CN115894356A - Crystal forms of regorafenib sulfate and hydrochloride and preparation method thereof - Google Patents
Crystal forms of regorafenib sulfate and hydrochloride and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a crystal form of regorafenib hydrochloride and sulfate and a preparation method thereof. The crystal form is 9.5-degree 0.2 degree, 11.8-degree 0.2 degree, 12.7-degree 0.2 degree, 15.2-degree 0.2 degree, 16.4-degree 0.2 degree, 19.1-degree 0.2 degree, 19.2-degree 0.2 degree, 19.5-degree 0.2 degree, 20.3-degree 0.2 degree, 21.6-degree 0.2 degree, 23.8-degree 0.2 degree, 24.5-degree 0.2 degree, 26.8-degree 0.2 degree, 27.9-degree 0.2 degree and 29.2-degree in X-ray powder diffraction pattern, or one or more of 7.4 earths 0.2 °, 10.7 earths 0.2 °, 12.0 earths 0.2 °, 13.3 earths 0.2 °, 14.7 earths 0.2 °, 15.8 earths 0.2 °, 18.1 earths 0.2 °, 20.6 earths 0.2 °, 22.7 earths 0.2 °, 24.0 earths 0.2 °, 24.5 earths 0.2 °, 26.3 earths 0.2 °, 27.2 earths 0.2 °, 28.7 earths 0.2 ° has a characteristic peak. The preparation method comprises the steps of dispersing regorafenib monohydrate in an organic solvent, and heating to reflux; and (3) dropwise adding hydrochloric acid or sulfuric acid under a reflux state, cooling, filtering and drying to obtain a solid. The water solubility and hygroscopicity of the hydrochloride and sulfate crystal forms are obviously improved, and the crystal forms are very stable.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a regorafenib sulfate and hydrochloride crystal form 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) is known by the chemical name 4- {4- [ ({ [ 4-chloro-3- (trifluoromethyl) phenyl ] amino } carbonyl) amino ] phenoxy } -N-methylpyridine-2-carboxamide and has the following chemical structural formula:
regorafenib is a new anti-cancer drug approved by the us FDA in 9 months 2012 for the treatment of metastatic colorectal cancer; in 2013, month 2, its new indication (advanced gastrointestinal stromal tumor) was approved by the FDA priority review procedure. Regorafenib is a novel multi-kinase inhibitor capable of blocking various enzymes that promote tumor growth; it was developed by Bayer (Bayer) under the trade name Stivarga and marketed as the monohydrate of regorafenib free base.
Few reports of the crystal forms of regorafenib exist, and a patent document W02005009961 discloses a preparation method of regorafenib and salts thereof for the first time. Patent document W02008043446 states that the crystalline Form of regorafenib obtained in compound patent W02005009961 is Form I, and also discloses regorafenib hydrate (i.e. compound IV) and a preparation method thereof for the first time, and also discloses a pharmaceutical composition containing regorafenib hydrate and a use thereof for controlling diseases. However, regorafenib hydrate disclosed in patent document W02008043446, the preparation thereof requires conversion from a specific crystalline Form (Form I) of regorafenib free base in an aqueous solvent (acetone, acetonitrile, etc.) by stirring for a long time (1-2 weeks); the preparation has long production period and poor repeatability, and is not beneficial to realizing industrial production. Although patent document W02011128261 discloses an industrial production method of regorafenib monohydrate, regorafenib monohydrate is inferior in stability, and is changed into regorafenib free base with worse solubility by removing crystal water in an organic solvent with high volatility, and the regorafenib monohydrate has a large hygroscopicity, which limits its application in preparation. Patent document CN101547903B discloses regorafenib monohydrate and a preparation method thereof, but regorafenib monohydrate has poor water solubility and certain hygroscopicity, which limits the application thereof in preparation. In addition, the imported regorafenib on the market in China is expensive and difficult to bear by many patients, so that the clinical application of the regorafenib is further limited.
Therefore, it is necessary to find and develop a new crystal form of regorafenib to improve its water solubility and hygroscopicity, reduce the process threshold of the preparation, and realize localization to replace import. The inventor obtains a new crystal form of regorafenib hydrochloride and sulfate through a large amount of crystal form screening, and the new crystal form can effectively improve the solubility and hygroscopicity of regorafenib.
