Rosaxostat new crystal form and preparation method thereof

Abstract

The invention discloses a novel crystal form RX-1 of rosaxostat and a preparation method thereof, the crystal form has excellent solubility, good physical stability and chemical stability, and is beneficial to improving the bioavailability and efficacy of drugs. In addition, the crystal form provided by the invention is simple in preparation method, good in repeatability and suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug crystals, and in particular to new crystal forms of rosuvastatin and salts thereof and a preparation method thereof. Background Art

[0002] Roxadustat is an oral small molecule hypoxia-inducible factor prolyl hydroxylase inhibitor with the structure of the following formula (I). It is clinically used to treat anemia in patients with chronic kidney disease. In December 2017, roxadustat capsules were included in the priority review public announcement list by the China Drug Evaluation Center and were approved for marketing on December 17, 2018. Roxadustat exists in multiple crystal forms. Patent CN109369524A discloses four crystal forms of roxadustat, namely Form A, Form B, Form C and Form D, of which Form A is a pure crystal form, Form B is a hydrate crystal form that can be spontaneously converted into Form A, Form C is a solvate containing hexafluoropropane-2-ol, and Form D is a solvate containing DMSO and water; Patent WO2013013069 discloses seven crystal forms of roxadustat, namely Form I, Form II, Form III, Form IV, Form V, Form VI and Form VII. Most of these crystal forms are solvates, which are not suitable for development as drug crystal forms; Patent CN109369525A discloses 12 crystal forms of roxadustat, namely, crystal form ARE-A, crystal form ARE-B, crystal form ARE-C, crystal form ARE-D, crystal form ARE-E, crystal form ARE-F, crystal form ARE-G, crystal form ARE-H, crystal form ARE-I, crystal form ARE-J, crystal form ARE-K and crystal form ARE-L. These crystal forms are solvates or metastable crystal forms with poor stability, and cannot be developed as drug crystal forms and cannot be industrialized. Therefore, among the many crystal forms of roxadustat, crystal form Form A is the most thermodynamically stable crystal form, which is suitable for development as a drug crystal form, but crystal form Form A has a major drawback, that is, the solubility of crystal form Form A is poor and it is almost insoluble in water, which directly leads to low solubility in the human body, affects absorption, and it is difficult to exert the efficacy.

[0003] Summary of the invention

[0004] In order to solve the problems of poor water solubility and low bioavailability of existing crystal forms, the present invention provides a new rosuvastat crystal form RX-1. The present invention also discloses a method for preparing the new rosuvastat crystal form. The inventor unexpectedly found that the new rosuvastat crystal form RX-1 has higher solubility than the rosuvastat crystal form Form A provided by the prior art patent CN109369524A, and has good physical and chemical stability, a simple preparation process, and is suitable for large-scale production.

[0005] In the first aspect of the present invention, a rosuvastatin crystal form RX-1 is provided, characterized in that its X-ray powder diffraction spectrum has characteristic peaks with diffraction angles 2θ of 8.94°, 12.85°, 16.20°, 20.57°, and 25.14°.

[0006] Further preferably, it is characterized in that the X-ray powder diffraction pattern also has characteristic peaks with diffraction angles 2θ of 15.72°, 20.15° and 28.51°.

[0007] More preferably, it is characterized in that the X-ray powder diffraction pattern also has characteristic peaks at diffraction angles 2θ of 17.38°, 17.83°, 18.54°, and 19.27°.

[0008] Preferably, the powder X-ray diffraction pattern of the rosuvastatin crystal form RX-1 described in the first aspect of the present invention is substantially as follows Figure 1 shown.

[0009] Preferably, in the thermogravimetric analysis (TGA) spectrum of the rosuvastatin crystal form RX-1 according to the first aspect of the present invention, there is a weight loss of 17.33% in the temperature range of 80-110°C.

[0010] Preferably, the thermogravimetric analysis curve (TGA) of the rosuvastatin crystal form RX-1 described in the first aspect of the present invention is substantially as follows Figure 2 In a second aspect, the first aspect of the present invention provides a method for preparing rosuvastatin crystal form RX-1, the method comprising: dissolving rosuvastatin in pyridine, adding a poor solvent after complete dissolution, precipitating solids, stirring, filtering, and drying.

[0011] Preferably, in the preparation method of the roxadustat crystal form RX-1 provided in the first aspect of the present invention, the dissolution temperature of roxadustat is 20 to 65°C.

[0012] Preferably, in the preparation method of the rosuvastatin crystal form RX-1 provided in the first aspect of the present invention, the stirring condition is stirring at room temperature for 2 to 48 hours.

