Gatifloxacin dicarboxylic acid eutectic compound as well as preparation method and application thereof

Abstract

The invention discloses a gatifloxacin dicarboxylic acid eutectic compound and a preparation method and application thereof.The eutectic compound is a strip-shaped single crystal, gatifloxacin and a proper eutectic forming agent are combined, and the eutectic compound is in a uniform and stable solid form. Moreover, the solubility of gatifloxacin in water is effectively improved, and absorption of gatifloxacin in a body is facilitated, so that the drug effect of gatifloxacin is improved, the stability and bioavailability of the drug are remarkably improved, and the clinical effect and patient compliance of gatifloxacin are improved.

Description

Technical Field

[0001] The invention relates to a cocrystal compound, in particular to a gatifloxacin dicarboxylic acid cocrystal compound, and also to a preparation method and application of the cocrystal compound. Background Art

[0002] Gatifloxacin, C 19 H 22 N3O4F is a fourth-generation fluoroquinolone antibiotic with the following chemical structure. Due to its broad-spectrum antibacterial activity and excellent pharmacokinetic properties, it is widely used in the treatment of various bacterial infections such as respiratory tract infections, urinary tract infections, skin and soft tissue infections, etc.

[0003]

[0004] Gatifloxacin inhibits bacterial DNA gyrase and topoisomerase IV, blocking the replication and transcription of bacterial DNA, thereby exerting its bactericidal effect. Compared with previous generations of fluoroquinolones, gatifloxacin exhibits a broader antibacterial spectrum and stronger antibacterial activity against Gram-positive and Gram-negative bacteria. In addition, gatifloxacin also has a certain inhibitory effect on certain drug-resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Gram-negative bacteria. Gatifloxacin is mainly used in the clinic to treat a variety of infectious diseases caused by sensitive bacteria, including acute bacterial sinusitis, acute exacerbation of chronic bronchitis, community-acquired pneumonia, complicated urinary tract infection, and acute pyelonephritis. Studies have shown that gatifloxacin has a good therapeutic effect in the above-mentioned infections, and has relatively few adverse reactions. Although gatifloxacin performs well in antibacterial therapy, its physicochemical properties, such as solubility and stability, still need to be improved, limiting its wide clinical application.

[0005] Common methods to improve drug solubility include crystal modification and drug cocrystals. The crystal modification method mainly adjusts the crystallization conditions of the drug to obtain an amorphous or metastable crystal with better solubility. However, these amorphous or metastable crystals are usually thermodynamically unstable and easily transformed into more stable crystals during storage or processing, resulting in decreased solubility or loss of efficacy. In contrast, the drug cocrystal method uses a crystal engineering strategy to combine the active ingredient of the drug with other physiologically acceptable ligands such as acids, bases or non-ionic compounds in the same crystal lattice through intermolecular forces. The drug cocrystals formed usually have good thermodynamic stability, can maintain efficacy and solubility for a long time, and reduce the risk of performance degradation during storage. At present, the research on the cocrystal ligand of gatifloxacin mainly selects monobasic acids containing benzene rings in the structure. This is because the benzene ring in the ligand can interact with gatifloxacin through π···π or CH···π to form a stable crystal structure. Although aromatic monobasic acids have this advantage, aliphatic dibasic acids have higher solubility and are therefore more suitable as cocrystal formers for gatifloxacin, making it easier to improve the drug's water solubility. However, how to successfully crystallize gatifloxacin with aliphatic dibasic acids and obtain high-quality crystals still faces great challenges. Summary of the invention

[0006] Purpose of the invention: The purpose of the present invention is to provide a gatifloxacin dicarboxylic acid cocrystal compound with good solubility and strong stability, and also relates to a preparation method and application of the above compound.

[0007] Technical solution: The gatifloxacin dicarboxylic acid cocrystal compound of the present invention has a structure as shown in Formula I:

[0008]

[0009] Among them, X is

[0010] Among them, the eutectic compound is a strip-shaped single crystal, and the gatifloxacin dicarboxylic acid eutectic compound is specifically compound 1 and compound 2.

