Crystal form of RP-6306, and preparation method therefor and use thereof

Abstract

A crystal form of Lunresertib (also referred to as RP-6306), and a preparation method therefor and the use thereof. The crystal form has at least one of the following excellent characteristics: good stability, high purity, good solubility, good dissolution, low hygroscopicity, good fluidity, good processibility, for example, good compressibility, more stable pressed tablets, good crystal morphology and good pressure resistance, and can be stably stored and prevent the drug from undergoing crystal transformation during the development process and storage, and the preparation method is simple and reliable. Therefore, the crystal form has a high development value.

Description

Crystal form of RP-6306, preparation method and use thereof

[0001] Citation of Related Applications

[0002] This application claims all rights and interests in the invention patent application with application number 202310814284.7 filed with the State Intellectual Property Office of the People's Republic of China on July 4, 2023, the invention patent application with application number 202311045738.5 filed with the State Intellectual Property Office of the People's Republic of China on August 18, 2023, and the invention patent application with application number 202311413800.1 filed with the State Intellectual Property Office of the People's Republic of China on October 27, 2023, and incorporates their entire contents into this application by reference. Technical Field

[0003] The present disclosure relates to the field of medicinal chemistry. Specifically, the present disclosure relates to a crystalline form of RP-6306, a preparation method thereof, and uses thereof. Background Art

[0004] Lunresertib (also known as RP-6306) is a highly potent and selective protein kinase PKMYT1 (membrane-associated tyrosine / threonine kinase 1) inhibitor developed by Repare Therapeutics. The drug preferentially and selectively kills tumor cells that overexpress CCNE1 and has been shown in preclinical xenograft / patient-derived xenograft (PDX) models to effectively inhibit the growth of a wide range of CCNE1-amplified tumors, both as a single agent and in combination with other therapies. It is currently used clinically to treat breast cancer and advanced cancers. The chemical name of RP-6306 is: (S)-2-amino-1-(3-hydroxy-2,6-dimethyl-phenyl)-5,6-dimethyl-pyrrolo[2,3-b]pyridine-3-carboxamide, and its structure is shown in the following formula (I):

[0005] WO2021195781A1 discloses a solid form of the compound of formula (I) obtained by SFC separation of a racemate. However, no reports on the crystalline form of the compound have been published. Therefore, it is necessary to screen the compound of formula (I) for polymorphs and select crystalline forms with superior properties for the development of formulation products of the compound of formula (I).

[0006] Summary of the Invention

[0007] During their research, the inventors of the present disclosure unexpectedly discovered four crystalline forms of RP-6306. The crystalline forms of RP-6306 provided herein exhibit at least one of the following excellent properties: good stability, high purity, good solubility, good dissolution, low hygroscopicity, good flowability, good processability (e.g., good compressibility and more stable tablets after compression), good crystal morphology, good compression resistance, stable storage, and the ability to avoid crystal transformation during drug development and storage. The preparation method is simple and reliable, and has great development value.

[0008] In particular, the crystalline form FB-1 provided by the present disclosure has at least one of the following excellent properties, such as improved physical stability in water-based formulations or water-based environments, no crystallization in high humidity environments, and no crystallization at high temperatures, such as 50-100°C or higher.

[0009] In particular, the crystalline form FB-4 provided by the present disclosure has at least one of the following excellent properties, such as excellent stability under long-term and accelerated conditions, extremely low hygroscopicity under 0% RH-60% RH and 0% RH-80% RH conditions, excellent plasticity (compressibility) and adhesion under 2 MPa pressure, and excellent mechanical stability under grinding conditions.

[0010] One aspect of the present disclosure is to provide a crystalline form FB-1 (hereinafter referred to as crystalline form FB-1) of a compound represented by formula (I):

[0011] Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-1 expressed in 2θ angles has characteristic peaks at at least one, two, or three of 8.4°±0.2°, 10.3°±0.2°, and 13.2°±0.2°.

[0012] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-1 has characteristic peaks at 8.4°±0.2°, 10.3°±0.2° and 13.2°±0.2°.

[0013] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-1 further has characteristic peaks at at least one of 11.9°±0.2°, 16.8°±0.2°, 19.6°±0.2° and 26.5°±0.2°2θ.

[0014] In the preferred technical solution of the present invention, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-1 further has characteristic peaks at at least one of 14.4°±0.2°, 17.8°±0.2°, 20.5°±0.2°, 22.1°±0.2° and 24.4°±0.2°2θ.

[0015] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-1 has characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine, or ten, or eleven, or twelve of 8.4°±0.2°, 10.3°±0.2°, 13.2°±0.2°, 11.9°±0.2°, 16.8°±0.2°, 19.6°±0.2°, 26.5°±0.2°2θ, 14.4°±0.2°, 17.8°±0.2°, 20.5°±0.2°, 22.1°±0.2°, and 24.4°±0.2°2θ.

[0016] Without limitation, the X-ray powder diffraction pattern of the crystalline form FB-1 is at 8.4°±0.2°, 10.3°±0.2°, 11.9°±0.2°, 13.2°±0.2°, 14.4°±0.2°, 16.8°±0.2°, 17.8°±0.2°, 19.6°±0.2°, 20.5°±0.2°, 21.3°±0.2°, 22.1°±0.2°, 24.4°±0.2°, 25.0°±0.2°, 25.8°±0.2°, 26.5°±0.2°, 27.2°±0.2°, 27.8°±0.2°, 28.5°±0.2°, 29.1°±0.2°, There are characteristic peaks at 2θ of 2θ: 29.7°±0.2°, 30.3°±0.2°, 30.9°±0.2°, 32.0°±0.2°, 32.6°±0.2°, 33.7°±0.2°, 34.3°±0.2°, 34.8°±0.2°, 35.3°±0.2°, 35.8°±0.2°, 36.8°±0.2°, 37.8°±0.2°, 38.3°±0.2°, 39.2°±0.2° and 39.7°±0.2°.

[0017] Without limitation, in a specific embodiment, the crystalline form FB-1 has an X-ray powder diffraction pattern substantially as shown in FIG1 .

[0018] In the preferred technical solution of the present disclosure, the crystalline form FB-1 has a purity greater than 90%; preferably, it has a purity greater than 95%; and more preferably, it has a purity greater than 99%.

[0019] In the preferred technical solution of the present disclosure, the Fourier transform infrared spectrum of the crystal form FB-1 is at 3473.18 cm -1 ±5cm -1 、3373.57cm -1 ±5cm -1 、2917.70cm -1 ±5cm-1 、1627.39cm -1 ±5cm -1 、1609.28cm -1 ±5cm -1 and 1514.68cm -1 ±5cm -1 At least one of them has a characteristic peak.

[0020] In the preferred technical solution of the present disclosure, the Fourier transform infrared spectrum of the crystal form FB-1 is at 1392.43 cm -1 ±5cm -1 、1270.46cm -1 ±5cm -1 、888.86cm -1 ±5cm -1 、823.73cm -1 ±5cm -1 、722.16cm -1 ±5cm -1 and 647.52cm -1 ±5cm -1 At least one of them has a characteristic peak.

[0021] Without limitation, in a specific embodiment, the crystalline form FB-1 has a Fourier transform infrared spectrum substantially as shown in FIG. 2 .

[0022] In the preferred technical solution of the present disclosure, the crystal form FB-1 is a combination of any two of the aforementioned embodiments of the X-ray powder diffraction pattern and any two of the aforementioned embodiments of the Fourier transform infrared spectrum, provided that they are not contradictory to each other.

[0023] Without limitation, the crystalline form FB-1 is an anhydrate or a hydrate.

[0024] In the preferred technical solution of the present disclosure, the Raman spectrum of the crystal form FB-1 is at 2923.17 cm -1 ±5cm -1 、1602.91cm - 1 ±5cm -1 、1511.47cm -1 ±5cm -1 、1389.18cm -1 ±5cm -1 、1261.62cm -1 ±5cm -1 、469.51cm -1 ±5cm -1 、223.56cm -1 ±5cm -1At least one of them has a characteristic peak.

[0025] In the preferred technical solution of the present disclosure, the Raman spectrum of the crystal form FB-1 is still at 1356.21 cm -1 ±5cm -1 、1261.62cm - 1 ±5cm -1 、749.88cm -1 ±5cm -1 、722.82cm -1 ±5cm -1 、697.94cm -1 ±5cm -1 、607.15cm -1 ±5cm -1 、347.60cm - 1 ±5cm -1 At least one of them has a characteristic peak.

[0026] Another aspect of the present disclosure provides a method for preparing the crystalline form FB-1, wherein the method is selected from any one of the following methods:

[0027] 1) dissolving the compound represented by formula (I) in an alcohol, ketone or nitrile solvent, filtering, and volatilizing to obtain crystal form FB-1;

[0028] 2) placing the compound represented by formula (I) in water or an aqueous mixed solvent, stirring, separating, and drying to obtain the crystalline form FB-1; the aqueous mixed solvent is selected from water and any solvent or combination of nitriles, alcohols, and ketones.

[0029] 3) dissolving the compound represented by formula (I) in an alcohol, ketone or tetrahydrofuran solvent, mixing the supernatant with an anti-solvent, precipitating a solid, separating, and drying to obtain Form FB-1; the anti-solvent is selected from water, alkanes, and ethers.

