Preparation method of betamethasone acetate single crystal form

Abstract

The invention relates to the technical field of medicines, in particular to a preparation method of a betamethasone acetate single crystal form, which comprises the following step: contacting a betamethasone acetate crude product with methanol to obtain an I beta crystal form betamethasone acetate crystal. Methanol is adopted as a crystallization solvent, the yield is high, isomeride impurities which are difficult to remove can be effectively removed, a single crystal form sample with few impurities and high purity is obtained, and the purification problem of the impurities which are difficult to remove and the problem that crystals are easy to mix when betamethasone acetate is used as a polycrystalline compound are well solved. The obtained I beta crystal form is a single crystal form, is good in physical and chemical stability, regular in crystal form, good in granularity uniformity and good in fluidity, well overcomes the defects that in the prior art, the crystallization process is tedious, materials are high in electrostatic property and prone to floating and adhering to walls, and particles are not uniform, and has excellent properties in the aspect of processing adaptability. The method is simple, efficient, convenient to operate, high in repeatability, small in pollution, good in impurity removal effect and high in yield, meets the factory GMP production requirement and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing a single crystal form of betamethasone acetate. Background Technology

[0002] Betamethasone acetate is an important glucocorticoid with various pharmacological effects, including anti-inflammatory, anti-allergic, and anti-shock properties. It is widely used in dermatology, rheumatology, respiratory medicine, and other medical fields, primarily in the form of liniments and injections. The acyloxy or carbonyl group at position 21 and the hydroxyl group at position 17 of betamethasone acetate are highly reactive, readily forming intramolecular hydrogen bonds or hydrogen bonds with water molecules. Therefore, its crystal form exhibits polymorphism, as shown in the following structural formula:

[0003]

[0004] Currently, existing literature indicates that betamethasone acetate exists in three anhydrous crystalline forms (Iα, Iβ, and II) and a hydrated crystalline form. These different crystalline forms have varying melting points, solubilities, and stability, and they can interconvert, making it difficult to obtain a stable single crystalline form. The Iβ crystalline form requires three purification processes, which are complex, result in significant yield losses, and, due to the numerous reaction steps, easily lead to mixed crystals during preparation. Furthermore, isomer impurities are prone to appear during the preparation of betamethasone acetate, as they are close to the main peak and difficult to remove. For example, purifying betamethasone acetate with acetone does not effectively remove isomer impurities, and acetone purification alone yields mixed crystals of Iα and II crystalline forms. Summary of the Invention

[0005] In view of this, the technical problem to be solved by the present invention is to provide a method for preparing a single crystal form of betamethasone acetate, which is simple and efficient.

[0006] To achieve the above objectives, the present invention provides a method for preparing a single crystal form of betamethasone acetate, comprising the following steps:

[0007] Crude betamethasone acetate was contacted with methanol to obtain betamethasone acetate crystals in the Iβ crystal form.

[0008] The order of contact between crude betamethasone acetate and methanol is not limited; the crude betamethasone acetate can be added to methanol, or methanol can be added to crude betamethasone acetate.

[0009] The preferred mass-to-volume ratio of crude betamethasone acetate to methanol is 1:10 to 20 (g / ml), including but not limited to 1:10, 1:15, 1:16, 1:17, 1:18, 1:19, and 1:20 (g / ml).

[0010] Preferably, the step of obtaining betamethasone acetate crystals of the Iβ crystal form includes:

[0011] Heating for concentration, cooling for crystallization, and segmented drying.

[0012] This invention uses methanol to refine crude betamethasone acetate, which is then concentrated by heating, cooled to crystallize, and dried in stages. This process not only effectively removes difficult-to-remove isomer impurities but also yields a single Iβ crystal form. Furthermore, the crystallization method described above has a high yield.

[0013] Preferably, the method for preparing the single crystal form of betamethasone acetate includes the following steps:

[0014] S1) The crude betamethasone acetate was contacted with methanol to obtain a methanol solution of the crude betamethasone acetate.

[0015] S2) The methanol solution of the crude betamethasone acetate was concentrated under reduced pressure;

[0016] S3) Cooling down, crystallization;

[0017] S4) Filter and dry to obtain a single Iβ crystal of betamethasone acetate.

[0018] Preferably, after contacting crude betamethasone acetate with methanol, the system is heated to dissolve the product. The preferred temperature for heating to dissolve the product is 45-65°C, including but not limited to 45, 50, 59, 60, 62, and 65°C.

[0019] The heating and dissolving process is preferably carried out under stirring conditions to better dissolve the crude betamethasone acetate in methanol.

