Crystal form of EGFR tyrosine kinase inhibitor and preparation method thereof

Abstract

The invention relates to the field of medicine crystal forms, in particular to a novel crystal form of a compound shown in the formula I and a preparation method of the novel crystal form, and the crystal form K of the compound shown in the formula I has the comprehensive advantages of excellent physical stability and chemical stability, high solubility and bioavailability, good fluidity and low hygroscopicity and can be developed as a medicinal crystal form. In addition, the crystal form K of the compound shown in the formula I is mild in preparation condition, simple to operate, good in process reproducibility, high in purity and suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present application belongs to the field of drug crystal forms, and specifically relates to a new crystal form of a compound of formula I and a method for preparing the same. Background Art

[0002] The compound of formula I is a Class 1.1 anti-tumor new drug independently developed by Beida Pharmaceutical Co., Ltd. The State Drug Administration approved the marketing of the compound of formula I on June 7, 2011 for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with sensitive mutations in the epidermal growth factor receptor (EGFR) gene, as well as locally advanced or metastatic NSCLC who have previously received platinum-containing chemotherapy. The chemical structure of the compound of formula I is shown below:

[0003]

[0004] Patent CN101878218A discloses four crystalline forms of the compound of formula I, namely, form I (anhydrate), form II (dihydrate), form III (dihydrate) and form IV (N,N-dimethylformamide solvate).

[0005] Patent CN114907362A discloses nine crystalline forms of the compound of formula I, namely, form R (semihydrate), form ICB-1 (anhydrate), form ICB-2, form ICB-3 (dihydrate), form ICB-4 (methanol solvate), form ICB-5, form ICB-6 (DMSO solvate), form ICB-7 and form ICB-8. Among them, only form R, form ICB-1 and form ICB-3 were determined to be more stable than form I at 25°C / 60%RH and 30°C / 75%RH for 15 days.

[0006] It is well known that different crystal forms of the same drug may differ significantly in appearance, solubility, melting point, dissolution, etc., thus affecting the stability, bioavailability and efficacy of the drug. Generally speaking, stable crystal forms have higher melting points, lower solubility and slower dissolution rates; unstable crystal forms, on the contrary, are easily transformed into other crystal forms. Selecting the most thermodynamically stable crystal form can ensure that crystal transformation does not occur during the production, storage and transportation of the API, but stable crystal forms often have poor bioavailability due to their low solubility, so it is necessary to develop pharmaceutical crystal forms that can take into account both stability and solubility / bioavailability.

[0007] In the formulation research, the presence of non-API ingredients in drugs in the form of solvates or hydrates often affects the compatibility of raw materials and excipients, the ratio of raw materials and excipients, the weight of the preparation, etc. In addition, drugs in the form of solvates or hydrates may also have stability defects. Therefore, in general, drug crystal forms in the form of solvates are not suitable for drug formulation development, while drug crystal forms in the form of hydrates should be carefully evaluated and selected.

[0008] Although patent CN101878218A discloses four crystal forms, crystal forms II and III are dihydrates, and crystal form IV is an N,N-dimethylformamide solvate (there is a risk of solvent residue), neither of which is suitable for drug preparation development. The anhydrous crystal form I has poor stability, and it is difficult to ensure the uniform and stable quality of the drug. Although patent CN114907362A reports the more stable crystal form R (semihydrate), crystal form ICB-1 (anhydrate), and crystal form ICB-3 (dihydrate), the solubility and bioavailability of these crystal forms have not been studied, so it is impossible to determine whether the above crystal forms can be used for drug preparation development.

[0009] Therefore, it is necessary to conduct a comprehensive study on the crystal forms of the compound of formula I, and to develop one or more crystal forms that have simple preparation methods, high chemical stability, good solubility, high purity, low hygroscopicity, and other comprehensive properties that meet the requirements of pharmaceutical development and are suitable for industrial production. Summary of the invention

[0010] In view of the shortcomings of the prior art of the poor stability of the crystal form of the compound of formula I and the difficulty in meeting the development needs of pharmaceutical crystal forms, the present application provides one or more pharmaceutically acceptable crystal forms that achieve a balance in comprehensive performance in terms of stability, hygroscopicity, solubility, bioavailability, etc., as well as a method for preparing the crystal form of the compound of formula I with simple steps, low cost, and conducive to industrial production.

[0011] On the one hand, the present application provides a crystalline form A of a compound of formula I, which has an X-ray powder diffraction pattern with characteristic peaks at 2θ angles of 5.8±0.2°, 11.6±0.2°, 17.4±0.2° and 21.3±0.2° using Cu-Ka radiation.

[0012] In some embodiments, the X-ray powder diffraction pattern of the crystalline form A under Cu-Kα radiation has characteristic peaks at 2θ angles of 5.8±0.2°, 10.4±0.2°, 11.6±0.2°, 17.4±0.2°, 21.3±0.2° and 26.6±0.2°.

[0013] In some specific embodiments, the X-ray powder diffraction pattern of the crystalline form A under Cu-Kα radiation is substantially as follows Figure 1 shown.

[0014] On the other hand, the present application provides a method for preparing Form A of a compound of Formula I, comprising: adding a compound of Formula I to hexafluoroisopropanol, stirring to obtain a clear solution, slowly adding an organic solvent, stirring to crystallize, filtering, and drying, and the resulting solid is Form A of the compound of Formula I.

[0015] In some embodiments, in the above method for preparing Form A, the organic solvent is selected from one or more of ethyl acetate, isopropyl acetate, dimethyl carbonate or methyl isobutyl ketone.

[0016] On the other hand, the present application provides a crystalline form B of a compound of formula I, which has an X-ray powder diffraction pattern using Cu-Ka radiation, with characteristic peaks at 2θ angles of 7.2±0.2°, 7.8±0.2°, 20.7±0.2°, 23.1±0.2° and 24.1±0.2°.

[0017] In some embodiments, the X-ray powder diffraction pattern of the crystalline form B under Cu-Kα radiation has characteristic peaks at 2θ angles of 7.2±0.2°, 7.8±0.2°, 15.8±0.2°, 16.9±0.2°, 20.7±0.2°, 23.1±0.2°, 23.8±0.2° and 24.1±0.2°.

