Crystal form of sparsentan as well as preparation method and pharmaceutical composition thereof

Abstract

The invention belongs to the technical field of medicine, and discloses a sparsentan crystal form, a preparation method thereof and a pharmaceutical composition, the crystal form is a crystal form A, and X-ray powder diffraction of the crystal form A has characteristic peaks at diffraction angles 2theta of 7.1 + / -0.2 degrees, 12.5 + / -0.2 degrees, 12.8 + / -0.2 degrees, 14.1 + / -0.2 degrees, 15.7 + / -0.2 degrees, 16.8 + / -0.2 degrees, 18.6 + / -0.2 degrees, 20.5 + / -0.2 degrees and 21.4 + / -0.2 degrees. According to the present invention, by reasonably designing the first solvent, adjusting the pH value of the system, the subsequent good solvent and / or poor solvent, the temperature and the time of cooling crystallization, and the like, the new sparsentan crystal form A is obtained, the purity of the obtained product is high, the product is in the crystalline state, and the stability is significantly improved. By adopting the crystallization method, the operation is simple, the amplification is easy, the production cost is greatly reduced, and the efficiency is greatly improved.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technologies, and particularly relates to a crystal form of sparspitant, a preparation method thereof, and a pharmaceutical composition. Background Art

[0002] Sparspitant is a drug with specifications of 200 mg and 400 mg approved by the FDA on February 17, 2023 by TRAVERE THERAPEUTICS INC. It is applicable to reducing proteinuria in adult patients with primary immunoglobulin A nephropathy (IgAN) at risk of rapid disease progression, and is the only approved endothelin-angiotensin dual blocker currently.

[0003] Angiotensin II (AngII) and endothelin-I (ET-1) are two of the most potent endogenous vasoactive peptides currently known, and are considered to play a role in controlling vasotension and pathological tissue remodeling associated with various diseases, including diabetic nephropathy, heart failure, and chronic or persistent hypertension. Angiotensin receptor blockers (ARBs) that block the activity of AngII have been used in the treatment of diabetic nephropathy, heart failure, and chronic or persistent hypertension. There is also growing data demonstrating the potential therapeutic benefits of endothelin receptor antagonists (ERAs) that block the activity of ET-1. Additionally, it is believed that AngII and ET-1 act together in blood pressure control and pathological tissue remodeling. Blocking the activities of both AngII and ET-1 simultaneously can provide better efficacy compared to blocking the activity of either molecule alone. In a rat model of human chronic or persistent hypertension, the combination of an ARB and an ERA has been shown to produce a synergistic effect. Furthermore, although ARBs are the standard treatment for patients with diabetic nephropathy, improved efficacy has been reported in phase 2 clinical development when co-administered with an ERA.

[0004] Currently, the preparation of sparspitant mainly adopts spray drying to prepare the amorphous form, attached Figure 1 is the XRPD spectrum of the spray-dried sample reported in the patent document with the publication number CN114126712A.

[0005] By querying the relevant literature and patents on the preparation of sparspitant raw materials, it can be seen that there are currently mainly amorphous patents (CN114126712A), which are prepared by spray drying. However, spray drying has the following disadvantages: In terms of equipment and operation costs: high equipment investment, large energy consumption, high maintenance costs, and low efficiency. In terms of product quality: relatively poor stability, which may in turn affect the active ingredient, large product bulk density; In terms of process operation: small operation flexibility, limited material adaptability, fine powder recovery problems, etc.

[0006] And there are currently no other reports on crystal form patents. In view of this, this patent application is proposed. Summary of the Invention

[0007] The object of the present invention is to provide a crystal form of spironolactone, and also provide a preparation method thereof, and provide a pharmaceutical composition. The spironolactone obtained in the present invention is a new crystal form A, which is in a crystalline state, with significantly improved stability, high purity, and uses a crystallization method, which is simple in operation, easy to scale up, and does not have problems such as those that may easily affect the active ingredient during the spray drying process.

