Adapalene crystal form II compound and preparation method thereof

Abstract

The invention discloses an adapalene crystal form II compound and a preparation method thereof, and the preparation method comprises the following steps: (1) dissolving an adapalene crude product in a mixed solvent of DMSO and THF to obtain a crude product solution; (2) adding activated carbon into the obtained crude product solution, stirring and decolorizing at room temperature, and filtering; and (3) adding water into the filtrate obtained in the step (2), stirring for crystallization, filtering, washing a filter cake with water and absolute ethyl alcohol in sequence, and drying to obtain the adapalene crystal form II compound. The preparation method provided by the invention is simple, mild in condition, safe to operate, high in product purity and single and stable in crystal form; the product has high solubility, is beneficial to development of a preparation process, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, in particular to an adapalene crystal form II compound and a preparation method thereof. Background Art

[0002] Adapalene, whose chemical name is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid, has the following structural formula:

[0003] Adapalene is an anti-acne drug developed by Galderma Pharmaceuticals of France. It is a third-generation retinoic acid drug. It was first launched in France in 1996, approved by the US FDA in July 2000, and launched in the US as an over-the-counter (OTC) drug in November 2000. Its gel (0.1%) is marketed under the trade name "Differin". It has been widely used in clinical practice because of its strong selectivity for receptors, low adverse reactions, low therapeutic concentration, and anti-inflammatory effects in the treatment of acne, and can effectively improve dermatitis lesions.

[0004] The crystal form of a drug is directly related to the quality and efficacy of the drug. The polymorphism phenomenon affects the preparation, stability, dissolution and bioavailability of the drug's raw materials and preparations, and further affects the drug's formulation and preparation process. For most drugs, different crystal forms have certain differences in physical and chemical properties, and this difference will inevitably affect the efficacy and toxic side effects of the drug. At present, there are relatively few reports on the crystal form of adapalene. The document "Polymorph Screening, Preparation and Characterization of Adapalene" discloses four crystal forms of adapalene, among which crystal form II is a stable crystal form, but the reported preparation method is not suitable for industrial production. At the same time, the characteristic peaks of its XRD are not described in detail, and only the first main strong peak is reported.

[0005] There are relatively many reports on the refining of adapalene, but they basically adopt the method of recrystallization under heating conditions using a single solvent or a mixed solvent. Due to the extremely poor solubility of adapalene, decolorization and filtration into the clean area through titanium rods during the industrial production process will cause decomposition, which seriously affects the removal effect of impurities, thereby reducing product quality. Summary of the invention

[0006] The present invention aims to overcome the above-mentioned problems existing in the prior art adapalene purification method, and provides an adapalene crystal form II compound and a preparation method thereof. The preparation method provided by the present invention is simple, mild in conditions, safe in operation, high in product purity, and single and stable in crystal form; the product has high solubility, is conducive to the development of preparation technology, and is suitable for industrial production.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions: A method for preparing an Adapalene crystal form II compound comprises the following steps: (1) dissolving the crude adapalene in a mixed solvent of DMSO and THF to obtain a crude product solution; (2) adding activated carbon to the obtained crude product solution, stirring at room temperature to decolorize, and then filtering; (3) adding water to the filtrate obtained in step (2), stirring to crystallize, filtering, washing the filter cake with water and anhydrous ethanol, and drying to obtain the adapalene crystal form II compound.

[0008] The invention firstly uses a mixed solvent of DMSO and THF to dissolve the crude adapalene, then adds activated carbon for decolorization, and then performs crystallization. The preparation method is simple, the conditions are mild, and the operation is safe. By selecting a crystallization system, the prepared product has high purity, a single and stable crystal form, and the product has high solubility, which is conducive to the development of preparation technology and is suitable for industrial production.

[0009] Preferably, in step (1), the mass volume ratio of crude adapalene to DMSO and THF is 1 g: 10-30 mL: 5-10 mL.

[0010] Preferably, the dissolution temperature of the crude adapalene in step (1) is 0 to 40°C.