[0018] In some specific embodiments, the X-ray powder diffraction pattern of the crystalline form B under Cu-Kα radiation is substantially as follows Figure 2 shown.

[0019] On the other hand, the present application provides a method for preparing Form B of the compound of Formula I, comprising: adding the compound of Formula I to trifluoroethanol, stirring to obtain a clear solution, slowly adding ethylene glycol methyl ether, stirring to crystallize, filtering, and drying, and the obtained solid is Form B of the compound of Formula I.

[0020] On the other hand, the present application provides a crystalline form C of a compound of formula I, which has an X-ray powder diffraction pattern using Cu-Ka radiation, with characteristic peaks at 2θ angles of 7.4±0.2°, 9.5±0.2°, 15.2±0.2°, 19.1±0.2° and 23.1±0.2°.

[0021] In some embodiments, the X-ray powder diffraction pattern of the crystalline form C under Cu-Kα radiation has characteristic peaks at 2θ angles of 7.4±0.2°, 9.5±0.2°, 15.2±0.2°, 17.4±0.2°, 19.1±0.2°, 23.1±0.2°, 24.6±0.2° and 30.3±0.2°.

[0022] In some specific embodiments, the X-ray powder diffraction pattern of the crystalline form C under Cu-Kα radiation is substantially as follows Figure 3 shown.

[0023] On the other hand, the present application provides a method for preparing Form C of the compound of Formula I, comprising: adding the compound of Formula I to trifluoroethanol, stirring to obtain a clear solution, slowly adding ethanol, stirring to crystallize, filtering, and drying, and the obtained solid is Form C of the compound of Formula I.

[0024] On the other hand, the present application provides a crystalline form D of a compound of formula I, which has an X-ray powder diffraction pattern using Cu-Ka radiation, with characteristic peaks at 2θ angles of 7.7±0.2°, 13.4±0.2°, 14.8±0.2°, 20.7±0.2° and 22.3±0.2°.

[0025] In some embodiments, the X-ray powder diffraction pattern of the crystalline form D under Cu-Kα radiation has characteristic peaks at 2θ angles of 7.4±0.2°, 7.7±0.2°, 13.4±0.2°, 14.8±0.2°, 20.0±0.2°, 20.7±0.2°, 22.3±0.2° and 26.2±0.2°.

[0026] In some specific embodiments, the X-ray powder diffraction pattern of the crystalline form D under Cu-Kα radiation is substantially as follows Figure 4 shown.

[0027] On the other hand, the present application provides a method for preparing Form D of the compound of Formula I, comprising: adding the compound of Formula I to trifluoroethanol, stirring to obtain a clear solution, slowly adding glacial acetic acid, stirring to crystallize, filtering, and drying, and the obtained solid is Form D of the compound of Formula I.

[0028] On the other hand, the present application provides a crystalline form E of a compound of formula I, which has an X-ray powder diffraction pattern using Cu-Ka radiation, with characteristic peaks at 2θ angles of 5.7±0.2°, 10.8±0.2°, 12.2±0.2°, 16.4±0.2°, 18.0±0.2° and 23.3±0.2°.

[0029] In some embodiments, the X-ray powder diffraction pattern of the crystalline form E under Cu-Kα radiation has characteristic peaks at 2θ angles of 5.7±0.2°, 7.8±0.2°, 10.8±0.2°, 12.2±0.2°, 16.4±0.2°, 18.0±0.2°, 21.7±0.2°, 22.7±0.2° and 23.3±0.2°.

[0030] In some specific embodiments, the X-ray powder diffraction pattern of the crystalline form E under Cu-Kα radiation is substantially as follows Figure 5 shown.

[0031] On the other hand, the present application provides a method for preparing Form E of the compound of Formula I, comprising: adding the compound of Formula I to trifluoroethanol, stirring to obtain a clear solution, then dropping the solution into n-heptane, stirring to crystallize, filtering, and drying, and the obtained solid is Form E of the compound of Formula I.

[0032] On the other hand, the present application provides a crystalline form F of a compound of formula I, which has an X-ray powder diffraction pattern using Cu-Ka radiation, with characteristic peaks at 2θ angles of 8.5±0.2°, 12.8±0.2°, 21.5±0.2°, 24.0±0.2° and 25.9±0.2°.

[0033] In some embodiments, the X-ray powder diffraction pattern of the crystalline form F under Cu-Kα radiation has characteristic peaks at 2θ angles of 7.6±0.2°, 8.5±0.2°, 12.8±0.2°, 17.1±0.2°, 21.5±0.2°, 24.0±0.2°, 25.9±0.2° and 27.4±0.2°.

[0034] In some specific embodiments, the X-ray powder diffraction pattern of the crystalline form F under Cu-Kα radiation is substantially as follows Figure 6 shown.

[0035] On the other hand, the present application provides a method for preparing Form F of the compound of Formula I, comprising: adding the compound of Formula I to hexafluoroisopropanol, stirring to obtain a clear solution, then dropping the solution into purified water, stirring to crystallize, filtering, and drying, and the obtained solid is Form F of the compound of Formula I.

[0036] On the other hand, the present application provides a crystalline form G of a compound of formula I, which has an X-ray powder diffraction pattern using Cu-Ka radiation, with characteristic peaks at 2θ angles of 10.5±0.2°, 15.5±0.2°, 17.8±0.2°, 21.7±0.2°, and 24.9±0.2°.

[0037] In some embodiments, the X-ray powder diffraction pattern of the crystalline form G under Cu-Kα radiation has characteristic peaks at 2θ angles of 9.7±0.2°, 10.5±0.2°, 15.5±0.2°, 17.8±0.2°, 21.7±0.2°, 22.7±0.2°, 24.2±0.2° and 24.9±0.2°.

[0038] In some specific embodiments, the X-ray powder diffraction pattern of the crystalline form G under Cu-Kα radiation is substantially as follows Figure 7 shown.

[0039] In some specific embodiments, the thermogravimetric analysis spectrum of the crystalline form G is substantially as follows Fig.11 Show.

