Baricitinib and methods of making the same

Abstract

The application discloses a baloxavir ester crystal form B1 and a preparation method thereof. Using Cu-Kα radiation, the X-ray powder diffraction pattern expressed by a 2θ angle has characteristic peaks at positions of 8.24°±0.2°, 9.80°±0.2°, 11.24°±0.2°, 11.76°±0.2°, 13.50°±0.2°, 14.80°±0.2°, 18.08°±0.2°, 19.44°±0.2°, 20.60°±0.2°, 21.18°±0.2°, 21.46°±0.2°, 22.58°±0.2°, 24.38°±0.2°, 25.28°±0.2°, 27.18°±0.2° and 33.42°±0.2°. The crystal habit is blocky, the filtration resistance is smaller than that of Form I with a fine needle-like crystal habit, the particle sample after grinding has a smaller angle of repose, has better particle flowability, and is more beneficial to subsequent preparation process treatment.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical crystal form technology, specifically relating to baloxavir ester crystal form B1 and its preparation method. Background Technology

[0002] The statements herein provide only background information in relation to this invention and do not necessarily constitute prior art.

[0003] Baloxavir Marboxil, chemically named (12AR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[B,E]thiacycloheptan-11-YL]-3,4,6,8,12,12,12A-hexahydro-6,8-dioxo-1H-[1,4]oxazinyl[3,4-C]pyridyl[2,1-F][1,2,4]triazin-7-yl]oxy]methyl carbonate, molecular formula C 27 H 23 F2N3O7S, with a molecular weight of 571.55, has the following structure:

[0004] Baloxaviridine is a novel Cap-dependent endonuclease inhibitor designed and synthesized by Shionogi & Co., Ltd. (Shionogi Pharmaceutical Co., Ltd., Japan) for the treatment of influenza A and B. Its mechanism of action involves inhibiting the acquisition of the CAP structure at the 5' end of host mRNA from host cells, thereby inhibiting the transcription of influenza virus mRNA. It has demonstrated significant antiviral efficacy in both non-clinical and clinical studies.

[0005] Baloxavir ester generally has a fine needle-like crystal habit, poor flowability, greater filtration resistance, and is prone to clogging and agglomeration during the formulation process, which can affect tableting performance. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the purpose of this invention is to provide a baloxavir ester crystal form B1 and its preparation method.

[0007] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0008] In a first aspect, the present invention provides a baloxavir ester crystal form B1, which, in an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation, has characteristic peaks at positions of 8.24°±0.2°, 9.80°±0.2°, 11.24°±0.2°, 11.76°±0.2°, 13.50°±0.2°, 14.80°±0.2°, 18.08°±0.2°, 19.44°±0.2°, 20.60°±0.2°, 21.18°±0.2°, 21.46°±0.2°, 22.58°±0.2°, 24.38°±0.2°, 25.28°±0.2°, 27.18°±0.2°, and 33.42°±0.2°.

[0009] In some embodiments, the infrared spectrum of baloxavir ester crystal form B1 is at 3642 cm⁻¹. -1 3073cm -1 2975cm -1 2864cm -1 1755cm -1 1674cm -1 1613cm -1 1532cm -1 1500cm -1 1464cm -1 1439cm -1 1385cm -1 and 130cm -1 There is a characteristic peak at this location.

[0010] In some embodiments, the baloxavir ester crystal form B1 has an endothermic peak around 105-130°C.

[0011] Secondly, the present invention provides a method for preparing the baloxavir ester crystal form B1, comprising the following steps:

[0012] Baloxavir ester was dissolved in methyl acetate and heated to 45-55℃ to dissolve. Then the temperature was lowered to 0-30℃ and allowed to stand, and crystals B1 precipitated.

[0013] In the preparation of this crystal form, the key parameter is the selection of the solvent methyl acetate, and the second is the rapid cooling within a specific temperature range to precipitate crystal form B1.

[0014] In some embodiments, 20-60 mg of baloxavir ester is added per milliliter of methyl acetate.

[0015] In some embodiments, the temperature for heating and melting is 50-55°C.

[0016] Preferably, the heating and melting temperature is 55°C.

[0017] In some embodiments, the temperature for cooling and settling is 0-10°C.

[0018] Preferably, the temperature for cooling and settling is 3-8℃.

[0019] Further preferred, the temperature for cooling and settling is 5°C.

[0020] Thirdly, the present invention provides another method for preparing the baloxavir ester crystal form B1, comprising the following steps:

[0021] Baloxavir ester solid was added to methyl acetate and stirred at 20-30℃ to dissolve. Then the solvent was evaporated at 0-30℃ to precipitate crystals B1.

[0022] In some embodiments, 20-60 mg of baloxavir ester is added per milliliter of methyl acetate.

[0023] These crystal forms can be produced using the methods described herein and are substantially free of other crystal forms. The term "substantially free" means that the content of another crystal form is 10% or less, preferably 8%, 5%, 4%, 3%, 2%, 1%, 0.5% or less.

