CN115536583A - Enrofloxacin-vanillin eutectic crystal and preparation method thereof - Google Patents

Enrofloxacin-vanillin eutectic crystal and preparation method thereof Download PDF

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CN115536583A
CN115536583A CN202210681602.2A CN202210681602A CN115536583A CN 115536583 A CN115536583 A CN 115536583A CN 202210681602 A CN202210681602 A CN 202210681602A CN 115536583 A CN115536583 A CN 115536583A
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enrofloxacin
vanillin
eutectic
crystal
preparation
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陈良柱
庞虹
方炳虎
潘志坤
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Guangdong Wens Dahuanong Biotechnology Co ltd
South China Agricultural University
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Guangdong Wens Dahuanong Biotechnology Co ltd
South China Agricultural University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C07C47/58—Vanillin
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses an enrofloxacin-vanillin eutectic and a preparation method thereof, relating to the technical field of pharmaceutical eutectic ... Pharmaceutical co-crystals formed by O hydrogen bonding; the preparation method adopts any one of a solvent evaporation crystallization method, a solution cooling crystallization method and a wet grinding crystallization methodA method for preparing a pharmaceutical composition. The enrofloxacin pharmaceutical co-crystal provided by the invention widens the solid form of enrofloxacin, improves the water solubility, stability and bioavailability of enrofloxacin, and has the advantages of simple preparation method and convenient operation.

Description

Enrofloxacin-vanillin eutectic crystal and preparation method thereof
The application is a divisional application with the publication number of CN113402458A 'enrofloxacin eutectic and a preparation method thereof', the application date of the original application is 2021.8.15, the application number is CN202110559996.X, and the name of the original invention creation is 'enrofloxacin eutectic and a preparation method thereof'.
Technical Field
The invention relates to the technical field of pharmaceutical co-crystals, in particular to enrofloxacin-vanillin co-crystals and a preparation method thereof.
Background
Enrofloxacin is a fluoroquinolone medicine for animals, and is a special antibacterial medicine for livestock, poultry and aquatic products. The medicine action mechanism is to inhibit the bacterial DNA gyrase and prevent the normal transcription and replication of the bacterial DNA, thereby presenting the antibacterial action. Enrofloxacin has a broad spectrum of antibacterial activity and strong permeability, but its extremely low solubility generally limits the bioavailability of poorly soluble drugs.
Pharmaceutical co-crystals, i.e. a new crystal form formed by the pharmaceutical active ingredient (API) and the co-crystal form (CCF) through weak intermolecular forces such as hydrogen bonding, halogen bonding, van der waals forces, etc. The pharmaceutical co-crystal does not change the molecular structure of the pharmaceutical active ingredient, but can change the solubility, dissolution rate, stability, bioavailability, compressibility, fluidity and the like of the pharmaceutical active ingredient, and is the leading edge and focus of current pharmaceutical crystal research. After the drug forms the eutectic crystal, the chemical degradation reactions such as hydrolysis, oxidation and the like or the crystal transformation of the drug can be prevented due to the change of intermolecular force and crystal accumulation mode in crystal lattices. For example, after hydrogen bonds are formed between API and CCF, groups capable of forming hydrogen bonds with water molecules in the structure are occupied, thereby hindering the interaction between the drug and water and reducing the hygroscopicity of the drug. There are many methods for synthesizing pharmaceutical co-crystals, among which the most common method is solution crystallization, i.e. adding API and CCF into a suitable solvent according to a certain stoichiometric ratio for co-crystallization, and solution crystallization is further classified into reaction crystallization, solvent-mediated phase transition, solvent volatilization, poor solvent diffusion, solvothermal, suspension, and melt crystallization.