[0030] In some specific embodiments, the antisolvent is water.

[0031] In the technical solutions 1) to 3) above, preferably, the alcohols are selected from C1-C8 alcohols, the ketones are selected from C3-C6 ketones, the nitriles are selected from C2-C4 nitriles, the ethers are selected from C2-C7 ethers, and the alkanes are selected from dichloromethane and n-heptane.

[0032] Preferably, the alcohols are selected from methanol and ethanol, the ketones are selected from acetone, the nitriles are selected from acetonitrile, and the ethers are selected from isopropyl ether.

[0033] Preferably, the volume percentage of water in the mixed solvent is 15%-100%;

[0034] Preferably, the volatilization temperature is 20°C-50°C; more preferably room temperature. Preferably, the stirring time is at least 1 day;

[0035] Preferably, the stirring temperature is 4°C-50°C; more preferably room temperature.

[0036] The crystal form FB-1 disclosed in the present invention has the following beneficial effects:

[0037] 1) Good stability. The crystalline form FB-1 provided in the present disclosure is stable for at least 30 days under long-term (25°C / 60% RH / unopen) and accelerated (40°C / 75% RH / unopen) conditions, with the crystal form and purity remaining essentially unchanged. This demonstrates that the crystalline form FB-1 maintains good physicochemical stability under both long-term and accelerated conditions, facilitating drug storage.

[0038] At the same time, the crystal form FB-1 remains unchanged in form and chemical purity after being placed under high humidity (25°C / 92.5% RH / open) conditions for 10 days, and the crystal form FB-1 can still maintain the same crystal form when heated to 150°C, indicating that the crystal form FB-1 has better stability under harsh conditions, which is beneficial to avoid the impact on drug quality due to crystal transformation or purity loss during drug storage.

[0039] At the same time, the crystalline form FB-1 can maintain its crystal form unchanged in pure water or an aqueous environment and has good stability in water. This makes the crystalline form FB-1 particularly suitable for the preparation of aqueous preparations, such as wet granulation, and also makes it easier for preparations prepared using the crystalline form FB-1 to maintain crystal stability in an environment with high humidity.

[0040] At the same time, the crystal form FB-1 remains unchanged after grinding and has good mechanical stability. Grinding and crushing of raw materials is often required during the preparation processing. Good mechanical stability can reduce the risk of reduced crystallinity and crystal transformation of raw materials during the preparation processing.

[0041] Form FB-1 is the most thermodynamically stable form in water or aqueous solvents at room temperature. A solid mixture of Forms FB-1, FB-2, FB-3, and FB-4 converted to Form FB-1 when stirred in water or water / acetonitrile at room temperature.

[0042] 2) Good solubility. The solubility of the crystalline form FB-1 provided in the present disclosure can meet the requirements for pharmaceutical use.

[0043] 3) Uniform particle size distribution. The crystalline form FB-1 provided in the present disclosure has a uniform particle size distribution. The uniform particle size helps to ensure content uniformity and reduce the variability of in vitro dissolution.

[0044] 4) Good compressibility. The crystalline form FB-1 provided in the present disclosure has good compressibility. This helps to improve problems such as cracking during the tableting process and improve production efficiency.

[0045] 5) High purity. The crystal form FB-1 provided herein has a purity exceeding 99.9%, making it suitable for industrial production. Crystal form FB-1 has a strong impurity removal capability, and the disclosed preparation method and crystallization process can yield a high-purity API, with minimal residual solvent issues, making it suitable for pharmaceutical use.

[0046] 6) Good crystallinity: The crystal form FB-1 provided in the present disclosure has good crystallinity and is suitable for pharmaceutical use.

[0047] 7) The preparation method is simple, highly reproducible and has great industrialization prospects.

[0048] Another aspect of the present disclosure is to provide a crystalline form FB-2 (hereinafter referred to as crystalline form FB-2) of a compound having a structural formula as shown in formula (I). Using Cu-Kα radiation, the crystalline form FB-2 has an X-ray powder diffraction pattern expressed in 2θ angles having characteristic peaks at at least one, two, or three of 9.9°±0.2°, 11.8°±0.2°, and 14.2°±0.2°.

[0049] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-2 expressed in 2θ angles has characteristic peaks at 9.9°±0.2°, 11.8°±0.2° and 14.2°±0.2°.

[0050] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-2 further has characteristic peaks at at least one of 14.9°±0.2°, 16.2°±0.2° and 17.2°±0.2°2θ.

[0051] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-2 further has characteristic peaks at at least one of 12.8°±0.2°, 19.6°±0.2° and 26.1°±0.2°2θ.

[0052] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-2 has characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine of 9.9°±0.2°, 11.8°±0.2°, 14.2°±0.2°, 14.9°±0.2°, 16.2°±0.2°, 17.2°±0.2°, 12.8°±0.2°, 19.6°±0.2°, and 26.1°±0.2°2θ.

[0053] Furthermore, the X-ray powder diffraction pattern of the crystalline form FB-2 has characteristic peaks at 11.8°±0.2° and 14.2°±0.2°2θ.

[0054] Furthermore, the X-ray powder diffraction pattern of the crystalline form FB-2 has characteristic peaks at 9.9°±0.2° and 11.8°±0.2°2θ.

[0055] Furthermore, the X-ray powder diffraction pattern of the crystalline form FB-2 has characteristic peaks at 10.1±0.2° and 11.8°±0.2°2θ.

[0056] Without limitation, the X-ray powder diffraction pattern of the crystalline form FB-2 is at 5.0°±0.2°, 9.9°±0.2°, 10.1°±0.2°, 11.8°±0.2°, 12.8°±0.2°, 13.0°±0.2°, 13.7°±0.2°, 14.2°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 15.1°±0.2°, 16.2°±0.2°, 16.8°±0.2°, 17.2°±0.2°, 17.9°±0.2°, 18.7°±0.2°, 19.6°±0.2°, 19. There are characteristic peaks at 2θ of 2θ: 2.8°±0.2°, 20.2°±0.2°, 20.5°±0.2°, 20.9°±0.2°, 21.8°±0.2°, 22.4°±0.2°, 22.6°±0.2°, 24.1°±0.2°, 24.4°±0.2°, 25.2°±0.2°, 26.1°±0.2°, 26.4°±0.2°, 27.1°±0.2°, 27.3°±0.2°, 27.7°±0.2°, 28.0°±0.2°, 28.6°±0.2°, 29.3°±0.2° and 29.6°±0.2°.

[0057] Without limitation, the crystalline form FB-2 has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .

[0058] In the preferred technical solution of the present disclosure, the crystalline form FB-2 has a purity greater than 90%; preferably, it has a purity greater than 95%; and more preferably, it has a purity greater than 99%.

[0059] In the preferred technical solution of the present disclosure, the Fourier transform infrared spectrum of the crystal form FB-2 is at 3470.25 cm -1 ±5cm -1 、3315.63cm -1 ±5cm -1 、3149.77cm -1 ±5cm -1 、1639.56cm -1 ±5cm -1 、1602.76cm -1 ±5cm -1 and 1504.03cm -1 ±5cm -1 At least one of the peaks has a characteristic peak.

[0060] In the preferred technical solution of the present disclosure, the Fourier transform infrared spectrum of the crystal form FB-2 is at 1385.19 cm -1 ±5cm -1 、1268.61cm -1 ±5cm -1 、1093.46cm -1 ±5cm -1 、813.93cm -1 ±5cm -1 、722.21cm -1 ±5cm -1 and 655.76cm -1 ±5cm -1 At least one of them has a characteristic peak.

[0061] Without limitation, the crystalline form FB-2 has a Fourier transform infrared spectrum substantially as shown in FIG8 .

[0062] Without limitation, the crystalline form FB-2 has a DSC spectrum substantially as shown in FIG9 .

[0063] Without limitation, the crystalline form FB-2 has a TGA pattern substantially as shown in FIG10 .

[0064] Without limitation, the crystalline form FB-2 is a solvate.

[0065] In some embodiments, the crystalline Form FB-2 is a hemiacetonitrile solvate.

[0066] In some embodiments, the single crystal data of the crystalline form FB-2 as a hemiacetonitrile solvate are shown in the following table:

[0067] In some embodiments, the single crystal simulated XRPD pattern of the hemiacetonitrile solvate form FB-2 is shown in FIG14 .

[0068] Another aspect of the present disclosure provides a method for preparing the crystalline form FB-2, which comprises dissolving the compound represented by formula (I) in acetonitrile or a mixed solvent of acetonitrile and other solvents, taking the supernatant, cooling and stirring, separating, and drying to obtain the crystalline form FB-2.

[0069] Preferably, the other solvent may be a solvent miscible with acetonitrile.

[0070] Preferably, the dissolving temperature is 4-90°C; more preferably 80°C.

[0071] Preferably, the stirring temperature is 4-90°C; more preferably 8°C.

[0072] The crystal form FB-2 disclosed herein has the following beneficial effects:

[0073] 1) Good stability. FB-2 is stable for at least 30 days under long-term conditions (25°C / 60% RH / open air), with its crystal form and purity remaining essentially unchanged. This indicates that crystal form FB-2 maintains good physicochemical stability under long-term conditions, which is beneficial for drug storage.