Disclosure of Invention
In order to solve the technical problems, the invention provides the following technical scheme:
on the one hand, the invention provides a crystal form of regorafenib hydrochloride, wherein the crystal form has characteristic peaks at one or more of diffraction angles 2 theta of 9.5X 0.2 °, 11.8X 0.2 °, 12.7X 0.2 °, 15.2X 0.2 °, 16.4X 0.2 °, 19.1X 0.2 °, 19.2X 0.2 °, 19.5X 0.2 °, 20.3+0.2 °, 21.6+0.2 °, 23.8+0.2 °, 24.5+0.2 °, 26.8+0.2 °, 27.9+0.2 °, 29.2+0.2 ° in an X-ray powder diffraction pattern.
According to an embodiment of the present invention, wherein the X-ray powder diffraction pattern data of the crystalline form is shown in table 3 in the specification.
The invention also provides a crystal form of regorafenib sulfate, wherein the crystal form has characteristic peaks at one or more of diffraction angles 2 theta of 7.4-day 0.2 °, 10.7-day 0.2 °, 12.0-day 0.2 °, 13.3-day 0.2 °, 14.7-day 0.2 °, 15.8-day 0.2 °, 18.1-day 0.2 °, 20.6-day 0.2 °, 22.7-day 0.2 °, 24.0-day 0.2 °, 24.5-day 0.2 °, 26.3-day 0.2 °, 27.2-day 0.2 °, and 28.7-day 0.2 ° in an X-ray powder diffraction pattern.
According to another embodiment of the present invention, wherein the X-ray powder diffraction pattern data of the crystalline form is shown in table 4 in the specification.
In another aspect, the present invention provides a method for preparing the above crystalline form of regorafenib hydrochloride, wherein the method comprises the steps of:
(a) Dispersing regorafenib monohydrate in an organic solvent, and heating to reflux;
(b) Dripping hydrochloric acid under the reflux state, cooling to 15-40 ℃, and stirring;
(c) Filtered and dried to obtain a solid.
Preferably, the volume of the organic solvent is 5 to 30 times, preferably 8 to 20 times, more preferably 10 to 15 times based on the mass of regorafenib monohydrate; the organic solvent is one or a combination of more of alcohols, ketones and esters; the alcohol solvent is preferably one or more of methanol, ethanol, isopropanol and n-propanol, the ketone solvent is preferably acetone, butanone or the combination thereof, and the ester solvent is preferably one or more of ethyl formate, butyl formate, methyl acetate, ethyl acetate, butyl acetate and isopropyl acetate; the organic solvent is more preferably one or a mixture of methanol, ethanol, n-propanol, acetone, and ethyl acetate.
Preferably, the molar ratio of regorafenib monohydrate to solute hydrochloride is 1:2 to 1, more preferably 1:4 to 1:8, most preferably 1:6; cooling to 20-30 ℃; drying at 50-70 deg.C, preferably 60 deg.C; a white solid was obtained.
The present invention further provides a process for preparing the crystalline form of regorafenib sulfate salt as described above, wherein the process comprises the steps of:
(a) Dispersing regorafenib monohydrate in an organic solvent, and heating to reflux;
(b) Dripping sulfuric acid under the reflux state, cooling to 15-40 ℃, and stirring;
(c) Filtered and dried to obtain a solid.
Preferably, the volume of the organic solvent is 5 to 30 times, preferably 8 to 20 times, more preferably 10 to 15 times based on the mass of regorafenib monohydrate; the organic solvent is one or a combination of more of alcohols, ketones and ester solvents; the alcohol solvent is preferably one or more of methanol, ethanol, isopropanol and n-propanol, the ketone solvent is preferably acetone, butanone or the combination thereof, and the ester solvent is preferably one or more of ethyl formate, butyl formate, methyl acetate, ethyl acetate, butyl acetate and isopropyl acetate; the organic solvent is further preferably one or more of methanol, ethanol, n-propanol, acetone, and ethyl acetate.
Preferably, the molar ratio of regorafenib monohydrate to sulfuric acid solute is 1:1 to 1:8, more preferably 1:2 to 1:6, most preferably 1:3; cooling to 20-30 ℃; drying at 50-70 deg.C, preferably 60 deg.C; a white solid was obtained.