Pharmaceutical co-crystals, as a new solid form, have become an important direction for the development of new drugs, and therefore, the number of patent applications for pharmaceutical co-crystals worldwide has increased year by year. In 1 month 2014, the first drug co-crystal diabetes drug, farxiga, was approved by the FDA for marketing. The FDA revises the drug cocrystal supervision and classification guide in 2016, and the drug cocrystal is classified as a drug preparation intermediate without being registered as a new raw material drug independently, so that the examination and approval procedures are simplified, the research and development cost is greatly saved, and the risk is reduced.
At present, the enrofloxacin preparations which are commonly used clinically mainly comprise enrofloxacin hydrochloride, enrofloxacin lactate, enrofloxacin soluble powder, enrofloxacin sodium, enrofloxacin solid dispersion, microcapsule preparations and the like, and no enrofloxacin eutectic preparation is on the market. The invention aims at finding a new veterinary drug molecular eutectic, is applied to a medicinal preparation, can improve the water solubility, the stability and the bioavailability of enrofloxacin, and has wide clinical application prospect.
Disclosure of Invention
The invention aims to provide an enrofloxacin eutectic so as to improve the water solubility, stability and bioavailability of enrofloxacin; the invention also aims to provide a preparation method of the enrofloxacin eutectic.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
an enrofloxacin eutectic is a pharmaceutical eutectic formed by combining enrofloxacin and an eutectic forming substance through O-H8230and O hydrogen bonds; the eutectic formation substance is any one of vanillin, saccharin and suberic acid.
Preferably, the enrofloxacin-vanillin eutectic formed by the enrofloxacin and vanillin is combined through O-H8230and O hydrogen bonds, the space group is a monoclinic system and P21/c, and the crystallographic data is as follows: length of the bond
Figure BDA0003696467450000021
A bond angle α =90 °, β =108.170 (5) °, γ =90 °, Z =4, v =2463.2 (2), the asymmetric structural unit comprising 1 enrofloxacin molecule, 1 vanillin molecule;
the enrofloxacin-saccharin eutectic formed by the enrofloxacin and saccharin is combined through O-H (8230), O hydrogen bonds, a space group is a monoclinic system and P21/c, and unit cell parameters are as follows: length of the bond
Figure BDA0003696467450000031
Figure BDA0003696467450000032
The bond angle α =90 °, β =98.967 (2) °, γ =90 °, the asymmetric structural unit comprises 1 enrofloxacin molecule, 1 saccharin molecule and 1H 2 An O molecule;
the enrofloxacin-suberic acid eutectic formed by the enrofloxacin and suberic acid is combined through O-H \8230andO hydrogen bonds, a space group of the eutectic system is a triclinic system and P-1, and unit cell parameters of the eutectic system are as follows: length of the bond
Figure BDA0003696467450000033
Figure BDA0003696467450000034
The bond angle α =91.066 (2) °, β =93.354 (2) °, γ =101.223 (2) °, and the asymmetric structural unit includes 1 enrofloxacin molecule and 1 suberic acid molecule.
In the invention, the chemical formula of the enrofloxacin-vanillin eutectic is shown as the formula (I):
Figure BDA0003696467450000035
the chemical formula of the enrofloxacin-saccharin eutectic is shown as the formula (II):
Figure BDA0003696467450000036
the chemical formula of the enrofloxacin-suberic acid eutectic is shown as the formula (III):
Figure BDA0003696467450000041
preferably, the characteristic diffraction peak 2 theta of the X-ray powder diffraction spectrum of the enrofloxacin-vanillin cocrystal is as follows: 5.325 +/-0.2 °, 8.736 +/-0.2 °, 11.606 +/-0.2 °, 12.906 +/-0.2 °, 15.830 +/-0.2 °, 16.588 +/-0.2 °, 17.617 +/-0.2 °, 19.946 +/-0.2 °, 21.787 +/-0.2 °, 23.249 +/-0.2 °, 24.170 +/-0.2 °, 24.874 +/-0.2 °, 25.848 +/-0.2 °, 26.444 +/-0.2 °, 28.502 +/-0.2 ° and 33.538 +/-0.2 °;
the infrared spectrogram of the enrofloxacin-vanillin cocrystal is 2713.22, 1711.24 and 1681.42cm -1 Has characteristic peak absorption;
the melting point of the enrofloxacin-vanillin eutectic is 110.73 +/-5 ℃.
