CN112608273A - Two solvates of flunixin and carbamazepine eutectic and preparation method thereof - Google Patents
Two solvates of flunixin and carbamazepine eutectic and preparation method thereof Download PDFInfo
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- 239000012453 solvate Substances 0.000 title claims abstract description 88
- 229960000623 carbamazepine Drugs 0.000 title claims abstract description 82
- NOOCSNJCXJYGPE-UHFFFAOYSA-N flunixin Chemical compound C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O NOOCSNJCXJYGPE-UHFFFAOYSA-N 0.000 title claims abstract description 69
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 229960000588 flunixin Drugs 0.000 title claims abstract description 68
- 230000005496 eutectics Effects 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 104
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 94
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 6
- 239000013078 crystal Substances 0.000 claims description 79
- 239000003814 drug Substances 0.000 claims description 46
- 239000002904 solvent Substances 0.000 claims description 45
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- 238000000034 method Methods 0.000 claims description 12
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- 230000008569 process Effects 0.000 claims description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical group NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 2
- 230000036541 health Effects 0.000 claims description 2
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- 238000012512 characterization method Methods 0.000 description 4
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- 238000007789 sealing Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010026749 Mania Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 208000020442 loss of weight Diseases 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
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- 239000002994 raw material Substances 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
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- MGCCHNLNRBULBU-WZTVWXICSA-N flunixin meglumine Chemical group CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O MGCCHNLNRBULBU-WZTVWXICSA-N 0.000 description 1
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- 230000000698 schizophrenic effect Effects 0.000 description 1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
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Abstract
The invention discloses two solvates of Flunixin (FLX) and Carbamazepine (CBZ) eutectic and a preparation method thereof, wherein the eutectic formed by 1 flunixin molecule and 1 carbamazepine molecule, acetone and ethanol respectively form solvates, and a basic structural unit is formed through hydrogen bond action. A first solvate: an ethanol solvate. 0.5 ethanol molecules are contained in the void of one unit cell of the eutectic ethanol solvate; a second solvate: an acetone solvate. In the eutectic acetone solvate, flunixin and carbamazepine form a eutectic, and a unit cell contains an acetone molecule. The preparation method is simple and easy to implement and low in cost. The two solvates of the prepared flunixin and carbamazepine eutectic have definite structures, and the solubility of the two solvates of the flunixin and carbamazepine eutectic in water is obviously improved compared with that of flunixin.
Description
Technical Field
The invention belongs to the technical field of drug crystallization, and particularly relates to two solvates of a flunixin and carbamazepine eutectic and a preparation method thereof.
Background
The pharmaceutical active molecules and other physiologically safe organic small molecules can form pharmaceutical co-crystals through the supermolecular action. On the premise of not damaging the molecular structure of the drug, the formation of the eutectic can improve the physicochemical property and the drug forming property of the drug active molecule. Drug-drug co-crystals formed by combining two known pharmaceutically active molecules together are expected to exhibit superior therapeutic effects to a single drug. After two drug molecules with synergistic therapeutic effect are combined together, respective solubility performances of the two drug molecules can possibly obtain an optimal balance, and the therapeutic effect of the drug can be exerted to the maximum extent. The medicine eutectic has the unique characteristic that the medicine eutectic is different from simple combined medicine, but two solid-state medicines can cooperate with each other under the driving of the supermolecule action when passing through the digestive tract of a human body, and finally the optimal medicine absorption effect is realized. In addition, after two drug molecules form a eutectic, the defect of solid stability of a single drug can be overcome. The drug-drug cocrystal does not involve the change of molecular structure, has obvious novelty, applicability and definition, and is a unique drug crystal form.
Flunixin is a nonsteroidal antipyretic analgesic and anti-inflammatory drug and is widely applied as a veterinary drug. Research into the use of flunixin for the treatment of human diseases is also underway today. The medicine on the market at present is flunixin meglumine, and can obviously improve the treatment effect and enhance the activity of antibiotics when being used together with antibiotics.
Carbamazepine is a widely used drug for seizures and neuropathic pain. The clinical application proves that the medicine can also be used for preventing or treating mania and depression, has obvious therapeutic effect on both mania and depression, and can also relieve or eliminate symptoms of mania and delusion of schizophrenic patients. Meanwhile, the carbamazepine is a drug with various crystal forms, and can form a eutectic crystal with a plurality of pharmaceutically active molecules so as to improve the physicochemical properties of the drug. Carbamazepine is slightly soluble in water, soluble in ethanol and acetone, and readily soluble in methylene chloride.
