A Baloxavir Marboxil sulfonate crystal form, its preparation method and application

Abstract

This invention provides a sulfonate crystal form of Baloxavir Marboxil, its preparation method, and its application. The sulfonate crystal forms include methanesulfonate crystal form I, ethanesulfonate crystal form I, benzenesulfonate crystal form I, and p-toluenesulfonate crystal form I of Baloxavir Marboxil. The sulfonate crystal forms of Baloxavir Marboxil provided by this invention not only improve the physicochemical properties of Baloxavir Marboxil but also offer more advantageous solid form options for its formulation development.

Description

Technical Field

[0001] This invention belongs to the field of drug crystal form preparation technology, and relates to a Baloxavir Marboxil sulfonate crystal form, its preparation method, and its application. Background Technology

[0002] Baloxavir Marboxil, with the molecular formula C2 27 H 23 F2N3O7S, with a molecular weight of 571.55 and CAS number 1985606-14-1, has the chemical structure shown in formula (Ⅰ). Baloxavir Marboxil is a small-molecule antiviral prodrug used to treat influenza virus infection. It exerts its anti-influenza effect by inhibiting the endonuclease activity of viral polymerase acid protein (PA). Clinically, it has shown good anti-influenza activity and a relatively convenient administration method.

[0003] .

[0004] Currently, the following patents have been reported regarding the crystal forms of Baloxavir Marboxil. The original drug manufacturer, Shionogi & Co., Ltd. of Japan, disclosed three crystal forms (crystal form I, crystal form II, and crystal form III) and their XRPD diagrams in WO2018030463. CN111377944 disclosed two crystal forms, crystal form A and crystal form B, and their TGA, DSC, and hygroscopicity were studied, confirming them as anhydrous crystal forms. WO2022100395 disclosed two crystal forms: methyl benzoate solvate crystal form C and anhydrous crystal form D. The solubility and stability of crystal form D are similar to those of crystal form I in WO2018030463. CN111875619 disclosed a new crystal form of Baloxavir Marboxil and its preparation method. This new crystal form showed a significantly higher dissolution rate within 30 minutes than crystal form I in WO2018030463. WO2020181025 discloses six crystal forms of Baloxavir Marboxil, one amorphous solid of Baloxavir Marboxil, and a crystal form MS-1 of Baloxavir Marboxil methanesulfonate, wherein crystal forms BM1, BM2, and BM3 are anhydrous, while crystal forms BM4, BM5, and BM6 are solvates of 1,4-dioxane, N,N-dimethylacetamide, and 2-methyltetrahydrofuran, respectively. IN202041016529A discloses an amorphous solid of Baloxavir Marboxil. IN202021003087A discloses crystal forms L and M of Baloxavir Marboxil, as well as an amorphous solid of Baloxavir Marboxil. IN202041027198A discloses a crystalline form M of Baloxavir Marboxil, an amorphous solid of Baloxavir Marboxil, and several dispersion systems of amorphous Baloxavir Marboxil with pharmaceutical excipients. WO2021057834 discloses an anhydrous crystalline form Form C of Baloxavir Marboxil, whose XRPD is similar to crystalline form II in WO2018030463.

[0005] CN120682249A discloses a co-crystal form of Baloxavir Marboxil and troponic acid, and a method for its preparation. CN120887901A discloses a co-crystal form of Baloxavir Marboxil and L-tartaric acid, and a method for its preparation. CN120887902A discloses a co-crystal form of Baloxavir Marboxil and vitamin C, and a method for its preparation.

[0006] Differences in crystal structure, stability, compressibility, density, and dissolution rate among different crystal forms or salt forms of the same drug directly affect formulation processing, storage stability, and bioavailability. Furthermore, differences in chemical reactivity and mechanical properties between different crystal forms or salts can lead to degradation, morphological transformation, or processing difficulties, thereby impacting drug quality and production controllability. Therefore, comprehensive and systematic screening of salt forms and crystal forms in drug development, selecting the most suitable solid-state salt form for development, is a crucial and indispensable research aspect. Simultaneously, these different crystal forms or salt forms each exhibit unique physical properties, such as melting point, thermal stability, X-ray diffraction patterns, infrared spectroscopy, Raman spectroscopy, and solid-state NMR, and one or more of these physical properties can be used to distinguish between different crystal forms.

[0007] The crystal forms of Baloxavir Marboxil reported in the current technology generally have poor solubility, which significantly affects their bioavailability in vivo. Therefore, further research on the crystal forms of Baloxavir Marboxil salts is of great significance for advancing subsequent drug development. Summary of the Invention

[0008] To address the shortcomings of existing technologies, the present invention aims to provide a sulfonate crystal form of Baloxavir Marboxil as shown in Formula (I), its preparation method, and its applications. This invention overcomes the low solubility of the existing solid form of Baloxavir Marboxil as shown in Formula (I). The sulfonate crystal form of this invention possesses high purity, good crystal stability, and exhibits significantly superior solubility compared to the active pharmaceutical ingredient, making it suitable for industrial-scale production. The sulfonate crystal form provided by this invention not only improves the physicochemical properties of Baloxavir Marboxil as shown in Formula (I) but also offers a more advantageous solid form option for its formulation development.

