Crystal Form of a Factor D Blocker and Preparation Method Thereof

Abstract

The present invention relates to the field of medicinal chemistry, and particularly relates to a crystal form of a D factor blocker and a preparation method thereof. The X-ray powder diffraction pattern of the crystal form comprises diffraction peaks at 2θ angles of 6.0, 16.1, and 17.9 degrees, or comprises diffraction peaks at 2θ angles of 6.7, 16.8, and 17.2 degrees, or comprises diffraction peaks at 2θ angles of 20.4, 21.8, and 26.3 degrees, or comprises diffraction peaks at 2θ angles of 10.5, 18.8, and 24.1 degrees. Among them, the crystal form has good performance and can be used for treating rare diseases mediated by the alternative pathway of complement activation; the preparation method of the crystal form is simple, convenient to operate, and has mild conditions.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry. Specifically, the present invention relates to a crystal form of a D - factor blocker and a preparation method thereof. Background Art

[0002] Danicopan (CAS No.: 1903768 - 17 - 1), with the chemical name of (2S,4R)-1-(2-(3 - acetyl - 5-(2 - methylpyrimidin - 5 - yl)-1H - indazol - 1 - yl)acetyl)-N-(6 - bromopyridin - 2 - yl)-4 - fluoropyrrolidine - 2 - carboxamide, is an oral D - factor blocker developed by ACHILLION Pharmaceuticals, Inc., and is applicable to rare diseases (C3 glomerulopathy, paroxysmal nocturnal hemoglobinuria) mediated by the alternative pathway of complement activation. Its structure is shown as follows:

[0003]

[0004] Patent WO2020051538A1 of ACHILLION Pharmaceuticals, Inc. first disclosed crystal forms A, II, III, VI, V, IV, and VII of Danicopan, and described the preparation methods of these crystal forms in the specification. Among them, crystal form A was obtained when studying the solubility of excipients with PEG300 as an excipient; crystal form II was obtained by evaporating after the raw material was dissolved in ethanol; crystal form III was obtained by stirring the crystal form II sample in water for 4 days; crystal form VI was obtained by filtration from PEG400; crystal form V was obtained when scaling up the preparation of crystal form VI; crystal form IV was a water / acetone solvate obtained when scaling up the preparation of crystal form VI; crystal form VII was found in the sample during the preparation for single - crystal structure analysis.

[0005] However, patent WO2020051538A1 did not conduct more screening and research work on the crystal forms of Danicopan, and there are still more crystal forms not developed.

[0006] A drug such as Danicopan may exist in different crystal forms. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution rate, bioavailability, etc., and will also have different effects on the stability, bioavailability, and efficacy of the drug. It is impossible to predict unknown crystal forms from known crystal forms, nor can it predict the processability when different crystal forms of the drug are formulated into preparations. Therefore, it is necessary to conduct sufficient research on the crystal forms and processes of Danicopan. Summary of the Invention Overview of the Invention

[0008] The present invention provides a new crystal form of Danicopan, a preparation method thereof, and a composition.

[0009] On the one hand, the present invention provides a crystal form of Danicopan, designated as crystal form E. The X-ray powder diffraction pattern of the crystal form E contains diffraction peaks at 2θ angles of 6.0, 16.1, and 17.9 degrees.

[0010] The crystal form E is a hydrate.

[0011] The differential scanning calorimetry curve of the crystal form E has an endothermic peak at 60°C - 120°C or an endothermic peak at 140°C - 170°C.

[0012] The present invention also provides a method for preparing the crystal form E, which includes: dissolving Danicopan in acetonitrile, then adding cyclohexane to the solution, and then cooling the solution to 10°C to precipitate crystals; or dissolving Danicopan in acetonitrile, then adding n-heptane to the solution, and then stirring at room temperature for 8 h - 16 h to precipitate crystals; filtering and drying to constant weight to obtain the crystal form E.

[0013] On the one hand, the present invention provides a crystal form of Danicopan, designated as crystal form F. The X-ray powder diffraction pattern of the crystal form F contains diffraction peaks at 2θ angles of 6.7, 16.8, and 17.2 degrees.

[0014] The crystal form F is a hydrate.

[0015] The differential scanning calorimetry curve of the crystal form F has an endothermic peak at 40°C - 120°C or an endothermic peak at 140°C - 170°C.

[0016] The present invention also provides a method for preparing the crystal form F, which includes: drying the aforementioned crystal form E sample in a vacuum drying oven at 50°C - 70°C for 8 h - 16 h to obtain the crystal form F.

[0017] On the one hand, the present invention provides a crystal form of Danicopan, designated as crystal form G. The X-ray powder diffraction pattern of the crystal form G contains diffraction peaks at 2θ angles of 20.4, 21.8, and 26.3 degrees.

[0018] The crystal form G is an N,N-dimethylacetamide solvate.

[0019] The differential scanning calorimetry curve of the crystal form G has an endothermic peak at 80°C - 110°C.

[0020] The present invention also provides a method for preparing the crystal form G, which includes: dissolving Danicopan in N,N-dimethylacetamide, clarifying, cooling to -5°C - 5°C to precipitate crystals, and filtering to obtain the crystal form G.

[0021] On the one hand, the present invention provides a crystal form of Danicopan, designated as crystal form H. The X-ray powder diffraction pattern of the crystal form H contains diffraction peaks at 2θ angles of 10.5, 18.8 and 24.1 degrees.

[0022] The crystal form is a DMF solvate.

[0023] The differential scanning calorimetry curve of the crystal form H has an endothermic peak at 145 °C - 165 °C.