[0008] The present invention is achieved by the following technical solutions: The first object of the present invention is to provide a crystal form of spironolactone, wherein the crystal form is crystal form A, and its X-ray powder diffraction has characteristic peaks at diffraction angles 2θ = 7.1° ± 0.2°, 12.5° ± 0.2°, 12.8° ± 0.2°, 14.1° ± 0.2°, 15.7° ± 0.2°, 16.8° ± 0.2°, 18.6° ± 0.2°, 20.5° ± 0.2°, 21.4° ± 0.2°.

[0009] Furthermore, its XRPD diffraction pattern is as shown in Figure 2 or Figure 4 as shown.

[0010] The second object of the present invention is to provide a preparation method of the spironolactone crystal form described in any one of the above, including the following process: (1) At a certain temperature, add the crude spironolactone salt to the first solvent to dissolve, adjust the pH of the system to 9.0, extract and concentrate to obtain the first product; (2) Add a good solvent to the first product to dissolve it clearly, cool down and stir to obtain the second product, or add a good solvent to the first product to dissolve it clearly and then add a poor solvent, and then cool down and stir to obtain the second product; (3) Filter, wash and dry the second product to obtain the crystal form A of spironolactone.

[0011] As a preferred design, in step (1), add the crude spironolactone salt to the first solvent to dissolve under the condition of 20 - 30°C.

[0012] As a preferred design, the first solvent is dichloromethane, and the pH of the system is adjusted with a 2M sodium carbonate solution.

[0013] As a preferred design, the good solvent is at least one of alcohols and ketones; Preferably, the alcohols are at least one of methanol, ethanol, isopropanol, and tert-butanol, and the ketones are at least one of acetone and butanone; Preferably, the good solvent is acetone; Preferably, the poor solvent is at least one of water, n-heptane, and n-hexane.

[0014] As a preferred design, the temperature reduction is to reduce the temperature to -10 - 30°C, and the crystallization time is 1 - 8 h; As a preferred design, the temperature reduction is to reduce the temperature to 10 - 20°C, and the crystallization time is 2 h.

[0015] As a preferred design, when a good solvent is added to the first product to dissolve it clearly, and then the temperature is reduced and stirred to obtain the second product, the washing solvent in step (3) is the good solvent; When a bad solvent is added after adding a good solvent to the first product to dissolve it clearly, and then the temperature is reduced and stirred to obtain the second product, the washing solvent in step (3) is the bad solvent; The drying in step (3) is vacuum drying.

[0016] In the present invention, by reasonably designing the first solvent, adjusting the pH value of the system, and subsequent good solvent and / or bad solvent, the temperature and time of temperature reduction and crystallization, etc., a new crystal form A of spironolactone is obtained. The above preparation method is simple in operation, easy to scale up, and the stability of process scale-up production is significantly improved.

[0017] The third object of the present invention is to provide a pharmaceutical composition, which contains the crystal form of spironolactone described in any one of the above and a pharmaceutically acceptable carrier.

[0018] The advantages and beneficial effects of the present invention compared with the prior art are: 1. In the present invention, by reasonably designing the first solvent, adjusting the pH value of the system, and subsequent good solvent and / or bad solvent, the temperature and time of temperature reduction and crystallization, etc., a new crystal form A of spironolactone is obtained. By using this crystallization method, the operation is simple, easy to scale up, and the stability of process scale-up production is significantly improved.

[0019] 2. The present invention adopts two crystallization methods to obtain the new crystal form A, and the purity of the obtained products is relatively high. After purity detection, it all reaches more than 99.7%.