[0009] To achieve this objective, the present invention adopts the following technical solution: On one hand, the present invention provides four sulfonate crystal forms of Baloxavir Marboxil as shown in Formula (I), wherein the sulfonate crystal forms of Baloxavir Marboxil as shown in Formula (I) include Baloxavir Marboxil methanesulfonate crystal form I, Baloxavir Marboxil ethanesulfonate crystal form I, Baloxavir Marboxil benzenesulfonate crystal form I, and Baloxavir Marboxil p-toluenesulfonate crystal form I; ; The methanesulfonate form I of Baloxavir Marboxil shown in formula (I) uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 7.2±0.3°, 13.0±0.3°, 14.4±0.3°, 18.0±0.3°, 19.1±0.3°, 22.8±0.3°, and 23.6±0.3°, preferably including 7.2±0.3°, 13.0±0.3°, 14.4±0.3°, 18.0±0.3°, and 19.1±0.3°. 0.1±0.3°, 19.8±0.3°, 21.6±0.3°, 22.0±0.3°, 22.8±0.3°, 23.6±0.3°, 25.0±0.3°, 26.2±0.3°, preferably including 7.2±0.3°, 11.4±0.3°, 13.0±0.3°, 14.4±0.3°, 15.3±0.3°, 15.8±0.3°, 16.9±0.3°, 18.0±0.3°, 19.1±0.3°, 19.8±0.3°, 21.6±0.3°, 22.0±0.3°, 22.8±0.3°, 23.6±0.3°, 25.0±0.3°, 26.2±0.3°, 27.3±0.3°, 28.3±0.3°, 29.0±0.3°, 29.6±0.3°; The ethanesulfonate form I of Baloxavir Marboxil shown in formula (I) uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 6.9±0.3°, 12.3±0.3°, 16.1±0.3°, 18.9±0.3°, 22.0±0.3°, 24.3±0.3°, and 25.1±0.3°; preferably, they include 6.9±0.3°, 11.0±0.3°, 12.3±0.3°, 15.1±0.3°, 16.1±0.3°, 17.3±0.3°, 18.9±0.3°, 20.8±0.3°, 22.0±0.3°, 22.9±0.3°, 24.3±0.3°, 25.1±0.3°, and 28.5±0.3°; preferably, they include 6.9±0.3°. ±0.3°, 7.3±0.3°, 9.4±0.3°, 11.0±0.3°, 12.3±0.3°, 13.8±0.3°, 14.6±0.3°, 15.1±0.3°, 15.7±0.3°, 16.1±0.3°, 17.3±0.3°, 18.9±0.3°, 20.8±0.3°, 21.5±0.3°, 22.0±0.3°, 22.9±0.3°, 24.3±0.3°, 25.1±0.3°, 28.5±0.3°, 31.6±0.3°; The benzenesulfonate form I of Baloxavir Marboxil shown in formula (I) uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 8.2±0.3°, 11.7±0.3°, 16.3±0.3°, 16.9±0.3°, 21.4±0.3°, 22.7±0.3°, 23.0±0.3°, and 24.8±0.3°, preferably including 8.2±0.3°, 9.4±0.3°, 9.9±0.3°, 11.7±0.3°, 14.7±0.3°, 15.9±0.3°, 16.3±0.3°, 16.9±0.3°, 18.8±0.3°, 20.2±0.3°, 21.4±0.3°, 22.3±0.3°, and 22.7±0.3°. 3°, 22.9±0.3°, 24.6±0.3°, 24.8±0.3°, 26.2±0.3°; preferably including 8.2±0.3°, 9.4±0.3°, 9.9±0.3°, 10.8±0.3°, 11.7±0.3°, 14.7±0.3°, 15.9±0.3°, 16.3±0.3°, 16.9±0.3°, 17.8±0.3°, 18.8±0.3°, 20.2±0.3°, 21.4±0.3°, 21.8±0.3°, 22.3±0.3°, 22.7±0.3°, 22.9±0.3°, 24.6±0.3°, 24.8±0.3°, 25.8±0.3°, 26.2±0.3°, 30.7±0.3°; The p-toluenesulfonate crystal form I of Baloxavir Marboxil shown in formula (I) uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 8.0±0.3°, 16.1±0.3°, 16.7±0.3°, 21.0±0.3°, 22.3±0.3°, and 24.1±0.3°, preferably including 8.0±0.3°, 9.2±0.3°, 9.9±0.3°, 11.5±0.3°, 16.1±0.3°, 16.7±0.3°, 18.5±0.3°, 21.0±0.3°, 22.3±0.3°, and 24.1±0.3°. 3°, 26.0±0.3°, preferably including 8.0±0.3°, 9.2±0.3°, 9.9±0.3°, 11.5±0.3°, 15.8±0.3°, 16.1±0.3°, 16.7±0.3°, 17.6±0.3°, 18.5±0.3°, 19.8±0.3°, 21.0±0.3°, 22.3±0.3°, 23.0±0.3°, 24.1±0.3°, 25.6±0.3°, 26.0±0.3°, 29.9±0.3°.

[0010] In the sulfonate crystal form of Baloxavir Marboxil shown in Formula (I) of this invention, the molar ratio of Baloxavir Marboxil shown in Formula (I) to sulfonic acid molecules or sulfonic acid anions is 1:(0.2~5), for example 1:0.2, 1:0.5, 1:1, 1:1.6, 1:2.3, 1:3, 1:3.7, 1:4.4 or 1:5, etc., preferably 1:(0.5~2).

[0011] The XRPD spectra of the methanesulfonate crystal form I, the ethanesulfonate crystal form I, the benzenesulfonate crystal form I, and the p-toluenesulfonate crystal form I of Baloxavir Marboxil shown in formula (I) of this invention are as follows: Figure 1 ~ Figure 4 As shown.