[0011] Among them, compound 1 is formed by two gatifloxacin molecules and one glutaric acid molecule through hydrogen bonds to form a basic structural unit, and then the basic structural unit is repeatedly arranged to form. The chemical formula of gatifloxacin cocrystal compound 1 is:

[0012] [C 19 H 23 N3O4F]2[C5H6O4], which crystallizes in the triclinic system, with a space group of The unit cell parameters are: β=94.381(8)°, γ=103.329(8)°, Z=2, Wherein, the structural formula of the basic structural unit is:

[0013]

[0014] Among them, compound 2 is formed by a gatifloxacin molecule and a maleic acid molecule through hydrogen bonding to form a basic structural unit, and then the basic structural unit is repeatedly arranged. The chemical formula of gatifloxacin cocrystal compound 2 is:

[0015] [C 19 H 23 N3O4F][C4H3O4], which crystallizes in the monoclinic system, with a space group of The unit cell parameters are: α=77.360(8)°, β=85.646(7)°, γ=86.084(7)°, Z=2, Wherein, the structural formula of the basic structural unit is:

[0016]

[0017] The preparation method of the above-mentioned gatifloxacin dicarboxylic acid cocrystal compound comprises dissolving the cocrystal former dicarboxylic acid in a mixed solvent prepared by an organic solvent and water, adding gatifloxacin, continuously stirring, filtering, and collecting the filtrate; during the crystal growth process, adding a crystal growth inhibitor to the filtrate, and the filtrate volatilizes in a dry environment to obtain strip crystals, thereby obtaining the gatifloxacin dicarboxylic acid cocrystal compound.

[0018] Wherein, the added molar ratio of the dicarboxylic acid to gatifloxacin is 1:1-4.

[0019] Wherein, the dicarboxylic acid is glutaric acid or maleic acid.

[0020] Wherein, the organic solvent is one of methanol, ethanol, acetonitrile or dichloromethane.

[0021] Wherein, in the mixed solvent, the volume ratio of the organic solvent to water is 5 to 10:1.

[0022] Wherein, the crystal growth inhibitor is an amine compound.

[0023] The ratio of the added amount of the crystal growth inhibitor to gatifloxacin is 1:25-40.

[0024] The gatifloxacin dicarboxylic acid cocrystal compound can also be used in the preparation of antibacterial drugs.

[0025] Principle of the invention: The gatifloxacin dicarboxylic acid cocrystal compound of the present invention combines gatifloxacin with an appropriate cocrystal former to form a strip-shaped single crystal, which is in a uniform and stable solid form, and can not only maintain the original drug activity of gatifloxacin, but also effectively improve the solubility of gatifloxacin in water, which is helpful for its absorption in the body, thereby improving its efficacy, significantly improving the stability and bioavailability of the drug, and thus improving its clinical effect and patient compliance. The improvement in solubility may be attributed to the rich hydrogen bond network structure in the gatifloxacin dicarboxylic acid cocrystal compound. Each dibasic acid molecule is connected to two to four adjacent gatifloxacin molecules through NH···O hydrogen bonds to form a one-dimensional chain stacking structure, thereby enhancing the polarity of the cocrystal.

[0026] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The gatifloxacin dicarboxylic acid cocrystal compound of the present invention has good solubility, strong stability, and high bioavailability. Compared with the gatifloxacin raw material, its solubility can be increased by up to 1.93 times, which is conducive to its absorption in the body and is very suitable for clinical application; (2) The raw materials are cheap and easy to obtain, and the preparation method is simple, which is suitable for large-scale production and supply. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is the asymmetric unit diagram of gatifloxacin-glutaric acid cocrystal compound 1;

[0028] Figure 2 It is a crystal stacking structure diagram of gatifloxacin-glutaric acid cocrystal compound 1;

[0029] Figure 3 is the infrared spectrum of gatifloxacin-glutaric acid cocrystal compound 1;

[0030] Figure 4 A comparison diagram of the PXRD spectrum obtained by testing the gatifloxacin-glutaric acid cocrystal compound 1 and the spectrum obtained by simulating the single crystal structure;

[0031] Figure 5 is the UV absorption spectrum of gatifloxacin at different concentrations;

[0032] Figure 6 is the standard curve of gatifloxacin solubility;

