Crystalline forms of glucosamine derivatives, methods of preparation and uses

Abstract

The present application relates to the crystal form I and crystal form II of compound N-butyryl-glucosamine and the preparation method and purposes thereof, wherein the crystal form I and crystal form II obtained by the present application have good water solubility, crystal form stability, and can be better used in pharmacy.

Description

TECHNICAL FIELD

[0001] The present application relates to crystalline form I, crystalline form II of N-butyryl-glucosamine, and a preparation method and use thereof. BACKGROUND

[0002] The crystal structure of a compound as a pharmaceutically active ingredient often affects the chemical stability of the drug. Different crystallization conditions and storage conditions can lead to changes in the crystal structure of the compound, and sometimes other forms of crystal are also produced.

[0003] Therefore, selecting a new pharmaceutically acceptable crystal form is a key step in the development of new drugs. This is because the crystal polymorphs of some drugs are often important determinants of the ease of preparation of the active pharmaceutical ingredient (API), solubility, stability during distribution and storage, ease of formulation, and pharmacokinetic properties. When crystallization occurs in different lattice arrangements with specific thermodynamic properties and stability, crystal polymorphs are produced.

[0004] The present inventors have found that the N-butyryl-glucosamine shown below (structure as follows, formula I) is a pharmaceutically active ingredient for preventing or treating osteoarthritis, for example, see Chinese patent application CN201711364533.8, which is incorporated herein by reference in its entirety).

[0005]

[0006] Therefore, it is necessary to further study the crystal forms of the N-butyryl-glucosamine compound and related preparation methods, and to improve the properties of the glucosamine compound in various aspects, especially the stability. SUMMARY

[0007] The purpose of the present application is to provide a crystal form of the compound N-butyryl-glucosamine and a preparation method and use thereof. The crystal form prepared by the present application has good water solubility, crystal form stability, low hygroscopicity, etc., meets the quality requirements of pharmaceutical preparations, can be stored for a long time, and can be applied to the production of preparations.

[0008] In a first aspect, the present application provides a crystal form I of a compound represented by the following formula I. In the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ using Cu-Kα radiation, the crystal form I has characteristic peaks at diffraction angles of 4.009°, 7.947°, 15.865°, 17.235°, 21.160°, 22.075°, 23.856°, 25.080°, 25.384°, 27.896°, 31.982°, 35.854° and 39.625, wherein the error range of each diffraction angle is ±0.2°:

[0009]

[0010] Further, for this crystalline Form I, the diffraction angle 2Q has characteristic peaks at 4.009°, 7.947°, 11.879°, 15.865°, 17.235°, 19.623°, 21.160°, 22.075°, 23.034°, 23.856°, 25.080°, 25.384°, 27.896°, 31.142°, 31.982°, 35.854°, and 39.625°, wherein the error range of each diffraction angle is ±0.2°. Further still, for this crystalline Form I, the diffraction angle 2Q has characteristic peaks at 4.009°, 7.165°, 7.947°, 11.879°, 15.865°, 17.235°, 19.623°, 20.008°, 21.160°, 22.075°, 23.034°, 23.856°, 25.080°, 25.384°, 27.896°, 29.870°, 31.142°, 31.982°, 33.552°, 34.329°, 34.936°, 35.468°, 35.854°, 36.949°, 37.867°, 39.625°, 40.244°, 41.330°, 43.588°, and 44.306°, wherein the error range of each diffraction angle is ±0.2°.

[0011] In a second aspect, the present application provides a crystalline Form II of the compound shown in formula I above, wherein the X-ray powder diffraction pattern in terms of diffraction angle 2Q has characteristic peaks at 4.028°, 8.093°, 12.161°, 16.258°, 24.524°, 32.888°, 39.720°, wherein the error range of each diffraction angle is ±0.2°, using Cu-Ka radiation.

[0012] Furthermore, for the crystalline form II, the diffraction angle 2θ has characteristic peaks at 4.028°, 7.288°, 8.093°, 12.161°, 16.258°, 20.046°, 20.860°, 22.993°, 24.524°, 26.218°, 28.687°, 29.717°, 32.888°, 35.863°, 37.130°, 39.720°, and 44.090°, wherein the error range of each diffraction angle is ±0.2°. Furthermore, for the crystalline form II, the diffraction angle 2θ has characteristic peaks at 4.028°, 7.288°, 8.093°, 12.161°, 16.258°, 17.716°, 20.046°, 20.860°, 22.126°, 22.993°, 24.524°, 25.066°, 26.218°, 28.687°, 29.717°, 32.888°, 35.863°, 36.661°, 37.130°, 39.720°, 40.917° and 44.090°, wherein the error range of each diffraction angle is ±0.2°.

