CN110790712A - Eutectic crystal of 5-fluorouracil and L-phenylalanine and preparation method thereof - Google Patents
Eutectic crystal of 5-fluorouracil and L-phenylalanine and preparation method thereof Download PDFInfo
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
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- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
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Abstract
The invention discloses a pharmaceutical co-crystal of 5-fluorouracil and L-phenylalanine and a preparation method thereof, and relates to the field of pharmaceutical co-crystals. The composition of the 5-fluorouracil-phenylalanine eutectic is [ C4H3FN2O2·C9H11NO2]The basic structural unit is formed by a 5-fluorouracil molecule and an L-phenylalanine molecule. The eutectic crystal belongs to an orthorhombic system and has a space group ofP212121. 5-fluorouracil and L-phenylalanine are used as raw materials, and a solvent volatilization method and a cooling method are adopted to prepare the pharmaceutical co-crystal. The pharmaceutical co-crystal improves the solubility of 5-fluorouracil, and lays a foundation for improving the bioavailability and the drug effect of the pharmaceutical co-crystal. The preparation method of the pharmaceutical cocrystal is simple and easy, low in cost and convenientIs widely popularized in industrial pharmacy.
Description
Technical Field
The invention relates to the field of pharmaceutical co-crystals, in particular to a pharmaceutical co-crystal of 5-fluorouracil and L-phenylalanine and a preparation method thereof.
Background
5-fluorouracil is a common clinical antitumor drug, is mainly used for treating cancers such as skin cancer, gastrointestinal tumor, liver cancer, breast cancer and the like, and is a first-choice chemotherapeutic drug for colon cancer. However, 5-fluorouracil has poor permeability and water solubility, resulting in low bioavailability, and thus the application of 5-fluorouracil in the medical field is limited. Therefore, improvement of the physicochemical properties of 5-fluorouracil is an important subject. At present, researchers at home and abroad try a plurality of methods including pharmacological methods, chemical structure modification and the like. Although these methods have made some progress in improving the physicochemical properties of 5-fluorouracil, practical application thereof is limited due to problems of complicated process, high cost, and the like. Therefore, it is of great practical significance to find a simple method for improving the physicochemical properties and improving the bioavailability.
The pharmaceutical co-crystal is a solid pharmaceutical form which is formed by combining a pharmaceutical active ingredient (API) and a co-crystal former (CCF) together according to a certain stoichiometric ratio through non-covalent interactions such as hydrogen bonds and the like. At present, the research of pharmaceutical co-crystals becomes an effective method for realizing the improvement of the physicochemical properties of the API without changing the covalent structure and the pharmacological behavior of the drug molecules. The drug cocrystal not only enlarges the variety and the number of the drug crystal forms by introducing CCF to regulate the crystal structure of the drug, but also forms a new solid form with the drug by selecting the physiologically acceptable CCF, which is beneficial to enhancing the drug effect of the drug, reducing the toxic and side effects and improving the physicochemical property of the drug. In the aspect of CCF selection, the zwitterionic amino acid is used As a pharmacologically acceptable GRAS (generally recognized As safe) substance, and has the advantages of safety, no toxicity, good water solubility, good biocompatibility and the like. Therefore, certain amino acids as CCF have been successfully applied to research and development of eutectic drugs, and a new way for applying the amino acids in the pharmaceutical field is opened up. Based on the background, the invention aims to realize the cocrystallization of L-phenylalanine and 5-fluorouracil by using L-phenylalanine which is necessary for human bodies as CCF through a cocrystallization technology. Structurally, amino and carboxyl in L-phenylalanine molecules can be used as hydrogen bond donors and acceptors, can form a new drug eutectic with potential hydrogen bond sites such as amide groups of 5-fluorouracil through molecular recognition and supermolecule self-assembly, and the L-phenylalanine has zwitterion characteristics and can form a more stable zwitterion eutectic with the 5-fluorouracil through charge-assisted hydrogen bonds; in addition, the L-phenylalanine is a hydrophobic amino acid with good water solubility, and is favorable for simultaneously improving the water solubility and the permeability of 5-fluorouracil after being eutectic with the 5-fluorouracil; more particularly, a large number of researches find that the L-phenylalanine plays a very important role in the growth process of tumor cells, can be used as a carrier of an anti-tumor medicament, introduces medicament molecules into a tumor region, and enhances the targeting property of the medicament. Based on the reasons, the invention adopts the co-crystallization technology to co-crystallize 5-fluorouracil and L-phenylalanine, and successfully prepares the 5-fluorouracil-phenylalanine eutectic; the advantages of good biocompatibility, water solubility and permeability of the L-phenylalanine are exerted, and the physicochemical property of the 5-fluorouracil is expected to be improved on the premise of not changing the covalent structure of the 5-fluorouracil drug, so that a foundation is laid for improving the bioavailability of the 5-fluorouracil.
