Crystal form of itraconazole and preparation method and application thereof

Abstract

The invention relates to a crystal form of itraconazole as well as a preparation method and application thereof. According to the crystal form of itraconazole, in an X-ray powder diffraction pattern represented by a diffraction angle 2 theta obtained through Cu-K alpha radiation, the diffraction angle 2 theta has characteristic peaks at 5.9 degrees, 17.4 degrees and 19.6 degrees, and the error range of 2 theta is + / -0.2 degrees. Compared with the existing crystal form, the novel itraconazole crystal form provided by the invention has the advantages that the flowability of itraconazole is obviously improved, so that the technical problem that the loading / weight and the medicine content are not uniform in the production process of the itraconazole medicine preparation can be well solved, and the quality of the preparation product is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of drug crystallization, and in particular to a crystal form of itraconazole and a preparation method and application thereof. Background Art

[0002] Itraconazole, chemical formula C 35 H 38 Cl2N8O4, chemical name is 4-[4-[4-(4-[[cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydroxy-3H-1,2,4-triazol-3-one, the structural formula is shown in the following formula (a):

[0003]

[0004] It is a triazole-type highly effective broad-spectrum antifungal drug that can bind to fungal cytochrome P450 isoenzymes and inhibit ergosterol synthesis. It is effective against infections such as dermatophytes, Candida, Cryptococcus neoformans, Pityrosporum, Aspergillus, Histoplasma, Paracoccidioides brasiliensis, Sporothrix schenckii, Chromatiaceae, Cladosporium, and Blastomyces dermatitidis.

[0005] PEETERS et al. (Acta Cryst. (1996). C52, 2225-2229) reported the single crystal structure of itraconazole form I in 1996, and then US2003 / 0100568A1 reported the structure of form II. ZHANG et al. (US20170319553A1) obtained two metastable forms II and III of itraconazole from melt crystallization, among which form III is unstable and will transform into form II and form I.

[0006] At present, itraconazole API in crystalline form is generally used to produce solid preparations such as itraconazole tablets, capsules, granules, and powder for injection. However, the fluidity of existing itraconazole crystal forms I, II, and III is not ideal. As is well known, the physical and chemical properties of different crystal forms of the same drug may vary greatly in terms of solubility, stability, fluidity, compressibility, bioavailability, etc., thus affecting the efficacy of the drug. The fluidity of pharmaceutical powders is an important factor that must be considered in the preparation of solid preparations. It not only affects the normal production process, but also affects the quality of the preparation products: powders with good fluidity can flow smoothly from the feed hopper to the tableting equipment, which is conducive to maintaining uniform tablet weight and drug content; powders with poor fluidity are often difficult to mix evenly with the various ingredients and affect the accurate content of the drug, causing differences in loading / weight during the molding or filling of tablets, capsules, etc.; during the storage and transportation of drugs, preparations made of materials with poor fluidity are easily affected by factors such as ambient temperature, ambient humidity, and mechanical force, which reduce the stability and effectiveness of the drug. Therefore, it is necessary to develop a new crystalline form of itraconazole with better fluidity, which is beneficial to formulation processing and clinical application. Summary of the invention

[0007] In view of the deficiencies mentioned in the above background technology, the purpose of the present invention is to solve the problem that the existing crystalline form of itraconazole has poor fluidity, thereby affecting the quality of the drug preparation product.

[0008] In order to achieve the above object, the present invention provides a crystal form of itraconazole and a preparation method and use thereof.

[0009] The present invention is achieved by adopting the following technical solutions.

[0010] On the one hand, the present invention provides a crystalline form of itraconazole, wherein an X-ray powder diffraction pattern represented by a diffraction angle 2θ obtained by using Cu-Kα radiation has characteristic peaks at diffraction angles 2θ of 5.9°, 17.4°, and 19.6°, wherein the error range of 2θ is ±0.2°.