The crystal forms of regorafenib hydrochloride, the crystal forms of regorafenib sulfate and the preparation methods thereof provided by the invention can effectively improve the solubility and hygroscopicity of regorafenib, and the crystal forms are very stable.
Drawings
The advantages and features of the present invention are described below with reference to the drawings, but the present invention is not limited thereto. Wherein:
figure 1 shows an X-ray powder diffraction pattern of a regorafenib hydrochloride sample according to one embodiment of the present invention;
fig. 2 shows an X-ray powder diffraction pattern of a regorafenib sulfate salt sample according to one embodiment of the present invention;
fig. 3 shows a nuclear magnetic resonance hydrogen spectrum of a regorafenib hydrochloride sample according to another embodiment of the present invention;
fig. 4 shows a nuclear magnetic resonance hydrogen spectrum of a regorafenib sulfate sample according to yet another embodiment of the present invention.
Detailed Description
For a more clear understanding of the present invention, the present invention will be described in detail below by way of preferred embodiments and with reference to the accompanying drawings, but the present invention is not limited thereto.
It is to be noted that the scientific terms and test methods mentioned in the present invention, which are not explained or detailed, have the same meanings and contents as understood by those skilled in the art.
In addition, the numerical ranges in the present invention include the endpoints and any point value between the endpoints. For example, a numerical range of 1 to 10 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; the numerical range of 0.1 to 0.9 includes 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9; the numerical range of 0.01 to 0.09 includes 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09; the numerical range of 0.08 to 0.21 includes 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21. In the present invention, "above", "below" and "within" include the number, and "above/above", "below/less than" and "insufficient" do not include the number.
The invention aims to provide a new crystal form of regorafenib hydrochloride and sulfate. In addition, the invention aims to provide a preparation method of the regorafenib hydrochloride and sulfate so as to obtain new crystal forms of the hydrochloride and the sulfate.
An X-ray powder diffraction pattern of the regorafenib sulfate crystal form measured by CuKa rays has characteristic peaks at one or more of diffraction angles 2 theta of 7.4 soil 0.2 degrees, 10.7 soil 0.2 degrees, 12.0 soil 0.2 degrees, 13.3 soil 0.2 degrees, 14.7 soil 0.2 degrees, 15.8 soil 0.2 degrees, 18.1 soil 0.2 degrees, 20.6 soil 0.2 degrees, 22.7 soil 0.2 degrees, 24.0 soil 0.2 degrees, 24.5 soil 0.2 degrees, 26.3 soil 0.2 degrees, 27.2 soil 0.2 degrees and 28.7 soil 0.2 degrees.
An X-ray powder diffraction pattern of the regorafenib hydrochloride measured by CuKa rays has characteristic peaks at one or more of diffraction angles 2 theta of 9.5-day 0.2 degrees, 11.8-day 0.2 degrees, 12.7-day 0.2 degrees, 15.2-earth 0.2 degrees, 16.4-day 0.2 degrees, 19.1-earth 0.2 degrees, 19.2-day 0.2 degrees, 19.5-day 0.2 degrees, 20.3-ton 0.2 degrees, 21.6-ton 0.2 degrees, 23.8-ton 0.2 degrees, 24.5-ton 0.2 degrees, 26.8-ton 0.2 degrees, 27.9-ton 0.2 degrees and 29.2-ton 0.2 degrees.
