Prednisolone dihydrate and its preparation method and application

Abstract

The present invention provides a prednisolone dihydrate and a preparation method and application thereof, and relates to the field of medical technology. The X-ray powder diffraction of prednisolone dihydrate has characteristic peaks at diffraction angles 2θ=7.2°±0.2°, 12.5°±0.2°, 14.2°±0.2°, 15.5°±0.2°, and 16.2°±0.2°. The present invention provides a brand-new prednisolone dihydrate, which can be dehydrated and converted into crystal form I at a relatively low temperature. Compared with the existing preparation of crystal form I from sesquihydrate, the time required is greatly shortened from more than 24 hours to less than 5 hours. This method overcomes the shortcomings of high baking temperature, long cycle, and yellowing and deterioration of products, and can meet the requirements of industrial production.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to prednisolone dihydrate and a preparation method and application thereof. Background Art

[0002] Prednisolone, English name: Prednisolone, is a commonly used adrenal cortex hormone, mainly used for allergic and autoimmune inflammatory diseases, collagen diseases, such as rheumatism, rheumatoid arthritis, lupus erythematosus, severe bronchial asthma, nephrotic syndrome, thrombocytopenic purpura, granulocytopenia, acute lymphocytic leukemia, various adrenal cortex insufficiency, exfoliative dermatitis, pemphigus, neurodermatitis, eczema, etc. Its structural formula is as follows:

[0003]

[0004] Prednisolone has three crystal forms, namely, Form I, Form II and hydrate, of which the hydrate is a sesquihydrate (1.5H2O). The crystal morphology of Form I and Form II is similar, but the crystal appearance of Form I is thinner than that of Form II in most cases, and the sesquihydrate crystallizes into very thin plate-like needle-shaped crystals. The main difference between Form I and Form II is the different ways in which hydrogen bonds are formed. In Form I, the molecules are connected in layers, while in Form II there are double chains bonded by hydrogen bonds, which are connected into a three-dimensional network through weak CH···O interactions. Form I has better solubility than Form II, and solubility is one of the key factors determining drug dissolution, and is more suitable for application in the pharmaceutical field. The current process for preparing Form I is to remove the crystal water from the hydrate to prepare it.

[0005] The preparation method of prednisolone hydrate is as follows:

[0006] The methods of US Patent US3062712 and German Patent GB836747A are the same. The specific process is as follows: dissolving anhydrous prednisolone in methanol containing water, clearing the solution, filtering to remove insoluble matter, cooling, precipitating crystals, and drying to obtain prednisolone hydrate.

[0007] The document Structural, Thermodynamic, and Kinetic Aspects of the Polymorphism and Pseudopolymorphism of Prednisolone discloses that a hydrate is obtained by slow evaporation in a solvent of acetonitrile / water = 90:10.

[0008] Patent CN105566425A and Patent CN102079768A disclose that crude prednisolone is dissolved in a mixture of an organic solvent and water in a certain proportion, and then cooled and crystallized to obtain high-purity prednisolone.

[0009] Patent CN104640406A discloses using a mixture of dichloromethane, methanol and water as a refining solvent, adding Girardt's reagent T, glacial acetic acid and prednisolone to the refining solvent, refluxing to dissolve, and then dripping water into the system at a certain speed at an appropriate temperature. During the dripping process, prednisolone is slowly precipitated to obtain refined prednisolone.

[0010] CN101891789A discloses that prednisolone is used as a raw material, acetone: water = 7:3 mixed solvent 15 times, dissolved at 15-20°C for 5-10 minutes, after dissolving, diluted with 80-100 times water, filtered, dried at 90-100°C, and the moisture content is controlled to below 7% to obtain prednisolone hydrate.

[0011] The prednisolone hydrates prepared by the above methods are all sesquihydrates, and the preparation method is single, and there are disadvantages such as long crystallization time and low yield. For example, the prednisolone hydrates prepared in patent US3062712 and patent GB836747A take up to 16 hours, and the yield is only 84.9%.

