Baloxavir marboxil and citric acid eutectic crystal form DCCI and preparation method thereof

Abstract

The invention discloses a Baloxavir marboxil and citric acid eutectic crystal form DCCI and a preparation method thereof. The Baloxavir marboxil and citric acid eutectic crystal form DCCI and the preparation method thereof have diffraction angle 2theta values of 14.2 + / -0.2 degrees, 16.7 + / -0.2 degrees, 17.9 + / -0.2 degrees, 18.2 + / -0.2 degrees, 19.5 + / -0.2 degrees, 21.8 + / -0.2 degrees, 23.9 + / -0.2 degrees, 25.1 + / -0.2 degrees, 26.1 + / -0.2 degrees, 27.5 + / -0.2 degrees, 28.0 + / -0.2 degrees, 28.9 + / -0.2 degrees, 30.0 + / -0.2 degrees, 31.1 + / -0.2 degrees, 31.4 + / -0.2 degrees, 33.2 + / -0.2 degrees, 33.7 + / -0.2 and characteristic peaks exist at the positions of 36.7 + / -0.2 degrees, 36.8 + / -0.2 degrees, 37.4 + / -0.2 degrees, 37.7 + / -0.2 degrees and 39.4 + / -0.2 degrees. The Baloxavir marboxil and citric acid eutectic crystal form DCCI provided by the invention has stable physicochemical properties, excellent solid stability and mechanical stability, and can be stably stored for a long time, the preparation method is simple and convenient, the repeatability is good, and the Baloxavir marboxil and citric acid eutectic crystal form DCCI has important application value for development of the medicine in the future.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug crystal forms, in particular to a baloxavir marboxil and citric acid co-crystal Form DCCI and a preparation method thereof. BACKGROUND

[0002] Baloxavir marboxil is an innovative CAP-dependent endonuclease inhibitor, and is also one of the few new drugs in the world that can treat influenza virus proliferation. It can target the key link of influenza virus replication, treat it to obtain the CAP structure of the host mRNA 5' end from the host cell, and thus treat the transcription of the influenza virus itself mRNA.

[0003] At present, there are many reports on the crystal form of baloxavir marboxil. Among them, the original research drug company Japan Yanyi has disclosed three crystal forms in WO2018030463, namely Form I, Form II, and Form III, but the DSC / TGA data are not collected in the document, so the crystal type cannot be obtained, and the stability data are also not reported in the document.

[0004] CN111377944 discloses two crystal forms, wherein Form A is Form I in WO2018030463, and the DSC research on the crystal form is also carried out in the document, confirming that it is an anhydrous crystal form; Form B is another anhydrous crystal form.

[0005] WO2022100395 discloses two crystal forms, namely methyl benzoate solvate Form C and anhydrous Form D.

[0006] CN111875619 discloses a new crystal form of baloxavir marboxil and a preparation method.

[0007] WO2020181025 discloses six crystal forms of baloxavir marboxil, including three anhydrous crystal forms Form BM1, BM2, and BM3, and three solvate crystal forms Form BM4, BM5, and BM6, and the solvents thereof are 1,4-dioxane, N,N-dimethylacetamide, and 2-methyltetrahydrofuran, respectively.

[0008] WO2021057834 discloses an anhydrous crystal form Form C of baloxavir marboxil.

[0009] Drug crystal form is an important factor affecting the quality of drug, different crystal forms of the same drug molecule will have significant differences in appearance, solubility, melting point, dissolution, bioavailability and other properties, thereby directly affecting the stability, bioavailability and efficacy of the drug.

[0010] From the above patents, it is not difficult to find that the crystal form of Baloxavir marboxil is more comprehensive, and most of the anhydrous crystal forms can be used as drugs, but Prior art Baloxavir marboxil crystal form has poor stability or solubility; therefore, it is of great significance to carry out crystal form research. SUMMARY

[0011] The present application aims to at least solve one of the technical problems in the related art. To this end, the present application also provides comprehensive characterization data of the above-mentioned Baloxavir marboxil and citric acid co-crystal form DCCI and its process preparation method, which has good solubility and stability.

