WO2024031226A1

WO2024031226A1 - Pharmaceutical composition and polymorphic substance of fgfr inhibitor, and pharmaceutical use thereof

Info

Publication number: WO2024031226A1
Application number: PCT/CN2022/110810
Authority: WO
Inventors: 高敏; 宋嘉琦; 张臻; 喻红平
Original assignee: 无锡和誉生物医药科技有限公司; 上海和誉生物医药科技有限公司
Priority date: 2022-08-08
Filing date: 2022-08-08
Publication date: 2024-02-15

Abstract

The present invention relates to a pharmaceutical composition and a polymorphic substance of an FGFR inhibitor, and pharmaceutical use thereof. The FGFR inhibitor is a fibroblast growth factor receptor inhibitor with a structure of Formula (I). By adopting a proper adhesive and a pharmaceutically acceptable carrier, a pharmaceutical preparation suitable for industrial production has been developed. A polymorph of a compound represented by Formula (I) has been further developed. According to the technical solutions, a pharmaceutical preparation meeting the requirements for clinical research and drug market entry can be developed, and the problem of drug accessibility can be solved.

Description

Pharmaceutical compositions, polymorphs and pharmaceutical applications of FGFR inhibitors

Technical field

The invention belongs to the field of drug development, and specifically relates to pharmaceutical compositions and polymorphs of FGFR inhibitors and their pharmaceutical applications.

Background technique

Protein kinases are a class of proteins (enzymes) that regulate various cellular functions. This is accomplished by phosphorylating specific amino acids on the protein substrate, causing conformational changes in the substrate protein. Conformational changes modulate the substrate activity or its ability to interact with other binding partners. The enzymatic activity of a protein kinase refers to the rate at which the kinase adds phosphate groups to a substrate. This can be determined, for example, by measuring the amount of substrate converted to product as a function of time. Phosphorylation of substrate occurs in the active site of protein kinases.

Tyrosine kinases are a subgroup of protein kinases that catalyze the conversion of the terminal phosphate of adenosine triphosphate (ATP) to tyrosine residues on protein substrates. These kinases play an important role in the propagation of growth factor signaling that leads to cell proliferation, differentiation, and migration.

Fibroblast growth factor (FGF) is considered an important mediator of many physiological processes such as morphogenesis during development and vasculogenesis. There are currently over 25 known FGF family members. The fibroblast growth factor receptor (FGFR) family includes four members, FGFR1, FGFR2, FGFR3, and FGFR4, each of which consists of an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular cytoplasmic protein tyrosine kinase domain. Upon FGF stimulation, FGFR dimerization and transphosphorylation occur, which results in receptor activation. Activation of the receptor is sufficient to restore and activate specific downstream signaling partners involved in various processes such as the regulation of cell growth, cell metabolism and cell survival (reviewed in Eswarakumar, V.P. et al., Cytokine & Growth Factor Reviews 2005, 16 , pp. 139-149). Thus, FGF and FGFR may cause and/or promote tumor formation.

Considerable evidence now implicates FGF signaling directly in human cancer. Increased expression of various FGFs has been reported in a diverse range of tumor types such as bladder, renal cell and prostate (among others) tumors. FGF has also been described as a potent angiogenic factor. It has also been reported that FGFR is expressed in endothelial cells. Activating mutations of various FGFRs are associated with bladder cancer and multiple myeloma (among others), and there is evidence that the receptor is also expressed in prostate and bladder cancer, among others (reviewed in Grose, R. et al., Cytokine & Growth Factor Reviews 2005, 16 , pp. 179-186 and Kwabi-Addo, B. et al., Endocrine-Related Cancer 2004, 11, pp. 709-724). For these reasons, and particularly because treatments targeting FGFR and/or FGF signaling can directly affect tumor cells and tumor angiogenesis, the FGF signaling system is an attractive therapeutic target.

In 2008, AstraZeneca (Sweden) Ltd. (ASTRAZENECA AB) disclosed compounds targeting FGFR and/or FGF signaling in a patent application WO2008075068A2. The most representative compound is the compound of Example 154. Chemistry The structure is as follows:

The Chinese name is: N-(3-(3,5-dimethoxyphenylethyl)-1H-pyrazol-5-yl)-4-((3S,5R)-3,5-dimethylpiper Azin-1-yl)benzamide (AZD4547), referred to as the compound of formula (I) herein, can be used as an FGFR activity modulator or inhibitor to meet the current domestic and foreign requirements for the treatment of proliferative and hyperproliferative diseases/diseases. of cancer, including but not limited to liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma. However, when the patent was applied for, no raw materials and processes suitable for clinical and industrial applications had been developed, and no further research was conducted on whether the compound of formula (I) was suitable for drug development.

During the later pharmaceutical research, it was found that the compound of formula (I) can form a viscous substance at low pH value, which has the effect of reducing the dissolution rate of the drug. Therefore, in 2014, AstraZeneca (Sweden) Co., Ltd. published another article Patent application: WO2014096828A1. In this patent application, the inventor uses an alkaline foaming agent to effectively improve the dissolution rate and extent of the compound of formula (I) at low pH. The pharmaceutical composition disclosed in this patent application has achieved Satisfactory in vitro solubility.

During the development of clinical preparations, although the solubility problem could be solved by following the prescription disclosed in patent application WO2014096828A1, the applicant found that during the industrial production process, there was a problem of film formation on the punch causing damage to the appearance of the tablets, and conventional means could not be used. be corrected. Therefore, there is an urgent need to develop new pharmaceutical compositions and formulation processes to overcome the above technical shortcomings and meet the needs of AZD4547 clinical research and drug marketing.

Contents of the invention

The purpose of the present invention is to provide pharmaceutical compositions and polymorphs of FGFR inhibitors to solve the problem of drug accessibility and meet the needs of AZD4547 clinical research and drug marketing.

In order to solve the problems existing in the existing technology, the inventors optimized the types and proportions of pharmaceutical carriers such as lubricants, disintegrants, and fillers by using appropriate binders, and at the same time conducted in-depth research on the aggregation state of the compound of formula (I). Through a large number of Crystal form screening experiments screen out crystal forms of compounds of formula (I) that can be used in formulation development. Combining the results of preparation research and crystal form research, we developed a pharmaceutical composition that is highly compressible and suitable for industrial production. We obtained a pharmaceutical preparation that meets clinical requirements in terms of stability, solubility and other physical and chemical properties, and can meet the clinical research of AZD4547. and the need for drug launches.

The first aspect of the present invention provides a pharmaceutical composition, which contains the crystal form of a compound of formula (I) as follows and one or more pharmaceutically acceptable carriers. The pharmaceutically acceptable carrier is a lubricant, a disintegrating agent, or a disintegrating agent. One or more of the decomposers and fillers, the pharmaceutical composition also includes hydroxypropyl cellulose as a binder, the binder is hydroxypropyl cellulose of LF and/or JF grade specifications, or the above Specifications mixed with other specifications of hydroxypropylcellulose,

As a preferred version, the pharmaceutical composition contains 0.1%-50% W/W crystalline form of the compound of formula (I) relative to the total weight of the composition.

As a further preferred embodiment, the pharmaceutical composition contains 1.0%-30% W/W crystalline form of the compound of formula (I) relative to the total weight of the composition.

As a further preferred embodiment, the pharmaceutical composition contains 10.0%-30% W/W crystalline form of the compound of formula (I) relative to the total weight of the composition.

As a preferred solution, the pharmaceutical composition contains 0.5%-20.0% W/W LF and/or JF grade specifications of hydroxypropyl cellulose relative to the total weight of the composition, or the above specifications are combined with other specifications of hydroxypropyl cellulose. Mixture of vegetarian ingredients.

As a further preferred solution, the other specifications of hydroxypropyl cellulose refer to EF, GF, MF or HXF grade hydroxypropyl cellulose.

As a further preferred option, the pharmaceutical composition contains 1.0%-10.0% W/W LF and/or JF grade hydroxypropyl cellulose relative to the total weight of the composition, or the above specifications are combined with other specifications of hydroxypropyl cellulose. A mixture of cellulose.

As a further preferred solution, the pharmaceutical composition contains 2.0%-8.0% W/W LF and/or JF grade hydroxypropyl cellulose relative to the total weight of the composition, or the above specifications are combined with other specifications of hydroxypropyl cellulose. A mixture of cellulose bases.

As a preferred solution, the pharmaceutical composition contains hydroxypropyl cellulose in LF and/or JF grade specifications.

As a further preferred embodiment, the pharmaceutical composition contains LF and/or JF grade hydroxypropylcellulose in an aqueous solution.

As a further preferred embodiment, the pharmaceutical composition contains an aqueous solution of hydroxypropylcellulose of LF and/or JF grade specifications at a concentration of 5% to 25% W/V relative to the total weight of the composition.

As the most preferred version, the pharmaceutical composition contains the hydroxypropylcellulose aqueous solution of LF and/or JF grade specifications at a concentration of 8% to 15% W/V relative to the total weight of the composition.

As a preferred version, the pharmaceutical composition further contains one or more foaming agents, which are inorganic salts or organic carbonates. The inorganic salts are selected from the group consisting of sodium carbonate, potassium carbonate, and magnesium carbonate. , calcium carbonate, aluminum carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium hydroxide; the organic acid salt is selected from sodium diglycinate carbonate, dimethyl Carbonate and ethylene carbonate.

As a further preferred version, the foaming agent is selected from the group consisting of sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, aluminum carbonate, sodium bicarbonate, potassium bicarbonate and calcium bicarbonate.

As a preferred version, the pharmaceutical composition contains 0.5%-50.0% W/W foaming agent relative to the total weight of the composition.

As a further preferred version, the pharmaceutical composition contains 2.0%-40.0% W/W foaming agent relative to the total weight of the composition.

As a further preferred embodiment, the pharmaceutical composition contains 10.0%-30.0% W/W foaming agent relative to the total weight of the composition.

As a further preferred version, the lubricant is one of glyceryl behenate, magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide, talc, hydrogenated vegetable oil and triglyceride. Kind or variety.

As a further preferred embodiment, the pharmaceutical composition contains 0.1%-30.0% W/W lubricant relative to the total weight of the composition.

As a further preferred embodiment, the pharmaceutical composition contains 1.0%-25.0% W/W lubricant relative to the total weight of the composition.

As a further preferred embodiment, the pharmaceutical composition contains 3.0%-18.0% W/W lubricant relative to the total weight of the composition.

As a further preferred embodiment, the disintegrant is one or more of sodium starch glycolate, sodium starch glycolate, cross-linked polyvinylpyrrolidone and croscarmellose sodium.

As a further preferred embodiment, the pharmaceutical composition contains 0.5%-20.0% W/W disintegrant relative to the total weight of the composition.

As a further preferred embodiment, the pharmaceutical composition contains 1.0%-10.0% W/W disintegrant relative to the total weight of the composition.

As a further preferred embodiment, the pharmaceutical composition contains 2.0%-8.0% W/W disintegrant relative to the total weight of the composition.

As a further preferred embodiment, the filler is one or more of mannitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, anhydrous calcium hydrogen phosphate and lactose monohydrate.

As a further preferred embodiment, the pharmaceutical composition contains 1.0%-90.0% W/W filler relative to the total weight of the composition.

As a further preferred embodiment, the pharmaceutical composition contains 5.0%-60.0% W/W filler relative to the total weight of the composition.

As a further preferred embodiment, the pharmaceutical composition contains 10.0%-45.0% W/W filler relative to the total weight of the composition.

As a further preferred embodiment, the pharmaceutical composition includes the crystal form of the compound of formula (I), LF grade hydroxypropyl cellulose and a lubricant, with a W/W mass ratio of (10.0-30.0): (2.0-8.0 ): (3.0-10.0), the lubricant is one or more of glyceryl behenate, magnesium stearate and silicon dioxide.

As a further preferred version, the pharmaceutical composition further contains sodium carbonate and/or magnesium carbonate as a foaming agent, the content of which is 2.0%-40.0% W/W relative to the total weight of the composition.

As a further preferred version, the pharmaceutical composition further contains sodium carbonate and/or magnesium carbonate as a foaming agent, the content of which is 10.0%-30.0% W/W relative to the total weight of the composition.

As a further preferred embodiment, the pharmaceutical composition further contains sodium starch glycolate as a disintegrant, the content of which is 2.0%-8.0% W/W relative to the total weight of the composition.

As a further preferred version, the pharmaceutical composition further contains microcrystalline cellulose and/or mannitol as fillers, the content of which is 5.0%-45.0% W/W relative to the total weight of the composition.

As a further preferred solution, the pharmaceutical composition further contains microcrystalline cellulose and/or mannitol as fillers, the content of which is 10.0%-35.0% W/W relative to the total weight of the composition.

As a further preferred solution, the pharmaceutical composition further contains microcrystalline cellulose and/or mannitol as fillers, the content of which is 15.0%-25.0% W/W relative to the total weight of the composition.

As a further preferred embodiment, the pharmaceutical composition further includes one or more coating powders as coating materials.

As a further preferred embodiment, the coating powder contained in the pharmaceutical composition is gastric-soluble film coating premix Opadry.

As a further preferred embodiment, the pharmaceutical composition is a tablet.

As a further preferred embodiment, the unit dosage form of the tablet contains 1 mg to 500 mg of the crystalline form of the compound of formula (I).

As a further preferred embodiment, the unit dosage form of the tablet contains 1 mg to 200 mg of the crystalline form of the compound of formula (I).

As a further preferred embodiment, the unit dosage form of the tablet contains 1 mg, 5 mg, 20 mg, 80 mg or 200 mg of the crystalline form of the compound of formula (I).

As a further preferred embodiment, the crystal form of the compound of formula (I) is anhydrous, hydrate or solvate of the compound of formula (I).

As a further preferred version, the solvate of the compound of formula (I) is 2-methyltetrahydrofuran solvate, isopropanol solvate and isopropanol-aqueous solvate.

As a further preferred embodiment, the pharmaceutical composition contains anhydrous crystal form I of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form I of the compound of formula (I) includes a Peaks at diffraction angles (2θ) of 22.86±0.2°, 7.81±0.2°, 29.89±0.2°, 21.35±0.2°, 16.16±0.2°, 20.73±0.2° and 27.04±0.2°.

As a further preferred embodiment, the pharmaceutical composition comprises the anhydrous crystalline form I of the compound of formula (I). The X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form I of the compound of formula (I) includes a position at 22.86 ±0.2°, 7.81±0.2°, 29.89±0.2°, 21.35±0.2°, 16.16±0.2°, 20.73±0.2°, 27.04±0.2°, 16.64±0.2°, 24.89±0.2°, 25.09±0.2°, 23.51 Peaks at diffraction angles (2θ) of ±0.2°, 13.37±0.2°, 21.84±0.2°, 12.71±0.2° and 17.85±0.2°.

As the most preferred version, the pharmaceutical composition contains the anhydrous crystalline form I of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form I of the compound of formula (I) includes a position at 22.86 ±0.2°, 7.81±0.2°, 29.89±0.2°, 21.35±0.2°, 16.16±0.2°, 20.73±0.2°, 27.04±0.2°, 16.64±0.2°, 24.89±0.2°, 25.09±0.2°, 23.51 ±0.2°, 13.37±0.2°, 21.84±0.2°, 12.71±0.2°, 17.85±0.2°, 12.86±0.2°, 24.30±0.2°, 26.53±0.2°, 23.74±0.2°, 18.24±0.2°, 28.75 Peaks at diffraction angles (2θ) of ±0.2°, 19.65±0.2°, 11.23±0.2°, 32.66±0.2° and 18.91±0.2°.

As a further preferred embodiment, the pharmaceutical composition contains the anhydrous crystalline form II of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form II of the compound of formula (I) includes a Peaks at diffraction angles (2θ) of 22.88±0.2°, 7.82±0.2°, 29.92±0.2°, 23.51±0.2°, 21.37±0.2°, 27.06±0.2° and 24.90±0.2°.

As a further preferred embodiment, the pharmaceutical composition contains the anhydrous crystalline form II of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form II of the compound of formula (I) includes a 22.88±0.2°, 7.82±0.2°, 29.92±0.2°, 23.51±0.2°, 21.37±0.2°, 27.06±0.2°, 24.90±0.2°, 16.65±0.2°, 20.76±0.2°, 25.11±0.2°, Peaks at diffraction angles (2θ) of 16.18±0.2°, 13.38±0.2°, 21.86±0.2°, 32.58±0.2° and 12.72±0.2°.

As the most preferred version, the pharmaceutical composition contains the anhydrous crystalline form II of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form II of the compound of formula (I) includes a position at 22.88 ±0.2°, 7.82±0.2°, 29.92±0.2°, 23.51±0.2°, 21.37±0.2°, 27.06±0.2°, 24.90±0.2°, 16.65±0.2°, 20.76±0.2°, 25.11±0.2°, 16.18 ±0.2°, 13.38±0.2°, 21.86±0.2°, 32.58±0.2°, 12.72±0.2°, 24.31±0.2°, 15.05±0.2°, 28.77±0.2°, 26.55±0.2°, 12.87±0.2°, 22.56 Peaks at diffraction angles (2θ) of ±0.2°, 17.85±0.2°, 23.76±0.2°, 18.26±0.2° and 31.11±0.2°.

As a further preferred embodiment, the pharmaceutical composition contains the anhydrous crystalline form III of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form III of the compound of formula (I) includes the Peaks at diffraction angles (2θ) of 5.85±0.2°, 21.34±0.2°, 14.96±0.2°, 20.57±0.2°, 19.78±0.2°, 24.12±0.2° and 18.71±0.2°.

As a further preferred embodiment, the pharmaceutical composition contains the anhydrous crystalline form III of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form III of the compound of formula (I) includes the 5.85±0.2°, 21.34±0.2°, 14.96±0.2°, 20.57±0.2°, 19.78±0.2°, 24.12±0.2°, 18.71±0.2°, 25.13±0.2°, 13.72±0.2°, 24.65±0.2°, Peaks at diffraction angles (2θ) of 22.76±0.2°, 26.75±0.2°, 14.61±0.2°, 10.81±0.2° and 16.81±0.2°.