[0040] In some specific embodiments, the weight loss of the crystalline form G in the range of 30°C-105°C is about 0.64%, where "%" means weight percentage.

[0041] On the other hand, the present application provides a method for preparing Form G of the compound of Formula I, comprising: adding the compound of Formula I to methanol, stirring for 2-48 hours, filtering, and drying at 60-80°C, and the obtained solid is Form G of the compound of Formula I.

[0042] On the other hand, the present application provides a crystalline form H of a compound of formula I, which has an X-ray powder diffraction pattern using Cu-Ka radiation, with characteristic peaks at 2θ angles of 6.2±0.2°, 10.5±0.2°, 13.6±0.2°, 16.4±0.2° and 24.7±0.2°.

[0043] In some embodiments, the X-ray powder diffraction pattern of the crystalline form H under Cu-Kα radiation has characteristic peaks at 2θ angles of 6.2±0.2°, 8.1±0.2°, 10.5±0.2°, 13.6±0.2°, 16.4±0.2°, 19.6±0.2°, 21.6±0.2°, 24.7±0.2° and 25.8±0.2°.

[0044] In some specific embodiments, the X-ray powder diffraction pattern of the crystalline form H under Cu-Kα radiation is substantially as follows Figure 8 shown.

[0045] In some specific embodiments, the thermogravimetric analysis spectrum of the crystalline form H is substantially as follows Fig.12 shown.

[0046] In some specific embodiments, the weight loss of the crystalline form H in the range of 30° C.-130° C. is about 3.43%, where “%” means weight percentage.

[0047] On the other hand, the present application provides a method for preparing the crystalline form H of the compound of formula I, comprising: adding the crystalline form ICB-3 of the compound of formula I to methanol, stirring for 2-24 hours, filtering, and drying at 30-50°C, and the obtained solid is the crystalline form H of the compound of formula I.

[0048] On the other hand, the present application provides a crystalline form J of a compound of formula I, which has an X-ray powder diffraction pattern using Cu-Ka radiation, with characteristic peaks at 2θ angles of 12.8±0.2°, 17.2±0.2°, 22.8±0.2°, 24.1±0.2°, 26.6±0.2° and 29.8±0.2°.

[0049] In some embodiments, the X-ray powder diffraction pattern of the crystalline form J under Cu-Kα radiation has characteristic peaks at 2θ angles of 7.2±0.2°, 10.7±0.2°, 12.8±0.2°, 16.0±0.2°, 17.2±0.2°, 20.0±0.2°, 20.9±0.2°, 22.8±0.2°, 24.1±0.2°, 26.6±0.2° and 29.8±0.2°.

[0050] In some embodiments, the X-ray powder diffraction pattern of Form J under Cu-Kα radiation is substantially as follows Fig. 9 shown.

[0051] On the other hand, the present application provides a method for preparing Form J of the compound of Formula I, comprising: adding the compound of Formula I to dimethyl sulfoxide, stirring for 2-24 hours, filtering, and drying, and the obtained solid is Form J of the compound of Formula I.

[0052] On the other hand, the present application provides a crystalline form K of a compound of formula I, which has an X-ray powder diffraction pattern using Cu-Ka radiation, with characteristic peaks at 2θ angles of 6.8±0.2°, 9.9±0.2°, 11.3±0.2°, 19.8±0.2°, 24.5±0.2° and 30.0±0.2°.

[0053] In some embodiments, the X-ray powder diffraction pattern of the crystalline form K under Cu-Kα radiation has characteristic peaks at 2θ angles of 6.8±0.2°, 9.9±0.2°, 11.3±0.2°, 12.8±0.2°, 15.7±0.2°, 19.8±0.2°, 20.7±0.2°, 24.5±0.2° and 30.0±0.2°.

[0054] In some embodiments, the X-ray powder diffraction pattern of the crystalline form K under Cu-Kα radiation has characteristic peaks at 2θ angles of 6.8±0.2°, 9.9±0.2°, 10.9±0.2°, 11.3±0.2°, 12.8±0.2°, 13.3±0.2°, 15.7±0.2°, 19.8±0.2°, 20.7±0.2°, 22.0±0.2°, 24.5±0.2°, 25.7±0.2° and 30.0±0.2°;

[0055] In some specific embodiments, the X-ray powder diffraction pattern of the crystalline form K under Cu-Kα radiation is substantially as follows Fig.10 shown.

[0056] In some specific embodiments, the thermogravimetric analysis spectrum of the crystal form K is substantially as follows Fig.13 shown.

[0057] In some specific embodiments, the weight loss of the crystalline form K in the range of 30°C-105°C is about 0.28%, where "%" means weight percentage.

[0058] On the other hand, the present application provides a method for preparing Form K of a compound of Formula I, comprising: adding the compound of Formula I to tetrahydrofuran, stirring at 20-50° C. for 12-60 h, filtering, and drying, and the resulting solid is Form K.

[0059] In some embodiments, the present application provides a method for preparing Form K of the compound of Formula I, the method comprising:

[0060] (1) dissolving the compound of formula I in hexafluoroisopropanol;

[0061] (2) taking an appropriate amount of seed crystals of the crystalline form K and adding them into an organic solvent to form a suspension;

[0062] (3) adding the solution obtained in step (1) dropwise to step (2), or adding the suspension obtained in step (2) dropwise to step (1), and crystallizing.

[0063] Preferably, in the above method, the organic solvent is selected from one or more of acetone, methyl isobutyl ketone and tetrahydrofuran.

[0064] Preferably, in the above method, the mass volume ratio (mg / ml) of the compound of formula I and hexafluoroisopropanol is 1:0.005.

[0065] Preferably, in the above method, the amount of seed crystals of the crystalline form K added is 0.1-1% by mass of the compound of formula I; preferably 0.1%.

[0066] Preferably, in the above method, after crystallization in step (3), filtration is performed, and the obtained solid is vacuum dried at 40° C., and the obtained solid is crystal form K.