[0074] At the same time, the crystal form FB-2 remains unchanged after grinding and has good mechanical stability. Grinding and crushing of raw materials is often required during the preparation processing. Good mechanical stability can reduce the risk of reduced crystallinity and crystal transformation of raw materials during the preparation processing.

[0075] At the same time, the acetonitrile removal temperature of the crystalline form FB-2 provided in the present disclosure is above 80°C, which means that FB-2 can maintain a stable crystalline form under conventional industrial thermal conditions and has good thermal stability.

[0076] 2) Good solubility. The solubility of the crystalline form FB-2 provided in the present disclosure can meet the requirements for pharmaceutical use.

[0077] 3) Uniform particle size distribution. The crystalline form FB-2 provided in the present disclosure has a uniform particle size distribution. The uniform particle size helps to ensure content uniformity and reduce the variability of in vitro dissolution.

[0078] 4) Good compressibility. The crystalline form FB-2 provided in the present disclosure has good compressibility. This helps to improve problems such as cracking during tableting and improve production efficiency.

[0079] 5) High purity. The purity of FB-2 is as high as 99.5%, which is conducive to industrial production.

[0080] 6) Good crystallinity.

[0081] 7) The preparation method is simple and highly reproducible. It is very suitable as a starting crystalline material for preparing other anhydrates, hydrates and amorphous forms.

[0082] Another aspect of the present disclosure is to provide a crystalline form FB-3 (hereinafter referred to as crystalline form FB-3) of a compound having a structural formula as shown in formula (I). Using Cu-Kα radiation, the crystalline form FB-3 has an X-ray powder diffraction pattern expressed in 2θ angles having characteristic peaks at at least one, two, or three of 11.0°±0.2°, 13.4°±0.2°, and 18.9°±0.2°.

[0083] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-3 expressed in 2θ angles has characteristic peaks at 11.0°±0.2°, 13.4°±0.2° and 18.9°±0.2°.

[0084] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-3 further has characteristic peaks at at least one of 9.1°±0.2°, 15.2°±0.2° and 22.3°±0.2°2θ.

[0085] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-3 further has characteristic peaks at at least one of 9.8°±0.2°, 15.0°±0.2° and 26.5°±0.2°2θ.

[0086] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-3 has characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine of 11.0°±0.2°, 13.4°±0.2°, 18.9°±0.2°, 9.1°±0.2°, 15.2°±0.2°, 22.3°±0.2°, 9.8°±0.2°, 15.0°±0.2°, and 26.5°±0.2°2θ.

[0087] Furthermore, the X-ray powder diffraction pattern of the crystalline form FB-3 has characteristic peaks at 11.0°±0.2° and 18.9°±0.2°2θ.

[0088] Furthermore, the X-ray powder diffraction pattern of the crystalline form FB-3 has characteristic peaks at 13.4°±0.2° and 18.9°±0.2°.

[0089] Furthermore, the X-ray powder diffraction pattern of the crystalline form FB-3 has characteristic peaks at 11.0°±0.2° and 13.4°±0.2°.

[0090] Without limitation, the X-ray powder diffraction pattern of the crystalline form FB-3 is at 9.1°±0.2°, 9.8°±0.2°, 11.0°±0.2°, 12.4°±0.2°, 12.9°±0.2°, 13.1°±0.2°, 13.4°±0.2°, 15.0°±0.2°, 15.2°±0.2°, 15.4°±0.2°, 16.1°±0.2°, 16. 6°±0.2°, 17.9°±0.2°, 18.3°±0.2°, 18.9°±0.2°, 20.1°±0.2°, 21.0°±0.2°, 21.3°±0.2°, 21.5°±0.2°, 22.0°±0.2°, 22.3°±0.2°, 22.8°±0.2°, 23.2°±0.2°, 23.7°±0.2°, 24.4°±0. 2°, 24.9°±0.2°, 25.3°±0.2°, 25.6°±0.2°, 25.8°±0.2°, 26.2°±0.2°, 26.5°±0.2°, 27.0°±0.2°, 28.1°±0.2°, 28.3°±0.2°, 28.9°±0.2°, 30.2°±0.2°, 30.4°±0.2°, 30.7°±0.2°, 31 There are characteristic peaks at 39.7°±0.2°, 39.7°±0.2°, 37.1°±0.2°, 37.9°±0.2°, and 39.7°±0.2° 2θ.

[0091] Without limitation, the crystalline form FB-3 has an X-ray powder diffraction pattern substantially as shown in FIG. 15 .

[0092] In the preferred technical solution of the present disclosure, the crystalline form FB-3 has a purity greater than 90%; preferably, it has a purity greater than 95%; more preferably, it has a purity greater than 99%; and more preferably, it has a purity greater than 99.5%.

[0093] Without limitation, the crystalline form FB-3 has a DSC spectrum substantially as shown in FIG16 .

[0094] Without limitation, the crystalline form FB-3 is an anhydrate.

[0095] Another aspect of the present disclosure provides a method for preparing the crystalline form FB-3, comprising heating a solvate of the compound represented by formula (I) to a desolvation temperature to obtain the crystalline form FB-3.

[0096] Preferably, the solvate of the compound represented by formula (I) is an acetonitrile solvate; more preferably, it is the crystalline form FB-2 disclosed herein.

[0097] Preferably, the heating to the desolvation temperature is 80-220°C; more preferably 160-220°C.

[0098] The crystal form FB-3 disclosed in the present disclosure has the following beneficial effects:

[0099] 1) Good stability. The crystalline form FB-3 provided by the present disclosure is stable for at least 30 days under long-term (25°C / 60% RH / unopen) and accelerated (40°C / 75% RH / unopen) conditions, with the crystal form and purity remaining essentially unchanged. This indicates that the crystalline form FB-1 maintains good physicochemical stability under both long-term and accelerated conditions, which is beneficial for drug storage.

[0100] At the same time, the melting point of the crystal form FB-3 is around 278°C, and it has good high-temperature stability.

[0101] At the same time, the crystal form FB-3 remains unchanged after grinding and has good mechanical stability. Grinding and crushing of raw materials is often required during the preparation processing. Good mechanical stability can reduce the risk of reduced crystallinity and crystal transformation of raw materials during the preparation processing.

[0102] 2) Good solubility: The equilibrium solubility of the crystalline form FB-3 provided in the present disclosure in water can reach 130.22 μg / mL after 1 hour, which meets the requirements for pharmaceutical use.

[0103] 3) Good compressibility. The crystalline form FB-3 provided in the present disclosure has good compressibility. This helps to improve problems such as cracking during tableting and improve production efficiency.

[0104] 4) High purity. The purity of FB-3 can reach over 99.9%, which is conducive to industrial production and suitable for medicinal use.

[0105] 5) Good crystallinity. FB-3 has good crystallinity and is suitable for medicinal use.

[0106] 6) Less solvent residue.

[0107] 7) The preparation method is simple, highly reproducible, and has industrial potential.

[0108] Another aspect of the present disclosure is to provide a crystalline form FB-4 of a compound having a structural formula as shown in formula (I): using Cu-Kα radiation, the FB-4 has an X-ray powder diffraction pattern expressed in 2θ angles having characteristic peaks at at least one, two, or three of 5.1°±0.2°, 8.4°±0.2°, and 16.0°±0.2°.

[0109] In the preferred technical solution of the present disclosure, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-4 has characteristic peaks at 5.1°±0.2°, 8.4°±0.2° and 16.0°±0.2°2θ.

[0110] In the preferred technical solution of the present invention, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-4 further has characteristic peaks at at least one of 12.3°±0.2°, 14.8°±0.2° and 16.8°±0.2°2θ; preferably, the X-ray powder diffraction pattern of the crystalline form FB-4 has characteristic peaks at 12.3°±0.2°, 14.8°±0.2° and 16.8°±0.2°2θ.

[0111] In the preferred technical solution of the present invention, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-4 further has characteristic peaks at at least one of 10.0°±0.2°, 18.9°±0.2° and 27.2°±0.2°2θ; preferably, the X-ray powder diffraction pattern of the crystalline form FB-4 has characteristic peaks at 10.0°±0.2°, 18.9°±0.2° and 27.2°±0.2°2θ.

[0112] On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-4 has characteristic peaks at any one, or two, or three, or four, or five, or six, or seven, or eight, or nine of 5.1°±0.2°, 8.4°±0.2°, 16.0°±0.2°, 12.3°±0.2°, 14.8°±0.2°, 16.8°±0.2°, 10.0°±0.2°, 18.9°±0.2°, and 27.2°±0.2°2θ.

[0113] Furthermore, the X-ray powder diffraction pattern of the crystalline form FB-4 has characteristic peaks at 5.0°±0.2° and 8.4°±0.2°2θ.

[0114] Furthermore, the X-ray powder diffraction pattern of the crystalline form FB-4 has characteristic peaks at 8.4°±0.2° and 16.0°±0.2°2θ.