[0012] However, when using the existing sesquihydrate to prepare the crystal form I, it is necessary to heat at 120-130°C for more than 24 hours to obtain the crystal form I. The dehydration temperature of sesquihydrate is high, the energy consumption is large, and the product is easy to turn yellow and deteriorate, so it is difficult to achieve industrial production.

[0013] In view of this, the present invention is proposed. Summary of the invention

[0014] The main purpose of the present invention is to provide a prednisolone dihydrate and a preparation method and application thereof, in order to at least partially solve at least one of the above technical problems.

[0015] As a first aspect of the present invention, the present invention provides a prednisolone dihydrate, the structural formula of which is as follows:

[0016]

[0017] The invention provides a new prednisolone dihydrate, which can be dehydrated and converted into crystal form I at a relatively low temperature. Compared with the existing preparation of crystal form I from sesquihydrate, the time required is greatly shortened from more than 24 hours to less than 5 hours. The method overcomes the disadvantages of high baking temperature, long cycle, and yellowing and deterioration of the product, and can meet the requirements of industrial production.

[0018] Furthermore, its X-ray powder diffraction has characteristic peaks at diffraction angles of 2θ=7.2°±0.2°, 12.5°±0.2°, 14.2°±0.2°, 15.5°±0.2°, and 16.2°±0.2°.

[0019] Furthermore, its X-ray powder diffraction has characteristic peaks at diffraction angles of 2θ=5.0°±0.2°, 7.2°±0.2°, 7.9°±0.2°, 10.5°±0.2°, 12.5°±0.2°, 14.2°±0.2°, 15.5°±0.2°, 15.8°±0.2°, 16.2°±0.2°, 17.5°±0.2°, 17.8°±0.2°, 18.8°±0.2°, and 19.2°±0.2°.

[0020] It should be noted that the diffraction intensity of the characteristic peak of X-ray powder diffraction may vary slightly with the crystal preparation technology, sample installation method and measuring instrument, which should also be within the scope of protection of the present invention. In addition, the difference in instruments and other factors may affect the diffraction 2θ value, so the diffraction angle 2θ value of the above-mentioned characteristic peak can vary within the existing value ±0.2°.

[0021] As a second aspect of the present invention, the present invention provides a method for preparing prednisolone dihydrate, comprising the following steps: dissolving prednisolone in a mixed solvent, and after the solution is clarified, adding water for crystallization to obtain prednisolone dihydrate;

[0022] Wherein, the mixed solvent is selected from a mixed solvent of solvent I, solvent II and water; the solvent I is selected from one or more of methanol, ethanol or isopropanol; the solvent II is selected from one or more of dichloromethane, chloroform, acetone or ethyl acetate.

[0023] The preparation method of prednisolone dihydrate provided by the present invention has a simple process and is easy to operate. The solvents used are all conventional industrial reagents, and specific solvents and proportions are preferably selected, which is very conducive to the industrialization of prednisolone dihydrate. In addition, compared with the methods in patent US3062712 and patent GB836747A, the time required is greatly shortened from the original 16 hours to within 5 hours, and the yield is significantly improved.

[0024] Furthermore, the solvent I is selected from methanol and / or ethanol; the solvent II is selected from dichloromethane and / or acetone.

[0025] Further, water is added for crystallization, and the temperature is lowered to 0-10° C. at a rate of 20-30° C. / h to obtain prednisolone dihydrate.

[0026] In the present invention, a typical but non-limiting cooling rate during the crystallization process may be, for example, 20°C / h, 21°C / h, 22°C / h, 23°C / h, 24°C / h, 25°C / h, 26°C / h, 27°C / h, 28°C / h, 29°C / h or 30°C / h; a typical but non-limiting temperature during the crystallization process may be, for example, 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C or 10°C.

