Crystalline forms of pyridazine derivatives

Abstract

Disclosed are a crystalline form I of a compound represented by formula (I) and a crystalline form II of a compound represented by formula (II), wherein the compound represented by (I) and the compound represented by formula (II) are as described in the present disclosure.

Description

[0001] Citation of Related Applications

[0002] This disclosure claims all rights and interests in the invention patent application with application number 202011114210.5 and invention name “Crystal form of Deucravacitinib and preparation method thereof” filed with the State Intellectual Property Office of the People's Republic of China on October 20, 2020, and incorporates its entire contents into this disclosure by reference.

[0003] field

[0004] The present disclosure relates generally to the field of medicinal chemistry, and more particularly, to crystalline forms of pyridazine derivatives.

[0005] background

[0006] JAK kinase (Janus kinase, JAK) belongs to the intracellular non-receptor tyrosine kinase family, mediates the signal of cytokine production, and transmits it through the JAK-STAT signaling pathway. Tyrosine kinase 2 (TYK2) is a member of the JAK family and plays an important role in mediating the signal transduction of proinflammatory cytokines (including IL-12, IL-23 and type I interferon). Deucravacitinib is a new type of selective TYK2 inhibitor, a pyridazine derivative, which is currently undergoing clinical studies for the treatment of a wide range of immune-mediated diseases.

[0007] Overview

[0008] In one aspect, the present disclosure relates to Form I of a compound represented by Formula (I):

[0009]

[0010] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern (XRPD) of the crystalline form I expressed in 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0011] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0012]

[0013] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angle has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°.

[0014] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0015]

[0016] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at at least three of the following 2θ angles: 6.4±0.2°, 10.1±0.2°, 12.6±0.2°, 14.5±0.2°, 16.3±0.2° and 16.4±0.2°.

[0017] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0018]

[0019] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at at least three of the following 2θ angles: about 6.4°, about 10.1°, about 12.6°, about 14.5°, about 16.3° and about 16.4°.

[0020] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0021]

[0022] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: 6.4±0.2°, 10.1±0.2°, 12.60±0.2°, 14.5±0.2°, 16.3±0.2° and 16.4±0.2°.

[0023] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0024]

[0025] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: about 6.4°, about 10.1°, about 12.6°, about 14.5°, about 16.3° and about 16.4°.

[0026] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0027]

[0028] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at at least three of the following 2θ angles: 14.8±0.2°, 18.3±0.2°, 18.5±0.2°, 19.9±0.2°, 21.5±0.2°, 24.3±0.2°, 25.0±0.2° and 27.8±0.2°.

[0029] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0030]

[0031] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at at least three of the following 2θ angles: about 14.8°, about 18.3°, about 18.5°, about 19.9°, about 21.5°, about 24.3°, about 25.0° and about 27.8°.

[0032] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0033]

[0034] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: 18.3±0.2°, 18.5±0.2°, 19.9±0.2°, 21.5±0.2°, 24.3±0.2°, 25.0±0.2° and 27.8±0.2°.

[0035] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0036]

[0037] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: about 18.3°, about 18.5°, about 19.9°, about 21.5°, about 24.3°, about 25.0° and about 27.8°.

[0038] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0039]

[0040] Wherein, using Cu-Kα radiation, the characteristic peaks and their relative intensities of the X-ray powder diffraction pattern of the crystal form I expressed at 2θ angles are approximately:

[0041]

[0042]

[0043] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0044]

[0045] Wherein, using Cu-Kα radiation, the crystalline form I has substantially the following Figure 1 The X-ray powder diffraction pattern is shown.

[0046] On the other hand, the present disclosure relates to a crystalline form I of a compound represented by formula (I) which is substantially free of solvent, wherein, using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0047] On the other hand, the present disclosure relates to a crystalline form I of a compound represented by formula (I) that is substantially free of water, wherein, using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0048] On the other hand, the present disclosure relates to a substantially pure crystalline form I of the compound represented by formula (I), wherein, using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0049] On the other hand, the present disclosure relates to a crystalline form I of a compound represented by formula (I) that is free of solvent and water, wherein, using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0050] On the other hand, the present disclosure relates to a method for preparing a crystalline form I of a compound represented by formula (I), comprising dissolving the compound represented by formula (I) in a halohydrin solvent, concentrating to obtain a solid, and drying the solid to obtain the crystalline form I, wherein, using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0051] On the other hand, the present disclosure relates to a method for preparing a crystalline form I of a compound represented by formula (I), comprising using a base to liberate the compound represented by formula (I) in a solution of an acid salt of the compound represented by formula (I) to obtain a solid, separating and drying the solid, and maintaining the solid at 120 to 180°C to obtain the crystalline form I, wherein, using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0052] In another aspect, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0053]

[0054] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angle has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

[0055] On the other hand, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0056]

[0057] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angle has the following characteristic peaks: about 3.3°, about 5.7°, about 8.6°, about 11.8°, about 14.2° and about 18.2°.

[0058] In another aspect, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0059]

[0060] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angles has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2°, 14.9±0.2°, 16.3±0.2°, 17.3±0.2°, 18.2±0.2°, 20.4±0.2°, 21.5±0.2° and 23.6±0.2°.

[0061] In another aspect, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0062]

[0063] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angles has the following characteristic peaks: about 3.3°, about 5.7°, about 8.6°, about 11.8°, about 14.2°, about 14.9°, about 16.3°, about 17.3°, about 18.2°, about 20.4°, about 21.5° and about 23.6°.

[0064] On the other hand, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0065]

[0066] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angles has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 6.5±0.2°, 8.6±0.2°, 11.3±0.2°, 11.8±0.2°, 14.2±0.2°, 14.9±0.2°, 16.3±0.2°, 17.3±0.2°, 18.2±0.2°, 19.9±0.2°, 20.4±0.2°, 21.5±0.2°, 23.6±0.2°, 24.8±0.2° and 26.0±0.2°.

[0067] In another aspect, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0068]

[0069] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angles has the following characteristic peaks: about 3.3°, about 5.7°, about 6.5°, about 8.6°, about 11.3°, about 11.8°, about 14.2°, about 14.9°, about 16.3°, about 17.3°, about 18.2°, about 19.9°, about 20.4°, about 21.5°, about 23.6°, about 24.8° and about 26.0°.

[0070] In another aspect, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0071]

[0072] Wherein, using Cu-Kα radiation, the characteristic peaks and their relative intensities of the X-ray powder diffraction pattern of the crystal form II expressed at 2θ angles are approximately:

[0073]

[0074]

[0075] On the other hand, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0076]

[0077] Wherein, using Cu-Kα radiation, the crystalline form II has substantially the following Figure 5 The X-ray powder diffraction pattern is shown.

[0078] On the other hand, the present disclosure relates to a substantially pure crystalline form II of a compound represented by formula (II), wherein, using Cu-Kα radiation, the crystalline form II has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

[0079] On the other hand, the present disclosure relates to a method for preparing a crystalline form II of a compound represented by formula (II), comprising mixing a solution containing a compound represented by formula (I) with an antisolvent to obtain a solid, separating and drying the solid to obtain the crystalline form II, wherein, using Cu-Kα radiation, the crystalline form II has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

[0080] On the other hand, the present disclosure relates to a method for preparing a crystalline form II of a compound represented by formula (II), comprising dissolving the compound represented by formula (I) in a mixed solvent of an organic solvent and water to form a solution, cooling the solution to obtain a solid, separating and drying the solid to obtain the crystalline form II, wherein, using Cu-Kα radiation, the crystalline form II has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

[0081] On the other hand, the present disclosure relates to a method for preparing a crystalline form II of a compound represented by formula (II), comprising stirring an aqueous suspension of a compound represented by formula (I), filtering and drying to obtain the crystalline form II, wherein, using Cu-Kα radiation, the crystalline form II has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

[0082] On the other hand, the present disclosure relates to a pharmaceutical composition, which comprises the crystalline form I of the compound represented by formula (I) of the present disclosure, the crystalline form II of the compound represented by formula (II) of the present disclosure, or any mixture of the crystalline form I of the compound represented by formula (I) of the present disclosure and the crystalline form II of the compound represented by formula (II) of the present disclosure, and a pharmaceutically acceptable carrier, diluent or excipient.

[0083] On the other hand, the present disclosure relates to a method for treating or preventing a disease or disease state associated with tyrosine kinase 2, comprising administering to an individual in need of the method a therapeutically or prophylactically effective amount of Form I of the compound represented by formula (I) of the present disclosure, Form II of the compound represented by formula (II) of the present disclosure, or any mixture of Form I of the compound represented by formula (I) of the present disclosure and Form II of the compound represented by formula (II) of the present disclosure, or a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0084] BRIEF DESCRIPTION OF THE DRAWINGS

[0085] Figure 1 The X-ray powder diffraction pattern of the crystalline form I of the compound represented by formula (I) in one embodiment of the present disclosure is shown;

[0086] Figure 2 The differential scanning calorimetry (DSC) curve of the crystalline form I of the compound represented by formula (I) in one embodiment of the present disclosure is shown;

[0087] Figure 3 The thermogravimetric analysis (TGA) curve of the crystalline form I of the compound represented by formula (I) in one embodiment of the present disclosure is shown;

[0088] Figure 4 The dynamic moisture sorption (DVS) curve of the crystalline form I of the compound represented by formula (I) in one embodiment of the present disclosure is shown;

[0089] Figure 5 The X-ray powder diffraction pattern of the crystalline form II of the compound represented by formula (II) in one embodiment of the present disclosure is shown.