[0024] The present invention also provides a method for preparing the crystal form H, which comprises: dissolving Danicopan in DMF, evaporating the solvent to precipitate crystals, and obtaining the crystal form H.

[0025] On the other hand, the present invention also provides a composition, which comprises any one or more of the aforementioned crystal forms of Danicopan. By mass ratio, the crystal form is at least 90% of Danicopan, or the crystal form does not exceed 0.5% - 5% of Danicopan.

[0026] Term Definitions

[0027] The term "comprising" or "including" is an open-ended expression, that is, it includes the content specified by the present invention, but does not exclude other aspects.

[0028] The term "crystal form" is used to describe the existence state of a solid compound, and describes a collection of various parameters of the internal ions, atoms or molecules of the crystal, the symmetry properties and the periodic arrangement rules.

[0029] The term "relative intensity" means that when the intensity of the first strong peak in a set of diffraction peaks attributed to a certain crystal form is defined as 100%, the intensity ratio of other peaks to the intensity of the first strong peak.

[0030] The term "substantially as shown" means that at least 70%, at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern are shown in the figure.

[0031] In the context of the present invention, the 2θ (also known as 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (°).

[0032] When referring to the data in the spectrum and / or figure, the term "diffraction peak" refers to a feature that those skilled in the art would not attribute to background noise.

[0033] For the X-ray powder diffraction peaks of the crystal form, there are experimental errors in the measurement of 2θ of the X-ray powder diffraction pattern or the diffraction peaks. There may be slight differences in the measurement of 2θ of the X-ray powder diffraction pattern or the diffraction peaks between one machine and another, and between one sample and another. The numerical values of the experimental errors or differences may be + / - 0.2 units, or + / - 0.1 units, or + / - 0.05 units. Therefore, the numerical values of the 2θ or the diffraction peaks cannot be regarded as absolute.

[0034] There are experimental errors in the differential scanning calorimetry curve (DSC) of the crystal form. There may be slight differences in the position and peak value of the endothermic peak between one machine and another, and between one sample and another. The numerical values of the experimental errors or differences may be less than or equal to 5 °C, or less than or equal to 4 °C, or less than or equal to 3 °C, or less than or equal to 2 °C, or less than or equal to 1 °C. Therefore, the numerical values of the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.

[0035] There are experimental errors in the thermogravimetric analysis (TGA) of the crystal form. There may be slight differences in the weight loss temperature and the amount of weight loss between one machine and another, and between one sample and another. The numerical values of the experimental errors or differences may be approximately + / - 0.1 unit, approximately + / - 0.05 unit, or approximately + / - 0.01 unit. Therefore, the numerical values of the weight loss temperature and the amount of weight loss cannot be regarded as absolute.

[0036] In the context of the present invention, all the numbers disclosed herein are approximate values, whether or not words such as "about" or "approximate" are used. Based on the disclosed numbers, there may be differences of ±1%, ±2%, or ±5% in the numerical value of each number.

[0037] "Room temperature" means a temperature of about 15 °C - 32 °C, or about 20 °C - 30 °C, or about 23 °C - 28 °C, or about 28 °C.

[0038] In the present invention, when it comes to the drying of solids, the solids are dried to a constant weight. Detailed Description of the Invention

[0040] The inventors have developed through research the crystal forms of the compound Danicopan and their preparation methods.

[0041] The crystal forms of Danicopan provided by the present invention are called crystal form E, crystal form F, crystal form G or crystal form H. These crystal forms have good properties, high solubility, high bioavailability; and / or are good in terms of stability, which is beneficial for storage and thus meets the requirements of drug stability; have low hygroscopicity, and / or have good properties in terms of electrostaticity, with low electrostaticity, which is beneficial for the operation in the production process.

[0042] In a first aspect, the present invention provides a new crystal form of Danicopan, designated as Crystal Form E.

[0043] Crystal Form E of Danicopan has the following characteristics: its X-ray powder diffraction pattern includes diffraction peaks at 2θ angles of 6.0, 16.1, and 17.9 degrees.

[0044] In some embodiments, Crystal Form E has the following characteristics: the X-ray powder diffraction pattern of Crystal Form E includes diffraction peaks at 2θ angles of 4.7, 6.0, 8.1, 13.7, 16.1, and 17.9 degrees.

[0045] In some embodiments, Crystal Form E has the following characteristics: the X-ray powder diffraction pattern of Crystal Form E includes diffraction peaks at 2θ angles of 4.7, 6.0, 8.1, 13.7, 15.1, 16.1, 17.9, 21.2, 25.8, and 28.4 degrees.

[0046] In some embodiments, Crystal Form E has the following characteristics: the X-ray powder diffraction pattern of Crystal Form E includes diffraction peaks at 2θ angles of 4.7, 6.0, 8.1, 13.7, 15.1, 16.1, and 17.9 degrees.

[0047] In some embodiments, Crystal Form E has the following characteristics: the X-ray powder diffraction pattern of Crystal Form E includes diffraction peaks at 2θ angles of 6.0, 8.1, 13.7, 15.1, 16.1, 17.9, and 21.2 degrees.

[0048] In some embodiments, Crystal Form E has the following characteristics: the X-ray powder diffraction pattern of Crystal Form E includes diffraction peaks at 2θ angles of 6.0, 16.1, 17.9, 21.2, 25.8, and 28.4 degrees.

[0049] Crystal Form E of Danicopan is a hydrate. In some embodiments, the water content of Crystal Form E is 5.0% - 10.0%. In some embodiments, the water content of Crystal Form E is 7.5%.

