CN111825607A - A kind of co-crystal of regorafenib and malonic acid and preparation method thereof - Google Patents

Abstract

The invention discloses a co-crystal of regorafenib and malonic acid and a preparation method thereof. The molar ratio of regorafenib to malonic acid in the co-crystal is 1:1, and the 2 theta values of the co-crystal X-ray powder diffraction pattern are 7.3±0.2°, 11.1±0.2°, 13.8±0.2°, 16.8±0.2 There are characteristic peaks at °, 19.3±0.2°, 20.0±0.2°, 21.2±0.2°, and 22.2±0.2°. The eutectic preparation method provided by the invention has the advantages of simple process, easy control of the crystallization process and good reproducibility, and is suitable for industrial production. Compared with regorafenib monohydrate, this co-crystal has lower hygroscopicity and higher apparent solubility, which is beneficial to improve the stability and oral absorption efficiency of regorafenib.

Description

A kind of co-crystal of regorafenib and malonic acid and preparation method thereof

technical field

The invention relates to the technical field of medicinal chemistry, in particular to a co-crystal of regorafenib and malonic acid and a preparation method thereof.

Background technique

Pharmaceutically active ingredients usually exist in crystalline forms such as polymorphs, hydrates, solvates, salts, co-crystals, and the like. For the same active pharmaceutical ingredient, different crystalline forms have different physicochemical properties. Therefore, in the pharmaceutical industry, it is of great significance to obtain suitable crystalline forms of drugs. Drugs exist in the form of co-crystals, which can improve the stability, solubility and processability of active pharmaceutical ingredients, and have significant advantages. Therefore, drug co-crystals are an effective means to improve the physicochemical properties of active pharmaceutical ingredients.

The chemical name of Regorafenib is 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-picoline -2-Carboxamide, its chemical structural formula is as follows:

Regorafenib is a new anticancer drug approved by the US FDA in September 2012 for the treatment of metastatic colorectal cancer. In February 2013, its new indication (advanced gastrointestinal stromal tumor) was approved by the FDA priority review process . Regorafenib is a novel multi-kinase inhibitor that blocks multiple enzymes that promote tumor growth. It was developed by Bayer under the trade name Stivarga and is marketed as a monohydrate of regorafenib free base. thing. Patent CN101547903B discloses regorafenib monohydrate and its preparation method. However, regorafenib monohydrate has poor water solubility and certain hygroscopicity, which limits its application in formulations. In addition, the imported regorafenib marketed in China is expensive and unbearable for many patients, further restricting its clinical application. Therefore, it is very necessary to find and develop a new crystalline form of regorafenib to improve its water solubility and hygroscopicity, lower the threshold of preparation process, and realize localization instead of imports. The inventors obtained a co-crystal of regorafenib and malonic acid by screening a large number of co-crystals, which can effectively improve the solubility and hygroscopicity of regorafenib.

SUMMARY OF THE INVENTION

One of the objects of the present invention is to provide a co-crystal of regorafenib and malonic acid; the other of the objects of the present invention is to provide a preparation method of this co-crystal of regorafenib and malonic acid; The third is to provide the application of this co-crystal of regorafenib and malonic acid.

After a lot of experimental research, the inventors tried to conduct co-crystal screening experiments of regorafenib with malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, etc., and finally successfully found The co-crystal of regorafenib with malonic acid, glutaric acid, pimelic acid and suberic acid can effectively reduce the hygroscopicity of regorafenib and improve the solubility of regorafenib. Stability and oral absorption provide the material basis.

The technical scheme adopted by the present invention is:

The invention provides a co-crystal of regorafenib and malonic acid.

A kind of regorafenib and malonic acid co-crystal, the structural formula of this co-crystal is as shown in formula (I):

In this co-crystal, the molar ratio of regorafenib to malonic acid is 1:1; the X-ray powder diffraction pattern of this co-crystal measured by Cu Kα rays at the diffraction angle 2theta is 7.3±0.2°, 11.1± There are characteristic peaks at 0.2°, 13.8±0.2°, 16.8±0.2°, 19.3±0.2°, 20.0±0.2°, 21.2±0.2°, and 22.2±0.2°.

Preferably, the X-ray powder diffraction pattern of the co-crystal of regorafenib and malonic acid measured by Cu Kα rays also has a diffraction angle 2theta of 9.2±0.2°, 14.5±0.2°, 15.1±0.2°, 18.6± One or more of 0.2°, 23.7±0.2°, 24.7±0.2°, 25.8±0.2°, 26.8±0.2°, and 30.4±0.2° have characteristic peaks.