As the most preferred version, the pharmaceutical composition contains the anhydrous crystalline form III of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form III of the compound of formula (I) includes a position at 5.85 ±0.2°, 21.34±0.2°, 14.96±0.2°, 20.57±0.2°, 19.78±0.2°, 24.12±0.2°, 18.71±0.2°, 25.13±0.2°, 13.72±0.2°, 24.65±0.2°, 22.76 ±0.2°, 26.75±0.2°, 14.61±0.2°, 10.81±0.2°, 16.81±0.2°, 21.14±0.2°, 22.54±0.2°, 9.74±0.2°, 21.79±0.2°, 25.74±0.2°, 17.71 Peaks at diffraction angles (2θ) of ±0.2°, 19.33±0.2°, 30.36±0.2°, 13.39±0.2° and 14.07±0.2°.

As a further preferred embodiment, the pharmaceutical composition contains the hydrate crystal form IV of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes a position located at 13.34± Peaks at diffraction angles (2θ) of 0.2°, 17.41±0.2°, 21.78±0.2°, 20.02±0.2°, 14.85±0.2° and 16.53±0.2°.

As a further preferred embodiment, the pharmaceutical composition contains the hydrate crystal form IV of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes a position located at 13.34± 0.2°, 17.41±0.2°, 21.78±0.2°, 20.02±0.2°, 14.85±0.2°, 16.53±0.2°, 19.35±0.2°, 18.64±0.2°, 11.19±0.2°, 5.98±0.2° and 22.67± Peak at diffraction angle (2θ) of 0.2°.

As the most preferred version, the pharmaceutical composition contains the hydrate crystalline form IV of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystalline form IV of the compound of formula (I) includes a position at 13.34±0.2 °, 17.41±0.2°, 21.78±0.2°, 20.02±0.2°, 14.85±0.2°, 16.53±0.2°, 19.35±0.2°, 18.64±0.2°, 11.19±0.2°, 5.98±0.2°, 22.67±0.2 °, 20.62±0.2°, 26.72±0.2°, 14.08±0.2°, 23.82±0.2° and 25.37±0.2° peaks at diffraction angles (2θ).

As a further preferred embodiment, the pharmaceutical composition contains the hydrate crystal form VIII of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes a position at 23.05± Peaks at diffraction angles (2θ) of 0.2°, 8.73±0.2°, 21.41±0.2°, 15.95±0.2°, 23.50±0.2°, 15.50±0.2° and 25.14±0.2°.

As a further preferred embodiment, the pharmaceutical composition contains the hydrate crystal form VIII of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes a position at 23.05± 0.2°, 8.73±0.2°, 21.41±0.2°, 15.95±0.2°, 23.50±0.2°, 15.50±0.2°, 25.14±0.2°, 27.00±0.2°, 31.15±0.2°, 27.70±0.2°, 16.81± Peaks at diffraction angles (2θ) of 0.2°, 19.70±0.2°, 13.22±0.2°, 24.34±0.2° and 19.32±0.2°.

As the most preferred version, the pharmaceutical composition contains the hydrate crystal form VIII of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes a position at 23.05±0.2 °, 8.73±0.2°, 21.41±0.2°, 15.95±0.2°, 23.50±0.2°, 15.50±0.2°, 25.14±0.2°, 27.00±0.2°, 31.15±0.2°, 27.70±0.2°, 16.81±0.2 °, 19.70±0.2°, 13.22±0.2°, 24.34±0.2°, 19.32±0.2°, 20.44±0.2°, 35.08±0.2°, 29.93±0.2°, 27.32±0.2°, 13.54±0.2°, 18.99±0.2 °, 12.89±0.2°, 17.49±0.2°, 30.49±0.2° and 18.59±0.2° peaks at diffraction angles (2θ).

As a further preferred embodiment, the pharmaceutical composition contains a crystalline form of a hydrate of the compound of formula (I), and the hydrate of the compound of formula (I) contains 0.5-3.0 water molecules per molecule.

As a further preferred embodiment, the pharmaceutical composition contains a crystalline form of a hydrate of the compound of formula (I), and the hydrate of the compound of formula (I) contains 0.9-1.8 water molecules per molecule.

As a further preferred embodiment, the pharmaceutical composition contains the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI, and the X of the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI - Ray powder diffraction pattern (XRPD) includes diffraction angles (2θ) at 22.44±0.2°, 5.63±0.2°, 16.81±0.2°, 20.43±0.2°, 21.57±0.2°, 16.15±0.2° and 22.71±0.2° The peak at.

As a further preferred embodiment, the pharmaceutical composition contains the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI, and the X of the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI -Ray powder diffraction pattern (XRPD) includes locations at 22.44±0.2°, 5.63±0.2°, 16.81±0.2°, 20.43±0.2°, 21.57±0.2°, 16.15±0.2°, 22.71±0.2°, 6.36±0.2°, Peaks at diffraction angles (2θ) of 12.60±0.2°, 25.95±0.2°, 24.92±0.2°, 13.69±0.2°, 19.65±0.2°, 15.13±0.2° and 12.11±0.2°.

As the most preferred version, the pharmaceutical composition contains the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI, and the X- of the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI The XRPD patterns include 22.44±0.2°, 5.63±0.2°, 16.81±0.2°, 20.43±0.2°, 21.57±0.2°, 16.15±0.2°, 22.71±0.2°, 6.36±0.2°, 12.60 ±0.2°, 25.95±0.2°, 24.92±0.2°, 13.69±0.2°, 19.65±0.2°, 15.13±0.2°, 12.11±0.2°, 24.25±0.2°, 11.16±0.2°, 31.57±0.2°, 14.55 Peaks at diffraction angles (2θ) of ±0.2°, 27.00±0.2°, 17.90±0.2°, 21.12±0.2°, 11.27±0.2°, 23.18±0.2° and 14.12±0.2°.

As a further preferred embodiment, the pharmaceutical composition contains the crystal form of the 2-methyltetrahydrofuran solvate of the compound of formula (I), and each molecule of the 2-methyltetrahydrofuran solvate of the compound of formula (I) contains 0.5 -3.0 molecules of 2-methyltetrahydrofuran.

As a further preferred embodiment, the pharmaceutical composition contains the crystal form of the 2-methyltetrahydrofuran solvate of the compound of formula (I), and each molecule of the 2-methyltetrahydrofuran solvate of the compound of formula (I) contains 1.0 2-methyltetrahydrofuran molecules.

As a further preferred embodiment, the pharmaceutical composition contains the isopropanol solvate crystal form V of the compound of formula (I), and the X-ray powder diffraction of the isopropyl alcohol solvate crystal form V of the compound of formula (I) The pattern (XRPD) includes peaks at diffraction angles (2θ) of 5.28±0.2°, 10.52±0.2°, 21.29±0.2°, 5.66±0.2°, 13.52±0.2°, 22.44±0.2° and 19.35±0.2°.

As a further preferred embodiment, the pharmaceutical composition contains the isopropanol solvate crystal form V of the compound of formula (I), and the X-ray powder diffraction of the isopropyl alcohol solvate crystal form V of the compound of formula (I) The graph (XRPD) includes locations at 5.28±0.2°, 10.52±0.2°, 21.29±0.2°, 5.66±0.2°, 13.52±0.2°, 22.44±0.2°, 19.35±0.2°, 18.48±0.2°, 16.77±0.2° , 24.68±0.2°, 19.97±0.2°, 25.67±0.2°, 15.13±0.2°, 17.82±0.2° and 20.96±0.2° peaks at diffraction angles (2θ).

As the most preferred version, the pharmaceutical composition contains the isopropyl alcohol solvate crystal form V of the compound of formula (I), and the X-ray powder diffraction pattern of the isopropyl alcohol solvate crystal form V of the compound of formula (I) (XRPD) includes locations at 5.28±0.2°, 10.52±0.2°, 21.29±0.2°, 5.66±0.2°, 13.52±0.2°, 22.44±0.2°, 19.35±0.2°, 18.48±0.2°, 16.77±0.2°, 24.68±0.2°, 19.97±0.2°, 25.67±0.2°, 15.13±0.2°, 17.82±0.2°, 20.96±0.2°, 14.86±0.2°, 12.48±0.2°, 11.94±0.2°, 14.24±0.2°, Peaks at diffraction angles (2θ) of 23.87±0.2°, 23.25±0.2°, 29.51±0.2° and 27.70±0.2°.

As a further preferred embodiment, the pharmaceutical composition contains the isopropanol solvate crystal form of the compound of formula (I), and the isopropyl alcohol solvate of the compound of formula (I) contains 1.0-5.0 isopropanol in each molecule. Propanol molecule.

As a further preferred embodiment, the pharmaceutical composition contains the isopropyl alcohol solvate crystal form of the compound of formula (I), and the isopropyl alcohol solvate of the compound of formula (I) contains 4.2 isopropyl alcohols per molecule. molecular.

As a further preferred embodiment, the pharmaceutical composition contains the isopropyl alcohol-aqueous solvate crystal form VII of the compound of formula (I), and the isopropyl alcohol-aqua solvate crystal form VII of the compound of formula (I) The X-ray powder diffraction pattern (XRPD) includes diffraction angles located at 23.77±0.2°, 24.36±0.2°, 18.56±0.2°, 5.94±0.2°, 22.59±0.2°, 20.30±0.2° and 17.79±0.2° ( 2θ) peak.

As a further preferred embodiment, the pharmaceutical composition contains the isopropyl alcohol-aqueous solvate crystal form VII of the compound of formula (I), and the isopropyl alcohol-aqua solvate crystal form VII of the compound of formula (I) The X-ray powder diffraction pattern (XRPD) includes locations at 23.77±0.2°, 24.36±0.2°, 18.56±0.2°, 5.94±0.2°, 22.59±0.2°, 20.30±0.2°, 17.79±0.2°, 10.33±0.2 °, 12.10±0.2°, 22.26±0.2°, 19.48±0.2°, 21.73±0.2°, 5.29±0.2°, 25.80±0.2° and 16.45±0.2° at diffraction angles (2θ).

As the most preferred version, the pharmaceutical composition contains the isopropyl alcohol-aqueous solvate crystal form VII of the compound of formula (I), and the isopropyl alcohol-aqueous solvate crystal form VII of the compound of formula (I) is X-ray powder diffraction patterns (XRPD) include locations at 23.77±0.2°, 24.36±0.2°, 18.56±0.2°, 5.94±0.2°, 22.59±0.2°, 20.30±0.2°, 17.79±0.2°, 10.33±0.2° , 12.10±0.2°, 22.26±0.2°, 19.48±0.2°, 21.73±0.2°, 5.29±0.2°, 25.80±0.2°, 16.45±0.2°, 21.94±0.2°, 28.33±0.2°, 25.04±0.2° , 11.89±0.2°, 17.26±0.2°, 28.85±0.2°, 16.79±0.2°, 23.34±0.2°, 30.31±0.2° and 14.26±0.2° peaks at diffraction angles (2θ).

As a further preferred embodiment, the pharmaceutical composition contains the isopropanol-aqueous solvate crystal form of the compound of formula (I), and each molecule of the isopropyl alcohol-aqueous solvate of the compound of formula (I) contains Contains 0.5-3 isopropyl alcohol molecules and 0.5-3.0 water molecules.

As a further preferred embodiment, the pharmaceutical composition contains the isopropanol-aqueous solvate crystal form of the compound of formula (I), and each molecule of the isopropyl alcohol-aqueous solvate of the compound of formula (I) contains Contains 2.0 molecules of isopropyl alcohol and contains 1.5 molecules of water.

A second aspect of the present invention provides a preparation method of the aforementioned pharmaceutical composition, comprising the following steps:

Step A: Mix the crystal form of the compound of formula (I) and/or one or more pharmaceutically acceptable carriers to obtain a premixed material;

Step B: Add the binder hydroxypropyl cellulose to the above premixed materials to form mixed particles;

Optionally, step C: add lubricant and/or disintegrant to the above mixed particles to form final mixed particles;

Optionally, step D: compress the final mixed granules prepared in the above step C to form tablets;

Wherein, the pharmaceutically acceptable carrier is one or more of lubricants, disintegrants and fillers.

As a further preferred option, a foaming agent is added during premixing in step A of the preparation method.

As a further preferred or alternative solution, the preparation method can mix the compound of formula (I), the binder hydroxypropyl cellulose, the foaming agent and one or more pharmaceutically acceptable carriers to obtain a premixed material.

As a further preferred option, step B of the preparation method is performed after mixing to form wet granules and then drying and/or dry granulation.

As a further preferred option, the mixture obtained in step A and/or step B of the preparation method is passed through a 30-100 mesh sieve.

A third aspect of the present invention provides the crystalline form of anhydride, hydrate or solvate of the compound of formula (I):

As a preferred version, the solvate of the compound of formula (I) is 2-methyltetrahydrofuran solvate, isopropyl alcohol solvate and isopropyl alcohol-water heterosolvate.

As a further preferred embodiment, the crystal form is the anhydrous crystal form I of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form I of the compound of formula (I) includes a position at 22.86± Peaks at diffraction angles (2θ) of 0.2°, 7.81±0.2°, 29.89±0.2°, 21.35±0.2°, 16.16±0.2°, 20.73±0.2° and 27.04±0.2°.

As a further preferred solution, the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form I of the compound of formula (I) includes positions at 22.86±0.2°, 7.81±0.2°, 29.89±0.2°, and 21.35±0.2 °, 16.16±0.2°, 20.73±0.2°, 27.04±0.2°, 16.64±0.2°, 24.89±0.2°, 25.09±0.2°, 23.51±0.2°, 13.37±0.2°, 21.84±0.2°, 12.71±0.2 ° and peaks at diffraction angles (2θ) of 17.85±0.2°.

As the most preferred version, the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form I of the compound of formula (I) includes positions at 22.86±0.2°, 7.81±0.2°, 29.89±0.2°, and 21.35±0.2°. , 16.16±0.2°, 20.73±0.2°, 27.04±0.2°, 16.64±0.2°, 24.89±0.2°, 25.09±0.2°, 23.51±0.2°, 13.37±0.2°, 21.84±0.2°, 12.71±0.2° , 17.85±0.2°, 12.86±0.2°, 24.30±0.2°, 26.53±0.2°, 23.74±0.2°, 18.24±0.2°, 28.75±0.2°, 19.65±0.2°, 11.23±0.2°, 32.66±0.2° and a peak at a diffraction angle (2θ) of 18.91±0.2°.

As a preferred solution, the crystal form is the anhydrous crystal form II of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form II of the compound of formula (I) includes a position at 22.88±0.2 °, 7.82±0.2°, 29.92±0.2°, 23.51±0.2°, 21.37±0.2°, 27.06±0.2° and 24.90±0.2° peaks at diffraction angles (2θ).

As a further preferred solution, the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form II of the compound of formula (I) includes positions at 22.88±0.2°, 7.82±0.2°, 29.92±0.2°, and 23.51±0.2°. , 21.37±0.2°, 27.06±0.2°, 24.90±0.2°, 16.65±0.2°, 20.76±0.2°, 25.11±0.2°, 16.18±0.2°, 13.38±0.2°, 21.86±0.2°, 32.58±0.2° and a peak at a diffraction angle (2θ) of 12.72±0.2°.

As the most preferred version, the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form II of the compound of formula (I) includes positions at 22.88±0.2°, 7.82±0.2°, 29.92±0.2°, and 23.51±0.2°. , 21.37±0.2°, 27.06±0.2°, 24.90±0.2°, 16.65±0.2°, 20.76±0.2°, 25.11±0.2°, 16.18±0.2°, 13.38±0.2°, 21.86±0.2°, 32.58±0.2° , 12.72±0.2°, 24.31±0.2°, 15.05±0.2°, 28.77±0.2°, 26.55±0.2°, 12.87±0.2°, 22.56±0.2°, 17.85±0.2°, 23.76±0.2°, 18.26±0.2° and a peak at a diffraction angle (2θ) of 31.11±0.2°.

As a preferred solution, the crystal form is the anhydrous crystal form III of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form III of the compound of formula (I) includes a position at 5.85±0.2 °, 21.34±0.2°, 14.96±0.2°, 20.57±0.2°, 19.78±0.2°, 24.12±0.2° and 18.71±0.2° peaks at diffraction angles (2θ).

As a further preferred solution, the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form III of the compound of formula (I) includes positions at 5.85±0.2°, 21.34±0.2°, 14.96±0.2°, and 20.57±0.2°. , 19.78±0.2°, 24.12±0.2°, 18.71±0.2°, 25.13±0.2°, 13.72±0.2°, 24.65±0.2°, 22.76±0.2°, 26.75±0.2°, 14.61±0.2°, 10.81±0.2° and a peak at a diffraction angle (2θ) of 16.81±0.2°.

As the most preferred solution, the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form III of the compound of formula (I) includes positions at 5.85±0.2°, 21.34±0.2°, 14.96±0.2°, and 20.57±0.2 °, 19.78±0.2°, 24.12±0.2°, 18.71±0.2°, 25.13±0.2°, 13.72±0.2°, 24.65±0.2°, 22.76±0.2°, 26.75±0.2°, 14.61±0.2°, 10.81±0.2 °, 16.81±0.2°, 21.14±0.2°, 22.54±0.2°, 9.74±0.2°, 21.79±0.2°, 25.74±0.2°, 17.71±0.2°, 19.33±0.2°, 30.36±0.2°, 13.39±0.2 ° and peaks at diffraction angles (2θ) of 14.07±0.2°.

As a preferred solution, the crystal form is the hydrate crystal form IV of the compound of formula (I). The X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes 13.34±0.2°, Peaks at diffraction angles (2θ) of 17.41±0.2°, 21.78±0.2°, 20.02±0.2°, 14.85±0.2° and 16.53±0.2°.

As a further preferred solution, the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes positions at 13.34±0.2°, 17.41±0.2°, 21.78±0.2°, 20.02±0.2°, Peaks at diffraction angles (2θ) of 14.85±0.2°, 16.53±0.2°, 19.35±0.2°, 18.64±0.2°, 11.19±0.2°, 5.98±0.2° and 22.67±0.2°.

