Trimethoprim-gentisic acid medicinal organic salt as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine crystallization, and particularly relates to trimethoprim-gentisic acid medicine organic salt and a preparation method and application thereof.The trimethoprim-gentisic acid medicine organic salt single crystal is obtained through a solvent slow volatilization method, and the trimethoprim-gentisic acid medicine organic salt single crystal is obtained through a chemical synthesis method. Trimethoprim-gentisic acid medicine organic salt powder is obtained through grinding or suspension, and the trimethoprim-gentisic acid medicine organic salt powder has excellent wet stability, thermal stability and light stability and better antibacterial effect and antioxidant effect; the solubility difference between trimethoprim and gentisic acid is reduced due to the formation of the medicine organic salt, synchronous release is realized, and synergistic effect is facilitated; the preparation method has the advantages of being simple and convenient to operate, green, safe and the like, and can replace trimethoprim medicine to be applied to treatment of inflammatory diseases caused by bacteria.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical crystallization, and particularly relates to a preparation method of trimethoprim-gentisic acid pharmaceutical organic salt. Background Art

[0002] Since the 21st century, the exacerbation of bacterial drug resistance caused by the abuse of antibiotics has become a major challenge in the global public health field. The World Health Organization (WHO) has warned about the problem of multi-drug resistant bacterial infections, and there is an urgent need to extend the life cycle of existing antibiotics through drug improvement strategies. Trimethoprim (TMP) is a dihydrofolate reductase inhibitor that exerts a broad-spectrum antibacterial effect by blocking bacterial folic acid metabolism. Its indications cover urinary tract infections, respiratory tract infections, intestinal infections, and malaria, etc., and it is used in veterinary medicine to treat bacterial infections in livestock and poultry. However, trimethoprim is prone to cause bacterial drug resistance when used alone. Moreover, trimethoprim is almost insoluble in water, resulting in limited absorption of oral preparations.

[0003] Gentisic Acid, namely 2,5-dihydroxybenzoic acid, also known as 5-hydroxybenzoic acid, is a natural phenolic acid that naturally exists in plants such as fruits of Gentiana, Citrus, grape, kiwifruit, etc. Gentisic Acid exhibits a wide range of biological activities, such as antioxidant, anti-inflammatory, antibacterial, antigenotoxic, hepatoprotective, neuroprotective effects, etc. Currently, Gentisic Acid is used as a food antioxidant; it can be used as an antioxidant excipient in the pharmaceutical industry. Existing studies have confirmed that Gentisic Acid, as a ligand of pharmaceutical multi-component crystal forms, can improve the solubility and stability of the parent drug.

[0004] Salt form screening is a commonly used strategy to optimize the physicochemical properties of active pharmaceutical ingredients (APIs). The solid-state properties of many drug molecules are not suitable for further development, while the physicochemical properties such as solubility, dissolution rate, stability, and processability can be improved through the salt formation strategy. The counterions of APIs used to form salts are usually pharmaceutically acceptable acids or bases. When the ligand molecule is a biologically active organic substance, the formed salt is called a pharmaceutical organic salt. Trimethoprim belongs to a weakly basic drug (the tertiary amino group of the pyrimidine ring has a pKa ≈ 7.2), and there is a possibility of proton transfer with Gentisic Acid having a carboxyl group (pKa ≈ 2.8). The formed pharmaceutical organic salt is expected to improve the solubility and dissolution rate of trimethoprim, increase the bioavailability and antibacterial effect. In addition, the antioxidant and anti-inflammatory properties of Gentisic Acid can also reduce the oxidative stress or inflammatory response related to trimethoprim treatment, thereby improving the overall tolerance. Currently, there is no public report on the pharmaceutical organic salt of trimethoprim-gentisic acid, its preparation method, and application. Summary of the Invention

[0005] To solve the above problems, the present invention provides a trimethoprim-gentisic acid drug organic salt, a preparation method thereof and an application thereof. The preparation method has the advantages of simple operation, green safety, etc., and has good wet stability, thermal stability and light stability.