[0012] In this invention, various crystal forms of Baloxavir Marboxil as shown in formula (I) were synthesized, including citric acid, tartaric acid, fumaric acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1,2-ethanedisulfonic acid, and 4-hydroxybenzenesulfonic acid. XRPD testing results showed that only four salts—Baloxavir Marboxil methanesulfonate, Baloxavir Marboxil ethanesulfonate, Baloxavir Marboxil benzenesulfonate, and Baloxavir Marboxil p-toluenesulfonate—were successfully prepared (Table 1). The products were stable, with high yields, and the preparation process was simple, stable, reproducible, easy to scale up, and had good solubility. Therefore, it has promising prospects for industrial development.

[0013] On the other hand, the present invention provides a method for preparing the sulfonate crystal form of Baloxavir Marboxil as shown in formula (I) as described above, the method comprising the following steps: (1) Add the Baloxavir Marboxil raw material shown in formula (I) to an organic solvent to obtain a suspension of Baloxavir Marboxil shown in formula (I); add the sulfonic acid raw material to an organic solvent to obtain a sulfonic acid solution; (2) Add sulfonic acid solution to the suspension of Baloxavir Marboxil shown in formula (I) and stir until clear; (3) Evaporate the organic solvent in the clear solution obtained in step (2) to obtain the sulfonate crystal form of Baloxavir Marboxil as shown in formula (I), or add a poor solvent to the clear solution obtained in step (2) and stir to crystallize to obtain the sulfonate crystal form of Baloxavir Marboxil as shown in formula (I).

[0014] Preferably, the organic solvent in step (1) includes any one or a combination of at least two of methanol, ethanol, isopropanol, n-propanol, n-butanol, acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, ethylene glycol dimethyl ether (DME), or ethyl acetate.

[0015] Preferably, in the preparation of the Baloxavir Marboxil suspension in step (1), the amount of organic solvent added relative to 1 mmol of Baloxavir Marboxil as shown in formula (I) is 5 to 20 mL (e.g., 5 mL, 7 mL, 9 mL, 11 mL, 13 mL, 15 mL, 17 mL or 20 mL, etc.).

[0016] Preferably, in the preparation of the sulfonic acid solution in step (1), the amount of organic solvent added is 5 to 20 mL relative to 1 mmol of sulfonic acid (e.g., 5 mL, 7 mL, 9 mL, 11 mL, 13 mL, 15 mL, 17 mL or 20 mL, etc.).

[0017] The molar ratio of Baloxavir Marboxil raw material to sulfonic acid raw material in step (2) is 1:(0.2~5), for example 1:0.2, 1:0.5, 1:1, 1:1.6, 1:2.3, 1:3, 1:3.7, 1:4.4 or 1:5, preferably 1:(0.5~2).

[0018] Preferably, the sulfonic acid solution in step (2) is added dropwise to the suspension of Baloxavir Marboxil shown in formula (I).

[0019] Preferably, the organic solvent in step (3) is evaporated at ambient or reduced pressure at a temperature of 20 to 80°C (e.g., 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 70°C or 80°C).

[0020] Preferably, the organic solvent in step (3) is at room temperature (20-30°C). o C evaporates at normal pressure, or at 40~80°C. oEvaporation under reduced pressure at C conditions yielded the sulfonate crystal form of Baloxavir Marboxil as shown in formula (I).

[0021] Preferably, in step (3), a poor solvent is added to the clear solution obtained in step (2) at room temperature, and the mixture is stirred to crystallize and obtain the Baloxavir Marboxil sulfonate crystal form shown in formula (I).

[0022] Preferably, the amount (volume) of the undesirable solvent added is 2 to 30 times the volume of the clarified solution (e.g., 2 times, 4 times, 6 times, 8 times, 10 times, 12 times, 14 times, 16 times, 18 times, 20 times, 22 times, 24 times, 26 times, 28 times or 30 times, etc.), preferably 5 to 10 times.

[0023] Preferably, the undesirable solvent in step (3) is added to the clear solution obtained in step (2) at room temperature.

[0024] Preferably, the undesirable solvent in step (3) includes any one or a combination of at least two of hexane, petroleum ether, diethyl ether, or methyl ethyl ether.

[0025] Preferably, the stirring in steps (2) and (3) is magnetic or mechanical stirring, and the stirring speed is 200-800 rpm, such as 200 rpm, 250 rpm, 300 rpm, 350 rpm, 400 rpm, 450 rpm, 500 rpm, 550 rpm, 600 rpm or 800 rpm, etc.

[0026] Preferably, after crystallization in step (3), the solid is filtered and separated at room temperature, washed with an organic solvent at 5 ~ 20°C (e.g., 5°C, 7°C, 9°C, 11°C, 13°C, 15°C, 17°C or 20°C), and dried under reduced pressure at 20 ~ 80°C (e.g., 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 70°C or 80°C) to obtain the sulfonate crystal form of Baloxavir Marboxil as shown in formula (I); Preferably, the organic solvent is selected from any one or a combination of at least two of methanol, ethanol, isopropanol, n-propanol, n-butanol, acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, or ethyl acetate.

[0027] The amount of organic solvent at 5~20℃ is 1 / 10 to 1 / 4 of the mass of the obtained crystals, for example 1 / 10, 1 / 9, 1 / 8, 1 / 7, 1 / 6, 1 / 5 or 1 / 4.

[0028] Preferably, the temperature of the vacuum drying is 40 to 50°C, such as 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, or 50°C.

[0029] On the other hand, the present invention provides the use of the sulfonate crystal form of Baloxavir Marboxil as shown in formula (I) as described above in the preparation of a medicament for treating influenza virus infection.