The structural formulas of the sulfate and the hydrochloride of regorafenib are respectively shown as the following formulas:
the invention provides a new crystal form of regorafenib hydrochloride and sulfate and discloses a preparation method thereof. The preparation process comprises the following steps: the regorafenib monohydrate is dispersed in an organic solvent with a volume of 5 to 30 times, preferably 8 to 20 times, more preferably 10 to 15 times based on the mass of the regorafenib monohydrate, heated to reflux, under reflux conditions concentrated hydrochloric acid (concentration range of 36 to 38%) or concentrated sulfuric acid (concentration of 98%) solution (molar ratio of regorafenib monohydrate to solute of hydrochloric acid is 1:2 to 1, more preferably 1:4 to 1:8, most preferably 1:6; for concentrated sulfuric acid, molar ratio of regorafenib monohydrate to solute of sulfuric acid is 1:1 to 1:8, more preferably 1:2 to 1:6, most preferably 1:3) is generally added dropwise, cooled to 15 to 40 ℃, preferably 20 to 30 ℃, stirred for 0.2 to 1h, preferably 0.5h, filtered in a box, dried by air blast, dried at 60 ℃ preferably 3270 ℃, and dried to obtain white solid at 50 ℃. The organic solvent is preferably one or the combination of more of alcohols, ketones and esters; wherein, the alcohol solvent is preferably one or a combination of more of methanol, ethanol, isopropanol and n-propanol; the ketone solvent is preferably acetone, butanone or a combination thereof, and the ester solvent is preferably one or a combination of ethyl formate, butyl formate, methyl acetate, ethyl acetate, butyl acetate and isopropyl acetate; the organic solvent is further preferably one or more of methanol, ethanol, n-propanol, acetone, and ethyl acetate.
In one embodiment of the invention, the crystalline form of regorafenib sulfate has characteristic peaks at diffraction angles 2 θ of 7.4 earth0.2 °, 10.7 earth0.2 °, 12.0 earth0.2 °, 13.3 tes0.2 °, 14.7 tes0.2 °, 15.8 earth0.2 °, 18.1 tes0.2 °, 20.6 tes0.2 °, 22.7 tes0.2 °, 24.0 tes0.2 °, 24.5 tes0.2 °, 26.3 tes0.2 °, 27.2 tes0.2 °, 28.7 tes0.2 ° in the X-ray powder diffraction pattern measured by CuKa radiation.
In one embodiment of the invention, the regorafenib hydrochloride has characteristic peaks at diffraction angle 2 θ of 9.5X 0.2 °, 11.8X 0.2 °, 12.7X 0.2 °, 15.2 ° 0.2 °, 16.4X 0.2 °, 19.1X 0.2 °, 19.2X 0.2 °, 19.5X 0.2 °, 20.3+0.2 °, 21.6+0.2 °, 23.8+0.2 °, 24.5+0.2 °, 26.8+0.2 °, 27.9+0.2 °, 29.2+0.2 ° in an X-ray powder diffraction pattern measured by CuKa radiation.
Through water-solubility experiments, the regorafenib raw material is respectively prepared into hydrochloride and sulfate, so that the water solubility of the regorafenib raw material is obviously increased and the regorafenib raw material is more stable; to date, the crystal forms of regorafenib hydrochloride and sulfate are not changed, and the crystal forms are very stable. This is because, when regorafenib raw material is prepared as hydrochloride and sulfate, respectively, their water solubility and hygroscopicity are both significantly improved. The preparation method of the crystalline form of the hydrochloride and the sulfate of the regorafenib disclosed by the invention is simple in process, easy to control the crystallization process, good in reproducibility and suitable for industrial production.
Examples
The invention will now be described with reference to specific embodiments. The following specific examples are illustrative and explanatory only and are not to be construed as limiting the spirit, spirit and scope of the invention.
In the following specific examples, details of the instruments and reagents used are shown in tables 1 and 2 below.
TABLE 1 details of the instruments used in the examples
| Name (R) | Model/number | Manufacturer(s) of |
| Electronic balance | MTS3000/DZTP-09 | Shenzhen Meifu Electronics Co., Ltd. |
| Heat collection type constant temperature magnetic stirrer | DF-101S | Beijing Kovian Yongxing instruments Co., ltd |
| Air-blast drying cabinet | DHG-9140A/GFGZ-06 | Shanghai Jinghong experiment equipment Co., ltd |
| HPLC | Agilent-1200/HPLC-40 | Agilent |
TABLE 2 details of the reagents used in the examples
Example 1
In a 100ml three-necked flask, 50ml of acetone and 5.0g regorafenib monohydrate (i.e., equivalent to regorafenib monohydrate: acetone = 10ml) were added and heated to reflux. Then, 1.5ml of concentrated hydrochloric acid is added, the temperature is reduced to 24 ℃, and the stirring is continued for 0.5h. Filtration and drying of the filter cake in a forced air drying oven at 60 ℃ for 5.0h gave 4.2g of white regorafenib hydrochloride. Yield 84.0%, HPLC:99.1 percent.