[0090] Figure 6 The differential scanning calorimetry (DSC) curve of the crystalline form II of the compound represented by formula (II) in one embodiment of the present disclosure is shown;

[0091] Figure 7 The thermogravimetric analysis (TGA) curve of the crystal form II of the compound represented by formula (II) in one embodiment of the present disclosure is shown;

[0092] Figure 8 A comparison of X-ray powder diffraction patterns of the crystalline form I of the compound represented by formula (I) in one embodiment of the present disclosure under long-term and accelerated open storage conditions is shown;

[0093] Fig. 9 A comparison of X-ray powder diffraction patterns of the crystal form II of the compound represented by formula (II) in one embodiment of the present disclosure under long-term and accelerated open storage conditions is shown;

[0094] Fig.10The competition experiment result diagram of the crystal form A obtained in Preparation Example 1 of the present disclosure and the crystal form II of the compound represented by formula (II) prepared in Example 3 is shown;

[0095] Fig.11 shows a particle size distribution (PSD) diagram of the crystalline form I of the compound represented by formula (I) in one embodiment of the present disclosure; and

[0096] Fig.12 The particle size distribution (PSD) diagram of the crystal form II of the compound represented by formula (II) in one embodiment of the present disclosure is shown.

[0097] Details

[0098] In the following description, certain specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, one skilled in the relevant art will recognize that the embodiments can be implemented without one or more of these specific details and with other methods, components, materials, etc.

[0099] Unless otherwise required by the present disclosure, throughout the specification and claims that follow, the words "including" and "comprising" should be interpreted in an open, inclusive sense, ie, "including, but not limited to."

[0100] As used in this disclosure and the appended claims, singular references without indications of quantity include plural references unless the context clearly dictates otherwise.

[0101] References throughout this specification to "one embodiment" or "another embodiment" or "an embodiment" or "certain embodiments" mean that the specific referenced elements, structures, or features described in connection with the embodiment are included in at least one embodiment. Thus, the phrases "one embodiment" or "an embodiment" or "another embodiment" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, the specific elements, structures, or features may be combined in any appropriate manner in one or more embodiments.

[0102] It should be understood that the singular article "a", "an" and "the" used in the specification of the present disclosure and the appended claims include plural objects unless the context clearly dictates otherwise. Thus, for example, a pharmaceutical composition referred to as comprising "a pharmaceutically acceptable carrier, diluent or excipient" includes one pharmaceutically acceptable carrier, diluent or excipient, or two or more pharmaceutically acceptable carriers, diluents or excipients.

[0103] definition

[0104] Accordingly, unless otherwise indicated to the contrary, the following terms used in the specification and appended claims shall have the following meanings:

[0105] In the present disclosure, the term "compound represented by formula (I)" refers to 6-(cyclopropanecarbonylamino)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide, the chemical common name of which is Deucravacitinib, and the structural formula thereof is as follows:

[0106]

[0107] In the present disclosure, the term "compound represented by formula (II)" refers to 6-(cyclopropanecarbonylamino)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide dihydrate, i.e., Deucravacitinib dihydrate, and its structural formula is as follows:

[0108]

[0109] In the present disclosure, the term "crystalline form" refers to a compound having a unique and ordered arrangement or configuration of molecules within a crystal lattice as evidenced by X-ray powder diffraction pattern characterization.

[0110] In the present disclosure, the use of the term "about" includes and describes the value or parameter itself. For example, "about x" includes and describes "x" itself. In certain embodiments, when used in conjunction with a measurement or to modify a value, unit, constant, or numerical range, the term "about" refers to a variation of + / - 5%.

[0111] In the present disclosure, when referring to X-ray powder diffraction patterns, differential scanning calorimetry (DSC) curves, thermogravimetric analysis (TGA) curves, infrared spectra (IR), the term "substantially as shown in..." means patterns and curves that are not necessarily the same as those depicted in the present disclosure, but fall within the limits of experimental error or deviation when considered by a person of ordinary skill in the art.

[0112] In the present disclosure, when referring to X-ray powder diffraction peak positions, the term "substantially the same" as used in the present disclosure means that typical peak position and intensity variability are taken into account. For example, those skilled in the art understand that peak positions (2θ) will show some variability, typically up to 0.1 to 0.2 degrees, depending on the solvent used and the equipment used to measure diffraction. Further, those skilled in the art understand that relative peak intensities will show variability between instruments as well as variability caused by crystallinity, preferred orientation, prepared sample surface and other factors known to those skilled in the art, and should only be regarded as qualitative measurements.

[0113] In the present disclosure, the term "2θ value" or "2θ" refers to the peak position in degrees based on the experimental setup of an X-ray powder diffraction experiment and is a common horizontal coordinate unit for diffraction patterns. The experimental setup requires that if the reflection is diffracted when the incident light beam forms an angle θ (θ) with a certain crystal plane, the reflected light beam is recorded at an angle of 2θ (2θ). It should be understood that the specific 2θ value of a specific crystalline form mentioned in the present disclosure is intended to refer to the 2θ value (in degrees) measured using the X-ray powder diffraction experimental conditions described in the present disclosure. For example, as described in the present disclosure, using Cu-Kα ( ) as a radiation source.

[0114] In this disclosure, for the purposes of "2θ", the term "about" refers to ±0.5°.

[0115] In the present disclosure, the term "substantially pure" refers to both chemical purity and crystalline purity. In certain embodiments, when "substantially pure" is used to refer to a new crystalline form, it means that the new crystalline form accounts for at least 80% by weight of the compound present, more preferably at least 90% by weight, especially at least 95% by weight, and especially at least 99% by weight.

[0116] In this disclosure, the term "substantially free" means containing no more than about 20% by weight. For example, substantially free of solvent means containing no more than about 20% by weight of solvent. Substantially free of water means containing no more than 20% by weight of water.

[0117] In the present disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans, etc. In certain embodiments, the mammal includes humans.

[0118] In the present disclosure, the term "patient" refers to animals (e.g., humans), companion animals (e.g., dogs, cats, or horses), and livestock (e.g., cattle, pigs, and sheep). In certain embodiments, the patient is a mammal, including males and females. In certain embodiments, the patient is a human.

[0119] In the present disclosure, the term "pharmaceutically acceptable" refers to the carrier, vehicle, diluent, excipient and / or salt which must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0120] In the present disclosure, the term "pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals, and various forms of carriers that have no side effects on the composition of the pharmaceutical composition.

[0121] In the present disclosure, the term "carrier" is defined as a compound that facilitates the introduction of a crystalline form of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is often used as a carrier because it facilitates the introduction of certain organic compounds into cells or tissues of an organism.

[0122] In the present disclosure, the term "pharmaceutical composition" refers to a preparation of the crystalline form I of the compound described in the present disclosure and a medium generally accepted in the art for delivering the bioactive compound to mammals such as humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients.

[0123] In the present disclosure, the term "therapeutically effective amount" refers to the amount of crystalline form I of the compound shown by formula (I) (or crystalline form II of the compound shown by formula (II) or any mixture of crystalline form I of the compound shown by formula (I) and crystalline form II of the compound shown by formula (II)) or a combination of crystalline form I of the compound shown by formula (I) (or a combination of crystalline form II of the compound shown by formula (II) or any mixture of crystalline form I of the compound shown by formula (I) and crystalline form II of the compound shown by formula (II)) that improves, reduces or eliminates a specific disease or condition and the symptoms of a specific disease or condition, or avoids or delays the onset of a specific disease or condition or the symptoms of a specific disease or condition. Depending on the crystalline form I of the compound represented by formula (I) (or the crystalline form II of the compound represented by formula (II) or any mixture of the crystalline form I of the compound represented by formula (I) and the crystalline form II of the compound represented by formula (II)), the disease state and its severity, and the age, weight, etc. of the mammal to be treated, the amount of the crystalline form I of the compound represented by formula (I) described in the present disclosure (or the crystalline form II of the compound represented by formula (II) or any mixture of the crystalline form I of the compound represented by formula (I) and the crystalline form II of the compound represented by formula (II)) that constitutes the "therapeutically effective amount" will be different, but those skilled in the art can determine the amount of the crystalline form I of the compound represented by formula (I) described in the present disclosure (or the crystalline form II of the compound represented by formula (II) or any mixture of the crystalline form I of the compound represented by formula (I) and the crystalline form II of the compound represented by formula (II)) according to convention based on their own knowledge and the present disclosure.

[0124] In the present disclosure, the term "prophylactically effective amount" refers to an amount sufficient to prevent a disease or disease state, or to prevent its recurrence. The prophylactically effective amount of any mixture of the crystalline form I of the compound shown in formula (I) or the crystalline form II of the compound shown in formula (II) or the crystalline form I of the compound shown in formula (I) and the crystalline form II of the compound shown in formula (II) refers to the amount of the therapeutic agent alone or in combination with other agents that provides a preventive benefit in preventing a disease or disease state. In the present disclosure, the term "prophylactically effective amount" may include an amount that improves overall prevention or enhances the preventive efficacy of another preventive agent.

[0125] As used in this disclosure, "treating" or "treatment" encompasses treating a relevant disease or condition in a mammal, such as a human, that suffers from the relevant disease or condition, and includes:

[0126] (i) inhibit the disease or disease state, i.e. prevent its occurrence; or

[0127] (ii) ameliorating a disease or condition, even if the disease or condition regresses or does not progress.