[0030] Compared with the prior art, the present invention has the following beneficial effects: The methanesulfonate crystal form I, ethanesulfonate crystal form I, benzenesulfonate crystal form I, and p-toluenesulfonate crystal form I of Baloxavir Marboxil shown in Formula (I) of the present invention all have good crystallinity, high stability, low hygroscopicity and high solubility, providing more advantageous solid form options for their formulation development. Attached Figure Description

[0031] Figure 1 The XPRD pattern of the methanesulfonate form I of Baloxavir Marboxil, as shown in formula (I), provided for the present invention.

[0032] Figure 2 The XPRD pattern of ethanesulfonate form I of Baloxavir Marboxil as shown in formula (I) provided by the present invention.

[0033] Figure 3 The XPRD pattern of the benzenesulfonate crystal form I of Baloxavir Marboxil as shown in formula (I) provided by the present invention.

[0034] Figure 4 The XPRD pattern of p-toluenesulfonate form I of Baloxavir Marboxil, as shown in formula (I) provided by the present invention.

[0035] Figure 5 The DSC spectrum of the methanesulfonate form I of Baloxavir Marboxil as shown in formula (I) provided by the present invention.

[0036] Figure 6 The DSC spectrum of ethanesulfonate form I of Baloxavir Marboxil as shown in formula (I) provided by the present invention.

[0037] Figure 7The DSC spectrum of the benzenesulfonate crystal form I of Baloxavir Marboxil as shown in formula (I) provided by the present invention.

[0038] Figure 8 The DSC spectrum of p-toluenesulfonate form I of Baloxavir Marboxil as shown in formula (I) provided by the present invention.

[0039] Figure 9 The XRPD pattern of Baloxavir Marboxil crystal form I shown in formula (I) provided by the present invention. Detailed Implementation

[0040] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0041] Table 1. Screening experiment and results of Baloxavir Marboxil salt crystal form as shown in formula (I) Example 1-12: Preparation of Baloxavir Marboxil sulfonate crystal form as shown in formula (I) Weigh 0.5 mmol or 286 mg of Baloxavir Marboxil active pharmaceutical ingredient as shown in Formula (I) into a 10-40 mL screw-top transparent borosilicate glass bottle, add 2-15 mL of organic solvent and stir to prepare a Baloxavir Marboxil suspension as shown in Formula (I). Then, dissolve the corresponding sulfonic acid (methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid) with a molar ratio of 1:1 to Baloxavir Marboxil as shown in Formula (I) into an organic solvent of the same type and volume as the organic solvent used to dissolve the Baloxavir Marboxil active pharmaceutical ingredient (see Table 2 for the specific amount of total solvent). Stir until clear, and then add the clear sulfonic acid solution dropwise to the Baloxavir Marboxil suspension as shown in Formula (I) while stirring. The total volume of the solution is 4-30 mL. Stir at room temperature until a clear solution forms. Then filter the resulting clear solution into another clean, screw-top, transparent borosilicate glass bottle. Seal the bottle tightly with sealing film, then poke 4-10 small holes in the film. Place the bottle in a fume hood at room temperature (20-30°C). o C) Slow evaporation yields four sulfonate crystals of Baloxavir Marboxil as shown in formula (I) within one week (Table 2). After filtration, the crystals are treated with a small amount of cold solvent (10~20). oC) Washing, vacuum drying, yield 82-92%. Their XRPD diffraction patterns are respectively compared with... Figure 1 ~ Figure 4 Basically the same.

[0042] Table 2. Preparation of Baloxavir Marboxil sulfonate crystal form as shown in formula (I) X-ray powder diffraction (XRPD) patterns were measured using a Bruker D8 ADVANCE diffractometer with Cu-Kα radiation (λ = 1.5418 Å). The measurements were performed at room temperature, with the X-ray operating voltage and current set to 40 kV and 40 mA, respectively. The scanning range was 2°–50° (2θ) with a step size of 0.05° (2θ), used to characterize the structural information and crystallinity of the samples.

[0043] The Baloxavir Marboxil mesylate crystal form I shown in Formula (I) obtained in Examples 1-3 was obtained using Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed as 2θ values, include 7.2±0.3°, 11.4±0.3°, 13.0±0.3°, 14.4±0.3°, 15.3±0.3°, 15.8±0.3°, 16.9±0.3°, 18.0±0.3°, 19.1±0.3°, 19.8±0.3°, 21.6±0.3°, 22.0±0.3°, 22.8±0.3°, 23.6±0.3°, 25.0±0.3°, 26.2±0.3°, 27.3±0.3°, 28.3±0.3°, 29.0±0.3°, and 29.6±0.3°.

[0044] The Baloxavir Marboxil ethanesulfonate crystal form I obtained in Examples 4-6 uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed as 2θ values, include 6.9±0.3°, 7.3±0.3°, 9.4±0.3°, 11.0±0.3°, 12.3±0.3°, 13.8±0.3°, 14.6±0.3°, 15.1±0.3°, 15.7±0.3°, 16.1±0.3°, 17.3±0.3°, 18.9±0.3°, 20.8±0.3°, 21.5±0.3°, 22.0±0.3°, 22.9±0.3°, 24.3±0.3°, 25.1±0.3°, 28.5±0.3°, and 31.6±0.3°. The Baloxavir Marboxil benzenesulfonate crystal form I obtained in Examples 7-9 uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 8.2±0.3°, 9.4±0.3°, 9.9±0.3°, 10.8±0.3°, 11.7±0.3°, 14.7±0.3°, 15.9±0.3°, 16.3±0.3°, 16.9±0.3°, 17.8±0.3°, 18.8±0.3°, 20.2±0.3°, 21.4±0.3°, 21.8±0.3°, 22.3±0.3°, 22.7±0.3°, 22.9±0.3°, 24.6±0.3°, 24.8±0.3°, 25.8±0.3°, 26.2±0.3°, and 30.7±0.3°. The Baloxavir Marboxil p-toluenesulfonate crystal form I obtained in Examples 10-12 was prepared using Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed as 2θ values, include 8.0±0.3°, 9.2±0.3°, 9.9±0.3°, 11.5±0.3°, 15.8±0.3°, 16.1±0.3°, 16.7±0.3°, 17.6±0.3°, 18.5±0.3°, 19.8±0.3°, 21.0±0.3°, 22.3±0.3°, 23.0±0.3°, 24.1±0.3°, 25.6±0.3°, 26.0±0.3°, and 29.9±0.3°.