As the most preferred version, the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes positions at 13.34±0.2°, 17.41±0.2°, 21.78±0.2°, 20.02±0.2°, 14.85±0.2°, 16.53±0.2°, 19.35±0.2°, 18.64±0.2°, 11.19±0.2°, 5.98±0.2°, 22.67±0.2°, 20.62±0.2°, 26.72±0.2°, 14.08±0.2°, Peaks at diffraction angles (2θ) of 23.82±0.2° and 25.37±0.2°.

As a preferred solution, the crystal form is the hydrate crystal form VIII of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes positions at 23.05±0.2°, Peaks at diffraction angles (2θ) of 8.73±0.2°, 21.41±0.2°, 15.95±0.2°, 23.50±0.2°, 15.50±0.2° and 25.14±0.2°.

As a further preferred solution, the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes positions at 23.05±0.2°, 8.73±0.2°, 21.41±0.2°, 15.95±0.2°, and Peak at diffraction angle (2θ) of 19.32±0.2°.

As the most preferred version, the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes locations at 23.05±0.2°, 8.73±0.2°, 21.41±0.2°, 15.95±0.2°, 23.50±0.2°, 15.50±0.2°, 25.14±0.2°, 27.00±0.2°, 31.15±0.2°, 27.70±0.2°, 16.81±0.2°, 19.70±0.2°, 13.22±0.2°, 24.34±0.2°, and Peak at diffraction angle (2θ) of 18.59±0.2°.

As a further preferred embodiment, the hydrate of the compound of formula (I) contains 0.5-3.0 water molecules per molecule.

As a further preferred embodiment, the hydrate of the compound of formula (I) contains 0.9-1.8 water molecules per molecule.

As a further preferred embodiment, the crystal form is the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI, and the X-ray of the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI Powder diffraction patterns (XRPD) include diffraction angles (2θ) at 22.44±0.2°, 5.63±0.2°, 16.81±0.2°, 20.43±0.2°, 21.57±0.2°, 16.15±0.2° and 22.71±0.2°. peak.

As a further preferred solution, the X-ray powder diffraction pattern (XRPD) of the crystal form VI of the 2-methyltetrahydrofuran solvate of the compound of formula (I) includes positions at 22.44±0.2°, 5.63±0.2°, and 16.81±0.2 °, 20.43±0.2°, 21.57±0.2°, 16.15±0.2°, 22.71±0.2°, 6.36±0.2°, 12.60±0.2°, 25.95±0.2°, 24.92±0.2°, 13.69±0.2°, 19.65±0.2 °, 15.13±0.2° and 12.11±0.2° peaks at diffraction angles (2θ).

As the most preferred version, the X-ray powder diffraction pattern (XRPD) of the crystal form VI of the 2-methyltetrahydrofuran solvate of the compound of formula (I) includes positions at 22.44±0.2°, 5.63±0.2°, and 16.81±0.2°. , 20.43±0.2°, 21.57±0.2°, 16.15±0.2°, 22.71±0.2°, 6.36±0.2°, 12.60±0.2°, 25.95±0.2°, 24.92±0.2°, 13.69±0.2°, 19.65±0.2° , 15.13±0.2°, 12.11±0.2°, 24.25±0.2°, 11.16±0.2°, 31.57±0.2°, 14.55±0.2°, 27.00±0.2°, 17.90±0.2°, 21.12±0.2°, 11.27±0.2° , 23.18±0.2° and 14.12±0.2° peaks at diffraction angles (2θ).

As a further preferred embodiment, each molecule of the 2-methyltetrahydrofuran solvate of the compound of formula (I) contains 0.5-3.0 2-methyltetrahydrofuran molecules.

As a further preferred embodiment, each molecule of the 2-methyltetrahydrofuran solvate of the compound of formula (I) contains 1.0 2-methyltetrahydrofuran molecules.

As a further preferred embodiment, the crystal form is the isopropyl alcohol solvate crystal form V of the compound of formula (I), and the X-ray powder diffraction pattern of the isopropyl alcohol solvate crystal form V of the compound of formula (I) is ( XRPD) includes peaks at diffraction angles (2θ) of 5.28±0.2°, 10.52±0.2°, 21.29±0.2°, 5.66±0.2°, 13.52±0.2°, 22.44±0.2° and 19.35±0.2°.

As a further preferred solution, the X-ray powder diffraction pattern (XRPD) of the isopropanol solvate crystal form V of the compound of formula (I) includes positions at 5.28±0.2°, 10.52±0.2°, 21.29±0.2°, 5.66±0.2°, 13.52±0.2°, 22.44±0.2°, 19.35±0.2°, 18.48±0.2°, 16.77±0.2°, 24.68±0.2°, 19.97±0.2°, 25.67±0.2°, 15.13±0.2°, Peaks at diffraction angles (2θ) of 17.82±0.2° and 20.96±0.2°.

As the most preferred version, the X-ray powder diffraction pattern (XRPD) of the isopropanol solvate crystal form V of the compound of formula (I) includes positions at 5.28±0.2°, 10.52±0.2°, 21.29±0.2°, 5.66 ±0.2°, 13.52±0.2°, 22.44±0.2°, 19.35±0.2°, 18.48±0.2°, 16.77±0.2°, 24.68±0.2°, 19.97±0.2°, 25.67±0.2°, 15.13±0.2°, 17.82 Diffraction of ±0.2°, 20.96±0.2°, 14.86±0.2°, 12.48±0.2°, 11.94±0.2°, 14.24±0.2°, 23.87±0.2°, 23.25±0.2°, 29.51±0.2° and 27.70±0.2° Peak at angle (2θ).

As a further preferred embodiment, each molecule of the isopropyl alcohol solvate of the compound of formula (I) contains 1.0-5.0 isopropyl alcohol molecules.

As a further preferred embodiment, each molecule of the isopropyl alcohol solvate of the compound of formula (I) contains 4.2 isopropyl alcohol molecules.

As a further preferred embodiment, the crystal form is the isopropanol-aqueous solvate crystal form VII of the compound of formula (I), and the X of the isopropyl alcohol-aqueous solvate crystal form VII of the compound of formula (I) - Ray powder diffraction pattern (XRPD) includes diffraction angles (2θ) at 23.77±0.2°, 24.36±0.2°, 18.56±0.2°, 5.94±0.2°, 22.59±0.2°, 20.30±0.2° and 17.79±0.2° The peak at.

As a further preferred solution, the X-ray powder diffraction pattern (XRPD) of the isopropyl alcohol-aqueous heterosolvate crystal form VII of the compound of formula (I) includes positions at 23.77±0.2°, 24.36±0.2°, and 18.56± 0.2°, 5.94±0.2°, 22.59±0.2°, 20.30±0.2°, 17.79±0.2°, 10.33±0.2°, 12.10±0.2°, 22.26±0.2°, 19.48±0.2°, 21.73±0.2°, 5.29± Peaks at diffraction angles (2θ) of 0.2°, 25.80±0.2° and 16.45±0.2°.

As the most preferred version, the X-ray powder diffraction pattern (XRPD) of the isopropyl alcohol-aqueous heterosolvate crystal form VII of the compound of formula (I) includes positions at 23.77±0.2°, 24.36±0.2°, and 18.56±0.2 °, 5.94±0.2°, 22.59±0.2°, 20.30±0.2°, 17.79±0.2°, 10.33±0.2°, 12.10±0.2°, 22.26±0.2°, 19.48±0.2°, 21.73±0.2°, 5.29±0.2 °, 25.80±0.2°, 16.45±0.2°, 21.94±0.2°, 28.33±0.2°, 25.04±0.2°, 11.89±0.2°, 17.26±0.2°, 28.85±0.2°, 16.79±0.2°, 23.34±0.2 °, 30.31±0.2° and 14.26±0.2° peaks at diffraction angles (2θ).

As a further preferred solution, each molecule of the isopropyl alcohol-water heterosolvate of the compound of formula (I) contains 0.5-3 isopropyl alcohol molecules and 0.5-3.0 water molecules.

As a further preferred embodiment, each molecule of the isopropanol-water heterosolvate of the compound of formula (I) contains 2.0 isopropanol molecules and 1.5 water molecules.

The fourth aspect of the present invention relates to the use of the above-mentioned pharmaceutical composition or crystal form in the preparation of FGFR inhibitors.

The fifth aspect of the present invention relates to the use of the above pharmaceutical composition or crystal form in the preparation and treatment of liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or Uses in drugs for rhabdomyosarcoma.

The present invention also provides a method for inhibiting FGFR activity, which method includes administering an effective therapeutic amount of the above pharmaceutical composition or crystal form to a patient in need of treatment.

The present invention also provides a method for treating liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma or rhabdomyosarcoma, the method comprising Administer an effective therapeutic amount of the above-mentioned pharmaceutical composition or crystal form to a patient in need of treatment.

The present invention also provides an above-mentioned pharmaceutical composition or crystal form, which is used as an FGFR inhibitor.

The present invention also provides the above pharmaceutical composition or crystal form, which is used to treat liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, breast cancer, ovarian cancer, colon cancer, skin cancer, and glioblastoma. tumor or rhabdomyosarcoma.

Description of drawings

Figure 1 is a DSC analysis chart of the compound of formula (I). The abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).

Figure 2 is a DSC analysis chart of glyceryl behenate. The abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).

Figure 3 is the XRPD pattern of the compound of formula (I) after different processing methods. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity. From top to bottom, the compound of formula (I) after wet granulation, unprocessed XRPD patterns of compounds of formula (I) and grinded compounds of formula (I).

Figure 4 is the XRPD pattern of granules at different stages of granulation. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity. From top to bottom are the compounds of formula (I) in the final mixture and the formula after fluidized bed drying. XRPD patterns of compound (I), wet granulated compound of formula (I), and untreated compound of formula (I).

Figure 5 is a comparison of the dissolution curves of the original prescription and the tablets obtained in Experiment 13 and Experiment 17. The abscissa is time (min), and the ordinate is dissolution percentage (%). From top to bottom, the original prescription, Experiment 17, Experiment 13 dissolution curve.

Figure 6 is a comparison chart of the dissolution curves of the tablets obtained from the original prescription and experiments 18-20. The abscissa is time (min), and the ordinate is dissolution percentage (%). From top to bottom, it is the original prescription, experiment 18, and experiment 20. Dissolution curve of Experiment 19.

Figure 7 is an XRPD diffraction spectrum of Form I. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

Figure 8 is a DSC chart of crystal form I. The abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).

Figure 9 is a TGA diagram of Form I. The abscissa represents temperature (° C.) and the ordinate represents weight change (%).

Figure 10 is a ¹ H-NMR chart of Form I, and the abscissa indicates chemical shift (ppm).

Figure 11 is the XRPD diffraction spectrum of Form II. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

Figure 12 is a DSC chart of crystal form II. The abscissa represents temperature (℃) and the ordinate represents heat flow A (w/g).

Figure 13 is a TGA diagram of crystal form II. The abscissa represents temperature (°C) and the ordinate represents weight change (%).

Figure 14 is a ¹ H-NMR chart of the crystal form II, and the abscissa represents the chemical shift (ppm).

Figure 15 is the XRPD diffraction spectrum of Form III. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

Figure 16 is a DSC chart of crystal form III. The abscissa represents temperature (℃) and the ordinate represents heat flow A (w/g).

Figure 17 is a TGA diagram of Form III. The abscissa represents temperature (°C) and the ordinate represents weight change (%).

Figure 18 is a ¹ H-NMR chart of Form III, and the abscissa represents the chemical shift (ppm).

Figure 19 is the XRPD diffraction spectrum of Form IV. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

Figure 20 is a DSC chart of crystal form IV. The abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).

Figure 21 is a TGA diagram of Form IV. The abscissa represents temperature (° C.), and the ordinate represents weight change (%).

Figure 22 is a ¹ H-NMR chart of Form IV, and the abscissa indicates chemical shift (ppm).

Figure 23 is the XRPD diffraction spectrum of crystal form V. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

Figure 24 is a DSC chart of crystal form V. The abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).

Figure 25 is a TGA diagram of crystal form V. The abscissa represents temperature (° C.), and the ordinate represents weight change (%).

Figure 26 is a ¹ H-NMR chart of Form V, and the abscissa indicates chemical shift (ppm).

Figure 27 is the XRPD diffraction spectrum of Form VI. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

Figure 28 is a DSC chart of Form VI. The abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).

Figure 29 is a TGA diagram of Form VI. The abscissa represents temperature (° C.), and the ordinate represents weight change (%).

Figure 30 is a ¹ H-NMR chart of Form VI. The abscissa represents the chemical shift (ppm).

Figure 31 is the XRPD diffraction spectrum of crystal form VII. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

Figure 32 is a DSC chart of crystal form VII. The abscissa represents temperature (°C), and the ordinate represents heat flow A (w/g).

Figure 33 is a TGA diagram of crystal form VII. The abscissa represents temperature (° C.), and the ordinate represents weight change (%).

Figure 34 is a ¹ H-NMR chart of Form VII. The abscissa represents the chemical shift (ppm).

Figure 35 is the XRPD diffraction spectrum of Form VIII. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

Figure 36 is a DSC chart of crystal form VIII. The abscissa represents temperature (℃), and the ordinate represents heat flow A (w/g).

Figure 37 is a TGA diagram of crystal form VIII. The abscissa represents temperature (° C.), and the ordinate represents weight change (%).

Figure 38 is a ¹ H-NMR chart of Form VIII, and the abscissa represents chemical shift (ppm).

Figure 39 is an electron microscope scanning image of Form I.

Figure 40 is the XRPD pattern after the volume stability experiment of crystal form I. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity. From top to bottom in the figure are the anhydrate of the compound of formula (I). I was placed in an open container at 25°C/92%RH, an open container at 40°C/75%RH, and a closed container at 60°C for 1 week, and the crystal form I was subjected to 120°C under visible light at 25°C. XRPD pattern of the sample after stress treatment of 10,000 lux-hrs.

Figure 41 is the water adsorption isotherm of crystalline form I. The abscissa is the water activity P/PO, and the ordinate is the mass scale change (%). From top to bottom in the figure are desorption in cycle 1, adsorption in cycle 1, and desorption in cycle 2. , cycle 2 adsorption curve.

Figure 42 is a water activity change curve and a mass change curve of Form I, in which the abscissa is time (minutes), the ordinate on the left is mass change (%), and the ordinate on the right is water activity (P/PO), From top to bottom in the figure are the water activity change curve and mass change curve of Form I.

Figure 43 shows the XRPD pattern of Form I before and after DSV testing. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

Figure 44 is the XRPD diagram of crystal form I before and after the compression simulation test. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity. From top to bottom in the figure are the starting crystal form I, the hydraulic press and the XRPD patterns of Form I after compression at 2MPa, 5MPa and 10MPa.

Figure 45 is the XRPD pattern of Form I before and after the wet granulation simulation experiment test. The abscissa indicates the 2θ value (degrees), and the ordinate indicates the peak intensity. From top to bottom in the figure, it is made with isopropyl alcohol and water. XRPD patterns of post-granulation form I and starting form I.

Detailed ways

1. Specific definition

Detailed description: Unless stated to the contrary or otherwise specified, the following terms used in the specification and claims have the following meanings.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or physiologically/pharmaceutically acceptable crystalline forms, salt forms or prodrugs thereof, and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable Medicinal carrier. The purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.

The pharmaceutical composition of the present invention may include one or more pharmaceutically acceptable carriers, which include but are not limited to: binders, lubricants, diluents, stabilizers, buffers, adjuvants, carriers, emulsifiers, Viscosity regulators, surfactants, preservatives, flavoring or coloring agents. Examples of medically acceptable excipients can be found in R.C. Rowe and P.J. Shesky's "Handbook of Pharmaceutical Excipients."

As used herein, the term "binder" or "binder" refers to a pharmaceutically acceptable compound or composition added to a formulation to hold active pharmaceutical ingredients and inactive ingredients together in a cohesive mixture. Dry binders used for direct compaction must exhibit cohesion and adhesion so that the particles coalesce when compacted. The binders used in wet granulation are hydrophilic and soluble in water, and usually dissolve in water to form a wet mass which is then granulated. Examples of suitable binders include (but are not limited to) providone, Plasdone K29/32, Plasdone S-630, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, aluminum stearate, hydroxypropyl Methylcellulose and its analogs. It is possible that these binders additionally act as water sequestrants (e.g. providone).

As used herein, the term "blowing agent" refers to any pharmaceutically acceptable substance that evolves gas in response to an irritant (eg, carbon dioxide upon acidification). Examples of blowing agents are carbonates, for example metal carbonates (such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate or aluminum carbonate) or organic carbonates (such as sodium diglycinate carbonate, dimethyl carbonate acid salt or ethylene carbonate). Another example of a blowing agent is a bicarbonate, for example a metal bicarbonate (such as sodium bicarbonate or potassium bicarbonate).

As used herein, the term "filler" refers to any pharmaceutically acceptable substance or composition added to a formulation to increase volume. Suitable fillers include, but are not limited to, mannitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, and dicalcium phosphate.

As used herein, the term "lubricant" refers to any pharmaceutically acceptable agent that reduces surface friction, lubricates the particle surface, reduces the tendency of static electricity to accumulate, and/or reduces the brittleness of the particle. Therefore, lubricants act as anti-aggregation agents. Conventional lubricants include stearic acid and related compounds such as magnesium stearate and sodium stearyl fumarate. Alternative lubricants include glycerol dibehenate, colloidal silica, talc, other hydrogenated vegetable oils, or triglycerides. Examples of suitable alternative lubricants include, but are not limited to, glyceryl dibehenate.

As used herein, the term "disintegrant" refers to a substance added to a composition to help it break apart (disintegrate) and release the pharmaceutical agent. Examples of disintegrants include, but are not limited to, non-sugar water-soluble polymers such as cross-linked polyvinylpyrrolidone. Other disintegrants that may also be used include, for example, croscarmellose sodium, sodium starch glycolate and the like, see for example Khattab (1992) J. Pharm. Pharmacol. 45:687-691.

