CN114502550A - Tegafur cocrystals - Google Patents
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- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention provides a tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal, and relates to the technical field of crystal form drug molecules. The tegafur eutectic crystal uses Cu-Kalpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 6.26 +/-0.2 degrees, 9.30 +/-0.2 degrees, 11.89 +/-0.2 degrees, 12.60 +/-0.2 degrees, 14.79 +/-0.2 degrees, 20.28 +/-0.2 degrees, 23.98 +/-0.2 degrees and 26.43 +/-0.2 degrees; the crystallography measurement parameters were: triclinic system, chiral space group is P-1; the unit cell parameters are: a =5.1391(4), b =9.7392(7), c =13.9658(10) a, α =96.008(6) a °, β =92.368(7) a °, γ =103.481(7) a °, unit cell volume V =674.44(9) a3(ii) a And provides related preparation methods andapplication is carried out. The tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal has good stability and higher solubility and dissolution rate.
Description
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a tegafur-1, 2-di (4-pyridyl) ethylene eutectic, a preparation method thereof and application thereof in preparing medicaments for treating diseases.
Tegafur (TF), its chemical name is 1- (tetrahydro-2-furyl) -5-fluoro-2, 4(1H,3H) -pyrimidinedione, is white or white-like crystalline powder, and its molecular formula is C8H 9FN 2O 3Molecular weight is 200, and the structural formula is shown as follows:
tegafur belongs to fluorouracil derivatives, and TF was successfully synthesized by Dr Hiller, former Soviet scientist in 1968. TF acts by being degraded in vivo by liver drug metabolizing enzymes and the cytochrome P-450 system to fluorouracil, which is the same as fluorouracil. TF has the advantages of high chemotherapeutic activity (two times that of 5-FU) and low toxicity (5-6 times lower than 5-FU), and is widely used for treating breast cancer and gastrointestinal cancer.
Although tegafur is widely used in antitumor therapy, it still has the side effects of severe myelosuppression, damage to human body and the like, so researchers are continuously searching for ways of reducing toxicity or improving bioavailability. The existence of racemic isomers of 2 'R and 2' S in tegafur is described in patent No.855121, but studies show that the biological activity and toxicity of the two isomers are the same: (YasumotoM . etal. ，” J. Med. Chem. ”， 1977 ， vol.41 ， No.9 ， 1632-1635) (ii) a Uchida T et al studied the crystal form of tegafur and succeeded in obtaining four crystal forms (alpha, beta, gamma, delta) thereof“ Chem. Pharm. Bull. ”， Vol.41 ， No.9 ， 1623-1625). The 4 crystal forms can be obtained by a simpler method, such as: adding tegafur into acetone for hot melting and cold separation to obtain an alpha crystal form; the saturated tegafur methanol solution is subjected to rotary evaporation to obtain a beta crystal form; the beta crystal form can be transformed at 130 ℃ to obtain a gamma crystal form; the delta crystalline form was obtained by recrystallization of tegafur in methanol solution and slow evaporation at room temperature. Although four crystal forms are successfully prepared, the physicochemical properties of tegafur are not remarkably improved and the treatment effect of tegafur is not greatly improved.
