CN114685512A - Ibutotinib-nicotinic acid eutectic crystal and preparation method thereof - Google Patents
Ibutotinib-nicotinic acid eutectic crystal and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of crystal form drug molecules, and particularly provides an ibrutinib-nicotinic acid eutectic. The ibrutinib-nicotinic acid eutectic prepared by the invention uses Cu-Ka radiation, and an X-ray diffraction spectrogram expressed by 2 theta has characteristic peaks at 5.46 +/-0.2 degrees, 15.22 +/-0.2 degrees, 20.10 +/-0.2 degrees, 20.97 +/-0.2 degrees, 24.57 +/-0.2 degrees, 25.71 +/-0.2 degrees, 26.78 +/-0.2 degrees and 27.76 +/-0.2 degrees. The method for preparing the ibrutinib-nicotinic acid eutectic is simple to operate, and the prepared crystal is high in yield and purity. The ibrutinib-nicotinic acid eutectic prepared by the method has good chemical stability and good solubility, and has important significance for improving the bioavailability and the drug effect of ibrutinib.
Description
Technical Field
The invention relates to the technical field of crystal form drug molecules, and particularly discloses an ibrutinib-nicotinic acid eutectic.
Background
Ibrutinib (Ibrutinib) was developed by a combination of pharmaceuticals and qiangsheng corporation, usa under the trade name of ibruvica, and its chemical name: 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one of the formula:
ibutinib is a pioneer drug for oral Bruton's Tyrosine Kinase (BTK) inhibitor, which irreversibly inhibits BTK by selectively covalently binding to cysteine residue (Cys-481) of the active site of BTK target protein, thereby effectively preventing tumor migration from B-cells to lymphoid tissues adapted to the tumor growth environment. In 11 months 2013, the united states Food and Drug Administration (FDA) approved it for marketing for the treatment of a rare invasive leukemia, Mantle Cell Lymphoma (MCL), and in 7 months 2014, the FDA approved it for the treatment of Chronic Lymphocytic Leukemia (CLL).
Patent WO2013/184572 applied by Pharmacyclics in 2013 discloses six crystal forms of ibrutinib, wherein crystal form D is a methyl isobutyl ketone solvate, crystal form E is a toluene solvate, and crystal form F is a methanol solvate, which are not suitable for pharmaceutical preparations. Among the other three crystal forms, the crystal form B has larger hygroscopicity, and in comparison, the crystal form A has difficulty in absorbing moisture, and stability and solubility data of the crystal form C are not reported. Thus, of the six forms, only form a is suitable for pharmaceutical formulation, but form a has an observed water solubility of only about 0.013mg/ml at about pH8, and BCS is classified as class II (poorly soluble, highly permeable). The FDA specifications mention: the absolute bioavailability of Ibrutinib is poor when the Ibrutinib is orally taken on an empty stomach, and is only 2.9 percent, and the Ibrutinib can be doubled when the Ibrutinib is orally taken along with meals.
Patent CN107286163A discloses an ibutinib crystal form 1, having a solubility in water of only 1.24 μ g/mL. Patent CN105646499A discloses ibrutinib form G having a solubility in water of 13.47 μ G/mL. Patent CN105646498A discloses crystalline form F of ibrutinib having a solubility in water of 11.63 μ g/mL. Patent CN109776543A discloses crystals of ibrutinib salts, specifically discloses the solubilities of ibrutinib hydrochloride crystals, ibrutinib hydrobromide crystals, ibrutinib benzoate crystals and ibrutinib sulfate crystals, wherein the solubility of ibrutinib hydrochloride crystals is highest and the solubility in water at pH8 is 5.2 × 10-5g/ml. Patent CN107530347AThe solubility of the ibrutinib-benzoic acid eutectic, the ibrutinib-succinic acid eutectic and the ibrutinib-salicylic acid eutectic is disclosed, wherein the solubility of the ibrutinib-benzoic acid eutectic and the ibrutinib-salicylic acid eutectic is lower than that of the crystal form A, and only the solubility of the ibrutinib-succinic acid eutectic is improved to about 2 times of that of the crystal form A.
Therefore, how to improve the solubility of ibrutinib is still a technical problem.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide an ibutinib crystal form with higher solubility, and particularly provides an ibutinib-nicotinic acid eutectic crystal.