[0033] Figure 7 is the ultraviolet absorption spectrum of gatifloxacin-glutaric acid cocrystal compound 1;

[0034] Figure 8 is the solubility standard curve of gatifloxacin-glutaric acid cocrystal compound 1;

[0035] Fig. 9 is the asymmetric unit diagram of gatifloxacin-maleic acid cocrystal compound 2;

[0036] Fig.10 It is the crystal stacking structure diagram of Gatifloxacin-maleic acid cocrystal compound 2;

[0037] Fig.11 is the infrared spectrum of gatifloxacin-maleic acid cocrystal compound 2;

[0038] Fig.12 A comparison diagram of the PXRD spectrum obtained by testing the gatifloxacin-maleic acid cocrystal compound 2 and the spectrum obtained by simulating the single crystal structure;

[0039] Fig.13 is the ultraviolet absorption spectrum of gatifloxacin-maleic acid cocrystal compound 2;

[0040] Fig.14 This is the solubility standard curve of gatifloxacin-maleic acid cocrystal compound 2. DETAILED DESCRIPTION

[0041] The technical scheme of the present invention is further described below in conjunction with the examples. The test materials used in the examples can all be purchased through conventional channels.

[0042] Example 1

[0043] The preparation method of the gatifloxacin co-compound 1 of the present invention is specifically as follows: 2 mmol of glutaric acid is weighed and dissolved in a mixed solution of acetonitrile and water, wherein the volume of acetonitrile is 18 mL and the volume of water is 2 mL, a glass container containing the mixed solution is placed on a stirrer, and stirred until the solution is clear; 2 mmol of gatifloxacin is then added thereto, stirring is continued for 10 min until all solids are dissolved, the solution is filtered, and the obtained filtrate is transferred to a clean beaker, the beaker is placed in a dry environment, and triethylamine, a crystal growth inhibitor, is added thereto, the solvent is slowly evaporated, and colorless transparent strip crystals (the outer diameter of the strip crystals is not less than 1 mm) are generated after 30 days, thereby obtaining the gatifloxacin-glutaric acid co-crystal compound 1, which has good crystal quality and a yield of 68% (based on gatifloxacin).

[0044] Example 2

[0045] The preparation method of the gatifloxacin co-compound 2 of the present invention is specifically as follows: 2 mmol of maleic acid is weighed and dissolved in a mixed solution of acetonitrile and water, wherein the volume of acetonitrile is 18 mL and the volume of water is 2 mL, a glass container containing the mixed solution is placed on a stirrer, and stirred until the solution is clear; 2 mmol of gatifloxacin is added thereto, stirring is continued for 10 minutes until all solids are dissolved, the solution is filtered, and the obtained filtrate is transferred to a clean beaker, the beaker is placed in a dry environment, and triethylamine, a crystal growth inhibitor, is added thereto, the solvent is slowly evaporated, and colorless transparent strip crystals (the outer diameter of the strip crystals is not less than 1 mm) are generated after 30 days, so as to obtain the gatifloxacin-maleic acid co-crystal compound 2, the crystal quality is good, and the yield is 61% (based on gatifloxacin).

[0046] Example 3

[0047] The preparation method of the gatifloxacin co-compound 1 of the present invention is specifically as follows: 2 mmol of glutaric acid is weighed and dissolved in a mixed solution of dichloromethane and water, wherein the volume of dichloromethane is 18 mL and the volume of water is 1 mL, a glass container containing the mixed solution is placed on a stirrer, and stirred until the solution is clear; 4 mmol of gatifloxacin is then added thereto, stirring is continued for 10 min until all solids are dissolved, the solution is filtered, and the obtained filtrate is transferred to a clean beaker, the beaker is placed in a dry environment, and triethylamine, a crystal growth inhibitor, is added thereto, the solvent is slowly evaporated, and colorless transparent strip crystals (the outer diameter of the strip crystals is not less than 1 mm) are generated after 20 days, thereby obtaining the gatifloxacin-glutaric acid co-crystal compound 1, which has good crystal quality and a yield of 52% (based on gatifloxacin).