In summary, the configuration or crystal form screening does not improve the curative effect or reduce the toxicity of tegafur well, and tegafur is currently used in combination with uracil, for example, Kagaway et al have demonstrated that the curative effect of tegafur can be effectively improved after tegafur and uracil are mixed in a molar ratio of 1:4 (a)“ Cancer Investigation ” , Vol.13, No.5, 470-474) (ii) a Sanchiz F, et al invented a compound (“ Jpn . Journal Clin.Oncol. ” ,1994,vol.24,No.6,322-326) So as to improve the bioavailability of the tegafur. Because uracil itself has some toxicity, Fujita H et al indicate that the toxicity is more significantly reduced when tegafur is used in combination with thymine, adenosine, thymidine, etc. (Experimental and Clinical Pharmacotherapy ， Issue 12 ， Riga ， 1983 ， p.205). U.S. Pat. No. 5, 6,538,001 reports that tegafur has improved solubility and bioavailability when it forms a molecular complex with methyl uracil in the ratio of 1:2 or 1:1. Srinivasulu A. et al reported the study of cocrystals of tegafur with nicotinamide, isonicotinamide, catechol, theophylline, p-hydroxybenzoic acid, and although the cocrystals were successfully prepared, they did not exhibit surprising physicochemical propertiesMass (A)Crystal Growth&Design 2014,14,12,6557-6569). At present, the combination is an effective method for improving the bioavailability of tegafur, so that a compound common scheme of tegafur needs to be developed, so as to improve the dissolution (dissolution) and solubility of tegafur and/or increase the bioavailability of tegafur, and reduce the toxic and side effects of tegafur.
In view of the problems of the prior art, the invention provides a tegafur-1, 2-di (4-pyridyl) ethene eutectic with high stability and solubility, wherein the eutectic has exact crystallography main parameters and atom space positions; the invention also provides a preparation method of the eutectic crystal.
The specific technical content of the invention is as follows:
in a first aspect, the present invention provides a tegafur-1, 2-bis (4-pyridyl) ethylene co-crystal, wherein the molar ratio of tegafur to 1, 2-bis (4-pyridyl) ethylene in the co-crystal is 1:1, and one tegafur molecule and one 1, 2-bis (4-pyridyl) ethylene molecule form a basic structural unit of a co-crystal, and the specific structure is as shown in formula I:
preferably, the tegafur-1, 2-bis (4-pyridyl) ethylene eutectic has characteristic peaks at 6.26 +/-0.2, 9.30 +/-0.2, 11.89 +/-0.2, 12.60 +/-0.2, 14.79 +/-0.2, 20.28 +/-0.2 and 23.98 +/-0.2 degrees in an X-ray diffraction spectrum expressed by 2 theta by using Cu-Ka radiation.
Preferably, the tegafur-1, 2-bis (4-pyridyl) ethylene eutectic has characteristic peaks at 6.26 + -0.2 °, 9.30 + -0.2 °, 10.59 + -0.2 °, 11.89 + -0.2 °, 12.60 + -0.2 °, 14.79 + -0.2 °, 18.74 + -0.2 °, 19.14 + -0.2 °, 20.28 + -0.2 °, 21.39 + -0.2 °, 22.32 + -0.2 °, 23.98 + -0.2 ° and 26.43 + -0.2 ° in an X-ray diffraction spectrum expressed in terms of 2 θ by using Cu-Ka radiation.
Preferably, the tegafur-1, 2-bis (4-pyridyl) ethene co-crystal uses Cu-Ka radiation, and the characteristic peak of the tegafur-1, 2-bis (4-pyridyl) ethene co-crystal accords with an X-ray powder diffraction pattern shown in figure 1.
Preferably, the tegafur-1, 2-bis (4-pyridyl) ethylene eutectic has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve, corresponding to a temperature range of 133.55-153.13 ℃, preferably 142.73 ℃.
Preferably, the tegafur-1, 2-bis (4-pyridyl) ethene co-crystal has the following crystallographic parameters: triclinic system, chiral space group is P-1; the unit cell parameters are: a =5.1391(4), b =9.7392(7), c =13.9658(10) a, α =96.008(6) a °, β =92.368(7) a °, γ =103.481(7) a °, unit cell volume V =674.44(9) a3。
In a second aspect, the invention provides a preparation method of tegafur-1, 2-bis (4-pyridyl) ethylene eutectic, which comprises the following specific preparation steps:
adding tegafur and 1, 2-di (4-pyridyl) ethylene into an organic solvent A, heating, stirring, dissolving, continuing to perform heat preservation reaction, finishing the reaction, filtering, volatilizing, crystallizing, filtering and drying to obtain the tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal.