[0011] Preferably, the mass of the activated carbon added in step (2) is 1 to 10% of the mass of the crude adapalene.

[0012] Preferably, the stirring decolorization time in step (2) is 1 to 5 hours.

[0013] Preferably, the volume mass ratio of water added to the filtrate in step (3) to the crude adapalene is 2-8 mL:1 g.

[0014] Preferably, the crystallization temperature in step (3) is 0 to 40° C., and the crystallization time is 1 to 24 h.

[0015] Preferably, vacuum drying is adopted during drying in step (3), the vacuum drying temperature is 50 to 80° C., and the vacuum drying time is 4 to 24 hours.

[0016] Preferably, after drying in step (3), the Adapalene Form II compound is crushed by a crushing method selected from the group consisting of air flow crushing, hammer crushing, turbine crushing, and tooth crushing.

[0017] The present invention also provides an Adapalene crystal form II compound prepared by the above method.

[0018] Preferably, the X-ray powder diffraction pattern has characteristic peaks at diffraction angles of 9.9±0.1°, 14.2±0.1°, 15.0±0.1°, 15.3±0.1°, 16.4±0.1°, 17.4±0.1°, 18.3±0.1°, 19.9±0.1°, 20.6±0.1°, 22.3±0.1°, 24.9±0.1°, 25.6±0.1°, and 26.9±0.1°.

[0019] Therefore, the present invention has the following beneficial effects: (1) The preparation method of the present invention is simple, mild in conditions, safe in operation, and suitable for industrial production; (2) The product prepared by the present invention has high purity and a single and stable crystal form; (3) The product prepared by the present invention has high solubility, which is conducive to the development of formulation technology; (4) The X-ray powder diffraction pattern of adapalene form II provides detailed characteristic peaks, filling the research gap. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the X-ray powder diffraction pattern of the Adapalene crystal form II compound obtained in Example 1 of the present invention.

[0021] Figure 2 This is the X-ray powder diffraction pattern of the Adapalene crystal form II compound obtained in Example 2 of the present invention.

[0022] Figure 3 This is the X-ray powder diffraction pattern of the Adapalene Form II compound obtained in Example 3 of the present invention after crushing.

[0023] Figure 4 It is the X-ray powder diffraction pattern of the Adapalene compound obtained in Comparative Example 1 of the present invention.

[0024] Figure 5 This is the X-ray powder diffraction pattern of the Adapalene crystal form II compound obtained in Example 3 of the present invention after being placed under the conditions of temperature 30° C. and humidity 65% ​​for 3 months.

[0025] Figure 6 This is the X-ray powder diffraction pattern of the Adapalene crystal form II compound obtained in Example 3 of the present invention after being placed under the conditions of temperature 30° C. and humidity 65% ​​for 12 months. DETAILED DESCRIPTION

[0026] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments.

[0027] In the present invention, unless otherwise specified, all equipment and raw materials can be purchased from the market or are commonly used in the industry. The methods in the following embodiments, unless otherwise specified, are conventional methods in the art.

[0028] In order to further understand the present invention, the preferred embodiments of the present invention are described below in conjunction with specific implementation methods, but it should be understood that these descriptions are only to further illustrate the features and advantages of the present invention rather than to limit the claims of the present invention.

[0029] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0030] Secondly, the term "one embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments.

[0031] The specific parameters of the X-ray powder diffraction instrument used in the embodiment of the present invention are: D8 ADVANCE, Cu, 40 kV, 40 mA, scanning range 3-40°, scanning step length 0.02°, and dwell time per step 0.1 s.

[0032] Overall embodiment: A method for preparing an Adapalene crystal form II compound comprises the following steps: (1) dissolving the crude adapalene in a mixed solvent of DMSO and THF to obtain a crude product solution; (2) adding activated carbon to the obtained crude product solution, stirring at room temperature to decolorize, and then filtering; (3) adding water to the filtrate obtained in step (2), stirring to crystallize, filtering, washing the filter cake with water and anhydrous ethanol, and drying to obtain the adapalene crystal form II compound.