[0115] Without limitation, the X-ray powder diffraction pattern of the crystalline form FB-4 is at 5.1°±0.2°, 8.4°±0.2°, 10.0°±0.2°, 11.0°±0.2°, 11.9°±0.2°, 12.3°±0.2°, 13.8°±0.2°, 14.8°±0.2°, 16.0°±0.2°, 16.8°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 20.3°±0.2°, 20.9°±0.2°, 21. There are characteristic peaks at .9°±0.2°, 24.2°±0.2°, 25.2°±0.2°, 25.7°±0.2°, 26.5°±0.2°, 27.2°±0.2°, 28.1°±0.2°, 28.2°±0.2°, 29.1°±0.2°, 29.8°±0.2°, 30.0°±0.2°, 30.4°±0.2°, 33.1°±0.2°, 33.6°±0.2°, 34.1°±0.2°, 35.8°±0.2° and 38.7°±0.2°2θ.

[0116] Without limitation, the Form FB-4 has an X-ray powder diffraction pattern of Form FB-4 substantially as shown in FIG17 .

[0117] In the preferred technical solution of the present disclosure, the Fourier transform infrared spectrum of the crystal form FB-4 is at 3163.49 cm -1 ±5cm -1 、1599.18cm -1 ±5cm -1 、1507.95cm -1 ±5cm -1 、1174.28cm -1 ±5cm -1 、975.44cm -1 ±5cm -1 and 661.52 cm -1 ±5cm -1 There is a band in at least one of the two.

[0118] Without limitation, the crystalline form FB-4 has a Fourier transform infrared spectrum substantially as shown in FIG. 18 .

[0119] Without limitation, the crystalline form FB-4 has a DSC spectrum substantially as shown in FIG19 .

[0120] Without limitation, the crystalline form FB-4 has a TGA pattern substantially as shown in FIG. 20 .

[0121] In the preferred technical solution of the present disclosure, the crystalline form FB-4 is a hydrate. In some embodiments, the crystalline form FB-4 is a sesquihydrate.

[0122] In the preferred technical solution of the present disclosure, the crystalline form FB-4 has a purity greater than 90%; preferably, it has a purity greater than 95%; and more preferably, it has a purity greater than 99%.

[0123] Another aspect of the present disclosure provides a method for preparing the crystalline form FB-4, which comprises dissolving the compound represented by formula (I) in solvent 1, taking the supernatant, adding solvent 2, precipitating the solid, separating, and drying to obtain the crystalline form FB-4.

[0124] Preferably, the solvent 1 is selected from tetrahydrofuran; and the solvent 2 is selected from alkane or ether solvents.

[0125] Preferably, the alkane solvent is selected from n-heptane and methylcyclohexane, and the ether solvent is selected from methyl tert-butyl ether.

[0126] Preferably, the dissolving temperature is 4-90°C; more preferably 85°C.

[0127] Preferably, the solvent 2 is added under stirring conditions.

[0128] Preferably, the stirring temperature is 4-90°C; more preferably room temperature.

[0129] The crystal form FB-4 disclosed in the present invention has the following beneficial effects:

[0130] 1) Good stability. The crystalline form FB-4 provided in the present disclosure is stable for at least 30 days under long-term (25°C / 60% RH / unopen) and accelerated (40°C / 75% RH / unopen) conditions, with the crystal form and purity remaining essentially unchanged. This demonstrates that the crystalline form FB-4 maintains good physicochemical stability under both long-term and accelerated conditions, facilitating drug storage.

[0131] At the same time, the crystal form FB-4 remains unchanged after grinding and has good mechanical stability. Grinding and crushing of raw materials is often required during the preparation processing. Good mechanical stability can reduce the risk of reduced crystallinity and crystal transformation of raw materials during the preparation processing.

[0132] At the same time, the crystalline form FB-4 is stable in water. In the absence of crystalline form FB-1 seed crystals, the crystalline form FB-4 does not re-crystallize in water for at least 24 hours.

[0133] 2) Good compressibility. The crystalline form FB-4 provided in the present disclosure has good compressibility. This helps to improve problems such as cracking during tableting and improve production efficiency.

[0134] 3) Good solubility. The solubility of the crystalline form FB-4 provided in the present disclosure can meet the requirements for pharmaceutical use.

[0135] 4) High purity. The purity of FB-4 is as high as 99.5%, which is conducive to industrial production.

[0136] 5) Good crystallinity.

[0137] 6) The preparation method is simple, highly reproducible, and has industrial potential.

[0138] Another aspect of the present disclosure is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more of the above-mentioned crystalline form FB-1, crystalline form FB-2, crystalline form FB-3 and crystalline form FB-4, and at least one pharmaceutically acceptable carrier.

[0139] The pharmaceutically acceptable carrier is selected according to the mode and route of administration.

[0140] Suitable carriers may be, without limitation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose.

[0141] Without limitation, the pharmaceutical compositions may also include lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl and propyl hydroxybenzoate; sweeteners; and flavoring agents.

[0142] Without limitation, the pharmaceutical composition may further comprise one or more pH adjusters or buffers, for example: an acid, such as any one of acetic acid, boric acid, citric acid, fumaric acid, maleic acid, tartaric acid, malic acid, lactic acid, phosphoric acid, hydrochloric acid, or a combination thereof; or a base, such as any one of sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tris(hydroxymethyl)aminomethane, or a combination thereof; or a buffer, such as citrate / dextrose, sodium bicarbonate, ammonium chloride, and the like; such buffers used as bases may have counterions other than sodium, such as potassium, magnesium, calcium, ammonium, and other counterions; and other amounts required to maintain the pH of the components within an acceptable range, comprising solutions or solids of such acids, bases, and buffers.

[0143] Without limitation, routes of administration of the pharmaceutical composition include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intracerebroventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration.

[0144] Another aspect of the present disclosure is to provide a preparation prepared from the above-mentioned pharmaceutical composition, wherein the preparation is in the form selected from oral preparations and parenteral preparations.

[0145] In the preferred technical solution of the present disclosure, the preparation form is tablets, capsules, powders, sustained-release preparations, immediate-release preparations, pills, suppositories, granules, fine granules / lozenges, sachets, cachets, tinctures, elixirs, suspensions, emulsions, creams, aerosols, gels, solutions and syrups.

[0146] In the preferred technical solution of the present disclosure, the preparation is in the form of an oral preparation.

[0147] Another aspect of the present disclosure is to provide the use of one or more of the above-mentioned crystalline form FB-1, crystalline form FB-2, crystalline form FB-3 and crystalline form FB-4, or their pharmaceutical compositions or preparations in the preparation of drugs for treating abnormal cell proliferation.

[0148] In common embodiments of the aspects described herein, the abnormal cell proliferation is cancer. In some such embodiments, the abnormal cell proliferation is a cancer that overexpresses CCNE1.

[0149] Preferably, the cancer is selected from breast cancer, uterine cancer, ovarian cancer, gastric cancer, esophageal cancer, lung cancer (eg, non-small cell lung cancer), endometrial cancer, hepatocellular carcinoma, colon cancer, neuroblastoma, and bladder cancer.

[0150] In certain embodiments, the cancer is breast cancer.

[0151] Another aspect of the present disclosure is to provide a method for treating abnormal cell proliferation, such as cancer, comprising administering to a patient a therapeutically effective amount of one or more of the crystalline forms FB-1, FB-2, FB-3 and FB-4 of the compound represented by the above formula (I) or their pharmaceutical compositions or preparations.

[0152] In some such embodiments, the cancer is a cancer that overexpresses CCNE1.

[0153] Preferably, the cancer is selected from breast cancer, uterine cancer, ovarian cancer, gastric cancer, esophageal cancer, lung cancer (eg, non-small cell lung cancer), endometrial cancer, hepatocellular carcinoma, colon cancer, neuroblastoma, and bladder cancer.

[0154] In certain embodiments, the cancer is breast cancer.

[0155] Another aspect of the present disclosure is to provide one or more of the above-mentioned crystalline form FB-1, crystalline form FB-2, crystalline form FB-3 and crystalline form FB-4, or their pharmaceutical compositions or preparations in combination with other drugs.

[0156] Preferably, the other drugs are selected from one or more of gemcitabine, FOLFIRI and Trastuzumab.

[0157] As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated.

[0158] The term "about" means having a value that falls within an acceptable standard of error of the mean when considered by one skilled in the art.

[0159] The term "channel hydrate" can be used to describe stoichiometric or non-stoichiometric hydrates with water-filled one-dimensional channels or two-dimensional planes in the crystal structure. The amount of water in the crystal lattice of a non-stoichiometric hydrate can vary with the water partial pressure in the surrounding atmosphere and temperature.

[0160] As used herein, the term "therapeutically effective amount" refers to an amount of a compound being administered that will alleviate to some extent one or more symptoms of the condition being treated. With respect to cancer treatment, a therapeutically effective amount refers to an amount that: (1) reduces tumor size, (2) inhibits (i.e., slows to some extent, preferably stops) tumor metastasis, (3) inhibits (i.e., slows to some extent, preferably stops) tumor growth or tumor invasion, and / or (4) alleviates to some extent (or preferably eliminates) one or more signs or symptoms associated with cancer.

[0161] As used herein, unless otherwise indicated, the term "treat" refers to reversing, alleviating the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treatment," unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The term "treatment" also includes adjuvant and neoadjuvant treatment of a subject.