[0006] To achieve the above object, the technical solution of the present invention is realized as follows:

[0007] The preparation method of the present application has the advantages of simple operation, green safety, etc. The obtained trimethoprim-gentisic acid drug organic salt has good wet stability, thermal stability and light stability; the formation of the drug organic salt increases the solubility of trimethoprim in pH 6.8 and pure water media by 4.94 times and 7.42 times respectively, reduces the solubility difference between trimethoprim and gentisic acid, and realizes the synchronous release of the two drug components in water and pH 6.8 intestinal simulated fluid, which is beneficial to the concentrations of the two active ingredients reaching the effective thresholds in the organism simultaneously; in addition, the drug organic salt has a synergistic antibacterial effect, which can also reduce the generation of drug-resistant strains to a certain extent, and can be used as a candidate drug composition for treating diseases caused by bacteria; moreover, the DPPH free radical scavenging rate of the drug organic salt is better than that of the raw drug, and it has stronger antioxidant activity.

[0008] On the one hand, the present application provides a trimethoprim-gentisic acid drug organic salt with the molecular formula C 14 H 18 N4O3·C7H6O4, in which the molar ratio of trimethoprim to gentisic acid is 1:1, and two N-H···O hydrogen bond interactions are formed between the NH+ and amino groups on the pyrimidine ring of the trimethoprim cation and the carboxyl group of gentisic acid respectively.

[0009] Preferably, the above trimethoprim-gentisic acid drug organic salt belongs to the monoclinic system, P21 / n space group, and the unit cell parameters are: α = 90°, β = 10.375(2)°, γ = 90°, Z = 4, ρ calc = 1.430 g / cm 3 .

[0010] Preferably, when the above trimethoprim-gentisic acid drug organic salt is analyzed by a powder X-ray diffractometer, its powder X-ray diffraction pattern has characteristic peaks at diffraction angles 2θ equal to 6.231°, 8.819°, 10.431°, 12.524°, 15.081°, 17.781°, 18.842°, 20.877°, 23.161°, 23.580°, 25.240°, 25.661°, 26.239°, 26.619°, 27.773°, 29.076° and 30.212°, etc., with an error range of ±0.3°.

[0011] Preferably, the differential scanning calorimetry curve of the above trimethoprim-gentisic acid drug organic salt shows a single and sharp melting endothermic peak at 252.6 ± 1.0 °C.

[0012] In a second aspect, the preparation method of the above trimethoprim-gentisic acid drug organic salt comprises the steps of: adding trimethoprim and gentisic acid to an organic solvent, stirring and heating to dissolve, filtering and then cooling to room temperature, and precipitating massive crystals by slow evaporation at room temperature to obtain single crystals of the trimethoprim-gentisic acid drug organic salt.

[0013] Preferably, the preparation method of the above trimethoprim-gentisic acid drug organic salt comprises the steps of: weighing trimethoprim and gentisic acid and mixing them evenly, adding a small amount of solvent and then carrying out mechanical grinding, and drying the solid product at room temperature to obtain the powder of the trimethoprim-gentisic acid drug organic salt.

[0014] Preferably, the preparation method of the above trimethoprim-gentisic acid drug organic salt comprises the steps of: weighing trimethoprim and gentisic acid and placing them in a glass bottle, adding an appropriate amount of solvent to form a suspension, stirring at room temperature, filtering, and drying and grinding the precipitate to obtain the powder of the trimethoprim-gentisic acid drug organic salt.

[0015] Preferably, the molar ratio of the above trimethoprim to gentisic acid is 1:1.

[0016] Preferably, the above organic solvent is any one of ethanol, methanol and acetonitrile.

[0017] In a third aspect, the application of the above trimethoprim-gentisic acid drug organic salt in the preparation of antibacterial, anti-inflammatory or antioxidant drugs.

[0018] The above trimethoprim-gentisic acid drug organic salt has a synergistic antioxidant and synergistic antibacterial effect, making it a candidate drug composition for treating inflammatory diseases caused by bacteria and scavenging free radicals in the body to a certain extent, and having a good application prospect.

[0019] The beneficial effects produced by the present invention are as follows:

[0020] 1. The present application prepares a trimethoprim-gentisic acid drug organic salt for the first time. Its preparation method has the advantages of simple operation, green and safe, etc. The product contains two drug active ingredients, namely trimethoprim and gentisic acid.