Preferably, the preparing step comprises: adding tegafur and 1, 2-di (4-pyridyl) ethylene into an organic solvent A, heating, stirring, dissolving, continuing to perform heat preservation reaction, finishing the reaction, filtering, and slowly cooling the filtrate to room temperature; and putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking, volatilizing, crystallizing, filtering, and drying under reduced pressure to obtain the tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal.
Preferably, the molar ratio of the tegafur to the 1, 2-bis (4-pyridyl) ethylene is 1:1 to 1.5, preferably 1: 1.1.
Preferably, the organic solvent A is one or two of acetonitrile, acetone, methanol and ethanol, and preferably methanol.
Preferably, the mass volume ratio of the tegafur to the organic solvent A is 1: 80-120 g/ml.
Preferably, the heating and dissolving temperature is 30-50 ℃.
Preferably, the heat preservation reaction time is 1-3 hours; the heat preservation reaction temperature is 30-50 ℃.
In a preferable scheme, the slow cooling mode of the filtrate is program cooling, and preferably, the cooling rate is 0.5 ℃/min.
In a third aspect, the present invention provides a pharmaceutical composition comprising a tegafur-1, 2-bis (4-pyridyl) etheno-cocrystal as described herein and other pharmaceutically acceptable ingredients.
Preferably, the other pharmaceutically acceptable components include other active ingredients, excipients, fillers, etc. that may be used in combination.
Preferably, the pharmaceutical composition of the present invention can be prepared using the following method: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare useful dosage forms.
Preferably, the pharmaceutical composition is a spray, a tablet, a capsule, a powder injection, a liquid injection and the like.
In a fourth aspect, the invention provides an application of tegafur-1, 2-di (4-pyridyl) ethylene eutectic serving as an active ingredient in preparation of an anti-tumor medicament.
Confirmation of the Crystal Structure
X-ray crystal data were collected on a Japan XtaLAB Synergy model instrument, the temperature was measured at 293(2) K, the data were collected by radiation with CuKa in an omega scan fashion and performedLAnd (4) p correction. 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.
Testing and analyzing the crystallographic data of the Tegafur crystal prepared by the inventionThe crystallographic parameters are (Table 1): triclinic system, chiral space group is P-1; the unit cell parameters are: a =5.1391(4), b =9.7392(7), c =13.9658(10) a, α =96.008(6) a °, β =92.368(7) a °, γ =103.481(7) a °, unit cell volume V =674.44(9) a3. The molecular formula is: c20H 19FN 4O 3The molecular weight is: 382.28. the stacking diagram of the tegafur-1, 2-di (4-pyridyl) ethene eutectic of the invention is shown in attached figure 3. The ORTEP diagram (figure 4) of the tegafur-1, 2-bis (4-pyridyl) ethylene eutectic of the invention shows that the eutectic of the invention is formed by combining one molecule of active pharmaceutical ingredient tegafur with one molecule of eutectic ligand 1, 2-bis (4-pyridyl) ethylene under the action of N-H … N hydrogen bond.
The X-ray powder diffraction test instrument and the test conditions of the invention are as follows: x-ray powder diffractometer PANalytical E; Cu-K alpha; a sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40 mA; a diverging slot 1/4; an anti-scatter slit 1; 0.04 rad of cable pull slit; step length: 0.5 s; scanning range: 3 to 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.
The samples prepared by the scheme of the invention have the same crystallographic parameters and X-ray powder diffraction spectrogram.
The TGA/DSC thermal analysis tester and the test conditions in the invention are as follows: TGA/DSC thermogram METTLER TOLEDO TGA/DSC3 +; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/min; segment gas N2(ii) a Gas flow rate: 50 mL/min; crucible: an aluminum crucible of 40. mu.l.
The DSC/TGA spectrum result of the tegafur-1, 2-di (4-pyridyl) ethylene eutectic prepared by the method is shown in figure 2, a Differential Scanning Calorimetry (DSC) curve only has one endothermic peak, the temperature range is 133.55-153.13 ℃, and the peak value is 142.73 ℃.
