A pipemidic acid-salicylic acid drug-drug salt and preparation method thereof

Abstract

The present invention relates to a pipemidic acid-salicylic acid drug-drug salt and a preparation method thereof; pipemidic acid, salicylic acid and an organic solvent are mixed, and the pipemidic acid-salicylic acid drug-drug salt is prepared by a volatile solvent crystallization method: the structural formula of the drug-drug salt is as follows; pipemidic acid and salicylic acid are mixed and added to an organic solvent, and heated to form a clear solution; then the volatile solvent is cooled until the total volatile amount of the solvent accounts for 80-90% of the initial organic solvent volume to obtain a slurry; filtered, and the filter cake is dried at 40-60°C. Pimidic acid-salicylic acid drug-drug salt has excellent wet stability and thermal stability, and a significant solubilization effect. The synergistic antibacterial effect of pipemidic acid and salicylic acid improves the antibacterial performance, showing an antibacterial effect of 1+1>2. The pipemidic acid-salicylic acid drug-drug salt of the present invention is used to replace the pipemidic acid drug; at the same time, the preparation method is simple to operate, has low energy consumption, a small amount of solvent, good product reproducibility, and a high yield. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of drug-drug salts, and in particular to a pipemidic acid-salicylic acid drug-drug salt and a preparation method thereof; a drug-drug salt formed by pipemidic acid and salicylic acid and a preparation method thereof are provided. Background Art

[0002] Pipemidic acid is one of the most representative drugs of the second-generation quinolones. It has a broad spectrum of antibacterial activity and is mainly used for urinary tract, intestinal and ear canal infections caused by sensitive Gram-negative bacilli and Staphylococci. The medicinal form of pipemidic acid is pipemidic acid trihydrate, with a molecular formula of C 14 H 17 N5O3·3H2O, the structural formula is shown in (I). Dissolution and dissolution rate are important indicators of drug performance. Soluble drugs have high dissolution concentration and fast dissolution rate. For example, the soluble drug bamipine chloride can reach the maximum dissolution concentration C in 1 minute in pure water at 37°C and pH 5.6. max In comparison, the dissolution concentration of pipemidic acid trihydrate in pure water at 37°C and pH 5.6 was 0.022±0.003 mg / mL in 1 minute, and the maximum dissolution concentration C max It is only 0.441±0.06mg / mL. The poor water solubility and slow dissolution of pipemidic acid lead to its low bioavailability in vivo, which affects its efficacy and clinical application. Therefore, improving the maximum solubility and dissolution rate of pipemidic acid is the key to improving the bioavailability and efficacy of pipemidic acid.

[0003]

[0004] Compared with active pharmaceutical ingredients, active pharmaceutical ingredients generally have greater solubility and dissolution rate, higher crystallinity and melting point after being salted, so preparing salts is a common form of improving the physical and chemical properties of active pharmaceutical ingredients. Fun (10.1107 / S0108270198018277) disclosed pipemidic acid-hydrochloride. Hydrochloric acid has no pharmaceutical activity, and hydrochloride is hygroscopic, which causes problems such as drug agglomeration, deliquescence or deterioration. Zhang et al. (DOI: 10.1039 / D1NJ03314J) disclosed two salts formed by pipemidic acid with 2,3-dihydroxybenzoic acid and m-hydroxybenzoic acid, respectively. Both salts are hydrates. Among them, the ligand 2,3-dihydroxybenzoic acid is not listed as GRAS (Generally Recognized As Safe) by the FDA, so pipemidic acid-2,3-dihydroxybenzoate hydrate cannot be used medicinally. Zhang et al. (DOI:10.1039 / D1NJ03314J) reported the dissolution curves of pipemidic acid-2,3-dihydroxybenzoate hydrate and pipemidic acid-m-hydroxybenzoate hydrate in pure water at 37°C and pH 5.6. The dissolution concentrations of the two salt hydrates reached the maximum dissolution concentrations at around 650 min and 600 min, respectively. max 0.668mg / mL and 0.252mg / mL respectively, see attached Figure 1 . The time for these two salt hydrates to reach the maximum dissolution concentration is too long, the dissolution rate is low, and the yields based on pipemidic acid are 63% and 58% respectively. The synthetic yield is too low, which is not conducive to industrial production. Compared with the anhydrous form, the active drug ingredient pipemidic acid or (and) ligands in the hydrate have formed hydrogen bonds, van der Waals and other molecular interactions with water molecules, thereby reducing the available hydration sites of the active drug molecules and reducing the solvation free energy. Therefore, the solubility of the drug salt hydrate is usually lower than that of its anhydrate, which is not conducive to improving water solubility. Patent CN1660812A discloses pipemidic acid-mandelate salt and its preparation method. A certain proportion of mandelic acid and pipemidic acid or pipemidic acid-hydrochloride is added to a certain amount of ethanol or isopropanol, stirred, heated to reflux for 2 to 5 hours, and after sufficient salt formation, an appropriate amount of activated carbon is added, and then refluxed for 0.5 hours, filtered while hot, the filtrate is cooled and crystallized, and then the slurry is filtered, and the filter cake is washed with an appropriate amount of ethanol. The filter cake is dried at 80°C to obtain. Patent CN102391107A discloses pipemidic acid-gallate and its preparation method, and the preparation method is similar to the method disclosed in patent CN1660812A. The methods disclosed in these two patents take a long time to prepare and are cumbersome; the reaction process requires heating and reflux, hot filtration requires pipeline insulation, the drying process continues at high temperature, and the heat and cold demand are large, especially the pipemidic acid-gallate drying process requires vacuum, which greatly increases energy consumption. The most disadvantageous thing is that gallic acid and mandelic acid are not listed as GRAS by the FDA, and their corresponding pipemidic acid salts cannot be used medicinally.