[0050] Crystal Form E of Danicopan further has the following characteristics: the thermogravimetric analysis curve (TGA) of Crystal Form E shows weight loss of Crystal Form E at 50°C - 100°C, and the weight loss is about 5.0% - 10.0%. In some specific embodiments, the thermogravimetric analysis curve (TGA) of Crystal Form E shows weight loss of Crystal Form E at 50°C - 100°C, and the weight loss is about 7.5%. In a specific embodiment, the thermogravimetric analysis curve (TGA) of Crystal Form E is substantially as Figure 3 shown.

[0051] The crystalline form E of Danicopan also has the following characteristics: its differential scanning calorimetry curve (DSC) has an endothermic peak at 60°C - 120°C. In some embodiments, the differential scanning calorimetry curve (DSC) of crystalline form E has an endothermic peak at 80°C - 100°C. In some examples, the differential scanning calorimetry curve (DSC) of crystalline form E has an endothermic peak at 82°C - 92°C. In some examples, the differential scanning calorimetry curve (DSC) of crystalline form E has an endothermic peak at 84°C - 90°C, and the peak top value of the endothermic peak is 87°C. In some embodiments, the differential scanning calorimetry curve (DSC) of crystalline form E has an endothermic peak at 140°C - 170°C. In some examples, the differential scanning calorimetry curve (DSC) of crystalline form E has an endothermic peak at 150°C - 160°C. In some examples, the differential scanning calorimetry curve (DSC) of crystalline form E has an endothermic peak at 152°C - 158°C. In some examples, the differential scanning calorimetry curve (DSC) of crystalline form E has endothermic peaks at 84°C - 90°C and 152°C - 158°C. In some examples, the differential scanning calorimetry curve (DSC) of crystalline form E is substantially as Figure 2 shown.

[0052] In some embodiments, the new crystalline form E of Danicopan has an X-ray powder diffraction pattern that includes at least one peak or at least two peaks or three peaks among the diffraction peaks at 2θ angles of 6.0, 16.1, and 17.9 degrees. In some examples, the X-ray powder diffraction pattern of crystalline form E includes a diffraction peak at a 2θ angle of 6.0 degrees; in some examples, the X-ray powder diffraction pattern of crystalline form E includes a diffraction peak at a 2θ angle of 16.1 degrees; in some examples, the X-ray powder diffraction pattern of crystalline form E includes a diffraction peak at a 2θ angle of 17.9 degrees; in some examples, the X-ray powder diffraction pattern of crystalline form E includes diffraction peaks at 2θ angles of 6.0 and 16.1 degrees; in some examples, the X-ray powder diffraction pattern of crystalline form E includes diffraction peaks at 2θ angles of 6.0 and 17.9 degrees; in some examples, the X-ray powder diffraction pattern of crystalline form E includes diffraction peaks at 2θ angles of 16.1 and 17.9 degrees; in some examples, the X-ray powder diffraction pattern of crystalline form E includes diffraction peaks at 2θ angles of 6.0, 16.1, and 17.9 degrees.

[0053] In some specific embodiments, the X-ray powder diffraction pattern of crystalline form E is substantially as Figure 1 shown.

[0054] In a second aspect, the present invention provides a method for preparing the crystalline form E of Danicopan.

[0055] The method for preparing the crystalline form E in the present invention is simple, convenient to operate, has mild conditions, high yield, and high purity, and is suitable for industrial production.

[0056] A method for preparing the crystalline form E, comprising: dissolving Danicopan in acetonitrile, then adding cyclohexane to the solution, and then cooling the solution to 5°C - 15°C to precipitate crystals; filtering and drying to obtain crystalline form E. In some embodiments, the temperature to which the solution is cooled can be 6°C - 14°C, or 7°C - 13°C, or 8°C - 12°C. In some examples, the temperature to which the solution is cooled can be 8°C, or 9°C, or 10°C, or 11°C, or 12°C.

[0057] A method for preparing the crystalline form E, comprising: dissolving Danicopan in acetonitrile, then adding n-heptane to the solution, and then stirring at room temperature for 8 h - 16 h to precipitate crystals; filtering and drying to obtain crystalline form E. In some embodiments, the stirring time can be 8 h - 12 h, or 8 h - 14 h, or 8 h - 10 h, or 10 h - 12 h, or 10 h - 14 h. In some examples, the stirring time can be 8 h, or 9 h, or 10 h, or 11 h, or 12 h, or 13 h, or 14 h, or 15 h, or 16 h.

[0058] In a third aspect, the present invention provides crystalline form F of Danicopan.

[0059] Crystalline form F of Danicopan has the following characteristics: its X-ray powder diffraction pattern contains diffraction peaks at 2θ angles of 6.7, 16.8 and 17.2 degrees.

[0060] In some embodiments, the crystalline form F has the following characteristics: the X-ray powder diffraction pattern of the crystalline form F contains diffraction peaks at 2θ angles of 6.7, 10.4, 16.8, 17.2, 24.8 and 25.9 degrees.

[0061] In some embodiments, the crystalline form F has the following characteristics: the X-ray powder diffraction pattern of the crystalline form F contains diffraction peaks at 2θ angles of 5.8, 6.7, 10.4, 13.4, 15.1, 16.8, 17.2, 20.6, 24.8, 25.9, 27.8, 29.2 and 30.2 degrees.

[0062] In some embodiments, the crystalline form F has the following characteristics: the X-ray powder diffraction pattern of the crystalline form F contains diffraction peaks at 2θ angles of 5.8, 6.7, 15.1, 16.8, 24.8, 29.2 and 30.2 degrees.