[0128] As used in this disclosure, the terms "disease" and "disease state" may be used interchangeably, or may be distinct in that a particular disease or disease state may have no known causative agent (and therefore cannot be explained etiologically) and therefore is not recognized as a disease, but rather is considered an undesirable disease state or condition in which clinicians have identified a more or less specific set of symptoms.

[0129] In this disclosure, the term "physiologically acceptable" refers to a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0130] In the present disclosure, the term "room temperature" refers to 10 to 30°C.

[0131] In the present disclosure, the term "concentrating" refers to a method of reducing the volume of a solvent by adjusting temperature, gas pressure, gas flow, or the like. DETAILED DESCRIPTION

[0132] In one aspect, the present disclosure relates to Form I of a compound represented by Formula (I):

[0133]

[0134] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angle has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0135] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0136]

[0137] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angle has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°.

[0138] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0139]

[0140] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at at least three of the following 2θ angles: 6.4±0.2°, 10.1±0.2°, 12.6±0.2°, 14.5±0.2°, 16.3±0.2° and 16.4±0.2°.

[0141] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0142]

[0143] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at at least three of the following 2θ angles: about 6.4°, about 10.1°, about 12.6°, about 14.5°, about 16.3° and about 16.4°.

[0144] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0145]

[0146] Wherein, using Cu-Ko radiation, the X-ray powder diffraction pattern of the crystalline form I expressed at 2θ angles has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: 6.4±0.2°, 10.1±0.2°, 12.60±0.2°, 14.5±0.2°, 16.3±0.2° and 16.4±0.2°.

[0147] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0148]

[0149] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: about 6.4°, about 10.1°, about 12.6°, about 14.5°, about 16.3° and about 16.4°.

[0150] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0151]

[0152] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at at least three of the following 2θ angles: 14.8±0.2°, 18.3±0.2°, 185±0.2°, 19.9±0.2°, 21.5±0.2°, 24.3±0.2°, 25.0±0.2° and 27.8±0.2°.

[0153] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0154]

[0155] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed at 20 degrees has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at at least three of the following 2θ angles: about 14.8°, about 18.3°, about 18.5°, about 19.9°, about 21.5°, about 24.3°, about 25.0° and about 27.8°.

[0156] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0157]

[0158] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: 18.3±0.2°, 18.5±0.2°, 19.9±0.2°, 21.5±0.2°, 24.3±0.2°, 25.0±0.2° and 27.8±0.2°.

[0159] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0160]

[0161] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed at 20 degrees has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: about 18.3°, about 18.5°, about 19.9°, about 21.5°, about 24.3°, about 25.0° and about 27.8°.

[0162] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0163]

[0164] Wherein, using Cu-Kα radiation, the characteristic peaks and their relative intensities of the X-ray powder diffraction pattern of the crystal form I expressed at 2θ angles are approximately:

[0165]

[0166]

[0167] In another aspect, the present disclosure relates to a crystalline form I of a compound represented by formula (I):

[0168]

[0169] Wherein, using Cu-Kα radiation, the crystalline form I has substantially the following Figure 1 The X-ray powder diffraction pattern is shown.

[0170] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least one substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0171] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least two substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0172] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least three substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0173] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least four substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0174] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least five substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0175] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least six substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0176] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least seven substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0177] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least eight substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0178] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least nine substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0179] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least ten substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0180] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least eleven substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0181] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least twelve substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0182] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least thirteen substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0183] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least fourteen substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0184] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least fifteen substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0185] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least sixteen substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0186] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least seventeen substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0187] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least eighteen substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0188] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least nineteen substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0189] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least twenty substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0190] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least twenty-one substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0191] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least twenty-two substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0192] In certain embodiments, the crystalline form I of the compound represented by formula (I) has at least twenty-three substantially Figure 1 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0193] In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), Form I of the compound represented by formula (I) has an endothermic peak at 259±3°C.

[0194] In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), Form I of the compound represented by formula (I) has an endothermic peak at 259±1°C.

[0195] In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), Form I of the compound represented by formula (I) has an endothermic peak at about 259°C.

[0196] In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), at a heating rate of 10°C / min, Form I of the compound represented by formula (I) has an endothermic peak at 259±3°C.

[0197] In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), at a heating rate of 10°C / min, Form I of the compound represented by formula (I) has an endothermic peak at 259±1°C.

[0198] In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), at a heating rate of 10°C / min, Form I of the compound represented by formula (I) has an endothermic peak at about 259°C.

[0199] In certain embodiments, the melting point of Form I of the compound represented by Formula (I) is 259±3°C.

[0200] In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), Form I of the compound of formula (I) has substantially the following Figure 2 The DSC curve is shown.

[0201] In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), at a heating rate of 10°C / min, Form I of the compound of Formula (I) has substantially the following Figure 2 The DSC curve is shown.

[0202] In certain embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA), the crystalline form I of the compound represented by formula (I) has substantially the following Figure 3 TGA curve shown.

[0203] In certain embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA), at a heating rate of 10°C / min, Form I of the compound of formula (I) has substantially the following Figure 3 TGA curve shown.

[0204] In certain embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA), there is a mass loss of less than 0.5% when heated to 150°C ± 3°C, indicating that Form I of the compound represented by Formula (I) is an anhydrate.

[0205] In certain embodiments, when analyzed using dynamic moisture sorption (DVS), Form I of the compound of formula (I) has substantially the following Figure 4 The DVS curve is shown.

[0206] In certain embodiments, when analyzed using dynamic moisture sorption (DVS), the crystalline form I of the compound represented by formula (I) has only a weight change of less than 0.03% in the relative humidity range of 0 to 80% and is not hygroscopic.

[0207] On the other hand, the present disclosure relates to a crystalline form I of a compound represented by formula (I) which is substantially free of solvent, wherein, using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0208] On the other hand, the present disclosure relates to a crystalline form I of a compound represented by formula (I) that is substantially free of water, wherein, using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0209] On the other hand, the present disclosure relates to a substantially pure crystalline form I of the compound represented by formula (I), wherein, using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0210] On the other hand, the present disclosure relates to a crystalline form I of a compound represented by formula (I) that is free of solvent and water, wherein, using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0211] In certain embodiments, the crystalline form I of the compound represented by formula (I) substantially has very uniform and fine particles.

[0212] In certain embodiments, the diameter of the crystal form I of the compound represented by formula (I) is generally below 50 μm, which can increase the specific surface area of ​​the drug, improve the dissolution rate, and facilitate the rapid absorption of the drug.

[0213] In certain embodiments, the crystalline form I of the compound represented by formula (I) of the present disclosure has a weight change of only less than 0.03% within the relative humidity range of 0-80%, is non-hygroscopic, has better stability and processability, and is more conducive to storage.

[0214] On the other hand, the present disclosure relates to a method for preparing a crystalline form I of a compound represented by formula (I), comprising dissolving the compound represented by formula (I) in a halohydrin solvent, concentrating to obtain a solid, and drying the solid to obtain the crystalline form I, wherein, using Cu-Kα radiation, the crystalline form I has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0215] In certain embodiments, illustrative examples of halogenated alcohols that can be used in the present disclosure include, but are not limited to, C 1-6 Halogenated alcohols.

[0216] In certain embodiments, C 1-6 Illustrative examples of halogenated alcohols include, but are not limited to, C 1-6 Chlorohydrin, C 1-6 Fluorinated alcohols and any mixtures thereof.

[0217] In certain embodiments, C 1-6 Illustrative examples of fluoroalcohols include, but are not limited to, trifluoroethanol.

[0218] In certain embodiments, illustrative examples of drying methods that can be used in the present disclosure include, but are not limited to, room temperature drying, forced air drying, and reduced pressure drying.

[0219] In certain embodiments, the drying apparatus and method are not limited and may be a fume hood, a forced air oven, a spray dryer, a fluidized bed dryer, and a vacuum oven.

[0220] In certain embodiments, drying can be performed under reduced pressure or normal pressure.

[0221] In certain embodiments, drying may be performed at a pressure of less than 0.09 MPa.

[0222] In certain embodiments, the drying temperature is about 10 to 50°C.

[0223] In certain embodiments, the drying temperature is about 40°C.

[0224] In certain embodiments, the drying time is about 0.5 to 5 hours.

[0225] In certain embodiments, the drying time is about 1 hour.

[0226] On the other hand, the present disclosure relates to a method for preparing a crystalline form I of a compound represented by formula (I), which comprises using a base to liberate the compound represented by formula (I) in a solution of an acid salt of the compound represented by formula (I) to obtain a solid, separating and drying the solid, and maintaining the solid at 120 to 180°C to obtain the crystalline form I, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°.

[0227] In certain embodiments, illustrative examples of acid salts of the compounds of formula (I) that can be used in the present disclosure include, but are not limited to, hydrochlorides, hydrobromides, sulfates, sulfonates, phosphates, and nitrates.

[0228] In certain embodiments, the acid salt of the compound of formula (I) that can be used in the present disclosure is a sulfate salt.

[0229] In certain embodiments, illustrative examples of bases that can be used in the present disclosure include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride.

[0230] In certain embodiments, the base that can be used in the present disclosure is sodium hydroxide.

[0231] In certain embodiments, illustrative examples of solutions of acid salts of compounds represented by formula (I) that can be used in the present disclosure include, but are not limited to, aqueous solutions.

[0232] In certain embodiments, illustrative examples of drying methods that can be used in the present disclosure include, but are not limited to, room temperature drying, forced air drying, and reduced pressure drying.