[0045] Examples 13-24: Preparation of Baloxavir Marboxil sulfonate crystal form as shown in formula (I) Weigh 0.5 mmol or 286 mg of Baloxavir Marboxil active pharmaceutical ingredient (PPI) into a 10–40 mL screw-top transparent borosilicate glass bottle. Add 2–15 mL of organic solvent and stir to prepare a Baloxavir Marboxil suspension as shown in Formula (I). Then, dissolve the corresponding sulfonic acid (methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid) with a molar ratio of 1:1 to Baloxavir Marboxil as shown in Formula (I) into an organic solvent of the same type and volume as that used to dissolve the Baloxavir Marboxil active pharmaceutical ingredient (see Table 3 for the specific total solvent amount). Stir until clear. Then, while stirring, add the clear sulfonic acid solution dropwise to the Baloxavir Marboxil suspension as shown in Formula (I), with a total solution volume of 4–30 mL. Stir at room temperature until a clear solution is formed. Then, filter the resulting clear solution into a 250 mL or 500 mL Erlenmeyer flask and add 40–300 mL of antisolvent dropwise while stirring. Continue stirring for 2 to 12 hours to obtain four sulfonate crystals of Baloxavir Marboxil as shown in formula (I). After filtration, the crystals are rinsed with a small amount of cold solvent (10-20 g / L). o C) Washing and vacuum drying, yield 87-95% (Table 3). Their XRPD diffraction patterns are respectively compared with those of the attached... Figure 1 (Methanesulfonate crystal form I), Appendix Figure 2 (Ethylenesulfonate crystal form I), Appendix Figure 3 (Benzenesulfonate crystal form I), and its appendix Figure 4 The results are essentially consistent with those shown in (p-toluenesulfonate crystal form I), confirming that the crystal form described in this invention has been obtained.

[0046] Table 3. Preparation of Baloxavir Marboxil sulfonate crystal form as shown in formula (I) X-ray powder diffraction (XRPD) patterns were measured using a Bruker D8 ADVANCE diffractometer with Cu-Kα radiation (λ = 1.5418 Å). The measurements were performed at room temperature, with the X-ray operating voltage and current set to 40 kV and 40 mA, respectively. The scanning range was 2°–50° (2θ) with a step size of 0.05° (2θ), used to characterize the structural information and crystallinity of the samples.

[0047] The Baloxavir Marboxil mesylate crystal form I shown in Formula (I) obtained in Examples 13-15 was obtained using Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 7.2±0.3°, 11.4±0.3°, 13.0±0.3°, 14.4±0.3°, 15.3±0.3°, 15.8±0.3°, 16.9±0.3°, 18.0±0.3°, 19.1±0.3°, 19.8±0.3°, 21.6±0.3°, 22.0±0.3°, 22.8±0.3°, 23.6±0.3°, 25.0±0.3°, 26.2±0.3°, 27.3±0.3°, 28.3±0.3°, 29.0±0.3°, and 29.6±0.3°. The Baloxavir Marboxil ethanesulfonate crystal form I shown in Examples 16-18 uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed as 2θ values, include 6.9±0.3°, 7.3±0.3°, 9.4±0.3°, 11.0±0.3°, 12.3±0.3°, 13.8±0.3°, 14.6±0.3°, 15.1±0.3°, 15.7±0.3°, 16.1±0.3°, 17.3±0.3°, 18.9±0.3°, 20.8±0.3°, 21.5±0.3°, 22.0±0.3°, 22.9±0.3°, 24.3±0.3°, 25.1±0.3°, 28.5±0.3°, and 31.6±0.3°. The Baloxavir Marboxil benzenesulfonate crystal form I shown in Examples 19-21 (I) was obtained using Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 8.2±0.3°, 9.4±0.3°, 9.9±0.3°, 10.8±0.3°, 11.7±0.3°, 14.7±0.3°, 15.9±0.3°, 16.3±0.3°, 16.9±0.3°, 17.8±0.3°, 18.8±0.3°, 20.2±0.3°, 21.4±0.3°, 21.8±0.3°, 22.3±0.3°, 22.7±0.3°, 22.9±0.3°, 24.6±0.3°, 24.8±0.3°, 25.8±0.3°, 26.2±0.3°, and 30.7±0.3°. Examples 22-24 show the Baloxavir Marboxil p-toluenesulfonate crystal form I obtained using Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed as 2θ values, include 8.0±0.3°, 9.2±0.3°, 9.9±0.3°, 11.5±0.3°, 15.8±0.3°, 16.1±0.3°, 16.7±0.3°, 17.6±0.3°, 18.5±0.3°, 19.8±0.3°, 21.0±0.3°, 22.3±0.3°, 23.0±0.3°, 24.1±0.3°, 25.6±0.3°, 26.0±0.3°, and 29.9±0.3°.

