Crystal form of dexamethasone sodium phosphate as well as preparation method and application of crystal form

Abstract

The invention relates to the field of medicines, in particular to a crystal form of dexamethasone sodium phosphate as well as a preparation method and application thereof. The crystal form provided by the invention is different from the existing known dexamethasone sodium phosphate crystal form, has distinct outlines, can be perfectly reproduced, shows good characteristics in the aspects of placing stability and solution clarity of subsequent finished products, and has wide application prospects in pharmaceutical development of dexamethasone sodium phosphate. The preparation method provided by the invention is simple and easy to operate, stable in process, green, environment-friendly and low in production cost, solves the problems of stability and dissolution clarity of the dexamethasone sodium phosphate, is suitable for industrial production of the dexamethasone sodium phosphate, improves the production efficiency and is beneficial to technical popularization.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to the crystal form of dexamethasone sodium phosphate, its preparation method, and its application. Background Technology

[0002] The chemical name of dexamethasone sodium phosphate is: 9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregn-1,4-diene-3,20-dione-21-phosphate disodium salt; its molecular formula is: C 22 H 28 FNa₂O₈P; its molecular weight is 516.41; its chemical structural formula is as follows:

[0003]

[0004] Dexamethasone sodium phosphate is a glucocorticoid drug primarily used for anti-inflammatory, anti-allergic, and immunosuppressive purposes. Currently, this drug is mainly used in formulation form, but poor solubility and decreased purity are common problems during formulation. Existing preparation methods generally suffer from residual insoluble substances in the solution and poor drug stability. For example, patent CN1318442 C discloses a method involving reaction with an alcohol solvent, followed by crystallization using water and other solvents to obtain a corresponding crystal form, which is named Crystal Form A in this patent. Subsequent investigations revealed that this crystal form also has issues with stability and solution clarity. Currently, no effective crystallization method has been developed to address these problems and resolve the stability and solubility issues of dexamethasone sodium phosphate. Therefore, there is an urgent need to develop a green, environmentally friendly, and low-cost crystallization method to improve the stability and solubility of the finished dexamethasone sodium phosphate product.

[0005] In view of this, the present invention is hereby proposed. Summary of the Invention

[0006] This invention provides a novel crystal form of dexamethasone sodium phosphate, its preparation method, and its applications. Details are as follows:

[0007] In a first aspect, the present invention provides a crystal form of dexamethasone sodium phosphate, said crystal form comprising at least one of the following crystal forms:

[0008] Crystal form B, wherein the X-ray powder diffraction pattern of crystal form B, expressed in terms of diffraction angles of 2θ ± 0.1°, shows characteristic diffraction peaks at least at 4.01, 4.27, 9.02, 9.74, 12.08, 16.22 and 16.75.

[0009] Crystal form C, wherein the X-ray powder diffraction pattern of crystal form C, expressed in terms of diffraction angles of 2θ ± 0.1°, shows characteristic diffraction peaks at at least 12.47, 13.57, 14.36, 15.00, 16.12 and 17.69.

[0010] Crystal form D, wherein the X-ray powder diffraction pattern of crystal form D, expressed in terms of diffraction angles of 2θ ± 0.1°, shows characteristic diffraction peaks at least at 4.59, 4.93, 10.52, 12.45, 12.83, 14.81, 17.61 and 20.72.

[0011] Crystal form E, wherein the X-ray powder diffraction pattern of crystal form E, expressed in terms of diffraction angles of 2θ ± 0.1°, shows characteristic diffraction peaks at at least 3.99, 4.38, 5.84, 9.01, 12.06, and 16.74.

[0012] Preferably,

[0013] The XRPD pattern of crystal form B is basically as follows: Figure 1 As shown;

[0014] The XRPD pattern of crystal form C is basically as follows Figure 2 As shown;

[0015] The XRPD pattern of crystal form D is basically as follows: Figure 3 As shown;

[0016] The XRPD pattern of crystal form E is basically as follows: Figure 4 As shown.

[0017] The dexamethasone sodium phosphate crystal form BE provided by this invention has a distinct outline and exhibits good properties in terms of solution clarity and stability, and has broad application prospects in the drug development of dexamethasone sodium phosphate.