Example 2
60ml of absolute ethanol and 5.0g of regorafenib monohydrate were added to a 100ml three-necked flask and heated to reflux. Then, 1.5ml of concentrated hydrochloric acid was added, the temperature was reduced to 23 ℃, and the stirring was continued for 0.5h. Filtration and drying of the filter cake in a forced air drying oven at 60 ℃ for 5.0h gave 4.0g of white regorafenib hydrochloride. Yield 80.0%, HPLC:99.3 percent.
The X-ray powder diffraction pattern data of the sample obtained in example 1 measured by CuKa radiation are shown in fig. 1 and table 3 below, respectively. The X-ray powder diffraction pattern data of the sample obtained in example 2 measured by CuKa radiation are similar to those of the sample obtained in example 1.
TABLE 3 Experimental data on X-ray powder diffraction patterns of the samples obtained in example 1
Example 3
50ml of acetone and 5.0g of regorafenib monohydrate were added to a 100ml three-necked flask and heated to reflux. Then, 1ml of concentrated sulfuric acid was slowly added thereto, the temperature was reduced to 23 ℃, and the stirring was continued for 0.5h. Filtration and drying of the filter cake in a forced air drying oven at 60 ℃ for 5.0h gave 4.3g of white regorafenib sulfate. Yield 86.0%, HPLC:99.2 percent.
Example 4
60ml of ethyl acetate and 5.0g of regorafenib monohydrate were added to a 100ml three-necked flask and heated to reflux. Then, 1.2ml of concentrated sulfuric acid was added, the temperature was reduced to 24 ℃, and the stirring was continued for 0.5h. Filtration and drying of the filter cake in a forced air drying oven at 60 ℃ for 5.0h gave 4.2g of white regorafenib hydrochloride. Yield 84.0%, HPLC:98.7 percent.
Example 5
60ml of a mixed solvent of ethyl acetate and acetone (30 ml of each of ethyl acetate and acetone) and 5.0g of regorafenib monohydrate were added to a 100ml three-necked flask, and heated to reflux. Then, 1.2ml of concentrated sulfuric acid was added, the temperature was reduced to 24 ℃, and the stirring was continued for 0.5h. Filtration and drying of the filter cake in a forced air drying oven at 60 ℃ for 5.0h gave 4.1g of white regorafenib hydrochloride. Yield 82.0%, HPLC:99.0 percent.
The X-ray powder diffraction pattern data of the sample obtained in example 3 measured by CuKa radiation are shown in fig. 2 and table 4 below, respectively. The X-ray powder diffraction pattern data of each of the samples obtained in examples 4 and 5, measured by CuKa radiation, were similar to the X-ray powder diffraction pattern data of the sample obtained in example 3, respectively.
TABLE 4 Experimental data for X-ray powder diffraction pattern of the sample obtained in example 3
The hydrogen nuclear magnetic resonance spectroscopy analysis of the regorafenib hydrochloride sample obtained in example 1 is shown in fig. 3. As can be seen from fig. 3, the peaks of regorafenib are: 1 h NMR (400MHz, DMSO). Delta.9.06-9.10 (t, 2H), 8.59 (m, 1H), 8.25-7.98 (m, 2H), 7.80-7.58 (m, 2H), 7.49-7.28 (m, 2H), 7.20 (t, 1H), 7.08-7.10 (m, 1H), 2.79 (s, 3H). The peaks for the hydrochloride salt are: 1 H NMR(400MHz,DMSO)10.37-10.38(s,1H)。
from the integration result of the characteristic peaks in fig. 3, the stoichiometric ratio of regorafenib and hydrochloric acid (HCl) is 1:1.
Further, the analysis results of the hydrogen nuclear magnetic resonance spectroscopy of the regorafenib sulfate sample obtained in example 3 are shown in fig. 4. As can be seen from fig. 4, the peaks of regorafenib are: 1 H NMR(400MHz,DMSO-d6)δ9.61(s,1H)，9.01(t,1H)，8.84(m,1H)，8.59(m,1H)，8.14-8.47(m,2H)，7.60-7.66(m,3H)，7.31-7.37(m,2H)，7.08-7.11(m,2H)，2.82(s,3H). The peak for sulfate is: 1 H NMR(400MHz,DMSO-d6)10.91(s,2H)。
from the integration results of the characteristic peaks in fig. 4, regorafenib and sulfuric acid (H) are known 2 SO 4 ) Is 1:2.