Nicotinic acid belongs to vitamin B3, also called nicotinic acid and pellagra resisting factor, the structural formula is as follows: c6H5NO2The chemical name of 3-picolinic acid, white or yellowish crystal, is one of 13 vitamins essential to human body, and belongs to vitamin B group. Nicotinic acid can affect the hematopoietic process, promote iron absorption and hematopoiesis; maintaining normal function of the skin and secretion of digestive glands; improving excitability of central nerve, cardiovascular system, reticuloendothelial system and endocrine function. The structural formula is as follows:
the molar ratio of ibrutinib to nicotinic acid in the ibrutinib-nicotinic acid cocrystal is 1: the specific technical scheme is as follows:
the invention provides an ibutinib-nicotinic acid eutectic, which uses Cu-Kalpha radiation, and has characteristic peaks at 5.46 +/-0.2 degrees, 15.22 +/-0.2 degrees, 20.10 +/-0.2 degrees, 20.97 +/-0.2 degrees, 24.57 +/-0.2 degrees, 25.71 +/-0.2 degrees, 26.78 +/-0.2 degrees and 27.76 +/-0.2 degrees in an X-ray diffraction spectrum expressed by 2 theta.
Preferably, the ibutinib-nicotinic acid eutectic has characteristic peaks at 5.46 +/-0.2 °, 10.38 +/-0.2 °, 15.22 +/-0.2 °, 18.77 +/-0.2 °, 20.10 +/-0.2 °, 20.97 +/-0.2 °, 21.45 +/-0.2 °, 23.35 +/-0.2 °, 24.57 +/-0.2 °, 25.71 +/-0.2 °, 26.78 +/-0.2 °, 27.76 +/-0.2 °, 28.95 +/-0.2 °, 31.99 +/-0.2 °, 33.92 +/-0.2 °, 35.50 +/-0.2 °, 38.04 +/-0.2 °, 39.62 +/-0.2 °, 40.80 +/-0.2 ° and 41.11 +/-0.2 ° in an X-ray diffraction spectrum expressed by 2 theta under the action of Cu-Kalpha radiation.
Preferably, the ibutinib-nicotinic acid eutectic is prepared by using Cu-Ka radiation, and the characteristic peaks of the ibutinib-nicotinic acid eutectic accord with an X-ray powder diffraction spectrum and detection data shown in figure 1 and table 2.
The invention provides a method for preparing the ibutinib-nicotinic acid eutectic, which comprises the following steps:
dissolving the ibrutinib and nicotinic acid in the mixed solvent A, heating for dissolving, cooling for crystallization after the solution is clarified, filtering and drying to obtain an ibrutinib-nicotinic acid eutectic; the mixed solvent A is selected from one of methanol-water, ethanol-water, acetonitrile-water and acetone-water.
Preferably, the volume ratio of methanol or ethanol or acetonitrile or acetone to water in the mixed solvent A is 1.5-5: 1; further preferably, the volume ratio of methanol or ethanol or acetonitrile or acetone to water in the mixed solvent A is 2-4: 1.
the molar ratio of ibrutinib to nicotinic acid is 1: 1-1.5; preferably, the molar ratio of the ibrutinib to the nicotinic acid is 1: 1-1.2.
The mass-volume ratio of ibrutinib to the mixed solvent A in the system is 9-15: 1, wherein mass is in mg and volume is in mL.
The temperature for dissolving and heating is 50-80 ℃.
The cooling crystallization temperature is 0-30 ℃; preferably, the temperature reduction and crystallization temperature is 10-20 ℃.
The crystallization time is 24-36 hours.
The drying temperature is 50-60 ℃, and the drying time is 5-10 hours.
Preferably, the preparation method of the ibrutinib-nicotinic acid eutectic comprises the following steps:
dissolving the ibrutinib and nicotinic acid in the mixed solvent A, heating and dissolving at 50-80 ℃, stirring and refluxing for reaction for 2-3 hours, cooling to 10-20 ℃, crystallizing for 24-36 hours, filtering, washing a filter cake, and drying to obtain an ibrutinib-nicotinic acid eutectic crystal; the mixed solvent A is selected from one of methanol-water, ethanol-water, acetonitrile-water and acetone-water; the solvent for washing the filter cake is selected from one of methanol, ethanol, acetone and acetonitrile.
In a third aspect, the invention provides a pharmaceutical composition, which comprises the ibrutinib-nicotinic acid eutectic prepared above and other active ingredients and/or pharmaceutically acceptable auxiliary components which can be used in combination.