[0018] Secondly, the present invention provides a method for preparing the crystal form of the aforementioned dexamethasone sodium phosphate, comprising the following steps:

[0019] (1) Dissolve dexamethasone phosphate in n-butanol, methanol or tetrahydrofuran;

[0020] (2) Add sodium hydroxide to the liquid to carry out the reaction;

[0021] (3) Add methyl ketone, acetonitrile or acetone to the reaction solution to crystallize and obtain the precipitate.

[0022] Preferably, between steps (1) and (2), the following steps are also included: adding medicinal charcoal to the liquid, heating to 35-45°C, and stirring for 1 ± 0.5 h.

[0023] Preferably, the pH value of the reaction solution is 8.5 to 11.0 when the reaction is carried out in step (2).

[0024] More preferably, step (2) includes: controlling the temperature of the liquid to 10-20°C and slowly and uniformly adding sodium hydroxide solution; after the addition is completed, stirring for 30±5 min, and the pH of the reaction solution is 8.5-11.0.

[0025] Preferably, step (3) includes: keeping the reacted liquid at a temperature of 10-20°C, adding methyl ketone, acetonitrile or acetone, and crystallizing; centrifuging at a speed of 1800±200 r / min and drying to obtain sodium dexamethasone phosphate.

[0026] In one more specific alternative embodiment, the method for preparing a new crystal form of dexamethasone sodium phosphate provided by the present invention comprises the following steps:

[0027] Dexamethasone phosphate was used as the starting material. It was dissolved in methanol and then decolorized and dissolved with activated charcoal. The molar ratio of dexamethasone phosphate, methanol and activated charcoal was 1:(110-130):(1-3). The temperature was set to 30-40℃. After filtration, sodium hydroxide solution was added to the filtrate, the temperature was lowered to 10-20℃, and the pH was adjusted to 8.0-11. Crystallization was carried out under different solvent combinations, and the dexamethasone sodium phosphate was obtained by centrifugation.

[0028] Preferably, the molar ratio of dexamethasone phosphate, methanol, and pharmaceutical charcoal is 1:110:1.7.

[0029] Preferably, the decolorization temperature is 35°C.

[0030] Preferably, the sodium hydroxide solution concentration is 10%.

[0031] Preferably, the temperature at which sodium hydroxide solution is added to the filtrate and then cooled is 15°C.

[0032] Preferably, sodium hydroxide solution is added to the filtrate, and the temperature is lowered to adjust the pH to 10.

[0033] Preferably, the crystallization temperature is 10–20°C, and most preferably 10–15°C.

[0034] Preferably, the sodium hydroxide solution is added at a rate of 5–10 L / h.

[0035] Preferably, the centrifugation speed is 800–1800 r / min, more preferably 1800 ± 200 r / min.

[0036] The preparation method provided by this invention is simple and easy to operate, with stable process, green and environmentally friendly, and low production cost. It greatly improves the solubility and clarity of dexamethasone sodium phosphate, solves the stability problem of dexamethasone sodium phosphate, is suitable for industrial production of dexamethasone sodium phosphate, reduces secondary purification time, improves production efficiency, and is conducive to technology promotion.

[0037] Thirdly, the present invention provides a pharmaceutical composition containing a therapeutically effective amount of the crystal form or the crystal form obtained by the preparation method, and further comprising pharmaceutically acceptable excipients.

[0038] Preferably, the pharmaceutically acceptable excipients include at least one of a carrier, a diluent, and an excipient. For example, when the composition is a lyophilized powder, the pharmaceutically acceptable carrier may be an excipient; when the composition is a tablet, the pharmaceutically acceptable carrier may be a disintegrant, an excipient, etc.

[0039] This invention compares the previously described dexamethasone sodium phosphate crystal form with the dexamethasone sodium phosphate disclosed in the prior art in pharmacodynamic tests, finding that their efficacy is comparable with no significant difference. Since the dexamethasone sodium phosphate crystal form obtained in this invention exhibits excellent stability and solution clarity in the subsequent finished product, those skilled in the art can foresee that, after being prepared into various pharmaceutical formulations, it will further improve the clarity and stability of the pharmaceutical formulations, thus providing an advantage in drug development. The specific dosage form and its formulation are determined by those skilled in the art.

[0040] Fourthly, the present invention provides the crystal form, or the crystal form obtained by the preparation method, or the use of the pharmaceutical composition in the preparation of anti-inflammatory, anti-allergic, or immunosuppressive drugs.

