CN111995571B - Eutectic crystal of regorafenib and maleic acid and preparation method thereof - Google Patents
Eutectic crystal of regorafenib and maleic acid and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a regorafenib and maleic acid eutectic crystal and a preparation method thereof. The molar ratio of regorafenib to maleic acid in the eutectic is 1: 1, and the eutectic X-ray powder diffraction pattern has characteristic peaks at 2theta values of 5.9 +/-0.2 degrees, 9.6 +/-0.2 degrees, 11.6 +/-0.2 degrees, 12.4 +/-0.2 degrees, 21.3 +/-0.2 degrees and 25.6 +/-0.2 degrees. The preparation method of the eutectic crystal provided by the invention has the advantages of simple process, easy control of the crystallization process, good reproducibility and suitability for industrial production. The eutectic is higher in apparent solubility than regorafenib monohydrate, and is beneficial to improving the oral absorption efficiency of regorafenib.
Description
Technical Field
The invention relates to the technical field of medical chemistry, in particular to a regorafenib-maleic acid eutectic crystal and a preparation method thereof.
Background
The pharmaceutically active ingredient is usually present in crystalline forms, such as polymorphs, hydrates, solvates, salts, co-crystals and the like. Different crystalline forms have different physicochemical properties for the same pharmaceutically active ingredient. Therefore, obtaining a suitable crystalline form of a drug is of great importance in the pharmaceutical industry. The medicament exists in a eutectic form, can improve the stability, solubility, processability and the like of active ingredients of the medicament, and has remarkable advantages. Therefore, the pharmaceutical co-crystal is an effective means for improving the physicochemical properties of the active ingredients of the drugs.
Regorafenib (Regorafenib) having the chemical name 4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenoxy } -N-methylpyridine-2-carboxamide, the chemical formula of which is:
regorafenib is a new drug approved by the U.S. FDA in month 9 2012 for the treatment of metastatic colorectal cancer, and its new indication (advanced gastrointestinal stromal tumor) in month 2 2013 was approved by the FDA priority review procedure. Regorafenib is a novel multi-kinase inhibitor capable of blocking a variety of enzymes that promote tumor growth, developed by Bayer corporation under the tradename Stivarga, marketed as regorafenib monohydrate. Patent CN101547903B discloses regorafenib monohydrate and a preparation method thereof. However, regorafenib monohydrate has poor water solubility, which limits its application in formulation. In addition, the price of the imported regorafenib on the market in China is high, and a plurality of patients are difficult to bear, so that the clinical application of the imported regorafenib is further limited. Therefore, it is necessary to find and develop a new crystal form of regorafenib to improve its water solubility, reduce the process threshold of the preparation, and realize the replacement of import for localization. The inventor obtains the eutectic of regorafenib and maleic acid through a large amount of eutectic screening, and can effectively improve the solubility of regorafenib.
Disclosure of Invention
One of the purposes of the invention is to provide a regorafenib and maleic acid eutectic crystal; the second purpose of the invention is to provide a preparation method of the regorafenib and maleic acid eutectic crystal; the invention also aims to provide the application of the regorafenib and maleic acid eutectic.
Through a large number of experimental researches, the inventor tries to perform a eutectic screening experiment on regorafenib and malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, fumaric acid, maleic acid and the like, and finally successfully finds that the regorafenib and malonic acid, glutaric acid, pimelic acid, suberic acid and maleic acid are eutectic, so that the solubility of regorafenib can be effectively improved, and a material basis is provided for improving the oral absorption of regorafenib.
The technical scheme adopted by the invention is as follows:
the invention provides a regorafenib and maleic acid eutectic crystal.
A regorafenib and maleic acid eutectic crystal has a structural formula shown in a formula (I):
in the eutectic, the molar ratio of regorafenib to maleic acid is 1: 1; the X-ray powder diffraction pattern of the eutectic measured by Cu Kalpha rays has characteristic peaks at diffraction angles 2theta of 5.9 +/-0.2 degrees, 9.6 +/-0.2 degrees, 11.6 +/-0.2 degrees, 12.4 +/-0.2 degrees, 21.3 +/-0.2 degrees and 25.6 +/-0.2 degrees.