[0063] In some embodiments, the crystalline form F has the following characteristics: the X-ray powder diffraction pattern of the crystalline form F contains diffraction peaks at 2θ angles of 10.4, 13.4, 15.1, 16.8, 17.2, 20.6, 25.9, 27.8 and 30.2 degrees.

[0064] In some embodiments, the crystalline form F has the following characteristics: the X-ray powder diffraction pattern of the crystalline form F contains diffraction peaks at 2θ angles of 5.8, 6.7, 10.4, 13.4, 17.2, 20.6, 24.8, 25.9, and 27.8 degrees.

[0065] The crystalline form F of Danicopan is a hydrate or an aqueous substance. In some embodiments, the water content of the crystalline form F is 6.0% - 11.0%. In some embodiments, the water content of the crystalline form F is 6.0% - 10.0%. In some embodiments, the water content of the crystalline form F is 8.5%.

[0066] The crystalline form F of Danicopan also has the following characteristics: the thermogravimetric analysis curve (TGA) of the crystalline form F shows weight loss of the crystalline form F at 30°C - 80°C, and the weight loss is about 6.0% - 11.0%. In some specific embodiments, the thermogravimetric analysis curve (TGA) of the crystalline form F shows weight loss of the crystalline form E at 30°C - 80°C, and the weight loss is 6.0% - 10.0%. In some specific embodiments, the thermogravimetric analysis curve (TGA) of the crystalline form F shows weight loss of the crystalline form E at 30°C - 80°C, and the weight loss is about 8.5%. In a specific embodiment, the thermogravimetric analysis curve (TGA) of the crystalline form F is substantially as Figure 6 shown.

[0067] The crystalline form F of Danicopan also has the following characteristics: its differential scanning calorimetry curve (DSC) has an endothermic peak at 40°C - 120°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form F has an endothermic peak at 80°C - 100°C; in some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form F has an endothermic peak at 82°C - 92°C; in some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form F has an endothermic peak at 84°C - 90°C, and the peak value of the endothermic peak is 87°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form F has an endothermic peak at 140°C - 170°C; in some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form F has an endothermic peak at 150°C - 160°C; in some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form F has an endothermic peak at 152°C - 158°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form F has endothermic peaks at 84°C - 90°C and 152°C - 158°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form F is substantially as Figure 5 shown.

[0068] In some embodiments, the polymorph F of Danicopan has an X-ray powder diffraction pattern comprising at least one peak or at least two peaks or three peaks among the diffraction peaks at 2θ angles of 6.7, 16.8 and 17.2 degrees. In some embodiments, the X-ray powder diffraction pattern of polymorph F comprises a diffraction peak at a 2θ angle of 6.7 degrees; in some embodiments, the X-ray powder diffraction pattern of polymorph F comprises a diffraction peak at a 2θ angle of 16.8 degrees; in some embodiments, the X-ray powder diffraction pattern of polymorph F comprises a diffraction peak at a 2θ angle of 17.2 degrees; in some embodiments, the X-ray powder diffraction pattern of polymorph F comprises diffraction peaks at 2θ angles of 6.7 and 16.8 degrees; in some embodiments, the X-ray powder diffraction pattern of polymorph F comprises diffraction peaks at 2θ angles of 6.7 and 17.2 degrees; in some embodiments, the X-ray powder diffraction pattern of polymorph F comprises diffraction peaks at 2θ angles of 16.8 and 17.2 degrees; in some embodiments, the X-ray powder diffraction pattern of polymorph F comprises diffraction peaks at 2θ angles of 6.7, 16.8 and 17.2 degrees.

[0069] In some specific embodiments, the X-ray powder diffraction pattern of polymorph F is substantially as Figure 4 shown.

[0070] Fourthly, the present invention provides a method for preparing the new polymorph F of Danicopan.

[0071] The method for preparing polymorph F in the present invention is simple, convenient to operate, with mild conditions, high yield and high purity, and is suitable for industrial production.

[0072] A method for preparing polymorph F includes: drying the aforementioned polymorph E in a vacuum drying oven at 50°C - 70°C for 8h - 16h. In some embodiments, the drying temperature can be 50°C - 55°C, or 50°C - 60°C, or 50°C - 65°C, or 55°C - 60°C, or 55°C - 65°C, or 55°C - 70°C, or 60°C - 65°C, or 60°C - 70°C; in some embodiments, the drying temperature can be 50°C, or 55°C, or 60°C, or 65°C, or 70°C. In some embodiments, the drying time can be 8h - 12h, or 8h - 14h, or 8h - 10h, or 10h - 12h, or 10h - 14h. In some embodiments, the drying time can be 8h, or 9h, or 10h, or 11h, or 12h, or 13h, or 14h, or 15h, or 16h.

[0073] Fifthly, the present invention provides polymorph G of Danicopan. The polymorph G has the following characteristics: the X-ray powder diffraction pattern of the polymorph G comprises diffraction peaks at 2θ angles of 5.9, 15.9, 19.1, 20.4, 21.8 and 26.3 degrees.

[0074] In some embodiments, the crystalline form G has the following characteristics: the X-ray powder diffraction pattern of the crystalline form G includes diffraction peaks at 2θ angles of 5.5, 5.9, 8.7, 10.2, 15.3, 15.9, 17.9, 19.1, 20.4, 21.8, 24.0, 26.3, and 30.9 degrees.

[0075] The crystalline form G of Danicopan is a solvate. In some embodiments, the crystalline form G is a solvate of N,N-dimethylacetamide. In some embodiments, the molar ratio of Danicopan to N,N-dimethylacetamide is 1:1.