[0041] Beneficial effects:

[0042] This invention provides a novel crystal form of dexamethasone sodium phosphate, along with a corresponding preparation method and applications. The crystal form provided by this invention differs from existing known crystal forms of dexamethasone sodium phosphate, each possessing a distinct outline that is perfectly reproducible. Furthermore, the samples exhibit excellent stability and solution clarity in subsequent product storage, demonstrating broad application prospects in the drug development of dexamethasone sodium phosphate. The preparation method provided by this invention is simple and easy to implement, with stable, environmentally friendly, and low-cost processes. It solves the dissolution problem of dexamethasone sodium phosphate, making it suitable for industrial production, improving production efficiency, and facilitating technology promotion. Attached Figure Description

[0043] Figure 1 This is an X-ray powder diffraction pattern of sodium dexamethasone phosphate crystal form B according to the present invention.

[0044] Figure 2 This is an X-ray powder diffraction pattern of dexamethasone sodium phosphate crystal form C according to the present invention.

[0045] Figure 3 This is an X-ray powder diffraction pattern of dexamethasone sodium phosphate crystal form D according to the present invention.

[0046] Figure 4This is an X-ray powder diffraction pattern of dexamethasone sodium phosphate crystal form E according to the present invention.

[0047] Figure 5 The image shows the X-ray powder diffraction pattern of sodium dexamethasone phosphate crystal form A (disclosed in patent CN 1318442C) of Comparative Example 2 of this invention.

[0048] Figure 6 X-ray powder diffraction pattern of amorphous crystal form F of sodium dexamethasone phosphate, Comparative Example 1 of this invention. Detailed Implementation

[0049] Dexamethasone sodium phosphate is a corticosteroid drug, and its solubility and crystal form directly affect its bioavailability and stability. While there are various methods for preparing dexamethasone sodium phosphate, research on its crystal forms is limited. To address the issues of solubility and sample stability of dexamethasone sodium phosphate, this invention utilizes different solvent combinations to prepare various novel crystal forms, effectively improving its stability while being environmentally friendly and increasing production efficiency.

[0050] This invention provides detailed preparation methods for preparing various new crystal forms by different solvent combinations.

[0051] As examples, here are some specific implementation methods:

[0052] 3.8 g of 0.0086 mol dexamethasone phosphate, 30.2 g of 0.94 mol methanol, and 172 mg of 0.0146 mmol pharmaceutical charcoal were added to a flask and heated to 35–40 °C, stirring for 1 hour. The mixture was filtered, and the temperature was maintained at 10–20 °C while sodium hydroxide solution was slowly and uniformly added dropwise. After the addition was complete, the mixture was stirred for 30 minutes until the pH of the reaction solution reached 8.5–11.0. The solution was kept at 10–20 °C, and 105 mL of methyl ketone solution was added with stirring to induce crystallization. The crystals were centrifuged at 1800 rpm and dried to obtain 3.96 g of sodium dexamethasone phosphate. PXRD results showed that the product was in crystal form B.

[0053] 3.8 g of 0.0086 mol dexamethasone phosphate, 30.2 g of 0.94 mol methanol, and 172 mg of 0.0146 mmol pharmaceutical charcoal were added to a flask and heated to 35–40 °C, stirring for 1 hour. The mixture was filtered, and the temperature was maintained at 10–20 °C while sodium hydroxide solution was slowly and uniformly added dropwise. After the addition was complete, the mixture was stirred for 30 minutes until the pH of the reaction solution reached 8.5–11.0. The solution was kept at 10–20 °C, and 105 mL of acetonitrile solution was added with stirring to induce crystallization. The crystals were centrifuged at 1800 rpm and dried to obtain 3.86 g of sodium dexamethasone phosphate. PXRD results showed that the product was in crystalline form C.

[0054] 3.8 g of 0.0086 mol dexamethasone phosphate, 67.95 g of 0.94 mol tetrahydrofuran, and 172 mg of 0.0146 mmol pharmaceutical charcoal were added to a flask and heated to 35–40 °C, stirring for 1 hour. The mixture was filtered, and the temperature was maintained at 10–20 °C while sodium hydroxide solution was slowly and uniformly added dropwise. After the addition was complete, the mixture was stirred for 30 minutes, and the pH of the reaction solution was 8.5–11.0. The solution was kept at 10–20 °C, and 105 mL of acetone solution was added with stirring to induce crystallization. The crystals were centrifuged at 1800 rpm and dried to obtain 3.86 g of sodium dexamethasone phosphate. PXRD results showed that the product was crystal form D.