[0067] In some embodiments, the present application provides a method for preparing Form K of the compound of Formula I, the method comprising:

[0068] (1) dissolving the compound of formula I in dimethyl sulfoxide;

[0069] (2) taking an appropriate amount of seed crystals of the crystalline form K and adding them into ethanol to form a suspension;

[0070] (3) The solution obtained in step (1) is added dropwise to step (2), or the suspension obtained in step (2) is added dropwise to step (1) to crystallize.

[0071] Preferably, the mass volume ratio (mg / ml) of the compound of formula I to dimethyl sulfoxide is 1:0.005.

[0072] Preferably, the amount of seed crystals of the crystalline form K added is 0.1-1% by mass of the compound of formula I; preferably 0.1%.

[0073] Preferably, the drying in step (3) refers to vacuum drying at 40-60°C.

[0074] The beneficial effects brought by this application are:

[0075] 1. Compared with Form I, Form K prepared in the present application has significantly improved physical stability and chemical stability, and has lower hygroscopicity, which can ensure the quality stability during the production and storage of raw materials and preparations; and Form K has better solubility and bioavailability on the basis of higher stability, achieving a balance between stability and solubility, and can be developed as a medicinal crystal form.

[0076] 2. Compared with the crystal form ICB-1, the crystal form K prepared in this application has significantly improved solubility and bioavailability while maintaining excellent stability. Considering the comprehensive stability and solubility, the use of crystal form K to develop preparations can not only ensure the stable and controllable quality of the raw material during production and storage, but also ensure that the preparation product has a high bioavailability, which is more valuable for industrial application than the crystal form ICB-1.

[0077] 3. After a large number of screening experiments, the applicant finally obtained 10 new crystal forms of icotinib hydrochloride. After further studying the performance of the crystal forms, it was found that crystal form K is the preferred crystal form. Compared with crystal form G, it has better stability and hygroscopicity, and better stability than crystal form H. In addition, crystal form K has a comprehensive effect of balance in all aspects and can be used as a pharmaceutical crystal form. This has taken a lot of creative work.

[0078] 4. The crystal form K of the present application has high purity, the residual solubility meets the limit standard, and the crystal quality is stable, so it is safer; and the crystal form K does not contain solvents and water, and is more suitable as a medicinal crystal form.

[0079] 5. The preparation conditions of the crystal form K of the present application are mild, the operation is simple, the process reproducibility is good, and the purity is high, so that the conditions for industrial production are controllable, which is conducive to large-scale industrialization.

[0080] In summary, the crystal form K prepared in the present application has excellent crystal stability and chemical stability, low hygroscopicity, and high solubility, and has achieved a balance between the desired properties of the crystal form (such as dissolution rate, solubility, bioavailability and / or storage stability), and has extremely high pharmaceutical development value. BRIEF DESCRIPTION OF THE DRAWINGS

[0081] Figure 1 The XRD pattern of Form A of the compound of Formula I is shown in FIG.

[0082] Figure 2 The XRD pattern of Form B of the compound of Formula I is shown in FIG.

[0083] Figure 3 The XRD pattern of Form C of the compound of Formula I is shown in FIG.

[0084] Figure 4 The XRD pattern of the crystalline form D of the compound of formula I is shown in FIG.

[0085] Figure 5 The XRD pattern of the crystalline form E of the compound of formula I is shown in FIG.

[0086] Figure 6 The XRD pattern of Form F of the compound of Formula I is shown in FIG.

[0087] Figure 7 The XRD pattern of the crystalline form G of the compound of formula I is shown in FIG.

[0088] Figure 8 The XRD pattern of the crystalline form H of the compound of formula I is shown in FIG.

[0089] Fig. 9 The XRD pattern of Form J of the compound of Formula I is shown in FIG.

[0090] Fig.10 The XRD pattern of the crystalline form K of the compound of formula I is shown in FIG.

[0091] Fig.11 The figure is the TGA spectrum of Form G of the compound of Formula I.

[0092] Fig.12 This is the TGA spectrum of Form H of the compound of Formula I.

[0093] Fig.13 The figure is the TGA spectrum of the crystalline form K of the compound of formula I.

[0094] Fig.14 The XRD comparison graphs of the crystalline form G of the compound of formula I before and after the influencing factors are placed.

[0095] Fig.15 The XRD comparison graphs of Form H of the compound of Formula I before and after being exposed to influencing factors.

[0096] Fig.16The XRD comparison chart of Form K of the compound of Formula I before and after the influencing factors are placed.

[0097] Fig.17 The XRD comparison graphs of the crystalline form I of the compound of formula I before and after the influencing factors are placed.

[0098] Fig.18 The XRD comparison chart of the crystalline form G of the compound of formula I before and after accelerated and long-term stability.

[0099] Fig.19 The XRD comparison chart of Form K of the compound of Formula I before and after accelerated and long-term stability.

[0100] Fig. 20 The XRD comparison chart of Form I of the compound of Formula I before and after accelerated and long-term stability.

[0101] Fig.21 The XRD comparison chart of the crystal form ICB-1 of the compound of formula I before and after accelerated and long-term stability.

[0102] Fig. 22 It is the DVS curve diagram of the crystalline form G of the compound of formula I.

[0103] Fig.23 It is the DVS curve diagram of the crystalline form K of the compound of formula I.

[0104] Fig.24 It is the DVS curve diagram of Form I of the compound of Formula I.

[0105] Fig.25 It is the DVS curve diagram of the crystalline form ICB-1 of the compound of formula I. DETAILED DESCRIPTION

[0106] In order to make the present invention more easily understood, the present invention will be described in detail below in conjunction with embodiments. These embodiments are only for illustration and are not intended to limit the application scope of the present invention.

[0107] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0108] The abbreviations used in this application are explained as follows:

[0109] XRD: X-ray powder diffraction

[0110] The X-ray powder diffraction (XRD) test described in this application is collected using a Malvern Panalytical Empyrea powder diffractometer, and the specific parameters are as follows:

[0111]

[0112] In the X-ray powder diffraction pattern of this application, the error of the 2θ diffraction angle is ±0.20°. In this article, "X-ray powder diffraction pattern is substantially as Figure 1 "shown" refers to the X-ray powder diffraction pattern and Figure 1 Substantially the same. The term "substantially the same" with respect to X-ray powder diffraction patterns is meant to take into account variations in representative peak positions and intensities.