[0011] Preferably, the crystalline form of itraconazole has characteristic peaks at diffraction angles 2θ of 5.9°, 8.1°, 16.0°, 17.4°, and 19.6° in an X-ray powder diffraction pattern obtained by using Cu-Kα radiation and represented by a diffraction angle 2θ, wherein the error range of 2θ is ±0.2°.

[0012] Preferably, the crystalline form of itraconazole has characteristic peaks at diffraction angles 2θ of 5.9°, 8.1°, 16.0°, 17.4°, 19.6°, 24.2°, 25.0°, and 25.7° in an X-ray powder diffraction pattern obtained by using Cu-Kα radiation and represented by a diffraction angle 2θ, wherein the error range of 2θ is ±0.2°.

[0013] Preferably, the crystalline form of itraconazole has an X-ray powder diffraction pattern represented by a diffraction angle 2θ obtained by using Cu-Kα radiation, and the diffraction angle 2θ has characteristic peaks at 5.9°, 8.1°, 8.8°, 9.2°, 16.0°, 17.4°, 18.6°, 19.6°, 24.2°, 25.0°, 25.7°, and 26.5°, wherein the error range of 2θ is ±0.2°.

[0014] Preferably, the crystalline form of itraconazole has an X-ray powder diffraction pattern represented by a diffraction angle 2θ obtained by using Cu-Kα radiation, and the diffraction angle 2θ has characteristic peaks at 5.9°, 8.1°, 8.8°, 9.2°, 16.0°, 16.4°, 17.4°, 18.6°, 19.6°, 20.8°, 22.2°, 22.7°, 24.2°, 25.0°, 25.7°, and 26.5°, wherein the error range of 2θ is ±0.2°.

[0015] Preferably, the crystalline form of itraconazole has an X-ray powder diffraction pattern represented by a diffraction angle 2θ obtained by using Cu-Kα radiation, and the diffraction angle 2θ has characteristic peaks at 5.9°, 8.1°, 8.8°, 9.2°, 11.0°, 16.0°, 16.4°, 17.4°, 18.6°, 19.6°, 20.8°, 22.2°, 22.7°, 24.2°, 25.0°, 25.7°, 26.5°, 29.8°, 30.5°, and 31.6°, wherein the error range of 2θ is ±0.2°.

[0016] Preferably, the crystalline form of itraconazole uses Cu-Kα radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and the diffraction angle 2θ and the relative intensity of the corresponding peak are shown in the following table, wherein the error range of 2θ is ±0.2°:

[0017]

[0018]

[0019] Preferably, the itraconazole crystalline form has an X-ray powder diffraction pattern expressed in diffraction angle 2θ obtained by using Cu-Kα radiation, which is substantially as follows Figure 1 shown.

[0020] Preferably, the differential scanning calorimetry analysis diagram of the itraconazole crystal form has endothermic peaks at 100.8±3°C and 168.4±3°C.

[0021] Preferably, the differential scanning calorimetry analysis diagram of the itraconazole crystal form is substantially as follows Figure 2 shown.

[0022] On the other hand, the present invention provides a method for preparing the above-mentioned crystalline form of itraconazole, the method comprising the following steps:

[0023] 1) dissolving itraconazole in an organic solvent (X);

[0024] 2) cooling and adding organic solvent (b) dropwise;

[0025] 3) Rapidly cool down while stirring to keep the temperature and grow the crystal.

[0026] Preferably, the organic solvent (X) consists of an organic solvent (a) and an organic solvent (b), the organic solvent (a) is dichloromethane, and the organic solvent (b) is at least one selected from methanol and ethanol.

[0027] Preferably, in the organic solvent (X), the volume ratio between the organic solvent (b) and the organic solvent (a) is 1:2-5.

[0028] Preferably, in step 1), the mass volume ratio of the itraconazole to the organic solvent (X) is 1:3 to 1:6.

[0029] Preferably, in step 2), the temperature is lowered to 0-5°C.

[0030] Preferably, in step 2), the amount of the organic solvent (b) added is 3 to 7 times the volume of the organic solvent (a) in step 1).