Preferably, the X-ray powder diffraction pattern of the regorafenib eutectic crystal with maleic acid measured by Cu Kalpha ray also has characteristic peaks at one or more of diffraction angles 2theta of 15.0 +/-0.2 degrees, 17.0 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.6 +/-0.2 degrees, 22.2 +/-0.2 degrees, 23.2 +/-0.2 degrees, 25.1 +/-0.2 degrees, 28.3 +/-0.2 degrees and 29.8 +/-0.2 degrees.
The invention provides a preparation method of the regorafenib and maleic acid eutectic crystal.
A preparation method of a regorafenib and maleic acid eutectic crystal comprises the following steps: feeding regorafenib and maleic acid according to the molar ratio of 1: 1, adding a proper amount of solvent, and stirring to obtain the eutectic crystal.
Preferably, in the method for preparing the co-crystal, the solvent is at least one of an alcohol solvent, an ester solvent, a ketone solvent, a nitrile solvent, and an alkane solvent. Wherein, the alcohol solvent includes but is not limited to methanol, ethanol, isopropanol; ester solvents include, but are not limited to, ethyl acetate; ketone solvents include, but are not limited to, acetone; nitrile solvents include, but are not limited to, acetonitrile; alkane solvents include, but are not limited to, n-heptane, dichloromethane; further preferably, the solvent is selected from one or more of methanol, ethanol, isopropanol, ethyl acetate, acetone, acetonitrile, n-heptane and dichloromethane.
Preferably, in the preparation method of the eutectic crystal, the ratio of the total mass of the regorafenib and the maleic acid to the using amount of the solvent during stirring is 1g to (8-27) mL.
In some preferred embodiments of the present invention, the preparation method of the eutectic is specifically as follows: feeding regorafenib and maleic acid according to a molar ratio of 1: 1, adding a solvent, stirring, filtering, and drying the obtained solid product to obtain the eutectic crystal.
The invention provides a pharmaceutical composition, which comprises the regorafenib eutectic crystal and maleic acid and a pharmaceutically acceptable excipient.
In the present invention, the pharmaceutically acceptable excipient refers to a pharmaceutically acceptable material, mixture or solvent related to the consistency of the administration form or pharmaceutical composition. Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific 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, solvents, co-solvents, suspending agents, emulsifiers, sweetening agents, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffers.
The invention also provides application of the regorafenib and maleic acid eutectic in preparation of a medicament for preventing and/or treating cancer.
The invention has the beneficial effects that:
according to the invention, regorafenib is converted into a brand new regorafenib and maleic acid eutectic for the first time, the eutectic has higher apparent solubility than regorafenib monohydrate, and a material basis is provided for improving the oral absorption efficiency of regorafenib.
The preparation method of the regorafenib-maleic acid eutectic crystal disclosed by the invention is simple in process, easy to control the crystallization process, good in reproducibility and suitable for industrial production.
The regorafenib and maleic acid eutectic crystal has wide application prospect in preparation of medicaments for preventing and/or treating cancers.
Drawings
Fig. 1 is an X-ray powder diffraction pattern of a eutectic of regorafenib and maleic acid prepared in example 1;
fig. 2 is a differential scanning calorimetry trace of a eutectic of regorafenib and maleic acid prepared in example 1;
fig. 3 is a thermogravimetric analysis chart of a eutectic of regorafenib and maleic acid prepared in example 1;
fig. 4 is a fourier transform infrared spectrum of a eutectic crystal of regorafenib and maleic acid prepared in example 1;
fig. 5 is a nuclear magnetic resonance hydrogen spectrum of a regorafenib eutectic crystal with maleic acid prepared in example 1;
fig. 6 is a powder dissolution profile of a regorafenib co-crystal with maleic acid, regorafenib monohydrate obtained in example 1.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The starting materials used in the examples are, unless otherwise specified, commercially available from conventional sources.