[0013] Furthermore, in differential scanning calorimetry analysis, the crystal form II showed a maximum endothermic peak at 207.7°C.

[0014] In a third aspect, the present invention provides a pharmaceutical composition comprising the above-mentioned crystalline form I or crystalline form II, and a pharmaceutically acceptable carrier.

[0015] In a fourth aspect, the present invention provides the use of the above-mentioned Form I or Form II or a pharmaceutical composition in the preparation of a medicament for preventing or treating a bone or joint disease. Preferably, the bone or joint disease is osteoporosis, osteopenia and / or arthritis. The arthritis is, for example, osteoarthritis, inflammatory arthritis (including rheumatoid arthritis or psoriatic arthritis), traumatic arthritis, degenerative arthritis or dysplastic arthritis.

[0016] In a fifth aspect, the present invention further provides two methods for preparing Form I. Specifically, one of the methods comprises:

[0017] The compound represented by Formula I is dissolved in a certain amount of a good solvent, and after the solution is clear, it is left to stand open at room temperature until the solvent is completely evaporated. In some embodiments, the good solvent is selected from methanol, ethanol, or a mixed solution of tetrahydrofuran and water.

[0018] Another method for preparing Form I comprises:

[0019] Mixing the compound represented by Formula I with a certain amount of poor solvent at 50 to 80° C. to form a suspension;

[0020] Gradually add preheated good solvent dropwise until the solid is completely dissolved, and transfer the solution to room temperature to cool;

[0021] Then cool to 4°C, then to -15°C and let stand for more than 2 hours;

[0022] Wherein, the poor solvent is selected from acetonitrile or isopropyl alcohol;

[0023] The good solvent is water.

[0024] In some embodiments, the volume ratio of the poor solvent to the good solvent is 2.0 to 3.0, specifically, 2.0, 2.2, 2.5, 2.8, or 3.0. Preferably, the volume ratio of the poor solvent to the good solvent is 2.5.

[0025] In a sixth aspect, the present invention further provides a method for preparing Form II. Specifically, the method comprises: mixing the compound represented by Formula I with a certain amount of a poor solvent at 50 to 80° C. to form a suspension;

[0026] Gradually add preheated good solvent dropwise until the solid is completely dissolved, and transfer the solution to room temperature to cool;

[0027] Let stand at room temperature for at least 2 hours.

[0028] In some embodiments, the poor solvent is selected from a mixture of one or more of n-propanol, 4-methyl-2-pentanone, ethyl acetate, dioxane, ethylene glycol dimethyl ether, acetonitrile, toluene, and isopropanol, and the good solvent is selected from a mixture of one or more of methanol, ethylene glycol methyl ether, or dimethylformamide.

[0029] Preferably, the volume ratio of the poor solvent to the good solvent may be 0.25 to 1.25, specifically, 0.25, 0.5, 0.75, 1.0, or 1.25.

[0030] And in some embodiments, the method further comprises further cooling the solution at 4°C to -15°C after standing.

[0031] The crystalline form I or II of the compound of formula I prepared by the present invention has good stability, high water solubility, and high purity. Therefore, it can meet the pharmaceutical requirements of production, transportation, and storage, and the production process is stable, repeatable, and controllable, making it suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 shows an XRPD spectrum of Form I according to the present invention;

[0033] Figure 2Shown is an XRPD spectrum of Form II according to the present invention;

[0034] Figure 3 The XRPD spectrum of the thermal transformation test of Form I is shown;

[0035] Figure 4 Shown are overlays of DSC and TGA of Form II according to the present invention;

[0036] Figure 5 shows a DVS diagram of Form II according to the present invention;

[0037] Figure 6 Shown are XRPD spectra of Form II according to the present invention before and after DVS testing;

[0038] Figure 7 shows a PLM diagram of Form I according to the present invention;

[0039] Figure 8 Showing polarizing microscope images and depolarizing microscope images of Form II according to the present invention;

[0040] Figure 9 Shown is an XRPD pattern in a stability study of Form II according to the present invention.