[0033] As a specific implementation manner, in step (1), the mass volume ratio of crude adapalene to DMSO and THF is 1 g: 10-30 mL: 5-10 mL.

[0034] As a specific implementation manner, the dissolution temperature of the crude adapalene in step (1) is 0 to 40°C.

[0035] As a specific implementation manner, the mass of the activated carbon added in step (2) is 1 to 10% of the mass of the crude adapalene.

[0036] As a specific implementation manner, the stirring decolorization time in step (2) is 1 to 5 hours.

[0037] As a specific implementation manner, the volume mass ratio of water added to the filtrate in step (3) to the crude adapalene is 2 to 8 mL: 1 g.

[0038] As a specific implementation, the crystallization temperature in step (3) is 0 to 40° C., and the crystallization time is 1 to 24 hours.

[0039] As a specific implementation manner, vacuum drying is adopted during drying in step (3), the vacuum drying temperature is 50 to 80° C., and the vacuum drying time is 4 to 24 hours.

[0040] As a specific implementation method, after drying in step (3), the Adapalene Form II compound is crushed by a crushing method selected from the group consisting of air flow crushing, hammer crushing, turbine crushing, and tooth crushing.

[0041] As a specific embodiment, the X-ray powder diffraction pattern of the obtained Adapalene Form II compound has characteristic peaks at diffraction angles of 9.9±0.1°, 14.2±0.1°, 15.0±0.1°, 15.3±0.1°, 16.4±0.1°, 17.4±0.1°, 18.3±0.1°, 19.9±0.1°, 20.6±0.1°, 22.3±0.1°, 24.9±0.1°, 25.6±0.1°, and 26.9±0.1°.

[0042] Embodiment 1: A method for preparing an Adapalene crystal form II compound comprises the following steps: (1) Add 50 g of crude adapalene, 750 mL of DMSO and 300 mL of THF to a 2 L reaction bottle, start stirring at 250 rpm, and stir at 25 ° C for 1 h until the solution becomes clear to obtain a crude solution; (2) Add 1.0 g of activated carbon to the crude solution, continue stirring to decolorize for 1 h, and filter; (3) The filtrate obtained in step (2) was transferred to another clean 2L reaction bottle, and 150mL of water was slowly added dropwise to the filtrate. After the addition was completed, stirring and crystallization were continued for 1h, and the filter cake was washed with 2*200mL of water and 2*200mL of anhydrous ethanol in turn. After drying at room temperature for 24h, 46.2g of adapalene crystal form II compound was obtained; the HPLC purity was 99.97% and the yield was 92.4%; its X-ray powder diffraction pattern was as follows: Figure 1As shown, it has characteristic peaks at diffraction angles (2θ±0.2°) of 10.0°, 14.2°, 15.0°, 15.4°, 16.4°, 17.5°, 18.3°, 20.0°, 20.7°, 22.4°, 25.0°, 25.7°, and 26.9°.

[0043] Embodiment 2: A method for preparing an Adapalene crystal form II compound comprises the following steps: (1) Add 50 g of crude adapalene, 750 mL of DMSO and 300 mL of THF to a 2 L reaction bottle, start stirring at 250 rpm, and stir at 25 ° C for 1 h until the solution becomes clear to obtain a crude solution; (2) Add 1.0 g of activated carbon to the crude solution, continue stirring to decolorize for 1 h, and filter; (3) The filtrate obtained in step (2) was transferred to another clean 2L reaction bottle, and 150mL of water was slowly added dropwise to the filtrate. After the addition was completed, stirring and crystallization were continued for 1h, and the filter cake was washed with 2*200mL of water and 2*200mL of anhydrous ethanol, and vacuum dried at 80°C for 24h to obtain 45.9g of adapalene crystal form II compound; HPLC purity was 99.96%, and the yield was 91.8%; its X-ray powder diffraction pattern was as follows: Figure 2 As shown, there are characteristic peaks at diffraction angles (2θ±0.2°) of 9.9°, 14.2°, 15.0°, 15.3°, 16.4°, 17.4°, 18.3°, 20.0°, 20.6°, 22.4°, 25.0°, 25.6°, and 26.9°.