[0012] In order to solve the above technical problems, the first aspect of the present application provides a Baloxavir marboxil and citric acid co-crystal form DCCI, the X-ray powder diffraction spectrum of the Baloxavir marboxil and citric acid co-crystal form DCCI under Cu-Ka radiation has characteristic peaks at diffraction angle 2theta values of 14.2±0.2°, 16.7±0.2°, 17.9±0.2°, 18.2±0.2°, 19.5±0.2°, 21.8±0.2°, 23.9±0.2°, 25.1±0.2°, 26.1±0.2°, 27.5±0.2°, 28.0±0.2°, 28.9±0.2°, 30.0±0.2°, 31.1±0.2°, 31.4±0.2°, 33.2±0.2°, 33.7±0.2°, 34.0±0.2°, 35.3±0.2°, 36.2±0.2°, 36.8±0.2°, 37.4±0.2°, 37.7±0.2°, 39.4±0.2°.

[0013] As a preferred embodiment, the differential scanning calorimetry spectrum of the Baloxavir marboxil and citric acid co-crystal form DCCI shows endothermic peaks near 142℃ and 188℃.

[0014] In a second aspect of the present application, a preparation method of the above-mentioned Baloxavir marboxil and citric acid co-crystal Form DCCI is provided. 1000 mg of Baloxavir marboxil and 262.6 mg of citric acid are weighed and added into a 40 ml vial, followed by adding a solvent to obtain a suspension. The suspension is stirred at room temperature for 48 h, and the solid is separated by centrifugation and dried, thereby obtaining the Baloxavir marboxil and citric acid co-crystal Form DCCI.

[0015] Compared with the prior art, the present application has the following beneficial effects: (1) The preparation process of the Baloxavir marboxil and citric acid co-crystal Form DCCI of the present application is simple, easy to operate, and easy to scale up; (2) The solvent required by the Baloxavir marboxil and citric acid co-crystal Form DCCI of the present application is a conventional organic solvent, the production amount is small, and the production cost is low.

[0016] The concept, specific structure and technical effects of the present application will be further described below with reference to the accompanying drawings, so as to fully understand the purpose, features and effects of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 is the XRPD spectrum of the Baloxavir marboxil and citric acid co-crystal Form DCCI prepared in Example 1 of the present application; Figure 2 is the DSC spectrum of the Baloxavir marboxil and citric acid co-crystal Form DCCI prepared in Example 1 of the present application; Figure 3 is the TGA spectrum of the Baloxavir marboxil and citric acid co-crystal Form DCCI prepared in Example 1 of the present application. 1 HNMR spectrum; DETAILED DESCRIPTION

[0019] In order to make the technical means, creative features, purposes and effects achieved by the present application easy to understand, the present application will be further described below in combination with specific drawings. However, the present application is not limited to the following examples.

[0020] It should be understood that the structures, proportions, sizes, etc. shown in the drawings attached to the present specification are only used to cooperate with the content disclosed in the specification, so as to be understood and read by those skilled in the art, and do not have technical substantial significance, and any modification of the structure, change of the proportion relationship or adjustment of the size, without affecting the effects and purposes that can be achieved by the present application, should fall within the scope of the technical content disclosed by the present application.

[0021] In the crystal forms of Baloxavir marboxil reported in the prior art, the problem of low solubility is common, which leads to poor efficacy and low bioavailability.

[0022] The present application obtains Baloxavir marboxil and citric acid co-crystal form DCCI from the perspective of changing the preparation method of Baloxavir marboxil. Baloxavir marboxil and citric acid co-crystal form DCCI has both stability and high solubility, which can avoid the risk of crystal transformation on the one hand, and facilitate drug absorption on the other hand, thereby improving bioavailability.

[0023] XRPD, i.e. X-ray powder diffraction, the X-ray powder diffraction pattern of the present application is collected on a Bruker D2 PHASER X-ray powder diffractometer. The method parameters of X-ray powder diffraction are as follows: X-ray source: Cu Ka; Kal (A): 1.54060; Ka2 (A) 1.54439; Ka2 / Ka1 intensity ratio: 0.50; Voltage: 30 kilovolts (kV); Current: 10 milliampere (mA); Scan range: 3.0-40.0°.

[0024] DSC, i.e. differential scanning calorimetry, the differential scanning calorimetry (DSC) pattern of the present application is collected on a TA company DSC X3, and the method parameters of differential scanning calorimetry (DSC) are as follows: scanning rate: 10 ℃ / min; protective gas: nitrogen.

[0025] TGA, i.e. thermal gravimetric analysis, the thermal gravimetric analysis (TGA) pattern of the present application is collected on a TA company TGA55, and the method parameters of thermal gravimetric analysis (TGA) are as follows: scanning rate: 10 ℃ / min; protective gas: nitrogen.