And (3) stability analysis:
1. experimental methods
(1) Chromatographic conditions
A chromatographic column: octadecylsilane chemically bonded silica as a filler (Welch Ultimate XB-C18, 4.6X 150mm,3 μm or equivalent performance column);
detection wavelength: 260nm; flow rate: 1.0ml/min; sample introduction volume: 20 mu l of the mixture; column temperature: 40 ℃; sample injector temperature: 10 ℃.
Mobile phase A:0.5% aqueous triethylamine (1000 ml water, 5ml triethylamine added, pH adjusted to 3.0 with phosphoric acid).
Mobile phase B: and (3) acetonitrile.
Mobile phase gradient elution procedure is as follows in table 5:
TABLE 5 procedure for mobile phase gradient elution
| Time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 70 | 30 |
| 5 | 70 | 30 |
| 50 | 30 | 70 |
| 60 | 15 | 85 |
| 75 | 15 | 85 |
| 76 | 70 | 30 |
| 90 | 70 | 30 |
(2) Solution preparation
Solvent: acetonitrile-water (75.
Test solution: an appropriate amount of the product is taken, precisely weighed, dissolved by adding an appropriate amount of methanol, and diluted by a solvent (namely acetonitrile-water 75 25) to prepare a solution containing about 1mg of regorafenib in each 1ml of the solution.
Control solution: taking a proper amount of regorafenib reference substances, precisely weighing, adding a proper amount of methanol to dissolve the regorafenib reference substances, and diluting the solution by using the solvent to prepare a solution containing about 1 mu g of regorafenib in 1 ml.
Sensitivity solution: an appropriate amount of the control solution was precisely measured and diluted with the above solvent to prepare a solution containing about 0.5. Mu.g of regorafenib per 1 ml.
System applicability solution: taking appropriate amount of regorafenib, impurity B, impurity C, impurity D, impurity E, impurity F, impurity G, impurity H and impurity I reference substances, precisely weighing, adding appropriate amount of methanol to dissolve, and quantitatively diluting with the above solvents to prepare a mixed solution containing about 1mg of regorafenib, about 2 mug of each of impurity B, impurity C, impurity D, impurity E, impurity F, impurity G, impurity H and impurity I in each 1 ml.
(3) Reagent information (see Table 6 below)
TABLE 6 reagent information
| Reagent and reagent | Grade/lot/content | Manufacturer of the product |
| Water for testing | Purified water | Ice dew |
| Acetonitrile | HPLC | MREDA |
| Methanol | HPLC | MREDA |
| Triethylamine | AR | Fine chemical reagent factory of Tianjin City Jindongtianzheng |
| Phosphoric acid | AR | FUCHEN (TIANJIN) CHEMICAL REAGENT Co.,Ltd. |
| Regorafenib reference substance | DZ20201224/96.2％ | Beijing Haitai Tianzheng Pharmaceutical Technology Co.,Ltd. |
| Reference substance of impurity B | 20190601/99.28％ | Shenzhen Ruixinda medicine science and technology Limited |
| Reference substance of impurity C | 20190601/98.60％ | Shenzhen Ruixinda medicine science and technology Limited |
| Reference substance of impurity D | 20190710/97.0％ | Beijing Sisi source biomedical science and technology Co Ltd |
| Reference substance of impurity E | 20180501/99.04％ | Shenzhen Ruixinda medicine science and technology Limited |
| Reference substance of impurity F | 20190710/99.3％ | Beijing Sisi source biomedical science and technology Co Ltd |
| Reference substance of impurity G | 20191023/99.1％ | Beijing Sisi source biomedical science and technology Co Ltd |
| Reference substance of impurity H | 20191001/96.65％ | Shenzhen ruixinda pharmaceutical technology limited |
| Reference substance of impurity I | 20181101/98.56％ | Shenzhen Ruixinda medicine science and technology Limited |
2. Stability analysis of regorafenib test samples
The results of stability analysis of the regorafenib test article are shown in table 7 below.
