1. An enrofloxacin eutectic crystal is characterized in that the enrofloxacin eutectic crystal is a pharmaceutical eutectic crystal formed by combining an enrofloxacin eutectic former through O-H.. O hydrogen bonds; the eutectic formation substance is any one of vanillin, saccharin and suberic acid.

2. The enrofloxacin eutectic of claim 1, wherein the enrofloxacin-vanillin eutectic formed by the enrofloxacin and vanillin is combined through O-H. Length of the bond The bond angle alpha is 90 degrees, beta is 108.170(5) degrees, gamma is 90 degrees, Z is 4, V is 2463.2(2), and the asymmetric structural unit comprises 1 enrofloxacin molecule and 1 vanillin molecule;

the enrofloxacin-saccharin eutectic formed by the enrofloxacin and saccharin is combined through O-H. Length of the bond The bond angle alpha is 90 degrees, beta is 98.967(2) degrees, gamma is 90 degrees, the asymmetric structural unit comprises 1 enrofloxacin molecule, 1 saccharin molecule and 1H₂An O molecule;

the enrofloxacin-suberic acid eutectic formed by the enrofloxacin and the suberic acid is combined through an O-H. Length of the bond The bond angle alpha is 91.066(2) ° beta is 93.354(2) ° gamma is 101.223(2) ° gamma, and the asymmetric structural unit comprises 1 enrofloxacin molecule and 1 suberic acid molecule.

3. The enrofloxacin co-crystal of claim 2, wherein the X-ray powder diffraction spectrum of the enrofloxacin-vanillin co-crystal has characteristic diffraction peaks 2 Θ of: 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, 23.249 +/-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;

the infrared spectrogram of the enrofloxacin-vanillin eutectic crystal is 2713.22, 1711.24 and 1681.42cm-¹Has characteristic peak absorption;

the melting point of the enrofloxacin-vanillin eutectic is 110.73 +/-5 ℃.

4. The enrofloxacin co-crystal of claim 2, wherein the enrofloxacin-saccharin co-crystal has an X-ray powder diffraction spectrum with characteristic diffraction peaks at 2 Θ of: 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 of the enrofloxacin-saccharin eutectic is 3510.97, 3445.33, 2611.42, 2462.99, 1718.72 and 1632.44cm^-1Has characteristic peak absorption;

the melting point of the enrofloxacin-saccharin eutectic is 223.93 +/-5 ℃.

5. The enrofloxacin co-crystal of claim 2, wherein the X-ray powder diffraction spectrum of the enrofloxacin-suberic acid co-crystal has characteristic diffraction peaks 2 Θ of: 7.545 +/-0.2 degrees, 9.711 +/-0.2 degrees, 11.173 +/-0.2 degrees, 11.769 +/-0.2 degrees, 13.394 +/-0.2 degrees, 14.477 +/-0.2 degrees, 15.884 +/-0.2 degrees, 18.159 +/-0.2 degrees, 18.971 +/-0.2 degrees, 19.567 +/-0.2 degrees, 20.325 +/-0.2 degrees, 21.191 +/-0.2 degrees, 23.087 +/-0.2 degrees, 24.549 +/-0.2 degrees, 25.686 +/-0.2 degrees, 26.877 +/-0.2 degrees and 30.505 +/-0.2 degrees;

the infrared spectrogram of the enrofloxacin-suberic acid eutectic has characteristic peak absorption at 3492.34, 3433.37, 2547.21, 2511.52, 2456.75, 1729.07 and 1629.76cm < -1 >;

the melting point of the enrofloxacin-suberic acid eutectic is 112.47 +/-5 ℃.

6. The preparation method of the enrofloxacin co-crystal based on any one of claims 1 to 5, which is characterized by adopting a solvent evaporation crystallization method, and comprises the following specific steps: mixing enrofloxacin and a eutectic formation 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; and standing and volatilizing at 0-40 ℃ for 1-5 days, separating out a light yellow crystal, and vacuum drying at 30-60 ℃ to obtain the enrofloxacin pharmaceutical co-crystal.

7. The preparation method of the enrofloxacin eutectic crystal based on any one of claims 1 to 5, characterized by adopting a solution cooling crystallization method, and comprising the following steps: mixing enrofloxacin and a eutectic formation substance according to a molar 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-10-15 ℃, cooling to separate out crystals, and filtering to obtain the enrofloxacin pharmaceutical co-crystal.

8. The preparation method of the enrofloxacin eutectic crystal based on any one of claims 1 to 5, characterized by adopting a wet grinding crystallization method, and comprising the following steps: mixing enrofloxacin and a eutectic formation 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.