Example 1
1000mg of regorafenib and 240mg of maleic acid are weighed and added into 20mL of n-heptane and 80 muL of methanol to obtain a suspension, the suspension is placed at room temperature and stirred for 4 hours, the suspension is filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of regorafenib and maleic acid, wherein the yield is 90.7%.
Example 2
60mg of regorafenib and 14.4mg of maleic acid are weighed and added into 2mL of n-heptane and 10 muL of ethanol to obtain a suspension, the suspension is placed at room temperature and stirred for 24h, the filtration is carried out, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the regorafenib and maleic acid eutectic crystal.
Example 3
60mg of regorafenib and 14.4mg of maleic acid are weighed and added into 2mL of dichloromethane to obtain a suspension, the suspension is placed at room temperature and stirred for 48 hours, the suspension is filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the regorafenib and maleic acid eutectic crystal.
Example 4
60mg of regorafenib and 14.4mg of maleic acid are weighed and added into 2mL of n-heptane and 10 muL of isopropanol to obtain a suspension, the suspension is placed at room temperature and stirred for 24h, and then filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the regorafenib and maleic acid eutectic crystal.
Example 5
60mg of regorafenib and 14.4mg of maleic acid are weighed and added into 2mL of n-heptane and 10 muL of ethyl acetate to obtain a suspension, the suspension is placed at room temperature and stirred for 72 hours, the suspension is filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the regorafenib and maleic acid eutectic crystal.
Example 6
60mg of regorafenib and 14.4mg of maleic acid are weighed and added into 2mL of n-heptane and 10 muL of acetone to obtain a suspension, the suspension is placed at room temperature and stirred for 72 hours, the filtration is carried out, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of regorafenib and maleic acid.
Example 7
60mg of regorafenib and 14.4mg of maleic acid are weighed and added into 2mL of n-heptane and 10 muL of acetonitrile to obtain a suspension, the suspension is placed at room temperature and stirred for 24h, the filtration is carried out, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the regorafenib and maleic acid eutectic crystal.
Example 8
60mg of regorafenib and 14.4mg of maleic acid are weighed and added into 2mL of n-heptane to obtain a suspension, the suspension is placed at room temperature and stirred for 72 hours, the suspension is filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of regorafenib and maleic acid.
Comparative example
Weighing 1g of regorafenib, adding 10mL of acetonitrile and 10mL of water to obtain a suspension, placing the suspension at room temperature, stirring for 24h, filtering, and drying the obtained white solid at room temperature to obtain a solid sample of regorafenib monohydrate.
Characterization analysis
The regorafenib and maleic acid eutectic crystal provided by the invention is characterized by methods such as X-ray powder diffraction, differential scanning calorimetry analysis, thermogravimetric analysis, Fourier transform infrared spectroscopy, nuclear magnetic resonance hydrogen spectrum and the like.
The solid sample of the eutectic crystal of regorafenib and maleic acid obtained in example 1 was subjected to X-ray powder diffraction analysis using a diffractometer of Rigaku MiniFlex 600 model, manufactured by Nippon chemical Co., Ltd., Cu Ka ray
A voltage of 40 kilovolts and a current of15 milliamperes, step size of 0.01 degrees, scanning speed of 20 degrees/min, scanning range of 5.0-40.0 degrees, and test temperature of room temperature. The analysis results are shown in the X-ray powder diffraction diagram of figure 1, and the X-ray powder diffraction data are shown in Table 1.
Table 1X-ray powder diffraction data of regorafenib co-crystal with maleic acid prepared in example 1
The X-ray powder diffraction data of the solid sample of regorafenib cocrystallized with maleic acid obtained in example 2 based on the same X-ray powder diffraction test method as example 1 are shown in table 2.