Disclosure of Invention
The invention aims to provide a 5-fluorouracil-phenylalanine eutectic crystal and a preparation method thereof, and the structure of the eutectic crystal is characterized, and the solubility of the eutectic crystal is tested.
The molecular formula of the 5-fluorouracil-phenylalanine eutectic is [ C4H3N2O2F·C9H11NO2]The basic structural unit is formed by a 5-fluorouracil molecule and an L-phenylalanine molecule, the 5-fluorouracil-phenylalanine eutectic is an orthorhombic system, and the space group isP2 12121The unit cell parameters are a = 6.80-7.20 Å, b = 12.19-12.59 Å, c = 14.93-15.33 Å =90.00 °, β = 91.323 °, γ =90.00 °, the PXRD characteristic diffraction peak appears at 13.918 ° ± 0.2 °, 15.438 ° ± 0.2 °, 18.663 ° ± 0.2 °, 19.098 ° ± 0.2 °, 19.982 ° ± 0.2 °, 25.398 ° ± 0.2 °, 27.063 ° ± 0.2 °, or the PXRD characteristic diffraction peak appears at 13.918 ° ± 0.1 °, 15.438 ° ± 0.1 °, 18.663 ° ± 0.1 °, 19.098 ° ± 0.1 °, 19.982 ° ± 0.1 °, 25.398 ° ± 0.1 °, 27.063 ° ± 0.1 °Now 13.918 °, 15.438 °, 18.663 °, 19.098 °, 19.982 °, 25.398 °, 27.063 °.
The preparation method of the 5-fluorouracil-phenylalanine eutectic crystal is realized according to the following steps:
mixing the 5-fluorouracil bulk drug and L-phenylalanine, adding 95% ethanol, stirring, filtering, standing the filtrate to separate out a solid phase substance, collecting the solid phase substance, and drying in vacuum to obtain the 5-fluorouracil-phenylalanine pharmaceutical co-crystal.
Further, the preparation method of the 5-fluorouracil-phenylalanine eutectic crystal is realized according to the following steps:
placing 5-fluorouracil bulk drug and L-phenylalanine in a round-bottom flask according to a molar ratio of 1:1, adding 95% ethanol to completely dissolve the mixture powder, stirring for 4-6 h, filtering, placing the filtrate for 2-5 days, collecting a solid phase, and drying in vacuum to obtain the 5-fluorouracil-phenylalanine eutectic crystal.
The preparation method of the 5-fluorouracil-phenylalanine eutectic crystal is realized according to the following steps:
mixing a 5-fluorouracil bulk drug and L-phenylalanine according to a molar ratio of 1:1, adding 95% ethanol, heating in a water bath to 70 ℃, stirring for 2-3 h, filtering while hot, standing the filtrate, cooling to room temperature, separating out a solid phase, and drying in vacuum to obtain the 5-fluorouracil-phenylalanine eutectic crystal.