[0076] The crystalline form G of Danicopan also has the following characteristics: the thermogravimetric analysis curve (TGA) of the crystalline form G shows weight loss at 120°C - 160°C, and the weight loss is about 5.0% - 15.0%. In some specific embodiments, the thermogravimetric analysis curve (TGA) of the crystalline form G shows weight loss at 120°C - 160°C, and the weight loss is about 10.7%. In a specific embodiment, the thermogravimetric analysis curve (TGA) of the crystalline form G is substantially as Figure 9 shown.

[0077] The crystalline form G of Danicopan also has the following characteristics: its differential scanning calorimetry curve (DSC) has an endothermic peak at 80°C - 110°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form G has an endothermic peak at 90°C - 100°C; in some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form G has an endothermic peak at 92°C - 98°C, and the peak top value of the endothermic peak is 95°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form G is substantially as Figure 8 shown.

[0078] In some specific embodiments, the X-ray powder diffraction pattern of the crystalline form G is substantially as Figure 7 shown.

[0079] In the sixth aspect, the present invention provides a method for preparing the crystalline form G of Danicopan.

[0080] The method for preparing the crystalline form G in the present invention is simple, convenient to operate, has mild conditions, high yield, and high purity, and is suitable for industrial production.

[0081] A method for preparing the crystalline form G, comprising: dissolving Danicopan in N,N-dimethylacetamide, clarifying the solution, cooling the solution to -5°C - 5°C to precipitate crystals, filtering, and drying to obtain crystalline form G. In some embodiments, a method for preparing the crystalline form G, comprising: dissolving Danicopan in N,N-dimethylacetamide, clarifying the solution, and cooling the solution to 0°C to precipitate crystals. In some embodiments, the temperature to which the solution is cooled can be -4°C - 4°C, or -3°C - 3°C, or -2°C - 2°C. In some examples, the temperature to which the solution is cooled can be -5°C, or -4°C, or -3°C, or -2°C, or -1°C, or 1°C, or 2°C, or 3°C, or 4°C, or 5°C.

[0082] In a seventh aspect, the present invention provides crystalline form H of Danicopan. The X-ray powder diffraction pattern of the crystalline form H of Danicopan includes diffraction peaks at 2θ angles of 7.0, 10.5, 14.0, 18.8, 21.6, and 24.1 degrees.

[0083] In some embodiments, the crystalline form H has the following characteristics: The X-ray powder diffraction pattern of the crystalline form H includes diffraction peaks at 2θ angles of 7.0, 10.5, 11.5, 14.0, 16.5, 18.8, 21.2, 21.6, 23.5, 24.1, and 25.9 degrees.

[0084] The new crystalline form H of Danicopan is a solvate. In some embodiments, the crystalline form H is a solvate of DMF. In some embodiments, the molar ratio of Danicopan to DMF is 2:1.

[0085] The crystalline form H of Danicopan further has the following characteristics: The thermogravimetric analysis curve (TGA) of crystalline form H shows that crystalline form H has weight loss at 130°C - 170°C, and the weight loss is about 1.0% - 11.0%. In some specific embodiments, the thermogravimetric analysis curve (TGA) of crystalline form H shows that crystalline form H has weight loss at 130°C - 170°C, and the weight loss is about 5.7%. In a specific embodiment, the thermogravimetric analysis curve (TGA) of crystalline form H is substantially as Figure 12 shown.

[0086] The crystalline form H of Danicopan further has the following characteristics: its differential scanning calorimetry curve (DSC) has an endothermic peak at 145°C - 165°C. In some embodiments, the differential scanning calorimetry curve (DSC) of crystalline form H has an endothermic peak at 150°C - 160°C; in some embodiments, the differential scanning calorimetry curve (DSC) of crystalline form H has an endothermic peak at 151°C - 157°C, and the peak value of the endothermic peak is 154°C. In some embodiments, the differential scanning calorimetry curve (DSC) of crystalline form H is substantially as Figure 11 shown.

[0087] In some specific embodiments, the X-ray powder diffraction pattern of crystalline form H is substantially as Figure 10 shown.

[0088] In a eighth aspect, the present invention provides a method for preparing the crystalline form H of Danicopan.

[0089] The method for preparing the crystalline form H in the present invention is simple, convenient to operate, with mild conditions, high yield and high purity, and is suitable for industrial production.

[0090] A method for preparing the crystalline form H includes: dissolving Danicopan in DMF, evaporating the solvent to precipitate crystals, and obtaining crystalline form H.

[0091] In a ninth aspect, the present invention further provides a composition, and the composition contains any one of the aforementioned crystalline forms of Danicopan.

[0092] Calculated by mass ratio, the crystalline form is at least 90% of Danicopan, or the crystalline form does not exceed 0.5% - 5% of Danicopan.

[0093] In some embodiments, a composition, by mass ratio, comprises the aforementioned crystalline form of Danicopan, wherein the crystalline form is at least 90% of Danicopan. In some embodiments, a composition, by mass ratio, comprises the aforementioned crystalline form of Danicopan, wherein the crystalline form is at least 95%, or at least 99% of Danicopan. In some embodiments, a composition, by mass ratio, comprises the aforementioned crystalline form of Danicopan, wherein the crystalline form is at least 0.5% - 5% of Danicopan. In some embodiments, a composition, by mass ratio, comprises the aforementioned crystalline form of Danicopan, wherein the crystalline form is at least 5% of Danicopan. In some embodiments, a composition, by mass ratio, comprises the aforementioned crystalline form of Danicopan, wherein the crystalline form does not exceed 0.5% - 5% of Danicopan. In some embodiments, a composition, by mass ratio, comprises the aforementioned crystalline form of Danicopan, wherein the crystalline form does not exceed 5% of Danicopan.