Preferably, the characteristic diffraction peak 2 theta of the X-ray powder diffraction spectrum of the enrofloxacin-saccharin eutectic is as follows: 9.711 + -0.2 °, 11.661 + -0.2 °, 13.123 + -0.2 °, 15.993 + -0.2 °, 19.729 + -0.2 °, 20.110 + -0.2 °, 20.704 + -0.2 °, 22.220 + -0.2 °, 24.386 + -0.2 °, 26.011 + -0.2 °, 28.069 + -0.2 °;
the infrared spectrogram of the enrofloxacin-saccharin eutectic is 3510.97, 3445.33, 2611.42, 2462.99, 1718.72 and 1632.44cm -1 Has characteristic peak absorption;
the melting point of the enrofloxacin-saccharin eutectic is 223.93 +/-5 ℃.
Preferably, the characteristic diffraction peak 2 theta of the X-ray powder diffraction spectrum of the enrofloxacin-suberic acid eutectic is as follows: 7.545 +/-0.2 °, 9.711 +/-0.2 °, 11.173 +/-0.2 °, 11.769 +/-0.2 °, 13.394 +/-0.2 °, 14.477 +/-0.2 °, 15.884 +/-0.2 °, 18.159 +/-0.2 °, 18.971 +/-0.2 °, 19.567 +/-0.2 °, 20.325 +/-0.2 °, 21.191 +/-0.2 °, 23.087 +/-0.2 °, 24.549 +/-0.2 °, 25.686 +/-0.2 °, 26.877 +/-0.2 ° and 30.505 +/-0.2 °;
the infrared spectrogram of the enrofloxacin-suberic acid eutectic crystal is 3492.34, 3433.37, 2547.21, 2511.52, 2456.75, 1729.07 and 1629.76cm -1 Has characteristic peak absorption;
the melting point of the enrofloxacin-suberic acid eutectic is 112.47 +/-5 ℃.
The invention also provides a preparation method of the enrofloxacin eutectic, which adopts a solvent evaporation crystallization method for preparation, and comprises the following specific steps: mixing enrofloxacin and a eutectic forming substance according to a molar ratio of 0.5-4: 1, mixing, adding an organic solvent, heating to 40-80 ℃, and stirring until the organic solvent is completely dissolved; then standing and volatilizing at 0-40 ℃ for 1-5 days to separate out light yellow crystals, and vacuum drying at 30-60 ℃ to obtain the enrofloxacin pharmaceutical co-crystal.
The organic solvent is one or more of methanol, ethanol, acetone, dichloromethane, chloroform, acetonitrile, and tetrahydrofuran, preferably dichloromethane or acetonitrile.
Preferably, after the organic solvent is added, the feed-liquid ratio g/mL is controlled to be 1:8 to 30.
The invention also provides a preparation method of the enrofloxacin eutectic, which adopts a solution cooling crystallization method for preparation, and comprises the following steps: mixing enrofloxacin and a eutectic forming substance according to a molar ratio of 0.5-4: 1, mixing, adding an organic solvent, heating to 40-80 ℃ for dissolving, filtering to remove insoluble substances while the solution is hot, and sealing; standing for 12-72 h at the temperature of-10-15 ℃, cooling to separate out crystals, and filtering to obtain the enrofloxacin pharmaceutical co-crystal.
The organic solvent comprises one or more of methanol, ethanol, DMF, dimethyl sulfoxide, acetone, dichloromethane, and acetonitrile, preferably dichloromethane or methanol.