[0055] 3.8 g of 0.0086 mol dexamethasone phosphate, 69.8 g of 0.94 mol n-butanol, and 172 mg of 0.0146 mmol pharmaceutical charcoal were added to a flask and heated to 35–40 °C, stirring for 1 hour. The mixture was filtered, and the temperature was maintained at 10–20 °C while sodium hydroxide solution was slowly and uniformly added dropwise. After the addition was complete, the mixture was stirred for 30 minutes, and the pH of the reaction solution was adjusted to 8.5–11.0. The solution was kept at 10–20 °C, and 105 mL of acetone solution was added with stirring to induce crystallization. The crystals were centrifuged at 1800 rpm and dried to obtain 3.86 g of sodium dexamethasone phosphate. PXRD results showed that the product was in crystal form E.

[0056] The method for preparing a new crystal form of dexamethasone sodium phosphate disclosed in this invention uses dexamethasone phosphate ester as raw material, and obtains dexamethasone sodium phosphate through decolorization, filtration, salt formation, and crystallization. By changing the reaction solvent and the crystallization solvent, a new crystal form of dexamethasone sodium phosphate can be obtained, which significantly improves the problems of poor stability and poor solubility of the original crystal form, reduces the cost of subsequent secondary purification, and is environmentally friendly.

[0057] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0058] The endpoints and any values ​​of the ranges disclosed in this specification are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0059] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "specific implementation," or "some specific implementations," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0060] In the embodiments provided in this specification, unless specific techniques or conditions are specified, the techniques or conditions described in the literature in this field, or the product instructions, shall be followed. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased from legitimate channels.

[0061] Example 1

[0062] This embodiment provides dexamethasone sodium phosphate crystal form B and the corresponding preparation method, and also tests the characteristics and subsequent storage stability of the obtained product.

[0063] The preparation method for crystal form B is as follows:

[0064] 3.8 g of 0.0086 mol dexamethasone phosphate, 30.2 g of 0.94 mol methanol, and 172 mg of 0.0146 mmol pharmaceutical charcoal were added to a flask and heated to 35–40 °C, stirring for 1 hour. The mixture was filtered, and the temperature was maintained at 10–20 °C while sodium hydroxide solution was slowly and uniformly added dropwise. After the addition was complete, the mixture was stirred for 30 minutes until the pH of the reaction solution reached 8.5–11.0. The solution was kept at 10–20 °C, and 105 mL of methyl ketone solution was added with stirring to induce crystallization. The solution was centrifuged at 1800 rpm and dried to obtain 3.96 g of dexamethasone sodium phosphate.

[0065] Example 2

[0066] This embodiment provides dexamethasone sodium phosphate crystal form C and the corresponding preparation method, and also tests the characteristics of the obtained product.

[0067] The preparation method for crystal form C is as follows:

[0068] 3.8 g of 0.0086 mol dexamethasone phosphate, 30.2 g of 0.94 mol methanol, and 172 mg of 0.0146 mmol pharmaceutical charcoal were added to a flask and heated to 35–40 °C, stirring for 1 hour. The mixture was filtered, and the temperature was maintained at 10–20 °C while sodium hydroxide solution was slowly and uniformly added dropwise. After the addition was complete, the mixture was stirred for 30 minutes until the pH of the reaction solution reached 8.5–11.0. The solution was kept at 10–20 °C, and 105 mL of acetonitrile solution was added with stirring to induce crystallization. The solution was centrifuged at 1800 rpm and dried to obtain 3.86 g of dexamethasone sodium phosphate.

[0069] Example 3

[0070] This embodiment provides dexamethasone sodium phosphate crystal form D, along with the corresponding preparation method, and also tests the characteristics of the obtained product.

[0071] The preparation method for crystal form D is as follows:

[0072] 3.8 g of 0.0086 mol dexamethasone phosphate, 67.95 g of 0.94 mol tetrahydrofuran, and 172 mg of 0.0146 mmol pharmaceutical-grade charcoal were added to a flask and heated to 35–40 °C, stirring for 1 hour. The mixture was filtered, and the temperature was maintained at 10–20 °C while sodium hydroxide solution was slowly and uniformly added dropwise. After the addition was complete, the mixture was stirred for 30 minutes until the pH of the reaction solution reached 8.5–11.0. The solution was kept at 10–20 °C, and 105 mL of acetone solution was added with stirring to induce crystallization. The crystals were centrifuged at 1800 rpm and dried to obtain 3.86 g of dexamethasone sodium phosphate.