[0162] Unless otherwise indicated, "abnormal cell growth" as used herein refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth can be benign (non-cancerous) or malignant (cancerous). In common embodiments of the methods provided herein, the abnormal cell growth is cancer.

[0163] Unless otherwise specified, the "room temperature" described in this disclosure refers to a temperature of 10 to 30°C.

[0164] The "separation" can be carried out by conventional methods in the art, such as centrifugation or filtration. Among them, the reduced pressure filtration is generally carried out at room temperature with a pressure less than atmospheric pressure.

[0165] The drying process can be accomplished using conventional techniques in the art, such as room temperature drying, forced air drying, or reduced pressure drying, and can be performed under reduced pressure or without reduced pressure. The drying apparatus and method are not limited and can include a fume hood, forced air oven, spray dryer, fluidized bed dryer, or vacuum oven; and can be performed under reduced pressure or without reduced pressure.

[0166] The "relative intensity (I%)" is expressed as a specific value in a specific XRPD pattern. Due to the anisotropic properties of crystals and the principles of X-ray powder diffraction, the relative intensity values ​​of diffraction peaks within the same crystal form may fluctuate due to the preferred orientation of the sample. It is common knowledge among those skilled in the art that such fluctuations do not affect the determination of the same crystal form.

[0167] Unless otherwise specified, the ratios involved in the present disclosure are mass-to-volume ratios between liquids and solids, and volume ratios between liquids. BRIEF DESCRIPTION OF THE DRAWINGS

[0168] FIG1 is an XRPD pattern of Form FB-1 in Example 1-1;

[0169] FIG2 is a Fourier transform infrared spectrum of the crystal form FB-1 in Example 1-1;

[0170] FIG3 is a DSC spectrum of the crystal form FB-1 in Example 1-1;

[0171] FIG4 is a comparison of hot stage XRPD images of Form FB-1 in Example 1-1 heated to 150° C.;

[0172] FIG5 is a TGA spectrum of the crystal form FB-1 in Example 1-1;

[0173] FIG6 is an XRPD pattern of Form FB-1 in Example 1-3;

[0174] FIG7 is an XRPD pattern of Form FB-2 in Example 2-1;

[0175] FIG8 is a Fourier transform infrared spectrum of the crystal form FB-2 in Example 2-1;

[0176] FIG9 is a DSC spectrum of Form FB-2 in Example 2-1;

[0177] Figure 10 is a TGA spectrum of Form FB-2 in Example 2-1;

[0178] Figure 11 is a DVS spectrum of Form FB-2 in Example 2-1;

[0179] FIG12 is an XRPD stack of Form FB-2 in Example 2-1 before and after DVS detection;

[0180] FIG13 is a structural diagram of the single crystal of Form FB-2 in Example 2-2;

[0181] Figure 14 is a simulated XRPD pattern of a single crystal of Form FB-2 in Example 2-2;

[0182] Figure 15 is the XRPD pattern of Form FB-3 in Example 3-1;

[0183] FIG16 is a DSC spectrum of Form FB-3 in Example 3-1;

[0184] FIG17 is an XRPD pattern of Form FB-4 in Example 4-1;

[0185] FIG18 is a Fourier transform infrared spectrum of the crystal form FB-4 in Example 4-1;

[0186] FIG19 is a DSC spectrum of Form FB-4 in Example 4-1;

[0187] Figure 20 is a TGA spectrum of Form FB-4 in Example 4-1;

[0188] FIG21 is an XRPD overlay of Form FB-1 in Example 5 before and after storage under long-term (25° C. / 60% RH / unopen) and accelerated (40° C. / 75% RH / unopen) conditions;

[0189] FIG22 is an XRPD stack of Form FB-1 in Example 5 before and after storage under high humidity (25° C. / 92.5% RH / open) conditions;

[0190] FIG23 is an XRPD stack of Form FB-1 before and after grinding in Example 6;

[0191] FIG24 is an XRPD stack of Form FB-1 before and after tableting in Example 7;

[0192] Figure 25 is a PSD spectrum of Form FB-1 in Example 8;

[0193] FIG26 is an XRPD stack of the sampled crystal forms of Form FB-1 during the equilibrium solubility test in Example 9;

[0194] FIG27 is an XRPD stack of Form FB-2 in Example 10 before and after long-term storage under conditions of 25° C. / 60% RH / open air;

[0195] FIG28 is an XRPD stack of Form FB-2 before and after grinding in Example 11;

[0196] FIG29 is an XRPD stack of Form FB-2 before and after tableting in Example 12;

[0197] Figure 30 is a PSD spectrum of Form FB-2 in Example 13;

[0198] FIG31 is an XRPD overlay of Form FB-3 in Example 15 before and after storage under long-term (25° C. / 60% RH / unopen) and accelerated (40° C. / 75% RH / unopen) conditions;

[0199] FIG32 is an XRPD stack of Form FB-3 before and after tableting in Example 16;

[0200] FIG33 is an XRPD stack of Form FB-3 before and after grinding in Example 17;

[0201] FIG34 is an XRPD stack of Form FB-4 in Example 19 before and after long-term storage under conditions of 25° C. / 60% RH / open air;

[0202] FIG35 is an XRPD stack of Form FB-4 before and after grinding in Example 20;

[0203] FIG36 is an XRPD stack of Form FB-4 before and after tableting in Example 21;

[0204] FIG37 is an XRPD stack of the sampled crystal forms of Form FB-4 during the equilibrium solubility test in Example 22;

[0205] FIG38 is an XRPD pattern of the solid mixed crystal forms (Forms FB-1 / FB-2 / FB-3 / FB-4) in Example 23 suspended in water at room temperature for 5 days;

[0206] FIG39 is an XRPD pattern of the solid mixed crystalline forms (Forms FB-1 / FB-2 / FB-3 / FB-4) in Example 23 suspended in acetonitrile / water (1:1) (v:v) at room temperature for 5 days;

[0207] Figure 40 is the XRPD spectrum of the solid mixed crystal form (form FB-1 / FB-2 / FB-3 / FB-4) in Example 23 suspended in acetonitrile at room temperature for 5 days. DETAILED DESCRIPTION

[0208] The following examples will help to further understand the present disclosure, but are not intended to limit the contents of the present disclosure.

[0209] Testing instruments and methods:

[0210] HPLC determination method: Chromatograph model: Agilent, chromatographic column: C18 3μm 4.6*50mm, column temperature: 30°C, flow rate: 1.0mL / min, detection wavelength: 210nm, run time: 13min, mobile phase A: 0.1% H3PO4 solution; mobile phase B: acetonitrile, running gradient is as follows:

[0211] In the present disclosure, the compound represented by the starting material formula (I) can be obtained commercially or prepared by existing technologies, such as the method mentioned in WO2021195781A1.

[0212] Example 1-1: Preparation of Crystalline Form FB-1

[0213] About 30 mg of the compound represented by formula (I) was added to 3.0 mL of ethanol, filtered, and evaporated at 40° C. to obtain Form FB-1. Its XRPD data are shown in the following table:

[0214] Its XRPD pattern is shown in Figure 1.

[0215] Its hot stage XRPD showed that the crystal form of FB-1 remained unchanged when heated to 150°C. Its hot stage XRPD pattern is shown in Figure 4.

[0216] The DSC spectrum thereof shows an endothermic peak at about 272° C. The DSC spectrum thereof is shown in FIG3 .

[0217] Its Fourier transform infrared spectrum is shown in Figure 2.

[0218] Its TGA spectrum shows a weight loss of about 5.25% before 100° C., and its TGA spectrum is shown in FIG5 .

[0219] The DVS water adsorption / desorption (DVS) behavior of Form FB-1 demonstrates that the structure gradually adsorbs and desorbs varying amounts of water in response to changes in relative humidity. This water profile is typical of channel (variable) hydrates. The desorption isotherm exhibits minimal hysteresis relative to the adsorption isotherm, another characteristic of channel hydrates.

[0220] For reference, stoichiometrically, the monohydrate corresponds to a mass change of 5.25%. In a specific embodiment, the measured TGA weight loss change of FB-1 substantially conforms to the theoretical stoichiometry of the monohydrate.

[0221] Example 1-2: Preparation of Crystalline Form FB-1

[0222] About 12 mg of the compound represented by formula (I) was taken, 3.0 mL of acetone was added, filtered, and evaporated at room temperature to obtain crystal form FB-1.

[0223] Example 1-3: Preparation of Crystalline Form FB-1

[0224] About 30 mg of the compound represented by formula (I) was added to 2.0 mL of a mixed solvent of water and acetonitrile (the volume ratio of water to acetonitrile was 1:1), stirred at room temperature for 3 days, centrifuged, and the solid was vacuum-dried at 40°C overnight to obtain Form FB-1.

[0225] After testing, its XRPD pattern is shown in Figure 6.

[0226] Example 1-4: Preparation of Crystalline Form FB-1

[0227] About 35 mg of the compound represented by formula (I) was added to 4.0 mL of water, stirred at room temperature for 3 days, centrifuged, and the solid was vacuum-dried at 40° C. overnight to obtain crystal form FB-1.

[0228] Example 1-5: Preparation of Crystalline Form FB-1

[0229] About 30 mg of the compound represented by formula (I) was taken, 0.5 mL of methanol was added to dissolve the clear solution, 4.0 mL of water was added to the clear solution, solid was precipitated, and the solution was centrifuged. The solid was taken and vacuum dried at 40°C overnight to obtain crystal form FB-1.