The invention also provides a preparation method of the enrofloxacin eutectic, which adopts a wet grinding crystallization method for preparation and comprises the following steps: mixing enrofloxacin and a eutectic forming substance according to a molar ratio of 0.5-4: 1, adding the mixture into a mortar, adding a small amount of solvent, and grinding for 15min to 4h to obtain the enrofloxacin pharmaceutical co-crystal.
The solvent comprises one of water, methanol and ethanol, preferably ethanol.
Compared with the prior art, the beneficial effects of the invention are embodied in the following aspects:
1. the enrofloxacin pharmaceutical co-crystal provided by the invention widens the solid form of enrofloxacin, and improves the water solubility, stability and bioavailability of enrofloxacin;
2. the preparation method is simple, can adopt a solvent evaporation crystallization method, a solution cooling crystallization method and a wet grinding crystallization method, and is convenient to operate.
Drawings
FIG. 1 is a schematic diagram of structural units of the enrofloxacin-vanillin eutectic crystal of the invention;
FIG. 2 is a structural stacking diagram of the enrofloxacin-vanillin cocrystal of the invention;
FIG. 3 is a powder diffraction contrast diagram of enrofloxacin and enrofloxacin-vanillin cocrystals in accordance with the present invention; wherein a is enrofloxacin, and b is enrofloxacin-vanillin eutectic crystal;
FIG. 4 is a FT-IR comparison graph of enrofloxacin and enrofloxacin-vanillin cocrystals in accordance with the present invention; wherein a is enrofloxacin, and b is enrofloxacin-vanillin eutectic crystal;
FIG. 5 is a DSC comparison chart of enrofloxacin and enrofloxacin-vanillin eutectic crystal in the invention; wherein a is enrofloxacin, and b is enrofloxacin-vanillin eutectic crystal;
fig. 6 is a schematic diagram of structural units of the enrofloxacin-saccharin eutectic of the present invention;
FIG. 7 is a powder diffraction contrast diagram of enrofloxacin, enrofloxacin-saccharin co-crystal of the present invention; wherein a is enrofloxacin, and b is enrofloxacin-saccharin eutectic;
FIG. 8 is a FT-IR comparison of enrofloxacin, enrofloxacin-saccharin eutectic, enrofloxacin-suberic acid eutectic of the present invention; wherein a is enrofloxacin, b is enrofloxacin-saccharin eutectic, and c is enrofloxacin-suberic acid eutectic;
FIG. 9 is a DSC comparison chart of enrofloxacin and enrofloxacin-saccharin eutectic crystal in the invention; wherein a is enrofloxacin, and b is enrofloxacin-saccharin eutectic;
FIG. 10 is a schematic diagram of structural units of the enrofloxacin-suberic acid eutectic of the present invention;
FIG. 11 is a powder diffraction contrast diagram of enrofloxacin and enrofloxacin-suberic acid eutectic crystal in the invention; wherein a is enrofloxacin, and b is enrofloxacin-suberic acid eutectic;
FIG. 12 is a DSC comparison chart of enrofloxacin and enrofloxacin-suberic acid eutectic crystal in the invention; wherein a is enrofloxacin and b is enrofloxacin-suberic acid eutectic.
Detailed Description
The technical solution of the present invention will be described in detail below with reference to specific examples.
The test instruments used in the examples of the present invention are referenced below: the crystal structure is formed by Rigaku Oxford Diffraction ultra-new star diffractometer copper target
Figure BDA0003696467450000071
Measuring; the powder XRD pattern is measured by Rigaku-Ultima IV ray powder diffractometer at 5-80 ℃ (
Figure BDA0003696467450000072
V =40kv, and i = 40a); the FT-IR spectrum is measured by a Vertex 70FT-IR infrared spectrometer of Bruker, germany, and the measuring range is 4000cm -1 ～400cm -1 (ii) a DSC is measured by adopting TA Q200, the temperature range is 25-280 ℃, the protection of nitrogen is carried out, and the heating rate is 20 ℃/min.