[0020] 3. The present invention adopts the crystallization method, which has low requirements for the preparation equipment and is easy to control the process. Compared with the spray drying method, it is significantly more suitable for industrial production. At the same time, by using the crystallization method to obtain crystal form A, compared with the current amorphous structure, the crystal form A of the present invention is in a crystalline state, and its stability is higher than that of the amorphous state. By using the crystallization method, problems that may affect the active ingredient, such as those easily occurring in the spray drying process, will not occur, and the operation flexibility is large, the adaptability of materials is wider, and there is no technical problem of fine powder recovery. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] To more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and should not be regarded as limiting the scope. For those of ordinary skill in the art, without creative efforts, other related drawings can also be obtained based on these drawings. In the drawings: Figure 1 is the XRPD pattern of amorphous spironolactone disclosed in the existing patent CN114126712A; Figure 2 is the XRPD pattern of spironolactone obtained in Example 1 of the present invention; Figure 3 is the HPLC chromatogram of spironolactone obtained in Example 1 of the present invention; Figure 4 is the XRPD pattern of spironolactone obtained in Example 2 of the present invention; Figure 5 is the HPLC chromatogram of spironolactone obtained in Example 2 of the present invention; Figure 6 is the XRPD pattern of spironolactone obtained in Example 3 of the present invention; Figure 7 is the HPLC chromatogram of spironolactone obtained in Example 3 of the present invention; Figure 8 is the XRPD pattern of spironolactone obtained in Example 4 of the present invention; Figure 9 is the HPLC chromatogram of spironolactone obtained in Example 4 of the present invention. Detailed Embodiments

[0022] To make the objectives, technical solutions, and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below in conjunction with the embodiments and the drawings. The illustrative embodiments of the present invention and their descriptions are only used to explain the present invention and are not used to limit the present invention.

[0023] In the following description, a large number of specific details are set forth in order to provide a thorough understanding of the present invention. However, it is obvious to those of ordinary skill in the art that: these specific details do not have to be adopted to implement the present invention. In other embodiments, well-known structures, materials, or methods are not specifically described in order to avoid obscuring the present invention.

[0024] Throughout the specification, references to "one embodiment", "an embodiment", "one example" or "an example" mean that a particular feature, structure, or characteristic described in connection with the embodiment or example is included in at least one embodiment of the present invention. Thus, the phrases "one embodiment", "an embodiment", "one example" or "an example" appearing throughout the specification do not necessarily all refer to the same embodiment or example. In addition, the specific features, structures, or characteristics may be combined in any suitable combination and / or sub-combination in one or more embodiments or examples. Furthermore, those of ordinary skill in the art should understand that the diagrams provided herein are for illustrative purposes only and are not necessarily drawn to scale. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0025] By querying the relevant literature and patents on the preparation of spironolactone API, it is known that there are currently amorphous patents (CN114126712A), which are prepared by spray drying. However, spray drying has the following disadvantages: In terms of equipment and operating costs: high equipment investment, large energy consumption, high operating and maintenance costs, and low production efficiency. In terms of product quality: relatively poor stability, which may affect the active ingredient, large product bulk density; In terms of process operation: small operating flexibility, limited material adaptability, and problems with fine powder recovery, etc.

[0026] To solve the above problems, in the present invention, a new crystal form A of spironolactone is obtained by selection area. By reasonably designing the first solvent, adjusting the pH value of the system, and subsequent good solvents and / or poor solvents, the temperature and time of cooling crystallization, etc., the new crystal form A of spironolactone is obtained. The above preparation method is simple to operate, easy to scale up, and the stability of process scale-up production is significantly improved.

[0027] Specifically, for the crystal form A of spironolactone obtained, its X-ray powder diffraction has characteristic peaks at diffraction angles 2θ = 7.1° ± 0.2°, 12.5° ± 0.2°, 12.8° ± 0.2°, 14.1° ± 0.2°, 15.7° ± 0.2°, 16.8° ± 0.2°, 18.6° ± 0.2°, 20.5° ± 0.2°, 21.4° ± 0.2°.