[0048] Example 4

[0049] The preparation method of the gatifloxacin co-compound 1 of the present invention is specifically as follows: 2 mmol of glutaric acid is weighed and dissolved in a mixed solution of ethanol and water, wherein the volume of ethanol in the mixed solution is 15 mL and the volume of water is 3 mL, a glass container containing the mixed solution is placed on a stirrer, and stirred until the solution is clear; 4 mmol of gatifloxacin is then added thereto, stirring is continued for 10 min until all solids are dissolved, the solution is filtered, and the obtained filtrate is transferred to a clean beaker, the beaker is placed in a dry environment, and triethylamine, a crystal growth inhibitor, is added thereto, the solvent is slowly evaporated, and colorless transparent strip crystals (the outer diameter of the strip crystals is not less than 1 mm) are generated after 25 days, thereby obtaining the gatifloxacin-glutaric acid co-crystal compound 1, which has good crystal quality and a yield of 59% (based on gatifloxacin).

[0050] In Examples 1, 3 and 4, by changing the type of organic solvent, the raw materials are dissolved more fully in the mixed solution, and the solute content is greatly increased, which is conducive to obtaining a larger single crystal. The solubility of gatifloxacin in the mixed solvent increases because it is affected by its solvate in the organic solvent environment; at the same time, the growth inhibitor triethylamine slows down the crystal growth rate by blocking the intermolecular force between glutaric acid or maleic acid and gatifloxacin along the a-axis, thereby obtaining a larger diameter and transparent colorless strip crystal.

[0051] The crystal structures of Gatifloxacin cocrystal compounds 1 and 2 prepared in the examples were determined:

[0052] The structural data of the single crystal obtained in the example was collected by Bruker D8 Venture diffractometer using Mo-Kα radiation. The incident light source was 293 K. The single crystal structure was solved by direct method using OLEX2 software package. Then, the non-hydrogen atoms were anisotropically refined using full matrix least squares method. The hydrogen atoms connected to carbon atoms were added theoretically, and the hydrogen atoms connected to nitrogen atoms and oxygen atoms were determined by finding the position of Q peak. The obtained crystallographic data are shown in Table 1.

[0053] The minimum asymmetric unit of the gatifloxacin-glutaric acid cocrystal compound 1 of the present invention is as follows Figure 1 As shown, it contains two gatifloxacin molecules and one glutaric acid molecule. The gatifloxacin-glutaric acid cocrystal compound 1 obtained by the present invention crystallizes in the triclinic system, and the space group is The unit cell parameters are: α=110.645(9)°, β=94.381(8)°, γ=103.329(8)°, Z=2, In the structure of the gatifloxacin-glutaric acid cocrystal compound 1 of the present invention, proton transfer occurs between glutaric acid and gatifloxacin molecules, and one glutaric acid molecule simultaneously forms a strong NH...O hydrogen bond with two gatifloxacin molecules to form a minimum asymmetric structural unit.

[0054] The minimum asymmetric unit of the gatifloxacin-maleic acid cocrystal compound 2 of the present invention is as follows Fig. 9 As shown, it contains a gatifloxacin molecule and a maleic acid molecule. The gatifloxacin-maleic acid eutectic compound 2 obtained by the present invention crystallizes in the triclinic system, and the space group is The unit cell parameters are: α=77.360(8)°, β=85.646(7)°, γ=86.084(7)°, Z=2, In the structure of the gatifloxacin-maleic acid cocrystal compound 2 described in the present invention, proton transfer occurs between maleic acid and gatifloxacin molecules, and a strong NH...O hydrogen bond is formed between one maleic acid molecule and one gatifloxacin molecule, forming a minimum asymmetric structural unit.