[0027] Furthermore, the mass volume ratio of the prednisolone to the solvent I is 1: (2-10) g / mL; the mass volume ratio of the prednisolone to the solvent II is 1: (0.6-2) g / mL; the mass volume ratio of the prednisolone to the water in the mixed solvent is 1: (0.6-2) g / mL; the mass volume ratio of the prednisolone to the water used for crystallization is 1: (1-10) g / mL.

[0028] In the present invention, a typical but non-limiting mass volume ratio of prednisolone to solvent I may be, for example, 1:2 g / mL, 1:3 g / mL, 1:4 g / mL, 1:5 g / mL, 1:6 g / mL, 1:7 g / mL, 1:8 g / mL, 1:9 g / mL or 1:10 g / mL; a typical but non-limiting mass volume ratio of prednisolone to solvent II may be, for example, 1:0.6 g / mL, 1:0.8 g / mL, 1:1 g / mL, 1:1.2 g / mL, 1:1.4 g / mL, 1:1.6 g / mL, 1:1.8 g / mL or 1:2 g / mL. L; a typical but non-limiting mass volume ratio of prednisolone to water in the mixed solvent can be, for example, 1:0.6 g / mL, 1:0.8 g / mL, 1:1 g / mL, 1:1.2 g / mL, 1:1.4 g / mL, 1:1.6 g / mL, 1:1.8 g / mL or 1:2 g / mL; the mass volume ratio of prednisolone to water used for crystallization is 1:1 g / mL, 1:2 g / mL, 1:3 g / mL, 1:4 g / mL, 1:5 g / mL, 1:6 g / mL, 1:7 g / mL, 1:8 g / mL, 1:9 g / mL or 1:10 g / mL.

[0029] Furthermore, the mass volume ratio of the prednisolone to the solvent I is 1: (3-8) g / mL; the mass volume ratio of the prednisolone to the solvent II is 1: (1-2) g / mL; the mass volume ratio of the prednisolone to the water in the mixed solvent is 1: (0.6-1) g / mL; the mass volume ratio of the prednisolone to the water used for crystallization is 1: (6-10) g / mL.

[0030] As a third aspect of the present invention, use of the prednisolone dihydrate provided by the present invention or the prednisolone dihydrate prepared by the preparation method provided by the present invention in preparing prednisolone crystal form I.

[0031] Furthermore, prednisolone dihydrate is heated to remove crystal water to obtain prednisolone crystal form I.

[0032] Further, the method comprises the following steps: heating prednisolone dihydrate at 70-80° C. to remove crystal water, thereby obtaining prednisolone crystal form I.

[0033] In the present invention, a typical but non-limiting temperature for removing crystal water may be, for example, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, 79°C or 80°C.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] The invention provides a new prednisolone dihydrate, which can be dehydrated and converted into crystal form I at a relatively low temperature. Compared with the existing preparation of crystal form I from sesquihydrate, the time required is greatly shortened from more than 24 hours to less than 5 hours. The method overcomes the disadvantages of high baking temperature, long cycle, and yellowing and deterioration of the product, and can meet the requirements of industrial production.

[0036] The preparation method of prednisolone dihydrate provided by the present invention has a simple process and is easy to operate. The solvents used are all conventional industrial reagents, and specific solvents and proportions are preferably selected, which is very conducive to the industrialization of prednisolone dihydrate. In addition, compared with the methods in patent US3062712 and patent GB836747A, the time required is greatly shortened from the original 16 hours to within 5 hours, and the yield is significantly improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0038] Figure 1 This is the TG-DTA analysis chart of prednisolone dihydrate obtained in Example 1-1.