[0020] In step S2), the temperature of the vacuum concentration is preferably 50-70°C, including but not limited to 50, 55, 58, 60, 65, and 70°C.

[0021] After vacuum concentration, the preferred mass-to-volume ratio of crude betamethasone acetate to the remaining concentrated mother liquor in the system is 1:0.5–2 (g / ml), including but not limited to 1:0.5, 1:0.75, 1:1, and 1:2 (g / ml). Controlling the amount of the remaining concentrated mother liquor helps to better balance crystal yield and purity.

[0022] In step S3), the temperature drop is 0 to -5°C, including but not limited to -5°C.

[0023] The cooling is a natural cooling process. Preferably, the cooling rate is 1°C / min.

[0024] The crystallization is preferably carried out by stirring.

[0025] The preferred temperature for stirring and crystallizing is 0 to -5°C, including but not limited to -5°C.

[0026] The stirring and crystallization time is greater than or equal to 0.5 h, preferably 0.5 to 2 h, and more preferably 0.5 to 1.5 h.

[0027] The stirring speed is preferably 30 to 60 r / min, including but not limited to 30, 50, and 60 r / min.

[0028] The above-mentioned parameters for cooling and crystallization help to improve the yield and purity of the product.

[0029] Preferably, in step S4), the drying includes:

[0030] After drying at low temperature for 2 to 8 hours, switch to high temperature drying for more than 5 hours.

[0031] The above drying methods help to better remove moisture and residual solvent from the crystals.

[0032] The preferred temperature for low-temperature drying is 70–75°C.

[0033] The preferred temperature for high-temperature drying is 115–125°C.

[0034] The Iβ crystals of betamethasone acetate prepared by the above method have an arbitrary single impurity of less than or equal to 0.1%, a total impurity of less than or equal to 0.2%, and a chromatographic purity of greater than or equal to 99.8%.

[0035] According to the present invention, the monocrystalline betamethasone acetate has the Iβ crystalline form, characterized in that its X-ray powder diffraction pattern has characteristic peaks at the following diffraction angles 2θ: 7.2±0.2°, 11.4±0.2°, 12.3±0.2°, 13.4±0.2°, 14.3±0.2°, 15.3±0.2°, 16.2±0.2° and 16.6±0.2°.

[0036] Furthermore, the X-ray powder diffraction pattern of the Iβ crystal form of the present invention has the 2θ values, interplanar spacing d, and relative intensity data shown in Table 1 below:

[0037] Table 1

[0038] Peak number 2θ(°) d(A) Relative strength (%) 1 7.2 12.3 12.22 2 11.4 7.7 7.24 3 12.3 7.2 10.49 4 13.4 6.6 100.00 5 14.3 6.2 3.85 6 15.3 5.8 37.19 7 16.2 5.5 33.02 8 16.6 5.3 7.32

[0039] Non-limiting, the X-ray powder diffraction pattern of the Iβ crystal form of the present invention is as follows: Figure 2 As shown, it is completely consistent with the Iβ crystal form described in the literature, which indicates that the present invention has prepared a single crystal form of Iβ betamethasone acetate crystal.

[0040] Compared with the prior art, the present invention provides a method for preparing a single crystal form of betamethasone acetate, comprising the following steps: contacting crude betamethasone acetate with methanol to obtain betamethasone acetate crystals of the Iβ crystal form.

[0041] The present invention achieves the following beneficial effects:

[0042] 1. Crystal form is one of the important physicochemical properties of a compound. For polymorphic drugs, due to differences in crystal structure, some physicochemical properties such as melting point, solubility, and stability may vary significantly. These characteristics may have a significant impact on drug production, stability, solubility, and bioavailability, thereby affecting drug safety and efficacy. The Iβ crystal form obtained in this invention is a single crystal form with good physicochemical stability, regular crystal form, good particle size uniformity, and good flowability. It effectively solves the shortcomings of existing technologies, such as cumbersome crystallization process, high electrostatic properties of materials leading to easy floating and adhesion to the wall, and uneven particle size. It also exhibits excellent properties in terms of processing adaptability.

[0043] 2. The preparation method of the present invention uses methanol as a crystallization solvent, which has a higher yield than acetone purification and can effectively remove difficult-to-remove isomer impurities. It can obtain a single crystal sample with fewer impurities and higher purity, which solves the purification problem of difficult-to-remove impurities and the problem of easy miscibility of betamethasone acetate as a polycrystalline compound.