[0233] In certain embodiments, the drying apparatus and method are not limited and may be a fume hood, a forced air oven, a spray dryer, a fluidized bed dryer, and a vacuum oven.

[0234] In certain embodiments, drying can be performed under reduced pressure or normal pressure.

[0235] In certain embodiments, drying may be performed at a pressure of less than 0.09 MPa.

[0236] In certain embodiments, the drying temperature is about 10 to 50°C.

[0237] In certain embodiments, the drying temperature is about 40°C.

[0238] In certain embodiments, the drying time is about 1 to 24 hours.

[0239] In certain embodiments, the drying time is about 16 hours.

[0240] In certain embodiments, the temperature maintained is about 140 to 150°C.

[0241] In certain embodiments, the temperature maintained is about 150°C;

[0242] In certain embodiments, the holding time is about 10 to 30 minutes.

[0243] In certain embodiments, the holding time is about 10 minutes.

[0244] In certain embodiments, the method for preparing the crystalline form I of the compound represented by formula (I) disclosed herein is simple, has fewer steps, and is more conducive to improving the efficiency of preparation and controlling parameters.

[0245] In another aspect, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0246]

[0247] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angle has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

[0248] On the other hand, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0249]

[0250] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angle has the following characteristic peaks: about 3.3°, about 5.7°, about 8.6°, about 11.8°, about 14.2° and about 18.2°.

[0251] In another aspect, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0252]

[0253] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angles has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2°, 14.9±0.2°, 16.3±0.2°, 17.3±0.2°, 18.2±0.2°, 20.4±0.2°, 21.5±0.2° and 23.6±0.2°.

[0254] In another aspect, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0255]

[0256] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angles has the following characteristic peaks: about 3.3°, about 5.7°, about 8.6°, about 11.8°, about 14.2°, about 14.9°, about 16.3°, about 17.3°, about 18.2°, about 20.4°, about 21.5° and about 23.6°.

[0257] On the other hand, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0258]

[0259] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angles has the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 6.5±0.2°, 8.6±0.2°, 11.3±0.2°, 11.8±0.2°, 14.2±0.2°, 14.9±0.2°, 16.3±0.2°, 17.3±0.2°, 18.2±0.2°, 19.9±0.2°, 20.4±0.2°, 21.5±0.2°, 23.6±0.2°, 24.8±0.2° and 26.0±0.2°.

[0260] In another aspect, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0261]

[0262] Wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form II expressed in 2θ angles has the following characteristic peaks: about 3.3°, about 5.7°, about 6.5°, about 8.6°, about 11.3°, about 11.8°, about 14.2°, about 14.9°, about 16.3°, about 17.3°, about 18.2°, about 19.9°, about 20.4°, about 21.5°, about 23.6°, about 24.8° and about 26.0°.

[0263] In another aspect, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0264]

[0265] Wherein, using Cu-Kα radiation, the characteristic peaks and their relative intensities of the X-ray powder diffraction pattern of the crystal form II expressed at 2θ angles are approximately:

[0266]

[0267]

[0268] On the other hand, the present disclosure relates to a crystalline form II of a compound represented by formula (II),

[0269]

[0270] Wherein, using Cu-Kα radiation, the crystalline form II has substantially the following Figure 5 The X-ray powder diffraction pattern is shown.

[0271] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least one substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0272] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least two substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0273] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least three substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0274] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least four substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0275] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least five substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0276] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least six substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0277] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least seven substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0278] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least eight substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0279] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least nine substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0280] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least ten substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0281] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least eleven substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0282] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least twelve substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0283] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least thirteen substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0284] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least fourteen substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0285] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least fifteen substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0286] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least sixteen substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0287] In certain embodiments, the crystalline form II of the compound represented by formula (II) has at least seventeen substantially Figure 5 The X-ray powder diffraction pattern has the characteristic peaks of the X-ray powder diffraction pattern shown in .

[0288] In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), the crystalline form II of the compound represented by formula (II) has substantially the following Figure 6 The DSC curve is shown.

[0289] In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), at a heating rate of 10°C / min, the crystalline form II of the compound represented by formula (II) has substantially the following Figure 6 The DSC curve is shown.

[0290] In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), Form II of the compound represented by formula (II) has a desolvation peak between 36°C and 110°C and between 110°C and 132°C, respectively.

[0291] In certain embodiments, when thermal analysis is performed using differential scanning calorimetry (DSC), at a heating rate of 10°C / min, Form II of the compound represented by formula (II) has a desolvation peak between 36°C and 110°C and between 110°C and 132°C, respectively.

[0292] In certain embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA), the crystalline form II of the compound represented by formula (II) has substantially the following Figure 7 TGA curve shown.

[0293] In certain embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA), at a heating rate of 10°C / min, the crystalline form II of the compound represented by formula (II) has substantially the following Figure 7 TGA curve shown.

[0294] In certain embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA), it is shown that Form II of the compound represented by Formula (II) has a step-wise weight loss, indicating that it is a hydrate.

[0295] In certain embodiments, when thermal analysis is performed using thermogravimetric analysis (TGA), it is shown that Form II of the compound represented by formula (II) has a step-wise weight loss of approximately 7.7%, indicating that it is a dihydrate.

[0296] On the other hand, the present disclosure relates to a substantially pure crystalline form II of a compound represented by formula (II), wherein, using Cu-Kα radiation, the crystalline form II has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

[0297] In certain embodiments, the crystal form II of the compound represented by formula (II) is a block-shaped granular crystal with a good morphology and better fluidity, which can reduce the filtering time of the raw material and the screening time of the preparation, and is conducive to accurate measurement and improved efficiency in the production of the preparation.

[0298] In certain embodiments, the crystal form II of the compound represented by formula (II) is a block-shaped granular crystal with a better morphology and better formulation processability, which can be used for direct powder tableting, avoiding the influence of wet granulation solvent on the raw material drug, facilitating the control of formulation quality and improving batch stability.

[0299] In certain embodiments, the crystalline form II of the compound represented by formula (II) has excellent stability in water, is more suitable for wet granulation, has superior crystalline stability in a crystallization process containing water, and has better storage stability.

[0300] On the other hand, the present disclosure relates to a method for preparing a crystalline form II of a compound represented by formula (II), comprising mixing a solution of a compound represented by formula (I) with an antisolvent to obtain a solid, separating and drying the solid to obtain the crystalline form II, wherein, using Cu-Kα radiation, the crystalline form II has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

[0301] In certain embodiments, illustrative examples of solvents that can be used to dissolve the compound represented by formula (I) include, but are not limited to, mixed solvents of organic solvents and water.

[0302] In certain embodiments, the volume ratio of the organic solvent to water in the solvent for dissolving the compound represented by formula (I) is about 1:0.1 to 0.5.

[0303] In certain embodiments, the volume ratio of the organic solvent to water in the solvent for dissolving the compound represented by formula (I) is about 1:0.2 to 0.4.

[0304] In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, ketones, cyclic ethers, and mixtures thereof.

[0305] In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, more preferably acetone, tetrahydrofuran, 1,4-dioxane, and mixtures thereof.

[0306] In certain embodiments, illustrative examples of antisolvents that can be used in the present disclosure include, but are not limited to, water.

[0307] In certain embodiments, the volume ratio of the organic solvent to the antisolvent in the solvent for dissolving the compound of formula (I) is about 1:1 to 10.

[0308] In certain embodiments, the volume ratio of the organic solvent to the antisolvent in the solvent for dissolving the compound of formula (I) is about 1:3 to 5.

[0309] In certain embodiments, the mass volume ratio of the compound represented by formula (I) to the solvent in which it is dissolved is about 10 to 100 mg / mL.

[0310] In certain embodiments, the mass volume ratio of the compound represented by formula (I) to the solvent in which it is dissolved is about 20 to 50 mg / mL.

[0311] In certain embodiments, illustrative examples of drying methods that can be used in the present disclosure include, but are not limited to, room temperature drying, forced air drying, and reduced pressure drying.

[0312] In certain embodiments, the drying apparatus and method are not limited and may be a fume hood, a forced air oven, a spray dryer, a fluidized bed dryer, and a vacuum oven.

[0313] In certain embodiments, drying can be performed under reduced pressure or normal pressure.

[0314] In certain embodiments, drying may be performed at a pressure of less than 0.09 MPa.

[0315] In certain embodiments, the drying temperature is about 10 to 50°C.

[0316] In certain embodiments, the drying temperature is about 40°C.

[0317] In certain embodiments, the drying time is about 1 to 24 hours.

[0318] In certain embodiments, the drying time is about 16 hours.

[0319] On the other hand, the present disclosure relates to a method for preparing a crystalline form II of a compound represented by formula (II), comprising dissolving the compound represented by formula (I) in a mixed solvent of an organic solvent and water to form a solution, cooling the solution to obtain a solid, separating and drying the solid to obtain the crystalline form II, wherein, using Cu-Kα radiation, the crystalline form II has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

[0320] In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, cyclic ethers.

[0321] In certain embodiments, illustrative examples of organic solvents that can be used in the present disclosure include, but are not limited to, tetrahydrofuran.

[0322] In certain embodiments, the volume ratio of the organic solvent to water in the mixed solvent is about 1:0.1 to 0.5.

[0323] In certain embodiments, the volume ratio of the organic solvent to water in the mixed solvent is about 1:0.2 to 0.4.

[0324] In certain embodiments, the mass volume ratio of the compound represented by formula (I) to the mixed solvent is about 10 to 100 mg / mL.