TABLE 7 Experimental data from stability analysis of regorafenib test articles
3. Stability analysis of regorafenib hydrochloride
The results of stability analysis of regorafenib hydrochloride are shown in table 8 below.
TABLE 8 stability analysis of regorafenib hydrochloride
4. Stability analysis of regorafenib sulfate
The results of stability analysis of regorafenib sulfate are shown in table 9 below.
TABLE 9 Experimental data from stability analysis of Regorafenib sulfate
The data of the hygroscopicity test of regorafenib test product, regorafenib hydrochloride, and regorafenib sulfate are shown in table 10 below.
TABLE 10 hygroscopicity test data for each of regorafenib test article, regorafenib hydrochloride, and regorafenib sulfate
As shown in tables 7 to 9 above, the regorafenib starting material (i.e., regorafenib test article) slowly degrades over time during laboratory stability studies. Specifically, after standing for 0h, 3h, 6h, 9h, 12h, 40h, 120h, the peak area of each impurity was increased compared to that at 0 h: the intermediate is increased by 10.6 percent (the peak area is increased from 62.3 to 68.9), the unknown monohetero 1 is increased by 10.0 percent (the peak area is increased from 42.1 to 43.8), and the total hetero peak area is increased by 13.5 percent (the peak area is increased from 311.2 to 353.2), which indicates that the regorafenib solution is unstable and the risk of impurity degradation is high.
In contrast, after regorafenib hydrochloride is placed for 0h, 3h, 6h, 9h, 12h, 40h and 120h, the intermediate is increased by 1.0% (the peak area is increased from 60.3 to 60.9), the unknown mono-impurity 1 is increased by 2.2% (the peak area is increased from 41.1 to 42.0), and the number of impurities is not increased. Therefore, regorafenib hydrochloride is more stable and the degradation rate of impurities is slower. Similarly, the regorafenib sulfate after being placed for 0h, 3h, 6h, 9h, 12h, 40h and 120h increases 1.2% of the intermediate (the peak area is increased from 60.5 to 61.2), 4.0% of the intermediate 1 (the peak area is increased from 42.1 to 43.8) and the number of impurities is not increased. Thus indicating that regorafenib sulfate is more stable and the rate of impurity degradation is slower.
As can be seen from the hygroscopicity test and the combination of table 10, the regorafenib hydrochloride or regorafenib sulfate is less hygroscopic, almost non-hygroscopic, and therefore more stable than the regorafenib raw material. Specifically, the regorafenib raw materials exist in the form of molecules, the molecules attract each other by virtue of van der waals force, and because the van der waals force is weak, when external energy acts on a system, a single molecule shares more energy, and because regorafenib is not good in stability, decomposition is caused. For regorafenib hydrochloride and regorafenib sulfate, the whole system exists in a state of a conjugated compound, and the whole system is connected into a whole by strong hydrogen bonds; when external energy acts on the system, the energy is uniformly dispersed, so that the system is more stable.
According to the examples and the specific implementation scheme of the invention, regorafenib is converted into a brand-new regorafenib hydrochloride and sulfate new crystal form, the crystal forms have high apparent solubility and good stability, and different crystal forms can be prepared according to the preparation requirements at the later stage. In addition, the preparation method of the regorafenib hydrochloride and sulfate disclosed by the invention is simple in process, easy to control the crystallization process, good in reproducibility and suitable for industrial production.
The present invention has been described in detail above by way of specific examples and preferred embodiments. However, various modifications, adaptations, variations, and alternatives to the embodiments and examples of the present invention may be made without departing from the spirit and scope of the invention. Also, various modifications, adaptations, variations and alterations to the embodiments and examples of the present invention do not affect the scope of the claims of the present invention, but rather fall within the scope of the claims of the present invention.
Claims (10)
1. A crystal form of regorafenib hydrochloride, wherein the crystal form has characteristic peaks at one or more of diffraction angles 2 theta of 9.5 th 0.2 degrees, 11.8 th 0.2 degrees, 12.7 th 0.2 degrees, 15.2 th 0.2 degrees, 16.4 th 0.2 degrees, 19.1 th 0.2 degrees, 19.2 th 0.2 degrees, 19.5 th 0.2 degrees, 20.3+0.2 degrees, 21.6+0.2 degrees, 23.8+0.2 degrees, 24.5+0.2 degrees, 26.8+0.2 degrees, 27.9+0.2 degrees and 29.2+0.2 degrees in an X-ray powder diffraction pattern.