Preferably, the other components include other active ingredients, fillers, disintegrants, lubricants, etc. which may be used in combination.
Preferably, the pharmaceutical composition can be prepared into spray, tablets, capsules, powder injections, liquid injections and the like by using standard and conventional technologies.
The fourth aspect of the application provides an application of the ibrutinib-nicotinic acid eutectic as an active ingredient in preparing an anticancer drug.
Confirmation of Crystal Structure
And selecting crystals meeting the specification size from the prepared samples, and carrying out X-ray single crystal diffraction test analysis on the crystals. X-ray crystal data were collected on a jtaab Synergy model instrument, japan, testing temperature 293(2) K, voltage 50kv, current 1mA, irradiation with CuKa, data collected in a ω -scan fashion and Lp corrected. Analyzing the structure by a direct method, finding out all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and refining the structure by a least square method.
The crystallographic data of the ibrutinib-nicotinic acid eutectic prepared by the invention are shown in table 1, and the crystallographic parameters are as follows: tetragonal system, chiral space group P21(ii) a The unit cell parameters are as follows:
α 90.00 °, β 101.19 °, γ 90.00 °, unit cell volume
The molecular formula is as follows: c31H29N7O4Molecular weight: 564.62. an ORTEP diagram of the structure analysis of the ibrutinib-nicotinic acid eutectic disclosed by the invention shows that one molecule of ibrutinib and one molecule of nicotinic acid exist in the crystal, and the crystal is shown in an attached figure 2. The stacking diagram of the ibrutinib-nicotinic acid eutectic is shown in attached figure 3.
TABLE 1 Ibritinib-nicotinic acid major crystallographic data
In the ibutinib-nicotinic acid eutectic crystal test, an X-ray powder diffraction test instrument and test conditions are as follows: PANALYTIC EMPyrean X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction path: PIXCEL, voltage 45KV, current 40mA, divergence slit 1/4 degrees, anti-divergence slit 1 degree, cable-stayed slit 0.04rad degree, counting time of each step 0.5s, and scanning range 3-50 degrees.
According to the crystallography data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Ka) are detailed in attached figure 1 and table 2.
Table 2 main PXRD peaks for ibrutinib-nicotinic acid cocrystal
All samples prepared in the examples have the same crystallographic parameters and X-ray powder diffraction patterns as described above.
Compared with the currently reported ibrutinib crystal form, the ibrutinib-nicotinic acid eutectic provided by the invention has the following advantages:
(1) the preparation method is simple and convenient, and the prepared crystal has high purity and yield.
(2) Has better chemical stability and better solubility.
(3) Provides a better basis for the application of the ibrutinib in the aspect of drug synergistic treatment, thereby more efficiently exerting the medicinal value of the ibrutinib.
Drawings
FIG. 1: an X-ray powder diffraction pattern of the ibutinib-nicotinic acid eutectic.
FIG. 2: ORTEP diagram of ibrutinib-niacin cocrystal.
FIG. 3: a stacking diagram of the ibutinib-nicotinic acid eutectic.
FIG. 4: comparative example 1X-ray powder diffraction pattern of ibutinib-niacin cocrystal.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Example 1
Adding 88.1mg (0.2mmol) of ibrutinib and 25.6mg (0.2mmol) of nicotinic acid into 6mL of ethanol and 4mL of water, heating to 65 ℃, stirring for dissolving, carrying out reflux reaction for 2 hours, slowly cooling to 10-20 ℃, standing at controlled temperature for crystallization for 25 hours, filtering, washing a filter cake with ethanol, and carrying out vacuum drying at 50 ℃ for 6 hours to obtain the ibrutinib-nicotinic acid eutectic crystal, wherein the yield is 91.55%, and the purity is 99.91%.
Example 2
Adding 88.1mg (0.2mmol) of ibrutinib and 29.5mg (0.24mmol) of nicotinic acid into 4mL of acetonitrile and 2mL of water, heating to 80 ℃, stirring for dissolving, carrying out reflux reaction for 3 hours, slowly cooling to 10-20 ℃, standing at controlled temperature for crystallization for 36 hours, filtering, washing a filter cake with acetonitrile, and carrying out vacuum drying at 50 ℃ for 10 hours to obtain the ibrutinib-nicotinic acid eutectic, wherein the yield is 94.05%, and the purity is 99.95%.