[0039] Figure 2 is the X-ray powder diffraction pattern of prednisolone dihydrate obtained in Example 1-1;

[0040] Figure 3 This is the DSC measurement spectrum of prednisolone dihydrate obtained in Example 1-1;

[0041] Figure 4 The X-ray powder diffraction pattern of prednisolone sesquihydrate obtained in Comparative Example 1-1;

[0042] Figure 5 This is the DSC measurement spectrum of prednisolone sesquihydrate obtained in Comparative Example 1-1;

[0043] Figure 6 The X-ray powder diffraction pattern of prednisolone crystal form I obtained in comparative example 2-1;

[0044] Figure 7 The X-ray powder diffraction pattern of the mixed crystal of prednisolone form I and its hydrate obtained in comparative example 2-2. DETAILED DESCRIPTION

[0045] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, conventional conditions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0046] Example 1 Preparation of prednisolone dihydrate

[0047] Example 1-1

[0048] 100 g of crude prednisolone was added to a mixed solvent of methanol (200 mL), dichloromethane (200 mL) and purified water (60 mL), heated to 35° C. to dissolve and clarify, filtered to remove insoluble impurities, and purified water (1000 mL) was added to the mixed solution at a rate of 300 mL / min using a constant pressure dropping funnel for crystallization. After mechanical stirring for 1 h, the mixture was cooled to 10° C. at a rate of 30° C. / h, filtered, and dried at 35° C. to constant weight to obtain 97.2 g of solid with a yield of 97.2%.

[0049] The obtained solid was analyzed by TG-DTA, and the weight loss was about 9.5%, which confirmed that it was prednisolone dihydrate. Figure 1 shown.

[0050] The obtained solid was subjected to X-ray diffraction measurement, and the characteristic peak positions were measured to be 2θ=7.2°±0.2°, 12.5°±0.2°, 14.2°±0.2°, 15.5°±0.2°, and 16.2°±0.2°. X-ray diffraction measurement was as follows Figure 2 shown.

[0051] The obtained solid was subjected to DSC measurement, and the dehydration endothermic peak was about 80°C. The DSC measurement spectrum is shown in Figure 3 shown.

[0052] Example 1-2

[0053] 100 g of crude prednisolone was added to a mixed solvent of ethanol (1000 mL), ethyl acetate (200 mL) and purified water (200 mL), heated to 75°C to dissolve and clarify, filtered to remove insoluble impurities, and purified water (100 mL) was added to the mixed solution at a rate of 200 mL / min using a constant pressure dropping funnel for crystallization. After mechanical stirring for 2 h, the mixture was cooled to 0°C at a rate of 20°C / h, filtered, and dried at 33°C to constant weight to obtain 97.5 g of solid with a yield of 97.5%.

[0054] Examples 1-3

[0055] 100 g of crude prednisolone was added to a mixed solvent of isopropanol (200 mL), chloroform (60 mL) and purified water (200 mL), heated to 60° C. to dissolve and clarify, filtered to remove insoluble impurities, and purified water (1000 mL) was added to the mixed solution at a rate of 250 mL / min using a constant pressure dropping funnel for crystallization. After mechanical stirring for 1 h, the mixture was cooled to 5° C. at a rate of 25° C. / h, filtered, and dried at 36° C. to constant weight to obtain 97.8 g of solid with a yield of 97.8%.

[0056] Examples 1-4

[0057] 100 g of crude prednisolone was added to a mixed solvent of methanol (900 mL), acetone (80 mL) and purified water (150 mL), heated to 55° C. to dissolve and clarify, filtered to remove insoluble impurities, and purified water (500 mL) was added to the mixed solution at a rate of 250 mL / min using a constant pressure dropping funnel for crystallization. After mechanical stirring for 1 h, the mixture was cooled to 8° C. at a rate of 22° C. / h, filtered, and dried at 36° C. to constant weight to obtain 97.9 g of solid with a yield of 97.9%.

[0058] Examples 1-5

[0059] 100 g of crude prednisolone was added to a mixed solvent of isopropanol (200 mL), dichloromethane (60 mL) and purified water (120 mL), heated to 35° C. to dissolve and clarify, filtered to remove insoluble impurities, and purified water (300 mL) was added to the mixed solution at a rate of 250 mL / min using a constant pressure dropping funnel for crystallization. After mechanical stirring for 1 h, the mixture was cooled to 7° C. at a rate of 23° C. / h, filtered, and dried at 36° C. to constant weight to obtain 97.4 g of solid with a yield of 97.4%.