[0044] Embodiment 3: A method for preparing an Adapalene crystal form II compound comprises the following steps: (1) Add 50 g of crude adapalene, 750 mL of DMSO and 300 mL of THF to a 2 L reaction bottle, start stirring at 250 rpm, and stir at 25 ° C for 1 h until the solution becomes clear to obtain a crude solution; (2) Add 1.0 g of activated carbon to the crude solution, continue stirring to decolorize for 1 h, and filter; (3) The filtrate obtained in step (2) was transferred to another clean 2L reaction bottle, and 150mL of water was slowly added dropwise to the filtrate. After the addition was completed, stirring and crystallization were continued for 1h, and the filter cake was washed with 2*200mL of water and 2*200mL of anhydrous ethanol, and vacuum dried at 80°C for 24h. After air flow pulverization, 45.5g of adapalene crystal form II compound was obtained; the HPLC purity was 99.98%, and the yield was 91.0%; its X-ray powder diffraction pattern was as follows: Figure 3As shown, it has characteristic peaks at diffraction angles (2θ±0.2°) of 9.9°, 14.2°, 15.0°, 15.3°, 16.4°, 17.4°, 18.3°, 19.9°, 20.6°, 22.3°, 24.9°, 25.6°, and 26.9°.

[0045] Embodiment 4: A method for preparing an Adapalene crystal form II compound comprises the following steps: (1) Add 50 g of crude adapalene, 1000 mL of DMSO and 350 mL of THF to a 2 L reaction bottle, start stirring at 400 rpm, and stir at 25 ° C for 1 h until the solution becomes clear to obtain a crude solution; (2) Add 2.5 g of activated carbon to the crude solution, continue stirring to decolorize for 1 h, and filter; (3) The filtrate obtained in step (2) was transferred to another clean 2L reaction bottle, and 250mL of water was slowly added dropwise to the filtrate. After the addition was completed, stirring and crystallization were continued for 3h, and the filter cake was washed with 2*200mL of water and 2*200mL of anhydrous ethanol, and vacuum dried at 80°C for 24h. After air flow milling, 46.8g of Adapalene Form II compound was obtained; HPLC purity was 99.96%, and the yield was 93.6%.

[0046] Embodiment 5: A method for preparing an Adapalene crystal form II compound comprises the following steps: (1) Add 50 g of crude adapalene, 500 mL of DMSO and 500 mL of THF to a 2 L reaction bottle, start stirring at 300 rpm, and stir at 25 ° C for 1 h until the solution becomes clear to obtain a crude solution; (2) Add 1.0 g of activated carbon to the crude solution, continue stirring to decolorize for 3 h, and filter; (3) The filtrate obtained in step (2) was transferred to another clean 2L reaction bottle, and 150mL of water was slowly added dropwise to the filtrate. After the addition was completed, stirring and crystallization were continued for 3h, and the filter cake was washed with 2*200mL of water and 2*200mL of anhydrous ethanol, and vacuum dried at 80°C for 24h. After air flow milling, 45.6g of adapalene crystal form II compound was obtained; HPLC purity was 99.97%, and the yield was 91.2%.

[0047] Embodiment 6: A method for preparing an Adapalene crystal form II compound comprises the following steps: (1) Add 50 g of crude adapalene, 1500 mL of DMSO and 250 mL of THF to a 2 L reaction bottle, start stirring at 400 rpm, and stir at 25 ° C for 1 h until the solution becomes clear to obtain a crude solution; (2) Add 1.0 g of activated carbon to the crude solution, continue stirring to decolorize for 1 h, and filter; (3) The filtrate obtained in step (2) was transferred to another clean 2L reaction bottle, and 150mL of water was slowly added dropwise to the filtrate. After the addition was completed, stirring and crystallization were continued for 3h, and the filter cake was washed with 2*200mL of water and 2*200mL of anhydrous ethanol, and vacuum dried at 80°C for 24h. After air flow milling, 45.8g of adapalene crystal form II compound was obtained; HPLC purity was 99.95%, and the yield was 91.6%.