[0026] Unless otherwise specified, the following examples are all operated at room temperature, and the "room temperature" is not a specific temperature value, but refers to a temperature range of 10-30 ℃.

[0027] The "stirring" described in the following examples is completed by using conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 revolutions per minute, wherein the magnetic stirring is preferably 300-900 revolutions per minute, and the mechanical stirring is preferably 100-300 revolutions per minute.

[0028] The "separation" described in the following examples is completed by using conventional methods in the art, such as centrifugation or filtration, and the operation of "centrifugation" is as follows: the sample to be separated is placed in a centrifuge tube, and centrifuged at a speed of 10000 revolutions per minute until the solid is completely settled at the bottom of the centrifuge tube.

[0029] The term "dry" as used in the following examples can be performed at room temperature or higher. The drying temperature can be from room temperature to about 50 °C, or to 40 °C. The drying time can be from 2 to 48 hours, or overnight. The drying can be performed in a fume hood, in a forced air oven, or in a vacuum oven.

[0030] The term "crystal" as used in the following examples refers to a solid as characterized by an X-ray powder diffraction pattern. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized with experimental error that depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray powder diffraction patterns can vary with the conditions of the instrument, and in particular, it is noted that the relative intensities of the diffraction peaks in an X-ray powder diffraction pattern can vary with experimental conditions, and therefore the order of the diffraction peaks cannot be used as the sole or determining factor. In fact, the relative intensities of the diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystal, and the intensities shown in the figures are illustrative and not for absolute comparison. In addition, the experimental error in the positions of the diffraction peaks is typically 5% or less, and an error of ±0.2 is generally allowed. In addition, a general shift in the diffraction peak angles can occur due to experimental factors such as sample thickness, and some shift is generally allowed. Thus, those skilled in the art will appreciate that the X-ray powder diffraction patterns of the crystal forms claimed in the present application need not be identical to the X-ray powder diffraction patterns shown in the examples herein, and any crystal form having an X-ray powder diffraction pattern that is the same or similar to the characteristic peaks of the patterns shown in the figures is within the scope of the present application.

[0031] Those skilled in the art can compare the X-ray powder diffraction patterns shown in the present application to the X-ray powder diffraction pattern of an unknown crystal form to determine whether the two sets of patterns reflect the same or different crystal forms.

[0032] The baloxavir marboxil co-crystal forms with citric acid of the present application are pure, substantially free of any other crystal form. The term "substantially free of" as used in the present application when referring to a new crystal form means that the crystal form contains less than 20% by weight of another crystal form, more particularly less than 10% by weight of another crystal form, more particularly less than 5% by weight of another crystal form, and more particularly less than 1% by weight of another crystal form.

[0033] The term "about" as used in the present application when used in reference to a measurable value such as an amount of mass, time, temperature, and the like, is intended to refer to a range of values that one of skill in the art would consider equivalent to the recited value in light of the nature of the measurement as well as its inherent inaccuracies. For example, "about 100%" can mean ±10%, ±5%, ±1%, ±0.5%, or ±0.1%.

[0034] Baloxavir marboxil as a raw material includes, but is not limited to, solid forms (crystalline or amorphous), oily, liquid forms and solutions. Preferably, it is in solid form.

[0035] The preparation method of the Baloxavir marboxil and citric acid co-crystal crystal form of the present application: 1000 mg of Baloxavir marboxil and 336.1 mg of citric acid are weighed into a 40 ml vial, then a solvent is added to obtain a suspension, the suspension is stirred at room temperature for 48 h, the solid is separated by centrifugation and dried, which is the Baloxavir marboxil and citric acid co-crystal crystal form DCCI.

[0036] In the preparation of the Baloxavir marboxil and citric acid co-crystal crystal form DCCI of the present application, the crystallization time is different, which also affects the degree of crystallization or the yield of crystals, which can be flexibly selected according to actual needs.

[0037] Example 1

[0038] 1000 mg of Baloxavir marboxil and 336.1 mg of citric acid are weighed into a 40 ml vial, then a solvent (see Table 1 for details) is added to obtain a suspension, the suspension is stirred at room temperature for 48 h, the solid is separated by centrifugation and dried, and the obtained solid is detected by XRPD, which is the co-crystal crystal form DCCI shown in the present application. Its XRPD chart is as shown in Figure 1 , and the XRPD data is as shown in Table 2, and its DSC chart is as shown in Figure 2 .