[0073] Example 4

[0074] This embodiment provides dexamethasone sodium phosphate crystal form E, along with the corresponding preparation method, and also tests the characteristics of the obtained product.

[0075] The preparation method for crystal form E is as follows:

[0076] 3.8 g of 0.0086 mol dexamethasone phosphate, 69.8 g of 0.94 mol n-butanol, and 172 mg of 0.0146 mmol pharmaceutical charcoal were added to a flask and heated to 35–40 °C, stirring for 1 hour. The mixture was filtered, and the temperature was maintained at 10–20 °C while sodium hydroxide solution was slowly and uniformly added dropwise. After the addition was complete, the mixture was stirred for 30 minutes until the pH of the reaction solution reached 8.5–11.0. The solution was kept at 10–20 °C, and 105 mL of acetone solution was added with stirring to induce crystallization. The crystals were centrifuged at 1800 rpm and dried to obtain 3.86 g of dexamethasone sodium phosphate.

[0077] Comparative Example 1

[0078] This comparative example provides the amorphous crystal form F of dexamethasone sodium phosphate and the corresponding preparation method, and also tests the characteristics of the obtained product.

[0079] The preparation method of amorphous crystal form F is as follows:

[0080] 3.8 g of 0.0086 mol dexamethasone phosphate, 69.8 g of 0.94 mol n-butanol, and 172 mg of 0.0146 mmol pharmaceutical charcoal were added to a flask and heated to 35–40 °C, stirring for 1 hour. The mixture was filtered, and the temperature was maintained at 10–20 °C while sodium hydroxide solution was slowly and uniformly added dropwise. After the addition was complete, the mixture was stirred for 30 minutes until the pH of the reaction solution reached 8.5–11.0. The solution was kept at 10–20 °C, and 105 mL of methyl ketone solution was added with stirring to induce crystallization. The crystals were centrifuged at 1800 rpm and dried to obtain 3.82 g of dexamethasone sodium phosphate.

[0081] Amorphous crystal form F, such as Figure 6 As shown, the X-ray powder diffraction pattern expressed in terms of diffraction angles of 2θ±0.1° shows characteristic diffraction peaks at least at 3.64, 3.92, 10.17, 14.83, 16.00 and 22.18.

[0082] Comparative Example 2

[0083] The method for preparing crystal form A of dexamethasone sodium phosphate provided in this comparative example is as follows:

[0084] 3.8 g of 0.0086 mol dexamethasone phosphate, 69.8 g of 0.94 mol methanol, and 172 mg of 0.0146 mmol pharmaceutical charcoal were added to a flask and heated to 35–40 °C, stirring for 1 hour. The mixture was filtered, and the temperature was maintained at 10–20 °C while sodium hydroxide solution was slowly and uniformly added dropwise. After the addition was complete, the mixture was stirred for 30 minutes until the pH of the reaction solution reached 8.5–11.0. The solution was kept at 10–20 °C, and 105 mL of a mixture of acetone and water was added and stirred to induce crystallization. The solution was centrifuged at 1800 rpm and dried to obtain 3.86 g of dexamethasone sodium phosphate.

[0085] Comparative Example 2 Crystal Form A Figure 5 As shown, the X-ray powder diffraction (XRPD) pattern, expressed as a diffraction angle of 2θ ± 0.1°, exhibits characteristic diffraction peaks at least at 4.44, 4.68, 12.02, 12.29, 14.05, 14.53, and 16.83.

[0086] Experimental Example 1

[0087] In this experiment, the finished products obtained from Examples 1-4 and Comparative Examples 1-2 were used to determine the stability of each finished product over six months and nine months.

[0088] The measurement results are shown in Table 1 below.

[0089] Table 1: HPLC results of finished product stability

[0090]

[0091] The above results indicate that the purity and stability of the new crystalline form BE obtained in the patent are significantly better, with no significant increase in the maximum single impurity after six and nine months of storage. In contrast, the amorphous crystalline forms F and A in Comparative Examples 1 and 2 are less stable, with single impurities approaching the limit after nine months of storage. This suggests that under the same storage conditions, crystalline form BE is more stable. The discovery and proof of the new crystalline form provides favorable support for extending the shelf life of dexamethasone sodium phosphate raw material.