[0044] 3. The crystallization process of this invention is simple, efficient, easy to operate, highly repeatable, with low pollution, good impurity removal effect, and high yield, which meets the GMP production requirements of factories and is suitable for industrial production. Attached Figure Description

[0045] Figure 1 X-ray powder diffraction pattern of the Iβ crystal form prepared in Example 1;

[0046] Figure 2 The DSC spectrum of the Iβ crystal form prepared in Example 1;

[0047] Figure 3 Microscopic photograph of the Iβ crystal form prepared in Example 1;

[0048] Figure 4 The high-performance liquid chromatography (HPLC) spectrum of high-purity betamethasone acetate prepared in Example 1;

[0049] Figure 5 The X-ray powder diffraction pattern of the Iβ crystal form prepared according to the literature method in Comparative Example 1;

[0050] Figure 6 This is an overlay of the X-ray powder diffraction patterns of Example 1 and Comparative Example 1. Detailed Implementation

[0051] To further illustrate the present invention, a detailed description is provided below with reference to embodiments. However, it should be understood that these descriptions are merely for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims.

[0052] The raw material used in the method of the present invention for preparing the Iβ crystal form can be the crude product of compound (I). The crude product of compound (I) can be prepared according to the scheme disclosed in patent CN101417912A or purchased by oneself, including but not limited to the above-mentioned sources.

[0053] There are no particular restrictions on the solvents used in this invention; commercially available conventional solvents can be used.

[0054] Unless otherwise stated, the "stirring" described in the method of the present invention can be performed using conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 10 to 300 rpm / min.

[0055] The X-ray powder diffraction instrument and testing conditions involved in this invention are as follows: X-ray diffraction instrument model: Aeris Cu target; operation method: scanning speed 68.595° / s, scanning step width 0.011°.

[0056] The DSC test conditions involved in this invention are as follows: DSC detector model: DSC3METTLER TOLEDO; operation method: heating rate 4℃ / min, temperature range: 25~400℃.

[0057] The microscope involved in this invention is model MC1200-MZ, with a mesh count of 10*10.

[0058] It should be emphasized that the numerical values ​​or numerical endpoints involved in the technical solutions of this invention are not limited to the numbers themselves. Those skilled in the art will understand that they include those permissible error ranges that have been widely accepted in the art, such as experimental errors, measurement errors, statistical errors, and random errors, etc., and these error ranges are all included within the scope of this invention.

[0059] Example 1

[0060] Preparation of betamethasone acetate I β crystal form:

[0061] 10 g of crude compound (I) was added to a reaction flask and mixed with 150 ml of methanol. The mixture was heated to 60 °C and stirred until dissolved. The solution was then concentrated under reduced pressure at 58 °C to a final volume of 10 ml of methanol. The mixture was then stirred and cooled to -5 °C. The stirring speed was 60 r / min and the cooling rate was 1 °C / min. After cooling to the target temperature, the mixture was filtered. The wet product was placed in a square oven and dried at 70 °C for 4 h, followed by drying at 115 °C for 6 h, yielding 9.38 g of crystals. The yield was 93.8%, the purity was 99.93%, the maximum single impurity was 0.03%, and the isomer impurity with an RRT of 1.16 was 0.03%.

[0062] Upon testing, its X-ray powder diffraction was as follows: Figure 1 As shown, the DSC spectrum is as follows Figure 2 As shown in the microscopic photograph of crystallinity, Figure 3 As shown, the comparison with the Iβ crystal form spectrum provided in the literature confirms that the crystal form is Iβ.

[0063] Example 2:

[0064] 20 g of crude compound (I) was added to a reaction flask and mixed with 200 ml of methanol. The mixture was heated to 58 °C and stirred until dissolved. The solution was then concentrated under reduced pressure at 55 °C to a final volume of 15 ml of methanol. The mixture was then cooled to -5 °C with stirring at a speed of 50 r / min and a cooling rate of 1 °C / min. After cooling to the target temperature, the mixture was filtered. The wet product was placed in a square oven and dried at 70 °C for 4 h, followed by drying at 120 °C for 6 h, yielding 18.82 g of crystals. The yield was 94.1%, the purity was 99.88%, the maximum single impurity was 0.03%, and the isomer impurity with an RRT of 1.19 was 0.02%.

[0065] X-ray powder diffraction (XRD) and DSC analysis confirmed it to be of the Iβ crystal form.

[0066] Example 3:

[0067] 50 g of crude compound (I) was added to a reaction flask and mixed with 900 ml of methanol. The mixture was heated to 62 °C and stirred until dissolved. The solution was then concentrated under reduced pressure at 58 °C to a remaining 50 ml of methanol. The mixture was then stirred and cooled to -5 °C. The stirring speed was 30 r / min, and the cooling rate was 1 °C / min. After cooling to the target temperature, the mixture was filtered. The wet product was placed in a square oven and dried at 75 °C for 3 h, followed by drying at 120 °C for 5 h, yielding 47.21 g of crystals. The yield was 94.42%, the purity was 99.85%, the maximum single impurity was 0.03%, and the isomer impurity with RRT = 1.19 was 0.03%.