The invention provides a novel tegafur-1, 2-di (4-pyridyl) ethylene eutectic which has determined crystallography main parameters and exact atom space positions; the preparation method of the eutectic crystal provided by the invention is simple to operate, and the prepared crystal has high yield and purity; the tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal has good stability and higher solubility and dissolution rate, can further increase the bioavailability of tegafur, improves the drug effect, and is suitable for large-scale popularization and application.
Figure 1X-ray powder diffraction pattern of tegafur co-crystal.
FIG. 2 is a Differential Scanning Calorimetry (DSC) curve and a thermal analysis (TGA) curve of a tegafur eutectic.
FIG. 3 is a single crystal diffraction stacking diagram of a tegafur eutectic.
Figure 4 ORTEP of tegafur co-crystal.
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.
Tegafur raw materials (beta crystal form, purity 99.91%) and 1, 2-di (4-pyridyl) ethylene used in the experiment of the invention are all commercial products, and the tegafur-isonicotinamide eutectic crystal is prepared according to the method disclosed in patent CN104496972A in example 1.
Examples
1
Adding tegafur (2.02 g) and 1, 2-di (4-pyridyl) ethylene (2.01 g) into methanol (200 ml), heating and stirring at 40 ℃ for dissolving, continuing to keep at 40 ℃ for reacting for 1 hour, finishing the reaction, filtering, and cooling the filtrate to room temperature at the speed of 0.5 ℃/min; putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking, volatilizing, crystallizing for 1 day, filtering, and drying under reduced pressure to obtain the tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal with the yield of 95 percent and the purity: 99.94 percent.
Examples
2
Adding tegafur (2.04 g) and 1, 2-di (4-pyridyl) ethylene (1.82 g) into methanol (200 ml), heating and stirring at 40 ℃ for dissolving, continuing to keep at 40 ℃ for reacting for 1 hour, finishing the reaction, filtering, and cooling the filtrate to room temperature at the speed of 0.5 ℃/min; putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking, volatilizing, crystallizing for 1 day, filtering, and drying under reduced pressure to obtain the tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal with the yield of 87 percent and the purity: 99.86 percent.
Examples
3:
Adding tegafur (2.05 g) and 1, 2-bis (4-pyridyl) ethylene (2.73 g) into methanol (240 ml), heating and stirring at 40 ℃ for dissolving, continuing to keep at 40 ℃ for reacting for 1 hour, finishing the reaction, filtering, and cooling the filtrate to room temperature at the speed of 0.5 ℃/min; putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking, volatilizing, crystallizing for 1 day, filtering, and drying under reduced pressure to obtain the tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal with the yield of 90 percent and the purity: 99.88 percent.
Examples
4
Adding tegafur (2.03 g) and 1, 2-di (4-pyridyl) ethylene (2.01 g) into acetone (160 ml), heating and stirring at 30 ℃ for dissolving, continuing to keep at 30 ℃ for reacting for 1 hour, finishing the reaction, filtering, and cooling the filtrate to room temperature at the speed of 0.5 ℃/min; putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking, volatilizing, crystallizing for 1 day, filtering, and drying under reduced pressure to obtain the tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal with the yield of 92 percent and the purity: 99.91 percent.
Examples
5
Adding tegafur (2.02 g) and 1, 2-bis (4-pyridyl) ethylene (2.02 g) into ethanol (220 ml), heating at 45 ℃, stirring, dissolving, keeping the temperature of 45 ℃ for reacting for 2 hours, filtering after the reaction is finished, and cooling the filtrate to room temperature at the speed of 0.5 ℃/min; putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking, volatilizing, crystallizing for 2 days, filtering, and drying under reduced pressure to obtain the tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal with the yield of 91 percent and the purity: 99.92 percent.