[0041] Figure 10 The NMR spectrum of N-butyryl-glucosamine is shown. DETAILED DESCRIPTION

[0042] In order to provide a clear and consistent understanding of the terms used in the specification of the present invention, some definitions are provided below. In addition, unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0043]

[00146] The term "crystalline form" or "crystal" as used herein refers to any solid material that exhibits a three-dimensional ordering, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.

[0044] As used herein, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to the X-ray powder diffraction pattern according to the Bragg formula 2dsinθ=nλ (where λ is the wavelength of the X-ray, The diffraction order n is any positive integer, generally taking the first order diffraction peak as n = 1. When X-rays are incident on a crystal or a portion of a crystalline sample at a grazing angle θ (the complementary angle to the incident angle, also known as the Bragg angle) on an atomic plane with a lattice spacing of d, the Bragg equation is satisfied, resulting in the measured X-ray powder diffraction pattern. XRPD patterns are typically characterized by peak position (on the abscissa) and / or peak intensity (on the ordinate).

[0045] As used herein, the term "differential scanning calorimetry or DSC" refers to measuring the temperature difference and heat flow difference between a sample and a reference during the process of heating or maintaining the sample at a constant temperature to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0046] As used herein, the term "thermogravimetric analysis or TGA" refers to measuring the relationship between the mass of a sample under program-controlled temperature and the change in temperature to study the thermal stability and composition of the material.

[0047] As used herein, the term "dynamic moisture sorption analysis or DVS" utilizes gravimetric principles to accurately characterize the moisture adsorption and interaction properties of a material.

[0048] As used herein, the term "2θ" or "2θ angle" refers to the peak position expressed in degrees based on the setup of an X-ray diffraction experiment and is typically the unit of the abscissa in a diffraction pattern. If the incident beam forms an angle θ with a certain lattice plane and the reflection is diffracted, the experimental setup requires that the reflected beam be recorded in 2θ angles. Unless otherwise specified, the 2θ value has an error range of ±0.2 degrees.

[0049] The term "polarizing microscopy," as used herein, refers to the identification of substances based on their optical characteristics, such as color, morphology, refractive index, pleochroism, extinction crosstalk, and dispersion staining. Each substance has unique optical characteristics, and identification can be accurately based on these characteristics.

[0050] The present application will be further described below in conjunction with examples, which are only used to illustrate the technical solutions of the present invention and are not intended to limit the essence and scope of the present invention. In addition, the reagents used in the following examples are all commercially available.

[0051] Preparation Example, Preparation of N-butyryl-glucosamine

[0052]

[0053] D-glucosamine hydrochloride (100 g, 464 mmol, 1 eq) was dispersed in 1 L of methanol, followed by the addition of triethylamine (94 g, 928 mmol, 2 eq) and stirring for 0.5 hours. Butyric anhydride (73.4 g, 464 mmol, 1 eq) was then added. The mixture was stirred at room temperature for 4-5 hours, followed by the addition of ethylamine (94 g, 928 mmol, 2 eq) and butyric anhydride (73.4 g, 464 mmol, 1 eq). The reaction mixture was stirred at 35°C for 15 hours, cooled to room temperature, and then filtered. The filter cake was washed twice with ethanol and then twice with ethyl acetate, and dried to yield N-butyryl-glucosamine (53 g, 45.8% yield).

[0054] 1H NMR (D2O, 500MHz) δppm 0.90-0.94(m,3H),1.59-1.67(m,2H),2.26-2.30(m,2H),3.45-3.55(m,2 H),3.67-3.92(m,4H),4.70(d,J=8.5Hz,0.6H),5.20(d,J=3.5Hz,0.4H).

[0055] Example

[0056] Crystalline form prepared by volatilization

[0057] N-butyryl-glucosamine was dissolved in a good solvent, and after the solution was clear, it was left to stand open at room temperature until the solvent was completely evaporated to obtain a solid. The results are shown in Table 1.

[0058] Table 1

[0059] Experiment number Sample amount (mg) Solvent Volume (mL) Result Example 1 20.1 Methanol 1.8 Crystalline form I Example 2 20.5 Ethanol 10.0 Crystalline form I Example 3 20.2 THF / water (95 / 5, v / v) 10.0 Crystalline form I

[0060] The obtained solid sample was analyzed by Bruker D8 Advance (Bruker, GER) and the following Figure 1 The XRPD pattern shown (test conditions are described in detail below) and its characteristic peak information are shown in Table 2. Therefore, Form I can be obtained by a simple solvent evaporation method.