[0021] 2. The stability test results show that the organic salt of the drug has good thermal stability, humidity stability, and light stability. The results of the equilibrium solubility experiment show that the solubility of trimethoprim in the organic salt of the drug increases by 7.5 times and 4.9 times in water and pH 6.8 intestinal simulated fluid, respectively, and the solubility of gentisic acid decreases greatly in different dissolution media, creating conditions for the synchronous release of the two drugs. The in vitro dissolution experiment shows that trimethoprim and gentisic acid in the organic salt of the drug are synchronously released in pH 4.5, pH 6.8 solutions, and pure water media, which is beneficial to the concentrations of the two active ingredients reaching the effective threshold simultaneously in vivo to achieve better therapeutic effects.

[0022] 3. The results of the in vitro antibacterial experiment show that compared with the single drug use, the inhibition zone size of the organic salt of trimethoprim-gentisic acid against Staphylococcus aureus and Escherichia coli has a large increase, indicating that there is a synergistic antibacterial effect between the drugs. The results of the in vitro antioxidant experiment show that compared with the single drug use, the DPPH scavenging rate of the organic salt of trimethoprim-gentisic acid is improved, indicating that there is a synergistic antioxidant effect between the drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0024] Figure 1 It is the crystal structure unit of the single crystal of the organic salt of trimethoprim-gentisic acid prepared in Example 1.

[0025] Figure 2 It is the powder X-ray diffraction pattern of the organic salt of trimethoprim-gentisic acid and the raw material drug prepared in Example 2.

[0026] Figure 3 It is the differential scanning calorimetry analysis chart obtained by testing the organic salt of trimethoprim-gentisic acid and the raw material drug prepared according to Example 2.

[0027] Figure 4 It is the crystal form stability test result of the organic salt of trimethoprim-gentisic acid obtained by testing the sample prepared according to Example 2.

[0028] Figure 5 It is the equilibrium solubility test result of the organic salt of trimethoprim-gentisic acid obtained by testing the sample prepared according to Example 2.

[0029] Figure 6It is the dissolution curve graph of the sample prepared according to Example 2 for in vitro dissolution experiment, where (a) is the dissolution medium of pH 4.5 acetate buffer solution; (b) is the dissolution medium of pH 6.8 phosphate buffer solution; (c) is the dissolution medium of pure water.

[0030] Figure 7 It is the result graph of the in vitro antibacterial experiment of the sample prepared according to Example 2.

[0031] Figure 8 It is the result graph of the in vitro antioxidant experiment of the sample prepared according to Example 2. Detailed implementation manners

[0032] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0033] Example 1

[0034] A preparation method of trimethoprim-gentisic acid drug organic salt in this embodiment is as follows:

[0035] Weigh 0.2 mmol of trimethoprim and 0.2 mmol of gentisic acid and heat to dissolve in 20 mL of ethanol. After filtration, a transparent and clear solution is obtained. Seal it with a sealing film at room temperature and make several small holes to allow it to slowly volatilize for 7 days, thus obtaining a single crystal of trimethoprim-gentisic acid drug organic salt.

[0036] Perform single crystal X-ray diffraction characterization on the single crystal of trimethoprim-gentisic acid drug organic salt obtained in this embodiment. The characterization results are shown in Figure 1 . The single crystal analysis results show that the crystal structure unit includes a trimethoprim cation and a gentisic acid anion, belonging to the monoclinic system, P2_1 / n space group, and the unit cell parameters are: α = 90°, β = 10.375(2)°, γ = 90°, Z = 4, ρcalc = 1.430 g / cm 3 .

[0037] Example 2

[0038] A preparation method of trimethoprim-gentisic acid drug organic salt in this embodiment is as follows:

[0039] Weigh 0.5 mmol of trimethoprim and 0.5 mmol of gentisic acid powder, mix them evenly, and place them into the tank of a grinder. Use a pipette to transfer 100 μL of methanol to the above powder. The ball mill grinds at a frequency of 1500 rpm for 20 min. After completion, dry and grind the solid product at room temperature to obtain the trimethoprim-gentisic acid drug organic salt powder.

[0040] Figure 2 It is the powder X-ray diffraction pattern of the trimethoprim-gentisic acid drug organic salt prepared in this example (instrument: Rigaku SmartLab, Cu Kα radiation). As can be seen from the figure, the prepared sample has characteristic peaks at diffraction angles 2θ equal to 6.231, 8.819, 10.431, 12.524, 15.081, 17.781, 18.842, 20.877, 23.161, 23.580, 25.240, 25.661, 26.239, 26.619, 27.773, 29.076, 30.212, etc., with an error range of ±0.3°. The trimethoprim-gentisic acid drug organic salt prepared in this example shows peaks at the same 2θ angles as the single crystal simulated powder XRD of Example 1, indicating that their crystal structures are the same.