[0013] Preferably, in the preparation method of the rosuvastatin crystal form RX-1 provided in the first aspect of the present invention, the poor solvent is selected from one or more of water, methanol, ethanol, acetonitrile, acetone, methyl tert-butyl ether, ethyl ether, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, toluene, cyclohexane, and n-heptane.

[0014] Preferably, in the preparation method of the rosuvastatin crystal form RX-1 provided in the first aspect of the present invention, the poor solvent is selected from any one of water, methanol, ethanol, acetonitrile and acetone.

[0015] Most preferably, the poor solvent is selected from water. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 Example 1 XRD pattern of rosuvastatin crystal form RX-1.

[0017] Figure 2 Example 1 Thermogravimetric analysis curve of rosuvastatin crystal form RX-1. DETAILED DESCRIPTION

[0018] Now describe in detail various exemplary embodiments of the present invention, this detailed description should not be considered as limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present invention. It should be understood that the terms described in the present invention are only for describing a particular embodiment, and are not used to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that the upper and lower limits of the range and each intermediate value therebetween are specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0019] Unless otherwise specified, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail. Unless otherwise specified, "%" is a percentage based on weight.

[0020] In the method of the present invention, rosuvastatin is generally used as a starting material to prepare the crystalline form of the present invention. Rosuvastatin as a starting material is prepared by the method mentioned in CN103435546B to obtain free rosuvastatin, and the crystalline form Form A is prepared according to the method of CN109369524A.

[0021] The term "room temperature" as used herein generally refers to 10-30°C, preferably 20±5°C.

[0022] In the present invention, the term "crystal form" refers to a certain lattice configuration of a crystalline substance. It is known in the art that crystal form is related to stability, dissolution and mechanical properties in pharmaceutical preparation. Different crystal forms of the same substance generally have their own unique physical properties and crystal lattices (e.g., unit cells). Different crystal forms can be characterized by methods known in the art. For example, it can be identified by solid-state characterization methods such as powder X-ray diffraction (PXRD). Other characterization methods include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid-state NMR, etc. The crystal form can be characterized using any of the above methods, or a combination of two or more methods can be used for characterization.

[0023] Except for special instructions in the present invention, other experimental methods are well-known methods in the art, and these methods can be referred to, for example, the Pharmacopoeia of the People's Republic of China. Among them, the parameters for detection are set as follows: the specific conditions for PXRD (powder X-ray diffraction) determination are: Bruker D8, Cu-Kα radiation, detection range 2θ: 5°-50°, step length 2θ: 0.02°, scanning rate 0.2s.step-1, current voltage 40mA, 40KV.

[0024] All reagents used in the examples were commercially available unless otherwise specified. Unless otherwise specified, the examples were operated at room temperature.

[0025] Example 1

[0026] Take about 100 mg of free roxadustat crystal form A, add 1 ml of pyridine, stir at 50°C for 1 hour, add 1 ml of water, slowly cool to room temperature, stir for 2 hours to obtain a white suspension. The obtained suspension is centrifuged and filtered, and the obtained solid is vacuum dried at 40°C for 12 hours to obtain roxadustat crystal form RX-1, whose melting point is: 220-222°C.

[0027] The sample of Example 1 was taken for characterization, as follows.

[0028] 1. PXRD pattern analysis

[0029] Figure 1 is the PXRD pattern of rosuvastatin crystalline form RX-1, and Table 1 lists the powder X-ray diffraction data of rosuvastatin crystalline form RX-1.

[0030] Table 1: Powder X-ray diffraction data of rosuvastatin Form RX-1

[0031] Peak angle 2θ(°) Peak intensity (%) 8.94 100 12.85 13.5 15.72 7.3 16.20 9.4 17.38 5.0 17.83 5.1 18.54 5.1 19.27 5.4 20.15 6.9 20.57 14.5 25.14 20.2 28.51 6.5

[0032] 2. TGA analysis

[0033] In the thermogravimetric analysis (TGA) spectrum of rosuvastatin crystal form RX-1, there is a 17.33% weight loss in the temperature range of 80 to 110°C. Figure 2 shown.

[0034] Example 2

[0035] Take about 100 mg of free roxadustat crystal form A, add 0.5 ml of pyridine, stir at 50°C for 1 hour, add 1 ml of water, slowly cool to room temperature, stir for 2 hours to obtain a white suspension. The obtained suspension is centrifuged and filtered, and the obtained solid is vacuum dried at 40°C for 12 hours to obtain roxadustat crystal form RX-1.

[0036] Example 3

[0037] Take about 100 mg of free roxadustat crystal form A, add 1 ml of pyridine, stir at 50°C for 1 hour, add 2 ml of acetone, slowly cool to room temperature, stir for 2 hours to obtain a white suspension. The obtained suspension is centrifuged and filtered, and the obtained solid is vacuum dried at 40°C for 12 hours to obtain roxadustat crystal form RX-1.