The invention relates to a preparation method of a 5-fluorouracil-phenylalanine eutectic, which selects 5-fluorouracil bulk drug and L-phenylalanine as initial components, adopts a solvent volatilization method and a cooling method to prepare the high-purity eutectic, and carries out X-ray single crystal diffraction, TG-DSC, PXRD and other related characterization and dissolution rate determination on a eutectic sample. The result shows that the molecular formula of the 5-fluorouracil-phenylalanine eutectic is [ C4H3N2O2F·C9H11NO2]The prepared pharmaceutical co-crystal has high purity and crystallinity, can be kept stable for a long time without deterioration, and has larger dissolution rate.
The invention adopts a cooling method and a solvent volatilization method to prepare the 5-fluorouracil-phenylalanine eutectic crystal. The preparation method of the eutectic is simple in process, mild in reaction conditions, high in yield and purity, low in cost and suitable for large-scale production.
Drawings
FIG. 1 is a molecular structure diagram of the 5-fluorouracil-phenylalanine eutectic of the present invention.
FIG. 2 is a diagram of a two-dimensional hydrogen bonding mode of the 5-fluorouracil-phenylalanine eutectic of the present invention.
FIG. 3 is a three-dimensional supramolecular stacking diagram of the 5-fluorouracil-phenylalanine eutectic disclosed by the invention.
FIG. 4 is a comparison graph of PXRD spectra of 5-fluorouracil and L-phenylalanine raw materials and 5-fluorouracil-phenylalanine eutectic obtained in example two.
FIG. 5 is a comparison of the simulated PXRD spectrum of the software and the PXRD spectrum of the 5-fluorouracil-phenylalanine co-crystal obtained in example two.
FIG. 6 is a TG-DSC curve of the 5-fluorouracil-phenylalanine cocrystal obtained in example two.
FIG. 7 is a comparison of dissolution rates of 5-fluorouracil-phenylalanine co-crystals and 5-fluorouracil bulk drug in buffer solutions.
Detailed Description
The first embodiment is as follows: the molecular formula of the 5-fluorouracil-phenylalanine eutectic in this embodiment is [ C ]4H3N2O2F·C9H11NO2]The basic structural unit is formed by a 5-fluorouracil molecule and an L-phenylalanine molecule, the 5-fluorouracil-phenylalanine eutectic belongs to an orthorhombic system, and the space group isP2 12121The unit cell parameters are a = 7.0087 Å, b =12.3981 Å, c = 15.1304 Å =90.00 °, β =90.00 °, γ =90.00 °, PXRD characteristic diffraction peaks thereof occur at 13.918 °, 15.438 °, 18.663 °, 19.098 °, 19.982 °, 25.398 °, 27.063 °.
The 5-fluorouracil-phenylalanine eutectic according to the embodiment is formed by combining a 5-fluorouracil molecule and an L-phenylalanine molecule through supramolecular actions such as hydrogen bonds. As shown in figure 1, the co-crystal is 5-fluorouracil andl-phenylalanine is a simple 1:1 complex, the proton of phenylalanine being located on the amino group. Formation of an R between 5-fluorouracil and phenylalanine2 2(9) Cyclic hydrogen bonds. As shown in FIG. 2, the remaining amide of 5-fluorouracil (N1) is bonded to two carboxyl O atoms of another phenylalanine [ O3 ]i, O4i, (i) 1-x, y+0.5, 0.5-z]By hydrogen bonding, further forming a bond withbAs shown in FIG. 3, 2 helices with parallel axes are present in the crystal, 5-fluorouracil and phenylalanine hydrophilic groups (amino, carboxyl) are located inside the helices, and hydrophobic benzene rings are located on both sides, the 2 helices formed by L-phenylalanine are somewhat similar to peptide chains but are formed by hydrogen bonds between amino groups and carboxyl groups instead of peptide bonds, hydrophobic benzene rings parallel to the a axis are also located on both sides, a 5-fluorouracil molecule is inserted between adjacent benzene rings, and aromatic ring stacking is produced, the distance between the center of the benzene ring and the pyrimidine ring of 5-fluorouracil located at the symmetrical position of 0.5-x, 1-y, z +0.5 (vi) is 3.650(13) Å, the dihedral angle is 10.53(11), and the atoms C1 overlapping each other is C1vi, N2viThe perpendicular distances of C12 and C13 from the opposite aromatic ring are 3.395(3), 3.458(2), 3.310(3) and 3.235(3) Å, respectively, meanwhile, the 5-fluorouracil molecule connects two L-phenylalanine helical chains adjacent in the C-axis direction with hydrogen bonds using amide groups and fluorine atoms.