[0060] Examples 1-6

[0061] 100 g of crude prednisolone was added to a mixed solvent of ethanol (900 mL), ethyl acetate (90 mL) and purified water (140 mL), heated to 75° C. to dissolve and clarify, filtered to remove insoluble impurities, and purified water (200 mL) was added to the mixed solution at a rate of 250 mL / min using a constant pressure dropping funnel for crystallization. After mechanical stirring for 2 h, the mixture was cooled to 6° C. at a rate of 24° C. / h, filtered, and dried at 36° C. to constant weight to obtain 97.6 g of solid with a yield of 97.6%.

[0062] Examples 1-7

[0063] 100 g of crude prednisolone was added to a mixed solvent of ethanol (300 mL), dichloromethane (200 mL) and purified water (60 mL), heated to 35° C. to dissolve and clarify, filtered to remove insoluble impurities, and purified water (1000 mL) was added to the mixed solution at a rate of 200 mL / min using a constant pressure dropping funnel for crystallization. After mechanical stirring for 1.5 h, the mixture was cooled to 3° C. at a rate of 27° C. / h, filtered, and dried at 34° C. to constant weight to obtain 98.6 g of solid with a yield of 98.6%.

[0064] Examples 1-8

[0065] 100 g of crude prednisolone was added to a mixed solvent of isopropanol (800 mL), ethyl acetate (100 mL) and purified water (100 mL), heated to 75° C. to dissolve and clarify, filtered to remove insoluble impurities, and purified water (600 mL) was added to the mixed solution at a rate of 200 mL / min using a constant pressure dropping funnel for crystallization. After mechanical stirring for 1 h, the mixture was cooled to 2° C. at a rate of 28° C. / h, filtered, and dried at 35° C. to constant weight to obtain 98.3 g of solid with a yield of 98.3%.

[0066] Examples 1-9

[0067] 100 g of crude prednisolone was added to a mixed solvent of methanol (300 mL), chloroform (100 mL) and purified water (70 mL), heated to 55° C. to dissolve and clarify, filtered to remove insoluble impurities, and purified water (700 mL) was added to the mixed solution at a rate of 300 mL / min using a constant pressure dropping funnel for crystallization. After mechanical stirring for 2 h, the mixture was cooled to 1° C. at a rate of 29° C. / h, filtered, and dried at 35° C. to constant weight to obtain 98.8 g of solid with a yield of 98.8%.

[0068] Examples 1-10

[0069] 100 g of crude prednisolone was added to a mixed solvent of ethanol (500 mL), dichloromethane (150 mL) and purified water (80 mL), heated to 35° C. to dissolve and clarify, filtered to remove insoluble impurities, and purified water (700 mL) was added to the mixed solution at a rate of 300 mL / min using a constant pressure dropping funnel for crystallization. After mechanical stirring for 2 h, the mixture was cooled to 0° C. at a rate of 30° C. / h, filtered, and dried at 35° C. to constant weight to obtain 98.5 g of solid with a yield of 98.5%.

[0070] Examples 1-11

[0071] 100 g of crude prednisolone was added to a mixed solvent of methanol (400 mL), acetone (100 mL) and purified water (90 mL), heated to 50° C. to dissolve and clarify, filtered to remove insoluble impurities, and purified water (900 mL) was added to the mixed solution at a rate of 300 mL / min using a constant pressure dropping funnel for crystallization. After mechanical stirring for 2 h, the mixture was cooled to 8° C. at a rate of 22° C. / h, filtered, and dried at 35° C. to constant weight to obtain 98.3 g of solid with a yield of 98.3%.