[0041] Figure 3 It is the differential scanning calorimetry analysis chart obtained by testing the trimethoprim-gentisic acid drug organic salt and the raw material drug prepared according to this example. The test is carried out in a NETZSCH DSC214 differential scanning calorimeter, using the same empty crucible as the reference. The test temperature range is 30 - 300 °C, the heating rate is 10 °C / min, nitrogen is passed as the protective gas, and the flow rate is 40 mL / min. It can be seen from the figure that a single and sharp melting endothermic peak appears at 252.6 ± 1.0 °C. This is different from trimethoprim and gentisic acid, indicating that the prepared sample is a new crystal form different from the raw material drug.

[0042] Example 3

[0043] A preparation method of a trimethoprim-gentisic acid drug organic salt in this example is as follows:

[0044] Weigh 0.5 mmol of trimethoprim and 0.5 mmol of gentisic acid and place them into a 20 mL glass bottle. Add 10 mL of ethanol and a magnetic rotor, then seal it. Magnetically stir at room temperature to form a suspension. After 24 hours, filter, and dry and grind the obtained precipitate to obtain the trimethoprim-gentisic acid drug organic salt powder.

[0045] The X-ray powder diffraction characterization results show that the powder X-ray diffraction pattern of the trimethoprim-gentisic acid drug organic salt prepared in this example shows peaks at the same 2θ angles as that of Example 2, indicating that their crystal structures are the same.

[0046] Test Example

[0047] 1. According to the standards of the Chinese Pharmacopoeia, the trimethoprim-gentisic acid drug organic salt prepared in Example 2 was stored under high temperature (60 °C), high humidity (90% RH) and strong light (4500 lx) conditions for 10 days to evaluate its stability. After the experiment was completed, the samples were characterized by PXRD.

[0048] Figure 4 It is the test result of the crystal form stability of the trimethoprim-gentisic acid drug organic salt obtained by testing the samples prepared in Example 2. Figure 4 The results showed that the crystal form of the drug organic salt did not change, that is, the drug organic salt had good thermal stability, humidity stability and light stability.

[0049] 2. Equilibrium solubility experiment of trimethoprim-gentisic acid drug organic salt.

[0050] Weigh 100 mg of trimethoprim-gentisic acid drug organic salt and an equimolar amount of the raw drug substance into a 10 mL centrifuge tube, add 2 mL of different media (pH 1.2, pH 4.5, pH 6.8 and pure water), and continuously shake in a constant temperature oscillator at 37 °C for 48 h. Take the supernatant and filter it through a 0.45 μm membrane, and then immediately dilute it with pure water by a certain multiple. Use a high performance liquid chromatograph (HPLC) to measure the saturated equilibrium solubility of the samples. The parallel samples are 3 groups (n = 3), and the solubility unit is mg / mL.

[0051] Figure 5 It is the experimental result of the equilibrium solubility test of the samples prepared in Example 2. Figure 5 The results showed that the solubility of trimethoprim changed to varying degrees in different pH media after forming a salt. Among them, the solubility increased to 7.5 times the original in water, 4.9 times the original in pH 6.8 buffer, and the solubility change was not significant in pH 1.2 and pH 4.5 buffers; while the solubility of gentisic acid changed greatly in different pH buffers after forming a salt. In pH 1.2, pH 4.5, pH 6.8 and pure water, the solubility of gentisic acid decreased to 9.0, 84.0, 40.8 and 55.5 times that of the raw drug substance respectively. The significant decrease in solubility not only helps to reduce the toxic and side effects caused by excessive gentisic acid in the body, but also creates conditions for the synchronous release of trimethoprim and gentisic acid.

[0052] 3. In vitro dissolution test of trimethoprim-gentisic acid drug organic salt.