Example 1
Preparation of enrofloxacin-vanillin eutectic
Step 1: weighing enrofloxacin (0.23g, 0.64mmol) and vanillin (0.09g, 0.64mmol), mixing, stirring well, pouring into a conical flask, adding 4ml dichloromethane solution, heating at 50 deg.C, and stirring to dissolve completely;
and 2, step: and sealing the bottle by using a glass plug, putting filter paper into the bottle mouth to leave a gap, standing and volatilizing for 3 days at 25 ℃, separating out a light yellow crystal, filtering, washing by using dichloromethane, and carrying out vacuum drying at 55 ℃ to obtain 0.158g of light yellow enrofloxacin-vanillin eutectic.
Example 2
Preparation of enrofloxacin-saccharin eutectic
Step 1: weighing enrofloxacin (0.23g, 0.64mmol) and saccharin (0.135g, 0.74mmol), mixing, stirring uniformly, pouring into an erlenmeyer flask, adding 5ml tetrahydrofuran solution, heating at 60 deg.C, and stirring to dissolve completely;
step 2: sealing with a glass plug, placing filter paper at the bottle mouth to leave a gap, standing at 20 ℃ for volatilizing for 5 days to precipitate a light yellow crystal, filtering, washing with tetrahydrofuran, and vacuum drying at 52 ℃ to obtain 0.167g of the white enrofloxacin-saccharin eutectic.
Example 3
Preparation of enrofloxacin-suberic acid eutectic
Step 1: weighing enrofloxacin (0.21g, 0.58mmol) and suberic acid (0.165g, 0.95mmol), mixing, stirring uniformly, pouring into a conical flask, adding 5ml acetone solution, heating at 56 deg.C, stirring until completely dissolving;
step 2: sealing with a glass plug, placing filter paper in the bottle mouth to leave a gap, standing at 35 ℃ for volatilizing for 5 days to precipitate a light yellow crystal, filtering, washing with acetone, and vacuum drying at 55 ℃ to obtain 0.172g of white or off-white enrofloxacin-suberic acid eutectic.
Example 4
Preparation of enrofloxacin-vanillin eutectic
Step 1: weighing 2.3g (6.4 mmol) of enrofloxacin and 0.9g (6.4 mmol) of vanillin in a 50ml flask, adding 70ml of acetonitrile, stirring for dissolving, filtering to remove insoluble substances, and adding the filtrate into a 100ml triangular flask;
step 2: sealing with a preservative film, pricking a plurality of small holes with the preservative film by using needles, placing in a fume hood for 3 days, separating out enrofloxacin-vanillin eutectic, filtering, and drying in vacuum at 60 ℃ to obtain 2.1g of light yellow eutectic.
Example 5
Preparation of enrofloxacin-vanillin eutectic
2.3g (6.4 mmol) of enrofloxacin and 0.9g (6.4 mmol) of vanillin are weighed and put into a mortar, 1ml of ethanol is added, and grinding is carried out for 90min, so as to obtain 1.9g of enrofloxacin-vanillin eutectic crystal.
Example 6
Preparation of enrofloxacin-vanillin eutectic
Step 1: weighing 2.3g (6.4 mmol) of enrofloxacin and 0.9g (6.4 mmol) of vanillin in a 100ml flask, adding 50ml of methanol, heating to 40 ℃, stirring for dissolving, filtering to remove insoluble substances while the solution is hot, and adding the filtrate into a 100ml triangular flask;
step 2: sealing the triangular flask, standing for 36h at 4 ℃ to precipitate enrofloxacin-vanillin eutectic, filtering, and vacuum drying at 60 ℃ to obtain light yellow eutectic compound 2.0g.
The enrofloxacin eutectic crystals prepared in the embodiments 1-6 of the invention are characterized and tested for performance.