[0048] Embodiment 7: A method for preparing an Adapalene crystal form II compound comprises the following steps: (1) Add 50 g of crude adapalene, 750 mL of DMSO and 300 mL of THF to a 2 L reaction bottle, start stirring at 250 rpm, and stir at 25 ° C for 1 h until the solution becomes clear to obtain a crude solution; (2) Add 0.5 g of activated carbon to the crude solution, continue stirring and decolorizing for 5 h, and filter; (3) The filtrate obtained in step (2) was transferred to another clean 2L reaction bottle, and 150mL of water was slowly added dropwise to the filtrate. After the addition was completed, stirring and crystallization were continued for 3h, and the filter cake was washed with 2*200mL of water and 2*200mL of anhydrous ethanol, and vacuum dried at 80°C for 24h. After air flow milling, 45.3g of adapalene crystal form II compound was obtained; HPLC purity was 99.93%, and the yield was 90.6%.

[0049] Embodiment 8: A method for preparing an Adapalene crystal form II compound comprises the following steps: (1) Add 50 g of crude adapalene, 750 mL of DMSO and 300 mL of THF to a 2 L reaction bottle, start stirring at 250 rpm, and stir at 25 ° C for 1 h until the solution becomes clear to obtain a crude solution; (2) Add 5.0 g of activated carbon to the crude solution, continue stirring to decolorize for 1 h, and filter; (3) The filtrate obtained in step (2) was transferred to another clean 2L reaction bottle, and 150mL of water was slowly added dropwise to the filtrate. After the addition was completed, stirring and crystallization were continued for 3h, and the filter cake was washed with 2*200mL of water and 2*200mL of anhydrous ethanol, and vacuum dried at 80°C for 24h. After air flow milling, 46.0g of adapalene crystal form II compound was obtained; HPLC purity was 99.97%, and the yield was 92.0%.

[0050] Embodiment 9: A method for preparing an Adapalene crystal form II compound comprises the following steps: (1) Add 50 g of crude adapalene, 750 mL of DMSO and 300 mL of THF to a 2 L reaction bottle, start stirring at 250 rpm, and stir at 25 ° C for 1 h until the solution becomes clear to obtain a crude solution; (2) Add 1.0 g of activated carbon to the crude solution, continue stirring to decolorize for 1 h, and filter; (3) The filtrate obtained in step (2) was transferred to another clean 2L reaction bottle, and 100mL of water was slowly added dropwise to the filtrate. After the addition was completed, stirring and crystallization were continued for 3h, and the filter cake was washed with 2*200mL of water and 2*200mL of anhydrous ethanol, and vacuum dried at 80°C for 24h. After air flow milling, 45.5g of adapalene crystal form II compound was obtained; HPLC purity was 99.96%, and the yield was 91.0%.

[0051] Embodiment 10: A method for preparing an Adapalene crystal form II compound comprises the following steps: (1) Add 50 g of crude adapalene, 750 mL of DMSO and 300 mL of THF to a 2 L reaction bottle, start stirring at 250 rpm, and stir at 25 ° C for 1 h until the solution becomes clear to obtain a crude solution; (2) Add 1.0 g of activated carbon to the crude solution, continue stirring to decolorize for 1 h, and filter; (3) The filtrate obtained in step (2) was transferred to another clean 2L reaction bottle, and 400mL of water was slowly added dropwise to the filtrate. After the addition was completed, stirring and crystallization were continued for 3h, and the filter cake was washed with 2*200mL of water and 2*200mL of anhydrous ethanol, and vacuum dried at 80°C for 24h. After air flow milling, 46.2g of adapalene crystal form II compound was obtained; HPLC purity was 99.98%, and the yield was 92.4%.