Example 3
Adding 88.1mg (0.2mmol) of ibrutinib and 27.1mg (0.22mmol) of nicotinic acid into 7mL of acetone and 2mL of water, heating to 50 ℃, stirring for dissolving, carrying out reflux reaction for 2 hours, slowly cooling to 10-20 ℃, standing at controlled temperature for crystallization for 24 hours, filtering, washing a filter cake with acetone, and carrying out vacuum drying at 50 ℃ for 5 hours to obtain the ibrutinib-nicotinic acid eutectic, wherein the yield is 95.32%, and the purity is 99.95%.
Example 4
Adding 132.2mg (0.3mmol) of ibrutinib and 36.9mg (0.3mmol) of nicotinic acid into 8mL of methanol and 2mL of water, heating to 60 ℃, stirring for dissolving, carrying out reflux reaction for 2 hours, slowly cooling to 10-20 ℃, standing at controlled temperature for crystallization for 25 hours, filtering, washing a filter cake with methanol, and carrying out vacuum drying at 50 ℃ for 6 hours to obtain the ibrutinib-nicotinic acid eutectic crystal, wherein the yield is 97.88%, and the purity is 99.97%.
Example 5
Adding 132.2mg (0.3mmol) of ibrutinib and 55.4mg (0.45mmol) of nicotinic acid into 10mL of ethanol and 2mL of water, heating to 70 ℃, stirring for dissolving, carrying out reflux reaction for 3 hours, slowly cooling to 20-30 ℃, standing at controlled temperature for crystallization for 30 hours, filtering, washing a filter cake with ethanol, and carrying out vacuum drying at 50 ℃ for 8 hours to obtain the ibrutinib-nicotinic acid eutectic crystal, wherein the yield is 90.58%, and the purity is 99.90%.
Example 6
Adding 88.1mg (0.2mmol) of ibrutinib and 25.6mg (0.2mmol) of nicotinic acid into 2.5mL of methanol and 2.5mL of water, heating to 60 ℃, stirring for dissolving, carrying out reflux reaction for 2 hours, slowly cooling to 0-10 ℃, standing at controlled temperature for crystallization for 30 hours, filtering, washing a filter cake with methanol, and carrying out vacuum drying at 50 ℃ for 6 hours to obtain the ibrutinib-nicotinic acid eutectic crystal, wherein the yield is 75.66%, and the purity is 99.81%.
Example 7
Adding 88.1mg (0.2mmol) of ibrutinib and 24.13mg (0.196mmol) of nicotinic acid into 11mL of isopropanol and 2mL of water, heating to 45 ℃, stirring for dissolving, carrying out reflux reaction for 2 hours, slowly cooling to 0-10 ℃, standing at controlled temperature for crystallization for 30 hours, filtering, washing a filter cake with isopropanol, and carrying out vacuum drying at 45 ℃ for 4 hours to obtain the ibrutinib-nicotinic acid eutectic crystal, wherein the yield is 68.89%, and the purity is 99.75%.
Comparative example 1 Ibritinib-nicotinic acid cocrystal
2.4g (5.5mmol) of ibrutinib form A are suspended in MeOH (50mL) together with 0.68g (5.5mmol) of nicotinic acid at 30 ℃. The suspension was stirred to give a clear solution. The solution was evaporated in a rotary evaporator until the volume was about 10 mL. A white solid began to precipitate. The solution was stirred at 30 ℃ overnight to allow complete precipitation. It was isolated by filtration and dried at 40 ℃/10mbar for 72 hours. The yield was 67.85% and the purity was 96.81%.
Ibutinib form a was obtained according to preparation route 3 of patent CN104736178A form a.
Comparative example 2 Ebritinib-benzoic acid cocrystal
2.4g (5.5mmol) of ibrutinib form A are suspended with 0.67g (5.5mmol) of benzoic acid in MeOH (50mL) at 30 ℃. The suspension was stirred to give a clear solution. The solution was evaporated in a rotary evaporator until the volume was about 10 mL. A white solid began to precipitate. The solution was stirred at 30 ℃ overnight to allow complete precipitation. It was isolated by filtration and dried at 40 ℃/10mbar for 72 hours. The yield was 69.66%, and the purity was 99.90%.
Ibutinib form a was obtained according to preparation route 3 of patent CN104736178A form a.
