio of the first solvent to the second solvent is 1:(0.01~5).

7. The preparation method according to claim 6, characterized in that, The haloalkane solvent is selected from C1~C5 haloalkane solvents; And / or, the aromatic hydrocarbon solvent is selected from C6 to C20 aromatic hydrocarbon solvents.

8. The preparation method according to claim 6, characterized in that, The crystallization temperature is -30~30℃; And / or, the crystallization is also carried out under antisolvent conditions; the antisolvent includes ether solvents, ester solvents, or combinations thereof.

9. A pharmaceutical composition, characterized in that, Includes crystal form 1 as described in any one of claims 1 to 5.

10. The use of crystal form 1 as described in any one of claims 1 to 5 in the preparation of a medicament for treating non-small cell lung cancer.

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