Examples
6
Adding tegafur (2.04 g) and 1, 2-bis (4-pyridyl) ethylene (2.03 g) into acetonitrile (240 ml), heating and stirring at 50 ℃ to dissolve, continuing to keep at 50 ℃ for reacting for 3 hours, finishing the reaction, filtering, and cooling the filtrate to room temperature at the speed of 0.5 ℃/min; putting the filtrate in a beaker, sealing the opening of the beaker by a sealing film, pricking, volatilizing, crystallizing for 3 days, filtering, and drying under reduced pressure to obtain the tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal with the yield of 89 percent and the purity: 99.90 percent.
Stability test
The specific stability test method is performed according to the guidance method for stability test specified in the fourth part of the chinese pharmacopoeia 2015 edition, and the specific experimental conditions and results are shown in table 3.
The experimental result shows that the purity and the appearance of the prepared tegafur-1, 2-di (4-pyridyl) ethylene eutectic are not obviously changed under the conditions of illumination, high temperature and high humidity, and the tegafur-1, 2-di (4-pyridyl) ethylene eutectic shows better stability; the purity of the beta crystal form and the tegafur-isonicotinamide eutectic crystal in the prior art is relatively greatly reduced under the same experimental conditions, and the impurity content of the beta crystal form and the tegafur-isonicotinamide eutectic crystal is obviously increased. Examples 1-6 of the present invention have similar stability test results.
Solubility test
The solubility test method specifically comprises the following steps: respectively measuring 10ml of media (water, 0.01mol/L HCl solution and phosphate buffer solution with pH = 6.8) into a penicillin bottle, adding an excessive sample to be detected, sealing the penicillin bottle, placing the penicillin bottle in a constant-temperature water bath at 25 ℃, stirring for 1 hour, filtering through a 0.45-micrometer filter membrane, and taking filtrate; the absorbance was measured at a wavelength of 271nm, and the solubility was calculated by measuring the absorbance of the standard control by HPLC, and the results are shown in Table 4.
The solubility test result shows that the solubility of the tegafur-1, 2-di (4-pyridyl) ethylene eutectic is obviously superior to that of a tegafur beta crystal form and a tegafur-isonicotinamide eutectic. Examples 1 to 6 of the present invention have similar solubility test results.
Dissolution Rate test
The experiment was carried out in a VK7010 (Warran, USA) dissolution apparatus equipped with a heated circulator for VK750D, approximately 500mg of the sample being compressed into 0.5cm2The disk of (1) was subjected to a 5-ton hydraulic press for 5 minutes by using an electric rotary disk inner die-casting method approved by the United states pharmacopoeia. Only one side of the disk was exposed to the vehicle throughout the experiment, and the surface of the disk was constant. This sample was placed in a tank containing 900mL of phosphate buffer (pH 6.8), preheated at 37 ℃ and stirred at 50 rpm. At regular intervals, 2 mL samples were manually withdrawn. The collected samples were filtered through a 0.4 μm nylon membrane and analyzed for calibration curves for each product using HPLC. Absorbance was measured at a wavelength of 271nm in phosphate buffer PH = 6.8.
As can be seen from dissolution rate test experiments, compared with tegafur beta crystal form and tegafur-isonicotinamide eutectic crystal disclosed in the prior art, the tegafur-1, 2-bis (4-pyridyl) ethylene eutectic crystal prepared by the invention is dissolved out quickly. The inventive examples 1-6 have similar dissolution rate test results.
In conclusion, the tegafur-1, 2-di (4-pyridyl) ethylene eutectic provided by the invention effectively improves the physicochemical property of tegafur, and provides possibility for reducing the toxic and side effects of tegafur and improving the biological activity of tegafur.
Claims (10)
- A tegafur co-crystal is characterized in that the co-crystal is composed of an active pharmaceutical ingredient tegafur and a co-crystal ligand 1, 2-bis (4-pyridyl) ethene.