[0113] TGA: Thermogravimetric analysis

[0114] The thermogravimetric analysis (TGA) measurement described in the present application was performed using a METTLER TOLEDO model TGA-2, with a heating rate of 10°C / min, a temperature range of 30-300°C, and a nitrogen purge rate of 20 mL / min during the test.

[0115] The error of TGA can be within about ±0.5 mass %. Fig.11 "shown" refers to the TGA spectrum and Fig.11 Substantially the same. The term "substantially the same" with respect to TGA patterns means that such error variations are taken into account.

[0116] DVS: Dynamic Vapor Sorption Analyzer

[0117] The dynamic vapor adsorption instrument Intrinsic (British SMS Instrument) described in this application detects the change of sample weight with humidity at 25°C. Specific parameters: start equilibrium at 25°C and 0% relative humidity. The weight change is less than 0.002% every 2 minutes. Jump 10% relative humidity to enter the next stage. The maximum equilibrium time of each stage is 360 minutes. After the relative humidity reaches 98% and the equilibrium is completed, a relative humidity jump is performed in the reverse direction. The relative humidity changes are as follows: 0%-10%-20%-30%-40%-50%-60%-70%-80%-90%-98%-90%-80%-70%-60%-50%-40%-30%-20%-10%-0%. Data analysis software DVS Control (British SMS Instrument)).

[0118] The moisture absorption evaluation is classified as follows:

[0119] For the description of hygroscopic characteristics and the definition of hygroscopic weight gain, please refer to Part IV of the 2020 edition of the Chinese Pharmacopoeia (9103 Guiding Principles for Drug Hygroscopicity Test):

[0120] Moisture Classification ΔW% deliquescence Absorbs enough water to form a liquid Highly hygroscopic ΔW%≥15% Hygroscopic 15%>ΔW%≥2% Slightly hygroscopic 2%>ΔW%≥0.2% No or almost no hygroscopicity ΔW%<0.2%

[0121] Note: ΔW% indicates the weight gain of the test sample at 25±1℃ and 80±2%RH.

[0122] Herein, percentages are by weight unless otherwise stated.

[0123] The moisture content in the embodiments of the present invention is determined by referring to the Karl-Fischer method specified in the current pharmacopoeia.

[0124] Those skilled in the art will appreciate that, in the preparation process of the specific crystal form described in the present invention, the compound of formula I as the starting material needs to be dissolved, so the compound of formula I is not limited to physical form, and may include a crude compound of formula I, a compound of formula I in an amorphous form, a compound of formula I in any crystalline form, or a mixture of the above-listed physical forms.

[0125] Preferably, the compound of formula I used in the present application is purchased from Shanghai Yuanhua Pharmaceutical Technology Co., Ltd.

[0126] Example 1: Preparation of Form A of Compound of Formula I

[0127] At 20°C, 15 mg of the compound of formula I was added to 0.075 mL of hexafluoroisopropanol, and a clear solution was obtained after stirring. 1.5 mL of ethyl acetate was added dropwise, stirred, and crystallized. The solution was filtered and dried under vacuum at 60°C for 24 h. The obtained solid was the crystalline form A of the compound of formula I. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its X-ray powder diffraction pattern was substantially as follows: Figure 1 shown.

[0128] Example 2: Preparation of Form B of Compound I

[0129] At 20°C, 15 mg of the compound of formula I was added to 0.075 mL of trifluoroethanol, and a clear solution was obtained after stirring. 1.5 mL of ethylene glycol methyl ether was added dropwise, stirred and crystallized, and filtered. The obtained solid was the crystal form B of the compound of formula I. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its X-ray powder diffraction pattern was substantially as follows: Figure 2 shown.

[0130] Example 3: Preparation of Form C of Compound of Formula I

[0131] At 20°C, 15 mg of the compound of formula I was added to 0.075 mL of trifluoroethanol, and a clear solution was obtained after stirring. 1.5 mL of ethanol was added dropwise, stirred, and crystallized. The solid obtained was the crystal form C of the compound of formula I. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its X-ray powder diffraction pattern was substantially as follows: Figure 3 shown.

[0132] Example 4: Preparation of Form D of Compound of Formula I

[0133] At 20°C, 15 mg of the compound of formula I was added to 0.075 mL of trifluoroethanol, and a clear solution was obtained after stirring. 1.5 mL of glacial acetic acid was added dropwise, stirred and crystallized, and filtered. The obtained solid was the crystal form D of the compound of formula I. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its X-ray powder diffraction pattern was substantially as follows: Figure 4 shown.

[0134] Example 5: Preparation of Form E of the Compound of Formula I

[0135] At 20°C, 15 mg of the compound of formula I was added to 0.075 mL of trifluoroethanol and stirred to obtain a clear solution. The solution was added dropwise to 1.5 mL of n-heptane and stirred for crystallization. The solid obtained was the crystalline form E of the compound of formula I. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its X-ray powder diffraction pattern was substantially as follows: Figure 5 shown.

[0136] Example 6: Preparation of Form F of Compound of Formula I

[0137] At 20°C, 15 mg of the compound of formula I was added to 0.075 mL of hexafluoroisopropanol, and a clear solution was obtained after stirring. The solution was added dropwise to 1.5 mL of purified water, stirred for crystallization, and filtered. The obtained solid was the crystalline form F of the compound of formula I. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its X-ray powder diffraction pattern was substantially as follows: Figure 6 shown.

[0138] Example 7: Preparation of Form G of the Compound of Formula I

[0139] At 20°C, 4.2 g of the compound of formula I was added to 84 mL of methanol, stirred for 24 h, filtered, and the obtained solid was vacuum dried at 80°C for 10 h to obtain the compound of formula I, form G. The HPLC purity of the obtained sample was 99.88%, the moisture content was 2.10%, and the methanol residue was 0.0068%. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its spectrum had the diffraction angle, crystal plane spacing and relative intensity shown in Table 1, and its X-ray powder diffraction spectrum was basically as shown in Table 1. Figure 7 The thermogravimetric analysis spectrum of the crystal form G is basically as shown Fig.11 It is shown that its weight loss in the range of 30°C-105°C is 0.64%.