[0038] Example 4

[0039] Take about 100 mg of free roxadustat crystal form A, add 1 ml of pyridine, stir at 50°C for 1 hour, add 2 ml of ethanol, slowly cool to room temperature, stir for 2 hours to obtain a white suspension. The obtained suspension is centrifuged and filtered, and the obtained solid is vacuum dried at 40°C for 12 hours to obtain roxadustat crystal form RX-1.

[0040] Example 5

[0041] Take about 100.0 mg of free roxadustat crystal form A, add 1 ml of pyridine, stir at 50°C for 1 hour, add 2 ml of acetonitrile, slowly cool to room temperature, stir for 2 hours to obtain a white suspension. The obtained suspension is centrifuged and filtered, and the obtained solid is vacuum dried at 40°C for 12 hours to obtain roxadustat crystal form RX-1.

[0042] Test Example 1: Stability Study of Roxadustat Crystalline Form RX-1

[0043] In order to investigate the stability of the rosuvastatin crystal form RX-1 prepared in Example 1 of the present invention, the obtained sample was subjected to a stability test under high humidity and light, and the long-term stability was investigated at 25±2°C / 60±5%RH and the accelerated stability was investigated at 40°C±2°C / 75±5%RH, and the results are shown in Table 2 below. It can be seen from the table that the stability of the rosuvastatin crystal form RX-1 obtained in Example 1 can meet the requirements for pharmaceutical use.

[0044] Table 2 Stability study of rosuvastatin crystal form RX-1

[0045]

[0046] Test Example 2 Solubility Comparison

[0047] According to the pharmacopoeia solubility test method, weigh the fine powder of the test sample, add it to a certain amount of solvent at 25℃±2℃, shake it vigorously for 30 seconds every 5 minutes, and observe the dissolution within 30 minutes. If no particles or droplets are visible, it is considered to be completely dissolved.

[0048] The solubility in water (25°C) of the crystal form Form A in CN109369524A of the prior art and the rosuvastat crystal form RX-1 in Example 1 were compared, and the results are shown in Table 3. It can be seen from the experimental results that the solubility of the rosuvastat crystal form RX-1 obtained in Example 1 is significantly better than that of the crystal form Form A.

[0049] Table 3 Solubility experiments of different rosuvastatin crystal forms

[0050] Crystal form Solubility in water (25℃) Crystal form Form A 2.43 μg / mL Crystal form RX-1 462 μg / mL

[0051] Although the present invention has been described with reference to exemplary embodiments, it should be understood that the present invention is not limited to the disclosed exemplary embodiments. Various adjustments or changes may be made to the exemplary embodiments of the present specification without departing from the scope or spirit of the present invention. The scope of the claims should be based on the broadest interpretation to cover all modifications and equivalent structures and functions.

Claims

1. A crystalline form of rosuvastatin RX-1, characterized in that: Its X-ray powder diffraction spectrum has a diffraction angle of 2 θ The characteristic peaks are 8.94°, 12.85°, 16.20°, 20.57°, and 25.14°.

2. The rosuvastatin crystal form RX-1 according to claim 1, characterized in that: The X-ray powder diffraction pattern also has characteristic peaks with diffraction angles 2θ of 15.72°, 20.15°, and 28.51°.

3. The rosuvastatin crystal form RX-1 according to claim 2, characterized in that: The X-ray powder diffraction pattern also has characteristic peaks at diffraction angles 2θ of 17.38°, 17.83°, 18.54°, and 19.27°.

4. The crystalline form RX-1 of roxadustat according to claim 1, characterized in that: It has an X-ray powder diffraction pattern as shown in FIG1 .

5. The rosuvastatin crystal form RX-1 according to any one of claims 1 to 4, characterized in that The melting point of the crystal form RX-1 is 220-222°C.

6. A method for preparing the crystal form RX-1 according to claim 1, characterized in that: The method comprises: dissolving rosuvastatin in pyridine, adding a poor solvent after the rosuvastatin is completely dissolved, precipitating a solid, stirring, filtering, and drying.

7. The method according to claim 6, characterized in that The dissolution temperature of rosuvastatin is 20-65° C.; the stirring condition is stirring at room temperature for 2-48 hours; the poor solvent is selected from one or more of water, methanol, ethanol, acetonitrile, acetone, methyl tert-butyl ether, ethyl ether, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, toluene, cyclohexane, and n-heptane.

8. The method according to claim 6, characterized in that The poor solvent is selected from any one of water, methanol, ethanol, acetonitrile and acetone.

9. The method according to claim 6, characterized in that The poor solvent is selected from water.

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