In conclusion, the two medicinal active molecules of flunixin and carbamazepine form medicament-medicament eutectic through supermolecule action, and have important significance for developing the application of flunixin and carbamazepine in the aspects of antipyretic analgesia, epilepsy resistance and the like. There is no published report of the solvate of flunixin and carbamazepine forming a drug-drug co-crystal.
Disclosure of Invention
Based on the defects of the prior art, the technical problem solved by the invention is to provide two solvates of flunixin and carbamazepine eutectic, the preparation method is simple and easy, the crystal structure is clear, two drug molecules of flunixin and carbamazepine are simultaneously contained in the structure, and the solvent molecules are contained in a unit cell. The solubility of the acetone solvate of the pharmaceutical co-crystal in water was increased by two-fold relative to flunixin, but the solubility of carbamazepine was reduced by half.
In order to solve the technical problems, the invention provides a flunixin and carbamazepine eutectic solvate: the flunixin and carbamazepine eutectic solvate is formed by a eutectic formed by 1 flunixin molecule and 1 carbamazepine molecule, and forms a solvate with ethanol or acetone, and forms a basic structural unit through hydrogen bond action.
Preferably, the solvate of the flunixin and carbamazepine eutectic provided by the invention further comprises part or all of the following technical characteristics:
as an improvement of the technical scheme, when the solvent is ethanol, the eutectic and the ethanol form an ethanol solvate, and meanwhile, a crystal structure basic unit of the ethanol solvate comprises a flunixin molecule, a carbamazepine molecule and a half ethanol molecule. The space group of the eutectic ethanol solvate is a triclinic system,
space group, unit cell parameters are:
the shaft angle α is 86.770(4) °, β is 78.355(4) °, γ is 83.773(4) °,
Z＝2，Dc＝1.357g/cm3the molecular formula is [ C ]14H11F3N2O2]·[C15H12N2O]·0.5[C2H6O]。
As an improvement of the technical scheme, in the unit cell of the eutectic ethanol solvate, the carboxylic acid group on the pyridine ring of flunixin and the formamide group on the azacyclo of carbamazepine form an eight-membered ring through hydrogen bonding, and the hydrogen bonding forms O-H … O and O-H … N.
In the improvement of the technical scheme, when the solvent is acetone, the eutectic and the acetone form a solvate, and in the acetone solvate of the eutectic, the flunixin and the carbamazepine form the eutectic and a unit cell contains an acetone molecule. The space group of the acetone solvate of the eutectic is a triclinic system,
space group, unit cell parameters are:
the shaft angle α is 88.1940(12) °, β is 78.8928(12) °, γ is 84.5652(13) °,
Z＝2，Dc＝1.354g/cm3the molecular formula is [ C ]14H11F3N2O2]·[C15H12N2O]·[C3H6O]。
As an improvement of the technical scheme, the ethanol or the acetone and the flunixin and carbamazepine eutectic crystal form a solvate, the unit cell of the flunixin and carbamazepine eutectic crystal contains the ethanol or the acetone, and the solvate adjusts the solubility of the drug, so that the solubility of the eutectic crystal is increased, and the unit content of the drug in the preparation is improved.
A method of preparing a solvate of flunixin and carbamazepine co-crystal as defined in any one of the preceding claims, comprising the steps of:
(1) mixing a mixture of 1: 1, putting flunixin and carbamazepine in a crystallizer, and simultaneously adding an ethanol or acetone solvent;
(2) completely dissolving the solute;
(3) slowly volatilizing the solvent to finally separate out colorless blocky crystals;
(4) when the solvent is not completely volatilized and crystals are precipitated, taking out the crystals, and removing the solvent on the surfaces of the crystals to obtain the ethanol or acetone solvate of the flunixin carbamazepine eutectic.
As a preferred aspect of the above technical solution, the preparation method of the flunixin and carbamazepine eutectic solvate further includes some or all of the following technical features:
as an improvement of the technical scheme, when the solvent is ethanol, the total content of the solute in the system in the step (1) is 6-10%.