[0140] Table 1 Diffraction angle, interplanar spacing and relative intensity of the crystalline form G of the compound of formula I

[0141]

[0142] Example 8: Preparation of Form H of Compound of Formula I

[0143] At 20°C, 2.0 g of the crystal form ICB-3 of the compound of formula I was added to 200 mL of methanol, stirred for 19 hours, filtered, and the obtained solid was vacuum dried at 40°C for 16 hours to obtain the crystal form H of the compound of formula I. The HPLC purity of the obtained sample was 100.00%, the moisture content was 3.71%, and the methanol residue was 0.79%. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its spectrum had the diffraction angle, crystal plane spacing and relative intensity shown in Table 2, and its X-ray powder diffraction spectrum was basically as shown in Table 2. Figure 8 The thermogravimetric analysis spectrum of the crystal form H is basically as shown. Fig.12 As shown, its weight loss in the range of 30°C-130°C is 3.43%.

[0144] Table 2 Diffraction angle, interplanar spacing and relative intensity of the crystalline form H of the compound of formula I

[0145]

[0146] Example 9: Preparation of Form J of Compound I

[0147] At 20°C, 4.8 g of the compound of formula I was added to 24 mL of dimethyl sulfoxide, stirred for 20 h, filtered, and the obtained solid was vacuum dried at 40°C for 16 h to obtain the crystalline form J of the compound of formula I. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its X-ray powder diffraction pattern was substantially as follows: Fig. 9 shown.

[0148] Example 10: Preparation of Form K of Compound of Formula I

[0149] 5.0 g of the compound of formula I was added to 150 mL of tetrahydrofuran, stirred at 20° C. for 40 h, then transferred to 50° C. and stirred for 6 h, filtered, and the obtained solid was vacuum dried at 40° C. for 16 h to obtain the crystalline form K of the compound of formula I. The HPLC purity of the obtained sample was 99.80%, the water content was 0.21%, and the tetrahydrofuran residue was 0.06% (meeting the limit standard).

[0150] The obtained sample was subjected to X-ray powder measurement using Cu-ka radiation, and its spectrum had the diffraction angle, interplanar spacing and relative intensity shown in Table 3. Its X-ray powder diffraction spectrum was basically as follows: Fig.10 The thermogravimetric analysis spectrum of the crystal form K is basically as shown. Fig.13 As shown, its weight loss in the range of 30°C-105°C is 0.28%, that is, the crystal form K is anhydrous.

[0151] Table 3 Diffraction angle, interplanar spacing and relative intensity of the crystal form K of the compound of formula I

[0152]

[0153] Example 11: Preparation of Form K of Compound of Formula I

[0154] At 20°C, 15 mg of the compound of formula I was dissolved in 0.075 mL of hexafluoroisopropanol to obtain a clear solution, and 2 mg of the seed crystals obtained in Example 10 were added to 1 mL of acetone to form a suspension. The clear solution of hexafluoroisopropanol was slowly added dropwise to the acetone suspension containing the seed crystals, stirred for crystallization, and filtered. The obtained solid was vacuum dried at 40°C for 16 h to obtain the crystal form K of the compound of formula I. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its X-ray powder diffraction pattern was basically consistent with that of Example 10.

[0155] Example 12: Preparation of Form K of Compound of Formula I

[0156] At 20°C, 15 mg of the compound of formula I was dissolved in 0.075 mL of hexafluoroisopropanol to obtain a clear solution, and 2 mg of the seed crystals obtained in Example 10 were added to 1 mL of methyl isobutyl ketone to form a suspension, and the clear solution of hexafluoroisopropanol was slowly added dropwise to the methyl isobutyl ketone suspension containing the seed crystals, stirred for crystallization, and filtered. The obtained solid was vacuum dried at 40°C for 16 h to obtain the crystal form K of the compound of formula I. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its X-ray powder diffraction pattern was basically consistent with that of Example 10.

[0157] Example 13: Preparation of Form K of Compound of Formula I

[0158] At 20°C, 15 mg of the compound of formula I was dissolved in 0.075 mL of hexafluoroisopropanol to obtain a clear solution. Another 2 mg of the seed crystals obtained in Example 10 were added to 1 mL of tetrahydrofuran to form a suspension. The clear solution of hexafluoroisopropanol was slowly added dropwise to the tetrahydrofuran suspension containing the seed crystals, stirred for crystallization, and filtered. The obtained solid was vacuum dried at 40°C for 16 h to obtain the crystal form K of the compound of formula I. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its X-ray powder diffraction pattern was basically consistent with that of Example 10. Example 14: Preparation of Crystal Form K of the Compound of Formula I

[0159] At 60°C, 15 mg of the compound of formula I was dissolved in 0.15 mL of dimethyl sulfoxide to obtain a clear solution, and 2 mg of the seed crystals obtained in Example 10 were added to 1 mL of ethanol to form a suspension. The clear dimethyl sulfoxide solution was slowly added dropwise to the ethanol suspension containing the seed crystals, stirred for crystallization, and filtered. The obtained solid was vacuum dried at 40°C for 16 h to obtain the crystal form K of the compound of formula I. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its X-ray powder diffraction pattern was basically consistent with that of Example 10.

[0160] Example 15: Preparation of Form K of Compound of Formula I

[0161] At 60°C, 15 mg of the compound of formula I was dissolved in 0.15 mL of dimethyl sulfoxide to obtain a clear solution, and 2 mg of the seed crystals obtained in Example 10 were added to 1 mL of ethanol to form a suspension. The ethanol suspension containing the seed crystals was slowly added dropwise to the dimethyl sulfoxide solution, stirred for crystallization, and filtered. The obtained solid was vacuum dried at 40°C for 16 h to obtain the crystal form K of the compound of formula I. The obtained sample was subjected to X-ray powder determination using Cu-ka rays, and its X-ray powder diffraction pattern was basically consistent with that of Example 10.