The term "hydroxypropyl cellulose" is a partially substituted poly(hydroxypropyl) ether of cellulose. Commercially available hydroxypropylcellulose is divided into many specifications according to different molecular weights, and its aqueous solutions also have different viscosities. For example, "hydroxypropyl cellulose LF" refers to hydroxypropyl cellulose with an average molecular weight of about 95,000, or hydroxypropyl cellulose with LF specifications. "Hydroxypropyl cellulose JF" refers to hydroxypropyl cellulose with an average molecular weight of about 140,000, or JF grade hydroxypropyl cellulose. "Hydroxypropyl cellulose EXF or EF" refers to hydroxypropyl cellulose with an average molecular weight of about 80,000, or hydroxypropyl cellulose with EXF or EF grade specifications.

规格(X表示细粒径)Specifications (X represents fine particle size)	平均分子量average molecular weight
羟丙基纤维素EXF；EFHydroxypropyl cellulose EXF; EF	8000080000
羟丙基纤维素LFHydroxypropyl cellulose LF	9500095000
羟丙基纤维素JFHydroxypropyl cellulose JF	140000140000
羟丙基纤维素GFHydroxypropyl cellulose GF	370000370000

羟丙基纤维素MFHydroxypropyl cellulose MF	850000850000
羟丙基纤维素HXFHydroxypropyl cellulose HXF	11500001150000

The English name of "silicified microcrystalline fiber" is Silicified microcrystalline cellulose, which refers to the preparation of microcrystalline cellulose and colloidal silica by blending and drying in water. Calculated as a dry product, it generally contains 94.0 to 100% microcrystalline cellulose. .

The terms "tabletting", "compaction" and "compression" refer to the process of applying compressive force (eg in a mold) to a formulation (powder or granules) to form tablets. The term "tablet" means any tablet formed by such a process. The term "tablet" is used in its common context and refers to a solid composition made by compressing and/or molding a mixture of the compositions into a form convenient for swallowing or application to any body cavity.

The term "punch sticking" refers to the adhesion of material to the surface of the tablet punch. If sufficient material is built up on the punch surface, the tablet weight may fall below acceptable limits, among other defects. (Journal of Pharmaceutical Sciences, Vol. 93(2), 2004).

"Polymorph" refers to a crystalline form that has the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions that make up the crystal. Although polymorphs have the same chemical composition, they differ in packing and geometric arrangement and may exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution velocity and similar properties. Depending on their temperature-stability relationship, two polymorphs can be monotropic or tautotropic. For a unidenaturing system, the relative stability between the two solid phases remains unchanged when the temperature changes. In contrast, in tautotropic systems, there is a transition temperature at which the stability of the two phases switches. The phenomenon of a compound existing in different crystal structures is called drug polymorphism.

2.Analysis method

The various crystalline structures of the present invention can be distinguished from each other using various analytical techniques known to those of ordinary skill in the art. Such techniques include, but are not limited to, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and/or thermogravimetric analysis (TGA).

2.1 X-ray powder diffraction

One of ordinary skill in the art will recognize that X-ray powder diffraction patterns can be obtained with measurement errors that depend on the measurement conditions used. The intensity in an X-ray powder diffraction pattern may fluctuate depending on the conditions of the material used. Relative strengths may also vary with experimental conditions, and accordingly, the exact strengths should not be taken into account. In addition, the measurement error of conventional powder X-ray powder diffraction angles is usually about 5% or less, and this degree of measurement error should be regarded as belonging to the above-mentioned diffraction angles. Accordingly, the crystal structures of the present invention are not limited to crystal structures that provide an X-ray powder diffraction pattern that is identical to the X-ray powder diffraction pattern depicted in the figures disclosed herein. Any crystal structure having an X-ray powder diffraction pattern substantially identical to those disclosed in the drawings falls within the scope of the present invention. Those skilled in the art should have the ability to determine that X-ray powder diffraction patterns are substantially the same. Other suitable standard calibrations are known to those skilled in the art. However, the relative strength may vary with crystal size and shape.

Crystalline forms of the compounds of the invention are characterized by their X-ray powder diffraction patterns. Therefore, using Cu Kα radiation with

The X-ray powder diffraction pattern of the salt was collected on a Bruker D8 Discover X-ray powder diffractometer operated in reflection mode with a GADDS (General Area Diffraction Detector System) CS. The tube voltage and current were set to 40kV and 40mA for acquisition scan respectively. Scan the sample over a 2θ range of 3.0° to 40° for a period of 60 seconds. The diffractometer was calibrated using corundum standards for peak positions expressed in 2θ. All analyzes were performed at typically 20°C-30°C. Data were acquired and integrated using GADDS for WNT software version 4.1.14T. Diffractograms were analyzed using DiffracPlus software with version 9.0.0.2 of Eva released in 2003.

To prepare XRPD samples, the sample is usually placed on a single crystal silicon wafer, and the sample powder is pressed with a glass plate or equivalent to ensure that the surface of the sample is flat and has an appropriate height. The sample holder was then placed into the Bruker XRPD instrument and X-ray powder diffraction patterns were collected using the instrument parameters described above. Measurement differences associated with the results of such X-ray powder diffraction analysis arise from a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, ( d) operator errors (including those occurring in determining peak positions), and (e) properties of the material (eg preferred orientation errors). Calibration errors and sample height errors often cause all peaks to be shifted in the same direction. Generally speaking, this calibration factor will bring the measured peak position consistent with the expected peak position and within ±0.2° of the expected 2θ value.

2.2 Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry (DSC) experiments were performed in a TA Instruments ^TM model Q2000. Samples (approximately 1-6 mg) were weighed in aluminum pans and recorded to the nearest hundredth of a mg and transferred to DSC. The instrument was purged with nitrogen at 50 ml/minute. Data were collected between room temperature and 350°C at a heating rate of 10°C/min. Plot with the endothermic peak facing downwards. However, those skilled in the art note that in DSC measurements, the measured starting and maximum temperatures have a certain degree of variability depending on the heating rate, crystal shape and purity, and other measurement parameters.

2.3 Thermogravimetric Analysis (TGA)

Thermogravimetric analysis (TGA) experiments were performed in a TA Instruments ^TM model Q500. Samples (approximately 10-30 mg) were placed in pre-tare platinum pans. Accurately measure the sample weight by instrument and record to the nearest thousandth of a mg. The furnace was purged with nitrogen at 100 ml/minute. Data were collected between room temperature and 300°C at a heating rate of 10°C/minute.

2.4 Dynamic moisture adsorption method (DVS)

The experimental method of using the dynamic moisture adsorption method (DVS) to characterize the acid salt of the compound of crystalline form (I) is to take a small amount of the acid salt powder of the compound of crystalline form (I) and place it in a precision sample tray matched with the instrument. After loading the sample , sent to the instrument for testing. All instruments used in the dynamic moisture adsorption method in this patent are DVS Intrinsic. The experimental parameters are set as follows: nitrogen is used as the carrier gas, the constant temperature is set to 25°C, and the mass percentage change rate per unit time (dm/dt) = 0.002% /min as the criterion for reaching equilibrium, the program humidity change cycle is set as follows: the initial relative humidity is 0%, the relative humidity at the end is 90%, the cycle is set 2 times, and each 10% R.H. change is a step.

The reagents in the embodiments of the present invention are known and can be purchased on the market. The reagents used are commercially available industrial grade or analytical grade reagents, or can be synthesized using or according to methods known in the art. In particular, the formula ( I) Compound API raw materials are prepared according to patent WO2008075068A1.

Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the temperature unit is degrees Celsius (°C). The term "room temperature" or "RT" as used herein refers to an ambient temperature of 20 to 25°C (68-770F).

3. Experimental instruments and materials

3.1 Instruments and equipment

3.2 Material information

The following examples further illustrate the present invention in detail and completely. They are only used to illustrate specific embodiments of the present invention and should not be construed as limiting the scope of the present invention in any way.

Preparation of specific embodiments

Example 1

1. Experiment to explore the causes of sticking in the preparation process

With reference to the pharmaceutical composition formula disclosed in the prior art WO2014096828A1 and the original clinical development prescription of AZD4547 (original prescription), magnesium carbonate, microcrystalline cellulose, mannitol, and hydroxypropyl fiber were added according to the components and contents recorded in Table 1 below. Vegetable EXF, carboxymethyl starch sodium and the compound of formula (I) are sieved and premixed, then poured into a wet granulation pot, purified water is added to the powder, and a wet granulator is used for granulation. After wet granulation, use a fluidized bed dryer to dry to appropriate moisture (≤2% w/w). After the dried granules are dried and granulated, glyceryl behenate is then added to the granules and mixed evenly to obtain final mixed granules, which are then compressed into tablets, resulting in sticking.

Subsequently, the components in the original prescription that may cause sticking were explored and optimized, and the tablets were mixed and compressed according to the components and contents recorded in Experiments 1-4 in Table 1 below.

Table 1

Note: NA means that it does not contain this component, and the following experiments have the same meaning. The API used in the original prescription was prepared according to WO2008075068A2, and the API used in Experiments 1-4 was the anhydrous crystal form I of the compound of formula (I). In addition, except for the API compound of formula (I) used in Example 6, which was prepared according to patent WO2008075068A1, other examples are not specifically specified. The APIs used in the experimental research are all anhydrous crystal form I of the compound of formula (I). .

2. Experimental results and analysis

2.1 Experiment 1 examined the effect of the compound of formula (I) on sticking

The experimental results show that the compound of formula (I) is in the shape of a sponge cake when pressed alone and clearly adheres to the punch, indicating that the compound of formula (I) has adhesive properties and will adhere when in contact with the punch.

In addition, in order to rule out whether the low melting point material (glyceryl behenate) or the compound of formula (I) after crystallization softens due to the heat generated during tableting, resulting in sticking, the hygroscopicity of the compound of formula (I) was also investigated. , and measured glyceryl behenate, compound of formula (I), ground compound of formula (I), compound of formula (I) processed by moist heat processing (simulated wet granulation), premixed powder, and wet granulation. The melting point (Tg) of the granules, fluidized bed dried granules, and final mixed granules is used to determine whether the compound of formula (I) undergoes crystal form transformation during the granulation process.

The experimental results are shown in Figures 1 to 4. The DSC and XRPD measurement results of the samples show that the melting point of the compound of formula (I) is 172.38°C, has no Tg value, and does not absorb moisture under the conditions of 25°C and 80% RH. The melting point of glyceryl behenate is: 71.63℃ and has no Tg value. It is preliminarily determined that the XRPD of the compound of formula (I) after moist heat treatment and grinding shows no crystalline change. The XRPD test results of the granules at each stage of granulation show no change in crystalline form, thus ruling out the possibility of sticking due to the melting of low-melting point materials and the conversion of the compound of formula (I) into amorphous form during the wet granulation process.

2.2 Experiment 2 examined the effect of the compound of formula (I) and magnesium carbonate binary mixture on sticking.

The experimental results show that the binary mixture of the compound of formula (I) and magnesium carbonate is in a loose shape when pressed into tablets. When the pressure is increased, it will stick to the punch, indicating that the compound of formula (I) has adhesiveness and can be dispersed after being mixed with magnesium carbonate. (I) compound to improve sticking phenomenon.

2.3 Experiment 3 investigated the effect of the compound of formula (I) and the binary mixture of colloidal silica on sticking.

The experimental results show that the binary mixture of the compound of formula (I) and colloidal silica cannot be pressed into tablets, but no material adheres to the punch, indicating that silica as a masking agent has the potential to improve sticking.

2.4 Experiment 4 examined the influence of the method of adding internal and external fillers on sticking.

The microcrystalline cellulose and mannitol in the original prescription were added internally and externally (1/2 was used for wet granulation and 1/2 was used for external mixing) to dilute the ungranulated compound of formula (I). The results show that : The prepared granules will stick to each other within 3 minutes of tableting.

Experimental results show that the physical and chemical properties of the compound of formula (I) itself are the main factors leading to sticking, and exclude the possibility of sticking due to the melting of low-melting point materials and the conversion of the compound of formula (I) into amorphous form during the wet granulation process. sex. The method of adding fillers internally and externally cannot improve the sticking phenomenon. It is still necessary to effectively reduce the amount of fine powder during the granulation stage to prevent sticking. At the same time, silica serves as a masking agent for the compound of formula (I) and has the potential to improve the sticking phenomenon.

Example 2

Based on the analysis of the reasons for sticking and the experimental results in the preparation process of the preparation in Example 1 above, the inventors tried to improve the sticking problem by optimizing the preparation process. During the granulation stage, the proportion of large particles was increased and the amount of fine powder was reduced. Exposure of compounds of formula (I) is the main research idea.

While the original recipe remains unchanged, try to change the way the adhesive is added based on the original preparation process (the adhesive is added from dry powder to an aqueous solution), and the amount of water added during granulation is increased (additional purified water is added) amount), change the dry and wet granulation methods (from mechanical sieving to manual sieving), the drying method (from fluidized bed drying to oven drying), and use chrome plating punching and other optimized formulation process plans in the tableting process, but None of them completely solved the sticking problem. The results of each experiment are as follows:

Table 2

Based on the above experimental research results, the inventors tried again to increase the concentration of hydroxypropyl cellulose EXF and add additional liquid, but failed to effectively reduce the proportion of fine powder, and could not effectively solve the sticking problem that occurred during the preparation process.

Example 3

Based on the experimental research results of the above-mentioned Examples 1 and 2, the inventor proposed the optimization idea of changing the specification of the adhesive (or binder) hydroxypropyl cellulose from EXF grade to LF grade, and continued to investigate the hydroxypropyl cellulose The concentration of cellulose LF and the type of added lubricant affect sticking. According to the components and contents recorded in experiments 10-17 in Table 3, sieve and premix magnesium carbonate, microcrystalline cellulose, sodium mannitol carboxymethyl starch and the compound of formula (I) and pour them into a wet granulation pot. An aqueous solution of propylcellulose LF was added to the powder. Use a wet granulator for granulation. After wet granulation, use a fluidized bed dryer to dry to appropriate moisture (≤2% w/w). After the dried granules are dried and granulated, lubricant is added to the granules and mixed evenly to obtain final mixed granules. The tablets are then pressed to observe the sticking situation. The experimental phenomena are described in Table 4.

table 3

Table 4 Summary of optimization experimental information for improving sticking

Experimental results and analysis

1. Experiment 10 examined the effects of changing the adhesive type and adding silica on sticking.

The experimental results show that the addition of silica makes the wet granulation process difficult. During the granulation process, additional water was added 4 times, the total water added was 75.61%, the granulation time was 34min31s, and the granules produced were fine. The obtained granules were tableted, and the experiment found that although the hardness and disintegration time of the tablets were not affected by the high proportion of silica added, sticking occurred within 2 minutes of tableting.

2. Experiments 11-13 examined the effects of higher dosage of adhesive and higher dosage of adhesive combined with additional silica or magnesium stearate on sticking.

The experimental results show that a higher dosage of hydroxypropyl cellulose LF (proportion: 7%, binder concentration: 12%) has a significant impact on the granulation effect. In the three experiments, there was no sticking phenomenon in the tableting. This is It shows that compact large particles can effectively alleviate the sticking phenomenon. However, hydroxypropylcellulose LF at this dosage will make the wet particles sticky and heavy, making it impossible to use fluidized bed drying. At the same time, after drying, the produced granules are too compact, resulting in rough tablet surfaces, prolonged disintegration time, and unstable tablet weight and hardness during tableting.

3. Experiments 15-17 investigate the effects of reducing the amount of adhesive, increasing the amount of glyceryl behenate, or combining it with silica or magnesium stearate on sticking.

The experimental results show that after the proportion of hydroxypropyl cellulose LF was reduced from 7% to 5%, and the concentration was reduced from 12% to 10%, the wet particles produced still had more large particles, but after fluidized bed drying, fine particles The proportion of fans increased. The increase in fine powder increased the exposure of the compound of formula (I), leading to the sticking phenomenon in Experiment 15. Comparing the tableting phenomenon in Experiments 15-17, it can be observed that when there is a large amount of fine powder, adding magnesium stearate and silicon dioxide can effectively prevent the occurrence of sticking. Therefore, the amount of adhesive is a key factor in solving the sticking problem.

4. Analysis of experimental results on the impact of different adhesive types on sticking

The tableting conditions of Comparative Experiments 11-13 show that when 3% glyceryl behenate is used alone, the lubrication effect is limited.

The tableting conditions of comparative experiments 11 and 15 show that when the amount of binder is reduced (the proportion of hydroxypropylcellulose LF is reduced from 7% to 5%, and the concentration is reduced from 12% to 10%), the fluidized bed is used at the same time. When drying, even if the dosage of glyceryl behenate is increased to 5%, sticking will still occur.

In Experiments 15-17, when glyceryl behenate is used in combination with magnesium stearate and silicon dioxide, it has a better anti-sticking effect. Among them, the tableting phenomenon in experiments 11-13 and 15-17 shows that magnesium stearate has a more significant effect on preventing sticking and tablet appearance than glyceryl behenate and silicon dioxide.

It is worth noting that although the addition of silica is also effective in preventing sticking, the tableting results of Experiment 16 show that the addition of 7% silica makes the hardness of the pressed tablets only 3kp. Therefore, the type of lubricant also plays an important role in solving the sticking problem.

Experimental results show that when selecting the adhesive LF grade hydroxypropyl cellulose, the dosage is 5% and the concentration is 10% for wet granulation; and glyceryl behenate and magnesium stearate are used together as external lubricants. When, it can effectively prevent the occurrence of sticking.