Comparative example 3 Ebritinib-fumaric acid cocrystal
At Room Temperature (RT), 3g (6.8mmol) of ibrutinib form A are suspended with 0.8g (6.8mmol) of fumaric acid in 27mL of MeOH. The suspension was heated to 70 ℃. A clear solution was obtained. The solution was slowly cooled to room temperature, at which time a white solid began to precipitate. The precipitate was isolated by filtration and dried at 40 ℃ and 10mbar for 72 hours. The yield was 70.18%, and the purity was 99.91%.
Ibutinib form a was obtained according to preparation route 3 of patent CN104736178A form a.
Comparative example 4 Ebritinib-succinic acid cocrystal
At Room Temperature (RT), 1g (2.3mmol) of ibutinib is suspended with 1g (8.5mmol) of succinic acid in 7mL of MeOH. After stirring for 15 minutes a clear solution was obtained. After 60 minutes, a white solid began to precipitate. The solution was left to stand at room temperature with stirring over the weekend to allow complete precipitation. The precipitate was isolated by filtration. Yield: 67.43%, purity: 99.90 percent.
Solubility test
1. Test materials: the ibutinib-nicotinic acid cocrystals prepared in examples 1-7, the ibutinib cocrystals prepared in comparative examples 1-4 and the ibutinib crystal form a.
2. The test method comprises the following steps: the solubility test is referred to the contents of the Chinese pharmacopoeia (2015 edition). Respectively measuring 10mL of medium (pH8.0 water, pH2.0 hydrochloric acid solution, pH6.8 phosphate buffer solution) into a penicillin bottle, adding excessive medicine, sealing the penicillin bottle, stirring in 37 deg.C water bath at constant temperature for 1 hr, filtering with 0.2 μm filter membrane, measuring absorbance of the filtrate at wavelength of 260nm, and measuring the absorbance of standard control to calculate its solubility.
3. And (3) test results: the results of the solubility test are shown in Table 3.
TABLE 3 solubility of ibrutinib-nicotinic acid cocrystals in different media
Through tests, the ibrutinib-nicotinic acid cocrystals prepared in the embodiments 1-7 of the invention have similar solubility effects, and compared with other types of ibrutinib cocrystals, the ibrutinib-nicotinic acid cocrystals have higher solubility in three media, namely pH8.0 water, pH2.0 hydrochloric acid solution and pH6.8 phosphate buffer solution, and have important significance for improving the bioavailability and the drug effect of ibrutinib.
Stability test
1. Test materials: ibutinib-nicotinic acid cocrystals obtained in examples 1 to 7 and ibutinib cocrystals obtained in comparative examples 1 to 4.
2. The test method comprises the following steps: the test is carried out according to the method of appendix <9001 raw material medicament and preparation stability test guiding principle > in the fourth part of Chinese pharmacopoeia (2015 edition), and the high-temperature test conditions are as follows: 60 ℃; conditions of the intense light irradiation test: 4500lx ± 500 lx; high humidity test conditions: the temperature is 40 ℃ and the relative humidity is 90% +/-5%. The purity was checked by HPLC and three replicates were performed, with the results averaged.
3. And (3) test results: the test results are shown in Table 4.
TABLE 4 Ibritinib-nicotinic acid cocrystal stability test results
Tests prove that the ibrutinib-nicotinic acid eutectic prepared in the embodiments 1-7 of the invention has high purity, and the purity of the sample is slightly changed under the conditions of high temperature, high humidity and strong light, and the stability is good. In addition, the ibrutinib-nicotinic acid cocrystal prepared by the invention is stored for 60 days under the conditions of relative humidity of 75 +/-5% and 40 ℃, and PXRD analysis shows that the crystal form is stable and no crystal transformation phenomenon occurs.
Claims (10)
1. An ibrutinib-nicotinic acid eutectic is characterized in that the ibrutinib-nicotinic acid eutectic has characteristic peaks at 5.46 +/-0.2 degrees, 15.22 +/-0.2 degrees, 20.10 +/-0.2 degrees, 20.97 +/-0.2 degrees, 24.57 +/-0.2 degrees, 25.71 +/-0.2 degrees, 26.78 +/-0.2 degrees and 27.76 +/-0.2 degrees in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Ka radiation.