2. The crystalline form of regorafenib hydrochloride according to claim 1 wherein the crystalline form has X-ray powder diffraction pattern data as set forth in table 3 of the specification.
3. A crystalline form of regorafenib sulfate salt, wherein the crystalline form has characteristic peaks in an X-ray powder diffraction pattern at one or more of diffraction angles 2 Θ of 7.4 degrees 0.2 °, 10.7 degrees 0.2 °, 12.0 degrees 0.2 °, 13.3 degrees 0.2 °, 14.7 degrees 0.2 °, 15.8 degrees 0.2 °, 18.1 degrees 0.2 °, 20.6 degrees 0.2 °, 22.7 degrees 0.2 °, 24.0 degrees 0.2 °, 24.5 degrees 0.2 °, 26.3 degrees 0.2 °, 27.2 degrees 0.2 °, 28.7 degrees 0.2 °.
4. The crystalline form of regorafenib sulfate according to claim 3, wherein the crystalline form has X-ray powder diffraction pattern data as set forth in table 4 of the specification.
5. A process for preparing a crystalline form of regorafenib hydrochloride salt according to claim 1 or 2, wherein the process comprises the steps of:
(a) Dispersing regorafenib monohydrate in an organic solvent, and heating to reflux;
(b) Dripping hydrochloric acid under the reflux state, cooling to 15-40 ℃, and stirring;
(c) Filtered and dried to give a solid.
6. The process according to claim 5, wherein the volume of the organic solvent is 5-30 times, preferably 8-20 times, more preferably 10-15 times based on the mass of the regorafenib monohydrate; the organic solvent is one or a combination of more of alcohols, ketones and esters; the alcohol solvent is preferably one or more of methanol, ethanol, isopropanol and n-propanol, the ketone solvent is preferably acetone, butanone or the combination thereof, and the ester solvent is preferably one or more of ethyl formate, butyl formate, methyl acetate, ethyl acetate, butyl acetate and isopropyl acetate; the organic solvent is further preferably one or a mixture of more of methanol, ethanol, n-propanol, acetone and ethyl acetate; and the hydrochloric acid is concentrated hydrochloric acid.
7. The process according to claim 5, wherein the molar ratio of regorafenib monohydrate to the solute hydrochloride is 1:2 to 1, more preferably 1:4 to 1:8, most preferably 1:6; cooling to 20-30 ℃; drying at 50-70 deg.C, preferably 60 deg.C; a white solid was obtained.
8. A process for preparing the crystalline form of regorafenib sulfate salt according to claim 3 or 4, wherein the process comprises the steps of:
(a) Dispersing regorafenib monohydrate in an organic solvent, and heating to reflux;
(b) Dripping sulfuric acid under the reflux state, cooling to 15-40 ℃, and stirring;
(c) Filtered and dried to obtain a solid.
9. The process according to claim 8, wherein the volume of the organic solvent is 5 to 30 times, preferably 8 to 20 times, more preferably 10 to 15 times based on the mass of the regorafenib monohydrate; the organic solvent is one or a combination of more of alcohols, ketones and esters; the alcohol solvent is preferably one or a combination of methanol, ethanol, isopropanol and n-propanol, the ketone solvent is preferably acetone, butanone or a combination of acetone and butanone, and the ester solvent is preferably one or a combination of ethyl formate, butyl formate, methyl acetate, ethyl acetate, butyl acetate and isopropyl acetate; the organic solvent is further preferably one or a mixture of more of methanol, ethanol, n-propanol, acetone and ethyl acetate; and the sulfuric acid is concentrated sulfuric acid.
10. The process according to claim 8, wherein the molar ratio of regorafenib monohydrate to the sulfuric acid solute is 1:1 to 1:8, more preferably 1:2 to 1:6, most preferably 1:3; cooling to 20-30 ℃; drying at 50-70 deg.c, preferably 60 deg.c; a white solid was obtained.
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