[0048] Example 25: Characterization of Baloxavir Marboxil sulfonate crystal form by DSC as shown in formula (I) DSC spectra of the four Baloxavir Marboxil sulfonate crystal forms shown in formula (I) were tested at room temperature. DSC analysis was performed using a Netzsch STA 449 F5. The sample (8 mg) was placed in a standard alumina crucible under nitrogen atmosphere at a heating rate of 1°C / min, with a temperature range of 30–400°C. The DSC spectra of the four Baloxavir Marboxil methanesulfonate crystal forms (I), (I) ethanesulfonate crystal form (I), (I) benzenesulfonate crystal form (I), and (I) p-toluenesulfonate crystal form (I) are shown in the attached figures. Figure 5-8 As shown.

[0049] Example 26: Comparison of the solubility of four Baloxavir Marboxil sulfonate crystal forms of formula (I) with Baloxavir Marboxil crystal form I of formula (I) disclosed in WO2018030463, with the experiment conducted in accordance with the USP method for determining the solubility of biological media.

[0050] At 37°C, 30 mg of each of the four Baloxavir Marboxil sulfonate crystals (I) were weighed and placed in 50 mL of PBS buffer solution with pH ~1.2 and pH ~6.8, respectively. The suspensions were stirred at 37°C and 200 r / min. The concentrations of each solution at different times (1, 2 and 4 hours) were tested by HPLC, and the solubility of different salts at different times was calculated. The results are shown in Table 4. As can be seen, 1) Baloxavir Marboxil itself is weakly alkaline, and Baloxavir Marboxil and its four sulfonate crystal forms exhibit high solubility under strongly acidic conditions, i.e., in PBS buffer solution with pH ~1.2; 2) Compared with Baloxavir Marboxil crystal form I, the solubility of the four Baloxavir Marboxil sulfonate crystal forms disclosed in this invention in PBS buffer solution with pH ~1.2 and pH ~6.8 is significantly improved, while the solubility of Baloxavir Marboxil p-toluenesulfonate crystal form I in PBS buffer solution with pH ~6 and pH ~3 of Baloxavir Marboxil crystal form I in PBS buffer solution with pH ~1.2 and pH ~6.8 respectively shows very good prospects for clinical application.

[0051] Duchuang (Shanghai) Pharmaceutical Technology Co., Ltd. disclosed three co-crystal forms of Baloxavir Marboxil: DCTRI (CN120682249A) with troponic acid, DCTI (CN120887901A) with L-tartaric acid, and DCVI (CN120887902A) with vitamin C. The solubility behavior of these three co-crystal forms and Baloxavir Marboxil crystal form I in simulated gastrointestinal fluids SGF, FeSSIF, and FaSSIF was compared (Table 5). Simulated gastric fluid SGF, with pH... A pH of 1.2–1.5, containing pepsin, is suitable for evaluating drug solubility under acidic conditions, while the pH of FaSSIF, which mimics intestinal fluid, is... 6.8~7.2, containing bile salts, lecithin, and pancreatic enzymes, exhibiting surface solubilization and providing a true intestinal dissolution environment. It can be seen that: 1) FaSSIF has varying degrees of solubilization effects on all but the Baloxavir Marboxil-Tropic Acid co-crystal form DCTRI, including L-tartaric acid co-crystal form DCTI, vitamin C co-crystal form DCVI, and Baloxavir Marboxil crystal form I; 2) In SGF solution, the solubility of Baloxavir Marboxil-Tropic Acid co-crystal form DCTRI is 3 times that of Baloxavir Marboxil crystal form I. In FaSSIF, the solubility of Baloxavir Marboxil-L-tartaric acid co-crystal form DCTI is 1.6~3.7 times that of Baloxavir Marboxil crystal form I.

[0052] Table 4 Table 5 Sonali S. Bharate's study on the solubility of 52 common drugs in simulated fluids by the 96-well plate method in early drug discovery (Bioorganic & Medicinal Chemistry Letters 25 (2015) 1561-1567, https: / / doi.org / 10.1016 / j.bmcl.2015.02.013) showed that, compared with PBS buffer at pH ~6.8, the pH of simulated intestinal fluid FaSSIF was significantly lower. The pH range is 6.8-7.2. Due to the presence of bile salts, lecithin, and trypsin, it has a surface solubilizing effect. The average solubility of 52 drugs in FaSSIF is 1.13 times that in PBS buffer at pH 6.8. Therefore, it can be inferred that the solubility of Baloxavir Marboxil p-toluenesulfonate crystal form I of the present invention in simulated intestinal fluid FaSSIF is slightly higher than that of the co-crystal form DCTI of Baloxavir Marboxil and L-tartaric acid disclosed in CN120887901A, which is 2.3-3.1 times that of Baloxavir Marboxil crystal form I, and 2.5-4.5 times that of the co-crystal form DCVI of Baloxavir Marboxil and vitamin C disclosed in CN120887902A and the co-crystal form DCTRI of Baloxavir Marboxil and troponic acid disclosed in CN120682249A.

[0053] As can be seen from the above discussion, in terms of solubility, Baloxavir Marboxil p-toluenesulfonate crystal form I has shown outstanding advantages over other existing crystal forms of Baloxavir Marboxil in different solvent environments.

[0054] Example 27: Hygroscopicity test of four Baloxavir Marboxil sulfonate crystal forms shown in formula (I) The hygroscopicity of drugs was determined according to the guidelines for hygroscopicity testing of drugs in General Chapter 9103 of the 2020 edition of the Chinese Pharmacopoeia. The test conditions were 25±1℃ and 80% relative humidity.