[0061] Table 2, characteristic peaks of Form I

[0062] Index Angle d. Value Rel. Intensity 1 4.009 22.02499A 100.0％ 2 7.165 12.32846A 0.2％ 3 7.947 11.11641A 96.3％ 4 11.879 7.44385A 0.8％ 5 15.865 5.58173A 5.1％ 6 17.235 5.14079A 1.4％ 7 19.623 4.52025A 0.9% 8 20.008 4.43430A 0.4％ 9 21.160 4.19536A 1.1％ 10 22.075 4.02351A 1.6％ 11 23.034 3.85802A 0.5％ 12 23.856 3.72702A 2.6％ 13 25.080 3.54777A 2.1％ 14 25.384 3.50592A 1.3％ 15 27.896 3.19577A 1.1％ 16 29.567 3.01877A 0.0％ 17 29.870 2.98885A 0.1％ 18 31.142 2.86961A 0.9％ 19 31.982 2.79618A 4.2％ 20 33.302 2.68826A 0.0％ 21 33.552 2.66881A 0.1％ 22 34.329 2.61015A 0.0％ 23 34.936 2.56618A 0.1％ 24 35.468 2.52893A 0.2％ 25 35.854 2.50253A 1.2％ 26 36.949 2.43087A 0.1% 27 37.867 2.37400A 0.0％ 28 38.099 2.36009A 0.0％ 29 39.625 2.27267A 3.2％ 30 40.244 2.23910A 0.2％ 31 41.330 2.18276A 0.1% 32 43.588 2.07475A 0.2％ 33 44.306 2.04279A 0.1％

[0063] Crystalline form prepared by binary solvent cooling

[0064] Using methanol, ethylene glycol monomethyl ether, DMF, DMSO, or water as good solvents in combination with various poor solvents, binary solvent cooling crystallization experiments were conducted at different temperatures. The solubility of the compounds in various solvents is shown in Table 3. The specific operation steps are as follows.

[0065] A certain amount of the product obtained in the preparation example was weighed and mixed with a certain amount of a poor solvent at 50° C. to 80° C. to form a suspension.

[0066] Gradually add preheated good solvent dropwise until the solid in the suspension is completely dissolved, and transfer the solution to room temperature for cooling.

[0067] If sufficient solid is not precipitated after standing at room temperature for more than 2 hours, the solution is then further cooled at 4°C to precipitate sufficient solid. If sufficient solid is still not precipitated, the solution is further cooled.

[0068] After sufficient solid was precipitated, the system was centrifuged to separate the solid, which was then dried under vacuum at room temperature.

[0069] Table 3: Compound solubility test

[0070]

[0071] The crystallization results of the binary solvent cooling method are shown in Table 4 below.

[0072] Table 4

[0073]

[0074] The solid precipitated in the above experiment was analyzed by Bruker D8 Advance (Bruker, GER). In addition to Form I, Form II was also obtained. Form II showed the following Figure 2 The XRPD pattern shown (the test conditions are shown in detail below) and its characteristic peak information are shown in Table 5 below.

[0075] Table 5, characteristic peaks of Form II

[0076] Index Angle d Value Rel. Intensity 1 4.028° 21.91607A 100.0% 2 7.288° 12.11988A 0.2％ 3 8.093° 10.91602A 77.2％ 4 12.161° 7.27214A 0.9％ 5 16.258° 5.44746A 3.4% 6 17.716° 5.00246A 0.1％ 7 20.046° 4.42595A 0.2％ 8 20.860° 4.25509A 0.4％ 9 22.126° 4.01438A 0.0％ 10 22.993° 3.86484A 0.5％％ 11 24.524° 3.62693A 1.1％ 12 25.066° 3.54972A 0.1％ 13 26.218° 3.39635A 0.6％ 14 28.687° 3.10934A 0.5％ 15 29.717° 3.00393A 0.5％ 16 31.058° 2.87723A 0.0％ 17 32.888° 2.72114A 2.0％ 18 35.863° 2.50194A 0.4％ 19 36.661° 2.44931A 0.1％ 20 37.130° 2.41945A 0.7％ 21 39.720° 2.26741A 0.9％ 22 40.917° 2.20384A 0.1％ 23 44.090° 2.05231A 0.2％

[0077] Thermal crystallization experiment

[0078] Thermal crystallization was performed using an Instec HCS424GXY hot stage (Instec Inc., USA). A 6-8 mg sample was placed on a glass slide on the hot stage and heated to the target temperature at a rate of 10°C / min. The temperature was kept constant for 2 min, and then the sample was naturally cooled to room temperature to obtain a solid, which was then subjected to XRPD analysis.