The second embodiment is as follows: the preparation method of the 5-fluorouracil-phenylalanine eutectic crystal according to the embodiment is implemented according to the following steps:
placing 5-fluorouracil bulk drug and L-phenylalanine in a round-bottom flask according to a molar ratio of 1:1, adding 95% ethanol into the mixed powder, stirring for 4-6 h, filtering, placing the filtrate for 2-5 days, collecting a solid phase, and drying in vacuum to obtain the 5-fluorouracil-phenylalanine eutectic crystal.
The third concrete implementation mode: the difference between the present embodiment and the second embodiment is that the solid-to-liquid ratio of the mixture powder to the solvent in the system is 100 mg (20-27) mL. Other steps and parameters are the same as those in the second embodiment.
The fourth concrete implementation mode: the second difference between this embodiment and the second embodiment is that the reaction system is left for 4 days and then the solid phase is collected. Other steps and parameters are the same as those in the second embodiment.
The fifth concrete implementation mode: the preparation method of the 5-fluorouracil-phenylalanine eutectic crystal according to the embodiment is implemented according to the following steps:
mixing the 5-fluorouracil bulk drug and L-phenylalanine in a molar ratio of 1:1, placing the mixture in a round-bottom flask, adding 95% ethanol, heating the mixture in a water bath to 70 ℃, stirring the mixture for 2-4 hours, filtering the mixture while the mixture is hot, standing the filtrate, cooling the filtrate to room temperature, separating out a solid phase substance, collecting the solid phase substance, and drying the solid phase substance in vacuum to obtain the 5-fluorouracil-phenylalanine eutectic crystal.
The embodiment and the second specific embodiment prepare the 5-fluorouracil-phenylalanine eutectic with good chemical stability, high purity and high yield.
The sixth specific implementation mode: the difference between the present embodiment and the fifth embodiment is that the solid-to-liquid ratio of the mixed powder to the solvent is 100 mg (13-20) mL. The other steps and parameters are the same as those in the fifth embodiment.
The first embodiment is as follows: the preparation method of the 5-fluorouracil-phenylalanine eutectic is implemented according to the following steps:
mixing 39.0 mg of 5-fluorouracil bulk drug and 49.5 mg of L-phenylalanine according to a molar ratio of 1:1, placing the mixture in a round-bottom flask, adding 22 mL of 95% ethanol, stirring at room temperature for 5 h, filtering, standing the filtrate for 4 days, collecting a solid phase substance, and drying in vacuum to obtain the 5-fluorouracil-phenylalanine eutectic crystal.
In the embodiment, the 5-fluorouracil-phenylalanine eutectic prepared by a solvent volatilization method is a colorless rod-shaped crystal, and a single crystal sample is selected from the colorless rod-shaped crystal for X-ray single crystal diffraction measurement, so that the accurate structure of the crystal is analyzed.
A single crystal sample with proper diffraction quality is selected from the 5-fluorouracil-phenylalanine eutectic crystal prepared by the solvent volatilization method in the embodiment, and X-ray single crystal diffraction measurement is carried out, an Xcalibur Eos diffractometer of the American Agilent company is adopted, and Cu-K α ray scanning monochromatized by a graphite monochromator is adopted, wherein the mode is omega scanning, and omega scanning is setThe current and voltage required for the diffraction experiments were 40 mA and 50 kV. The results show that the molecular formula of the 5-fluorouracil-phenylalanine eutectic in the example is [ C ]4H3N2O2F·C9H11NO2]The 5-fluorouracil-phenylalanine eutectic crystal is characterized in that a 5-fluorouracil molecule and an L-phenylalanine molecule are combined together through non-covalent bond interaction such as hydrogen bond to form a basic structural unit, the 5-fluorouracil-phenylalanine eutectic crystal belongs to an orthorhombic system, and the space group isP2 12121The unit cell parameters are a = 7.0087 Å, b =12.3981 Å, c = 15.1304 Å =90.00 °, β =90.00 °, γ =90.00 °.