The present invention provides a preparation method of the co-crystal of regorafenib and malonic acid.

A method for preparing a co-crystal of regorafenib and malonic acid, comprising the following steps: charging regorafenib and malonic acid according to a molar ratio of 1:1, adding an appropriate amount of solvent, and then grinding and stirring to obtain a co-crystal.

Preferably, in the preparation method of this co-crystal, the solvent is at least one of an alcohol solvent and an alkane solvent. Wherein, alcohol solvents include but are not limited to methanol and ethanol; alkane solvents include but are not limited to n-heptane and dichloromethane; further preferably, the solvent is selected from one of methanol, ethanol, n-heptane and dichloromethane or more.

Preferably, in the preparation method of this co-crystal, the ratio of the total mass of regorafenib and malonic acid to the amount of solvent during grinding is 1 g: (100-200) μL; when stirring, regorafenib and malonic acid are The ratio of the total mass of the solvent to the amount of the solvent is 1 g: (2-28) mL.

In some preferred embodiments of the present invention, the preparation method of this co-crystal is as follows: feeding regorafenib and malonic acid in a molar ratio of 1:1, adding a solvent and grinding to obtain a co-crystal.

In other preferred embodiments of the present invention, the preparation method of this co-crystal is specifically as follows: charging regorafenib and malonic acid according to a molar ratio of 1:1, adding a solvent, stirring, filtering, and mixing the obtained solid product Dry to give a co-crystal.

In other preferred embodiments of the present invention, the preparation method of this co-crystal is specifically: charging Regorafenib and malonic acid according to a molar ratio of 1:1, adding a solvent and grinding, and adding a solvent to the obtained solid after adding the solvent. Stir, filter, and dry the resulting solid product to yield a co-crystal.

Preferably, in the preparation method of this co-crystal, the ratio of the total mass of regorafenib and malonic acid to the amount of solvent used during grinding is 1 g: (100-200) μL.

Preferably, in the preparation method of this co-crystal, the ratio of the total mass of regorafenib and malonic acid to the amount of solvent used during stirring is 1 g: (2-28) mL.

The present invention provides a pharmaceutical composition comprising the co-crystal of regorafenib and malonic acid and a pharmaceutically acceptable excipient.

In the present invention, pharmaceutically acceptable excipients refer to pharmaceutically acceptable materials, mixtures or vehicles that are related to the consistency of dosage forms or pharmaceutical compositions. Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected based on their particular function in the composition.

Preferably, the pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents Agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste-masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants , preservatives, stabilizers, surfactants and buffers.

The present invention also provides the application of the co-crystal of regorafenib and malonic acid in the preparation of a medicament for preventing and/or treating cancer.

The beneficial effects of the present invention are:

The present invention converts regorafenib into a new co-crystal of regorafenib and malonic acid for the first time, and the co-crystal has lower hygroscopicity and higher apparent solubility than regorafenib monohydrate, It provides a material basis for improving the stability and oral absorption efficiency of regorafenib.

The preparation method of the co-crystal of regorafenib and malonic acid disclosed by the invention has simple process, easy control of the crystallization process, good reproducibility, and is suitable for industrial production.

The co-crystal of regorafenib and malonic acid of the present invention has broad application prospects in preparing medicines for preventing and/or treating cancer.

Description of drawings

Fig. 1 is the X-ray powder diffractogram of the regorafenib and malonic acid co-crystal obtained in Example 1;

Fig. 2 is the differential scanning calorimetry analysis diagram of the co-crystal of Regorafenib and malonic acid prepared in Example 1;

Fig. 3 is the thermogravimetric analysis figure of the regorafenib and malonic acid co-crystal obtained in Example 1;

Fig. 4 is the Fourier transform infrared spectrogram of the regorafenib and malonic acid co-crystal obtained in Example 1;

Fig. 5 is the proton nuclear magnetic resonance spectrogram of the regorafenib and malonic acid co-crystal obtained in Example 1;

Fig. 6 is the dynamic moisture adsorption curve diagram of regorafenib and malonic acid co-crystal and regorafenib monohydrate prepared in Example 1;

7 is a powder dissolution curve diagram of regorafenib and malonic acid co-crystal and regorafenib monohydrate prepared in Example 1.

Detailed ways

The content of the present invention will be further described in detail below through specific embodiments. The raw materials used in the examples can be obtained from conventional commercial channels unless otherwise specified.

Example 1

Weigh 1000 mg of regorafenib and 216 mg of malonic acid, add them into 20 mL of dichloromethane to obtain a suspension, stir the suspension at room temperature for 12 h, filter, and dry the obtained white solid at 40 °C to obtain regorafenib A solid sample co-crystallized with malonic acid in 84.5% yield.