2. The ibutinib-niacin eutectic according to claim 1, wherein said ibutinib-niacin eutectic has characteristic peaks at 5.46 ± 0.2 °, 10.38 ± 0.2 °, 15.22 ± 0.2 °, 18.77 ± 0.2 °, 20.10 ± 0.2 °, 20.97 ± 0.2 °, 21.45 ± 0.2 °, 23.35 ± 0.2 °, 24.57 ± 0.2 °, 25.71 ± 0.2 °, 26.78 ± 0.2 °, 27.76 ± 0.2 °, 28.95 ± 0.2 °, 31.99 ± 0.2 °, 33.92 ± 0.2 °, 35.50 ± 0.2 °, 38.04 ± 0.2 °, 39.62 ± 0.2 °, 40.80 ± 0.2 °, 41.11 ± 0.2 ° in an X-ray diffraction pattern expressed in 2 Θ using Cu-ka radiation.
3. The ibutinib-nicotinic acid eutectic according to claim 1, wherein the ibutinib-nicotinic acid eutectic is subjected to Cu-Ka radiation, and the characteristic peaks of the ibutinib-nicotinic acid eutectic accord with the X-ray powder diffraction pattern and detection data shown in figure 1 and table 2.
4. The ibutinib-niacin cocrystal according to claim 1, characterized in that the crystallographic parameters of the ibutinib-niacin cocrystal are: tetragonal system, chiral space group P21(ii) a The unit cell parameters are:
90.00 degree for alpha, 101.19 degree for beta, 90.00 degree for gamma, unit cell volume
5. A preparation method of the ibutinib niacin-co-crystal according to any one of claims 1 to 4, comprising the following steps: dissolving the ibrutinib and nicotinic acid in the mixed solvent A, heating for dissolving, cooling for crystallization after the solution is clarified, filtering and drying to obtain an ibrutinib-nicotinic acid eutectic; the mixed solvent A is selected from one of methanol-water, ethanol-water, acetonitrile-water and acetone-water.
6. The preparation method of ibrutinib-niacin cocrystal according to claim 5, wherein the volume ratio of methanol or ethanol or acetonitrile or acetone to water in the mixed solvent A is 1.5-5: 1.
7. the preparation method of ibutinib-nicotinic acid co-crystal according to claim 5, wherein the molar ratio of ibutinib to nicotinic acid is 1:1 to 1.5.
8. The preparation method of ibrutinib-niacin cocrystal according to claim 5, wherein the mass-to-volume ratio of ibrutinib to the mixed solvent A is 9-15: 1, wherein mass is in mg and volume is in mL.
9. A pharmaceutical composition, which comprises the ibrutinib-nicotinic acid eutectic crystal as claimed in any one of claims 1 to 4, and other active ingredients and/or pharmaceutically acceptable auxiliary components which can be used in combination.
10. Use of the ibutinib-nicotinic acid co-crystal as claimed in any one of claims 1 to 4 as an active ingredient for preparing an anticancer drug.
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| CN107530347A (en) * | 2015-03-27 | 2018-01-02 | 药品循环有限责任公司 | The co-crystal thereof of bruton's tyrosine kinase inhibitor |
| CN110283052A (en) * | 2019-07-19 | 2019-09-27 | 黄泳华 | The eutectic compound that is made of resveratrol and kinases inhibitor and containing the composition of the eutectic compound |
| CN110317203A (en) * | 2019-07-08 | 2019-10-11 | 浙江工业大学 | It is a kind of to replace Buddhist nun and the total amorphous article of carboxylic acid and preparation method thereof according to Shandong |
| CN110452240A (en) * | 2019-07-26 | 2019-11-15 | 广州白云山天心制药股份有限公司 | Eliquis crystal form and preparation method thereof |
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2020
- 2020-12-31 CN CN202011629203.9A patent/CN114685512B/en active Active
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|---|---|---|---|---|
| CN107530347A (en) * | 2015-03-27 | 2018-01-02 | 药品循环有限责任公司 | The co-crystal thereof of bruton's tyrosine kinase inhibitor |
| CN110317203A (en) * | 2019-07-08 | 2019-10-11 | 浙江工业大学 | It is a kind of to replace Buddhist nun and the total amorphous article of carboxylic acid and preparation method thereof according to Shandong |
| CN110283052A (en) * | 2019-07-19 | 2019-09-27 | 黄泳华 | The eutectic compound that is made of resveratrol and kinases inhibitor and containing the composition of the eutectic compound |
| CN110452240A (en) * | 2019-07-26 | 2019-11-15 | 广州白云山天心制药股份有限公司 | Eliquis crystal form and preparation method thereof |
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| Title |
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| 陈燕洁: "药物共晶的设计、合成及性质研究", 《华东师范大学硕士学位论文》 * |
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