[0079] Using Form I as the raw material, it was heated to the target temperature on a hot plate and kept at this temperature for 2 minutes. The solid was then cooled to room temperature and subjected to XRPD testing. The results of the thermal transformation experiment showed that Form I transformed into Form II after being heated to 150°C.

[0080] Using Form II as the raw material, it was heated to the target temperature on a hot plate and kept at this temperature for 2 minutes. The solid was then cooled to room temperature and subjected to XRPD testing. The results of the thermal crystallization experiment showed that Form II would not change its crystal form when heated to 150°C.

[0081] like Figure 3 As shown, compared with Form I, Form II is more stable.

[0082] Evaluation of the physicochemical properties of the two crystal forms

[0083] The crystalline form I and crystalline form II of the present invention were analyzed using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic water sorption analysis (DVS), polarizing microscope analysis (PLM), and melting point analysis. In performing each of the above analyses, it should be noted that the results obtained may vary within the allowable instrument error and operating error. For example, in differential scanning calorimetry (DSC), the maximum endothermic peak obtained may vary within a range of less than ±5°C, such as ±3°C, ±2°C, or ±1°C.

[0084] Specific conditions or parameters of the above analysis are shown below.

[0085] XRPD: The solid samples were analyzed using a Bruker D8 Advance X-ray powder diffractometer (Bruker, Germany). The 2θ scan angle ranged from 3° to 45°, with a scan step size of 0.02° and an exposure time of 0.12 seconds. The tube voltage and current were 40 kV and 40 mA, respectively, and the sample pan was a zero-background pan.

[0086] DSC: Differential Scanning Calorimetry (DSC) was performed using a TA Discovery 2500 (TA, US). 1-2 mg of sample was accurately weighed and placed in a perforated DSC Tzero sample pan. The sample was heated to the final temperature at a rate of 10°C / min, with a nitrogen purge rate of 50 mL / min.

[0087] TGA: Thermogravimetric analyzer (TGA) was a TA Discovery 55 (TA, US). A 2-5 mg sample was placed in a equilibrated open aluminum sample pan and automatically weighed in the TGA furnace. The sample was heated to the final temperature at a rate of 10°C / min. A nitrogen purge rate of 60 mL / min was maintained at the sample and 40 mL / min at the balance.

[0088] DVS: Dynamic moisture sorption / desorption analysis was performed using a DVS Intrinsic (SMS, UK). The test used a gradient mode with humidity changes from 50% to 95% to 0% to 50%, with each step increasing by 10% within the 0% to 90% range. The gradient endpoint was determined using the dm / dt method, with a dm / dt of less than 0.002% maintained for 10 minutes. After the test, the sample was analyzed by XRPD to confirm any changes in the solid state.

[0089] PLM: The polarizing microscope model is Nikon Ci-POL (Nikon, Japan). A small amount of sample is placed on a glass slide and the sample morphology is observed using a suitable lens.

[0090] Melting point apparatus: The melting point was detected using a SGW X-4 micro melting point apparatus.

[0091] The above test results are shown in Figure 1 to Figure 8 Among them Figure 1 shows an XRPD spectrum of Form I according to the present invention; Figure 2 Shown is an XRPD spectrum of Form II according to the present invention; Figure 3 The XRPD spectrum of Form I after thermal transformation experiment is shown; Figure 4 Shown are overlays of DSC and TGA of Form II according to the present invention; Figure 5 shows a DVS diagram of Form II according to the present invention; Figure 6 Shown are XRPD spectra of Form II according to the present invention before and after DVS testing; Figure 7 shows a PLM diagram of Form I according to the present invention; Figure 8 The polarizing microscope image and the depolarizing microscope image of the crystal form II according to the present invention are shown; the crystal form II was tested using a melting point apparatus, and the melting point of the crystal form II was 202°C.

[0092] See also Figure 1 It can be seen that Form I is a solid with good crystallinity. Figure 6 The PLM images shown indicate that Form I is rod-shaped crystals with a particle size much larger than 20 μm.