[0055] Definition of hygroscopic weight gain: extremely hygroscopic (hygroscopic weight gain not less than 15.0%); hygroscopic (hygroscopic weight gain less than 15.0%, but not less than 2.0%); slightly hygroscopic (hygroscopic weight gain less than 2.0%, but not less than 0.2%); no or almost no hygroscopicity (hygroscopic weight gain less than 0.2%).

[0056] Approximately 100 mg of each of the four Baloxavir Marboxil sulfonate crystal forms shown in Formula (I) prepared in Examples 1, 4, 7, and 10 of this application were weighed and placed at 25±1°C and 80% relative humidity for 24 hours. The mass of the samples before and after the treatment was recorded, and the specific results are shown in Table 6. The weight gain percentage of each crystal form was 0.2-0.6%, indicating that they are all slightly hygroscopic. Moreover, their hygroscopicity is comparable to that of Baloxavir Marboxil crystal form I (WO2018030463) and the Baloxavir Marboxil-tropinic acid co-crystal form DCTRI (CN120682249A), but significantly lower than that of Baloxavir Marboxil-vitamin C co-crystal form DCVI (CN120887902A) and Baloxavir Marboxil-L-tartaric acid co-crystal form DCTI (CN120887901 A). Meanwhile, XRPD measurements showed that the XRPD patterns of the four samples after 24 hours were respectively compared with... Figure 1 The positions and intensities of the diffraction peaks shown in Figures 2, 3, and 4 are basically consistent, indicating that there is no significant change in the crystal form and crystallinity of each sample.

[0057] Table 6 In summary, the method for preparing the Baloxavir Marboxil sulfonate crystal form shown in Formula (I) provided by this invention is simple, reproducible, and yields crystal forms with high purity, good stability, and significantly improved solubility. This provides a new and advantageous solid form of active pharmaceutical ingredient (API) for developing more bioavailable Baloxavir Marboxil drug formulations shown in Formula (I), and has significant industrial application value.

[0058] The applicant declares that the present invention illustrates the sulfonate crystal form of Baloxavir Marboxil shown in formula (I), its preparation method, and its application through the above embodiments. However, the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials used in the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. The sulfonate crystal form of Baloxavir Marboxil as shown in formula (I), characterized in that, The sulfonate crystal forms of Baloxavir Marboxil shown in Formula (I) include methanesulfonate crystal form I of Baloxavir Marboxil shown in Formula (I), ethanesulfonate crystal form I of Baloxavir Marboxil shown in Formula (I), benzenesulfonate crystal form I of Baloxavir Marboxil shown in Formula (I), and p-toluenesulfonate crystal form I of Baloxavir Marboxil shown in Formula (I); ； The methanesulfonate form I of Baloxavir Marboxil shown in formula (I) uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 7.2±0.3°, 13.0±0.3°, 14.4±0.3°, 18.0±0.3°, 19.1±0.3°, 22.8±0.3°, and 23.6±0.3°. The ethanesulfonate form I of Baloxavir Marboxil shown in formula (I) uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 6.9±0.3°, 12.3±0.3°, 16.1±0.3°, 18.9±0.3°, 22.0±0.3°, 24.3±0.3°, and 25.1±0.3°. The benzenesulfonate form I of Baloxavir Marboxil shown in formula (I) uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 8.2±0.3°, 11.7±0.3°, 16.3±0.3°, 16.9±0.3°, 21.4±0.3°, 22.7±0.3°, 23.0±0.3°, and 24.8±0.3°. The p-toluenesulfonate crystal form I of Baloxavir Marboxil shown in formula (I) uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 8.0±0.3°, 16.1±0.3°, 16.7±0.3°, 21.0±0.3°, 22.3±0.3°, and 24.1±0.3°.