As an improvement of the technical scheme, in the step (2), the temperature of the system is raised to 50-60 ℃ until the solute is completely dissolved; and (3) slowly cooling the system to room temperature, slowly volatilizing the solvent, and finally separating out colorless blocky crystals.
The preparation method of the ethanol solvate of the flunixin and carbamazepine eutectic is a method combining solution cooling crystallization and natural volatilization, and comprises the following specific steps:
(1) mixing a mixture of 1: 1, putting flunixin and carbamazepine in a crystallizer, and simultaneously adding an ethanol solvent, wherein the total content of solutes in the system is 6-10%;
(2) heating the system to 50-60 ℃ until the solute is completely dissolved;
(3) slowly cooling the system, slowly volatilizing the solvent after cooling to room temperature, and finally separating out colorless blocky crystals;
(4) when the solvent is not completely volatilized and crystals are precipitated, the crystals are taken out, and the solvent on the surfaces of the crystals is removed to obtain the ethanol solvate of the flunixin carbamazepine eutectic.
As an improvement of the technical scheme, when the solvent is acetone, the total content of the solute in the system in the step (1) is 8-12%.
The preparation method of the acetone solvate of the flunixin and carbamazepine eutectic is a natural volatilization method and comprises the following specific steps:
(1) mixing a mixture of 1: 1, putting flunixin and carbamazepine in a crystallizer, and simultaneously adding an acetone solvent, wherein the total content of solute in the system is 8-12%;
(2) at normal temperature, solute is completely dissolved;
(3) the system slowly volatilizes the solvent, and colorless blocky crystals can be separated out in the volatilization process;
(4) when the solvent is not completely volatilized and crystals are precipitated, the crystals are taken out, the solvent on the surfaces of the crystals is removed, and the acetone solvate of the eutectic crystal of the flunixin and the carbamazepine is obtained.
Use of a solvate of flunixin co-crystal with carbamazepine as defined in any one of the preceding claims: application in preparing medicinal preparation or health product.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects: the preparation method is simple and easy to implement, the ethanol solvent used by the technology is cheap and easy to obtain, and the eutectic ethanol solvate can be quickly obtained by a heating-cooling crystallization method. The crystal structure is clear, the structure simultaneously comprises two drug molecules of flunixin and carbamazepine, and solvent molecules are contained in a unit cell. The solubility of the acetone solvate of the drug co-crystal in water was increased by a factor of two relative to flunixin. Thus, it is possible to achieve the effect of improving the solubility of a certain drug by the technique of co-crystallization.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical means of the present invention more clearly understood, the present invention may be implemented in accordance with the contents of the description, and in order to make the above and other objects, features, and advantages of the present invention more clearly understood, the following detailed description is given in conjunction with the preferred embodiments.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings of the embodiments will be briefly described below.
FIG. 1 is a block diagram of the unit cell structure of an ethanol solvate of a flunixin-carbamazepine pharmaceutical co-crystal prepared in accordance with one example;
FIG. 2 is a unit cell structure diagram of the acetone solvate of the flunixin-carbamazepine pharmaceutical co-crystal prepared in example three;
FIG. 3 is an X-ray powder diffraction (XRD) pattern of the ethanol solvate of the flunixin-carbamazepine pharmaceutical co-crystal prepared in example one;
FIG. 4 is an X-ray powder diffraction (XRD) pattern of the acetone solvate of the flunixin-carbamazepine drug co-crystal prepared in example three;
FIG. 5 is a graph of the ultraviolet absorption (UV) of the ethanol solvate of the flunixin-carbamazepine pharmaceutical co-crystal prepared in accordance with example one;
FIG. 6 is a graph of the ultraviolet absorption (UV) of the acetone solvate of the flunixin-carbamazepine pharmaceutical co-crystal prepared in example three;
FIG. 7 is a thermogravimetric analysis (TGA) of the ethanol solvate of the flunixin-carbamazepine drug co-crystal of example one prepared;
fig. 8 is a thermogravimetric analysis (TGA) of the acetone solvate of the flunixin-carbamazepine drug co-crystal prepared in example three.
Detailed Description
Other aspects, features and advantages of the present invention will become apparent from the following detailed description, which, when taken in conjunction with the drawings, illustrate by way of example the principles of the invention.