[0028] And its preparation method is as follows: At a certain temperature, the crude spironolactone salt is adjusted to a pH of the system with an alkali solution, extracted and concentrated, a solvent is added for crystallization, filtered, washed, and dried. The product obtained is the crystal form A of spironolactone API.

[0029] Specifically, the preparation method is as follows: Step (1): At a certain temperature, the crude spironolactone salt is added to the first solvent for dissolution, the pH of the system is adjusted to 9.0, extracted and concentrated to obtain a first product; Step (2): Dissolve the first product in a good solvent until clear, cool down the temperature and stir to obtain the second product, or add a bad solvent after dissolving the first product in a good solvent until clear, then cool down the temperature and stir to obtain the second product; Step (3): Filter, wash and dry the second product to obtain the crystalline form A of sparfosentan.

[0030] In step (2), there are two cases. The first case is to add a good solvent to the obtained first product, and then cool down the temperature to crystallize to obtain the second product; the second case is to add a bad solvent after dissolving the obtained first product in a good solvent until clear and then cool down the temperature to crystallize, which is more conducive to the precipitation of sparfosentan. The above two crystallization methods can both obtain the new crystalline form A, and the purity of the obtained products is relatively high, and all reach more than 99.7% after purity detection.

[0031] The following is a more detailed description of the preparation of sparfosentan through specific examples.

[0032] Experimental Example 1: At 20 - 30 °C, add 50 g of the crude sparfosentan salt to 200 mL of dichloromethane, and adjust the pH of the system to 9 using a 2 M sodium carbonate solution. Separate the liquid, concentrate the organic phase to dryness, add 100 mL of acetone, heat to dissolve until clear, then cool down the system to 0 - 10 °C, keep stirring at 0 - 10 °C for 2 h and then filter. Wash the filter cake with 20 mL of acetone, drain, and dry the filter cake to obtain 25.02 g of sparfosentan.

[0033] After detection, the purity is 99.78%, and the crystalline form is crystalline form A. Its XRPD spectrum is shown in the appendix Figure 2 , and the corresponding data are shown in Table 1. The HPLC spectrum is shown in the appendix Figure 3 and Table 2.

[0034] The instrument model used for XRPD detection is XD6, using a copper target, with a wavelength of 0.154 nm, the starting angle of detection is 3°, the ending angle is 60°, the scanning speed is 8° / min, the sampling step width is 0.01, the high voltage is set at 36 KV, the current is 20 mA, and the power is 1.5 kW.

[0035] It can be seen from the XRPD pattern that it has characteristic peaks at 2θ = 7.1°, 12.5°, 12.8°, 14.1°, 15.7°, 16.8°, 18.6°, 20.5°, 21.4°.

[0036] Table 1

[0037] Table 2:

[0038] Experimental Example 2: At 20 - 30 °C, 50 g of the crude sparsentan salt was added to 200 mL of dichloromethane, and the pH of the system was adjusted to 9 using a 2 M sodium carbonate solution. The phases were separated, and the organic phase was concentrated to dryness. 100 mL of acetone was added, and the mixture was heated to dissolve completely. Then 500 mL of purified water was added dropwise, and the temperature of the system was lowered to 0 - 10 °C. After stirring at 0 - 10 °C for 2 h, filtration was carried out. The filter cake was washed with 50 mL of purified water, drained, and dried to obtain 30.23 g of sparsentan.

[0039] After detection, the purity was 99.81%, and the crystal form was crystal form A. The XRPD spectrum is shown in the appendix Figure 4 , and the corresponding data are shown in Table 3. The HPLC spectrum is shown in the appendix Figure 5 and Table 4.

[0040] The instrument model used for XRPD detection was XD6. The starting angle of detection was 3°, the ending angle was 60°, the scanning speed was 8° / min, the sampling step width was 0.01, the high voltage was set at 36 kV, the current was 20 mA, and the power was 1.5 kW.