[0053] Weigh the organic salt of trimethoprim and gentisic acid and the raw material powder in an equimolar amount. Use a dissolution tester in the experiment, with a paddle speed of 75 rpm. Prepare pH 4.5 acetate duodenal simulated fluid, pH 6.8 phosphate small intestine simulated fluid, and purified water as dissolution media. When the temperature stabilizes at 37 °C, put the samples into the dissolution media. Samples are taken at 5, 10, 15, 30, 45, 60, 90, and 120 min respectively. After passing all the extracted solutions through a 0.45 μm membrane, measure their concentrations by HPLC, with 3 parallel samples (n = 3).

[0054] Figure 6 It is the experimental result of the dissolution test conducted on the samples prepared according to Example 2. In the pH 4.5 dissolution medium, the two drugs in the organic salt of trimethoprim and gentisic acid showed a certain synchronous sustained-release effect; in the pH 6.8 small intestine simulated fluid dissolution medium and pure water medium, the formation of the organic salt of trimethoprim and gentisic acid significantly reduced the dissolution rate of gentisic acid, effectively avoiding the toxic and side effects caused by the excessive concentration of gentisic acid in the body in a short time, and the dissolution curves of trimethoprim and gentisic acid in the drug organic salt basically coincided, indicating that the two were released synchronously, which had a positive effect on the synergistic effect of the drug and was conducive to achieving better therapeutic effects.

[0055] IV. In vitro antibacterial experiment of the organic salt of trimethoprim and gentisic acid.

[0056] The modified Kirby-Bauer agar diffusion method was used in the experiment. Escherichia coli (ATCC 11775) and Staphylococcus aureus (ATCC 6538) were used as experimental strains to determine the in vitro antibacterial activities of trimethoprim, gentisic acid, and the drug organic salt. The specific experimental steps include:

[0057] (1) Add the stored strains to an appropriate amount of NB nutrient broth and incubate in a 37 °C constant temperature shaker for 12 h.

[0058] (2) Prepare NA nutrient agar medium, sterilize it at a high temperature of 121 °C, and place it in a 50 °C incubator for heat preservation and standby after sterilization.

[0059] (3) Adjust the bacterial suspension to an appropriate concentration with NB nutrient broth, take 200 μL of the bacterial suspension and pour it into the NA nutrient agar medium at about 50 °C, and shake well.

[0060] (4) Pour 15 mL of the NA nutrient agar medium containing bacteria into a petri dish and wait for it to cool and solidify.

[0061] (5) Sterile filter papers soaked in 20 μL of 0.5 mmol / L and 1.0 mmol / L trimethoprim, gentisic acid, trimethoprim-gentisic acid drug organic salt, and sterile water were placed on the agar plate respectively.

[0062] (6) The agar plate with the drug-containing filter paper was incubated at 37 °C for 12 h, and the diameter of the blank area of the filter paper was measured as the antibacterial standard. The parallel samples were in 3 groups (n = 3).

[0063] Figure 7 It is the experimental result of the in vitro antibacterial experiment conducted on the sample prepared according to Example 2. Table 1 shows the inhibition zone diameters of trimethoprim-gentisic acid drug organic salt and the raw drug against Escherichia coli and Staphylococcus aureus. It can be seen from Table 1 that gentisic acid did not show antibacterial activity, probably because these two concentrations did not reach the minimum inhibitory concentration of gentisic acid; however, at the same concentration, the drug organic salt had better inhibitory effects on Escherichia coli and Staphylococcus aureus than trimethoprim, indicating that trimethoprim and gentisic acid had a synergistic antibacterial effect.

[0064] Table 1 Results of in vitro antibacterial experiment

[0065]

[0066] V. In vitro antioxidant experiment of trimethoprim-gentisic acid drug organic salt.

[0067] DPPH is a free radical, and its full name is 1,1-diphenyl-2-trinitrophenylhydrazine. The DPPH alcohol solution is dark purple, and its maximum absorption wavelength is 519 nm. When there is a free radical scavenger, the single electron of DPPH will pair with it, making the solution turn colorless or light yellow, and at the same time, the absorbance value at the maximum absorption wavelength decreases. The decrease in the absorbance level indicates that the sample has antioxidant properties, so it is often used to evaluate the antioxidant ability of the sample. The specific operation steps include:

[0068] (1) Prepare stock solutions with concentration gradients (10, 9, 8, 7, 6, 5, 4, 3, 2 μmol / mL) of the sample using ethanol.

[0069] (2) Prepare a 0.1 mmol / L DPPH ethanol solution using ethanol, and ensure it is prepared and used immediately.