Example one
Cooling crystallization to prepare the ethanol solvate of the flunixin-carbamazepine eutectic:
(1) mixing a mixture of 1: 1, putting flunixin (200mg) and carbamazepine (159mg) into a crystallizer, and simultaneously adding 4mL of ethanol solvent, wherein the total content of solute in the initial system is 6-10 percent, so that the medicine is completely dissolved;
(2) heating the system to 55 ℃ until the solute is completely dissolved;
(3) slowly cooling the system, cooling to room temperature, standing overnight, and finally precipitating colorless blocky crystals;
(4) when the solvent is not completely volatilized and crystals are precipitated, the crystals are taken out, and the solvent on the surfaces of the crystals is removed by using a dry filter paper, so that the ethanol solvate of the eutectic crystal of flunixin and carbamazepine is obtained.
Assuming that the product spectrum in the figure is the characterization spectrum of this example, the following description is made, and the same characterization and analysis should be made for several examples below.
Fig. 1 is a unit cell structure diagram of an ethanol solvate of a flunixin-carbamazepine pharmaceutical co-crystal prepared in example one. It can be seen from the figure that in the unit cell, there is one molecule of ethanol between 2 molecules of flunixin and 2 molecules of carbamazepine, and a basic unit is formed by hydrogen bonding.
FIG. 3 is an X-ray powder diffraction (XRD) pattern of the ethanol solvate of the flunixin-carbamazepine pharmaceutical co-crystal prepared in example one, from which it can be seen that the X-ray powder diffraction pattern of the ethanol solvate, expressed as the diffraction angle 2 θ ° ± 0.1, is: characteristic diffraction peaks are arranged at 5.8 degrees, 7.4 degrees, 9.2 degrees, 9.6 degrees, 11.7 degrees, 12.0 degrees, 12.2 degrees, 13.5 degrees, 14.3 degrees, 15.0 degrees, 15.8 degrees, 16.1 degrees, 17.5 degrees, 17.6 degrees, 18.1 degrees, 18.4 degrees, 18.9 degrees, 19.4 degrees, 20.0 degrees, 20.4 degrees, 24.4 degrees, 22.4 degrees, 23.2 degrees, 23.6 degrees, 24.2 degrees, 24.5 degrees, 24.7 degrees, 24.9 degrees, 25.6 degrees, 25.8 degrees, 26.5 degrees, 27.1 degrees, 27.5 degrees, 28.4 degrees, 29.4 degrees, 29.6 degrees, 30.3 degrees, 30.8 degrees, 31.1 degrees, 31.3 degrees, 32.2 degrees and 32.9 degrees. Fig. 5 is a graph of the ultraviolet absorption (UV) of the ethanol solvate of the flunixin-carbamazepine drug co-crystal prepared in the examples, from which it can be seen that the co-crystal dissolves in water as a whole, rather than the two drugs it contains dissolving in water independently. Fig. 7 is a thermogravimetric analysis (TGA) plot of the ethanol solvate of the flunixin-carbamazepine drug co-crystal prepared in the example, from which it can be seen that the ethanol solvate began to lose solvent at 90 c, began to decompose with loss of weight at 170 c, had a melting decomposition peak at 173.3 c as measured by differential scanning calorimetry, and had a weaker absorption peak at 106 c.
Example two
Natural volatilization method for preparing flunixin-carbamazepine eutectic ethanol solvate
(1) Mixing a mixture of 1: 1, putting flunixin (200mg) and carbamazepine (159mg) in a glass bottle, and simultaneously adding 6mL of ethanol solvent, wherein the total content of solute in the initial system is 6-10 percent, so that the medicine is completely dissolved;
(2, sleeving a sealing film on the bottle, and leaving a plurality of small holes on the sealing film to allow the solvent to slowly volatilize at room temperature;
(3) after one week, colorless massive crystals are separated out;
(4) when the solvent is not completely volatilized and crystals are precipitated, the crystals are taken out, and the solvent on the surfaces of the crystals is removed by using a dry filter paper, so that the ethanol solvate of the eutectic crystal of flunixin and carbamazepine is obtained.