[0325] In certain embodiments, the mass volume ratio of the compound represented by formula (I) to the mixed solvent is about 20 to 50 mg / mL.

[0326] In certain embodiments, the temperature at which the solution is formed is about 60 to 80°C.

[0327] In certain embodiments, the temperature at which the solution is formed is about 65 to 75°C.

[0328] In certain embodiments, the cooling temperature is about -5 to 10°C.

[0329] In certain embodiments, the cooling temperature is about 0 to 4°C.

[0330] In certain embodiments, illustrative examples of drying methods that can be used in the present disclosure include, but are not limited to, room temperature drying, forced air drying, and reduced pressure drying.

[0331] In certain embodiments, the drying apparatus and method are not limited and may be a fume hood, a forced air oven, a spray dryer, a fluidized bed dryer, and a vacuum oven.

[0332] In certain embodiments, drying can be performed under reduced pressure or normal pressure.

[0333] In certain embodiments, drying may be performed at a pressure of less than 0.09 MPa.

[0334] In certain embodiments, the drying temperature is about 10 to 50°C.

[0335] In certain embodiments, the drying temperature is about 40°C.

[0336] In certain embodiments, the drying time is about 1 to 24 hours.

[0337] In certain embodiments, the drying time is about 16 hours.

[0338] On the other hand, the present disclosure relates to a method for preparing a crystalline form II of a compound represented by formula (II), comprising stirring an aqueous suspension of a compound represented by formula (I), filtering and drying to obtain the crystalline form II, wherein, using Cu-Kα radiation, the crystalline form II has an X-ray powder diffraction pattern expressed in 2θ angles having the following characteristic peaks: 3.3±0.2°, 5.7±0.2°, 8.6±0.2°, 11.8±0.2°, 14.2±0.2° and 18.2±0.2°.

[0339] In certain embodiments, the stirring temperature is about 10 to 45°C.

[0340] In certain embodiments, the stirring temperature is about room temperature.

[0341] In certain embodiments, illustrative examples of drying methods that can be used in the present disclosure include, but are not limited to, room temperature drying, forced air drying, and reduced pressure drying.

[0342] In certain embodiments, the drying apparatus and method are not limited and may be a fume hood, a forced air oven, a spray dryer, a fluidized bed dryer, and a vacuum oven.

[0343] In certain embodiments, drying can be performed under reduced pressure or normal pressure.

[0344] In certain embodiments, drying may be performed at a pressure of less than 0.09 MPa.

[0345] In certain embodiments, the method for preparing the crystalline form II of the compound represented by formula (II) disclosed herein is simple, requires a small type and amount of organic solvents, is more conducive to green pharmaceutical manufacturing, and has simpler steps.

[0346] In certain embodiments, the crystalline form I of the compound represented by formula (I) substantially has very uniform and fine particles.

[0347] In certain embodiments, the diameter of the crystal form I of the compound represented by formula (I) is generally below 50 μm, which can increase the specific surface area of ​​the drug, improve the dissolution rate, and facilitate the rapid absorption of the drug.

[0348] In certain embodiments, the crystalline form I of the compound represented by formula (I) of the present disclosure has a weight change of only less than 0.03% in the relative humidity range of 0-80%. In certain embodiments, the crystalline form II of the compound represented by formula (II) is a block-shaped granular crystal with a better morphology and better fluidity, which can reduce the filtration time of the raw material and the sieving time of the preparation, and is conducive to accurate measurement and improved efficiency in the production of the preparation.

[0349] In certain embodiments, the crystal form II of the compound represented by formula (II) is a block-shaped granular crystal with a better morphology and better formulation processability, which can be used for direct powder tableting, avoiding the influence of wet granulation solvent on the raw material drug, facilitating the control of formulation quality and improving batch stability.

[0350] In certain embodiments, the crystalline form II of the compound represented by formula (II) has excellent stability in water, is more suitable for wet granulation, has superior crystalline stability in a crystallization process containing water, and has better storage stability.

[0351] Pharmaceutical composition

[0352] On the other hand, the present disclosure relates to a pharmaceutical composition, which comprises the crystalline form I of the compound represented by formula (I) of the present disclosure, the crystalline form II of the compound represented by formula (II) of the present disclosure, or any mixture of the crystalline form I of the compound represented by formula (I) of the present disclosure and the crystalline form II of the compound represented by formula (II) of the present disclosure, and a pharmaceutically acceptable carrier, diluent or excipient.

[0353] In certain embodiments, the administration routes of Form I of the compound represented by formula (I) disclosed herein for treating or preventing diseases or disease states associated with tyrosine kinase 2 include but are not limited to oral, sublingual, subcutaneous, intravenous, intramuscular, nasal, topical and rectal administration routes.

[0354] In certain embodiments, illustrative examples of oral formulations that can be used in the present disclosure include, but are not limited to, tablets, capsules, powders, granules, solutions, and suspensions.

[0355] Examples of pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers that have been approved by the U.S. Food and Drug Administration and can be used for humans or animals, and various forms of carriers that have no side effects on the composition of the pharmaceutical composition. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field. The pharmaceutical composition of the present disclosure can be administered by any method that achieves its intended purpose. For example, administration can be carried out by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intraarticular, intraspinal, transtracheal, ocular, subcutaneous, intraperitoneal, transdermal or oral routes. The route of administration can be parenteral, oral, and rectal routes. The dose administered will depend on the recipient's age, health status, and weight, and if there is concurrent treatment, it also depends on the type of concurrent treatment, the frequency of treatment, and the nature of the desired effect.

[0356] Suitable dosage forms include, but are not limited to, capsules, tablets, pills, dragees, semisolid preparations, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, which can be prepared according to methods known in the art.

[0357] Particularly suitable for oral administration are ordinary tablets (plain tablets), sugar-coated tablets, film-coated tablets, pills, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, and can also be oil-based solutions or aqueous solutions, in addition to suspensions, emulsions or implants, and suitable for local use are ointments, creams, frosts, suppositories or powders. The products in the present disclosure can also be freeze-dried, and the resulting freeze-dried materials are used, for example, to prepare injections. The products in the present disclosure can also be made into solid dispersions for oral preparations, such as tablets or capsules. The method for preparing solid dispersions can be conventional, such as spray drying / hot melt extrusion / freeze drying, etc., and the compounds of the present application can be uniformly dispersed in polymers, and the polymers include but are not limited to celluloses,? The celluloses may be one or more of hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate and hydroxyethyl ethyl cellulose acetate and combinations thereof, and the non-celluloses may be one or more of polyacrylates, acrylates and methacrylate copolymers and combinations thereof. The given preparations may be sterilized and / or contain assistants, such as wetting agents, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for changing the osmotic pressure, buffer substances, dyes, flavoring agents and / or numerous additional active ingredients, such as one or more vitamins.

[0358] Preservatives, stabilizers, dyes, sweeteners, aromatics, spices, etc. can be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid can be added as preservatives. In addition, antioxidants and suspending agents can be used.

[0359] In different embodiments, alcohols, esters, sulfated aliphatic alcohols, etc. can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium aluminate methyl silicate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogen phosphate, hydroxymethylcellulose calcium, etc. can be used as excipients; magnesium stearate, talc, hardened oil, etc. can be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, soybean can be used as suspending agents or lubricants; cellulose acetate phthalate, which is a derivative of sugars such as cellulose or sugar, or methyl acetate-methacrylate copolymer, which is a derivative of polyethylene, can be used as suspending agents; and plasticizers such as phthalates can be used as suspending agents.

[0360] Suitable routes of administration may include, for example, oral administration (immediate release, sustained release or controlled release), rectal administration, transmembrane administration, parenteral delivery, transdermal administration, topical administration or enteral administration; parenteral delivery includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection and intrathecal injection, direct intraventricular injection, intraperitoneal injection, intranasal injection or intraocular injection. The compound can also be extended and / or timed, pulsed at a predetermined rate in a sustained-release or controlled-release dosage form including depot injections, osmotic pumps, pills, transdermal (including electromigration) patches, etc.

[0361] The pharmaceutical compositions of the present disclosure can be produced in a known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting operations.

[0362] Therefore according to the present disclosure, the pharmaceutical composition used can be prepared in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants, which are conducive to processing the active compound into a pharmaceutically available preparation. Suitable preparations depend on the selected route of administration. Any known technology, carrier and excipient can be used as suitable and understood in the art.

[0363] Injection can be prepared into the following conventional forms: as a solution or suspension, a solid dosage form suitable for making a solution or suspension before injection, or as an emulsion. Suitable excipients are, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine ​​hydrochloride, etc. In addition, if necessary, the injection pharmaceutical composition can contain a small amount of non-toxic adjuvants, such as wetting agents, pH buffers, etc. Physiologically suitable buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer. If necessary, absorption enhancing preparations (such as liposomes) can be used.

[0364] For oral administration, the compounds can be easily formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, lozenges, capsules, liquids, gels, syrups, pastes, suspensions, solutions, powders, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral administration can be obtained by mixing the active compounds with solid excipients, optionally grinding the resulting mixture and processing the granular mixture, if necessary, after adding suitable auxiliary agents to obtain tablets or lozenge cores. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). Disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or alginates such as sodium alginate may be added if necessary. The lozenge core is carried out to suitable coating.For this purpose, concentrated sugar solution can be used, and this sugar solution can optionally include gum arabic, talcum, polyvinyl pyrrolidone, carbopol gel (carbopol gel), polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.In order to identify or characterize the different combinations of active compound dosage, dyestuff or pigment can be added in tablet or lozenge coating.For this purpose, concentrated sugar solution can be used, and this sugar solution can optionally include gum arabic, talcum, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.