2. The sulfonate crystal form of Baloxavir Marboxil according to formula (I) of claim 1, characterized in that, The methanesulfonate form I of Baloxavir Marboxil shown in formula (I) uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 7.2±0.3°, 13.0±0.3°, 14.4±0.3°, 18.0±0.3°, 19.1±0.3°, 19.8±0.3°, 21.6±0.3°, 22.0±0.3°, 22.8±0.3°, 23.6±0.3°, 25.0±0.3°, and 26.2±0.3°, preferably including 7.2±0.3°, 11.4±0.3°, 13.0±0.3°, 14.4±0.3°, 15.3±0.3°, and 15.8±0.3°. 16.9±0.3°, 18.0±0.3°, 19.1±0.3°, 19.8±0.3°, 21.6±0.3°, 22.0±0.3°, 22.8±0.3°, 23.6±0.3°, 25.0±0.3°, 26.2±0.3°, 27.3±0.3°, 28.3±0.3°, 29.0±0.3°, 29.6±0.3°; Preferably, the ethanesulfonate form I of Baloxavir Marboxil shown in formula (I) uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 6.9±0.3°, 11.0±0.3°, 12.3±0.3°, 15.1±0.3°, 16.1±0.3°, 17.3±0.3°, 18.9±0.3°, 20.8±0.3°, 22.0±0.3°, 22.9±0.3°, 24.3±0.3°, 25.1±0.3°, and 28.5±0.3°; preferably, they include 6.9±0.3° and 7.3±0.3°. , 9.4±0.3°, 11.0±0.3°, 12.3±0.3°, 13.8±0.3°, 14.6±0.3°, 15.1±0.3°, 15.7±0.3°, 16.1±0.3°, 17.3±0.3°, 18.9±0.3°, 20.8±0.3°, 21.5±0.3°, 22.0±0.3°, 22.9±0.3°, 24.3±0.3°, 25.1±0.3°, 28.5±0.3°, 31.6±0.3°; Preferably, the benzenesulfonate crystal form I of Baloxavir Marboxil shown in formula (I) uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 8.2±0.3°, 9.4±0.3°, 9.9±0.3°, 11.7±0.3°, 14.7±0.3°, 15.9±0.3°, 16.3±0.3°, 16.9±0.3°, 18.8±0.3°, 20.2±0.3°, 21.4±0.3°, 22.3±0.3°, 22.7±0.3°, 22.9±0.3°, 24.6±0.3°, 24.8±0.3°, and 26.2±0.3°. Preferably, the following values ​​are included: 8.2±0.3°, 9.4±0.3°, 9.9±0.3°, 10.8±0.3°, 11.7±0.3°, 14.7±0.3°, 15.9±0.3°, 16.3±0.3°, 16.9±0.3°, 17.8±0.3°, 18.8±0.3°, 20.2±0.3°, 21.4±0.3°, 21.8±0.3°, 22.3±0.3°, 22.7±0.3°, 22.9±0.3°, 24.6±0.3°, 24.8±0.3°, 25.8±0.3°, 26.2±0.3°, and 30.7±0.3°. Preferably, the p-toluenesulfonate crystal form I of Baloxavir Marboxil shown in formula (I) uses Cu K The characteristic diffraction peaks of the X-ray powder diffraction pattern, expressed in 2θ values, include 8.0±0.3°, 9.2±0.3°, 9.9±0.3°, 11.5±0.3°, 16.1±0.3°, 16.7±0.3°, 18.5±0.3°, 21.0±0.3°, 22.3±0.3°, 24.1±0.3°, and 26.0±0.3°, preferably including 8.0±0.3°, 9.2±0.3°, 24.1±0.3°, and 26.0±0.3°, with a preference for 8.0±0.3° and 9.2±0.3°. 0.3°, 9.9±0.3°, 11.5±0.3°, 15.8±0.3°, 16.1±0.3°, 16.7±0.3°, 17.6±0.3°, 18.5±0.3°, 19.8±0.3°, 21.0±0.3°, 22.3±0.3°, 23.0±0.3°, 24.1±0.3°, 25.6±0.3°, 26.0±0.3°, 29.9±0.3°.

3. The sulfonate crystal form of Baloxavir Marboxil according to formula (I) of claim 1, characterized in that, The sulfonate crystal form of Baloxavir Marboxil shown in Formula (I) has a molar ratio of Baloxavir Marboxil to sulfonic acid molecules or sulfonic acid anions of 1:(0.2 ~ 5), preferably 1:(0.5 ~ 2).

4. A method for preparing the sulfonate crystal form of Baloxavir Marboxil according to any one of claims 1-3, characterized in that, The preparation method includes the following steps: (1) Add the Baloxavir Marboxil raw material shown in formula (I) to an organic solvent to obtain a suspension of Baloxavir Marboxil shown in formula (I); add the sulfonic acid raw material to an organic solvent to obtain a sulfonic acid solution; (2) Add sulfonic acid solution to the suspension of Baloxavir Marboxil shown in formula (I) and stir until clear; (3) Evaporate the organic solvent in the clear solution obtained in step (2) to obtain the sulfonate crystal form of Baloxavir Marboxil as shown in formula (I), or add a poor solvent to the clear solution obtained in step (2) and stir to crystallize to obtain the sulfonate crystal form of Baloxavir Marboxil as shown in formula (I).

5. The preparation method according to claim 4, characterized in that, The organic solvent in step (1) includes any one or a combination of at least two of methanol, ethanol, isopropanol, n-propanol, n-butanol, acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether or ethyl acetate; Preferably, in the preparation of the Baloxavir Marboxil suspension in step (1), the amount of organic solvent added is 5 to 20 mL relative to 1 mmol of Baloxavir Marboxil as shown in formula (I); Preferably, in the preparation of the sulfonic acid solution in step (1), the amount of organic solvent added is 5 to 20 mL relative to 1 mmol of sulfonic acid.

6. The preparation method according to claim 4, characterized in that, In step (2), the molar ratio of Baloxavir Marboxil raw material to sulfonic acid raw material is 1:(0.2~5), preferably 1:(0.5~2); Preferably, the sulfonic acid solution in step (2) is added dropwise to the suspension of Baloxavir Marboxil shown in formula (I).

7. The preparation method according to claim 4, characterized in that, In step (3), the organic solvent in the clarified solution is evaporated at atmospheric or reduced pressure at a temperature of 20-80°C. Preferably, the undesirable solvent in step (3) includes any one or a combination of at least two of hexane, petroleum ether, diethyl ether, or methyl ethyl ether; Preferably, the amount of the undesirable solvent added in step (3) is 2 to 30 times the volume of the clarified solution; Preferably, the undesirable solvent in step (3) is added to the clear solution obtained in step (2) at room temperature.

8. The preparation method according to claim 4, characterized in that, The stirring in steps (2) and (3) is magnetic or mechanical stirring, and the stirring speed is 200 to 800 revolutions per minute.

9. The preparation method according to claim 4, characterized in that, After crystallization in step (3), the solid was filtered and separated at room temperature, washed with an organic solvent at 5 to 20°C, and dried under reduced pressure at 20 to 80°C to obtain the sulfonate crystal form of Baloxavir Marboxil as shown in formula (I). Preferably, the organic solvent is selected from any one or a combination of at least two of methanol, ethanol, isopropanol, n-propanol, n-butanol, acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, or ethyl acetate. Preferably, the temperature of the vacuum drying is 40 to 50°C.

10. Use of the sulfonate crystal form of Baloxavir Marboxil as shown in formula (I) according to any one of claims 1-3 in the preparation of a medicament for treating influenza virus infection.

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