Table 2X-ray powder diffraction data of regorafenib co-crystal with maleic acid prepared in example 2
The X-ray powder diffraction data of the solid sample of regorafenib cocrystallized with maleic acid obtained in example 3 based on the same X-ray powder diffraction test method as example 1 are shown in table 3.
Table 3X-ray powder diffraction data of regorafenib co-crystal with maleic acid prepared in 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 patterns typically vary with the test conditions of the instrument. It is particularly noted that the relative intensities of the X-ray diffraction patterns may vary with the experimental conditions, so that the relative intensity order of the X-ray diffraction peaks cannot be a sole or determining factor in the characterization of crystalline material. In addition, the peak angle is usually allowed to have an error of ± 0.2 °, and the overall shift of the peak angle is caused due to the influence of experimental factors such as the sample height and the test temperature, and a certain shift is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of the eutectic crystal of regorafenib and maleic acid according to the present invention does not necessarily coincide exactly with the X-ray diffraction pattern in the present embodiment, and any situation having the same or similar characteristic peaks in this pattern is within the scope of the present invention. One skilled in the art can compare the profile listed in the present invention with a profile of an unknown substance to confirm whether the unknown substance is or is not the regorafenib co-crystal with maleic acid as described herein.
Differential scanning calorimetry analysis was performed on the solid sample of the eutectic crystal of regorafenib and maleic acid prepared in example 1, and the differential scanning calorimetry was performed by using a DSC 214 type differential calorimeter of german seikh scientific instruments ltd, wherein the atmosphere was nitrogen, and the temperature rise rate was 10 ℃/min. The analysis result is shown in the differential scanning calorimetry diagram of figure 2. As shown in fig. 2, the eutectic crystal of regorafenib and maleic acid shows a melting endothermic peak at 122 ℃.
The solid sample of the regorafenib eutectic crystal with maleic acid prepared in example 1 was subjected to thermogravimetric analysis using a model TG 209F 3 thermogravimetric analyzer from german chi-resistant scientific instruments ltd under nitrogen atmosphere at a temperature rise rate of 10 ℃/min. The analysis result is shown in the thermogravimetric analysis chart of figure 3. As shown in fig. 3, the regorafenib eutectic with maleic acid is heated to around 140 ℃ to start decomposition, and there is no weight loss until this temperature.
Infrared spectrum analysis is carried out on the regorafenib and maleic acid eutectic crystal sample prepared in the example 1, and the regorafenib and maleic acid eutectic crystal sample is detected by a Frontier Mid-IR FTIR Fourier transform infrared spectrometer of Perkin Elmer company in USA, and the detection range is 4000-500 cm-1The analysis result is shown in the Fourier transform infrared spectrogram of figure 4. As can be seen from FIG. 4, the characteristic peak position of the infrared spectrum is (cm)-1)：3328、3085、3053、2958、1692、1605、1549、1488、1351、1320、1268、1197、 1168、1125、1033、969、905、868、832、767、730、665、578、542。
The regorafenib/maleic acid eutectic sample prepared in example 1 was analyzed by nmr hydrogen spectroscopy, and detected by an Avance III 400M nmr spectrometer, Bruker, germany, and the analysis result is shown in the nmr hydrogen spectroscopy of fig. 5. As can be seen from fig. 5, the peaks of regorafenib are:1h NMR (400MHz, DMSO-d6) δ 9.55(s, 1H), 8.88-8.69(m, 2H), 8.54(d, J ═ 5.6Hz, 1H), 8.25-8.0(m, 2H), 7.65(d, J ═ 8.7Hz, 2H), 7.48-7.31(m, 2H), 7.20(dd, J ═ 5.5, 2.4Hz, 1H), 7.09(d, J ═ 8.8Hz, 1H), 2.79(d, J ═ 4.7Hz, 3H). The maleic acid peaks are:1h NMR (400MHz, DMSO-d6) delta 6.27(s, 2H). From the integration results of the respective peaks, the stoichiometric ratio of regorafenib to maleic acid in the co-crystal was 1: 1.