[0031] Preferably, in step 3), the temperature is lowered by 1 to 5° C. per minute.

[0032] Preferably, in step 3), the temperature is rapidly lowered to -10 to -5°C under stirring.

[0033] Preferably, in step 3), the crystal growing temperature is -10 to -5°C.

[0034] Preferably, in step 3), the crystal growing time is 0.5 to 10 hours.

[0035] Preferably, the method further comprises step 4) after the crystal growing is completed, filtering, washing, and vacuum drying;

[0036] Preferably, in step 4), the solvent used for washing is an organic solvent (b). Generally speaking, the organic solvent (b) in step 4) is the same as the organic solvent (b) in step 2).

[0037] Preferably, in step 4), the drying temperature is 40-60°C.

[0038] In a specific embodiment, the method for preparing the crystalline form of itraconazole comprises the following steps:

[0039] 1) dissolving itraconazole in an organic solvent (X), wherein the organic solvent (X) consists of an organic solvent (a) and an organic solvent (b), wherein the organic solvent (a) is dichloromethane, and the organic solvent (b) is at least one selected from methanol and ethanol, and the volume ratio of the organic solvent (b) to the organic solvent (a) is 1:2-5;

[0040] 2) Cooling to 0-5°C, adding organic solvent (b) dropwise;

[0041] 3) While stirring, quickly cool down to -10~-5℃, keep warm and stir to grow crystals until crystallization is complete;

[0042] 4) collecting the crystals by suction filtration, washing with a small amount of organic solvent (b), and vacuum drying to obtain itraconazole crystals.

[0043] In yet another aspect, the present invention provides an itraconazole composition, comprising the itraconazole crystal form and optionally a pharmaceutically acceptable excipient.

[0044] Preferably, the composition is an inhalation formulation.

[0045] In another aspect, the itraconazole crystal form or itraconazole composition of the present invention is used in the preparation of a drug for preventing and / or treating lung or respiratory diseases.

[0046] Preferably, the lung or respiratory disease is pulmonary fibrosis.

[0047] Compared with the prior art, this application has at least the following beneficial technical effects:

[0048] The new itraconazole crystal form provided by the present invention significantly improves the fluidity of itraconazole compared with the existing crystal form, thereby being able to well solve the technical problems of uneven filling / weight and drug content in the production process of itraconazole pharmaceutical preparations, and improving the quality of the preparation products.

[0049] The preparation method of the invention is simple, has low cost and is easy to realize large-scale and industrialized production.

[0050] The preparation method of the invention improves the solubility of itraconazole crystals. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 The X-ray powder diffraction pattern of the itraconazole crystal form provided by the present invention;

[0052] Figure 2 The differential scanning calorimetry analysis diagram of the itraconazole crystal form provided by the present invention is shown in FIG. DETAILED DESCRIPTION

[0053] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments. The following embodiments are explanations of the present invention, and the present invention is not limited to the following embodiments.

[0054] In the following examples, unless otherwise specified, Form I was obtained from the China Food and Drug Inspection Institute, and Form II was prepared by referring to the method of patent US2003 / 0100568A1.

[0055] Example 1

[0056] Take 10g of itraconazole sample and place it in a reaction bottle, add 30ml of dichloromethane and 10ml of methanol, stir and dissolve at room temperature, cool down by 0-5℃, add 140ml of methanol dropwise, and continue to cool down to -10--5℃ at a rate of 2℃ per minute, grow crystals for 2 hours, filter, and dry the filter cake in vacuum at 50℃ for 4h to obtain 8.1g of target crystals.

[0057] The itraconazole crystal prepared above was subjected to X-ray powder diffraction.