EXAMPLE III
Cooling crystallization to prepare the acetone solvate of the flunixin-carbamazepine eutectic:
(1) mixing a mixture of 1: 1, putting flunixin (200mg) and carbamazepine (159mg) in a crystallizer, and simultaneously adding 2mL of acetone solvent, wherein the total content of solute in an initial system is 6-10%, so that the medicine is completely dissolved;
(2) heating the system to 50 ℃ until the solute is completely dissolved;
(3) slowly cooling the system, cooling to room temperature, standing overnight, and finally precipitating colorless blocky crystals;
(4) when the solvent was not completely volatilized and crystals were precipitated, the crystals were taken out, and the solvent on the surface of the crystals was removed with a dry filter paper to obtain an acetone solvate of a cocrystal of flunixin and carbamazepine.
Assuming that the product spectrum in the figure is the characterization spectrum of this example, the following description is made, and the same characterization and analysis should be made for several examples below.
Fig. 2 is a unit cell structure diagram of the acetone solvate of the flunixin-carbamazepine pharmaceutical co-crystal prepared in example three. The flunixin forms a eutectic with carbamazepine, and a unit cell contains an acetone molecule.
FIG. 4 is an X-ray powder diffraction (XRD) pattern of the acetone solvate of the flunixin-carbamazepine pharmaceutical co-crystal prepared in example III, from which it can be seen that the X-ray powder diffraction pattern of the acetone solvate, expressed as the diffraction angle 2 θ ° ± 0.1, is: characteristic diffraction peaks are present at 5.8 °, 7.4 °, 9.4 °, 9.5 °, 11.5 °, 12.0 °, 12.2 °, 13.5 °, 13.7 °, 14.2 °, 14.9 °, 15.6 °, 16.1 °, 17.3 °, 17.5 °, 17.6 °, 18.1 °, 18.3 °, 19.0 °, 20.0 °, 21.0 °, 21.4 °, 22.0 °, 22.5 °, 23.0 °, 23.4 °, 23.5 °, 24.2 °, 24.3 °, 24.4 °, 24.6 °, 24.9 °, 25.4 °, 25.9 °, 26.8 °, 27.1 °, 28.3 °, 28.9 °, 29.5 °, 29.7 °, 30.2 °, 30.9 °, 31.6 °, 32.4 °, 32.6 °, 32.9 °. Fig. 6 is a graph of the ultraviolet absorption (UV) of the acetone solvate of the flunixin-carbamazepine drug co-crystal prepared in the examples, from which it can be seen that the co-crystal dissolves in water as a whole, rather than the two drugs it contains dissolving in water independently. Fig. 8 is a thermogravimetric analysis (TGA) of the acetone solvate of the flunixin-carbamazepine drug co-crystal prepared in the example, which began to lose solvent at 85 ℃, began to decompose with loss of weight at 170 ℃, and had a melting decomposition peak at 168.8 ℃ as measured by differential scanning calorimetry and a weaker absorption peak at 100 ℃.
Example four
Acetone solvate for preparing flunixin-carbamazepine eutectic by natural volatilization method
(1) Mixing a mixture of 1: 1, placing flunixin (200mg) and carbamazepine (159mg) in a glass bottle, and simultaneously adding 4mL of acetone solvent, wherein the total content of solutes in an initial system is 6-10%, so that the medicine is completely dissolved;
(2, sleeving a sealing film on the bottle, and leaving a plurality of small holes on the sealing film to allow the solvent to slowly volatilize at room temperature;
(3) after one day, colorless massive crystals are separated out;
(4) when the solvent was not completely volatilized and crystals were precipitated, the crystals were taken out, and the solvent on the surface of the crystals was removed with a dry filter paper to obtain an acetone solvate of a cocrystal of flunixin and carbamazepine.
The raw materials listed in the invention, the upper and lower limits and interval values of the raw materials of the invention, and the upper and lower limits and interval values of the process parameters (such as temperature, time and the like) can all realize the invention, and the examples are not listed.
While the foregoing is directed to the preferred embodiment of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.
Claims (10)
1. A flunixin and carbamazepine eutectic solvate, which is characterized in that: the flunixin and carbamazepine eutectic solvate is formed by a eutectic formed by 1 flunixin molecule and 1 carbamazepine molecule, forming a solvate with ethanol or acetone, and forming a basic structural unit through hydrogen bond action.