Evaluation of solubility
Powder dissolution data of regorafenib co-crystal with maleic acid and regorafenib monohydrate were compared.
The source of the test sample is: the regorafenib and maleic acid eutectic crystal is prepared by the method provided by embodiment 1 of the invention; regorafenib monohydrate is prepared by the process provided by the comparative examples of the present invention.
Powder dissolution test method: grinding powder samples of regorafenib and maleic acid eutectic and regorafenib monohydrate, and then respectively sieving the powder samples through 100-200 meshes of sieve, wherein the particle size is controlled to be 75-150 mu m. Respectively weighing 21mg regorafenib monohydrate, 24mg regorafenib and maleic acid eutectic, adding into 65mL dissolution medium, taking 0.5mL solution at intervals, filtering by a 0.45 mu m microporous membrane, diluting to proper times, monitoring the drug concentration at each time point by using high performance liquid chromatography, and finally obtaining the powder dissolution curve of each sample.
Powder dissolution conditions:
dissolution medium: acetic acid-sodium acetate buffer solution of pH 4.5 containing 0.1% SDS;
stirring speed: 150 revolutions per minute;
dissolution temperature: 37 plus or minus 0.5 ℃;
sampling time: 1, 2, 3, 5, 10, 15, 30, 60, 90, 120, 240 minutes;
liquid phase conditions:
the instrument comprises the following steps: SHIMADZU LC-2030C 3D;
a chromatographic column: inertsil ODS C18 column (4.6 mm. times.150 mm, 5 μm);
ultraviolet detection wavelength: 261 nm;
mobile phase: acetonitrile to 0.1% trifluoroacetic acid in water 60: 40;
column temperature: 40 ℃;
flow rate: 1 mL/min;
sample introduction amount: 20 μ L.
The results are shown in the powder dissolution profile of figure 6. As shown in fig. 6, the maximum apparent solubilities of regorafenib monohydrate and regorafenib co-crystal with maleic acid were 0.28 ± 0.034 and 4.60 ± 0.49 μ g/mL, respectively. It can be seen that the apparent solubility of the eutectic of regorafenib and maleic acid is significantly better than that of regorafenib monohydrate, and the value of the eutectic is 16.4 times that of regorafenib monohydrate.
The regorafenib and maleic acid eutectic crystal provided by the invention can be applied to preparation of a medicament for preventing and/or treating cancers, and has a wide application prospect.
The above embodiments are only examples of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents and are included in the scope of the present invention.
Claims (7)
1. A regorafenib co-crystal with maleic acid, characterized in that: the structural formula of the eutectic is shown as the formula (I):
in the eutectic, the molar ratio of regorafenib to maleic acid is 1: 1; the X-ray powder diffraction pattern of the eutectic measured by Cu Kalpha rays has characteristic peaks at diffraction angles 2theta of 5.9 +/-0.2 degrees, 9.6 +/-0.2 degrees, 11.6 +/-0.2 degrees, 12.4 +/-0.2 degrees, 21.3 +/-0.2 degrees and 25.6 +/-0.2 degrees.
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 15.0 +/-0.2 degrees, 17.0 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.6 +/-0.2 degrees, 22.2 +/-0.2 degrees, 23.2 +/-0.2 degrees, 25.1 +/-0.2 degrees, 28.3 +/-0.2 degrees and 29.8 +/-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 maleic acid according to the molar ratio of 1: 1, adding a proper amount of solvent, and stirring to obtain the eutectic crystal.
4. The production method according to claim 3, characterized in that: the solvent is at least one of an alcohol solvent, an ester solvent, a ketone solvent, a nitrile solvent and an alkane solvent.
5. The production method according to claim 3, characterized in that: during stirring, the total mass of regorafenib and maleic acid and the dosage of the solvent are 1g to (8-27) mL.
6. A pharmaceutical composition characterized by: comprising a co-crystal according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient.
7. Use of the co-crystal of any one of claims 1 to 2 in the manufacture of a medicament for the treatment of cancer.
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