[0058] A Malvern Panalytical X-ray diffractometer (Empyrean3) was used, with a Cu target tube, a voltage and current of 45 kV, 40 mA, a divergence slit of 1 / 8°, a 2θ angle range of 3° to 50°, a step length of 0.013°, and a scanning time of 20.4 s per step. An appropriate amount of sample was taken, placed on the resin gasket in the mold, and tested after lightly pressing the surface with a glass slide. The X-ray powder diffraction pattern of the itraconazole crystal form provided by the present invention is as follows: Figure 1 The peaks and intensities corresponding to the 2θ diffraction angles are shown in Table 1.

[0059] Table 1

[0060]

[0061]

[0062] The differential scanning calorimetry (DSC) curve of the itraconazole crystal prepared above was measured.

[0063] DSC measurement was performed using TA Instruments (Waters Technology (Shanghai) Co., Ltd., DSC250) from the United States. Test procedure: Rapidly heat up / cool down to 30.00°C, and linearly heat up to 300.00°C at 10.00°C / min. Take an appropriate amount of sample, accurately weigh it, place it in a plate, gently press the sealing cover on it, and test it after tableting using a DSC tablet press. The differential scanning calorimetry analysis diagram of the itraconazole crystal form provided by the present invention is shown in FIG. Figure 2 As shown, the horizontal axis represents temperature (Temperature, ℃), and the vertical axis represents the heat flow (Heat Flow, W / g) released by unit mass of substance.

[0064] Example 2

[0065] Take 10g of itraconazole sample and place it in a reaction bottle, add 20ml of dichloromethane and 10ml of methanol, stir at room temperature to dissolve, cool down by 0-5°C, add 60ml of methanol dropwise, and continue to cool down to -10--5°C at a rate of 5°C per minute, grow crystals for 2 hours, filter, and vacuum dry the filter cake at 40°C for 4h to obtain 8.8g of target crystals with a yield of 88%. The characteristic peaks of the X-ray powder diffraction spectrum of the obtained crystals measured using Cu-Kα ray are Figure 1 The differential scanning calorimetry analysis of the obtained crystals is consistent with Figure 2 Consistent.

[0066] Example 3

[0067] Take 10g of itraconazole sample and place it in a reaction bottle, add 50ml of dichloromethane and 10ml of methanol, stir at room temperature to dissolve, cool down by 0-5°C, add 340ml of methanol dropwise, and continue to cool down to -10--5°C at a rate of 1°C per minute, grow crystals for 5 hours, filter, and vacuum dry the filter cake at 60°C for 6 hours to obtain 8.9g of target crystals with a yield of 89%. The characteristic peaks of the X-ray powder diffraction spectrum of the obtained crystals measured using Cu-Kα rays are Figure 1 The differential scanning calorimetry analysis of the obtained crystals is consistent with Figure 2 Consistent.

[0068] Example 4

[0069] Take 10g of itraconazole sample and place it in a reaction bottle, add 30ml of dichloromethane and 10ml of ethanol, stir at room temperature to dissolve, cool to 0-5°C, add 80ml of ethanol dropwise, continue to cool to -10--5°C at a rate of 3°C per minute, grow crystals for 2 hours, filter, and vacuum dry the filter cake at 60°C for 6 hours to obtain 8.0g of target crystals with a yield of 80%. The characteristic peaks of the X-ray powder diffraction spectrum of the obtained crystals measured using Cu-Kα rays are Figure 1 The differential scanning calorimetry analysis of the obtained crystals is consistent with Figure 2 Consistent.

[0070] Example 5

[0071] Take 10g of itraconazole sample and place it in a reaction bottle, add 40ml of dichloromethane and 10ml of methanol / ethanol mixed solution (the volume ratio of methanol to ethanol is 1:1), stir at room temperature to dissolve, cool to 0-5°C, add 190ml of methanol / ethanol mixed solution (the volume ratio of methanol to ethanol is 1:1), continue to cool to -10--5°C at a rate of 3°C per minute, grow crystals for 10 hours, filter, and vacuum dry the filter cake at 60°C for 6 hours to obtain 8.8g of target crystals with a yield of 88%. The characteristic peaks of the X-ray powder diffraction spectrum of the obtained crystals measured using Cu-Kα rays are Figure 1 The differential scanning calorimetry analysis of the obtained crystals is consistent with Figure 2 Consistent.