[0041] It can be seen from the XRPD pattern that it has characteristic peaks at 2θ = 7.2°, 12.6°, 12.9°, 14.2°, 15.8°, 16.9°, 18.7°, 20.6°, and 21.5°.

[0042] Table 3

[0043] Table 4:

[0044] Experimental Example 3: At 20 - 30 °C, 50 g of the crude sparsentan salt was added to 200 mL of dichloromethane, and the pH of the system was adjusted to about 9 using a 2 M sodium carbonate solution. The phases were separated, and the organic phase was concentrated to dryness. 100 mL of acetone was added, and the mixture was heated to dissolve completely. Then 500 mL of n - heptane was added dropwise, and the temperature of the system was lowered to 0 - 10 °C. After stirring at 0 - 10 °C for 2 h, filtration was carried out. The filter cake was washed with 50 mL of n - heptane, drained, and dried to obtain 30.11 g of sparsentan.

[0045] After detection, the purity was 99.73%, and the crystal form was crystal form A. Its XRPD spectrum is shown in the appendix Figure 6 , and the corresponding data are shown in Table 5. The HPLC spectrum is shown in the appendix Figure 7 and Table 6.

[0046] The instrument model used for XRPD detection was XD6. The starting angle of detection was 3°, the ending angle was 60°, the scanning speed was 8° / min, the sampling step width was 0.01, the high voltage was set at 36 kV, the current was 20 mA, and the power was 1.5 kW.

[0047] As can be seen from the XRPD pattern, it has characteristic peaks at 2θ = 7.0°, 12.4°, 12.7°, 14.1°, 15.7°, 16.8°, 18.6°, 20.5°, and 21.4°.

[0048] Table 5

[0049] Table 6

[0050] Experimental Example 4: At 20 - 30 °C, 50 g of the crude spironolactone salt was added to 200 mL of dichloromethane, and the system was adjusted to a pH of about 9 using 2 M sodium carbonate solution. After liquid separation, the organic phase was concentrated to dryness, 100 mL of acetone was added, and it was heated to dissolve clearly. 500 mL of n - hexane was added dropwise, and the system was cooled to 0 - 10 °C. After stirring at 0 - 10 °C for 2 h, it was filtered. The filter cake was washed with 50 mL of n - hexane, drained, and the filter cake was dried to obtain 30.18 g of spironolactone.

[0051] After testing, the purity was 99.84%, and the crystal form was Crystal Form A.

[0052] Its XRPD pattern is shown in the appendix Figure 8 , and the corresponding data are shown in Table 7. The HPLC pattern is shown in the appendix Figure 9 and Table 8.

[0053] The instrument model used for XRPD detection was XD6, the starting angle of detection was 3°, the ending angle was 60°, the scanning speed was 8° / min, the sampling step width was 0.01, the high - voltage setting was 36 kV, the current was 20 mA, and the power was 1.5 kW.

[0054] As can be seen from the XRPD pattern, it has characteristic peaks at 2θ = 7.2°, 12.6°, 12.9°, 14.2°, 15.8°, 16.9°, 18.6°, 20.5°, and 21.4°.

[0055] Table 7

[0056] Table 8

[0057] In the present invention, the crystallization method is adopted, which has low requirements for the preparation equipment, easy process control, simple operation, and is easy to scale up. Compared with the spray drying method, it is obviously more suitable for industrial production. At the same time, the crystalline form A is obtained by the crystallization method. Compared with the current amorphous structure, the crystalline form A of the present invention is in a crystalline state and has higher stability than the amorphous state. By using the crystallization method, problems such as relatively poor stability of the product obtained by spray drying, which may affect the active ingredient, will not occur, and it has a large operation flexibility, wider adaptability to materials, and there is no technical problem of fine powder recovery.

[0058] The inventor carried out particle size and particle size distribution detection on the product obtained in Example 2, wherein the particle size D(90) is less than 20 μm, the bulk density is 0.33 g / ml, and the tapped density is 0.49 g / ml. Both the bulk density and the tapped density are relatively small.