Example two: the preparation method of the 5-fluorouracil-phenylalanine eutectic is implemented according to the following steps:
putting 390 mg of 5-fluorouracil bulk drug and 495 mg of L-phenylalanine into a flask according to the molar ratio of 1:1, adding 140 mL of 95% ethanol, stirring and heating to 70 ℃, stirring for 3 h, filtering while hot, standing the filtrate, cooling to room temperature, separating out a solid phase, collecting the solid phase, and drying in vacuum to obtain 812.5 mg of 5-fluorouracil-phenylalanine eutectic.
In this example, the molecular formula of the 5-fluorouracil-phenylalanine eutectic prepared by the cooling method is [ C4H3N2O2F·C9H11NO2]The yield is 91.8%, the eutectic crystal has good chemical stability, can still maintain the framework structure of the crystal after being placed for a long time at room temperature, and has no deterioration phenomenon.
Purity determination of 5-fluorouracil-phenylalanine eutectic:
PXRD diffraction experiments are carried out on the powder samples obtained by the cooling method in the second embodiment, PXRD diffraction data are measured on a D8 type X-ray diffractometer of BRUKER company in Germany, the test conditions are that the tube voltage of a Cu-K α target is 40 kV, the tube current is 10 mA, and the scanning speed is 2 DEG/min, as shown in figure 4, the characteristic diffraction peak position and the diffraction intensity of the obtained 5-fluorouracil-phenylalanine eutectic crystal are obviously changed by comparing with the raw material, which indicates that a new phase is generated.
In order to further determine the phase and purity of the 5-fluorouracil-phenylalanine eutectic obtained by the cooling method, in this example, the PXRD spectrogram of the measured 5-fluorouracil-phenylalanine eutectic sample is compared with the theoretical spectrogram of the 5-fluorouracil-phenylalanine eutectic simulated by Mercury software according to crystal data obtained by an X-ray single crystal diffraction test. As shown in figure 5, PXRD characteristic diffraction peaks appear at 13.918 degrees, 15.438 degrees, 18.663 degrees, 19.098 degrees, 19.982 degrees, 25.398 degrees and 27.063 degrees, and powder diffraction peaks are sharp and are matched with diffraction peaks of a theoretical simulation spectrogram of a 5-fluorouracil-phenylalanine eutectic sample, so that the prepared 5-fluorouracil-phenylalanine eutectic has high crystallinity and purity. On the basis, the 5-fluorouracil-phenylalanine eutectic obtained in example two was subjected to thermal analysis by using a Netzsch STA 409PC synchronous thermal analyzer, and the thermogravimetry-differential scanning calorimetry (TG-DSC) thereof is shown in fig. 6. As can be seen from the figure, a sharp endothermic peak appears at 257.1 ℃, which corresponds to the melting point of the 5-fluorouracil-phenylalanine eutectic, and the obtained eutectic can be concluded to be a homogeneous phase; in addition, no weight loss behavior of water was observed with the TG curve, demonstrating that the co-crystal is anhydrous, consistent with the X-ray single crystal diffraction results.
Intrinsic Dissolution Rate (IDR) determination of 5-fluorouracil-phenylalanine co-crystals:
IDRs of a 5-fluorouracil-phenylalanine eutectic sample and a 5-fluorouracil bulk drug are respectively determined in a phosphate buffer medium with pH = 7.4 by a Rotating disk method, and the result is shown in figure 7. As can be seen from the figure, IDR of the 5-fluorouracil-phenylalanine eutectic is improved by 2.18 times compared with 5-fluorouracil, which indicates that the pharmaceutical eutectic can improve the solubility of 5-fluorouracil, and the research result provides scientific basis for improving the bioavailability of 5-fluorouracil.