[0070] (3) Add 180 μL of DPPH ethanol solution to each well of a 96-well plate under dark conditions, and then add 20 μL of the sample solution respectively. The final concentrations of the sample in the 96-well plate are 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2 μmol / mL respectively. Add 20 μL of anhydrous ethanol to the last column as a negative control. After thorough mixing, react for 30 minutes in the dark.

[0071] (4) The absorbance value was measured at 519 nm using a microplate reader and denoted as the A value. The negative control was denoted as the A0 value. There were 3 sets of parallel samples (n = 3). Calculate the DPPH free radical scavenging rate = (1 - A / A0) * 100%.

[0072] Figure 8 It is the experimental result of the in vitro antioxidant experiment conducted on the sample prepared according to Example 2. From Figure 8 it can be seen that the DPPH scavenging rates of gentisic acid and the drug organic salt increase with the increase of the drug concentration at lower concentrations and basically level off after reaching a concentration of 0.6 μmmol / L, indicating that the DPPH scavenging rate has reached the maximum. At this time, the DPPH scavenging rate of trimethoprim is only about 15%. Gentisic acid has a relatively strong antioxidant ability, with a DPPH scavenging rate of about 45%. The formation of the drug organic salt enhances the antioxidant ability of the active pharmaceutical ingredient, and the DPPH scavenging rate reaches more than 60%. The antioxidant abilities of gentisic acid and trimethoprim show a synergistic or additive effect; while at a concentration of 0.3 - 0.5 μmmol / L, the DPPH of the drug organic salt is significantly higher than the sum of trimethoprim and gentisic acid, showing a synergistic antioxidant effect.

[0073] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A trimethoprim-gentisic acid pharmaceutical organic salt, characterized in that: The molecular formula of the trimethoprim-gentisic acid pharmaceutical organic salt is C 14 H 18 N4O3·C7H6O4, belonging to the monoclinic system, P 21 / n space group, and the unit cell parameters are: a a = 6.9970(2) Å, b = b = 28.1246(7) Å, c c = 10.7843(3) Å, α= α = 90º, β= β = 10.375(2) º, γ = γ = 90º, V V = 2064.66(10) Å 3 , Z = 4, ρ calc ρ = 1.430 g / cm 3 .

2. The trimethoprim-gentisic acid pharmaceutical organic salt according to claim 1, wherein: The molar ratio of trimethoprim to gentisic acid in the trimethoprim-gentisic acid pharmaceutical organic salt is 1:

1.

3. The trimethoprim-gentisic acid pharmaceutical organic salt according to claim 2, wherein: The trimethoprim-gentisic acid pharmaceutical organic salt exhibits a single and sharp melting endothermic peak at 252.6 ± 1.0 °C.

4. The preparation method of the trimethoprim-gentisic acid pharmaceutical organic salt according to claim 1, characterized in that, The steps are as follows: Add trimethoprim and gentisic acid to a solvent, stir and heat to dissolve, filter, and then cool to room temperature. Blocky crystals are precipitated by slow evaporation at room temperature to obtain the product.

5. The preparation method of the trimethoprim-gentisic acid pharmaceutical organic salt according to claim 1, characterized in that, The steps are as follows: Weigh trimethoprim and gentisic acid and mix them evenly. Add a solvent and carry out mechanical grinding. Dry the solid product at room temperature to obtain the product.

6. The preparation method of the trimethoprim-gentisic acid pharmaceutical organic salt according to claim 1, characterized in that, The steps are as follows: Weigh trimethoprim and gentisic acid and place them in a glass bottle. Add an appropriate amount of solvent to form a suspension. Stir at room temperature, filter, and then dry and grind the precipitate to obtain the product.

7. The preparation method according to any one of claims 4 to 6, characterized in that: The molar ratio of trimethoprim to gentisic acid is 1:

1.

8. The preparation method according to any one of claims 4 to 6, characterized in that: The solvent is any one of ethanol, methanol, and acetonitrile.

9. Use of the trimethoprim-gentisic acid pharmaceutical organic salt according to any one of claims 1-3 in the preparation of antibacterial drugs.

10. Use of the trimethoprim-gentisic acid pharmaceutical organic salt according to any one of claims 1-3 in the preparation of anti-inflammatory or antioxidant drugs.

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