[0094] In some embodiments, a composition comprises the aforementioned crystalline forms of Danicopan, which are crystalline form E, crystalline form F, crystalline form G, and / or crystalline form H. In some embodiments, a composition comprises the aforementioned crystalline forms of Danicopan, which are crystalline form E, crystalline form F, crystalline form G, and / or crystalline form H.

[0095] In some embodiments, a composition, by mass ratio, comprises the aforementioned crystalline form E of Danicopan, wherein crystalline form E is at least 90% of Danicopan. In some embodiments, a composition, by mass ratio, comprises the aforementioned crystalline form E of Danicopan, wherein crystalline form E is at least 95%, or at least 99% of Danicopan. In some embodiments, a composition, by mass ratio, comprises the aforementioned crystalline form E of Danicopan, wherein crystalline form E is at least 0.5% - 5% of Danicopan. In some embodiments, a composition, by mass ratio, comprises the aforementioned crystalline form E of Danicopan, wherein crystalline form E is at least 5% of Danicopan. In some embodiments, a composition, by mass ratio, comprises the aforementioned crystalline form E of Danicopan, wherein crystalline form E does not exceed 0.5% - 5% of Danicopan. In some embodiments, a composition, by mass ratio, comprises the aforementioned crystalline form E of Danicopan, wherein crystalline form E does not exceed 5% of Danicopan.

[0096] In some embodiments, by mass ratio, a composition comprises the aforementioned crystalline form F of Danicopan, wherein crystalline form F is at least 90% of Danicopan. In some embodiments, by mass ratio, a composition comprises the aforementioned crystalline form F of Danicopan, wherein crystalline form F is at least 95%, or at least 99% of Danicopan. In some embodiments, by mass ratio, a composition comprises the aforementioned crystalline form F of Danicopan, wherein crystalline form F is at least 0.5%-5% of Danicopan. In some embodiments, by mass ratio, a composition comprises the aforementioned crystalline form F of Danicopan, wherein crystalline form F is at least 5% of Danicopan. In some embodiments, by mass ratio, a composition comprises the aforementioned crystalline form F of Danicopan, wherein crystalline form F does not exceed 0.5%-5% of Danicopan. In some embodiments, by mass ratio, a composition comprises the aforementioned crystalline form F of Danicopan, wherein crystalline form F does not exceed 5% of Danicopan.

[0097] In some embodiments, by mass ratio, a composition comprises the aforementioned crystalline form G of Danicopan, wherein crystalline form G is at least 90% of Danicopan. In some embodiments, by mass ratio, a composition comprises the aforementioned crystalline form G of Danicopan, wherein crystalline form G does not exceed 0.5%-5% of Danicopan. In some embodiments, by mass ratio, a composition comprises the aforementioned crystalline form G of Danicopan, wherein crystalline form G does not exceed 5% of Danicopan. In some embodiments, by mass ratio, a composition comprises the aforementioned crystalline form H of Danicopan, wherein crystalline form H is at least 90% of Danicopan. In some embodiments, by mass ratio, a composition comprises the aforementioned crystalline form H of Danicopan, wherein crystalline form H does not exceed 0.5%-5% of Danicopan.

[0098] The composition may further comprise a pharmaceutically acceptable excipient or carrier, such as a filler, a diluent, a lubricant, etc. In some embodiments, the composition further comprises a pharmaceutically acceptable excipient or carrier, and the pharmaceutically acceptable excipient or carrier comprises a lubricant. In some embodiments, the lubricant is magnesium stearate.

[0099] The composition can be formulated into any suitable pharmaceutical preparation, such as tablets, capsules, granules, suspensions, or injections, etc. Description of the Drawings

[0100] Figure 1X-ray powder diffraction pattern (XRPD) showing Danicopan polymorph E;

[0101] Figure 2 Differential scanning calorimetry curve (DSC) showing Danicopan polymorph E;

[0102] Figure 3 Thermogravimetric analysis curve (TGA) showing Danicopan polymorph E;

[0103] Figure 4 X-ray powder diffraction pattern (XRPD) showing Danicopan polymorph F;

[0104] Figure 5 Differential scanning calorimetry curve (DSC) showing Danicopan polymorph F;

[0105] Figure 6 Thermogravimetric analysis curve (TGA) showing Danicopan polymorph F;

[0106] Figure 7 X-ray powder diffraction pattern (XRPD) showing Danicopan polymorph G;

[0107] Figure 8 Differential scanning calorimetry curve (DSC) showing Danicopan polymorph G;

[0108] Figure 9 Thermogravimetric analysis curve (TGA) showing Danicopan polymorph G;

[0109] Figure 10 X-ray powder diffraction pattern (XRPD) showing Danicopan polymorph H;

[0110] Figure 11 Differential scanning calorimetry curve (DSC) showing Danicopan polymorph H;

[0111] Figure 12 Thermogravimetric analysis curve (TGA) showing Danicopan polymorph H;

[0112] Figure 13 X-ray powder diffraction pattern (XRPD) of the stability test of Danicopan polymorph E under high temperature conditions (from top to bottom: 15 days at high temperature, 10 days at high temperature, 5 days at high temperature, 0 days);

[0113] Figure 14 X-ray powder diffraction pattern (XRPD) of the stability test of Danicopan polymorph E under strong light conditions (from top to bottom: 15 days of light exposure, 10 days of light exposure, 5 days of light exposure, 0 days);