[0072] Examples 1-12

[0073] 100 g of crude prednisolone was added to a mixed solvent of isopropanol (300 mL), chloroform (200 mL) and purified water (60 mL), heated to 60° C. to dissolve and clarify, filtered to remove insoluble impurities, and purified water (600 mL) was added to the mixed solution at a rate of 300 mL / min using a constant pressure dropping funnel for crystallization. After mechanical stirring for 2 h, the mixture was cooled to 2° C. at a rate of 28° C. / h, filtered, and dried at 35° C. to constant weight to obtain 98.2 g of solid with a yield of 98.2%.

[0074] The solids obtained in Examples 1-2 to 1-12 were analyzed by TG-DTA, which proved that the solids obtained in Example 1-1 were all dihydrates; X-ray powder diffraction analysis showed that the diffraction angle 2θ value of the characteristic peak varied within ±0.2° from the diffraction angle 2θ value of the solid obtained in Example 1-1, proving that the solids obtained in Example 1-1 were all dihydrates and had the same crystal form.

[0075] Example 2 Preparation of Prednisolone Crystal Form I

[0076] Example 2-1

[0077] 10 g of the solid obtained in Example 1-1 was dried in a forced air drying oven at 78° C. for 4 h to obtain the product.

[0078] The obtained product was subjected to X-ray diffraction measurement, and the characteristic peak positions were measured to be 2θ=8.0°±0.2°, 10.5°±0.2°, 13.9°±0.2°, 15.5°±0.2°, 15.8°±0.2°, 16.2°±0.2°, 17.6°±0.2°, and 21.2°±0.2°, which are the same as the parameters of Form I reported in the literature, proving that the product obtained in Example 1-1 is Prednisolone Form I. X-ray diffraction measurement Figure 6 shown.

[0079] Example 2-2

[0080] 10 g of the solid obtained in Example 1-2 was dried in a forced air drying oven at 70° C. for 5 h to obtain the product.

[0081] Example 2-3

[0082] 10 g of the solid obtained in Example 1-3 was dried in a forced air drying oven at 80° C. for 3 h to obtain the product.

[0083] The products obtained in Examples 2-2 to 2-3 and the product obtained in Example 2-1 were measured by X-ray powder diffraction, and the diffraction angle 2θ value of the characteristic peak was measured to vary within ±0.2° from the diffraction angle 2θ value of the product obtained in Example 2-1, proving that the solids obtained in Example 2-1 were all prednisolone crystal form I.

[0084] Comparative Example 1

[0085] Comparative Example 1-1

[0086] The difference between this comparative example and Example 1-1 is that the amount of methanol added is 100 mL, and the other conditions are the same. After post-treatment, 95.9 g of solid is obtained, and the yield is 95.9%.

[0087] The obtained solid was analyzed by TG-DTA, and the weight loss was about 6.8%, which confirmed that it was prednisolone sesquihydrate.

[0088] The obtained solid was subjected to X-ray diffraction measurement, and the characteristic peak positions were measured to be 2θ=5.0°±0.2°, 7.1°±0.2°, 7.9°±0.2°, 10.0°±0.2°, 12.9°±0.2°, 14.2°±0.2°, 14.7°±0.2°, 15.5°±0.2°, 17.5°±0.2°, 17.8°±0.2°, 18.9°±0.2°, and 20.2°±0.2°. X-ray diffraction measurement was performed as follows Figure 4 shown.

[0089] The obtained solid was subjected to DSC measurement, and the peak value of the dehydration endothermic peak was about 120°C. The DSC measurement spectrum is shown in Figure 5 shown.

[0090] Comparative Example 1-2

[0091] The difference between this comparative example and Example 1-1 is that the amount of methanol added is 1500 mL, and the other conditions are the same. After post-treatment, 95.1 g of solid is obtained, and the yield is 95.1%.

[0092] Comparative Examples 1-3

[0093] The difference between this comparative example and Example 1-1 is that the amount of chloroform added is 20 mL, and the other conditions are the same. After post-treatment, 94.9 g of solid is obtained, and the yield is 94.9%.