1. Characterization of enrofloxacin medicament eutectic structure
The crystal structure is collected by a Nippon Rigaku Oxford Diffraction Innova diffractometer by CuK alpha rays
Figure BDA0003696467450000091
The voltage is 50KV, the current is 30mA, and the collected data is subjected to structural analysis by OLEX2 software.
The schematic diagram of the structural units of the enrofloxacin-vanillin cocrystals prepared in the embodiments 1 and 4-6 of the invention is shown in fig. 1, the structural stacking diagram is shown in fig. 2, the asymmetric structural unit comprises 1 enrofloxacin molecule and 1 vanillin molecule, and the structural units are bonded through an O-H \8230andO hydrogen bond, the space group is a monoclinic system and P21/c, and the crystallographic data is as follows: length of the bond
Figure BDA0003696467450000092
Key angle α =90 °, β =108.170 (5) °, γ =90 °, Z =4, v =2463.2 (2); the eutectic melting point is 110.73 +/-5 ℃.
The powder diffraction contrast diagram of the enrofloxacin-vanillin eutectic is shown in fig. 3, and it can be seen from the diagram that the characteristic diffraction peak 2 theta of the X-ray powder diffraction spectrum of the enrofloxacin-vanillin eutectic is: 5.325 +/-0.2 degrees, 8.736 +/-0.2 degrees, 11.606 +/-0.2 degrees, 12.906 +/-0.2 degrees, 15.830 +/-0.2 degrees, 16.588 +/-0.2 degrees, 17.617 +/-0.2 degrees, 19.946 +/-0.2 degrees, 21.787 +/-0.2 degrees, 2 degrees3.249 +/-0.2 degrees, 24.170 +/-0.2 degrees, 24.874 +/-0.2 degrees, 25.848 +/-0.2 degrees, 26.444 +/-0.2 degrees, 28.502 +/-0.2 degrees and 33.538 +/-0.2 degrees, has obvious difference with the characteristic peaks of enrofloxacin raw materials, and indicates that a new crystalline phase is generated; the FT-IR chart is shown in FIG. 4, which shows that the position of infrared absorption peak is obviously shifted and the migration range is 1628.7cm because the ketone carbonyl of enrofloxacin in the enrofloxacin-vanillin eutectic forms hydrogen bond with the hydroxyl of vanillin -1 To 1681.4cm -1 The result was consistent with single crystal analysis; the DSC chart is shown in figure 5, and the DSC endothermic peak position of enrofloxacin is 228.06 ℃, the DSC endothermic peak position of enrofloxacin-vanillin eutectic is 110.73 ℃, and a new phase is generated.
Fig. 6 shows a schematic diagram of structural units of the enrofloxacin-saccharin cocrystal prepared in example 2, where the asymmetric structural units include 1 enrofloxacin molecule, 1 saccharin molecule, and 1H 2 The O molecule is combined through O-H \8230andO hydrogen bonds, the space group is monoclinic system, P21/c, and the unit cell parameters are as follows: length of the bond
Figure BDA0003696467450000101
Figure BDA0003696467450000102
Key angles α =90 °, β =98.967 (2) °, γ =90 °;
fig. 7 to 9 are respectively a powder diffraction contrast chart, an FT-IR contrast chart and a DSC contrast chart of enrofloxacin and enrofloxacin-saccharin eutectic, and it can be seen from the charts that characteristic diffraction peaks 2 theta of the X-ray powder diffraction spectrum of the enrofloxacin-saccharin eutectic are: 9.711 +/-0.2 degrees, 11.661 +/-0.2 degrees, 13.123 +/-0.2 degrees, 15.993 +/-0.2 degrees, 19.729 +/-0.2 degrees, 20.110 +/-0.2 degrees, 20.704 +/-0.2 degrees, 22.220 +/-0.2 degrees, 24.386 +/-0.2 degrees, 26.011 +/-0.2 degrees and 28.069 +/-0.2 degrees; the infrared spectrogram is 3510.97, 3445.33, 2611.42, 2462.99, 1718.72 and 1632.44cm -1 Has characteristic peak absorption; the eutectic melting point is 223.93 +/-5 ℃.