[0365] Pharmaceutical preparations that can be used for oral administration include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch and / or a lubricant such as talc or magnesium stearate and optionally a stabilizer. In soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, a stabilizer can be added. All formulations for oral administration should be in a dosage suitable for such administration.

[0366] In certain embodiments, the pharmaceutical composition of the present disclosure may contain 0.1%-95% of the crystalline form I of the compound represented by formula (I) of the present disclosure.

[0367] In certain embodiments, the pharmaceutical composition of the present disclosure may contain 1%-70% of the crystalline form I of the compound represented by formula (I) of the present disclosure.

[0368] In any case, the composition or formulation to be administered will contain an amount of the crystalline Form I of the compound of formula (I) disclosed herein that is effective to treat the disease / condition of the subject being treated.

[0369] In certain embodiments, the pharmaceutical composition of the present disclosure may contain 0.1%-95% of the crystalline form II of the compound represented by formula (II) of the present disclosure.

[0370] In certain embodiments, the pharmaceutical composition of the present disclosure may contain 1%-70% of the crystalline form II of the compound represented by formula (II) of the present disclosure.

[0371] In any case, the composition or formulation to be administered will contain an amount of Form II of the compound of formula (II) disclosed herein that is effective to treat the disease / condition of the subject being treated.

[0372] On the other hand, the present disclosure relates to a method for treating or preventing a disease or disease state associated with tyrosine kinase 2, comprising administering to an individual in need of the method a therapeutically or prophylactically effective amount of Form I of the compound represented by formula (I) of the present disclosure, Form II of the compound represented by formula (II) of the present disclosure, or any mixture of Form I of the compound represented by formula (I) of the present disclosure and Form II of the compound represented by formula (II) of the present disclosure, or a therapeutically effective amount of a pharmaceutical composition of the present disclosure.

[0373] In certain embodiments, the individual is a mammal.

[0374] In certain embodiments, the individual is a human.

[0375] In certain embodiments, illustrative examples of diseases or conditions that can be used in the present disclosure include, but are not limited to, diseases or conditions associated with TYK2.

[0376] In certain embodiments, illustrative examples of diseases or conditions that can be used in the present disclosure include, but are not limited to, autoimmune and autoinflammatory related diseases or conditions.

[0377] In certain embodiments, illustrative examples of autoimmune and autoinflammatory related diseases or conditions that can be used in the present disclosure include, but are not limited to, psoriasis, plaque psoriasis, psoriatic arthritis, lupus, lupus nephritis, Sjogren's syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and ankylosing spondylitis.

[0378] In certain embodiments, a method for treating or preventing a disease or condition associated with tyrosine kinase 2 comprises administering 1 mg-10 g of crystalline form I of the compound of formula (I) of the present disclosure, crystalline form II of the compound of formula (II) of the present disclosure, or a mixture thereof to an individual in need of the method.

[0379] In certain embodiments, a method for treating or preventing a disease or condition associated with tyrosine kinase 2 comprises administering 10 mg to 3000 mg of crystalline form I of the compound of formula (I) of the present disclosure, crystalline form II of the compound of formula (II) of the present disclosure, or a mixture thereof to an individual in need of the method.

[0380] In certain embodiments, a method for treating or preventing a disease or condition associated with tyrosine kinase 2 comprises administering 1 mg to 200 mg of crystalline form I of the compound of formula (I) of the present disclosure, crystalline form II of the compound of formula (II) of the present disclosure, or a mixture thereof to an individual in need of the method.

[0381] In certain embodiments, a method for treating or preventing a disease or disease state associated with tyrosine kinase 2 comprises administering to an individual in need thereof about 1-500 mg, specifically 1 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 24 mg, 25 mg, 30 mg, 35 mg, 36 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 90 mg, 100 mg, 120 mg, 150 mg, or 200 mg of the crystalline form I of the compound represented by formula (I) of the present disclosure, the crystalline form II of the compound represented by formula (II), or a mixture thereof. The number of administrations may be once a day, once every other day, twice a day, three times a day, and the like.

[0382] In certain embodiments, the method for treating or preventing a disease or condition associated with tyrosine kinase 2 further comprises administering simultaneously or sequentially at least one other active ingredient capable of treating or preventing a disease or condition associated with tyrosine kinase 2.

[0383] In certain embodiments, illustrative examples of other active ingredients that can be used in the present disclosure include, but are not limited to, corticosteroids, rolipram, calphostin, cytokine suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, celecoxib, and rofecoxib; steroids, such as prednisone, ne) or dexamethasone; antiviral agents, such as abacavir; antiproliferative agents, such as methotrexate, leflunomide, FK506 (tacrolimus); antimalarials, such as hydroxychloroquine; cytotoxic drugs, such as azathiprine and cyclophosphamide; TNF-α inhibitors, such as tenidap, anti-TNF antibodies or soluble TNF receptors and rapamycin (sirolimus) or its derivatives.

[0384] Dosage

[0385] At least one crystalline form I of the compound represented by formula (I) of the present invention, crystalline form II of the compound represented by formula (II), or a mixture of crystalline form I of the compound represented by formula (I) and crystalline form II of the compound represented by formula (II), or a pharmaceutical composition comprising at least one crystalline form I of the compound represented by formula (I) of the present invention, crystalline form II of the compound represented by formula (II), or a mixture of crystalline form I of the compound represented by formula (I) and crystalline form II of the compound represented by formula (II) can be administered to a patient by any method suitable for systemically and / or locally delivering crystalline form I of the compound represented by the present invention. Non-limiting examples of administration methods include (a) administration by oral route, which includes administration in the form of capsules, tablets, granules, sprays, syrups or other such forms; (b) administration by non-oral route, such as rectal, vaginal, intraurethral, ​​intraocular, intranasal or intraaural, which includes administration in the form of aqueous suspensions, oily preparations, etc. or in the form of drops, sprays, suppositories, ointments, ointments, etc.; (c) administration by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intracapsular injection, intraspinal injection, sternal injection, etc. (d) local administration such as injection directly in the kidney area or heart area, for example, by reservoir implantation; and (e) local administration; as the appropriate mode of administration considered by those skilled in the art is the contact of the mixture of the crystalline form I of the compound shown in the formula (I) described in the present disclosure, the crystalline form II of the compound shown in the formula (II) or the crystalline form I of the compound shown in the formula (I) and the crystalline form II of the compound shown in the formula (II) with living tissue. For example, transdermal administration, the administration includes administration in the form of an ointment, cream, gel, aerosol, suspension, emulsion, cream or other such forms.

[0386] The most suitable route depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining the method of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, appropriate pharmaceutical excipients and other matters related to delivering the crystalline form of the compound to a subject in need.

[0387] Pharmaceutical compositions suitable for administration include compositions containing an effective amount of active ingredients to achieve their desired effects. The dosage required for the therapeutically effective amount of the pharmaceutical composition described in the present disclosure depends on the route of administration, the type of animal being treated, including humans, and the physical characteristics of the particular animal under consideration. The dosage can be adjusted to achieve the desired effect, but this will depend on the following factors: body weight, diet, simultaneous drug therapy, and other factors recognized by technicians in other medical fields. More specifically, a therapeutically effective amount refers to the amount of a crystalline form of a compound that effectively prevents, alleviates or improves symptoms of a disease, or prolongs the life span of an individual receiving treatment. The actual ability of those skilled in the art can well determine the therapeutically effective amount, especially in accordance with the detailed disclosure provided by the present disclosure.

[0388] As will be apparent to those skilled in the art, the dosage and specific mode of administration for in vivo administration will vary depending on the age, weight and type of mammal being treated, the crystalline form of the specific compound used, and the specific use of the crystalline form of these compounds used. Those skilled in the art can achieve the purpose of determining the effective dosage level, i.e., the dosage level necessary for the desired effect, using conventional pharmacological methods. Typically, human clinical use of the product is initiated at a lower dosage level, with the dosage level increasing until the desired effect is achieved. Alternatively, using established pharmacological methods, acceptable in vitro studies can be used to establish the effective dosage and route of administration of the composition identified by the present method.

[0389] In non-human animal studies, the use of potential products begins with a higher dose level, with the dose reduced until the desired effect is no longer achieved or the adverse side effects disappear. Depending on the expected effect and the therapeutic indication, the dosage range can be relatively wide. Typically, the dosage can be about 10 μg / kg body weight to 1000 mg / kg body weight, and in certain embodiments about 100 μg / kg body weight to 300 mg / kg body weight. Alternatively, as will be appreciated by those skilled in the art, the dosage can be based on and calculated according to the patient's body surface area.

[0390] Each physician can select the exact formulation, route of administration and dosage of the pharmaceutical composition described in the present disclosure according to the patient's condition. Typically, the dosage range of the composition administered to the patient can be about 0.5 mg / kg to 1000 mg / kg of the patient's body weight. Depending on the patient's needs, the dosage can be given once or twice or more during one day or several days. In the case where the human dosage of the crystalline form of the compound has been established due to at least some conditions, the present disclosure will use those same dosages, or a dosage range of about 0.1% to 500% of the determined human dosage, and in certain embodiments, a dosage range of 25% to 250% of the determined human dosage. In the absence of a determined human dosage, such as the case of a newly discovered drug compound, a suitable human dosage can be inferred from the median value of the half effective dose or the infectious dose, or other suitable values ​​from in vitro or in vivo studies, as quantified in toxicity studies and efficacy studies in animals.