[0162] Comparative Example 1: Preparation of Form I of Compound of Formula I

[0163] At 20°C, 2.0 g of the compound of formula I was added to 10 mL of trifluoroethanol, stirred to obtain a clear solution, 200 mL of 1,4-dioxane was added, stirred and crystallized, filtered, and the obtained solid was vacuum dried at 60°C for 16 h to obtain the crystal form I of the compound of formula I. The HPLC purity of the obtained sample was 99.86%, and the water content was 0.16%. The XRD spectrum detection results were basically consistent with those disclosed in patent CN101878218A.

[0164] Comparative Example 2: Preparation of Crystalline Form ICB-1 of Compound of Formula I

[0165] At 60°C, 5.0 g of the compound of formula I was added to 75 mL of ethanol, the resulting suspension was stirred at 60°C for 20 h, filtered, and the resulting solid was vacuum dried at 40°C for 16 h to obtain the crystalline form ICB-1 of the compound of formula I. The HPLC purity of the obtained sample was 99.94%, and the moisture content was 0.20%. The XRD spectrum test results were basically consistent with those disclosed in patent CN114907362A.

[0166] Test Example 1: Investigation of Stability of Influencing Factors

[0167] In order to investigate the stability of the crystal form of the compound of formula I of the present application, the crystal form G prepared in Example 7, the crystal form H prepared in Example 8, the crystal form K prepared in Example 10, and the crystal form I prepared in Comparative Example 1 were placed open for 30 days under high temperature, high humidity and light conditions, and samples were taken for XRD and HPLC testing on the 5th and 30th days, respectively, and compared with the results on the 0th day. The specific data are shown in Tables 4 and Figure 14-17 As shown,

[0168] Table 4 Test results of factors affecting different crystal forms of compound of formula I

[0169] “-” means not determined.

[0170] As can be seen from Table 4, the crystal form of Form K can remain stable under high temperature (60°C), high humidity (75% RH) and light (4500lx±500lx) conditions for 30 days, without crystal transformation, and the purity remains basically unchanged, with high physical and chemical stability. However, Form G, Form H and Form I all undergo crystal transformation under high humidity (75% RH) conditions, and the purity of Form G decreases from 99.88% to 99.56% under light conditions for 30 days, the purity of Form H decreases from 100.00% to 99.72% under light conditions for 30 days, and the purity of Form I decreases from 99.87% to 98.70% under light conditions for 30 days, and the total impurity content increases significantly.

[0171] In summary, the crystal form K prepared in the present application has excellent crystal stability and chemical stability under the conditions of influencing factors, which can ensure the quality stability during the storage of the drug, and avoid the crystal form from changing due to pressure, heating, solvents, moisture (or humidity), excipients, mechanical force and other factors during the drug preparation process, thereby affecting the effectiveness and safety of the drug.

[0172] Test Example 2: Accelerated and long-term stability studies

[0173] In order to investigate the stability of the crystal form of the compound of formula I of the present application, the crystal form G prepared in Example 7, the crystal form K prepared in Example 10, the crystal form I prepared in Comparative Example 1 and the crystal form ICB-1 prepared in Comparative Example 2 were packed in aluminum foil bags and placed under two conditions of 25° C., 60% RH (long-term conditions) and 40° C., 75% RH (accelerated conditions) for 3 months, and the samples were tested by XRD and HPLC, and compared with the results of 0 day. The specific data are shown in Tables 5 and 6. Figure 18-21 As shown:

[0174] Table 5 Long-term and accelerated test results of different crystalline forms of the compound of formula I

[0175]

[0176] As can be seen from Table 5, Form K did not undergo crystal transformation when placed under the conditions of 25°C, 60% RH and 40°C, 75% RH for 3 months, and the purity remained basically unchanged, while Form G and Form I both under the conditions of 25°C, 60% RH or 40°C, 75% RH for 3 months experienced crystal transformation. In summary, Form K prepared in the present application has excellent crystal stability and chemical stability under accelerated and long-term conditions.

[0177] Test Example 3: Hygroscopicity Investigation In order to investigate the hygroscopicity of the crystal forms of the compound of Formula I prepared in the present application, the crystal form G prepared in Example 7, the crystal form K prepared in Example 10, the crystal form I prepared in Comparative Example 1, and the crystal form ICB-1 prepared in Comparative Example 2 were placed in a dynamic moisture adsorption instrument to investigate the weight change of the samples in the range of 0-98%-0 humidity. The hygroscopicity results of different crystal forms of the compound of Formula I are shown in Tables 6 and Figure 20-23 As shown:

[0178] Table 6 Hygroscopicity of different crystalline forms of the compound of formula I at 80% RH to 90% RH

[0179]

[0180] From Table 6 and Figure 22-25 It can be seen that the moisture gain of Form K at 80% RH is only 0.15%, which is non-hygroscopic. Compared with Form G (hygroscopic), Form I (slightly hygroscopic) is significantly better, and when the humidity increases to 90% RH, the moisture gain of Form K is also significantly lower than that of Form G and Form I, indicating that Form K has better quality controllability during the storage of raw materials and preparations.

[0181] Test Example 4: Solubility Investigation

[0182] In order to investigate the solubility of different crystalline forms of the compound of formula I, an experiment was designed according to the solubility test guidelines of the current Chinese Pharmacopoeia. The crystalline form K prepared in Example 10, the crystalline form I prepared in Comparative Example 1, and the crystalline form ICB-1 samples prepared in Comparative Example 2 were added to pure water, pH 1.0, and pH 2.0 to test their equilibrium solubility. The results are shown in Table 7:

[0183] Table 7 Equilibrium solubility of different crystalline forms of the compound of formula I in pure water, pH 1.0 and pH 2.0 media

[0184]

[0185] As can be seen from Table 7, in pure water, the equilibrium solubility of Form K is 1.3 times that of Form ICB-1; in a pH 1.0 medium, the solubility of Form K is 2 times that of Form ICB-1 and 1.5 times that of Form I; in a pH 2.0 medium, the solubility of Form K is 1.8 times that of Form ICB-1 and 1.5 times that of Form I. The above results show that Form K of Formula I has good solubility in pure water, pH 1.0 and pH 2.0, and has better solubility than Form I and Form ICB-1, that is, it has better bioavailability.