9. The preparation method of enrofloxacin eutectic crystal according to claim 6, wherein the ratio of material to liquid g/mL is controlled to be 1: 8-30.

Background

Enrofloxacin is a fluoroquinolone medicine for livestock, 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 broad-spectrum antibacterial activity and strong permeability, but generally limits the bioavailability of poorly soluble drugs due to its extremely low solubility.

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 cocrystal 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, farmxiga, was approved by the FDA for marketing. The FDA revises the drug cocrystal supervision and classification guidelines in 2016, and the drug cocrystal is classified as a drug preparation intermediate without being independently registered as a new raw material drug, thereby simplifying the examination and approval procedures, greatly saving the research and development cost and reducing the risk.

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 former through O-H.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 by O-H. Length of the bondThe bond angle alpha is 90 degrees, beta is 108.170(5) degrees, gamma is 90 degrees, Z is 4, V is 2463.2(2), and the asymmetric structural unit comprises 1 enrofloxacin molecule and 1 vanillin molecule;

formed by the enrofloxacin and saccharinThe enrofloxacin-saccharin eutectic is combined through O-H. Length of the bond The bond angle alpha is 90 degrees, beta is 98.967(2) degrees, gamma is 90 degrees, the asymmetric structural unit comprises 1 enrofloxacin molecule, 1 saccharin molecule and 1H₂An O molecule;

the enrofloxacin-suberic acid eutectic formed by the enrofloxacin and the suberic acid is combined through an O-H. Length of the bond The bond angle alpha is 91.066(2) ° beta is 93.354(2) ° gamma is 101.223(2) ° gamma, and the asymmetric structural unit comprises 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):

the chemical formula of the enrofloxacin-saccharin eutectic is shown as the formula (II):

the chemical formula of the enrofloxacin-suberic acid eutectic is shown as the formula (III):

preferably, the characteristic diffraction peak 2 theta of the X-ray powder diffraction spectrum of the enrofloxacin-vanillin eutectic is as follows: 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, 23.249 +/-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;

the infrared spectrogram of the enrofloxacin-vanillin eutectic crystal is 2713.22, 1711.24 and 1681.42cm-¹Has 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 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 of the enrofloxacin-saccharin eutectic is 3510.97, 3445.33, 2611.42, 2462.99, 1718.72 and 1632.44cm^-1Has 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 degrees, 9.711 +/-0.2 degrees, 11.173 +/-0.2 degrees, 11.769 +/-0.2 degrees, 13.394 +/-0.2 degrees, 14.477 +/-0.2 degrees, 15.884 +/-0.2 degrees, 18.159 +/-0.2 degrees, 18.971 +/-0.2 degrees, 19.567 +/-0.2 degrees, 20.325 +/-0.2 degrees, 21.191 +/-0.2 degrees, 23.087 +/-0.2 degrees, 24.549 +/-0.2 degrees, 25.686 +/-0.2 degrees, 26.877 +/-0.2 degrees and 30.505 +/-0.2 degrees;

the infrared spectrogram of the enrofloxacin-suberic acid eutectic is 3492.34, 3433.37, 2547.21, 2511.52, 2456.75, 1729.07 and 1629.76cm^-1Has 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 crystal, which adopts a solvent evaporation crystallization method for preparation, and comprises the following specific steps: mixing enrofloxacin and a eutectic formation 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; and standing and volatilizing at 0-40 ℃ for 1-5 days, separating out a light yellow crystal, 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: 8-30.

The invention also provides a preparation method of the enrofloxacin eutectic crystal, which adopts a solution cooling crystallization method for preparation, and comprises the following steps: mixing enrofloxacin and a eutectic formation substance according to a molar 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-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 crystal, which is prepared by a wet grinding crystallization method and comprises the following steps: mixing enrofloxacin and a eutectic formation 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 of enrofloxacin and enrofloxacin-saccharin co-crystal in accordance with the present 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 of the present 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 equipment used in the examples of the present invention was referred to as follows: the crystal structure is formed by Rigaku Oxford Diffraction ultra-new star diffractometer copper targetMeasuring; the powder XRD pattern is determined by Rigaku-Ultima IV ray powder diffractometer at 5-80 ℃ (V-40 KV, and I-40A); the FT-IR spectrum is measured by a Vertex 70FT-IR infrared spectrometer of Bruker, Germany, and the test range is 4000cm^-1～400cm^-1(ii) a And 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 uniformly, pouring into a conical flask, adding 4ml dichloromethane solution, heating at 50 deg.C, and stirring to dissolve completely;

step 2: 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 of tetrahydrofuran solution, heating at 60 ℃, and stirring until completely dissolving;

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 of acetone solution, heating at 56 ℃, and stirring until the acetone solution is completely dissolved;

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 (6.4mmol) of enrofloxacin and 0.9g (6.4mmol) 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 (6.4mmol) of enrofloxacin and 0.9g (6.4mmol) 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 (6.4mmol) of enrofloxacin and 0.9g (6.4mmol) of vanillin in a 100ml flask, adding 50ml of methanol, heating to 40 ℃, stirring for dissolving, filtering to remove insoluble substances while 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 2.0 g.