[0230] Example 1-6: Preparation of Crystalline Form FB-1

[0231] Take about 20 mg of the compound represented by formula (I), add 1.0 mL of tetrahydrofuran, filter, add 4.0 mL of water to the clear liquid, precipitate the solid, centrifuge, and take the solid to 40°C and vacuum dry overnight to obtain crystal form FB-1.

[0232] Example 2-1: Preparation of Crystal Form FB-2

[0233] Take about 10 mg of the compound represented by formula (I), add 1.5 mL of acetonitrile, dissolve at 80°C, stir at 8°C overnight, precipitate the solid, centrifuge, and vacuum dry at 40°C overnight to obtain crystal form FB-2.

[0234] The XRPD data are shown in the following table:

[0235] Its XRPD pattern is shown in Figure 7.

[0236] Its Fourier transform infrared spectrum is shown in Figure 8.

[0237] Its DSC spectrum is shown in Figure 9.

[0238] Its TGA spectrum is shown in FIG10 , which shows a mass loss of 5.9% starting at 80° C., corresponding to the removal of the acetonitrile solvent from the crystal lattice of the crystalline form FB-2.

[0239] The DVS pattern is shown in Figure 11, and the hygroscopic weight gain of crystal form FB-2 under 0-60% RH conditions is 0.4%. The XRPD patterns before and after DVS testing are shown in Figure 12, indicating that the crystal form has not changed.

[0240] Example 2-2: Preparation of Form FB-2 Single Crystal

[0241] Take about 10 mg of the compound represented by formula (I), add 1.5 mL of acetonitrile, dissolve in an 80°C water bath, and naturally cool to room temperature overnight to obtain a single crystal of crystal form FB-2.

[0242] Through X-ray single crystal diffraction testing and analysis, the unit cell parameters of crystal form FB-2 are obtained, as shown in the following table:

[0243] Its single crystal structure is shown in Figure 13.

[0244] Its single crystal XRPD data are shown in the following table:

[0245] Its single crystal XRPD simulation image is shown in Figure 14.

[0246] Example 3-1: Preparation of Crystalline Form FB-3

[0247] About 5 mg of the crystalline form FB-2 of the compound represented by formula (I) was taken, heated to 220°C at 60°C / min, held for 10 minutes, and cooled to room temperature to obtain the crystalline form FB-3.

[0248] The XRPD data are shown in the following table:

[0249] Its XRPD pattern is shown in Figure 15.

[0250] Its DSC spectrum is shown in Figure 16.

[0251] Example 4-1: Preparation of Crystalline Form FB-4

[0252] Take about 25 mg of the compound represented by formula (I), add 0.8 mL of tetrahydrofuran, dissolve in an 85°C water bath, add 3 mL of n-heptane under stirring at room temperature, crystallize, centrifuge, and dry with air at 50°C for 3 h to obtain crystal form FB-4.

[0253] The XRPD data are shown in the following table:

[0254] Its XRPD pattern is shown in Figure 17.

[0255] Its Fourier transform infrared spectrum is shown in FIG18 .

[0256] Its DSC spectrum is shown in Figure 19.

[0257] Its TGA spectrum is shown in Figure 20, which shows a mass loss of about 7.1% starting at 140°C, indicating that the crystalline form FB-4 is a sesquihydrate.

[0258] Example 4-2: Preparation of Crystalline Form FB-4

[0259] Take about 25 mg of the compound represented by formula (I), add 0.8 mL of tetrahydrofuran, dissolve in an 85°C water bath, add 3 mL of methylcyclohexane under stirring at room temperature, crystallize, centrifuge, and dry with air at 50°C for 3 h to obtain crystal form FB-4.

[0260] Example 4-3: Preparation of Crystalline Form FB-4

[0261] Take about 25 mg of the compound represented by formula (I), add 0.8 mL of tetrahydrofuran, dissolve in an 85°C water bath, add 3 mL of methyl tert-butyl ether under stirring at room temperature, crystallize, centrifuge, and dry with air at 50°C for 3 h to obtain crystal form FB-4.

[0262] Example 5: Physicochemical Stability of Form FB-1

[0263] Appropriate samples of the disclosed Form FB-1 were placed under long-term (25°C / 60% RH / uncovered) and accelerated (40°C / 75% RH / uncovered) conditions, and the chemical purity and crystal form were regularly determined by HPLC and XRPD. The results are shown in Table 1 and Figure 21.

[0264] Table 1

[0265] An appropriate amount of the crystal form FB-1 sample of the present disclosure was taken and placed under high humidity (25°C / 92.5% RH / open) conditions for 10 days. The crystal form was determined by XRPD. The comparison diagram before and after placement is shown in Figure 22.

[0266] The results showed that Form FB-1 was stable for at least 30 days under long-term (25°C / 60% RH / unopen) and accelerated (40°C / 75% RH / unopen) conditions, demonstrating good stability under both long-term and accelerated conditions. Form FB-1 was also stable for at least 10 days under high humidity (25°C / 92.5% RH / unopen) conditions, demonstrating excellent stability even under more stringent conditions.

[0267] Example 6: Mechanical stability of crystal form FB-1

[0268] An appropriate amount of the crystal form FB-1 sample of the present disclosure was manually ground for 1 minute, and XRPD tests were performed before and after grinding. The XRPD patterns before and after grinding are shown in Figure 23. The results show that the crystal form FB-1 did not change after grinding.

[0269] Example 7: Compressibility of Form FB-1

[0270] An appropriate amount of the disclosed Form FB-1 sample was placed in an infrared tablet press and held at 2 MPa for 1 minute. XRPD analysis was performed before and after tableting. The XRPD patterns before and after tableting are shown in Figure 24. The results indicate that Form FB-1 remained unchanged.

[0271] Example 8: Particle size distribution of crystal form FB-1

[0272] A sample of Form FB-1 was taken, an appropriate amount of water was added, vortexed, and then added to the PSD instrument for testing. The results are shown in Table 2 and Figure 25.

[0273] Table 2

[0274] The results showed that the particle size distribution of Form FB-1 was relatively uniform and normal. Uniform particle size is beneficial for simplifying the preparation production process and improving product quality.

[0275] Example 9: Equilibrium Solubility of Form FB-1

[0276] About 30 mg of Form FB-1 was added to 5 mL of water and stirred at room temperature. After 1 hour, a sample was taken to test the equilibrium solubility and XRPD. The results are shown in Table 3 and Figure 26.

[0277] Table 3

[0278] The results showed that the solubility of the crystalline form FB-1 met the pharmaceutical requirements, and the crystalline form did not change after 1 hour in water. The inventors further took samples for XRPD testing at 4 hours and 24 hours. The results are shown in Figure 26, and it was found that it was still the crystalline form FB-1 and had not changed.

[0279] Example 10: Physicochemical Stability of Form FB-2

[0280] An appropriate amount of the disclosed crystal form FB-2 sample was taken and placed under long-term conditions (25°C / 60% RH / uncovered), and the chemical purity and crystal form were regularly determined by HPLC and XRPD. The results are shown in Table 4 and Figure 27.

[0281] Table 4

[0282] The results show that the crystalline form FB-2 is stable for at least 30 days under 25°C / 60% RH conditions, indicating that the crystalline form FB-2 can maintain good stability under long-term conditions.

[0283] Example 11: Mechanical stability of crystal form FB-2

[0284] An appropriate amount of the crystal form FB-2 sample of the present disclosure was manually ground for 1 minute, and XRPD tests were performed before and after grinding. The XRPD patterns before and after grinding are shown in Figure 28. The results show that the crystal form FB-2 did not change after grinding.

[0285] Example 12: Compressibility of Form FB-2

[0286] An appropriate amount of the disclosed Form FB-2 sample was placed in an infrared tablet press and held at 2 MPa for 1 minute. XRPD analysis was performed before and after tableting. The XRPD patterns before and after tableting are shown in Figure 29. The results indicate that Form FB-2 remained unchanged.

[0287] Example 13: Particle size distribution of crystal form FB-2

[0288] A sample of Form FB-2 was taken, an appropriate amount of water was added, vortexed, and then added to the PSD instrument for testing. The results are shown in Table 5 and Figure 30.

[0289] Table 5

[0290] The results showed that the particle size distribution of Form FB-2 was relatively uniform and normal. Uniform particle size is beneficial for simplifying the preparation production process and improving product quality.

[0291] Example 14: Equilibrium Solubility of Form FB-2

[0292] About 30 mg of Form FB-2 was added to 5 mL of water and stirred at room temperature. After 1 hour, a sample was taken to test the equilibrium solubility. The results are shown in Table 6.

[0293] Table 6

[0294] The results showed that the solubility of crystal form FB-2 met the pharmaceutical requirements.

[0295] Example 15: Physicochemical Stability of Crystalline Form FB-3

[0296] Appropriate samples of the disclosed Form FB-3 were placed under long-term (25°C / 60% RH / uncovered) and accelerated (40°C / 75% RH / uncovered) conditions, and the chemical purity and crystal form were regularly determined by HPLC and XRPD. The results are shown in Table 7 and Figure 31.