Example 4

(Evaluate the effects of filler, disintegrant dosage, and lubricant dosage on tablet dissolution)

Experiments 13 and 17 used a higher viscosity adhesive (hydroxypropyl cellulose LF), added the lubricant magnesium stearate, and increased the dosage of glyceryl behenate to solve the sticking problem. . At the same time, the properties of the final mixed particles were changed, so the tablet dissolution efficiency of the coated tablets prepared in Experiment 13 and Experiment 17 was evaluated. The solubility was measured in a pH 6.8 phosphate buffer solution at 37°C ± 0.5°C using a paddle method with a stirring speed of 50 rpm. At 15, 30 and 60 minutes, the dissolution medium was withdrawn and the concentration in the solution was determined by UV broad spectrum method at 311 nm wavelength against an external standard solution. The experimental data are detailed in Table 5, and the dissolution curve comparison is shown in Figure 5.

table 5

The experimental results show that as the amount of adhesive decreases, the release degree of the lubricant magnesium stearate added in Experiment 17 in 30 minutes is greater than that of the lubricant magnesium stearate added in Experiment 13, although the dissolution rate of the new prescription meets the release standard (30 minutes release greater than 75%), but the dissolution and release degree of the two batches at T ₀ point 30 minutes are lower than the original prescription.

Considering that the amount of adhesive and lubricant magnesium stearate are the key to solving the sticking problem, based on the aforementioned experimental results, the amount and adding method of disintegrant, filler (mannitol, microcrystalline The proportion and dosage of cellulose) have been adjusted. The quantitative composition and adding method are detailed in Table 6.

According to the components and contents recorded in experiments 10-17 in Table 6, sieve and premix magnesium carbonate, microcrystalline cellulose, sodium mannitol carboxymethyl starch and the compound of formula (I) and pour them into a wet granulation pot. An aqueous solution of propylcellulose LF was added to the powder. Use a wet granulator for granulation. After wet granulation, use a fluidized bed dryer to dry to appropriate moisture (≤2% w/w). After the dried granules are dry granulated, lubricants and/or disintegrants are then added to the granules and mixed evenly to obtain final mixed granules, which are then tableted.

Solubility was measured in pH 6.8 phosphate buffer solution using a paddle method with a stirring speed of 50 rpm. At 15, 30, and 60 minutes, the dissolution medium was withdrawn and the concentration of the solution was determined by UV broad spectrum method at 311 nm wavelength against an external standard solution. The experimental data are detailed in Table 7, and the dissolution curve is shown in Figure 6.

Table 6

Table 7

The experimental results show that although the proportion of components was adjusted on the basis of Experiment 17, no sticking occurred during tableting of the three batches of Experiments 18-20.

Experiment 18 examined the improvement of dissolution release by the amount of filler. The results showed that after the proportion of microcrystalline cellulose increased from 9.685% to 30.182%, the dissolution release of the tablets in Experiment 17 at 30 minutes improved to a certain extent. This may be due to the microcrystalline cellulose. When the amount of cellulose is greater than 30%, the disintegration ability is enhanced. However, it can still be observed that the tablet disintegrates slowly during the dissolution process, and larger lumps can be observed to accumulate at the bottom of the cup at 20 minutes.

Experiment 19 examined the improvement of dissolution release by adjusting filler dosage, disintegrant dosage, and adding method. The results showed that based on Experiment 17, the disintegrant proportion was increased (7.5% to 10%) and the dosage was increased to 5. After % internal addition and 5% external addition, the dissolution difference was larger. Some tablets had less accumulation at the bottom of the cup. At this time, the dissolution and release degree was higher, reaching 90% in 30 minutes. However, some tablets have larger pieces accumulated at the bottom of the cup, resulting in reduced dissolution. Only 73% is released in 30 minutes. When accelerated to 250 rpm, the lumps can be seen to quickly disintegrate.

Experiment 20 considers the insoluble particles that appear during the dissolution process. Based on Experiment 18, the proportion of water-soluble mannitol is increased and the proportion of microcrystalline cellulose is reduced (microcrystalline cellulose is 20% and mannitol is 20.63%). At the same time, after reducing the amount of lubricant (glyceryl behenate was reduced from 5% to 3%, and magnesium stearate was reduced from 3% to 1.5%), the results showed that although there were still small agglomerates during the dissolution process , but the dissolution release is the best.

Example 5

(Stability production of 20mg and 80mg specifications products and comparison with original prescription tablets)

Based on the above experimental results and analysis, the inventor produced 20 mg and 80 mg tablet products according to the components and contents recorded in Experiment 20 in Table 8.

Table 8 Comparison of original prescription and experimental 20 components

1. Preparation of 20mg tablets

1) Wet granulation: First, premix magnesium carbonate that has passed through a 35-mesh sieve and the compound of formula (I) to obtain mixture material 1. Pass microcrystalline cellulose, mannitol, and sodium starch carboxylate through a 35-mesh sieve respectively, and then pour them into a wet granulation pot with mixture 1 for premixing. Granulate and knead the premix according to the set parameters. The whole process lasted 12 minutes and 43 seconds, and no additional water was added during the process.

2) Wet granulation: Use Comil U5 to wet granulate the granules. The screen aperture is 6350μm and the rotation speed is 1750rpm to prevent the production of excessive fine powder.

3) Fluidized bed drying: transfer the wet particles to a 3L fluidized bed for drying. When the moisture content of the particles is <2%, drying is stopped. The final moisture content of the pellets was 1.4%.

4) Dry granulation: Use Comil U5 for wet granulation, with a screen aperture of 1575 μm and a rotation speed of 2500 rpm. Since a certain amount of larger particles remain on the screen and cannot pass through the screen, the rotation speed is increased to 2700 rpm. The granules after dry granulation have a larger amount of fine powder.

5) Adding disintegrant and lubrication: Calculate the proportion of external excipients based on the quality of the dried particles. The additional auxiliary materials are weighed and sieved and then mixed according to the set parameters. The mixing times for adding croscarmellose sodium, glyceryl behenate, and magnesium stearate are 8 minutes, 30 minutes, and 3 minutes respectively.

6) BU sampling and powder central control: Use a sampler to sample the final mixed particles to measure BU, and at the same time detect the powder bulk density, tap density, and particle size distribution. The experimental results are shown in Table 9. The BU result measurement showed that it was qualified (mean value: 100.9%), and there was no excess.

7) Tablet compression: The target tablet weight of 20mg specification is 96.81mg, the single tablet limit is 92.5%-107.5%, and the tablet weight range is 89.55-104.07mg. During tableting, the 20mg specification uses two sets of 6mm non-chrome plated punches at 30rpm for tableting. Due to the large amount of fine powder, the main pressure fluctuates greatly during the tableting process, but the tablet weight is relatively stable. The tableting process of 20mg specification lasted for 90 minutes, and the appearance of the tablets was smooth and smooth, with no sticking phenomenon during the process. However, due to the large amount of fine powder, powder leakage occurred during the tableting process, and the yield was reduced. The final tablet was 442.74g (about 4500EA).

8) Coating: Coat the pressed tablets, and the solid content of the coating liquid is 18%. The target weight gain is 3%, and the weight gain range is 2.% to 3.4%. Use a 2.5L coating pot and a 1.0mm nozzle to coat according to the set parameters. The final weight gain of the 20mg specification was 3.3%, and the final yield was 453.4g. The surface of the coated tablet was smooth and there was no color difference.

9) Bottled: Packed at 24EA/bottle, each bottle contains one bag of 1g desiccant. The equipment is debugged according to the set parameters for bottling, and finally the bottled samples are sent to analysis and testing for sampling.

10) Test results.

2. Preparation of 80mg tablets

1) Wet granulation: First, premix magnesium carbonate that has passed through a 35-mesh sieve and the compound of formula (I) to obtain mixture material 1. Pass microcrystalline cellulose, mannitol, and sodium starch carboxylate through a 35-mesh sieve respectively, and then pour them into a wet granulation pot with mixture 1 for premixing. Granulate and knead the premix according to the set parameters. The entire process lasted for 14min16s and 15min39s respectively in the two sub-batches, and no additional water was added during the process.

2) Wet granulation: Combine the two sub-batches, use Comil U5 to wet granulate the granules, the screen aperture is 6350μm, and the rotation speed is 1750rpm.

3) Fluidized bed drying: Transfer the combined wet particles to a 6L fluidized bed for drying. When the moisture content of the particles is <2%, drying is stopped. The final moisture content of the pellets was 0.94%.

4) Dry granulation: Use Comil U5 to wet granulate the granules, the screen aperture is 1575μm, and the rotation speed is 2250rpm. The granules after dry granulation have a larger amount of fine powder.

6) BU sampling and powder central control: Use a sampler to sample the final mixed particles to measure BU, and at the same time detect the powder bulk density, tap density, and particle size distribution. The experimental results are shown in Table 9. The BU result measurement showed that it was qualified (mean value: 101.7%), and no single value exceeded the limit.

7) Tablet compression: The target tablet weight of 80mg specification is 387.22mg, the single tablet limit is 95%-105%, and the tablet weight range is 367.86-406.58mg. When pressing, use 2 sets of 6mm and 11mm non-chrome plated punches and press at 30rpm. During the tableting process, the main pressure is relatively stable and powder leakage is significantly improved. The compression of 80 mg tablets lasted for 60 minutes. The appearance of the tablets was smooth and smooth, and there was no sticking phenomenon during the process. The final film was 1404.9g (about 3600EA).

8) Coating: Coat the pressed tablets, and the solid content of the coating liquid is 18%. The target weight gain is 3%, and the weight gain range is 2.% to 3.4%. Use a 2.5L coating pot and a 1.0mm nozzle to coat according to the set parameters. The final weight gain of the 80mg specification is 2.84%, and the final yield is 1433.0g. The coated tablet has a smooth surface and no color difference.

10) Test results: The test results all meet the release requirements.

Table 9 Powder properties of 20mg, 80mg batches and original prescription granules

During the production process, it was found that the original prescription had a serious sticking phenomenon, but the tablets prepared with the new prescription after optimization of the prescription and process did not have this phenomenon. In addition, from the particle size distribution data, it can be seen that the new prescription is less than the original prescription. There are relatively many coarse particles and relatively few very fine powders. The dissolution results of 20mg and 80mg tablets are shown in Table 10 below:

Table 10

Example 6

(Preparation of Crystal Form I and Evaluation of Related Properties)

1. Preparation of crystal form I (1)

Equilibrate approximately 30-50 mg of the compound of formula (I) in 0.2-0.5 mL of different solvents (see Table 11 for details) at 25°C for 2 weeks using a stirring bar on a magnetic stirring plate at a rate of 300-400 rpm. The obtained suspension was centrifuged at 14,000 rpm, filtered through a 0.45 μm nylon membrane filter, and dried to obtain the anhydrous crystalline form of the compound of formula (I) (designated as crystalline form I).

Table 11 Equilibration in different solvents at 25°C for 2 weeks

序号 serial number		溶剂Solvent
11	甲苯 Toluene
22	乙酸乙酯 Ethyl acetate
33	异丙醇 Isopropyl alcohol
44	异丙醇/水(98:2,v:v),a.w.＝0.22Isopropyl alcohol/water (98:2, v:v), a.w.＝0.22
55	异丙醇/水(95:5,v:v),a.w.＝0.44Isopropyl alcohol/water (95:5, v:v), a.w.＝0.44
66	异丙醇/水(90:10,v:v),a.w.＝0.67Isopropyl alcohol/water (90:10, v:v), a.w.＝0.67
77	异丙醇/水(85:15,v:v),a.w.＝0.80Isopropyl alcohol/water (85:15, v:v), a.w.＝0.80
88	异丙醇/水(77:23,v:v),a.w.＝0.90Isopropyl alcohol/water (77:23, v:v), a.w.＝0.90
99	水water
备注：Remark:	表示水活性，通过Unifac方法计算。Indicates water activity, calculated by the Unifac method.

2. Preparation of crystal form I (2)

At 50°C, approximately 30-50 mg of the compound of formula (I) was equilibrated in 0.2-0.5 mL of different solvents (see Table 12 for details) using a stirring bar on a magnetic stirring plate at a rate of 300-400 rpm for 1 week. The suspension obtained was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm, and crystals were obtained after drying and were identified as Form I.

Table 12 Equilibrate in different solvents at 50℃ for 1 week

序号 serial number		溶剂Solvent
11	甲苯 Toluene
22	乙酸乙酯 Ethyl acetate
33	2-甲基-四氢呋喃2-Methyl-tetrahydrofuran
44	异丙醇 Isopropyl alcohol
55	异丙醇/水(98:2,v:v),a.w.＝0.23Isopropyl alcohol/water (98:2, v:v), a.w.＝0.23
66	异丙醇/水(95:5,v:v),a.w.＝0.45Isopropyl alcohol/water (95:5, v:v), a.w.＝0.45
77	异丙醇/水(90:10,v:v),a.w.＝0.67Isopropyl alcohol/water (90:10, v:v), a.w.＝0.67
88	异丙醇/水(85:15,v:v),a.w.＝0.80Isopropyl alcohol/water (85:15, v:v), a.w.＝0.80
99	异丙醇/水(77:23,v:v),a.w.＝0.89Isopropyl alcohol/water (77:23, v:v), a.w.＝0.89
1010	水water
备注：Remark:	表示水活性，通过Unifac方法计算。Indicates water activity, calculated by the Unifac method.

3. Preparation of crystal form I (3)

Equilibrate approximately 30-50 mg of the compound of formula (I) in 0.2-1 mL of different solvents (see Table 13 for details) for 2 weeks at 5°C using a stirring bar on a magnetic stirring plate at a rate of 300-400 rpm. The suspension obtained was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm, and crystals were obtained after drying and were identified as Form I.

Table 13 Using different solvents to equilibrate at 5°C for 2 weeks

序号 serial number		溶剂Solvent
11	甲苯 Toluene
22	乙酸乙酯Ethyl acetate

33	异丙醇 Isopropyl alcohol
44	异丙醇/水(98:2,v:v),a.w.＝0.21Isopropyl alcohol/water (98:2, v:v), a.w.＝0.21
55	水water
备注Remark	表示水活性，通过Unifac方法计算。Indicates water activity, calculated by the Unifac method.

4. Preparation of crystal form I (4)

Approximately 50 mg of the compound of formula (I) was equilibrated in 0.2-0.5 ml of different solvents (see Table 14 for details) for 10 cycles at a temperature cycle from 5°C to 50°C with a heating/cooling rate of 0.1°C/minute. Equilibrate with a stir bar on a magnetic stirring plate at 300-400 rpm. The suspension obtained was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm, and crystals were obtained after drying and were identified as Form I.

Table 14 Equilibrium under different temperature cycles

序号 serial number		溶剂Solvent
11	甲苯 Toluene
22	乙酸乙酯 Ethyl acetate
33	异丙醇 Isopropyl alcohol
44	异丙醇/水(90:10,v:v)Isopropyl alcohol/water (90:10,v:v)
55	异丙醇/水(80:20,v:v)Isopropyl alcohol/water (80:20,v:v)
66	异丙醇/水(50:50,v:v)Isopropyl alcohol/water (50:50,v:v)
77	异丙醇/水(30:70,v:v)Isopropyl alcohol/water (30:70,v:v)
88	异丙醇/水(10:90,v:v)Isopropyl alcohol/water (10:90, v:v)
99	水water
备注：Remark:	表示水活性，通过Unifac方法计算。Indicates water activity, calculated by the Unifac method.

5. Preparation of Form I (5)

Dissolve approximately 50 mg of the compound of formula (I) in 3.5 ml of 2-methyl-tetrahydrofuran at ambient temperature (approximately 20-25°C). To the resulting clear solution, 14 ml of toluene was slowly added until a large amount of solid precipitated. The precipitate was collected by centrifugal filtration at 14,000 rpm through a 0.45 μm nylon membrane filter and dried to obtain crystals, which were identified as crystalline form I.

6. Preparation of Form I (6)

Dissolve about 50 mg of the compound of formula (I) in 3.5 ml of 2-methyl-tetrahydrofuran at ambient temperature (about 20-25°C) and place it in a 4 ml capless glass bottle. Then place the 4ml capless vial into the 50ml glass bottle. Add 40 ml of toluene to the 50 ml vial. The 50ml vials are then capped and left under ambient conditions for up to 14 days. The precipitate was collected by centrifugal filtration at 14,000 rpm through a 0.45 μm nylon membrane filter and dried to obtain crystals, which were identified as crystalline form I.

7. Evaluation of physical and chemical properties

The XRPD diffraction patterns of the anhydrate (form I) crystals of the compound of formula (I) obtained by the above preparation methods are the same as shown in Figure 7, and the DSC, TGA, and ¹ H-NMR analysis patterns are shown in Figures 8-10. DSC shows a melting point (Tonset) of 171.6°C and an enthalpy of approximately 87 J/g. TGA showed about 0.2% weight loss at about 150°C. ¹ H-NMR showed no residual solvent detected. KF indicates that it contains approximately 0.1% water by weight. The SEM image is shown in Figure 39, and its sub-grain size is <10 μm.

8. Volume stability test

About 10-15 mg of Form I crystals were placed in an open container at 25°C/92%RH, an open container at 40°C/75%RH, and a closed container at 60°C for 1 week. A stress of 1.2 million lux-hrs was applied to the crystal under visible light at 25°C.

The experimental results are shown in Figure 39, showing the volume stability of Form I in an open container at 25°C/92% relative humidity, in an open container at 40°C/75% relative humidity, and in a closed container at 60°C. Evaluate in container over 1 week. Photostability was evaluated under visible light at 25°C and 1.2 million lux-hrs. Form I is physically and chemically stable under these conditions.

9. Water adsorption and desorption experiment

The hygroscopicity of Form I crystals was evaluated by the dynamic vapor sorption (DVS) test at 25°C, and the water adsorption and desorption behavior was determined by DVS at 25°C at 40-0-95-0-40% RH, dm/dt= The cycle of 0.002 (%/min) was studied. Equilibration time is up to 60 minutes. Equilibration time is 360 minutes. XRPD was measured after DVS testing to determine crystal form changes.

The experimental report is shown in the table above, and the DVS analysis chart is shown in Figures 40-43. The results show that the crystalline form I does not absorb moisture when it is lower than 80% RH, and is slightly hygroscopic when it is higher than 80% RH. At 25°C, it absorbs <0.1% water from 40% relative humidity to 80% relative humidity, and about 0.4% water from 80% relative humidity to 95% relative humidity. After the DVS test, the sample obtained was still Form I.