[0055] Table 1. Crystal data of Gatifloxacin cocrystal compounds 1 and 2 obtained in Examples

[0056]

[0057]

[0058] The gatifloxacin-glutaric acid cocrystal compound 1 and gatifloxacin-maleic acid cocrystal compound 2 prepared in Example 1 were subjected to infrared spectroscopy testing. The infrared spectra of the obtained single crystals were collected on a Nicolet 5700 FT-IR spectrometer, with KBr as the substrate and a scanning range of 500-4000 cm -1 The infrared spectrum of Gatifloxacin-glutaric acid cocrystal compound 1 is attached. Figure 3 The main characteristic peaks of infrared spectrum are: 814, 1049, 1610, 1718, 3427cm -1 .1610cm -1 The absorption peak of NH belongs to the in-plane bending vibration of (NH), and its intensity is stronger than that of gatifloxacin raw material, indicating that it has been protonated. -1 The characteristic peaks are the stretching vibrations of (C=O), which are generated at 814, 1049, and 3427 cm -1 The characteristic peak is (OH) stretching vibration. As can be seen in the figure, the infrared absorption spectrum of gatifloxacin-glutaric acid cocrystal compound 1 contains the characteristic peaks of gatifloxacin raw materials and glutaric acid, proving that the gatifloxacin-glutaric acid drug cocrystal was successfully synthesized. The infrared spectrum of gatifloxacin-maleic acid cocrystal compound 2 is attached. Fig.11 The main characteristic peaks of infrared spectrum are: 1718, 1622, 2830, 3423cm -1 Among them, 1718cm -1 Attributable to (C=O) stretching vibration, 1622 cm -1 Attributable to (NH) in-plane bending vibration, 2830 cm -1 Attributable to (OH) stretching vibration, 3423 cm -1 It is attributed to (NH) stretching vibration. Its characteristic absorption peak is slightly shifted, indicating that hydrogen bonds are formed between gatifloxacin and maleic acid molecules, and the change in hydrogen bond pattern leads to peak displacement. Infrared spectrum shows that in gatifloxacin-maleic acid cocrystal compound 2, there are characteristic peaks of both gatifloxacin raw materials and maleic acid, indicating that the drug cocrystal has been successfully synthesized.

[0059] The gatifloxacin-glutaric acid cocrystal compound 1 and gatifloxacin-maleic acid cocrystal compound 2 prepared in Example 1 were subjected to powder X-ray diffraction (PXRD) test. The PXRD data were collected on a Rigaku Ultima IV diffractometer using Cu-Kα radiation ( 40kV, 40mA) as the incident light source, the test temperature was 293K, the 2θ angle range was 5°~40°, and the scanning speed was 5° / min. The spectrum of gatifloxacin-glutaric acid cocrystal compound 1 is shown in the attached figure. Figure 4 As shown in FIG. 1 , the obtained single crystal has strong diffraction peaks at 5.24, 10.09, 10.57, 13.38, 14.21, 16.27, 21.12, and 24.25°. The PXRD spectrum of gatifloxacin-maleic acid cocrystal compound 2 is shown in FIG. Fig.12 As shown, the obtained single crystal has strong diffraction peaks at 10.01, 12.70, 13.36, 15.50, 17.25, 22.79, 26.93, and 28.11°. According to the single crystal structure of gatifloxacin-glutaric acid cocrystal compound 1 and gatifloxacin-maleic acid cocrystal compound 2, their PXRD spectra were simulated by Mercury2024.1.0 software. The PXRD spectrum obtained by the experimental test matches well with the spectrum obtained by single crystal structure simulation, verifying the purity of the two single crystals of gatifloxacin-glutaric acid cocrystal compound 1 and gatifloxacin-maleic acid cocrystal compound 2.

[0060] The solubility test was performed on the gatifloxacin-glutaric acid cocrystal compound 1 and the gatifloxacin-maleic acid cocrystal compound 2 obtained in the examples:

[0061] At room temperature, accurately weigh 10 mg of gatifloxacin API powder using an analytical balance and pipette 20 mL of distilled water to completely dissolve it. The concentration of the solution is 0.5 mg / mL. -1 , dilute the mother solution with distilled water to 0.05, 0.04166, 0.03333, 0.025mgmL -1 The standard solution was prepared, and then a supersaturated solution was filtered through a filter membrane and diluted to an appropriate multiple for testing. The absorbance of the diluted gatifloxacin solution was tested using a Shimadzu UV-2450 ultraviolet spectrophotometer (see Appendix Figure 5 ), Table 2 shows the solution concentration (mgmL -1 ) and the maximum absorbance, and a standard curve was drawn based on this (see Appendix Figure 6 ). According to the ultraviolet absorption curve of gatifloxacin saturated solution, the maximum absorbance value was substituted into the regression equation, and the maximum solubility of gatifloxacin was calculated to be 1.064 mg mL -1 .