[0094] Comparative Examples 1-4

[0095] The difference between this comparative example and Example 1-1 is that the amount of chloroform added is 400 mL, and the other conditions are the same. After post-treatment, 95.0 g of solid is obtained, and the yield is 95.0%.

[0096] Comparative Examples 1-5

[0097] The difference between this comparative example and Example 1-1 is that the amount of purified water added to the mixed solvent is 50 mL, and the other conditions are the same. After post-treatment, 95.7 g of solid is obtained, and the yield is 95.7%.

[0098] Comparative Examples 1-6

[0099] The difference between this comparative example and Example 1-1 is that the amount of purified water added to the mixed solvent is 30 mL, and the other conditions are the same. After post-treatment, 94.5 g of solid is obtained, and the yield is 94.5%.

[0100] Comparative Examples 1-7

[0101] The difference between this comparative example and Example 1-1 is that the amount of purified water added for crystallization is 90 mL, and the other conditions are the same. After post-treatment, 94.3 g of solid is obtained, and the yield is 94.3%.

[0102] Comparative Examples 1-8

[0103] The difference between this comparative example and Example 1-1 is that the amount of purified water added for crystallization is 1100 mL, and the other conditions are the same. After post-treatment, 94.3 g of solid is obtained, and the yield is 94.3%.

[0104] Comparative Examples 1-9

[0105] 10 g of crude prednisolone was added to ethanol (100 mL), and after heating to 75°C to dissolve and clarify, 200 mL of water was added, and then the temperature was cooled to room temperature (25°C) at a rate of 0.1°C / min, filtered, and dried to constant weight to obtain 9.1 g of solid with a yield of 91.0%.

[0106] Comparative Examples 1-10

[0107] 10 g of crude prednisolone was added to a mixed solvent of methanol (10 mL) and purified water (90 mL), heated to reflux to dissolve, refluxed for 30 min, cooled to 25°C, and then cooled to -2°C, crystallized for 9 h, filtered, and dried to constant weight to obtain 9.5 g of solid with a yield of 95.0%.

[0108] Comparative Examples 1-11

[0109] 20 g of crude prednisolone was added to a mixed solvent of dichloromethane (45 mL), methanol (27 mL), water (1.8 mL), Girardt's reagent T (0.2 g) and glacial acetic acid (1 mL), and the temperature was raised to reflux. After dissolution and clarification, the mixture was refluxed for 1 h, cooled to 4°C, and 60 mL of purified water was slowly added dropwise within 8 h. The mixture was stirred for another 2 h, filtered, and dried to constant weight to obtain 19.4 g of solid with a yield of 97.0%.

[0110] Comparative Examples 1-12

[0111] 15 g of crude prednisolone was added to a mixed solvent of acetone (157.5 mL) and water (67.5 mL), dissolved at 15° C. for 8 min, and after dissolving, diluted with 100 times water, filtered, and dried at 95° C. to obtain 14.0 g of solid with a yield of 93.3%.

[0112] The solids obtained from Comparative Examples 1-2 to 1-12 were analyzed by TG-DTA, which showed that they were all sesquihydrates like the solid obtained from Comparative Example 1-1.

[0113] Comparative Example 2

[0114] Comparative Example 2-1

[0115] 10 g of the solid obtained in Comparative Example 1-1 was dried in a forced air drying oven at 120° C. for 24 h to obtain a product.

[0116] The product obtained in Comparative Example 2-1 was measured by X-ray diffraction, 2θ=8.0°±0.2°, 10.5°±0.2°, 13.9°±0.2°, 15.5°±0.2°, 15.8°±0.2°, 16.2°±0.2°, 17.6°±0.2°, 21.2°±0.2°, which are the same as the parameters of Form I reported in the literature, proving that the product obtained in Comparative Example 1-1 is Prednisolone Form I.