[0024] The beneficial effects achieved by one or more embodiments of the present invention described above are as follows:

[0025] The baloxavir ester crystal form B1 of the present invention has a blocky crystal habit, which has better flowability and lower filtration resistance compared to the fine needle-like crystal habit, and is more conducive to subsequent formulation process processing.

[0026] This invention provides a new crystal form of baloxavir ester, offering more options for formulation production. Attached Figure Description

[0027] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0028] Figure 1 Powder diffraction pattern of baloxavir ester crystal form B1 prepared in this invention;

[0029] Figure 2 The DSC spectrum of baloxavir ester crystal form B1 prepared in this invention;

[0030] Figure 3 Infrared spectrum of baloxavir ester crystal form B1 prepared in this invention;

[0031] Figure 4 Crystal habit image of baloxavir ester crystal form B1 prepared in this invention;

[0032] Figure 5 Crystallographic image of Form I baloxavir ester prepared for Comparative Example 1. Detailed Implementation

[0033] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0034] Example 1

[0035] Testing instruments:

[0036] 1. Powder X-ray diffractometer

[0037] Model: Bruker D8 Advance X-ray powder diffractometer.

[0038] Test conditions: copper target, voltage 40kV, current 40mA, continuous scanning mode, scanning range 5-40°, step size 0.1.

[0039] 2. DSC thermal analyzer

[0040] Model: Netzsch DSC 214 Polyma thermal analyzer (Germany).

[0041] Test conditions: Nitrogen purging, heating rate of 10℃ / min.

[0042] 3. Fourier Transform Infrared Spectrometer (IR)

[0043] Model: Nicolet Nexus 670 Fourier Transform Infrared Spectrometer, Inc., USA.

[0044] Test conditions: Scan range: 4000cm -1 -500cm -1 Resolution: 0.09cm -1 .

[0045] A method for preparing baloxavir ester crystal form B1 includes the following steps: 180 mg of baloxavir ester is added to 3 ml of methyl acetate solvent, the mixture is heated to 55 °C and stirred at 500 rpm until dissolved. The solution is filtered through a 0.22 μm filter into a glass bottle, sealed with a sealing film and perforated, and rapidly cooled at 5 °C to obtain crystals of crystal form B1. Its PXRD pattern is shown below. Figure 1 As shown, the DSC spectrum is as follows Figure 2 As shown. The infrared spectrum of baloxavir ester crystal form B1 is as follows. Figure 3 As shown in the image. Crystal habit image of baloxavir ester crystal form B1 is shown below. Figure 4As shown in the figure, the crystals of this crystal form are distinctly massive.

[0046] Comparative Example 1

[0047] The difference from Example 1 is that methyl acetate was replaced with ethanol, and recrystallization yielded crystals. The prepared crystals were Form I with a fine needle-like crystal habit, see... Figure 5 This crystal habit exhibits distinct fine needle-like structures with an aspect ratio reaching 100:1.

[0048] Example 2

[0049] A method for preparing baloxavir ester crystal form B1 includes the following steps: 180 mg of baloxavir ester is added to 3 ml of methyl acetate solvent, heated to 55 °C and stirred at 500 rpm until dissolved, the solution is filtered through a 0.22 μm filter into a glass bottle, sealed with a sealing film and perforated, and rapidly cooled at 5 °C to obtain crystals of crystal form B1.

[0050] Example 3

[0051] A method for preparing baloxavir ester crystal form B1: 120 mg of baloxavir ester is added to 3 ml of methyl acetate solvent and stirred at 500 rpm at room temperature until dissolved. The solution is filtered through a 0.22 μm filter into a glass bottle, sealed with sealing film and perforated, and allowed to evaporate slowly at 25 °C to obtain crystals of crystal form B1.

[0052] Example 4

[0053] A method for preparing baloxavir ester crystal form B1: 60 mg of baloxavir ester is added to 3 ml of methyl acetate solvent and stirred at 500 rpm at room temperature until dissolved. The solution is filtered through a 0.22 μm filter into a glass bottle, sealed with a sealing film and perforated, and allowed to evaporate slowly at 5 °C to obtain crystals of crystal form B1.

[0054] Regarding crystal morphology, high-powered microscopy reveals that the crystal form B1 of this invention exhibits a bulky crystal habit, while the known Form I has a needle-like crystal habit with an aspect ratio reaching 100:1. Compared to the bulky crystal habit, the needle-like crystal habit is more prone to clogging and aggregation due to its inherent morphological characteristics, resulting in greater filtration resistance. Furthermore, needle-like agglomerations easily create cavities that encapsulate the solvent, leading to excessive solvent residue.