Claims (6)
1. A pharmaceutical co-crystal of 5-fluorouracil and L-phenylalanine (hereinafter referred to as 5-fluorouracil-phenylalanine co-crystal) is characterized in that the molecular formula of the pharmaceutical co-crystal is [ C4H3N2O2F·C9H11NO2]Consisting of a 5-fluorouracil molecule andone L-phenylalanine molecule constitutes the basic structural unit; the pharmaceutical co-crystal belongs to an orthorhombic system and has a space group ofP212121The unit cell parameters are a = 6.80-7.20 Å, b = 12.19-12.59 Å, c = 14.93-15.33 Å = β = gamma =90.00 degrees, and PXRD characteristic diffraction peaks of the unit cell diffraction pattern are appeared at 13.918 degrees +/-0.2 degrees, 15.438 degrees +/-0.2 degrees, 18.663 degrees +/-0.2 degrees, 19.098 degrees +/-0.2 degrees, 19.982 degrees +/-0.2 degrees, 25.398 degrees +/-0.2 degrees and 27.063 degrees +/-0.2 degrees.
2. The preparation method of the 5-fluorouracil-phenylalanine eutectic crystal as claimed in claim 1, characterized in that the preparation method of the eutectic crystal is realized by the following steps:
mixing the 5-fluorouracil bulk drug and L-phenylalanine, adding 95% ethanol, stirring, filtering, standing the filtrate to separate out a solid phase substance, collecting the solid phase substance, and drying in vacuum to obtain the 5-fluorouracil-phenylalanine eutectic crystal.
3. The preparation method of the 5-fluorouracil-phenylalanine pharmaceutical co-crystal as claimed in claim 1, characterized in that the preparation method of the co-crystal is realized by the following steps:
mixing a 5-fluorouracil bulk drug and L-phenylalanine according to a molar ratio of 1:1, placing the mixture in a round-bottom flask, adding 95% ethanol into the mixture powder, stirring for 4-6 h, filtering, placing the filtrate for 2-5 days, collecting a solid phase, and drying in vacuum to obtain the 5-fluorouracil-phenylalanine eutectic crystal.
4. The preparation method of the 5-fluorouracil-phenylalanine eutectic crystal according to claim 3, wherein the solid-to-liquid ratio of the mixture powder to the solvent in the system is 100 mg (20-27) mL.
5. The preparation method of the 5-fluorouracil-phenylalanine eutectic crystal as claimed in claim 1, characterized in that the preparation method of the eutectic crystal is realized by the following steps:
mixing a 5-fluorouracil bulk drug and L-phenylalanine according to a molar ratio of 1:1, adding 95% ethanol, heating and stirring in a 70 ℃ water bath for 2-3 h, filtering while hot, standing and cooling the filtrate to room temperature to separate out a solid phase, collecting the solid phase, and drying in vacuum to obtain the 5-fluorouracil-phenylalanine eutectic crystal.
6. The preparation method of the 5-fluorouracil-phenylalanine eutectic crystal according to claim 5, wherein the solid-to-liquid ratio of the mixture powder to the solvent in the system is 100 mg (13-20) mL.
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| CN110590678A (en) * | 2019-09-03 | 2019-12-20 | 中国海洋大学 | Preparation method and crystal structure of 5-fluorouracil phenformin salt |
| CN111440124A (en) * | 2020-04-27 | 2020-07-24 | 中国海洋大学 | Eutectic crystal of 5-fluorouracil and caffeic acid and preparation method thereof |
| CN113234028A (en) * | 2021-04-29 | 2021-08-10 | 上海大学 | 5-fluorouracil and sarcosine cocrystal and preparation method and application thereof |
| CN114105888A (en) * | 2020-08-25 | 2022-03-01 | 天津大学 | Eutectic crystal of propylthiouracil and small nutrient molecules with antioxidant activity and preparation method thereof |
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| CN109096207A (en) * | 2018-08-28 | 2018-12-28 | 中国海洋大学 | A kind of salt, preparation method and the crystal structure of 5 FU 5 fluorouracil and melbine |
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