[0072] Example 6 Fluidity determination

[0073] Take appropriate amount of samples of Form I, Form II and the new crystalline itraconazole prepared in Examples 1-5, sieve them (1.00 mm No. 18), accurately weigh them, slowly pour them into a glass graduated cylinder, scrape the top flat, record the apparent volume, and calculate the bulk density; tap the cylinder so that the solid volume no longer changes, record the apparent volume, and calculate the tap density; then calculate the compressibility coefficient and Hausner ratio based on the data of the bulk density and tap density. The experimental results are shown in Table 2.

[0074] Table 2

[0075] Crystal <![CDATA[Bulk density (g / cm 3 )]]> <![CDATA[Tap density (g / cm 3 )]]> Compressibility coefficient (%) Hausner ratio Crystalline Form I 0.18 0.27 33.33％ 1.50 Crystal form II 0.31 0.44 29.55％ 1.42 Crystal form of Example 1 0.54 0.64 15.63％ 1.19 Crystal form of Example 2 0.55 0.65 15.38％ 1.18 Crystal form of Example 3 0.53 0.63 15.87％ 1.19 Crystal form of Example 4 0.53 0.63 15.87％ 1.19 Crystal form of Example 5 0.54 0.65 16.92％ 1.20

[0076] The corresponding relationship between compressibility coefficient, Hausner ratio and fluidity is shown in Table 3

[0077] Table 3

[0078] Compressibility Hausner ratio Liquidity ≤10％ 1.00～1.11 very good 11％～15％ 1.12～1.18 good 16％～20％ 1.19～1.25 generally 21％～25％ 1.26～1.34 qualified 26％～31％ 1.35～1.45 Difference 32％～37％ 1.46～1.59 Very bad ＞38％ ＞1.60 Very bad

[0079] Example 7 Filling volume difference determination

[0080] Take appropriate amounts of Form I, Form II, and the new crystal form itraconazole prepared in Examples 1-5, respectively, and pass them through a 200-mesh sieve, fix the capsule shell on the capsule plate, fill the body plate with powder, pour the powder on the body plate and scrape it back and forth with a powder scraper, and after the capsule shell is filled with powder, scrape off the excess powder on the body plate to obtain capsules. Then, refer to the inspection method for capsules [filling amount difference] in 0103 General Rules for Capsules in the Pharmacopoeia of the People's Republic of China (2020 edition) to measure the filled capsules, and calculate the filling amount difference value X (%) of each grain filling amount corresponding to each group of Form I, Form II, and the new crystal form of Examples 1-4 compared with the average filling amount of the group, and then take the absolute value of each filling amount difference value, calculate the average value of each group, and the results are shown in Table 4.

[0081] Table 4

[0082] Crystal Average loading volume difference (%) Crystalline Form I 8.6 Crystalline Form II 5.3 Crystal form of Example 1 1.6 Crystal form of Example 2 1.6 Crystal form of Example 3 1.7 Crystal form of Example 4 1.8 Crystal form of Example 5 1.7

[0083] Example 8 : Comparison of the solubility of the new crystalline itraconazole of the present invention and the crystalline forms (crystalline form I and crystalline form II) of the prior art in 50% ethanol solution at room temperature.

[0084] Determination method: Place an excess of the test substance and the reference substance in a 50 ml conical flask, add 25 ml of 50% ethanol solution, and stir at room temperature for 48 hours. Take a sample of 400 μL, filter the sample through a 0.22 μm microporous filter membrane, discard the primary filtrate, take 20 μL of the subsequent filtrate, and determine the drug content, which is the solubility in 50% ethanol solution (mg / ml). The results are shown in Table 5.