[0114] Figure 15 X-ray powder diffraction pattern (XRPD) of the stability test of Danicopan polymorph E under high humidity conditions (from top to bottom: 15 days under high humidity, 10 days under high humidity, 5 days under high humidity, 0 day);

[0115] Figure 16 X-ray powder diffraction pattern (XRPD) of the stability test of Danicopan polymorph F under high temperature conditions (from top to bottom: 15 days at high temperature, 10 days at high temperature, 5 days at high temperature, 0 day);

[0116] Figure 17 X-ray powder diffraction pattern (XRPD) of the stability test of Danicopan polymorph F under strong light conditions (from top to bottom: 15 days of light exposure, 10 days of light exposure, 5 days of light exposure, 0 day);

[0117] Figure 18 X-ray powder diffraction pattern (XRPD) of the stability test of Danicopan polymorph F under high humidity conditions (from top to bottom: 15 days under high humidity, 10 days under high humidity, 5 days under high humidity, 0 day);

[0118] Figure 19 X-ray powder diffraction pattern (XRPD) of the stability test of Danicopan polymorph H under high temperature conditions (from top to bottom: 15 days at high temperature, 10 days at high temperature, 5 days at high temperature, 0 day);

[0119] Figure 20 X-ray powder diffraction pattern (XRPD) of the stability test of Danicopan polymorph H under strong light conditions (from top to bottom: 15 days of light exposure, 10 days of light exposure, 5 days of light exposure, 0 day);

[0120] Figure 21 X-ray powder diffraction pattern (XRPD) of the stability test of Danicopan polymorph H under high humidity conditions (from top to bottom: 15 days under high humidity, 10 days under high humidity, 5 days under high humidity, 0 day).

[0121] Among them, Intensity (counts) represents intensity (counts), 2Theta (°) represents 2θ (degrees), Temperature (°C) represents temperature (°C), Heat Flow (W / g) represents heat flow (watts / gram), and Weight represents weight. Detailed implementation manners

[0122] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further elaborate on the present invention in detail.

[0123] All the reagents used in the present invention can be purchased from the market or can be prepared by methods of the prior art or by the methods described in the present invention.

[0124] In the present invention, °C represents degrees Celsius, mg represents milligram, mL represents milliliter, h represents hour, min represents minute, and DMF is N,N-dimethylformamide.

[0125] Instrument parameters

[0126] Unless otherwise specified in the parameters, all the following analyses are carried out at room temperature.

[0127] X-ray powder diffraction (XRPD)

[0128] X-ray powder diffraction (XRPD) patterns are collected on a PANalytical Empyrean X-ray diffractometer in the Netherlands equipped with a transmission-reflection sample stage with an automated 3*15 zero-background sample holder. The radiation source used is (Cu, kα, Kα1 1.540598; Kα2 1.544426; Kα2 / Kα1 intensity ratio: 0.50), where the voltage is set at 45 kV and the current is set at 40 mA. The X-ray beam divergence, that is, the effective size of the X-ray constraint on the sample, is 10 mm. The θ-θ continuous scanning mode is adopted to obtain an effective 2θ range of 3° to 40°. An appropriate amount of the sample is gently pressed with a clean glass slide at the circular groove of the zero-background sample holder under ambient conditions (about 18°C to 32°C) to obtain a flat surface, and the zero-background sample holder is fixed. The sample is scanned at a step size of 0.0167° in the range of 3 to 40° 2θ ± 0.2° to generate a conventional XRPD pattern. The software used for data collection is Data Collector, and the data is analyzed and displayed using Data Viewer and HighScore Plus. In the X-ray powder diffraction pattern, the ordinate represents the diffraction intensity expressed in counts, and the abscissa represents the diffraction angle 2θ expressed in degrees (°).

[0129] Differential scanning calorimetry (DSC)

[0130] Using TA Instruments TMPerformed using a sealed pan device in Model Q2000. Weigh the sample (about 1 - 3 mg) in an aluminum pan, cap it with a Tzero, precisely record to the nearest 0.01 mg, and transfer the sample to the instrument for measurement. The instrument is purged with nitrogen at 50 mL / min. Collect data at a heating rate of 10 °C / min between room temperature and 300 °C. Plot with the endothermic peak downward, and analyze and display the data using TA Universal Analysis. In the DSC graph, the abscissa represents temperature (Temperature, °C), and the ordinate represents the heat flow released per unit mass of the substance (Heat Flow, W / g).

[0131] Thermogravimetric analysis (TGA)

[0132] Using TA Instruments TM Performed in Model Q500. The operating procedure is to tare an empty crucible, take about 10 mg of a solid sample and place it in the tared empty crucible, and spread it evenly. After the instrument runs stably, collect data at a heating rate of 10 °C / min between room temperature and 300 °C under nitrogen purge, and record the spectrum. In the TGA graph, the abscissa represents temperature (Temperature, °C), and the ordinate represents mass percentage (Weight, %).

[0133] Preparation of Danicopan Polymorph E

[0134] Example 1

[0135] Add 60 mg of Danicopan to 0.3 ml of acetonitrile to dissolve it completely, then add 0.6 mL of cyclohexane dropwise to the acetonitrile solution of Danicopan, stir for about half an hour to precipitate the product, stir for 10 h, and filter to obtain a white powder. After determination, its X-ray powder diffraction pattern is Figure 1 substantially the same as, its DSC pattern is Figure 2 substantially the same as, and its TGA pattern is Figure 3 substantially the same as.