[0059] Furthermore, the stability verification was carried out on the product obtained according to Example 2, and the results are shown in Table 9: Table 9:

[0060] Note: N.D. means not detected. The accelerated conditions are 40 ± 2°C and 75% ± 5% RH.

[0061] As can be seen from Table 9, the stability of the new crystalline form A of spironolactone obtained in the present invention meets the requirements. The maximum single impurity and total impurities both meet the requirements after 6 months of acceleration and 12 months of long-term storage, and the water content and content also meet the requirements. It can be seen that the new crystalline form A of the present invention has high stability.

[0062] Example 5: The present invention also provides a pharmaceutical composition, which includes spironolactone obtained in any one of Examples 1 to 4, and also includes a pharmaceutically acceptable carrier, which can be ethanol, polyethylene glycol, starch, microcrystalline cellulose, magnesium stearate, etc. This pharmaceutical composition can be used as an endothelin-angiotensin dual blocker to reduce proteinuria in adult patients with primary immunoglobulin A nephropathy (IgAN).

[0063] The above specific embodiments further elaborate on the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not used to limit the protection scope of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A crystal form of spironolactone, characterized in that, The crystal form is crystal form A, and its X-ray powder diffraction has characteristic peaks at diffraction angles 2θ = 7.1° ± 0.2°, 12.5° ± 0.2°, 12.8° ± 0.2°, 14.1° ± 0.2°, 15.7° ± 0.2°, 16.8° ± 0.2°, 18.6° ± 0.2°, 20.5° ± 0.2°, 21.4° ± 0.2°.

2. The crystalline form of spironolactone according to claim 1, wherein Its XRPD diffraction pattern is as shown in Figure 2 or Figure 4.

3. A method for preparing a crystal form of sparsentan according to any one of claims 1 to 2, characterized in that, It includes the following process: (1) Under the condition of 20~30 °C, the crude product of sparspitant salt is added to the first solvent for dissolution, the pH of the system is adjusted to 9.0, extracted and concentrated to obtain the first product; (2) Add a good solvent to the first product to dissolve it clearly, cool down and stir to obtain the second product, or add a good solvent to the first product to dissolve it clearly and then add a poor solvent, and then cool down and stir to obtain the second product; (3) Filter, wash and dry the second product to obtain crystal form A of sparspitant; The first solvent is dichloromethane; The good solvent is at least one of alcohols and ketones; The poor solvent is at least one of water, n-heptane and n-hexane.

4. The preparation method of a crystal form of spironolactone according to claim 3, characterized in that, The pH of the system is adjusted with a 2M sodium carbonate solution.

5. The preparation method of a crystal form of sparsentan according to claim 3, characterized in that, The alcohols are at least one of methanol, ethanol, isopropanol and tert-butanol, and the ketones are at least one of acetone and butanone.

6. The preparation method of a crystalline form of sparsentan according to claim 3, wherein, The good solvent is acetone.

7. A method for preparing a crystal form of spironolactone according to claim 3, characterized in that, The cooling is to cool the temperature to -10 - 30 °C, and the crystallization time is 1 - 8 h.

8. A method for preparing the crystal form of sparsentan according to claim 3, characterized in that, The cooling is to cool the temperature to 10 - 20 °C, and the crystallization time is 2 h.

9. The preparation method of a crystal form of sparsentan according to claim 3, characterized in that, When adding a good solvent to the first product to dissolve it clearly, cooling down and stirring to obtain the second product, the washing solvent in step (3) is the good solvent; When adding a good solvent to the first product to dissolve it clearly and then adding a poor solvent, and then cooling down and stirring to obtain the second product, the washing solvent in step (3) is the poor solvent; The drying in step (3) is vacuum drying.

10. A pharmaceutical composition, characterized in that, It contains the crystal form of sparspitant as described in any one of claims 1~2 and a pharmaceutically acceptable carrier.

Images