[0052] Comparative Example 1: A method for preparing an adapalene compound comprises the following steps: (1) Add 50 g of crude adapalene, 750 mL of THF and 300 mL of anhydrous ethanol to a 2 L reaction bottle, start stirring at 250 rpm, and stir at 25 ° C for 1 h until the solution becomes clear to obtain a crude solution; (2) Add 1.0 g of activated carbon to the crude solution, continue stirring to decolorize for 1 h, and filter; (3) The filtrate obtained in step (2) was transferred to another clean 2L reaction bottle, and 150mL of water was slowly added dropwise to the filtrate. After the addition was completed, stirring and crystallization were continued for 1h, and the filter cake was washed with 2*200mL of water and 2*200mL of anhydrous ethanol in turn. After drying at room temperature for 24h, 47.0g of adapalene compound was obtained; the HPLC purity was 99.95%, and the yield was 94.0%; its X-ray powder diffraction pattern was as follows: Figure 4 As shown, there are characteristic peaks at diffraction angles (2θ±0.2°) of 9.8°, 13.2°, 14.2°, 14.9°, 15.3°, 16.3°, 16.5°, 17.3°, 18.2°, 19.8°, 20.6°, 22.3°, 23.2°, 24.9°, 25.5°, and 26.6°.

[0053] from Figure 1 and Figure 4 It can be seen from the comparison that in Comparative Example 1, by changing the solvent type in step (1) and the crystallization system, the resulting adapalene crystal system is different from that in Example 1, and a stable adapalene crystal form II compound cannot be obtained.

[0054] In Example 1 and Example 2, the Adapalene Form II compound was air-dried at room temperature and dried at 80° C. for 24 h, respectively. The comparison of the characteristic 2θ values ​​is shown in Table 1.

[0055] Table 1: Comparison of characteristic 2θ values ​​of Adapalene Form II compound after drying at room temperature and at 80°C for 24h. Serial number Example 1 Characteristic 2θ Value Example 2 Characteristic 2θ Value 1 10.0° 9.9° 2 14.2° 14.2° 3 15.0° 15.0° 4 15.4° 15.3° 5 16.4° 16.4° 6 17.5° 17.4° 7 18.3° 18.3° 8 20.0° 20.0° 9 20.7° 20.6° 10 22.4° 22.4° 11 25.0° 25.0° 12 25.7° 25.6° 13 26.9° 26.9°

[0056] It can be seen that the Adapalene crystal form II compound prepared by the method of the present invention in the example is dried at 80° C. for 24 hours, and the crystal form is stable without obvious changes.

[0057] Example 3 The Adapalene crystal form II compound obtained in Example 2 was crushed, and the characteristic 2θ value comparison is shown in Table 2.

[0058] Table 2: Comparison of characteristic 2θ values ​​of Adapalene Form II compound before and after crushing. Serial number Example 2 Characteristic 2θ Value Example 3 Characteristic 2θ Value 1 9.9° 9.9° 2 14.2° 14.2° 3 15.0° 15.0° 4 15.3° 15.3° 5 16.4° 16.4° 6 17.4° 17.4° 7 18.3° 18.3° 8 20.0° 19.9° 9 20.6° 20.6° 10 22.4° 22.3° 11 25.0° 24.9° 12 25.6° 25.6° 13 26.9° 26.9°

[0059] The results show that the adapalene crystal form II compound prepared by the method of the present invention in the example has a stable crystal form before and after crushing without obvious changes.

[0060] The crushed Adapalene crystal form II compound obtained in Example 3 of the present invention was placed under the conditions of temperature 30° C. and humidity 65% ​​for 3 months and 12 months. Its X-ray powder diffraction pattern is as follows: Figure 5 and Figure 6As shown in , the characteristic 2θ value comparison is shown in Table 3.