[0085] Table 5

[0086] Crystal Solubility (mg / ml) Crystalline Form I 0.03 Crystalline Form II 0.11 Crystal form of Example 1 0.22 Crystal form of Example 2 0.21 Crystal form of Example 3 0.18 Crystal form of Example 4 0.18 Crystal form of Example 5 0.19

[0087] Example 9 :High temperature experiment of new crystal form

[0088] The new crystal form of Example 1 of the present invention was placed in a culture dish, spread into a thin layer ≤5 mm thick, and placed at 60°C±2°C. Samples were taken for testing at 5, 10, and 30 days. The results are shown in Table 6 below.

[0089] Table 6

[0090] time Appearance Single impurity (%) Total impurities (%) content(%) 0 White powder 0.02 0.10 99.7 5 White powder 0.02 0.09 99.7 10 White powder 0.03 0.12 99.7 30 White powder 0.03 0.12 99.6

[0091] The results show that the high temperature conditions have not changed significantly and are relatively stable.

[0092] Example 10 :High humidity experiment of new crystal form

[0093] The new crystal form of Example 1 of the present invention was placed in a culture dish and spread into a thin layer ≤5 mm thick. It was placed under the conditions of 25°C±2°C and 92.5%RH±5%RH. Samples were taken for testing at 5, 10 and 30 days. The results are shown in Table 7 below.

[0094] Table 7

[0095] time Appearance Single impurity (%) Total impurities (%) content(%) 0 White powder 0.02 0.10 99.7 5 White powder 0.02 0.11 99.7 10 White powder 0.02 0.10 99.6 30 White powder 0.02 0.11 99.7

[0096] The results show that the high humidity conditions have not changed significantly and are relatively stable.

[0097] Embodiment 11 :Lighting experiment of new crystal form

[0098] The new crystal form of Example 1 of the present invention was placed in a culture dish and spread into a thin layer ≤5 mm thick. It was placed under an illumination of 4500 lx±500 lx. Samples were taken for testing on days 5 and 10. The results are shown in Table 8 below.

[0099] Table 8

[0100] time Appearance Single impurity (%) Total impurities (%) content(%) 0 White powder 0.02 0.10 99.7 5 White powder 0.02 0.11 99.7 10 White powder 0.03 0.12 99.7

[0101] The results show that the lighting conditions have not changed significantly and are relatively stable.

[0102] In summary, the present invention provides a new crystal form of itraconazole, which has good fluidity and stability, and significantly improved solubility in ethanol solution. At the same time, the preparation process of the crystal form provided by the present invention is simple, which is conducive to cost control in industrial production and has high economic value.

Claims

1. A crystalline form of itraconazole, characterized in that: In the X-ray powder diffraction pattern represented by the diffraction angle 2θ obtained by using Cu-Kα radiation, the diffraction angle 2θ has characteristic peaks at 5.9°, 17.4°, and 19.6°, wherein the error range of 2θ is ±0.2°.

2. The crystal form according to claim 1, characterized in that: The crystalline form of itraconazole has characteristic peaks at diffraction angles 2θ of 5.9°, 8.1°, 16.0°, 17.4°, and 19.6° in an X-ray powder diffraction pattern obtained by using Cu-Kα radiation, wherein the error range of 2θ is ±0.2°; Preferably, the crystalline form of itraconazole has characteristic peaks at diffraction angles 2θ of 5.9°, 8.1°, 16.0°, 17.4°, 19.6°, 24.2°, 25.0°, and 25.7° in an X-ray powder diffraction pattern obtained by using Cu-Kα radiation and represented by a diffraction angle 2θ, wherein the error range of 2θ is ±0.2°; Preferably, the crystalline form of itraconazole has an X-ray powder diffraction pattern represented by a diffraction angle 2θ obtained by using Cu-Kα radiation, and the diffraction angle 2θ has characteristic peaks at 5.9°, 8.1°, 8.8°, 9.2°, 16.0°, 17.4°, 18.6°, 19.6°, 24.2°, 25.0°, 25.7°, and 26.5°, wherein the error range of 2θ is ±0.2°.