[0117] Comparative Example 2-2

[0118] 10 g of the solid obtained in Comparative Example 1-6 was dried in a forced air drying oven at 70° C. for 5 h to obtain a product.

[0119] The obtained product was measured by X-ray diffraction, and the characteristic peak positions were measured to be 2θ=7.1°±0.2, 8.0°±0.2°, 10.5°±0.2°, 13.6°±0.2°, 13.9°±0.2°, 14.2°±0.2°, 15.5°±0.2°, 15.8°±0.2°, 16.2°±0.2°, 17.6°±0.2°, 21.2°±0.2°. The parameters of Form I reported in the literature are different, and it is speculated that it is a mixed crystal of sesquihydrate and Form I. X-ray diffraction measurement is as follows Figure 7 shown.

[0120] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A prednisolone dihydrate, characterized in that: The structural formula is as follows: Its X-ray powder diffraction has characteristic peaks at diffraction angles of 2θ=7.2°±0.2°, 12.5°±0.2°, 14.2°±0.2°, 15.5°±0.2°, and 16.2°±0.2°.

2. The prednisolone dihydrate according to claim 1, characterized in that Its X-ray powder diffraction has characteristic peaks at diffraction angles of 2θ=5.0°±0.2°, 7.2°±0.2°, 7.9°±0.2°, 10.5°±0.2°, 12.5°±0.2°, 14.2°±0.2°, 15.5°±0.2°, 15.8°±0.2°, 16.2°±0.2°, 17.5°±0.2°, 17.8°±0.2°, 18.8°±0.2°, and 19.2°±0.2°.

3. A method for preparing the prednisolone dihydrate according to any one of claims 1 to 2, characterized in that: The method comprises the following steps: dissolving prednisolone in a mixed solvent, and after the solution is clarified, adding water for crystallization to obtain prednisolone dihydrate; wherein the mixed solvent is selected from a mixed solvent of solvent I, solvent II and water; the solvent I is selected from one or more of methanol, ethanol or isopropanol; and the solvent II is selected from one or more of dichloromethane, chloroform, acetone or ethyl acetate.

4. The method for preparing prednisolone dihydrate according to claim 3, characterized in that: The solvent I is selected from methanol and / or ethanol; the solvent II is selected from dichloromethane and / or acetone.

5. The method for preparing prednisolone dihydrate according to claim 3, characterized in that: Add water for crystallization, and cool to 0-10°C at a rate of (20-30)°C / h to obtain prednisolone dihydrate.

6. The method for preparing prednisolone dihydrate according to claim 3, characterized in that: The mass volume ratio of the prednisolone to the solvent I is 1: (2-10) g / mL; the mass volume ratio of the prednisolone to the solvent II is 1: (0.6-2) g / mL; the mass volume ratio of the prednisolone to the water in the mixed solvent is 1: (0.6-2) g / mL; the mass volume ratio of the prednisolone to the water used for crystallization is 1: (1-10) g / mL.

7. The method for preparing prednisolone dihydrate according to claim 6, characterized in that: The mass volume ratio of the prednisolone to the solvent I is 1: (3-8) g / mL; the mass volume ratio of the prednisolone to the solvent II is 1: (1-2) g / mL; the mass volume ratio of the prednisolone to the water in the mixed solvent is 1: (0.6-1) g / mL; the mass volume ratio of the prednisolone to the water used for crystallization is 1: (6-10) g / mL.

8. Use of the prednisolone dihydrate according to any one of claims 1 to 2 or the prednisolone dihydrate prepared by the preparation method according to any one of claims 3 to 7 in the preparation of prednisolone crystal form I.

9. The use according to claim 8, characterized in that: The method comprises the following steps: heating prednisolone dihydrate to remove crystal water to obtain prednisolone crystal form I.

10. The use according to claim 9, characterized in that: The method comprises the following steps: heating prednisolone dihydrate at 70-80° C. to remove crystal water, thereby obtaining prednisolone crystal form I.

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