[0061] Table 3: Comparison of characteristic 2θ values ​​of Adapalene Form II compound stored at 30°C and 65% humidity for 3 months and 12 months. Serial number Example 3 Characteristic 2θ Values ​​after 3 Months of Storage Example 3 Characteristic 2θ value after 12 months of storage 1 10.0° 9.9° 2 14.3° 14.2° 3 15.1° 15.0° 4 15.4° 15.3° 5 16.5° 16.4° 6 17.5° 17.4° 7 18.4° 18.3° 8 20.0° 19.9° 9 20.7° 20.6° 10 22.4° 22.3° 11 25.0° 24.9° 12 25.7° 25.6° 13 27.0° 26.9°

[0062] It can be seen from the above results that the adapalene crystal form II compound prepared by the method of the present invention in the example is stable without obvious changes when placed at 30° C. and 65% humidity for 3 months and 12 months.

[0063] The solubility of the Adapalene Form II compound before and after crushing in Example 2 and Example 3 of the present invention was compared, and the results are shown in Table 4.

[0064] Table 4: Comparison of solubility of Adapalene Form II compounds before and after crushing.

[0065] The results show that the adapalene crystal form II compound prepared by the method of the present invention is almost insoluble in water and 96% ethanol before and after crushing, but the solubility of the crushed adapalene in tetrahydrofuran is significantly improved, which is beneficial to the development of the preparation process.

[0066] The above content is a further detailed description of the technical solution of the present invention in combination with a specific preferred implementation method, and should not be understood as a limitation on the applicable scope of the present invention. For ordinary technicians in the field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the present invention, which should be deemed to fall within the scope of patent protection determined by the claims submitted for the present invention.

Claims

1. A method for preparing an Adapalene crystal form II compound, characterized in that: The steps include: (1) dissolving the crude adapalene in a mixed solvent of DMSO and THF to obtain a crude solution; (2) Add activated carbon to the obtained crude product solution, stir at room temperature to decolorize, and then filter; (3) adding water to the filtrate obtained in step (2), stirring to crystallize, filtering, washing the filter cake with water and anhydrous ethanol, and drying to obtain the adapalene crystal form II compound.

2. The method for preparing the Adapalene crystal form II compound according to claim 1, characterized in that: The mass volume ratio of crude adapalene to DMSO and THF in step (1) is 1 g: 10-30 mL: 5-10 mL.

3. The method for preparing the Adapalene crystal form II compound according to claim 1 or 2, characterized in that: The dissolution temperature of the crude adapalene in step (1) is 0-40°C.

4. The method for preparing the Adapalene crystal form II compound according to claim 1, characterized in that: The mass of the activated carbon added in step (2) is 1-10% of the mass of the crude adapalene.

5. The method for preparing the Adapalene crystal form II compound according to claim 1 or 4, characterized in that: The stirring decolorization time in step (2) is 1 to 5 hours.

6. The method for preparing the Adapalene crystal form II compound according to claim 1, characterized in that: The volume mass ratio of water added to the filtrate in step (3) to the crude adapalene is 2-8 mL:1 g.

7. The method for preparing the Adapalene crystal form II compound according to claim 1 or 6, characterized in that: The crystallization temperature in step (3) is 0-40°C, and the crystallization time is 1-24h.

8. The method for preparing the Adapalene crystal form II compound according to claim 1, characterized in that: In step (3), vacuum drying is adopted during drying, the vacuum drying temperature is 50-80° C., and the vacuum drying time is 4-24 h.

9. An Adapalene crystal form II compound, characterized in that: It is prepared using the preparation method described in any one of claims 1 to 8.

10. The adapalene crystal form II compound according to claim 9, characterized in that: The X-ray powder diffraction pattern has characteristic peaks at diffraction angles of 9.9±0.1°, 14.2±0.1°, 15.0±0.1°, 15.3±0.1°, 16.4±0.1°, 17.4±0.1°, 18.3±0.1°, 19.9±0.1°, 20.6±0.1°, 22.3±0.1°, 24.9±0.1°, 25.6±0.1°, and 26.9±0.1°.

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