[0068] X-ray powder diffraction (XRD) and DSC analysis confirmed it to be of the Iβ crystal form.

[0069] Comparative Example 1

[0070] The Iβ crystal form was prepared according to the method disclosed in the literature (Journal of China Pharmaceutical University 2003, 34(5): 430-432). The specific method is as follows:

[0071] Take an appropriate amount of crude betamethasone acetate, dissolve it in acetone, heat to boiling, filter while hot, let the filtrate stand until a precipitate forms, filter under vacuum, and dry under an infrared lamp to obtain betamethasone acetate type II crystals; dissolve an appropriate amount of type II crystals in acetone, evaporate the acetone in a 70℃ oil bath until a solid precipitates, add an appropriate amount of water to the solid, grind in a ball mill for 1 hour, filter under vacuum, and dry under vacuum at 40℃; place in an oven at 160℃ for 15 minutes to obtain betamethasone acetate type I β crystals.

[0072] A comparison of the superimposed spectra of the Iβ crystal form obtained in Example 1 of this invention and the crystal form obtained by the literature method is shown in the figure. Figure 6 .

[0073] As can be seen from the comparison diagram, the peak shape and number of peaks of the crystal form obtained in Example 1 of the present invention are basically the same as those of the crystal form obtained by the literature method, confirming that the crystal form is the Iβ crystal form.

[0074] The Iβ crystal form obtained in Example 1 of this invention and the Iβ crystal form obtained in Comparative Example 1, as well as the crude betamethasone acetate, were analyzed by HPLC. The results are shown in Table 2.

[0075] Table 2

[0076]

[0077] As shown in Table 2, the Iβ crystal form provided by this patent is superior to the methods in the literature in removing difficult-to-remove isomer impurities.

[0078] Microscopic images show that the Iβ crystal particles prepared by this invention are uniform in size and shape, cuboid or needle-like, with a small specific surface area, low intercrystalline friction, and good particle flowability. This indicates that the method provided by this invention has a good removal effect on difficult-to-remove isomer impurities, with high yield, good repeatability, and is easy to store, transport, and process.

[0079] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing a single crystal form of betamethasone acetate, comprising the following steps: Crude betamethasone acetate was contacted with methanol to obtain betamethasone acetate crystals in the Iβ crystal form.

2. The preparation method according to claim 1, characterized in that, The steps for obtaining betamethasone acetate crystals of the Iβ crystal form include: Heating for concentration, cooling for crystallization, and segmented drying.

3. The preparation method according to claim 1, characterized in that, Includes the following steps: S1) The crude betamethasone acetate was contacted with methanol to obtain a methanol solution of the crude betamethasone acetate. S2) The methanol solution of the crude betamethasone acetate was concentrated under reduced pressure; S3) Cooling down, crystallization; S4) Filter and dry to obtain betamethasone acetate crystals of type Iβ.

4. The preparation method according to claim 3, characterized in that, Crude betamethasone acetate was contacted with methanol and the system was heated to dissolve it, thus obtaining betamethasone acetate crystals of the Iβ crystal form. The mass-to-volume ratio of crude betamethasone acetate to methanol is 1:10-20 (g / ml); The heating and dissolving temperature is 45–65°C.

5. The preparation method according to claim 3, characterized in that, The temperature for vacuum concentration is 50–70°C; After vacuum concentration, the mass-to-volume ratio of crude betamethasone acetate to the remaining concentrated mother liquor in the system is 1:0.5–2 (g / ml).

6. The preparation method according to claim 3, characterized in that, The cooling rate is 0 to -5°C; The cooling process is a natural cooling process.

7. The preparation method according to claim 3, characterized in that, The crystallization is a stirred crystallization; The temperature for the stirring crystallization is 0 to -5℃; The stirring and crystallization time is greater than or equal to 0.5 hours.

8. The preparation method according to claim 3, characterized in that, The drying process includes: After drying at low temperature for 2 to 8 hours, switch to high temperature drying for more than 5 hours.

9. The preparation method according to claim 8, characterized in that, The temperature for the low-temperature drying is 70–75°C; The high-temperature drying temperature is 115–125°C.

10. The preparation method according to claim 1, characterized in that, The betamethasone acetate crystals of the Iβ crystal form have an individual impurity content of less than or equal to 0.1%, a total impurity content of less than or equal to 0.2%, and a chromatographic purity of greater than or equal to 99.8%.

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