10. Process feasibility study

(1) Compression simulation experiment

Approximately 10 mg of Form I crystals were pressed with a hydraulic press at 2 MPa, 5 MPa and 10 MPa, and potential morphological changes and crystallinity were evaluated by XRPD. The experimental results are shown in Figure 44. After compression, Form I showed no morphological changes, but its crystallinity decreased slightly with increasing pressure.

(2) Wet granulation simulation experiment

Water or isopropyl alcohol was added dropwise to approximately 10 mg of crystals of Form I until the sample was fully wetted. Gently grind the wet sample with a mortar and pestle. The granulated samples were dried under ambient conditions for 10 minutes. Potential morphological changes and crystallinity were assessed by XRPD. The experimental results shown in Figure 45 show that when granulated with isopropyl alcohol or water, Form I did not show morphological changes, but its crystallinity decreased slightly.

Example 7

(Preparation of crystal form II and evaluation of related properties)

1. Preparation of crystal form II (1)

Approximately 50 mg of the compound of formula (I) was dissolved in a minimum amount of ethyl acetate solvent at 50°C. The obtained solution was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. Place the obtained solution into a 4°C refrigerator. Centrifuge at 14,000 rpm through a 0.45 μm nylon membrane filter, and collect the precipitate by filtration to obtain the anhydrate crystal form of the compound of formula (I) (designated as crystal form II).

2. Preparation of crystal form II (2)

Weigh about 200 mg of the compound of formula (I) and put it into a 40 ml glass bottle. After stirring at 50°C for about 30 minutes, add 28 ml of ethyl acetate into the vial to obtain a saturated solution. The saturated solution was filtered through a 0.45 μm nylon membrane filter to obtain a clear solution. About 0.5 mg of the anhydrous crystal form (form II) of the compound of formula (I) was added to the above solution as a seed crystal. After stirring at 50°C for 5 minutes, the solution was placed in a magnetic stirring plate at 5°C. The solution gradually transforms into a suspension. The suspension was kept stirred at 5°C for approximately 2 hours. The solid was collected by centrifugal filtration and then dried under ambient conditions for about 2 hours to obtain 152 mg of off-white solid (yield 76%), which was identified as crystal form II.

3. Evaluation of physical and chemical properties

The XRPD diffraction patterns of the anhydrous crystal form (form II) of the compound of formula (I) obtained by the above preparation methods are the same, as shown in Figure 11, and the DSC, TGA, and ¹ H-NMR analysis patterns are shown in Figures 12-14. DSC shows an endothermic peak at T _onset of 155.5°C, with an enthalpy of approximately 6J/g, a melting point (T _onset ) of 171.3°C, and an enthalpy of approximately 87J/g. TGA showed about 1.4% weight loss at about 155°C and about 0.2% weight loss from about 155°C to 170°C. ¹ H-NMR showed 0.2% by weight of ethyl acetate remaining. KF indicates that it contains approximately 0.4% water by weight.

Example 8

(Preparation of crystal form III and evaluation of related properties)

1. Preparation of crystal form III

Dissolve about 50 mg of the compound of formula (I) in 8 ml of ethyl acetate at ambient temperature (about 20-25°C) and place it in a 10 ml glass bottle without a cap. Then place the 10ml capless vial into the 40ml glass bottle. Add 32 ml of toluene to the 40 ml vial. The 40ml vials are then capped and left under ambient conditions for up to 14 days. Centrifuge at 14,000 rpm through a 0.45 μm nylon membrane filter, and filter to collect the precipitate to obtain the anhydrate crystal form of the compound of formula (I) (designated as crystal form III).

2. Evaluation of physical and chemical properties

The XRPD, DSC, TGA, and ¹ H-NMR analysis patterns of the anhydrous crystal form (form III) of the compound of formula (I) obtained by the above preparation method are shown in Figures 15-18. DSC showed a melting peak at a tensile strength of 168.8°C with an enthalpy of approximately 137 J/g. TGA showed about 2.1% weight loss at about 160°C and about 0.7% weight loss from about 160°C to 180°C. KF shows that it contains 0.5 wt% water and converts to Form II after one week of exposure to the environment.

Example 9

(Preparation of Crystal Form IV and Evaluation of Related Properties)

1. Preparation of crystal form IV (1)

Approximately 50 mg of compound of formula (I) are equilibrated in 3-8 ml of ethyl acetate. The obtained solution was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. The clear solution obtained is slowly evaporated under ambient conditions (about 20-25°C, 40%-70% RH) to obtain the crystalline form of the hydrate of the compound of formula (I) (designated Form IV).

2. Preparation of crystal form IV (2)

Approximately 50 mg of the compound of formula (I) was dissolved in 8 ml of isopropanol at ambient temperature (approximately 20-25°C). To the resulting clear solution, 26 ml of water was slowly added until a large amount of solid precipitated. Centrifuge at 14,000 rpm through a 0.45 μm nylon membrane filter, filter and collect the precipitate to obtain crystals, which are identified as crystal form IV.

3. Evaluation of physical and chemical properties

The XRPD diffraction patterns of the crystalline form (form IV) of the hydrate of the compound of formula (I) obtained by the above preparation methods are the same as shown in Figure 19, and the DSC, TGA, and ¹ H-NMR analysis patterns are shown in Figures 20-22. DSC shows a dehydration peak at a T _onset of 41.8°C with an enthalpy of approximately 23 J/g, an endothermic peak with an enthalpy of approximately 30 J/g at a T _onset of 116.5°C, and an exothermic peak at a T _onset of 127.4°C. , the enthalpy is about 51J/g. It then melts at a T _onset of 171.0°C with an enthalpy of approximately 69 J/g. TGA showed a weight loss of approximately 2.8% at approximately 170°C. KF shows it contains about 6.4% water by weight, equivalent to 1.8 water molecules.

Example 10

(Preparation of crystal form V and evaluation of related properties)

1. Preparation of crystal form V

Approximately 50 mg of the compound of formula (I) is dissolved in a minimum amount of isopropanol solvent at 50°C. The obtained solution was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. Place the obtained solution into a 4°C refrigerator. Centrifuge at 14,000 rpm through a 0.45 μm nylon membrane filter, filter and collect the precipitate to obtain the crystal form of the isopropanol solvate of the compound of formula (I) (designated as crystal form V).

2. Evaluation of physical and chemical properties

The XRPD, DSC, TGA, and ¹ H-NMR analysis diagrams of the crystal form (form V) of the isopropanol solvate of the compound of formula (I) obtained by the above preparation method are shown in Figures 23-26. DSC showed a desolvation peak at a Tonset of 86.7°C with an enthalpy of approximately 41 J/g, and an exothermic peak at a Tonset of 103.8°C with an enthalpy of approximately 19 J/g. It then melts at Tonset of 171.4°C with an enthalpy of about 77 J/g. TGA showed a weight loss of approximately 6.1% at approximately 150°C. 1H-NMR showed 35.8 wt% isopropanol remaining, equivalent to 4.2 isopropanol molecules.

Example 11

(Preparation of crystal form VI and evaluation of related properties)

1. Preparation of crystal form VI (1)

Equilibrate approximately 50 mg of the compound of formula (I) in 0.5 ml of 2-methyl-tetrahydrofuran at 25°C for 2 weeks using a stir bar on a magnetic stirring plate at a rate of 300-400 rpm. The obtained suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm and dried to obtain the crystalline form of the 2-methyltetrahydrofuran solvate of the compound of formula (I) (designated as Form VI).

2. Preparation of crystal form VI (2)

Equilibrate approximately 50 mg of the compound of formula (I) in 1 ml of 2-methyl-tetrahydrofuran for 2 weeks at 5°C using a stirring bar on a magnetic stirring plate at a rate of 300-400 rpm. By centrifuging at 14,000 rpm, the suspension obtained was filtered through a 0.45 μm nylon membrane filter, and after drying, crystals were obtained, which were identified as Form VI.

3. Preparation of crystal form VI (3)

Approximately 50 mg of the compound of formula (I) was equilibrated in 0.5 ml of 2-methyl-tetrahydrofuran for 10 cycles at a temperature cycle from 5°C to 50°C with a heating/cooling rate of 0.1°C/minute. Equilibrate with a stir bar on a magnetic stirring plate at 300-400 rpm. By centrifuging at 14,000 rpm, the suspension obtained was filtered through a 0.45 μm nylon membrane filter, and after drying, crystals were obtained, which were identified as Form VI.

4. Preparation of crystal form VI (4)

Approximately 50 mg of the compound of formula (I) is dissolved in a minimum amount of 2-methyltetrahydrofuran solvent at 50°C. The obtained solution was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. Place the obtained solution into a 4°C refrigerator. Centrifuge at 14,000 rpm through a 0.45 μm nylon membrane filter, filter and collect the precipitate to obtain crystals, which are identified as crystal form VI.

5. Evaluation of physical and chemical properties

The XRPD diffraction patterns of the crystalline form (form VI) of the 2-methyltetrahydrofuran solvate of the compound of formula (I) obtained by the above preparation methods are the same, as shown in Figure 27, and the DSC, TGA, and ¹ H-NMR analysis patterns are as shown in Figure 28 -30 shown. DSC shows a desolvation peak at Tonset of 97.3°C with an enthalpy of approximately 62 J/g, and an exothermic peak at Tonset of 117.9°C with an enthalpy of approximately 41 J/g. It then melts at Tonset of 170.5°C with an enthalpy of about 61 J/g. TGA showed approximately 9.9% weight loss at approximately 150°C. ¹ H-NMR showed 15.7% by weight of 2-methyltetrahydrofuran remaining, equivalent to 1.0 molecules of 2-methyltetrahydrofuran.

Example 12

(Preparation of crystal form VII and evaluation of related properties)

1. Preparation of crystal form VII (1)

Equilibrate approximately 30-50 mg of the compound of formula (I) in 0.2-1 mL of isopropanol/water solvent at 5°C for 2 weeks using a stirring bar on a magnetic stirring plate at a speed of 300-400 rpm. The obtained suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm and dried to obtain the crystalline form of the isopropanol/water solvate of the compound of formula (I) (designated as Form VII).

2. Preparation of crystal form VII (2)

Approximately 50 mg of compound of formula (I) are equilibrated in 3-8 ml of isopropanol. The obtained solution was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. The clear solution obtained was slowly evaporated under ambient conditions (about 20-25°C, 40%-70% RH) to obtain crystals, which were identified as Form VII.

3. Preparation of crystal form VII (3)

Dissolve about 50 mg of the compound of formula (I) in 8 ml of 2-methyl-tetrahydrofuran at ambient temperature (about 20-25°C) and place it in a 10 ml capless glass bottle. Then place the 10ml capless vial into the 50ml glass bottle. Add 40 ml of toluene to the 50 ml vial. The 50ml vials are then capped and left under ambient conditions for up to 14 days. Centrifuge at 14,000 rpm through a 0.45 μm nylon membrane filter, filter and collect the precipitate to obtain crystals, which are identified as crystal form VII.

4. Evaluation of physical and chemical properties

The XRPD diffraction patterns of the isopropanol/water solvate crystal form (form VII) of the compound of formula (I) obtained by the above preparation methods are the same, as shown in Figure 31, and the DSC, TGA, and ¹ H-NMR analysis patterns are as shown in Figure 32 -34 shown. DSC shows a desolvation peak at a Tonset of 37.8°C with an enthalpy of approximately 59 J/g, an endothermic peak at a Tonset of 88.1°C with an enthalpy of approximately 95 J/g, and a desolvation peak at a Tonset of 114.1°C. Thermal peak, enthalpy is about 36J/g. The weight loss is about 3.6% from about 65°C to 100°C, and the weight loss is about 2.2% from about 100°C to 130°C. ¹ H-NMR showed 20.1% by weight of isopropanol remaining, equivalent to 2.0 molecules of isopropanol. KF indicates that it contains approximately 4.3% water, equivalent to 1.5 water molecules.

Example 13

(Preparation of crystal form VIII and evaluation of related properties)

1. Preparation of crystal form VIII

Approximately 50 mg of the compound of formula (I) was dissolved in 8 ml of isopropanol at ambient temperature (approximately 20-25°C). To the resulting clear solution, 26 ml of water was slowly added until a large amount of solid precipitated. Centrifuge at 14,000 rpm through a 0.45 μm nylon membrane filter, and collect the precipitate by filtration to obtain the crystal form of the isomorphous solvate of the compound of formula (I) (designated as crystal form VIII).

2. Evaluation of physical and chemical properties

The XRPD, DSC, TGA, and ¹ H-NMR analysis diagrams of the crystal form (form VIII) of the isomorphous solvate of the compound of formula (I) obtained by the above preparation method are shown in Figures 35-38. DSC shows that Tonset at 37.4°C There is a dehydration peak at 79.0°C with an enthalpy of about 76 J/g, and an exothermic peak at 79.0°C with an enthalpy of about 5 J/g. It then melts at Tonset at 171.3°C with an enthalpy of approximately 83 J/g. TGA showed approximately 3.8% weight loss at approximately 150°C. ¹ H-NMR showed no residual solvent detected. KF indicates that it contains approximately 3.3% water, equivalent to 0.9 water molecules.

Example 14

(Study on the relationship between polymorphs)

1. Competitive equilibrium experiments of crystal form I, crystal form II, crystal form VII and crystal form VIII in different solvent systems

About 5-10 mg of the free form of crystal form I, 5-10 mg of the free form of crystal form II, 5-10 mg of the free form of crystal form VIII and 5-10 mg of the free form of crystal form VII, add 0.5 mL of saturated solution of the selected solvent in the table below in solution. The suspension obtained was stirred at 25°C and 50°C for 1 week respectively. The solid fraction (wet cake) was separated by centrifugal filtration and studied by XRPD. The results show that crystalline form I is the most stable unsolvated form and is suitable for clinical formulation development. The specific experimental results are shown in the following table:

2. Solvent activity experiment

Solvent activity experiments were performed in an isopropanol/water system at 25°C to determine the critical water activity between the free forms Form I, Form II, Form VII and Form VIII.

Approximately 5-10 mg of crystalline form I, 5-10mg free form crystalline form II, 5-10mg free form crystalline form VIII of the compound of formula (I) and 5-10mg of free form crystalline form VIII of the compound of formula (I) are added to the selected in a certain saturated solvent. The obtained suspensions were stirred at 5°C, 10°C and 25°C for 1 week. The solid fraction (wet cake) was separated by centrifugal filtration and studied by XRPD.

Table 15 Water Activity Experiment

The experimental results show that at 5°C, when a.w. is between 0.20 and 0.96, and the isopropyl alcohol activity is between 0.93 and 0.52, crystal form VII is a thermodynamic product, corresponding to the isopropyl alcohol/water (v/v) from 98/2 to 50/50; and at 25°C, when a.w. is between 0.66 and 0.96 and isopropanol activity is between 0.73 and 0.52, Form VII is a thermodynamic product corresponding to isopropanol/water ( v/v) from 90/10 to 50/50. In other isopropanol/water ratios, Form I is the thermodynamic product.

3. Variable temperature XRPD experiment

3.1 Variable temperature XRPD experiment of crystal form V

Using the free form Form V, initial XRPD analysis was performed under ambient conditions. All other XRPD analyzes were performed in a nitrogen atmosphere at each specific temperature. Cycle: 25℃(initial)-60℃(5 minutes)-102℃(5 minutes)-115℃(5 minutes)-115℃(30 minutes)-115℃(60 minutes)-25℃(5 minutes). The results show that crystal form V is unstable above 25°C and gradually transforms into crystal form I as the temperature increases. It shows that crystal form I has high temperature stability and is suitable for wet granulation in high-temperature environments (the temperature of the fluidized bed during the drying process of wet granulation can reach 80°C). The specific experimental results are shown in the following table:

实验序号Experiment serial number	温度(平衡时间)Temperature (equilibration time)	XRPD XRPD
11	25℃(初始)25℃(initial)	晶型Ⅴ+晶型ⅠCrystal form V + crystal form I
22	60℃(5min)60℃(5min)	晶型Ⅴ+晶型ⅠCrystal form V + crystal form I
33	102℃(5min)102℃(5min)	晶型Ⅴ+晶型ⅠCrystal form V + crystal form I
44	115℃(5min)115℃(5min)	晶型Ⅴ+晶型ⅠCrystal form V + crystal form I
55	115℃(30min)115℃(30min)	晶型Ⅴ+晶型Ⅰ(主要)Crystal form V + crystal form I (main)
66	115℃(60min)115℃(60min)	晶型ⅠCrystal form I
77	25℃(5min)25℃(5min)	晶型ⅠCrystal form I

3.2 Variable temperature XRPD experiment of crystal form VI

The free form of Form VI was used as starting material. Initial XRPD analysis was performed under ambient conditions. All other XRPD analyzes were performed in a nitrogen atmosphere at each specific temperature. Cycle: 25℃(initial)-70℃(5 minutes)-110℃(5 minutes)-158℃(5 minutes)-25℃(5 minutes). The results show that crystal form V is unstable above 25°C and gradually transforms into crystal form I as the temperature increases. The specific experimental results are shown in the following table:

实验序号Experiment serial number	温度(平衡时间)Temperature (equilibration time)	XRPD XRPD
11	25℃(初始)25℃(initial)	晶型ⅥForm VI
22	70℃(5min)70℃(5min)	中间形态 intermediate form
33	110℃(5min)110℃(5min)	中间形态 intermediate form
44	158℃(5min)158℃(5min)	类似晶型ⅠSimilar to Form I
55	25℃(5min)25℃(5min)	晶型ⅠCrystal form I

3.3 Variable temperature XRPD experiment of crystal form VII

Using the free form of Form VII, initial XRPD analysis was performed under ambient conditions. All other XRPD analyzes were performed in a nitrogen atmosphere at each specific temperature. Cycle: 25℃(initial)-70℃(5 minutes)-117℃(5 minutes)-145℃(5 minutes)-25℃(5 minutes). The results show that crystal form VII is unstable above 25°C and gradually transforms into crystal form I as the temperature increases. The specific experimental results are shown in the following table:

实验序号Experiment serial number	温度(平衡时间)Temperature (equilibration time)	XRPD XRPD
11	25℃(初始)25℃(initial)	晶型ⅦCrystal form VII
22	70℃(5min)70℃(5min)	中间形态 intermediate form
33	117℃(5min)117℃(5min)	中间形态 intermediate form
44	145℃(5min)145℃(5min)	类似晶型ⅠSimilar to Form I
55	25℃(5min)25℃(5min)	晶型ⅠCrystal form I

Claims

A pharmaceutical composition comprising a crystal form of a compound of formula (I) as follows and one or more pharmaceutically acceptable carriers, characterized in that the pharmaceutically acceptable carriers are lubricants and disintegrants and one or more fillers, the pharmaceutical composition also includes hydroxypropyl cellulose as a binder, and the binder is hydroxypropyl cellulose with LF and/or JF grade specifications, or the above specifications are consistent with Mixtures of other specifications of hydroxypropyl cellulose,
The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition contains 0.1%-50% W/W crystal form of the compound of formula (I) relative to the total weight of the composition; preferably, it contains relative to the total weight of the composition 1.0%-30% W/W crystalline form of the compound of formula (I) based on the total weight of the composition; more preferably, 10.0%-30% W/W crystalline form of the compound of formula (I) relative to the total weight of the composition.
The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition contains 0.5%-20.0% W/W LF and/or JF grade hydroxypropyl cellulose relative to the total weight of the composition, Or a mixture of the above specifications and other specifications of hydroxypropylcellulose; preferably, containing 1.0%-10.0% W/W LF and/or JF grade hydroxypropylcellulose relative to the total weight of the composition, or the above specifications Mixtures with other specifications of hydroxypropylcellulose; more preferably, containing 2.0%-8.0% W/W LF and/or JF grade hydroxypropylcellulose relative to the total weight of the composition, or the above specifications with other Specifications Hydroxypropyl Cellulose Blend.
The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition contains hydroxypropyl cellulose of LF and/or JF grade specifications; preferably, the hydroxypropyl cellulose of LF and/or JF grade specifications Cellulose is an aqueous solution; more preferably, the concentration of the hydroxypropyl cellulose aqueous solution of the LF and/or JF grade specifications is 5%-25% W/V; most preferably, the LF and/or JF grade The concentration of the specified hydroxypropyl cellulose aqueous solution is 8%-15% W/V.
The pharmaceutical composition according to claim 1, characterized in that, the pharmaceutical composition further contains one or more foaming agents, the foaming agent is an inorganic salt or an organic carbonate, and the inorganic salt Selected from sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, aluminum carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium hydroxide; the organic acid salt is selected from Sodium diglycinate carbonate, dimethyl carbonate and ethylene carbonate;

In particular, the foaming agent is selected from the group consisting of sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, aluminum carbonate, sodium bicarbonate, potassium bicarbonate and calcium bicarbonate;

In particular, the pharmaceutical composition contains 0.5%-50.0% W/W foaming agent relative to the total weight of the composition; preferably, it contains 2.0%-40.0% W/W foaming agent relative to the total weight of the composition. Foaming agent; more preferably, 10.0%-30.0% W/W foaming agent relative to the total weight of the composition.
The pharmaceutical composition according to claim 1, wherein the lubricant is glyceryl behenate, magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide, talc, hydrogenated One or more of vegetable oil and triglycerides;

In particular, the pharmaceutical composition contains 0.1%-30.0% W/W lubricant relative to the total weight of the composition; preferably, 1.0%-25.0% W/W lubricant relative to the total weight of the composition ;More preferably, 3.0%-18.0% w/w lubricant is included relative to the total weight of the composition.
The pharmaceutical composition according to claim 1, wherein the disintegrant is one of sodium starch glycolate, sodium starch glycolate, cross-linked polyvinylpyrrolidone and croscarmellose sodium. species or species;

In particular, the pharmaceutical composition contains 0.5%-20.0% W/W disintegrant relative to the total weight of the composition; preferably, 1.0%-10.0% W/W disintegrant relative to the total weight of the composition. Disintegrant; more preferably, 2.0%-8.0% W/W disintegrant relative to the total weight of the composition.
The pharmaceutical composition according to claim 1, wherein the filler is mannitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, calcium hydrogen phosphate anhydrous and lactose monohydrate. one or more;

In particular, the pharmaceutical composition contains 1.0%-90.0% W/W filler relative to the total weight of the composition; preferably, 5.0%-60.0% W/W filler relative to the total weight of the composition. ;More preferably, 10.0%-45.0% W/W filler is included relative to the total weight of the composition.
The pharmaceutical composition according to any one of claims 1 to 8, characterized in that the pharmaceutical composition contains the crystal form of the compound of formula (I), LF grade hydroxypropyl cellulose and a lubricant, which is /W mass ratio is (10.0-30.0): (2.0-8.0): (3.0-10.0), and the lubricant is one or more of glyceryl behenate, magnesium stearate and silicon dioxide.
The pharmaceutical composition according to claim 9, characterized in that the pharmaceutical composition further comprises sodium carbonate and/or magnesium carbonate as a foaming agent, the content of which is 2.0%-40.0% relative to the total weight of the composition. /W; preferably 10.0%-30.0%W/W; and/or

The pharmaceutical composition also contains sodium starch glycolate as a disintegrant, its content is 2.0%-8.0% W/W relative to the total weight of the composition; and/or

The pharmaceutical composition also contains microcrystalline cellulose and/or mannitol as a filler, the content of which is 5.0%-45.0% W/W relative to the total weight of the composition; preferably 10.0%-35.0% W/W; More preferably, it is 15.0%-25.0% W/W.
The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition further comprises one or more coating powders as coating materials; preferably, the coating powder is a gastric-soluble film coating Clothing premix Opadry.
The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a tablet.
The pharmaceutical composition according to claim 12, wherein the unit dosage form of the tablet contains 1 mg to 500 mg of the crystal form of the compound of formula (I); preferably, the unit dosage form contains 1 mg to 200 mg of the crystal form of the compound of formula (I). ; More preferably, the unit dosage form contains 1 mg, 5 mg, 20 mg, 80 mg or 200 mg of the crystalline form of the compound of formula (I).
The pharmaceutical composition according to claim 1, wherein the crystal form of the compound of formula (I) is anhydrous, hydrate or solvate of the compound of formula (I),

In particular, the solvates of the compound of formula (I) are 2-methyltetrahydrofuran solvate, isopropyl alcohol solvate and isopropyl alcohol-water heterosolvate,

especially,

The hydrate of the compound of formula (I) contains 0.5-3.0 water molecules per molecule; preferably, the hydrate of the compound of formula (I) contains 0.9-1.8 water molecules per molecule;

Each molecule of the 2-methyltetrahydrofuran solvate of the compound of formula (I) contains 0.5-3.0 2-methyltetrahydrofuran molecules; preferably, the 2-methyltetrahydrofuran solvate of the compound of formula (I) contains Each molecule contains 1.0 2-methyltetrahydrofuran molecules;

The isopropyl alcohol solvate of the compound of formula (I) contains 1.0-5.0 isopropyl alcohol molecules per molecule; preferably, the isopropyl alcohol solvate of the compound of formula (I) contains 4.2 molecules per molecule. isopropyl alcohol molecule;

Each molecule of the isopropyl alcohol-water heterosolvate of the compound of formula (I) contains 0.5-3 isopropyl alcohol molecules and 0.5-3.0 water molecules; preferably, the isopropyl alcohol-water solvate of the compound of formula (I) The alcohol-water heterosolvate contains 2.0 molecules of isopropyl alcohol and 1.5 molecules of water per molecule.
The pharmaceutical composition according to claim 14, characterized in that the pharmaceutical composition comprises the anhydrous crystalline form I of the compound of formula (I), and the X-ray of the anhydrous crystalline form I of the compound of formula (I) Powder diffraction patterns (XRPD) include diffraction angles (2θ) at 22.86±0.2°, 7.81±0.2°, 29.89±0.2°, 21.35±0.2°, 16.16±0.2°, 20.73±0.2° and 27.04±0.2°. peak;

Preferably, the X-ray powder diffraction pattern (XRPD) of the anhydrate crystal form I of the compound of formula (I) includes positions at 22.86±0.2°, 7.81±0.2°, 29.89±0.2°, 21.35±0.2°, 16.16± 0.2°, 20.73±0.2°, 27.04±0.2°, 16.64±0.2°, 24.89±0.2°, 25.09±0.2°, 23.51±0.2°, 13.37±0.2°, 21.84±0.2°, 12.71±0.2° and 17.85± Peak at diffraction angle (2θ) of 0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the anhydrate crystal form I of the compound of formula (I) includes positions at 22.86±0.2°, 7.81±0.2°, 29.89±0.2°, 21.35±0.2°, 16.16 ±0.2°, 20.73±0.2°, 27.04±0.2°, 16.64±0.2°, 24.89±0.2°, 25.09±0.2°, 23.51±0.2°, 13.37±0.2°, 21.84±0.2°, 12.71±0.2°, 17.85 ±0.2°, 12.86±0.2°, 24.30±0.2°, 26.53±0.2°, 23.74±0.2°, 18.24±0.2°, 28.75±0.2°, 19.65±0.2°, 11.23±0.2°, 32.66±0.2° and 18.91 Peak at diffraction angle (2θ) of ±0.2°;

or,

The pharmaceutical composition contains the anhydrous crystalline form II of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form II of the compound of formula (I) includes positions at 22.88±0.2°, 7.82± Peaks at diffraction angles (2θ) of 0.2°, 29.92±0.2°, 23.51±0.2°, 21.37±0.2°, 27.06±0.2° and 24.90±0.2°;

Preferably, the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form II of the compound of formula (I) includes locations at 22.88±0.2°, 7.82±0.2°, 29.92±0.2°, 23.51±0.2°, 21.37± 0.2°, 27.06±0.2°, 24.90±0.2°, 16.65±0.2°, 20.76±0.2°, 25.11±0.2°, 16.18±0.2°, 13.38±0.2°, 21.86±0.2°, 32.58±0.2° and 12.72± Peak at diffraction angle (2θ) of 0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form II of the compound of formula (I) includes positions at 22.88±0.2°, 7.82±0.2°, 29.92±0.2°, 23.51±0.2°, 21.37 ±0.2°, 27.06±0.2°, 24.90±0.2°, 16.65±0.2°, 20.76±0.2°, 25.11±0.2°, 16.18±0.2°, 13.38±0.2°, 21.86±0.2°, 32.58±0.2°, 12.72 ±0.2°, 24.31±0.2°, 15.05±0.2°, 28.77±0.2°, 26.55±0.2°, 12.87±0.2°, 22.56±0.2°, 17.85±0.2°, 23.76±0.2°, 18.26±0.2° and 31.11 Peak at diffraction angle (2θ) of ±0.2°;

or,

The pharmaceutical composition contains the anhydrous crystalline form III of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form III of the compound of formula (I) includes positions at 5.85±0.2°, 21.34± Peaks at diffraction angles (2θ) of 0.2°, 14.96±0.2°, 20.57±0.2°, 19.78±0.2°, 24.12±0.2° and 18.71±0.2°;

Preferably, the X-ray powder diffraction pattern (XRPD) of the anhydrate crystal form III of the compound of formula (I) includes positions at 5.85±0.2°, 21.34±0.2°, 14.96±0.2°, 20.57±0.2°, and 19.78± 0.2°, 24.12±0.2°, 18.71±0.2°, 25.13±0.2°, 13.72±0.2°, 24.65±0.2°, 22.76±0.2°, 26.75±0.2°, 14.61±0.2°, 10.81±0.2° and 16.81± Peak at diffraction angle (2θ) of 0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form III of the compound of formula (I) includes positions at 5.85±0.2°, 21.34±0.2°, 14.96±0.2°, 20.57±0.2°, 19.78 ±0.2°, 24.12±0.2°, 18.71±0.2°, 25.13±0.2°, 13.72±0.2°, 24.65±0.2°, 22.76±0.2°, 26.75±0.2°, 14.61±0.2°, 10.81±0.2°, 16.81 ±0.2°, 21.14±0.2°, 22.54±0.2°, 9.74±0.2°, 21.79±0.2°, 25.74±0.2°, 17.71±0.2°, 19.33±0.2°, 30.36±0.2°, 13.39±0.2° and 14.07 Peak at diffraction angle (2θ) of ±0.2°.
The pharmaceutical composition according to claim 14, characterized in that the pharmaceutical composition contains the compound hydrate crystal form IV of the formula (I), and the X-ray powder diffraction of the hydrate crystal form IV of the compound formula (I) The pattern (XRPD) includes peaks at diffraction angles (2θ) of 13.34±0.2°, 17.41±0.2°, 21.78±0.2°, 20.02±0.2°, 14.85±0.2°, and 16.53±0.2°;

Preferably, the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes positions at 13.34±0.2°, 17.41±0.2°, 21.78±0.2°, 20.02±0.2°, and 14.85±0.2 Peaks at diffraction angles (2θ) of °, 16.53±0.2°, 19.35±0.2°, 18.64±0.2°, 11.19±0.2°, 5.98±0.2° and 22.67±0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes 13.34±0.2°, 17.41±0.2°, 21.78±0.2°, 20.02±0.2°, 14.85± 0.2°, 16.53±0.2°, 19.35±0.2°, 18.64±0.2°, 11.19±0.2°, 5.98±0.2°, 22.67±0.2°, 20.62±0.2°, 26.72±0.2°, 14.08±0.2°, 23.82± Peaks at diffraction angles (2θ) of 0.2° and 25.37±0.2°;

or,

The pharmaceutical composition contains the hydrate crystal form VIII of the compound of formula (I), and the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes positions at 23.05±0.2° and 8.73±0.2°. , peaks at diffraction angles (2θ) of 21.41±0.2°, 15.95±0.2°, 23.50±0.2°, 15.50±0.2° and 25.14±0.2°;

Preferably, the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes positions at 23.05±0.2°, 8.73±0.2°, 21.41±0.2°, 15.95±0.2°, and 23.50±0.2 °, 15.50±0.2°, 25.14±0.2°, 27.00±0.2°, 31.15±0.2°, 27.70±0.2°, 16.81±0.2°, 19.70±0.2°, 13.22±0.2°, 24.34±0.2° and 19.32±0.2 The peak at the diffraction angle (2θ) of °;

More preferably, the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes 23.05±0.2°, 8.73±0.2°, 21.41±0.2°, 15.95±0.2°, 23.50± 0.2°, 15.50±0.2°, 25.14±0.2°, 27.00±0.2°, 31.15±0.2°, 27.70±0.2°, 16.81±0.2°, 19.70±0.2°, 13.22±0.2°, 24.34±0.2°, 19.32± 0.2°, 20.44±0.2°, 35.08±0.2°, 29.93±0.2°, 27.32±0.2°, 13.54±0.2°, 18.99±0.2°, 12.89±0.2°, 17.49±0.2°, 30.49±0.2° and 18.59± Peak at diffraction angle (2θ) of 0.2°.
The pharmaceutical composition according to claim 14, characterized in that the pharmaceutical composition contains the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI, and the compound of formula (I) 2-methyltetrahydrofuran The X-ray powder diffraction pattern (XRPD) of the solvate crystal form VI includes locations at 22.44±0.2°, 5.63±0.2°, 16.81±0.2°, 20.43±0.2°, 21.57±0.2°, 16.15±0.2° and 22.71± Peak at diffraction angle (2θ) of 0.2°;

Preferably, the X-ray powder diffraction pattern (XRPD) of the crystal form VI of the 2-methyltetrahydrofuran solvate of the compound of formula (I) includes positions at 22.44±0.2°, 5.63±0.2°, 16.81±0.2°, and 20.43± 0.2°, 21.57±0.2°, 16.15±0.2°, 22.71±0.2°, 6.36±0.2°, 12.60±0.2°, 25.95±0.2°, 24.92±0.2°, 13.69±0.2°, 19.65±0.2°, 15.13± Peaks at diffraction angles (2θ) of 0.2° and 12.11±0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the 2-methyltetrahydrofuran solvate crystal form VI of the compound of formula (I) includes positions at 22.44±0.2°, 5.63±0.2°, 16.81±0.2°, and 20.43 ±0.2°, 21.57±0.2°, 16.15±0.2°, 22.71±0.2°, 6.36±0.2°, 12.60±0.2°, 25.95±0.2°, 24.92±0.2°, 13.69±0.2°, 19.65±0.2°, 15.13 ±0.2°, 12.11±0.2°, 24.25±0.2°, 11.16±0.2°, 31.57±0.2°, 14.55±0.2°, 27.00±0.2°, 17.90±0.2°, 21.12±0.2°, 11.27±0.2°, 23.18 Peaks at diffraction angles (2θ) of ±0.2° and 14.12±0.2°.
The pharmaceutical composition according to claim 14, characterized in that the pharmaceutical composition contains the isopropyl alcohol solvate crystal form V of the compound of formula (I), and the isopropyl alcohol solvate crystal form of the compound of formula (I) The X-ray powder diffraction pattern (XRPD) of Type V includes diffraction at 5.28±0.2°, 10.52±0.2°, 21.29±0.2°, 5.66±0.2°, 13.52±0.2°, 22.44±0.2° and 19.35±0.2° Peak at angle (2θ);

Preferably, the X-ray powder diffraction pattern (XRPD) of the isopropyl alcohol solvate crystal form V of the compound of formula (I) includes positions at 5.28±0.2°, 10.52±0.2°, 21.29±0.2°, and 5.66±0.2°. , 13.52±0.2°, 22.44±0.2°, 19.35±0.2°, 18.48±0.2°, 16.77±0.2°, 24.68±0.2°, 19.97±0.2°, 25.67±0.2°, 15.13±0.2°, 17.82±0.2° and a peak at a diffraction angle (2θ) of 20.96±0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the isopropyl alcohol solvate crystal form V of the compound of formula (I) includes positions at 5.28±0.2°, 10.52±0.2°, 21.29±0.2°, and 5.66±0.2 °, 13.52±0.2°, 22.44±0.2°, 19.35±0.2°, 18.48±0.2°, 16.77±0.2°, 24.68±0.2°, 19.97±0.2°, 25.67±0.2°, 15.13±0.2°, 17.82±0.2 °, 20.96±0.2°, 14.86±0.2°, 12.48±0.2°, 11.94±0.2°, 14.24±0.2°, 23.87±0.2°, 23.25±0.2°, 29.51±0.2° and 27.70±0.2° ( 2θ) peak.
The pharmaceutical composition according to claim 14, characterized in that the pharmaceutical composition contains the isopropyl alcohol-aqueous heterosolvate crystal form VII of the compound of formula (I), and the isopropyl alcohol-aqueous heterosolvate of the compound of formula (I) is The X-ray powder diffraction pattern (XRPD) of the aqueous solvate crystal form VII includes locations at 23.77±0.2°, 24.36±0.2°, 18.56±0.2°, 5.94±0.2°, 22.59±0.2°, 20.30±0.2° and Peak at diffraction angle (2θ) of 17.79±0.2°;