Characterization and performance test are carried out on the enrofloxacin eutectic prepared in the embodiments 1-6 of the invention.

1. Characterization of enrofloxacin medicament eutectic structure

The crystal structure is collected by a Nippon Rigaku Oxford Diffraction supernova diffractometer by CuK alpha raysThe voltage was 50KV, the current was 30mA, and the collected data were analyzed by the OLEX2 software.

The schematic diagram of the structural units of the enrofloxacin-vanillin cocrystal prepared in the embodiment 1 and the embodiments 4 to 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 which are combined through an O-H. Length of the bondA bond angle α of 90 °, β of 108.170(5 °), γ of 90 °, Z of 4, and V of 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, 23.249 +/-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, and has obvious characteristic peak difference with enrofloxacin raw material, thereby indicating that a new crystal phase is generated; the FT-IR diagram is shown in FIG. 4, from which it can be seen that the position of the infrared absorption peak is obviously shifted due to the formation of hydrogen bond with the hydroxyl group of vanillin by the ketocarbonyl group of enrofloxacin in the enrofloxacin-vanillin eutectic, and the migration range is from 1628.7cm-¹To 1681.4cm-¹The 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 ℃, and the enrofloxacin-vanillin eutectic crystalThe DSC endotherm peak position of (a) was at 110.73 ℃, a new phase was produced.

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 1H₂O molecules, bonded by O-h. Length of the bond The bond angle α is 90 °, β is 98.967(2 °), γ is 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-¹Has characteristic peak absorption; the eutectic melting point is 223.93 +/-5 ℃.

A schematic diagram of a structural unit of the enrofloxacin-suberic acid eutectic prepared in example 3 is shown in fig. 10, where the asymmetric structural unit includes 1 enrofloxacin molecule and 1 suberic acid molecule bonded by an O-h. Length of the bond A bond angle α of 91.066(2) ° β of 93.354(2) ° γ of 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 degrees, 9.711 +/-0.2 degrees, 11.173 +/-0.2 degrees, 11.769 +/-0.2 degrees, 13.394 +/-0.2 degrees, 14.477 +/-0.2 degrees, 15.884 +/-0.2 degrees, 18.159 +/-0.2 degrees, 18.971 +/-0.2 degrees, 19.567 +/-0.2 degrees, 20.325 +/-0.2 degrees, 21.191 +/-0.2 degrees, 23.087 +/-0.2 degrees, 24.549 +/-0.2 degrees, 25.686 +/-0.2 degrees, 26.877 +/-0.2 degrees and 30.505 +/-0.2 degrees; the infrared spectrogram has characteristic peak absorption at 3492.34, 3433.37, 2547.21, 2511.52, 2456.75, 1729.07 and 1629.76cm < -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 excess enrofloxacin pharmaceutical co-crystal into a 5ml test tube, adding 2.5ml ultrapure water, whirling for half a minute, putting into a constant temperature oscillator at 25 +/-5 ℃, 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 performing three parallels on samples. The results are shown in Table 1.

TABLE 1 solubility data of enrofloxacin pharmaceutical co-crystals in water

The result shows that compared with enrofloxacin, the solubility of the enrofloxacin eutectic is increased by 5-120 times, and the solubility of enrofloxacin is obviously improved.

3. Stability test (influence factor test) of enrofloxacin-vanillin eutectic crystal

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, standing at the temperature of 25 ℃ and the relative humidity (90 +/-5)% for 10 days, and sampling and detecting the test articles on the 0 th, 5 th and 10 th days;

c. strong light irradiation test: 3 batches of samples (placed in brown bottles) were prepared according to the recipe, placed in a light box with fluorescent lamps at an intensity of 4500 + -500 lx for 10 days, and sampled and tested at 0, 5, and 10 days.

The results are shown in Table 2.

TABLE 2 stability data of enrofloxacin-vanillin cocrystals

According to the experimental result, compared with the experimental sample, the appearance color and luster of the enrofloxacin-vanillin eutectic is not changed, and the content 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.