3. The crystal form according to claim 1 or 2, characterized in that: The crystalline form of itraconazole has characteristic peaks at diffraction angles 2θ of 5.9°, 8.1°, 8.8°, 9.2°, 16.0°, 16.4°, 17.4°, 18.6°, 19.6°, 20.8°, 22.2°, 22.7°, 24.2°, 25.0°, 25.7°, and 26.5° in an X-ray powder diffraction pattern obtained by using Cu-Kα radiation and represented by a diffraction angle 2θ, wherein the error range of 2θ is ±0.2°; Preferably, the crystalline form of itraconazole has an X-ray powder diffraction pattern represented by a diffraction angle 2θ obtained by using Cu-Kα radiation, and the diffraction angle 2θ has characteristic peaks at 5.9°, 8.1°, 8.8°, 9.2°, 11.0°, 16.0°, 16.4°, 17.4°, 18.6°, 19.6°, 20.8°, 22.2°, 22.7°, 24.2°, 25.0°, 25.7°, 26.5°, 29.8°, 30.5°, and 31.6°, wherein the error range of 2θ is ±0.2°.

4. The crystalline form according to any one of claims 1 to 3, characterized in that: The crystalline form of itraconazole, using Cu-Kα radiation to obtain an X-ray powder diffraction pattern represented by a diffraction angle 2θ, the diffraction angle 2θ and the relative intensity of the corresponding peak are shown in the following table, wherein the error range of 2θ is ±0.2°: ； Preferably, the itraconazole crystalline form has an X-ray powder diffraction pattern represented by a diffraction angle 2θ obtained by using Cu-Kα radiation as shown in FIG. 1 .

5. The crystalline form according to any one of claims 1 to 4, characterized in that: The differential scanning calorimetry analysis diagram of the itraconazole crystal form has endothermic peaks at 100.8±3°C and 168.4±3°C; Preferably, the differential scanning calorimetry analysis diagram of the itraconazole crystal form is substantially as shown in FIG2 .

6. A method for preparing the crystal form according to any one of claims 1 to 5, characterized in that The method comprises the following steps: 1) dissolving itraconazole in an organic solvent (X); 2) cooling and adding organic solvent (b) dropwise; 3) Cooling down to the crystal growing temperature and keeping the temperature to grow the crystal; Preferably, the organic solvent (X) consists of an organic solvent (a) and an organic solvent (b); The organic solvent (a) is dichloromethane; The organic solvent (b) is selected from at least one of methanol and ethanol; Preferably, in the organic solvent (X), the volume ratio between the organic solvent (b) and the organic solvent (a) is 1:2-5.

7. The preparation method according to claim 6, characterized in that: In step 1), the mass volume ratio of the itraconazole to the organic solvent (X) is 1:3 to 1:6; Preferably, in step 2), the temperature is lowered to 0-5°C; Preferably, in step 2), the amount of the organic solvent (b) added is 3 to 7 times the volume of the organic solvent (a) in step 1); Preferably, in step 3), the temperature is lowered by 1 to 5°C per minute; Preferably, in step 3), the crystal growing temperature is -10 to -5°C; Preferably, in step 3), the crystal growing time is 0.5 to 10 hours.

8. The preparation method according to claim 6 or 7, characterized in that: The method further comprises step 4) after the crystal growing is completed, filtering, washing, and vacuum drying; Preferably, in step 4), the solvent used for washing is an organic solvent (b); Preferably, in step 4), the drying temperature is 40-60°C.

9. An itraconazole composition, characterized in that: The composition comprises the itraconazole crystal form according to any one of claims 1 to 5 and optionally a pharmaceutically acceptable excipient; Preferably, the composition is an inhalation formulation.

10. Use of the itraconazole crystal form according to any one of claims 1 to 5 or the itraconazole composition according to claim 9 in the preparation of a method for preventing and / or treating lung or respiratory diseases; Preferably, the lung or respiratory disease is pulmonary fibrosis.

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