[0093] See also Figure 2 It can be seen that Form II is a solid with good crystallinity. Figure 4 It shows that Form II loses 0.7% of its weight when heated to 150°C and may decompose above 200°C. Its DSC results show that there is an endothermic signal of melting accompanied by decomposition near 208°C. Figure 5 The results show that Form II gained 2.24% weight at 95% humidity and lost 0.22% weight at 0% humidity, indicating that Form II is slightly hygroscopic and Figure 6 This indicates that the sample did not undergo any crystal change after the DVS test. Figure 8 The results showed that Form II was rod-shaped particles with a particle size generally less than 20 μm.

[0094] Stability studies

[0095] The stability of Form II was studied under high temperature (60°C, high humidity (25°C, 92.5% RH), light (25°C, 4500 Lux), accelerated (40°C, 75% RH), and 25°C, 60% RH conditions. During the study, samples were taken for XRPD characterization at 7 days and 15 days, and the results are shown in Table 6. Form II has good stability. The XRPD results show that Figure 9 middle.

[0096] Table 6. Results of stability study of Form II

[0097] Conditions 7-day result 15-day result High temperature 60°C No change No change High humidity 25°C / 92.5% RH, No change No change Light 25°C / 4500 lux, No change No change Accelerated 40°C / 75% RH No change No change Temperature: 25°C, Humidity: 60% RH No change No change

[0098] The two crystal forms disclosed in the present application are both good crystalline solids, especially Form II, which has good stability and meets the quality requirements of pharmaceutical preparations, can be stored for a long time, and can be applied in the production of preparations.

[0099] The present application is not limited by the embodiments shown and described above, but can vary within the scope of the claims.

Claims

1. A crystalline form II of the compound represented by the following formula I, wherein: In the X-ray powder diffraction pattern obtained using Cu-Kα radiation and expressed in diffraction angle 2θ, there are characteristic peaks at diffraction angles of 4.028°, 8.093°, 12.161°, 16.258°, 24.524°, 32.888°, and 39.720°, where the error range of each diffraction angle is ±0.2°: The melting point of the crystal form II is 202°C.

2. The crystalline form II according to claim 1, wherein The diffraction angle 2θ has characteristic peaks at 4.028°, 7.288°, 8.093°, 12.161°, 16.258°, 20.046°, 20.860°, 22.993°, 24.524°, 26.218°, 28.687°, 29.717°, 32.888°, 35.863°, 37.130°, 39.720°, and 44.090°, wherein the error range of each diffraction angle is ±0.2°.

3. The crystalline form II according to claim 1, wherein The diffraction angle 2θ has characteristic peaks at 4.028°, 7.288°, 8.093°, 12.161°, 16.258°, 17.716°, 20.046°, 20.860°, 22.126°, 22.993°, 24.524°, 25.066°, 26.218°, 28.687°, 29.717°, 32.888°, 35.863°, 36.661°, 37.130°, 39.720°, 40.917° and 44.090°, wherein the error range of each diffraction angle is ±0.2°.

4. The crystalline form II according to any one of claims 1 to 3, wherein In differential scanning calorimetry analysis, the crystalline form II exhibited a maximum endothermic peak at 207.7°C.

5. A pharmaceutical composition comprising the crystalline form II according to any one of claims 1 to 4, and a pharmaceutically acceptable carrier.

6. Use of the crystalline form II according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for preventing or treating a bone or joint disease, wherein the bone or joint disease is osteoporosis, osteopenia and / or arthritis.

7. The use according to claim 6, wherein the arthritis is osteoarthritis.

8. The use according to claim 6, wherein the arthritis is inflammatory arthritis, traumatic arthritis, degenerative arthritis or dysplastic arthritis.

9. The use according to claim 6, wherein the arthritis is rheumatoid arthritis or psoriatic arthritis.

10. A method for preparing the crystalline form II according to any one of claims 1 to 4, wherein The method comprises: Mixing the compound represented by Formula I with a certain amount of poor solvent at 50 to 80° C. to form a suspension; Gradually add preheated good solvent dropwise until the solid is completely dissolved, and transfer the solution to room temperature to cool; Let it sit at room temperature for more than 2 hours; Wherein, the poor solvent is selected from a mixture of one or more of n-propanol, 4-methyl-2-pentanone, ethyl acetate, dioxane, ethylene glycol dimethyl ether, acetonitrile, toluene, and isopropanol; The good solvent is selected from a mixture of one or more of methanol, ethylene glycol methyl ether or dimethylformamide.

11. The method according to claim 10, wherein: The volume ratio of the poor solvent to the good solvent is 0.25 to 1.

25.

12. The method according to claim 11, wherein The method further comprises: after standing, further cooling the solution at 4°C to -15°C.

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