FIG. 10 shows a schematic diagram of structural units of the enrofloxacin-suberic acid eutectic prepared in example 3, where the asymmetric structural units include 1 enrofloxacin molecule and 1 suberic acid molecule through O-H \8230Ohhydrogen bonding, whose space group is triclinic system, P-1, and its unit cell parameters are: length of the bond
Figure BDA0003696467450000103
Figure BDA0003696467450000104
Key angles α =91.066 (2) °, β =93.354 (2) °, γ =101.223 (2) °;
fig. 11, fig. 8 and fig. 12 are a powder diffraction contrast chart, an FT-IR contrast chart and a DSC contrast chart of enrofloxacin and enrofloxacin-suberic acid eutectic, respectively, and it can be seen from the graphs that characteristic diffraction peaks 2 θ of the X-ray powder diffraction spectrum of the enrofloxacin-suberic acid eutectic are: 7.545 +/-0.2 °, 9.711 +/-0.2 °, 11.173 +/-0.2 °, 11.769 +/-0.2 °, 13.394 +/-0.2 °, 14.477 +/-0.2 °, 15.884 +/-0.2 °, 18.159 +/-0.2 °, 18.971 +/-0.2 °, 19.567 +/-0.2 °, 20.325 +/-0.2 °, 21.191 +/-0.2 °, 23.087 +/-0.2 °, 24.549 +/-0.2 °, 25.686 +/-0.2 °, 26.877 +/-0.2 ° and 30.505 +/-0.2 °; the infrared spectrogram has characteristic peak absorption at 3492.34, 3433.37, 2547.21, 2511.52, 2456.75, 1729.07 and 1629.76 cm-1; the eutectic melting point is 112.47 +/-5 ℃.
2. And (3) testing the solubility of the enrofloxacin pharmaceutical co-crystal in water.
Putting the excessive enrofloxacin pharmaceutical co-crystal into a 5ml test tube, adding 2.5ml ultrapure water, swirling for half minute, putting into a constant temperature oscillator at 25 +/-5 ℃ for shaking for 24 hours, filtering by using a 0.22um filter membrane, properly diluting, testing by using an Agilent 1260Infinity II high performance liquid chromatography, and carrying out three parallels on samples. The results are shown in Table 1.
Table 1 solubility data of enrofloxacin pharmaceutical co-crystals in water
Sample (I) Solubility (mg/mL) of enrofloxacin as active pharmaceutical ingredient
Enrofloxacin 0.14
Enrofloxacin-vanillin eutectic crystal 0.75
Enrofloxacin-saccharin eutectic 12.6
Enrofloxacin-suberic acid eutectic 16.3
The result shows that compared with enrofloxacin, the solubility of the enrofloxacin eutectic is increased by 5 to 120 times, and the solubility of enrofloxacin is obviously improved.
3. Stability test (influence factor test) of enrofloxacin-vanillin cocrystal
a. High-temperature test: preparing 3 batches of samples according to the prescription, placing the samples in a sealed clean container, standing at 60 ℃ for 10 days, and sampling and detecting on 0 th, 5 th and 10 th days;
b. high humidity test: preparing 3 batches of test articles according to the prescription, placing the test articles in a sealed clean container at 25 ℃ and relative humidity (90 +/-5)% for 10 days, and sampling and detecting the test articles at 0, 5 and 10 days;
c. strong light irradiation test: 3 batches of samples (placed in brown bottles) are prepared according to the prescription, placed in a lighting box with a fluorescent lamp under the condition of the intensity of 4500 +/-500 lx for 10 days, and sampled and detected on the 0 th, 5 th and 10 th days.
The results are shown in Table 2.