Example 2

Weigh 30 mg of regorafenib and 6.5 mg of malonic acid, add them to a ball milling jar, then add 5 μL of methanol, grind at 20 Hz for 60 min, add 1 mL of dichloromethane to obtain a suspension, and place the suspension at room temperature After stirring for 12 h, the white solid obtained was dried at 40° C. to obtain a solid sample of co-crystal of regorafenib and malonic acid.

Example 3

Weigh 60 mg of regorafenib and 13 mg of malonic acid, add 2 mL of n-heptane and 20 μL of ethanol to obtain a suspension, stir the suspension at room temperature for 12 h, filter, and dry the obtained white solid at 40 ° C to obtain Rui Solid samples of co-crystals of gofenib and malonic acid.

Example 4

Weigh 60 mg of regorafenib and 13 mg of malonic acid, add 2 mL of n-heptane and 20 μL of methanol to obtain a suspension, stir the suspension at room temperature for 12 h, filter, and dry the obtained white solid at 40° C. Solid samples of co-crystals of gofenib and malonic acid.

Example 5

Weigh 30 mg of regorafenib and 6.5 mg of malonic acid, add them to a ball milling jar, then add 5 μL of methanol, and grind at 20 Hz for 60 min. The obtained white solid is dried at 40 °C to obtain a co-crystal of regorafenib and malonic acid. of solid samples.

Comparative ratio

Weigh 1000 mg of regorafenib, add 10 mL of acetonitrile and 10 mL of water to obtain a suspension, stir the suspension at room temperature for 24 h, filter, and dry the obtained white solid at room temperature to obtain a solid sample of regorafenib monohydrate .

Characterization Analysis

The co-crystal of regorafenib and malonic acid provided by the invention is characterized by methods such as X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared spectroscopy, hydrogen nuclear magnetic resonance spectroscopy and the like.

电压为40干伏，电流为15毫安，步长0.01°，扫描速度20°/min，扫描范围5.0～40.0°，测试温度为室温。其分析结果见附图1的X射线粉末衍射图，X射线粉末衍射数据如表1所示。X-ray powder diffraction analysis was carried out on the solid sample of the co-crystal of regorafenib and malonic acid prepared in Example 1, using a Rigaku MiniFlex 600 diffractometer of Japan Rigaku Co., Ltd., Cu Kα ray

The voltage is 40 dry volts, the current is 15 mA, the step size is 0.01°, the scanning speed is 20°/min, the scanning range is 5.0-40.0°, and the test temperature is room temperature. The analysis results are shown in the X-ray powder diffraction pattern of FIG. 1 , and the X-ray powder diffraction data are shown in Table 1.

Table 1 X-ray powder diffraction data of the co-crystal of regorafenib and malonic acid of Example 1

Based on the same X-ray powder diffraction test method as in Example 1, the X-ray powder diffraction data of the solid sample of the co-crystal of regorafenib and malonic acid prepared in Example 2 are shown in Table 2.

Table 2 X-ray powder diffraction data of the co-crystal of regorafenib and malonic acid of Example 2

Based on the same X-ray powder diffraction test method as in Example 1, the X-ray powder diffraction data of the solid sample of the co-crystal of regorafenib and malonic acid prepared in Example 3 are shown in Table 3.

Table 3 X-ray powder diffraction data of the co-crystal of regorafenib and malonic acid of Example 3

It is well known to those skilled in the art that crystalline materials can be characterized by X-ray diffraction techniques, but the X-ray diffraction pattern will generally vary with the testing conditions of the instrument. In particular, the relative intensities of X-ray diffraction patterns may vary with experimental conditions, so the relative intensity order of X-ray diffraction peaks cannot be used as the sole or decisive factor for the characterization of crystalline substances. In addition, the peak angle is usually allowed to have an error of ±0.2°. Due to the influence of experimental factors such as sample height and test temperature, the overall peak angle will be shifted, and a certain shift is usually allowed. Therefore, those skilled in the art can understand that the X-ray diffraction pattern of the co-crystal of regorafenib and malonic acid described in the present invention does not have to be completely consistent with the X-ray diffraction pattern in this example, and any X-ray diffraction pattern having the same pattern as this pattern is not necessary. The cases where the characteristic peaks in the same or similar are all within the scope of the present invention. A person skilled in the art can compare the spectrum listed in the present invention with that of an unknown substance to confirm that the unknown substance is or is not the co-crystal of regorafenib and malonic acid according to the present invention.