[0391] It should be noted that due to toxicity and organ dysfunction, the attending physician will know how and when to terminate, interrupt or adjust the administration. On the contrary, if the clinical response is insufficient (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. The size of the dosage in the treatment of the disease concerned will vary with the severity of the disease state to be treated and the change of the route of administration. For example, the severity of the disease state can be evaluated in part by standard prognostic evaluation methods. In addition, the dosage and possible dosage frequency will also vary according to the age, weight, and response of the individual patient. A scheme comparable to the above-mentioned discussion scheme can be used in veterinary medicine.

[0392] Although the exact dosage can be determined based on drug-by-drug analysis, in most cases, some generalizations can be made about the medicament. The daily dosing regimen for adult patients is, for example, an oral dose of 0.1 mg to 2000 mg of each active ingredient, 1 mg to 2000 mg of each active ingredient in certain embodiments, such as 5 mg to 1500 mg of each active ingredient. In other embodiments, the intravenous, subcutaneous or intramuscular dose of each active ingredient used is 0.01 mg to 1000 mg, 0.1 mg to 1000 mg in certain embodiments, such as 1 mg to 800 mg. In the case of administering a pharmaceutically acceptable salt, the dosage can be calculated according to the free alkali. In certain embodiments, the composition is administered 1 to 4 times a day. Alternatively, the composition described in the present disclosure can be administered by continuous intravenous infusion, and in certain embodiments, the dosage of each active ingredient up to 2000 mg per day is administered. As will be appreciated by those skilled in the art, in some cases, it is necessary to administer the compounds described in the present disclosure in an amount exceeding or far exceeding the above dosage range in order to effectively and rapidly treat rapidly developing diseases or infections. In certain embodiments, the compounds are administered during continuous treatment, such as one or several weeks, or several months or years.

[0393] Dosage and dosing interval can be adjusted individually to provide the plasma level of the active part that is enough to maintain the adjustment effect or minimum effective concentration (MEC). The MEC of each compound is different, but MEC can be assessed from in vitro data. The required dosage reaching MEC depends on individual characteristics and route of administration. However, HPLC (high performance liquid chromatography) can be used to measure or bioassay to determine plasma concentration.

[0394] The MEC value also enables determination of dosing intervals.Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, in certain embodiments 30-90% of the time, and in certain embodiments 50-90% of the time.

[0395] In cases of local administration or selective uptake, the effective local concentration of the drug is independent of plasma concentration.

[0396] The amount of composition administered will, of course, be dependent upon the individual being treated, on the individual's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

[0397] The efficacy and toxicity of the compounds described in the present disclosure can be evaluated using known methods. For example, the toxicology of a particular compound or a subset of such compounds that share certain chemical moieties can be established by determining the toxicity of a cell line in vitro, such as a mammalian cell line and in some embodiments a human cell line. The results of such studies can generally predict toxicity in an animal such as a mammal, or more specifically, in a human. Alternatively, the toxicity of a particular compound in an animal model such as a mouse, rat, rabbit or monkey can be determined using known methods. The efficacy of a particular compound can be determined using several recognized methods, such as in vitro methods, animal models or human clinical trials. There are recognized in vitro models for almost every disease state, including but not limited to cancer, cardiovascular disease and a variety of immune dysfunctions. Similarly, acceptable animal models can be used to determine the efficacy of chemical drugs for treating these disease states. When selecting a model to determine efficacy, a technician can select an appropriate model, dosage and route of administration, and treatment regimen under the guidance of the prior art in the art. Of course, human clinical trials can also be used to determine the efficacy of a compound in the human body.

[0398] If desired, the composition can be placed in a package or dispensing device, which can contain one or more unit dosage forms containing active ingredients. The package can, for example, include metal or plastic foil, such as a blister package. The package or dispensing device can be provided with instructions for administration. The package or dispensing device can also be provided with precautions associated with the container, which are provided by a government agency that manages drug production, use or sales, and which reflect that the drug form has been approved by the agency for human or veterinary administration. Such precautions, for example, can be labels for prescription drugs approved by the State Food and Drug Administration or the U.S. Food and Drug Administration, or approved product instructions. Compositions comprising compounds of the present disclosure, stereoisomers thereof, or pharmaceutically acceptable salts thereof, which can also be prepared in suitable containers and placed in compatible pharmaceutical carriers, and marked for use in the treatment of specified disease states.

[0399] Hereinafter, the present disclosure will be explained in detail by the following examples in order to better understand the various aspects and advantages of the present application. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present application.

[0400] Example

[0401] Testing instruments and methods:

[0402] X-ray powder diffraction (XRPD): The instrument was a Bruker D8 Advance diffractometer. The samples were tested at room temperature. The detection conditions were as follows: angle range: 3 to 40° 2θ, step length: 0.02° 2θ, speed: 0.2 sec / step.

[0403] Polarized light microscopy (PLM) images were collected from an XP-500E polarized light microscope. A small amount of powder sample was placed on a glass slide, a small amount of mineral oil was added to disperse the sample, a cover glass was placed, and the sample was placed on a stage for observation and photography.

[0404] Differential scanning calorimetry (DSC) data were collected from TA Instruments Q200 MDSC. The detection method is as follows: 1 to 10 mg of sample is placed in a closed small hole aluminum crucible (wherein the crystal form I of the compound represented by formula (I) is covered but not perforated, and the crystal form II of the compound represented by formula (II) is covered and perforated), and the sample is heated from room temperature to 300°C at a heating rate of 10°C / min under the protection of 50mL / min dry N2.

[0405] Thermogravimetric analysis (TGA) data were collected from TA Instruments Q500 TGA. The detection method is as follows: 5 to 15 mg of sample was placed in a platinum crucible, and the sample was heated from room temperature to 300°C at a heating rate of 10°C / min under the protection of 40 mL / min dry N2 using segmented high-resolution detection.

[0406] Dynamic moisture sorption analysis (DVS) data and isothermal sorption analysis data were collected from TA Instruments Q5000TGA. The detection method is: 1 to 10 mg of sample is placed in a platinum crucible, and the weight change is detected when the relative humidity changes from 0% to 80% to 0%.

[0407] Unless otherwise specified, all reagents used in the examples of the present disclosure are commercially available.

[0408] Unless otherwise specified, the embodiments of the present disclosure are all operated at room temperature.

[0409] Preparation Example 1

[0410] According to the preparation method of Example 2 of patent application CN110914260A, the crystalline form A of Deucravacitinib (i.e., the compound represented by formula (I)) was prepared, and the specific steps were as follows:

[0411] The solution was prepared by mixing 2g of the compound shown in formula (I) into 143mL of tetrahydrofuran and 7mL of water at room temperature (25°C) until the compound shown in formula (I) was completely dissolved. The solution was polished and filtered at room temperature and then dried overnight using Speed ​​vac. The obtained solid was suspended in 12mL of ethyl acetate at 60°C, and the obtained slurry was aged overnight at 60°C. The slurry was filtered and the wet cake was washed with 5mL of ethyl acetate. In a vacuum oven, the wet cake was dried at a temperature in the range of 50 to 60°C to obtain 1.4g of the crystalline form A of the compound shown in formula (I).

[0412] Example 1

[0413] Weigh 100 mg of the compound represented by formula (I), add 6.5 mL of trifluoroethanol until dissolved and clarified, evaporate and concentrate under reduced pressure at 50° C. until the solvent is dry to obtain a solid, and vacuum dry the solid at 40° C. for 1 hour to obtain Form I of the compound represented by formula (I).

[0414] The XRPD pattern of the crystalline form I of the compound represented by formula (I) is as follows Figure 1 shown.

[0415] The DSC curve of the crystalline form I of the compound represented by formula (I) is as follows Figure 2 shown.

[0416] The TGA curve of the crystalline form I of the compound represented by formula (I) is as follows Figure 3 shown.

[0417] The DVS curve of the crystalline form I of the compound represented by formula (I) is as follows Figure 4 shown.

[0418] Example 2

[0419] Weigh 40 mg of the compound represented by formula (I), add 2 mL of tetrahydrofuran and 0.1 mL of water in sequence, ultrasonicate for 10 minutes until dissolved and clarified, add 6 μL of concentrated sulfuric acid (98%), stir at 4°C for 40 minutes, precipitate a yellow solid, and centrifuge. Dissolve the separated yellow solid with 2 mL of water by ultrasonication, add sodium hydroxide solution (10 mg of sodium hydroxide dissolved in 0.5 mL of water) dropwise, precipitate a white solid, and centrifuge. Dry the separated white solid in vacuum at 40°C for 16 hours, and then keep it at 150°C for 10 minutes to obtain the crystalline form I of the compound represented by formula (I).

[0420] The product prepared in Example 2 has the same or similar XRPD spectrum, DSC curve, TGA curve and DVS curve as the product prepared in Example 1, which indicates that the product prepared in Example 2 has the same crystal form as the product prepared in Example 1.

[0421] Example 3

[0422] Weigh 30 mg of the compound represented by formula (I), add 1.0 mL of acetone and 0.4 mL of water in sequence at room temperature until dissolved and clarified to obtain a solution. Add 3.0 mL of water to the solution to precipitate a white solid, continue stirring for 10 minutes, and separate the solid by centrifugation. The solid is vacuum dried at 40°C for 16 hours to obtain the crystalline form II of the compound represented by formula (II).

[0423] The XRPD pattern of the crystalline form II of the compound shown in formula (II) is as follows Figure 5 shown.