TABLE 2 stability data of enrofloxacin-vanillin cocrystals
Figure BDA0003696467450000111
Figure BDA0003696467450000121
From the experimental results, compared with the initial experimental sample, the appearance color and luster of the enrofloxacin-vanillin eutectic crystal are not changed, and the content of the enrofloxacin-vanillin eutectic crystal is not obviously changed (the content change is less than 5%). Therefore, the enrofloxacin vanillin eutectic crystal has a stable crystal structure and is suitable for long-term storage.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.

Claims (7)

1. The enrofloxacin-vanillin eutectic is characterized in that the enrofloxacin-vanillin eutectic is a pharmaceutical eutectic formed by combining enrofloxacin and vanillin through O-H.
2. The enrofloxacin-vanillin eutectic of claim 1, wherein the enrofloxacin-vanillin eutectic formed by the enrofloxacin and vanillin is bonded through O-H. Length of the bond
Figure FDA0003696467440000011
Figure FDA0003696467440000012
Bond angle α =90 °, β =108.170 (5) °, γ =90 °, Z =4, v =2463.2 (2), and the asymmetric structural unit includes 1 enrofloxacin molecule and 1 vanillin molecule.
3. The enrofloxacin-vanillin cocrystal according to claim 2, wherein the characteristic diffraction peak 2 θ of the X-ray powder diffraction spectrum of the enrofloxacin-vanillin cocrystal is: 5.325 +/-0.2 °, 8.736 +/-0.2 °, 11.606 +/-0.2 °, 12.906 +/-0.2 °, 15.830 +/-0.2 °, 16.588 +/-0.2 °, 17.617 +/-0.2 °, 19.946 +/-0.2 °, 21.787 +/-0.2 °, 23.249 +/-0.2 °, 24.170 +/-0.2 °, 24.874 +/-0.2 °, 25.848 +/-0.2 °, 26.444 +/-0.2 °, 28.502 +/-0.2 ° and 33.538 +/-0.2 °;
the infrared spectrogram of the enrofloxacin-vanillin cocrystal is 2713.22, 1711.24 and 1681.42cm -1 Has characteristic peak absorption;
the melting point of the enrofloxacin-vanillin eutectic is 110.73 +/-5 ℃.
4. The preparation method of the enrofloxacin-vanillin eutectic crystal based on any one of claims 1 to 3, is characterized by adopting a solvent evaporation crystallization method, and comprises the following specific steps: mixing enrofloxacin and vanillin according to a molar ratio of 0.5-4: 1, mixing, adding an organic solvent, heating to 40-80 ℃, and stirring until the organic solvent is completely dissolved; then standing and volatilizing for 1-5 days at 0-40 ℃ to separate out light yellow crystals, and vacuum drying at 30-60 ℃ to obtain the enrofloxacin pharmaceutical co-crystal.
5. The preparation method of the enrofloxacin-vanillin eutectic crystal based on any one of claims 1 to 3 is characterized by adopting a solution cooling crystallization method, and comprises the following steps: enrofloxacin and vanillin are mixed according to the mol ratio of 0.5-4: 1, mixing, adding an organic solvent, heating to 40-80 ℃ for dissolution, filtering to remove insoluble substances while the solution is hot, and sealing; standing for 12-72 h at the temperature of-10-15 ℃, cooling to separate out crystals, and filtering to obtain the enrofloxacin pharmaceutical co-crystal.
6. The preparation method of the enrofloxacin-vanillin eutectic crystal based on any one of claims 1 to 3, is characterized by adopting a wet grinding crystallization method, and comprises the following steps: mixing enrofloxacin and vanillin according to a molar ratio of 0.5-4: 1, adding a small amount of solvent into a mortar, and grinding for 15 min-4 h to obtain the enrofloxacin pharmaceutical co-crystal.
7. The preparation method of enrofloxacin-vanillin eutectic crystal as claimed in claim 4, wherein the ratio of material to liquid g/mL is controlled to be 1:8 to 30.
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