- The tegafur eutectic of claim 1, wherein said eutectic basic unit consists of one tegafur molecule and one 1, 2-bis (4-pyridyl) ethylene molecule, and the crystallographic parameters are: triclinic system, chiral space group is P-1; the unit cell parameters are: a =5.1391(4), b =9.7392(7), c =13.9658(10) a, α =96.008(6) a °, β =92.368(7) a °, γ =103.481(7) a °, unit cell volume V =674.44(9) a3The structure is as follows:。
- the tegafur eutectic of claim 1, wherein the eutectic has characteristic peaks at 6.26 ± 0.2 °, 9.30 ± 0.2 °, 11.89 ± 0.2 °, 12.60 ± 0.2 °, 14.79 ± 0.2 °, 20.28 ± 0.2 °, 23.98 ± 0.2 ° in an X-ray diffraction pattern expressed in terms of 2 Θ, using Cu-ka radiation.
- The tegafur eutectic of claim 1, wherein the eutectic has characteristic peaks at 6.26 ± 0.2 °, 9.30 ± 0.2 °, 10.59 ± 0.2 °, 11.89 ± 0.2 °, 12.60 ± 0.2 °, 14.79 ± 0.2 °, 18.74 ± 0.2 °, 19.14 ± 0.2 °, 20.28 ± 0.2 °, 21.39 ± 0.2 °, 22.32 ± 0.2 °, 23.98 ± 0.2 °, 26.43 ± 0.2 ° in an X-ray diffraction pattern expressed in terms of 2 Θ using Cu-ka radiation.
- The tegafur co-crystal of claim 1, wherein the co-crystal has an X-ray powder diffraction pattern as shown in fig. 1.
- A method for preparing the tegafur eutectic of any one of claims 1 to 5, characterized in that the method comprises the steps of: adding tegafur and 1, 2-di (4-pyridyl) ethylene into an organic solvent A, heating, stirring, dissolving, continuing to perform heat preservation reaction, finishing the reaction, filtering, volatilizing and crystallizing the filtrate, filtering, and drying to obtain the tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal.
- The preparation method of tegafur eutectic crystal according to claim 6, wherein the feed molar ratio of tegafur to 1, 2-bis (4-pyridyl) ethylene is 1:1 to 1.5.
- The preparation method of tegafur eutectic crystal according to claim 6, characterized in that the organic solvent A is one or two of acetonitrile, acetone, methanol and ethanol; the mass volume ratio of the tegafur to the organic solvent A is 1: 80-120 g/ml.
- The preparation method of tegafur eutectic crystal according to claim 6, characterized in that the heating dissolution temperature is 30-50 ℃; the heat preservation reaction temperature is 30-50 ℃.
- Use of the tegafur co-crystal according to any one of claims 1 to 5 as an active ingredient for the preparation of an antitumor medicament.
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| CN (1) | CN114502550B (en) |
| WO (1) | WO2021072771A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159746A (en) * | 2011-12-12 | 2013-06-19 | 山东新时代药业有限公司 | Industrial tegafur synthesizing method |
| CN104496972A (en) * | 2014-12-04 | 2015-04-08 | 浙江大学 | Novel pharmaceutical tegafur co-crystal and preparation method thereof |
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2019
- 2019-10-18 CN CN201980042572.7A patent/CN114502550B/en active Active
- 2019-10-18 WO PCT/CN2019/112026 patent/WO2021072771A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159746A (en) * | 2011-12-12 | 2013-06-19 | 山东新时代药业有限公司 | Industrial tegafur synthesizing method |
| CN104496972A (en) * | 2014-12-04 | 2015-04-08 | 浙江大学 | Novel pharmaceutical tegafur co-crystal and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| PIOTR CYSEWSKI: "Transferability of cocrystallization propensities between aromatic and heteroaromatic amides", 《STRUCT CHEM》 * |
| SRINIVASULU AITIPAMULA等: "Crystal Engineering of Tegafur Cocrystals: Structural Analysis and Physicochemical Properties", 《CRYST.GROWTH DES.》 * |
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| CN114502550B (en) | 2023-11-14 |
| WO2021072771A1 (en) | 2021-04-22 |
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