[0039] Number Sample mass (mg) Citric acid mass (mg) Solvent Solvent volume (ml) XRPD Sample 1 1000 336.1 Acetic acid 5 Co-crystal DCCI Sample 2 1000 336.1 Isopropanol 5 Co-crystal DCCI Sample 3 1000 336.1 Dichloromethane 5 Co-crystal DCCI

[0040] Diffraction angle 2 theta d-value Relative intensity Diffraction angle 2 theta d-value Relative intensity Diffraction angle 2 theta d-value Relative intensity 14.21 6.23 16.70% 26.11 3.41 100.00% 33.67 2.66 34.80% 16.68 5.31 12.50% 27.50 3.24 11.10% 34.00 2.63 20.60% 17.92 4.95 38.30% 28.02 3.18 7.40% 35.31 2.54 13.10% 18.22 4.87 98.20% 28.92 3.08 35.90% 36.15 2.48 51.10% 19.54 4.54 64.00% 29.96 2.98 10.60% 36.76 2.44 27.90% 21.78 4.08 16.60% 31.14 2.87 23.00% 37.42 2.40 15.80% 23.95 3.71 39.70% 31.35 2.85 52.10% 37.65 2.39 22.80% 25.07 3.55 13.70% 33.16 2.70 10.50% 39.36 2.29 8.40%

[0041] As can be seen from Figure 2 , the Baloxavir marboxil and citric acid co-crystal crystal form DCCI prepared in Example 1 has an endothermic peak near 142℃ and 188℃, respectively.

[0042] The nuclear magnetic chart is as shown in Figure 3 , and the specific data is: 1 H-NMR (400 MHz, DMSO-D6) delta 7.52-7.37 (m,2H), 7.34-7.00 (m, 4H), 6.87-6.83 (m, 1H), 5.78-5.65 (m, 4H), 5.42 (d, J=15.9 Hz, 1H), 4.52-4.39 (m, 2H), 4.08-3.91 (m, 2H), 3.80-3.63 (m, 4H), 2.98-2.89 (m, 1H), 2.80-2.74 (m, 3H), 2.65 (d, J = 15.4 Hz, 3H)

[0043] The preferred embodiments of the present invention have been described in detail above. It should be understood that those skilled in the art can make numerous modifications and variations based on the concept of the present invention without creative effort. Therefore, all technical solutions that can be obtained by those skilled in the art based on the concept of the present invention through logical analysis, reasoning, or limited experimentation on the basis of existing technology should be within the scope of protection defined by the claims.

Claims

1. A eutectic form of Baloxavir marboxil and citric acid, DCCI, and its preparation method, characterized in that, The X-ray powder diffraction patterns of the Baloxavir marboxil and citric acid eutectic DCCI under Cu-Ka radiation showed diffraction angles of 2θ values ​​of 14.2±0.2°, 16.7±0.2°, 17.9±0.2°, 18.2±0.2°, 19.5±0.2°, 21.8±0.2°, 23.9±0.2°, 25.1±0.2°, 26.1±0.2°, and 27.5±0.2°. Characteristic peaks are present at 28.0±0.2°, 28.9±0.2°, 30.0±0.2°, 31.1±0.2°, 31.4±0.2°, 33.2±0.2°, 33.7±0.2°, 34.0±0.2°, 35.3±0.2°, 36.2±0.2°, 36.8±0.2°, 37.4±0.2°, 37.7±0.2°, and 39.4±0.2°.

2. A method for preparing a eutectic form of Baloxavir marboxil and citric acid DCCI, characterized in that, Baloxavir marboxil and citric acid were placed in an organic solvent at a molar ratio of 1:1 to obtain a suspension. The resulting suspension was stirred, separated, and dried to obtain DCCI, a eutectic crystal form with citric acid.

3. The method for preparing the eutectic form of Baloxavir marboxil and citric acid DCCI as described in claim 2, characterized in that, The organic solvent is selected from any one of acetic acid, dichloromethane, methanol, ethanol, isopropanol, n-propanol, acetone, and tetrahydrofuran.

4. The method for preparing the eutectic form of Baloxavir marboxil and citric acid DCCI as described in claim 2, characterized in that, The crystallization temperature is 0-40℃.

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