Differential scanning calorimetry analysis was performed on the solid sample of the co-crystal of regorafenib and malonic acid prepared in Example 1, which was detected by a DSC 214 differential calorimeter of NETZSCH Scientific Instruments Co., Ltd., and the atmosphere was nitrogen. , and the heating rate was 10 °C/min. The analysis results are shown in the differential scanning calorimetry analysis diagram of FIG. 2 . As shown in Figure 2, the co-crystal of regorafenib and malonic acid began to melt at 132 °C, accompanied by a thermal decomposition process.

Thermogravimetric analysis was carried out on the solid sample of the regorafenib and malonic acid eutectic obtained in Example 1, using a TG209 F3 thermogravimetric analyzer from NETZSCH Scientific Instruments Co., Ltd., the atmosphere was nitrogen, and the heating rate was 10 °C/min. The analysis results are shown in the thermogravimetric analysis diagram of FIG. 3 . As shown in Figure 3, the co-crystal of regorafenib and malonic acid was heated to around 145°C and began to decompose, and there was no weight loss before this temperature.

The co-crystal sample of regorafenib and malonic acid prepared in Example 1 was analyzed by infrared spectroscopy, which was detected by a Vertex 70 Fourier transform infrared spectrometer from Bruker, Germany, with a detection range of 4000-500 cm ^-1 . See the Fourier transform infrared spectrogram of accompanying drawing 4. As can be seen from Figure 4, the characteristic peak positions of its infrared spectrum are (cm ^-1 ): 3384, 3371, 3298, 3116, 2939, 2871, 2642, 2559, 2372, 1735, 1712, 1639, 1593, 1542, 1490 , 1419, 1382, 1326, 1303, 1265, 1230, 1195, 1172, 1128, 1031, 997, 966, 898, 860, 837, 748, 700, 576.

The regorafenib and malonic acid eutectic samples prepared in Example 1 were subjected to hydrogen nuclear magnetic resonance spectrum analysis, and were detected by an Avance III 400 M nuclear magnetic resonance spectrometer from Bruker, Germany, and the analysis results were shown in Figure 5. Spectrogram. As can be seen from Figure 5, the peaks of regorafenib are: ¹ H NMR (400MHz, DMSO-d6) δ 9.54 (s, 1H), 8.99-8.65 (m, 2H), 8.54 (d, J= 5.6Hz, 1H), 8.25-7.98(m, 2H), 7.80-7.58(m, 2H), 7.49-7.28(m, 2H), 7.20(dd, J=5.6, 2.6Hz, 1H), 7.13-7.01 (m, 1H), 2.79 (d, J=4.8 Hz, 3H); peak of malonic acid ¹ H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 2H), 3.25 (s, 2H). According to the integration results of the characteristic peaks, the stoichiometric ratio of regorafenib and malonic acid in the cocrystal is 1:1.

Dynamic Moisture Sorption Analysis

The powder samples of regorafenib and malonic acid co-crystal and regorafenib monohydrate were subjected to dynamic moisture adsorption comparative analysis.

Sources of tested samples: co-crystals of regorafenib and malonic acid were prepared by the method provided in Example 1 of the present invention; regorafenib monohydrate was prepared by the method provided by the comparative examples of the present invention.

The powder samples of co-crystal of regorafenib and malonic acid and regorafenib monohydrate were ground and passed through 100 and 200 mesh sieves respectively, and the particle size was controlled to be 75-150 μm. Using the DVS Intrinsic dynamic moisture adsorption instrument of British SMS company, the temperature was constant at 25 °C, the system was kept in equilibrium under a nitrogen flow with a relative humidity of 0% until the mass remained unchanged, and then the relative humidity was controlled at a gradient of 10% according to 0%-95 %-0% to run a cycle to test how the weight of the sample changes with humidity. The analysis results are shown in the dynamic moisture adsorption/desorption isotherms of FIG. 6 . As can be seen from Figure 6, Regorafenib monohydrate is dry and balanced at 0% relative humidity, when the relative humidity rises to 10%, the hygroscopic weight gain is 1.54%, and the relative humidity continues to rise to 95%, the mass remained stable, and no significant weight gain occurred; when the relative humidity decreased, the moisture desorption curve and the adsorption curve basically coincided. In contrast, the hygroscopicity of the co-crystal of regorafenib and malonic acid was significantly improved. With the increase of the relative humidity, the co-crystal of regorafenib and malonic acid slowly absorbed moisture and gained weight. When the relative humidity reached 70%, the weight gain was 0.06%. The relative humidity continued to increase, and the water absorption rate accelerated until the relative humidity reached 70%. At 95%, the hygroscopic weight gain was 0.31%; when the relative humidity decreased, the moisture desorption curve and the adsorption curve basically overlapped.