[0297] Table 7

[0298] The results showed that crystalline FB-3 was stable for at least 30 days at 25°C / 60% RH and 40°C / 75% RH, indicating that crystalline FB-3 maintained good stability under both long-term and accelerated conditions.

[0299] Example 16: Compressibility of Form FB-3

[0300] An appropriate amount of the disclosed crystal form FB-3 sample was placed in an infrared tablet press and held at 2 MPa for 1 minute. XRPD analysis was performed before and after tableting. The XRPD patterns before and after tableting are shown in Figure 32. The results indicate that the crystal form FB-3 remained unchanged.

[0301] Example 17: Mechanical stability of crystal form FB-3

[0302] An appropriate amount of the crystal form FB-3 sample of the present disclosure was manually ground for 1 minute, and XRPD tests were performed before and after grinding. The XRPD patterns before and after grinding are shown in Figure 33. The results show that the crystal form FB-3 did not change after grinding.

[0303] Example 18: Solubility of Form FB-3

[0304] About 30 mg of Form FB-3 was added to 5 mL of water and stirred at room temperature. After 1 hour, a sample was taken to test the equilibrium solubility and XRPD. The results are shown in Table 8.

[0305] Table 8

[0306] The results showed that the solubility of crystalline form FB-3 met the pharmaceutical requirements.

[0307] Example 19: Physicochemical Stability of Crystalline Form FB-4

[0308] Appropriate samples of the disclosed Form FB-4 were placed under long-term (25°C / 60% RH / uncovered) and accelerated (40°C / 75% RH / uncovered) conditions, and the chemical purity and crystal form were regularly determined by HPLC and XRPD. The results are shown in Table 9 and Figure 34.

[0309] Table 9

[0310] The results showed that crystalline FB-4 was stable for at least 30 days at 25°C / 60% RH and 40°C / 75% RH, indicating that crystalline FB-4 maintained good stability under both long-term and accelerated conditions.

[0311] Example 20: Mechanical stability of crystal form FB-4

[0312] An appropriate amount of the crystal form FB-4 sample of the present disclosure was manually ground for 1 minute, and XRPD tests were performed before and after grinding. The XRPD patterns before and after grinding are shown in Figure 35. The results show that the crystal form FB-4 did not change after grinding.

[0313] Example 21: Compressibility of Form FB-4

[0314] An appropriate amount of the disclosed crystal form FB-4 sample was placed in an infrared tablet press and held at 2 MPa for 1 minute. XRPD analysis was performed before and after tableting. The XRPD patterns before and after tableting are shown in Figure 36. The results indicate that the crystal form FB-4 remained unchanged and exhibited no fracturing, demonstrating high plasticity.

[0315] Example 22: Solubility of Form FB-4

[0316] About 30 mg of Form FB-4 was added to 5 mL of water and stirred at room temperature. After 1 hour, a sample was taken to test the equilibrium solubility and XRPD. The results are shown in Table 10 and Figure 37.

[0317] Table 10

[0318] The results showed that the solubility of the crystalline form FB-4 met the pharmaceutical requirements, and the crystalline form did not change after 1 hour in water. The inventors further took samples for XRPD testing at 4 hours and 24 hours. The results are shown in Figure 37, and it was found that it was still the crystalline form FB-4 and had not changed.

[0319] Example 23: Suspension competition experiment

[0320] At room temperature, appropriate amounts of Form FB-1, Form FB-2, Form FB-3, and Form FB-4 samples were taken and mixed uniformly. 1 mL of the corresponding solvent was added to form a suspension. The suspension was stirred at room temperature for 5 days, and samples were taken for XRPD characterization. The results are shown in Table 11 and Figures 38-40.

[0321] Table 11

[0322] The results showed that at room temperature, the FB-1 crystal in water and acetonitrile / water was more stable, and the FB-2 crystal in acetonitrile was more stable at room temperature.

[0323] The above description is merely a specific embodiment of the present disclosure, but the scope of protection of the present disclosure is not limited thereto. Any changes or substitutions that can be conceived by a person skilled in the art within the technical scope disclosed in the present disclosure without inventive effort should be included in the scope of protection of the present disclosure. Therefore, the scope of protection of the present disclosure should be based on the scope of protection defined in the claims.

Claims

1. A crystalline form FB-1 of a compound having a structural formula as shown in formula (I): It is characterized in that Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-1 expressed in 2θ angle has characteristic peaks at at least one, two or three of 8.4°±0.2°, 10.3°±0.2° and 13.2°±0.2°.

2. The crystal form FB-1 according to claim 1, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-1 has characteristic peaks at 8.4°±0.2°, 10.3°±0.2° and 13.2°±0.2°.

3. The crystal form FB-1 according to claim 1 or 2, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-1 further has characteristic peaks at at least one of 11.9°±0.2°, 16.8°±0.2°, 19.6°±0.2° and 26.5°±0.2°2θ.

4. The crystal form FB-1 according to any one of claims 1 to 3, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-1 further has characteristic peaks at at least one of 14.4°±0.2°, 17.8°±0.2°, 20.5°±0.2°, 22.1°±0.2° and 24.4°±0.2°2θ.

5. The crystal form FB-1 according to any one of claims 1 to 4, characterized in that: The crystalline form FB-1 has an X-ray powder diffraction pattern substantially as shown in FIG1 .

6. The crystal form FB-1 according to any one of claims 1 to 5, characterized in that: The crystalline form FB-1 has a purity greater than 90%, preferably greater than 95%, and more preferably greater than 99%.

7. The crystal form FB-1 according to any one of claims 1 to 6, characterized in that: The Fourier transform infrared spectrum of the crystal form FB-1 is at 3473.18 cm -1 ±5cm -1 、3373.57cm -1 ±5cm -1 、2917.70cm -1 ±5cm -1 、1627.39cm -1 ±5cm -1 、1609.28cm -1 ±5cm -1 and 1514.68cm -1 ±5cm -1 At least one of them has a characteristic peak.

8. The crystal form FB-1 according to any one of claims 1 to 7, characterized in that: The Fourier infrared spectrum of the crystal form FB-1 is 1392.43 cm -1 ±5cm -1 、1270.46cm -1 ±5cm -1 、888.86cm -1 ±5cm -1 、823.73cm -1 ±5cm -1 、722.16cm -1 ±5cm -1 and 647.52cm -1 ±5cm -1 At least one of them has a characteristic peak.

9. The crystal form FB-1 according to any one of claims 1 to 8, characterized in that: The crystal form FB-1 has a Fourier transform infrared spectrum substantially as shown in FIG. 2 .

10. A method for preparing the crystal form FB-1 according to any one of claims 1 to 9, characterized in that: The preparation method is selected from any one of the following methods: 1) dissolving the compound represented by formula (I) in an alcohol, ketone or nitrile solvent, filtering and volatilizing to obtain a crystalline form FB-1; 2) placing the compound represented by formula (I) in water or a mixed solvent containing water, stirring, separating, and drying to obtain the crystalline form FB-1; the mixed solvent containing water is selected from water and any solvent of nitriles, alcohols, ketones, or a mixture of combined solvents; 3) dissolving the compound represented by formula (I) in an alcohol, ketone or tetrahydrofuran solvent, mixing the supernatant with an anti-solvent, precipitating a solid, separating and drying to obtain the crystalline form FB-1; the anti-solvent is selected from water, alkanes and ethers. In some specific embodiments, the antisolvent is water. In the above technical solutions 1)-3), preferably, the alcohols are selected from C1-C8 alcohols, the ketones are selected from C3-C6 ketones, the nitriles are selected from C2-C4 nitriles, the ethers are selected from C2-C7 ethers, and the alkanes are selected from dichloromethane and n-heptane. Preferably, the alcohols are selected from methanol and ethanol, the ketones are selected from acetone, the nitriles are selected from acetonitrile, and the ethers are selected from isopropyl ether. Preferably, the volume percentage of water in the mixed solvent is 15%-100%; Preferably, the volatilization temperature is 20°C-50°C; more preferably room temperature. Preferably, the stirring time is at least 1 day; preferably, the stirring temperature is 4°C-50°C; more preferably room temperature.

11. A crystalline form FB-2 of a compound having a structural formula as shown in formula (I), characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-2 expressed in 2θ angle has characteristic peaks at at least one, two or three of 9.9°±0.2°, 11.8°±0.2° and 14.2°±0.2°.

12. The crystal form FB-2 according to claim 11, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-2 expressed in 2θ angle has characteristic peaks at 9.9°±0.2°, 11.8°±0.2° and 14.2°±0.2°.

13. The crystalline form FB-2 according to claim 11 or 12, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-2 further has characteristic peaks at at least one of 14.9°±0.2°, 16.2°±0.2° and 17.2°±0.2°2θ.

14. The crystal form FB-2 according to any one of claims 11 to 13, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-2 further has characteristic peaks at at least one of 12.8°±0.2°, 19.6°±0.2° and 26.1°±0.2°2θ.

15. The crystal form FB-2 according to any one of claims 11 to 14, characterized in that: The crystalline form FB-2 has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .

16. The crystal form FB-2 according to any one of claims 11 to 15, characterized in that: The crystalline form FB-2 has a purity greater than 90%, preferably greater than 95%, and more preferably greater than 99%.