[0055] For ground powder particles, the angle of repose is a characteristic parameter related to the frictional force or relative motion resistance between particles; the smaller the angle of repose, the better the flowability. To quantitatively evaluate the particle flowability of the present invention, the angle of repose of crystal form B1 prepared in Examples 1-4 of the present invention and Form I with needle-like crystal habit prepared in Comparative Example 1 were measured to compare the particle flow characteristics of different solids.

[0056] After the crystal sample is ground into powder, it is first passed through a sieve with a 1.0 mm aperture. Then, the angle of repose is measured using an angle of repose measuring instrument. After the sample passes through the measuring instrument, it forms a powder cone. The angle of repose α can be calculated by measuring the height of the powder cone, using the following formula: tan(α) = cone height / base radius.

[0057] Table 1 Results of the Angle of Repose Experiment

[0058]

[0059]

[0060] Test results show that the angle of repose of crystal form B1 in this invention is less than 43°, which is much smaller than the 68.4° angle of repose corresponding to Form I. Research indicates that an angle of repose between 40° and 50° can meet the powder flowability requirements of the production process. When the angle of repose exceeds 50°, the powder flowability is difficult to meet production needs. Therefore, compared to Form I, crystal form B1 significantly improves particle flowability, which is more beneficial for subsequent industrial production and processing.

[0061] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing baloxavir ester crystal form B1, characterized in that: The baloxavir ester crystal form B1, when subjected to Cu-Kα radiation and expressed in 2θ angles, exhibits characteristic peaks at positions of 8.24°±0.2°, 9.80°±0.2°, 11.24°±0.2°, 11.76°±0.2°, 13.50°±0.2°, 14.80°±0.2°, 18.08°±0.2°, 19.44°±0.2°, 20.60°±0.2°, 21.18°±0.2°, 21.46°±0.2°, 22.58°±0.2°, 24.38°±0.2°, 25.28°±0.2°, 27.18°±0.2°, and 33.42°±0.2°. The preparation method of the baloxavir ester crystal form B1 includes the following steps: Baloxavir ester was dissolved in methyl acetate and heated to 45-55℃ to dissolve. Then the temperature was lowered to 0-30℃ and allowed to stand to precipitate crystals B1. The baloxavir ester crystal form B1 has a massive crystal habit; The repose angle of the baloxavir ester crystal form B1 is less than 43°.

2. The method for preparing baloxavir ester crystal form B1 according to claim 1, characterized in that: The infrared spectrum of baloxavir ester crystal form B1 is at 3642 cm⁻¹. 1 3073cm 1 2975cm 1 2864cm 1 1755cm 1 1674cm 1 1613cm 1 1532cm 1 1500cm 1 1464cm 1 1439cm 1 1385cm 1 and 1301cm 1 There is a characteristic peak at this location.

3. The method for preparing baloxavir ester crystal form B1 according to claim 1, characterized in that: The baloxavir ester crystal form B1 has an endothermic peak around 105-130℃.

4. The method for preparing baloxavir ester crystal form B1 according to claim 1, characterized in that: Add 20-60 mg of baloxavir ester per milliliter of methyl acetate.

5. The method for preparing baloxavir ester crystal form B1 according to claim 1, characterized in that: The temperature for heating and melting is 50-55℃.

6. The method for preparing baloxavir ester crystal form B1 according to claim 5, characterized in that: The temperature for heating and melting is 55℃.

7. The method for preparing baloxavir ester crystal form B1 according to claim 1, characterized in that: The temperature for cooling and settling is 0-10℃.

8. The method for preparing baloxavir ester crystal form B1 according to claim 7, characterized in that: The temperature for cooling and settling should be 3-8℃.

9. The method for preparing baloxavir ester crystal form B1 according to claim 8, characterized in that: The temperature for cooling and settling is 5℃.

10. A method for preparing baloxavir ester crystal form B1, characterized in that: The baloxavir ester crystal form B1, when subjected to Cu-Kα radiation and expressed in 2θ angles, exhibits characteristic peaks at positions of 8.24°±0.2°, 9.80°±0.2°, 11.24°±0.2°, 11.76°±0.2°, 13.50°±0.2°, 14.80°±0.2°, 18.08°±0.2°, 19.44°±0.2°, 20.60°±0.2°, 21.18°±0.2°, 21.46°±0.2°, 22.58°±0.2°, 24.38°±0.2°, 25.28°±0.2°, 27.18°±0.2°, and 33.42°±0.2°. The preparation method of the baloxavir ester crystal form B1 includes the following steps: Baloxavir ester solid was added to methyl acetate and stirred at 20-30℃ to dissolve. Then the solvent was evaporated at 0-30℃ to precipitate crystals B1. The baloxavir ester crystal form B1 has a massive crystal habit; The repose angle of the baloxavir ester crystal form B1 is less than 43°.

11. The method for preparing baloxavir ester crystal form B1 according to claim 10, characterized in that: Add 20-60 mg of baloxavir ester per milliliter of methyl acetate.

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