[0424] The DSC curve of the crystalline form II of the compound shown in formula (II) is as follows Figure 6 shown.

[0425] The TGA curve of the crystalline form II of the compound represented by formula (II) is as follows Figure 7 shown.

[0426] Example 4

[0427] Weigh 45 mg of the compound represented by formula (I), add 1.5 mL of tetrahydrofuran and 0.3 mL of water at room temperature until dissolved and clarified to obtain a solution. Add the solution to 6.0 mL of water, stir, precipitate a white solid, continue stirring for 10 minutes, and separate the solid by centrifugation. The solid is vacuum dried at 40°C for 16 hours to obtain the crystalline form II of the compound represented by formula (II).

[0428] Example 5

[0429] Weigh 25 mg of the compound represented by formula (I), add 1.0 mL of 1,4-dioxane and 0.2 mL of water at room temperature until dissolved and clarified to obtain a solution. Add 3.0 mL of water to the solution to precipitate a white solid, continue stirring for 10 minutes, and separate the solid by centrifugation. The solid is vacuum dried at 40°C for 16 hours to obtain the crystalline form II of the compound represented by formula (II).

[0430] Example 6

[0431] Weigh 60 mg of the compound represented by formula (I), add 2.0 mL of tetrahydrofuran and 0.8 mL of water in sequence, heat at 70°C until dissolved and clarified, stir at 4°C for 16 hours, precipitate a white solid, separate the solid by centrifugation. Dry the solid in vacuum at 40°C for 16 hours to obtain the crystalline form II of the compound represented by formula (II).

[0432] Example 7

[0433] Take 30 mg of the crystal form A of the compound represented by formula (I) in Preparation Example 1, add 2 mL of water to form a suspension, stir at room temperature for crystallization for 29 hours, filter, and vacuum dry at room temperature for 8 hours to obtain the crystal form II of the compound represented by formula (II).

[0434] Example 8

[0435] Take 50 mg of the crystalline form I of the compound represented by formula (I) prepared according to Example 1, add 3 mL of water to form a suspension, stir and crystallize at room temperature for 26 hours, filter, and vacuum dry at room temperature for 8 hours to obtain the crystalline form II of the compound represented by formula (II).

[0436] The products prepared in Examples 4 to 8 have the same or similar XRPD spectra, DSC curves, and TGA curves as the product prepared in Example 3, which indicates that the products prepared in Examples 4 to 8 have the same crystal form as the product prepared in Example 3.

[0437] Example 9

[0438] Crystal stability

[0439] Weigh appropriate amounts of the crystal form I prepared in Example 1 and the crystal form II prepared in Example 3, and expose each crystal form sample under long-term and accelerated conditions, and perform XRPD tests regularly. The experimental results show that the crystal form I and the crystal form II did not transform into crystals after long-term exposure and accelerated exposure for 93 days ( Figure 8 and Fig. 9 ).

[0440] Take 10 mg of Form A in Preparation Example 1 and 10 mg of Form II sample, place them in a 5 mL glass vial, add 2 mL of water, stir for 3 hours, and detect XRPD. All of them are converted to Form II ( Fig.10 ).

[0441] Example 10

[0442] Chemical stability

[0443] Appropriate amounts of the crystal form I prepared in Example 1 and the crystal form II prepared in Example 3 were weighed, and each crystal form sample was placed under long-term (25°C-60% RH, sealed), accelerated (40°C-75% RH, open), high temperature (50°C, sealed) and light (4500 lux ± 500 lux, with UV, sealed) conditions, and purity was tested regularly. The test method is shown in Table 1, and the test results are shown in Table 2.

[0444] Table 1. HPLC related substances detection method

[0445]

[0446] Table 2. Chemical stability test results

[0447]

[0448]

[0449] The results show that both Form I and Form II have considerable chemical stability, with the purity decreasing by no more than 0.5% after 81 days.

[0450] Embodiment 11

[0451] Particle size distribution

[0452] Appropriate amounts of the Form I samples prepared in Example 1 and the Form II samples prepared in Example 3 were weighed respectively, dispersed with water, and the flow rate was set to 55%, and PSD detection was performed using volume distribution.

[0453] Table 3 Fig.11 and Fig.12 The experimental results shown in the figure show that the samples of Form I and Form II are unimodal, and the D( 90 ) is about 50 μm, and the D( 90 ) is around 180μm.

[0454] Table 3. Particle size distribution test results of Form I and Form II

[0455] Crystal form <![CDATA[D (10) (μm)]]> <![CDATA[D (50) (μm)]]> <![CDATA[D (90) (μm)]]> Crystalline Form I 23.2 37.5 46.2 Crystalline Form II 59.6 97.6 176.9

[0456] Example 12

[0457] Solubility in water

[0458] A mixture containing the crystal form I prepared in Example 1 was prepared and then shaken at 25°C±2°C. Samples were taken after 60 minutes and the solubility of the samples was tested by HPLC (HPLC method see Table 1).

[0459] The experimental results shown in Table 4 show that the solubility of Form I is 17 μg / mL.

[0460] Table 4. Solubility test results of Form I in water

[0461]

[0462]

[0463] Embodiment 13

[0464] Tablet dissolution

[0465] 1) Take the crystal form I prepared in Example 1, mix the crystal form I, anhydrous lactose, microcrystalline cellulose and hydroxypropyl cellulose K4M according to the prescription amount in Table 5, and screen the mixed combination. Mix the screened mixture with magnesium stearate, mix the screened mixture with magnesium stearate, dry granulate (slug / rolling process), and then grind. Further mix with magnesium stearate to prepare tablets, each weighing about 300 mg.

[0466] Table 5. Formulation I Tablets

[0467] Raw materials Proportion(%) Crystalline Form I 5 Hydroxypropyl Cellulose K4M 20 Anhydrous lactose 37 Microcrystalline Cellulose 37 Magnesium Stearate 1 total 100

[0468] 2) Prepare pH 6.8 phosphate buffer.

[0469] 3) Dissolution method: temperature 37°C, rotation speed 100 rpm, medium volume 900 mL, slurry method.

[0470] 4) Samples were taken and tested at nine time points: 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h. The results are shown in Table 6.

[0471] Table 6. Dissolution test results of Form I tablets

[0472] time Dissolution rate of crystal form I (%) 10min 3.9 30min 26.51 60min 44.32 120min 62.53 240min 72.37 6 hours 76.59 8 hours 80.29 12 hours 89.17 24 hours 91.93

[0473] According to Table 6, the ordinary tablets directly made from Form 1 have good dissolution.

[0474] In the present disclosure, relational terms such as first and second, etc. are used merely to distinguish one entity or operation from another entity or operation, but do not necessarily require or imply any such actual relationship or order between these entities or operations.

[0475] It can be understood from the foregoing that although the specific embodiments of the present disclosure are described for the purpose of illustrative illustration, various modifications or improvements may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. These modifications or improvements should all fall within the scope of the claims appended to the present disclosure.

Claims

1. Crystalline Form I of the compound represented by formula (I): in, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: 8.2±0.2°, 11.3±0.2°, 19.3±0.2°, 20.5±0.2° and 23.2±0.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: 6.4±0.2°, 10.1±0.2°, 12.6±0.2°, 14.5±0.2°, 16.3±0.2° and 16.4±0.2°.

2. Crystalline Form I of the compound represented by formula (I): in, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form I expressed in 2θ angles has the following characteristic peaks: about 8.2°, about 11.3°, about 19.3°, about 20.5° and about 23.2°, and the X-ray powder diffraction pattern of the crystalline form I also has characteristic peaks at the following 2θ angles: about 6.4°, about 10.1°, about 12.6°, about 14.5°, about 16.3° and about 16.4°.

3. Crystalline Form I of the compound represented by formula (I): in, Using Cu-Kα radiation, the characteristic peaks and their relative intensities of the X-ray powder diffraction pattern of the crystal form I expressed in 2θ angles are approximately:

4. Crystalline Form I of the compound represented by formula (I): in, Using Cu-Kα radiation, the crystalline form I substantially has an X-ray powder diffraction pattern as shown in FIG. 1 .

5. A crystalline form I of the compound of formula (I) according to any one of claims 1 to 4 which is substantially free of solvent.

6. A crystalline form I of the compound of formula (I) according to any one of claims 1 to 5 which is substantially free of water.

7. A substantially pure crystalline form I of the compound of formula (I) as claimed in any one of claims 1 to 6.

8. A crystalline form I of the compound of formula (I) according to any one of claims 1 to 7 which does not contain solvent and water.

9. A method for preparing a crystalline form I of a compound shown in the formula (I) according to any one of claims 1 to 8, comprising dissolving the compound shown in the formula (I) in a halohydrin solvent, concentrating to obtain a solid, and drying the solid to obtain the crystalline form I.

10. A method for preparing a crystalline form I of a compound shown in the formula (I) according to any one of claims 1 to 8, comprising: dissociating the compound of formula (I) with a base in a solution of an acid salt of the compound shown in formula (I) to obtain a solid, separating and drying the solid, and maintaining the crystalline form I at 120 to 180° C.

11. A pharmaceutical composition comprising the crystalline form I of the compound represented by formula (I) according to any one of claims 1 to 8, and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 11, which is prepared as a preparation for topical administration.

13. The pharmaceutical composition according to claim 11, which is prepared as a preparation for oral, subcutaneous, intravenous, intramuscular, nasal or rectal administration.

14. The pharmaceutical composition according to claim 13, wherein the oral preparation is a tablet, capsule, powder, granule, solution or suspension.

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