[0136] Preparation of Danicopan Polymorph F

[0137] Example 2

[0138] Place Danicopan Polymorph E in a vacuum drying oven at 60 °C for 10 h to obtain a loose white powder product. After determination, its X-ray powder diffraction pattern is Figure 4 substantially the same as, its DSC pattern is Figure 5 substantially the same as, and its TGA pattern is Figure 6 substantially the same as.

[0139] Preparation of Danicopan Polymorph G

[0140] Example 3

[0141] 50 mg of Danicopan was added to 0.2 ml of N,N-dimethylacetamide and heated to dissolve. Then the system was cooled to 0 °C for crystallization, filtered by suction and placed in a drying oven for vacuum drying at 50 °C for 8 h. After measurement, its X-ray powder diffraction pattern was consistent with Figure 7 basically the same, its DSC pattern was consistent with Figure 8 basically the same, and its TGA pattern was consistent with Figure 9 basically the same.

[0142] Preparation of Danicopan Polymorph H

[0143] Example 4

[0144] 60 mg of Danicopan raw material was added to 1 ml of DMF for dissolution, and then 2 mL of purified water was added dropwise to the solution for antisolvent crystallization reaction. The mixture was stirred to precipitate a yellow colloidal substance, stirred for 8 h to obtain a white crystalline substance, filtered by suction and placed in a drying oven for vacuum drying at 50 °C for 10 h. After measurement, its X-ray powder diffraction pattern was consistent with Figure 10 basically the same, its DSC pattern was consistent with Figure 11 basically the same, and its TGA pattern was consistent with Figure 12 basically the same.

[0145] Example 5

[0146] 50 mg of danicopan was added to 0.5 ml of DMF for dissolution, and then the system was placed in a fume hood with an open mouth for solvent evaporation to obtain a solid product. Its X-ray powder diffraction pattern was consistent with Figure 10 basically the same, its DSC pattern was consistent with Figure 11 basically the same, and its TGA pattern was consistent with Figure 12 basically the same.

[0147] Stability Test 1

[0148] The polymorph F sample was taken and placed in a stability test chamber under high temperature, high humidity and strong light conditions for stability test. The test results are shown in Table 1.

[0149] Table 1

[0150] Sample Crystal form Properties 0 days Form F Loose powder 5 days at high temperature Form F Loose powder 10 days at high temperature Form E Slightly agglomerated powder 5 days under light Form E Slightly agglomerated powder 10 days under light Form E Moderately agglomerated powder 5 days under high humidity Form E Slightly agglomerated powder 10 days under high humidity Form E Moderately agglomerated powder

[0151] The results showed that: for the polymorph F sample at high temperature for 5 days, the polymorph remained unchanged (Form F). For the samples under the conditions of high temperature for 10 days, light for 5 days, light for 10 days, high humidity for 5 days, and high humidity for 10 days, polymorph transformation occurred and the transformation was to polymorph E. After the polymorph transformation to polymorph E under the conditions of light for 5 days and high humidity for 5 days, this polymorph no longer changed.

[0152] The polymorph H sample was placed in an open state in a stability test chamber under high temperature, high humidity, and strong light conditions for a stability test. Samples were taken for testing on the 5th day and the 10th day respectively. The results showed that the polymorph of the polymorph H sample did not change.

[0153] Stability Test 2

[0154] Take a small amount of each of the polymorph E / F / H samples and place them in an open state in a stability test chamber under high temperature (60 °C / 75% RH), high humidity (92.5% RH), and strong light (4500 Lx ± 500 Lx) for a stability test. The test results are shown in Table 2. The X-ray diffraction patterns of the stability tests of each polymorph sample under different conditions are shown in Figure 13 - Figure 21 .

[0155] Table 2

[0156]

[0157] The results showed that: The polymorph stability of the polymorph E sample was the best, and the polymorph could remain unchanged under high temperature / light / high humidity conditions. The polymorph F sample changed to polymorph E on the 5th day under high temperature / light / high humidity conditions; on the 10th day and the 15th day, the polymorph remained unchanged and was still polymorph E. The polymorph H sample had good polymorph stability under light / high humidity conditions and could keep the polymorph unchanged. However, for the polymorph H sample under high temperature conditions, the crystallinity gradually deteriorated, and the polymorph converted to amorphous, and became amorphous on the 10th day.

[0158] The method of the present invention has been described through preferred embodiments. Relevant personnel can obviously make changes or appropriate modifications and combinations to the methods and applications described herein within the content, spirit, and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can draw on the content of this article and appropriately modify the process parameters to achieve it. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A Danicopan crystal form, which is crystal form E. The X-ray powder diffraction pattern of this crystal form contains diffraction peaks at 2θ angles of 4.7, 6.0, 8.1, 13.7, 15.1, 16.1, 17.9, 21.2, 25.8 and 28.4 degrees; this crystal form is a hydrate.

2. The Danicopan crystal form according to claim 1, wherein the thermogravimetric analysis curve of this crystal form shows that crystal form E has weight loss at 50°C - 100°C, and the weight loss is 5.0% - 10.0%; or the differential scanning calorimetry curve of this crystal form has an endothermic peak at 60°C - 120°C.

3. The Danicopan crystal form according to claim 1, wherein the water content of this crystal form is 5.0% - 10.0%.

4. A method for preparing the Danicopan crystal form according to any one of claims 1-3, comprising: Dissolve Danicopan in acetonitrile, then add cyclohexane to the solution, and then cool the solution to 5°C - 15°C to precipitate crystals; filter and dry to constant weight to obtain crystal form E.

5. A composition, comprising: The Danicopan crystal form as described in any one of claims 1 - 3 and a pharmaceutically acceptable excipient or carrier, wherein, by mass ratio, this crystal form is at least 90% of Danicopan.

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