[0186] Test Example 5: Pharmacokinetics in rats

[0187] (1) Purpose of the test

[0188] The plasma drug concentration levels and pharmacokinetic characteristics of the compound of formula I were investigated after a single oral administration of crystal form K, crystal form I, and crystal form ICB-1 to rats at the same dosage.

[0189] (2) Materials and methods

[0190] ①Test drug

[0191] Form K prepared in Example 10;

[0192] Crystal form I prepared in Comparative Example 1;

[0193] Crystal form ICB-1 prepared in Comparative Example 2;

[0194] ② Experimental animals

[0195] There were 18 SD rats, 9 females and 9 males.

[0196] ③Test methods

[0197] The test drug was prepared into a suspension of 8.75 mg / ml with corn oil and immediately orally administered to rats at a volume of 4 mL / kg. 0.2 mL of blood was collected from the jugular sinus before administration and 20 min, 40 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration, placed in an EDTA-K2 anticoagulant tube, and centrifuged at 4500 r / min for 10 min. 50 ul of plasma was separated and placed in a centrifuge tube and frozen in a -80°C refrigerator.

[0198] ④LC / MS / MS biological sample analysis:

[0199] Take 50μL of plasma and mix it with 5mL of working solution or blank diluent, add 150μL of acetonitrile precipitant containing internal standard, vortex for 2min, centrifuge at 12000r / min for 10min, take 20μL of supernatant and mix it with 200μL of acetonitrile aqueous solution (acetonitrile: water = 1:1), and inject it into the sample with a volume of 2μL for analysis. ⑤Test results:

[0200] The main pharmacokinetic parameters in the plasma of rats after a single oral administration of different crystalline samples are shown in Table 8:

[0201] Table 8 Main pharmacokinetic parameters in plasma of rats after single oral administration of different crystalline samples

[0202]

[0203]

[0204] As can be seen from Table 8, the maximum blood drug concentration C of crystal form K in rats max It is 3 times that of crystalline ICB-1, AUClast It is higher than that of Form I and Form ICB-1, indicating that Form K of the compound of Formula 1 has good bioavailability in rats.

[0205] The crystal form K prepared in the present application has excellent crystal stability and chemical stability, low hygroscopicity, high solubility and bioavailability, and has extremely high medicinal development value. At the same time, the preparation conditions of the crystal form K in the present application are mild, the operation is simple, and the process reproducibility is good, so that the conditions for industrial production can be controlled, which is conducive to large-scale industrialization.

[0206] It is obvious to those skilled in the art that various modifications and changes may be made to the compounds of the present application and their preparation methods without departing from the spirit or scope of the present application. Therefore, the scope of protection of the present application covers various modifications and changes made to the present application, as long as the modifications or changes are within the scope covered by the claims and their equivalent embodiments.

Claims

1. A crystalline form K of a compound of formula I, characterized in that: The X-ray powder diffraction spectrum of the crystal form K has characteristic peaks at 2θ angles of 6.8±0.2°, 9.9±0.2°, 11.3±0.2°, 19.8±0.2°, 24.5±0.2° and 30.0±0.2°; 2. The crystal form K according to claim 1, characterized in that The X-ray powder diffraction pattern of the crystal form K has characteristic peaks at 2θ angles of 6.8±0.2°, 9.9±0.2°, 11.3±0.2°, 12.8±0.2°, 15.7±0.2°, 19.8±0.2°, 20.7±0.2°, 24.5±0.2° and 30.0±0.2°; Preferably, the X-ray powder diffraction pattern of the crystalline form K has characteristic peaks at 2θ angles of 6.8±0.2°, 9.9±0.2°, 10.9±0.2°, 11.3±0.2°, 12.8±0.2°, 13.3±0.2°, 15.7±0.2°, 19.8±0.2°, 20.7±0.2°, 22.0±0.2°, 24.5±0.2°, 25.7±0.2° and 30.0±0.2°.

3. The crystal form K according to claim 1, characterized in that The X-ray powder diffraction pattern of the crystal form K is basically shown in Figure 10.

4. The crystal form K according to any one of claims 1 to 3, characterized in that The thermogravimetric analysis spectrum of the crystal form K is basically shown in Figure 13.

5. A method for preparing the crystal form K according to any one of claims 1 to 4, characterized in that: The method comprises: adding the compound of formula I into tetrahydrofuran, stirring at 20-50° C. for 12-60 hours, filtering, and drying, and the obtained solid is crystal form K.

6. A method for preparing the crystal form K according to any one of claims 1 to 4, characterized in that: The method comprises: (1) dissolving the compound of formula I in hexafluoroisopropanol; (2) taking an appropriate amount of seed crystals of the crystalline form K and adding them into an organic solvent to form a suspension; (3) adding the solution obtained in step (1) dropwise to step (2), or adding the suspension obtained in step (2) dropwise to step (1), and crystallizing.

7. The method according to claim 6, characterized in that The organic solvent is selected from one or more of acetone, methyl isobutyl ketone or tetrahydrofuran; and / or, The mass volume ratio (mg / ml) of the compound of formula I to hexafluoroisopropanol is 1:0.005; and / or, The amount of the seed crystals of the crystal form K added is 0.1-1% of the mass of the compound of formula I; preferably 0.1%; and / or, After crystallization in step (3), filtration is performed, and the obtained solid is vacuum dried at 40° C. The obtained solid is crystal form K.

8. A method for preparing the crystal form K according to any one of claims 1 to 4, characterized in that: The method comprises: (1) dissolving the compound of formula I in dimethyl sulfoxide; (2) taking an appropriate amount of seed crystals of the crystalline form K and adding them into ethanol to form a suspension; (3) Add the solution obtained in step (1) dropwise to step (2), or add the suspension obtained in step (2) dropwise to step (1), crystallize, filter, and dry to obtain a solid, which is Form K.

9. The method according to claim 8, characterized in that The mass volume ratio (mg / ml) of the compound of formula I to dimethyl sulfoxide is 1:0.005; and / or, The amount of the seed crystals of the crystal form K added is 0.1-1% of the mass of the compound of formula I; preferably 0.1%; and / or, The drying in step (3) refers to vacuum drying at 40-60°C.

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