[0092] Experiment Example 2

[0093] The solubility of dexamethasone sodium phosphate was tested using the general rules method of the 2025 edition of the Chinese Pharmacopoeia, and the results are as follows:

[0094]

[0095]

[0096] As shown in Experimental Example 2, the clarity of the solution containing the BE crystalline form mentioned in the patent was significantly improved. Furthermore, no insoluble matter precipitated after prolonged standing. Considering that a large proportion of dexamethasone sodium phosphate dosage forms are injectable, the discovery and verification of this new crystalline form provides a better option for assessing the stability of blank dexamethasone sodium phosphate solutions.

[0097] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. The crystal form of dexamethasone sodium phosphate, characterized in that, The crystal form of the dexamethasone sodium phosphate includes at least one of the following crystal forms: Crystal form B, wherein the X-ray powder diffraction pattern of crystal form B, expressed in terms of diffraction angles of 2θ ± 0.1°, shows characteristic diffraction peaks at least at 4.01, 4.27, 9.02, 9.74, 12.08, 16.22 and 16.

75. Crystal form C, wherein the X-ray powder diffraction pattern of crystal form C, expressed in terms of diffraction angles of 2θ ± 0.1°, shows characteristic diffraction peaks at at least 12.47, 13.57, 14.36, 15.00, 16.12 and 17.

69. Crystal form D, wherein the X-ray powder diffraction pattern of crystal form D, expressed in terms of diffraction angles of 2θ ± 0.1°, shows characteristic diffraction peaks at least at 4.59, 4.93, 10.52, 12.45, 12.83, 14.81, 17.61 and 20.

72. Crystal form E, wherein the X-ray powder diffraction pattern of crystal form E, expressed in terms of diffraction angles of 2θ ± 0.1°, shows characteristic diffraction peaks at at least 3.99, 4.38, 5.84, 9.01, 12.06, and 16.

74.

2. The crystal form of dexamethasone sodium phosphate according to claim 1, characterized in that, The XRPD pattern of crystal form B is basically shown in Figure 1; The XRPD pattern of crystal form C is basically shown in Figure 2; The XRPD pattern of crystal form D is basically shown in Figure 3; The XRPD pattern of crystal form E is shown in Figure 4.

3. The method for preparing the crystal form of dexamethasone sodium phosphate according to claim 1 or 2, characterized in that, The process includes the following steps: (1) dissolving dexamethasone phosphate in n-butanol, methanol or tetrahydrofuran; (2) adding sodium hydroxide to the solution and reacting; (3) adding methyl ketone, acetonitrile or acetone to the solution after reaction and crystallizing to obtain the precipitate.

4. The method for preparing the crystal form of dexamethasone sodium phosphate according to claim 3, characterized in that, Between steps (1) and (2), the following steps are also included: adding medicinal charcoal to the liquid, heating to 35-45°C, and stirring for 1 ± 0.5 h.

5. The method for preparing the crystal form of dexamethasone sodium phosphate according to claim 3 or 4, characterized in that, When the reaction is carried out in step (2), the pH value of the reaction solution is 8.5 to 11.

0.

6. The method for preparing the crystal form of dexamethasone sodium phosphate according to any one of claims 3-5, characterized in that, Step (2) includes: controlling the temperature of the liquid to 10-20℃ and slowly and uniformly adding sodium hydroxide solution; after the addition is completed, stirring for 30±5 minutes, and the pH of the reaction solution is 8.5-11.

0.

7. The method for preparing the crystal form of dexamethasone sodium phosphate according to any one of claims 3-6, characterized in that, Step (3) includes: keeping the reaction solution at 10-20°C, adding methyl ketone, acetonitrile or acetone, and crystallizing; centrifuging at 1800±200 r / min and drying to obtain dexamethasone sodium phosphate.

8. A pharmaceutical composition, characterized in that, The crystal form containing a therapeutically effective amount of the crystal form according to claim 1 or 2 or the crystal form prepared by any one of claims 3-7, further includes pharmaceutically acceptable excipients.

9. The use of the crystal form according to claim 1 or 2, or the crystal form obtained by the preparation method according to any one of claims 3-7, or the use of the pharmaceutical composition according to claim 8 in the preparation of anti-inflammatory, anti-allergic or immunosuppressive drugs.

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