2. The solvate of flunixin with carbamazepine co-crystal of claim 1, characterized in that: when the solvent is ethanol, the eutectic and the ethanol form an ethanol solvate, and meanwhile, a crystal structure basic unit of the ethanol solvate comprises a flunixin molecule, a carbamazepine molecule and a half ethanol molecule; the space group of the eutectic ethanol solvate is a triclinic system,
space group, unit cell parameters are:
the shaft angle α is 86.770(4) °, β is 78.355(4) °, γ is 83.773(4) °,
Z＝2，Dc＝1.357g/cm3the molecular formula is [ C ]14H11F3N2O2]·[C15H12N2O]·0.5[C2H6O]。
3. The solvate of flunixin with carbamazepine cocrystal according to claim 2, characterized in that: in the unit cell of the eutectic ethanol solvate, the carboxylic acid group on the pyridine ring of flunixin and the formamide group on the azacyclo of carbamazepine form an eight-membered ring through hydrogen bonding in the forms of O-H … O and O-H … N.
4. The solvate of flunixin with carbamazepine co-crystal of claim 1, characterized in that: when the solvent is acetone, the eutectic and acetone form a solvate, and in the acetone solvate of the eutectic, the unit cell contains an acetone molecule while the flunixin and the carbamazepine form the eutectic. The space group of the acetone solvate of the eutectic is a triclinic system,
space group, unit cell parameters are:
the shaft angle α is 88.1940(12) °, β is 78.8928(12) °, γ is 84.5652(13) °,
Z＝2，Dc＝1.354g/cm3the molecular formula is [ C ]14H11F3N2O2]·[C15H12N2O]·[C3H6O]。
5. The solvate of flunixin with carbamazepine co-crystal of claim 1, characterized in that: the ethanol or acetone and the flunixin and carbamazepine eutectic form a solvate, the unit cell of the flunixin and carbamazepine eutectic contains the ethanol or the acetone, and the solvate adjusts the solubility of the medicine, so that the solubility of the eutectic is increased, and the unit content of the medicine in the preparation is improved.
6. A process for the preparation of a solvate of a flunixin and carbamazepine co-crystal according to any one of claims 1 to 5, comprising the steps of:
(1) mixing a mixture of 1: 1, putting flunixin and carbamazepine in a crystallizer, and simultaneously adding an ethanol or acetone solvent;
(2) completely dissolving the solute;
(3) slowly volatilizing the solvent to finally separate out colorless blocky crystals;
(4) when the solvent is not completely volatilized and crystals are precipitated, taking out the crystals, and removing the solvent on the surfaces of the crystals to obtain the ethanol or acetone solvate of the flunixin and carbamazepine eutectic.
7. The method of claim 6 for preparing a solvate of a flunixin and carbamazepine co-crystal, characterized in that: when the solvent is ethanol, the total content of solute in the system in the step (1) is 6-10%.
8. The method of claim 6 for preparing a solvate of a flunixin and carbamazepine co-crystal, characterized in that: heating the system to 50-60 ℃ in the step (2) until the solute is completely dissolved; and (3) slowly cooling the system to room temperature, slowly volatilizing the solvent, and finally separating out colorless blocky crystals.
9. The method of claim 6 for preparing a solvate of a flunixin and carbamazepine co-crystal, characterized in that: when the solvent is acetone, the total content of solute in the system in the step (1) is 8-12%.
10. Use of a solvate of flunixin with carbamazepine according to any one of claims 1 to 9, characterized in that: application in preparing medicinal preparation or health product.
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| CN103288724A (en) * | 2013-05-31 | 2013-09-11 | 天津大学 | Flunixin and carbamazepine cocrystal and preparation method thereof |
| CN104042561A (en) * | 2013-03-15 | 2014-09-17 | 天津新济复兴药业科技有限公司 | Carbamazepine cocrystal solid dispersion and preparation method thereof |
| CN110283131A (en) * | 2019-06-28 | 2019-09-27 | 鲁南制药集团股份有限公司 | A kind of Gefitinib and vanillic acid eutectic Methanol solvate and preparation method thereof |
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| CN104042561A (en) * | 2013-03-15 | 2014-09-17 | 天津新济复兴药业科技有限公司 | Carbamazepine cocrystal solid dispersion and preparation method thereof |
| CN103288724A (en) * | 2013-05-31 | 2013-09-11 | 天津大学 | Flunixin and carbamazepine cocrystal and preparation method thereof |
| CN110283131A (en) * | 2019-06-28 | 2019-09-27 | 鲁南制药集团股份有限公司 | A kind of Gefitinib and vanillic acid eutectic Methanol solvate and preparation method thereof |
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