[0062] Table 2. Data table of the relationship between the concentration of gatifloxacin raw material and the maximum absorbance

[0063]

[0064] Using the same method, 10 mg of the powder of gatifloxacin-glutaric acid cocrystal compound 1 was accurately weighed with an analytical balance and diluted to perform a UV absorption curve test (see Appendix Figure 7 ), Table 3 shows the solution concentration (mgmL -1 ) and the maximum absorbance, and a standard curve was drawn based on this (see Appendix Figure 8 ). According to the ultraviolet absorption curve of the saturated solution of gatifloxacin-glutaric acid cocrystal compound 1, the maximum absorbance value was substituted into the regression equation, and the maximum solubility of gatifloxacin-glutaric acid cocrystal compound 1 was calculated to be 2.049 mg mL -1 Compared with the solubility of gatifloxacin API, the solubility of cocrystal compound 1 increased by 1.93 times. This indicates that gatifloxacin-glutaric acid cocrystal compound 1 effectively improves the solubility of gatifloxacin in water and facilitates its absorption in the body.

[0065] Table 3. Data table of the relationship between the concentration and maximum absorbance of gatifloxacin-glutaric acid cocrystal compound 1

[0066]

[0067] Similarly, 10 mg of the powder of gatifloxacin-maleic acid cocrystal compound 2 was accurately weighed using an analytical balance and diluted to perform a UV absorption curve test (see Appendix Fig.13 ), Table 4 shows the solution concentration (mgmL -1 ) and the maximum absorbance, and a standard curve was drawn based on this (see Appendix Fig.14 ).

[0068] Table 4. Data table of the relationship between the concentration and maximum absorbance of Gatifloxacin-Maleic Acid Cocrystal Compound 2

[0069]

[0070] According to the UV absorption curve of the saturated solution of gatifloxacin-glutaric acid cocrystal compound 1, the maximum absorbance value was substituted into the regression equation, and the maximum solubility of gatifloxacin-maleic acid cocrystal compound 2 was calculated to be 1.730 mg mL -1 Compared with the solubility of gatifloxacin API, the solubility of cocrystal compound 2 increased by 1.63 times. This indicates that gatifloxacin-maleic acid cocrystal compound 2 effectively improves the solubility of gatifloxacin in water and facilitates its absorption in the body.

Claims

1. A gatifloxacin dicarboxylic acid cocrystal compound, characterized in that: The compound structure is shown in Formula I: Among them, X is 2. The gatifloxacin dicarboxylic acid cocrystal compound according to claim 1, characterized in that: The eutectic compound is a strip-shaped single crystal.

3. A method for preparing the gatifloxacin dicarboxylic acid cocrystal compound according to claim 1, characterized in that: The preparation method comprises the following steps: dissolving a cocrystal former dicarboxylic acid in a mixed solvent prepared from an organic solvent and water, adding gatifloxacin, continuously stirring, filtering, and collecting the filtrate; during the crystal growth process, adding a crystal growth inhibitor to the filtrate, and volatilizing the filtrate in a dry environment to obtain strip crystals, thereby obtaining a gatifloxacin dicarboxylic acid cocrystal compound.

4. The preparation method according to claim 3, characterized in that: The added molar ratio of the dicarboxylic acid to gatifloxacin is 1:1-4.

5. The preparation method according to claim 3, characterized in that: The dicarboxylic acid is glutaric acid or maleic acid.

6. The preparation method according to claim 3, characterized in that: The organic solvent is one of methanol, ethanol, acetonitrile or dichloromethane.

7. The preparation method according to claim 3, characterized in that: In the mixed solvent, the volume ratio of the organic solvent to water is 5 to 10:

1.

8. The preparation method according to claim 3, characterized in that: The crystal growth inhibitor is an amine compound.

9. The preparation method according to claim 3, characterized in that: The ratio of the added crystal growth inhibitor to gatifloxacin is 1:25-40.

10. Use of the gatifloxacin dicarboxylic acid cocrystal compound according to claim 1 in the preparation of antibacterial drugs.

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