Solubility evaluation

The powder dissolution data of regorafenib, co-crystal of malonic acid and regorafenib monohydrate were compared.

Sources of tested samples: co-crystals of regorafenib and malonic acid were prepared by the method provided in Example 1 of the present invention; regorafenib monohydrate was prepared by the method provided by the comparative examples of the present invention.

Powder dissolution test method: The powder samples of co-crystal of regorafenib and malonic acid and regorafenib monohydrate were ground and passed through 100 and 200 mesh sieves respectively, and the particle size was controlled at 75-150 μm. Weigh 21mg of regorafenib monohydrate, 25mg of regorafenib and malonic acid co-crystal, add them to 65mL of dissolution medium, take 0.5mL of solution at regular intervals, filter through 0.45μm microporous membrane, and dilute To an appropriate multiple, the drug concentration at each time point was monitored by high performance liquid chromatography, and the powder dissolution curve of each sample was finally obtained.

Powder dissolution conditions:

Dissolution medium: pH 4.5 acetic acid-sodium acetate buffer solution containing 0.1% SDS;

Stirring speed: 150 rpm;

Dissolution temperature: 37±0.5℃;

Sampling time: 1, 2, 5, 10, 30, 60, 120, 240 minutes;

Liquid phase conditions:

Instrument: SHIMADZU LC-2030C 3D;

Chromatographic column: Inertsil ODS C18 column (4.6mm×150mm, 5μm);

UV detection wavelength: 261nm;

Mobile phase: acetonitrile: aqueous solution containing 0.1% trifluoroacetic acid = 60:40;

Column temperature: 40℃;

Flow rate: 1mL/min;

Injection volume: 20 μL.

The experimental results are shown in the powder dissolution curve diagram of FIG. 7 . As shown in Figure 7, the maximum apparent solubility of regorafenib monohydrate and regorafenib co-crystal with malonic acid were 0.28 ± 0.034 and 0.44 ± 0.15 μg/mL, respectively. It can be seen that the apparent solubility of the co-crystal of regorafenib with malonic acid is increased by 57%, which is unexpectedly significantly better than that of regorafenib monohydrate.

The co-crystal of regorafenib and malonic acid provided by the invention can be used for preparing medicines for preventing and/or treating cancer, and has broad application prospects.

The above-mentioned embodiment is an embodiment with better effect of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, combinations made without departing from the spirit and principle of the present invention , simplification, all should be equivalent replacement modes, and are all included in the protection scope of the present invention.

Claims (8)

1. A regorafenib and malonic acid eutectic crystal is characterized in that: the structural formula of the eutectic is shown as the formula (I):

in the eutectic, the molar ratio of regorafenib to malonic acid is 1: 1; the eutectic has characteristic peaks at diffraction angles 2theta of 7.3 +/-0.2 degrees, 11.1 +/-0.2 degrees, 13.8 +/-0.2 degrees, 16.8 +/-0.2 degrees, 19.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 21.2 +/-0.2 degrees and 22.2 +/-0.2 degrees by an X-ray powder diffraction pattern measured by Cu Kalpha rays.

2. The co-crystal of claim 1, wherein: the X-ray powder diffraction pattern of the eutectic also has characteristic peaks at one or more of diffraction angles 2theta of 9.2 +/-0.2 degrees, 14.5 +/-0.2 degrees, 15.1 +/-0.2 degrees, 18.6 +/-0.2 degrees, 23.7 +/-0.2 degrees, 24.7 +/-0.2 degrees, 25.8 +/-0.2 degrees, 26.8 +/-0.2 degrees and 30.4 +/-0.2 degrees.

3. A method of preparing a co-crystal according to any one of claims 1 to 2, wherein: the method comprises the following steps of feeding regorafenib and malonic acid according to the molar ratio of 1: 1, adding a proper amount of solvent, and then grinding or stirring to obtain the eutectic crystal.

4. The production method according to claim 3, characterized in that: the solvent is at least one of alcohol solvent and alkane solvent.

5. The production method according to claim 3, characterized in that: during grinding, the total mass of the regorafenib and the malonic acid and the dosage of the solvent are 1g to (100-200) mu L.

6. The production method according to claim 3, characterized in that: during stirring, the total mass of the regorafenib and the malonic acid and the dosage of the solvent are 1g to (2-28) mL.

7. A pharmaceutical composition characterized by: comprising a co-crystal according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient.

8. Use of the co-crystal of any one of claims 1 to 2 in a medicament for the treatment of cancer.

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