17. The crystal form FB-2 according to any one of claims 11 to 16, characterized in that: The Fourier infrared spectrum of the crystal form FB-2 is at 3470.25 cm -1 ±5cm -1 、3315.63cm -1 ±5cm -1 、3149.77cm -1 ±5cm -1 、1639.56cm -1 ±5cm -1 、1602.76cm -1 ±5cm -1 and 1504.03cm -1 ±5cm -1 At least one of them has a characteristic peak.

18. The crystal form FB-2 according to any one of claims 11 to 17, characterized in that: The Fourier infrared spectrum of the crystal form FB-2 is at 1385.19 cm -1 ±5cm -1 、1268.61cm -1 ±5cm -1 、1093.46cm -1 ±5cm -1 、813.93cm -1 ±5cm -1 、722.21cm -1 ±5cm -1 and 655.76cm -1 ±5cm -1 At least one of them has a characteristic peak.

19. The crystalline form FB-2 according to any one of claims 11 to 17, characterized in that: The crystal form FB-2 has a Fourier transform infrared spectrum substantially as shown in FIG. 8 .

20. The crystal form FB-2 according to any one of claims 11 to 17, characterized in that: The crystalline form FB-2 is a semi-acetonitrile solvate.

21. A method for preparing the crystal form FB-2 according to any one of claims 11 to 20, characterized in that: The preparation method comprises dissolving the compound represented by formula (I) in acetonitrile or a mixed solvent of acetonitrile and other solvents, taking the clear solution, cooling and stirring, separating, and drying to obtain the crystal form FB-2. Preferably, the other solvent may be a solvent miscible with acetonitrile. Preferably, the dissolving temperature is 4-90°C; more preferably 80°C. Preferably, the stirring temperature is 4-90°C; more preferably 8°C.

22. A crystalline form FB-3 of a compound having a structural formula as shown in formula (I), characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-3 expressed in 2θ angle has characteristic peaks at at least one, two or three of 11.0°±0.2°, 13.4°±0.2° and 18.9°±0.2°.

23. The crystalline form FB-3 according to claim 22, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-3 expressed in 2θ angle has characteristic peaks at 11.0°±0.2°, 13.4°±0.2° and 18.9°±0.2°.

24. The crystalline form FB-3 according to claim 22 or 23, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-3 further has characteristic peaks at at least one of 9.1°±0.2°, 15.2°±0.2° and 22.3°±0.2°2θ.

25. The crystalline form FB-3 according to any one of claims 22 to 24, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-3 further has characteristic peaks at at least one of 9.8°±0.2°, 15.0°±0.2° and 26.5°±0.2°2θ.

26. The crystalline form FB-3 according to any one of claims 22 to 25, characterized in that: The crystalline form FB-3 has an X-ray powder diffraction pattern substantially as shown in FIG. 15 .

27. The crystalline form FB-3 according to any one of claims 22 to 26, characterized in that: The crystalline form FB-3 has a purity greater than 90%; preferably, a purity greater than 95%; more preferably, a purity greater than 99%; and more preferably, a purity greater than 99.5%.

28. The crystalline form FB-3 according to any one of claims 22 to 27, characterized in that: The crystalline form FB-3 has a DSC spectrum substantially as shown in FIG. 16 .

29. The crystalline form FB-3 according to any one of claims 22 to 27, characterized in that: The crystalline form FB-3 is an anhydrate.

30. A method for preparing the crystalline form FB-3 according to any one of claims 22 to 29, characterized in that: The preparation method comprises heating the solvate of the compound represented by formula (I) to a desolvation temperature to obtain the crystalline form FB-3. Preferably, the solvate of the compound represented by formula (I) is an acetonitrile solvate; more preferably, it is the crystalline form FB-2 disclosed in the present invention. Preferably, the heating to the desolvation temperature is 80-220°C; more preferably 160-220°C.

31. A crystalline form FB-4 of a compound having a structural formula as shown in formula (I), characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the FB-4 expressed in 2θ angle has characteristic peaks at at least one, two or three of 5.1°±0.2°, 8.4°±0.2° and 16.0°±0.2°.

32. The crystalline form FB-4 according to claim 31, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-4 has characteristic peaks at 5.1°±0.2°, 8.4°±0.2° and 16.0°±0.2°2θ.

33. The crystalline form FB-4 according to claim 31 or 32, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-4 further has characteristic peaks at at least one of 12.3°±0.2°, 14.8°±0.2° and 16.8°±0.2° 2θ.

34. The crystalline form FB-4 according to any one of claims 31 to 33, characterized in that: Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form FB-4 further has characteristic peaks at at least one of 10.0°±0.2°, 18.9°±0.2° and 27.2°±0.2°2θ.

35. The crystalline form FB-4 according to any one of claims 31 to 34, characterized in that: The crystalline form FB-4 has an X-ray powder diffraction pattern of the crystalline form FB-4 substantially as shown in FIG. 17 .

36. The crystalline form FB-4 according to any one of claims 31 to 35, characterized in that: The Fourier infrared spectrum of the crystal form FB-4 is 3163.49 cm -1 ±5cm -1 、1599.18cm -1 ±5cm -1 、1507.95cm -1 ±5cm -1 、1174.28cm -1 ±5cm -1 、975.44cm -1 ±5cm -1 and 661.52cm -1 ±5cm -1 There is a band in at least one of the regions.

37. The crystalline form FB-4 according to any one of claims 31 to 36, characterized in that: The crystalline form FB-4 has a Fourier transform infrared spectrum substantially as shown in FIG. 18 .

38. The crystalline form FB-4 according to any one of claims 31 to 37, characterized in that: The crystalline form FB-4 has a DSC spectrum substantially as shown in FIG. 19 .

39. The crystalline form FB-4 according to any one of claims 31 to 38, characterized in that: The crystal form FB-4 is a hydrate 40. The crystalline form FB-4 according to any one of claims 31 to 38, characterized in that: The crystalline form FB-4 has a purity greater than 90%, preferably greater than 95%, and more preferably greater than 99%.

41. A method for preparing the crystal form FB-4 according to any one of claims 31 to 40, characterized in that: The preparation method comprises dissolving the compound represented by formula (I) in solvent 1, taking the clear solution, adding solvent 2, precipitating solid, separating, and drying to obtain crystal form FB-4. Preferably, the solvent 1 is selected from tetrahydrofuran; and the solvent 2 is selected from alkane or ether solvents. Preferably, the alkane solvent is selected from n-heptane and methylcyclohexane, and the ether solvent is selected from methyl Tert-butyl ether. Preferably, the dissolving temperature is 4-90°C; more preferably 85°C. Preferably, the solvent 2 is added under stirring conditions. Preferably, the stirring temperature is 4-90°C; more preferably room temperature.

42. A pharmaceutical composition comprising a therapeutically effective amount of one or more of the crystalline form FB-1 described in any one of claims 1 to 9, the crystalline form FB-2 described in any one of claims 11 to 20, the crystalline form FB-3 described in any one of claims 22 to 29, and the crystalline form FB-4 described in any one of claims 31 to 40, and at least one pharmaceutically acceptable carrier.

43. A preparation prepared from the pharmaceutical composition of claim 42, wherein the preparation is in the form selected from oral preparations and parenteral preparations. Preferably, the preparation is in the form of an oral preparation.

44. Use of one or more of the crystalline form FB-1 according to any one of claims 1 to 9, the crystalline form FB-2 according to any one of claims 11 to 20, the crystalline form FB-3 according to any one of claims 22 to 29, and the crystalline form FB-4 according to any one of claims 31 to 40, or the pharmaceutical composition according to claim 42 or the formulation according to claim 43 in the preparation of a medicament for treating abnormal cell proliferation. Preferably, the abnormal cell proliferation is cancer.

45. The use according to claim 44, characterized in that The cancer is selected from breast cancer, uterine cancer, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, endometrial cancer, hepatocellular carcinoma, colon cancer, neuroblastoma and bladder cancer; preferably breast cancer.

46. ​​A method for treating abnormal cell proliferation, comprising applying to a patient a therapeutically effective amount of one or more of the crystalline form FB-1 according to any one of claims 1 to 9, the crystalline form FB-2 according to any one of claims 11 to 20, the crystalline form FB-3 according to any one of claims 22 to 29, and the crystalline form FB-4 according to any one of claims 31 to 40, or the pharmaceutical composition according to claim 42 or the preparation according to claim 43; preferably, the abnormal cell proliferation is cancer.

47. The method of claim 46, wherein: The cancer is selected from breast cancer, uterine cancer, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, endometrial cancer, hepatocellular carcinoma, colon cancer, neuroblastoma and bladder cancer; preferably breast cancer.

48. A combination of one or more of the crystalline form FB-1 according to any one of claims 1 to 9, the crystalline form FB-2 according to any one of claims 11 to 20, the crystalline form FB-3 according to any one of claims 22 to 29, and the crystalline form FB-4 according to any one of claims 31 to 40, or the pharmaceutical composition according to claim 42 or the preparation according to claim 43 and other drugs.

49. The combined use according to claim 48, characterized in that: The other drugs are selected from one or more of gemcitabine, FOLFIRI and Trastuzumab.

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