Preferably, the X-ray powder diffraction pattern (XRPD) of the isopropyl alcohol-aqueous heterosolvate crystal form VII of the compound of formula (I) includes positions at 23.77±0.2°, 24.36±0.2°, 18.56±0.2°, 5.94 ±0.2°, 22.59±0.2°, 20.30±0.2°, 17.79±0.2°, 10.33±0.2°, 12.10±0.2°, 22.26±0.2°, 19.48±0.2°, 21.73±0.2°, 5.29±0.2°, 25.80 Peaks at diffraction angles (2θ) of ±0.2° and 16.45±0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the isopropanol-aqueous solvate crystal form VII of the compound of formula (I) includes positions at 23.77±0.2°, 24.36±0.2°, 18.56±0.2°, 5.94±0.2°, 22.59±0.2°, 20.30±0.2°, 17.79±0.2°, 10.33±0.2°, 12.10±0.2°, 22.26±0.2°, 19.48±0.2°, 21.73±0.2°, 5.29±0.2°, 25.80±0.2°, 16.45±0.2°, 21.94±0.2°, 28.33±0.2°, 25.04±0.2°, 11.89±0.2°, 17.26±0.2°, 28.85±0.2°, 16.79±0.2°, 23.34±0.2°, Peaks at diffraction angles (2θ) of 30.31±0.2° and 14.26±0.2°.
A preparation method of pharmaceutical composition according to claim 1, characterized in that it includes the following steps:

Step A: Mix the crystal form of the compound of formula (I) and/or one or more pharmaceutically acceptable carriers to obtain a premixed material;

Step B: Add the binder hydroxypropyl cellulose to the above premixed materials to form mixed particles;

Optionally, step C: add lubricant and/or disintegrant to the above mixed particles to form final mixed particles;

Optionally, step D: compress the final mixed granules prepared in the above step C to form tablets;

Wherein, the pharmaceutically acceptable carrier is one or more of lubricants, disintegrants and fillers.
The preparation method according to claim 20, characterized in that, a foaming agent is added during premixing in step A;

Specifically, the crystal form of the compound of formula (I), the binder hydroxypropyl cellulose, the foaming agent and one or more pharmaceutically acceptable carriers are mixed to obtain a premixed material;

In particular, step B is performed after mixing to form wet granules and then drying and/or dry granulation;

Typically, the mixture obtained in step A and/or step B is passed through a 30-100 mesh screen.
The crystalline form of the anhydrate, hydrate or solvate of the compound of formula (I):

In particular, the solvates of the compound of formula (I) are 2-methyltetrahydrofuran solvate, isopropanol solvate and isopropanol-aqueous solvate;

especially,

The hydrate of the compound of formula (I) contains 0.5-3.0 water molecules per molecule; preferably, the hydrate of the compound of formula (I) contains 0.9-1.8 water molecules per molecule;

Each molecule of the 2-methyltetrahydrofuran solvate of the compound of formula (I) contains 0.5-3.0 2-methyltetrahydrofuran molecules; preferably, the 2-methyltetrahydrofuran solvate of the compound of formula (I) contains Each molecule contains 1.0 2-methyltetrahydrofuran molecules;

The isopropyl alcohol solvate of the compound of formula (I) contains 1.0-5.0 isopropyl alcohol molecules per molecule; preferably, the isopropyl alcohol solvate of the compound of formula (I) contains 4.2 molecules per molecule. isopropyl alcohol molecule;

Each molecule of the isopropyl alcohol-water heterosolvate of the compound of formula (I) contains 0.5-3 isopropyl alcohol molecules and 0.5-3.0 water molecules; preferably, the isopropyl alcohol-water solvate of the compound of formula (I) The alcohol-water heterosolvate contains 2.0 molecules of isopropanol and 1.5 molecules of water per molecule.
The crystal form according to claim 22, characterized in that the crystal form is the anhydrous crystal form I of the compound of formula (I), and the X-ray powder diffraction of the anhydrous crystal form I of the compound of formula (I) The pattern (XRPD) includes peaks at diffraction angles (2θ) of 22.86±0.2°, 7.81±0.2°, 29.89±0.2°, 21.35±0.2°, 16.16±0.2°, 20.73±0.2°, and 27.04±0.2°;

Preferably, the X-ray powder diffraction pattern (XRPD) of the anhydrate crystal form I of the compound of formula (I) includes positions at 22.86±0.2°, 7.81±0.2°, 29.89±0.2°, 21.35±0.2°, 16.16± 0.2°, 20.73±0.2°, 27.04±0.2°, 16.64±0.2°, 24.89±0.2°, 25.09±0.2°, 23.51±0.2°, 13.37±0.2°, 21.84±0.2°, 12.71±0.2° and 17.85± Peak at diffraction angle (2θ) of 0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the anhydrate crystal form I of the compound of formula (I) includes positions at 22.86±0.2°, 7.81±0.2°, 29.89±0.2°, 21.35±0.2°, 16.16 ±0.2°, 20.73±0.2°, 27.04±0.2°, 16.64±0.2°, 24.89±0.2°, 25.09±0.2°, 23.51±0.2°, 13.37±0.2°, 21.84±0.2°, 12.71±0.2°, 17.85 ±0.2°, 12.86±0.2°, 24.30±0.2°, 26.53±0.2°, 23.74±0.2°, 18.24±0.2°, 28.75±0.2°, 19.65±0.2°, 11.23±0.2°, 32.66±0.2° and 18.91 Peak at diffraction angle (2θ) of ±0.2°;

or,

The crystal form is the anhydrous crystalline form II of the compound of formula (I). The X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form II of the compound of formula (I) includes locations at 22.88±0.2°, 7.82±0.2 Peaks at diffraction angles (2θ) of °, 29.92±0.2°, 23.51±0.2°, 21.37±0.2°, 27.06±0.2° and 24.90±0.2°;

Preferably, the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form II of the compound of formula (I) includes locations at 22.88±0.2°, 7.82±0.2°, 29.92±0.2°, 23.51±0.2°, 21.37± 0.2°, 27.06±0.2°, 24.90±0.2°, 16.65±0.2°, 20.76±0.2°, 25.11±0.2°, 16.18±0.2°, 13.38±0.2°, 21.86±0.2°, 32.58±0.2° and 12.72± Peak at diffraction angle (2θ) of 0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form II of the compound of formula (I) includes positions at 22.88±0.2°, 7.82±0.2°, 29.92±0.2°, 23.51±0.2°, 21.37 ±0.2°, 27.06±0.2°, 24.90±0.2°, 16.65±0.2°, 20.76±0.2°, 25.11±0.2°, 16.18±0.2°, 13.38±0.2°, 21.86±0.2°, 32.58±0.2°, 12.72 ±0.2°, 24.31±0.2°, 15.05±0.2°, 28.77±0.2°, 26.55±0.2°, 12.87±0.2°, 22.56±0.2°, 17.85±0.2°, 23.76±0.2°, 18.26±0.2° and 31.11 Peak at diffraction angle (2θ) of ±0.2°;

or,

The crystal form is the anhydrous crystalline form III of the compound of formula (I). The X-ray powder diffraction pattern (XRPD) of the anhydrous crystalline form III of the compound of formula (I) includes locations at 5.85±0.2° and 21.34±0.2 Peaks at diffraction angles (2θ) of °, 14.96±0.2°, 20.57±0.2°, 19.78±0.2°, 24.12±0.2° and 18.71±0.2°;

Preferably, the X-ray powder diffraction pattern (XRPD) of the anhydrate crystal form III of the compound of formula (I) includes positions at 5.85±0.2°, 21.34±0.2°, 14.96±0.2°, 20.57±0.2°, and 19.78± 0.2°, 24.12±0.2°, 18.71±0.2°, 25.13±0.2°, 13.72±0.2°, 24.65±0.2°, 22.76±0.2°, 26.75±0.2°, 14.61±0.2°, 10.81±0.2° and 16.81± Peak at diffraction angle (2θ) of 0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the anhydrous crystal form III of the compound of formula (I) includes positions at 5.85±0.2°, 21.34±0.2°, 14.96±0.2°, 20.57±0.2°, 19.78 ±0.2°, 24.12±0.2°, 18.71±0.2°, 25.13±0.2°, 13.72±0.2°, 24.65±0.2°, 22.76±0.2°, 26.75±0.2°, 14.61±0.2°, 10.81±0.2°, 16.81 ±0.2°, 21.14±0.2°, 22.54±0.2°, 9.74±0.2°, 21.79±0.2°, 25.74±0.2°, 17.71±0.2°, 19.33±0.2°, 30.36±0.2°, 13.39±0.2° and 14.07 Peak at diffraction angle (2θ) of ±0.2°.
The crystal form according to claim 22, characterized in that the crystal form is the compound hydrate crystal form IV of the formula (I), and the X-ray powder diffraction pattern of the compound hydrate crystal form IV of the formula (I) ( XRPD) includes peaks at diffraction angles (2θ) of 13.34±0.2°, 17.41±0.2°, 21.78±0.2°, 20.02±0.2°, 14.85±0.2° and 16.53±0.2°;

Preferably, the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes positions at 13.34±0.2°, 17.41±0.2°, 21.78±0.2°, 20.02±0.2°, and 14.85±0.2 Peaks at diffraction angles (2θ) of °, 16.53±0.2°, 19.35±0.2°, 18.64±0.2°, 11.19±0.2°, 5.98±0.2° and 22.67±0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form IV of the compound of formula (I) includes 13.34±0.2°, 17.41±0.2°, 21.78±0.2°, 20.02±0.2°, 14.85± 0.2°, 16.53±0.2°, 19.35±0.2°, 18.64±0.2°, 11.19±0.2°, 5.98±0.2°, 22.67±0.2°, 20.62±0.2°, 26.72±0.2°, 14.08±0.2°, 23.82± Peaks at diffraction angles (2θ) of 0.2° and 25.37±0.2°;

or,

The crystal form is the hydrate crystal form VIII of the compound of formula (I). The X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes locations at 23.05±0.2°, 8.73±0.2°, Peaks at diffraction angles (2θ) of 21.41±0.2°, 15.95±0.2°, 23.50±0.2°, 15.50±0.2° and 25.14±0.2°;

Preferably, the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes positions at 23.05±0.2°, 8.73±0.2°, 21.41±0.2°, 15.95±0.2°, and 23.50±0.2 °, 15.50±0.2°, 25.14±0.2°, 27.00±0.2°, 31.15±0.2°, 27.70±0.2°, 16.81±0.2°, 19.70±0.2°, 13.22±0.2°, 24.34±0.2° and 19.32±0.2 The peak at the diffraction angle (2θ) of °;

More preferably, the X-ray powder diffraction pattern (XRPD) of the hydrate crystal form VIII of the compound of formula (I) includes 23.05±0.2°, 8.73±0.2°, 21.41±0.2°, 15.95±0.2°, 23.50± 0.2°, 15.50±0.2°, 25.14±0.2°, 27.00±0.2°, 31.15±0.2°, 27.70±0.2°, 16.81±0.2°, 19.70±0.2°, 13.22±0.2°, 24.34±0.2°, 19.32± 0.2°, 20.44±0.2°, 35.08±0.2°, 29.93±0.2°, 27.32±0.2°, 13.54±0.2°, 18.99±0.2°, 12.89±0.2°, 17.49±0.2°, 30.49±0.2° and 18.59± Peak at diffraction angle (2θ) of 0.2°.
The crystal form according to claim 22, characterized in that the crystal form is the compound of formula (I) 2-methyltetrahydrofuran solvate crystal form VI, and the compound of formula (I) 2-methyltetrahydrofuran solvate is The X-ray powder diffraction pattern (XRPD) of Form VI includes locations at 22.44±0.2°, 5.63±0.2°, 16.81±0.2°, 20.43±0.2°, 21.57±0.2°, 16.15±0.2° and 22.71±0.2° The peak at the diffraction angle (2θ);

Preferably, the X-ray powder diffraction pattern (XRPD) of the crystal form VI of the 2-methyltetrahydrofuran solvate of the compound of formula (I) includes positions at 22.44±0.2°, 5.63±0.2°, 16.81±0.2°, and 20.43± 0.2°, 21.57±0.2°, 16.15±0.2°, 22.71±0.2°, 6.36±0.2°, 12.60±0.2°, 25.95±0.2°, 24.92±0.2°, 13.69±0.2°, 19.65±0.2°, 15.13± Peaks at diffraction angles (2θ) of 0.2° and 12.11±0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the 2-methyltetrahydrofuran solvate crystal form VI of the compound of formula (I) includes positions at 22.44±0.2°, 5.63±0.2°, 16.81±0.2°, and 20.43 ±0.2°, 21.57±0.2°, 16.15±0.2°, 22.71±0.2°, 6.36±0.2°, 12.60±0.2°, 25.95±0.2°, 24.92±0.2°, 13.69±0.2°, 19.65±0.2°, 15.13 ±0.2°, 12.11±0.2°, 24.25±0.2°, 11.16±0.2°, 31.57±0.2°, 14.55±0.2°, 27.00±0.2°, 17.90±0.2°, 21.12±0.2°, 11.27±0.2°, 23.18 Peaks at diffraction angles (2θ) of ±0.2° and 14.12±0.2°.
The crystal form according to claim 22, characterized in that the crystal form is the isopropyl alcohol solvate crystal form V of the compound of formula (I), and the isopropyl alcohol solvate crystal form V of the compound of formula (I) is The X-ray powder diffraction pattern (XRPD) includes diffraction angles located at 5.28±0.2°, 10.52±0.2°, 21.29±0.2°, 5.66±0.2°, 13.52±0.2°, 22.44±0.2° and 19.35±0.2° ( The peak at 2θ);

Preferably, the X-ray powder diffraction pattern (XRPD) of the isopropyl alcohol solvate crystal form V of the compound of formula (I) includes positions at 5.28±0.2°, 10.52±0.2°, 21.29±0.2°, and 5.66±0.2°. , 13.52±0.2°, 22.44±0.2°, 19.35±0.2°, 18.48±0.2°, 16.77±0.2°, 24.68±0.2°, 19.97±0.2°, 25.67±0.2°, 15.13±0.2°, 17.82±0.2° and a peak at a diffraction angle (2θ) of 20.96±0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the isopropyl alcohol solvate crystal form V of the compound of formula (I) includes positions at 5.28±0.2°, 10.52±0.2°, 21.29±0.2°, and 5.66±0.2 °, 13.52±0.2°, 22.44±0.2°, 19.35±0.2°, 18.48±0.2°, 16.77±0.2°, 24.68±0.2°, 19.97±0.2°, 25.67±0.2°, 15.13±0.2°, 17.82±0.2 °, 20.96±0.2°, 14.86±0.2°, 12.48±0.2°, 11.94±0.2°, 14.24±0.2°, 23.87±0.2°, 23.25±0.2°, 29.51±0.2° and 27.70±0.2° ( 2θ) peak.
The crystal form according to claim 22, characterized in that the crystal form is the isopropyl alcohol-aqua solvate crystal form VII of the compound of formula (I), and the isopropyl alcohol-aqua solvate of the compound of formula (I) is The X-ray powder diffraction pattern (XRPD) of the solvate crystal form VII includes locations at 23.77±0.2°, 24.36±0.2°, 18.56±0.2°, 5.94±0.2°, 22.59±0.2°, 20.30±0.2° and 17.79± Peak at diffraction angle (2θ) of 0.2°;

Preferably, the X-ray powder diffraction pattern (XRPD) of the isopropyl alcohol-aqueous heterosolvate crystal form VII of the compound of formula (I) includes positions at 23.77±0.2°, 24.36±0.2°, 18.56±0.2°, 5.94 ±0.2°, 22.59±0.2°, 20.30±0.2°, 17.79±0.2°, 10.33±0.2°, 12.10±0.2°, 22.26±0.2°, 19.48±0.2°, 21.73±0.2°, 5.29±0.2°, 25.80 Peaks at diffraction angles (2θ) of ±0.2° and 16.45±0.2°;

More preferably, the X-ray powder diffraction pattern (XRPD) of the isopropyl alcohol-aqueous heterosolvate crystal form VII of the compound of formula (I) includes positions at 23.77±0.2°, 24.36±0.2°, 18.56±0.2°, 5.94±0.2°, 22.59±0.2°, 20.30±0.2°, 17.79±0.2°, 10.33±0.2°, 12.10±0.2°, 22.26±0.2°, 19.48±0.2°, 21.73±0.2°, 5.29±0.2°, 25.80±0.2°, 16.45±0.2°, 21.94±0.2°, 28.33±0.2°, 25.04±0.2°, 11.89±0.2°, 17.26±0.2°, 28.85±0.2°, 16.79±0.2°, 23.34±0.2°, Peaks at diffraction angles (2θ) of 30.31±0.2° and 14.26±0.2°.
Use of the pharmaceutical composition according to any one of claims 1-19 or the crystal form according to any one of claims 22-27 in the preparation of an FGFR inhibitor.
The pharmaceutical composition according to any one of claims 1-19 or the crystal form according to any one of claims 22-27 is used in the preparation and treatment of liver cancer, prostate cancer, pancreatic cancer, esophageal cancer, gastric cancer, lung cancer, Use in medicines for breast cancer, ovarian cancer, colon cancer, skin cancer, glioblastoma, or rhabdomyosarcoma.