[0005] At present, pipemidic acid and its salts have the problems of low dissolution rate, low maximum dissolution concentration, easy hygroscopicity, and the salt-forming ligand cannot be used for medicine. The preparation method has the problems of many steps, low yield, and high energy consumption. It is necessary to develop a solid form of pipemidic acid that is pharmaceutically safe and reliable, has a high maximum dissolution concentration, a high dissolution rate, and good wet stability, and the preparation method thereof is simple to operate, has a high yield, and has low energy consumption. Summary of the invention

[0006] According to the deficiencies of the prior art, the present invention proposes a pipemidic acid-salicylic acid drug-drug salt and a preparation method thereof; because most active drug molecules have deficiencies in pharmacokinetics and physicochemical properties (dissolution, dissolution rate, hygroscopicity and chemical stability, etc.), these properties will greatly affect the clinical treatment effect. We prepare the active drug ingredient with complementary physicochemical properties and another ligand that also has pharmaceutical activity into a drug-drug salt, which may not only make up for the deficiencies in the physicochemical properties of the active drug ingredient, but also is expected to improve the bioavailability of the drug and achieve a therapeutic effect of 1+1>2.

[0007] Salicylic acid is a well-known anti-inflammatory drug. Its salt with choline has been used to treat mild to moderate pain and reduce fever and inflammation. In addition, salicylic acid is also an antibacterial agent used in combination with fluoroquinolone antibiotics to treat pseudomonal keratitis. Salicylic acid has been listed as GRAS by the FDA and is a pharmaceutically acceptable drug ingredient; the pKa values ​​of pipemidic acid and salicylic acid were calculated by ChemAxon. In the molecular structure of pipemidic acid, the nitrogen atom on the piperazine ring imino group has the largest pKa value of 8.66, and the carboxyl group of salicylic acid has the smallest pKa value of 2.97. The △pKa value of pipemidic acid and salicylic acid is 5.69, which is greater than 3, and proton transfer is easy to occur between them to form salts. Furthermore, the molecular electrostatic potential surface of pipemidic acid and salicylic acid was calculated by quantum chemistry (see Appendix). Figure 2 and attached Figure 3 ). Compared with the carbonyl oxygen in the carboxyl group of pipemidic acid (electrostatic potential of -56.01 kcal / mol), the hydroxyl group in the molecular structure of salicylic acid is closest to the carboxyl group. This special position makes the hydroxyl group (electrostatic potential of 17.95 kcal / mol) very easy to form hydrogen bonds with the carbonyl oxygen on its own carboxyl group (electrostatic potential of -29.05 kcal / mol) and the electrostatic potential is complementary. Therefore, the only hydroxyl group on the benzene ring of salicylic acid is very likely to form intramolecular hydrogen bonds. Therefore, salicylic acid can not only interact with pipemidic acid to form synthons through hydrogen bonds, but also the intermolecular interaction network formed is relatively simple, which is conducive to the dissolution of pipemidic acid. Compared with single-component pipemidic acid and salicylic acid, the drug-drug salt formed by the two components may enhance the leakage of bacterial cell contents due to synergistic effects, significantly improve antibacterial activity and bioavailability, thereby achieving a therapeutic effect of 1+1>2.

[0008] The purpose of the present invention is to disclose a pipemidic acid-salicylic acid drug-drug salt and a preparation method thereof. The prepared pipemidic acid-salicylic acid drug-drug salt is a colorless, transparent prism-shaped crystal with good stability and a maximum dissolution concentration C max The method has high dissolution rate, which helps to improve the bioavailability. In addition, the amount of solvent used is small, the method is simple to operate and easy to repeat.

[0009] The molecular formula of the pipemidic acid-salicylic acid drug-drug salt is [C 14 H 18 N5O3·C7H5O3], the structural formula is shown in II, and the stoichiometric ratio of pipemidic acid to salicylic acid is 1:1. The drug-drug salt is a monoclinic crystal system with a space group of P21 / n and unit cell parameters of: α=90°,β=98.019(5)°,γ=90°,the unit cell volume is Each unit cell contains 4 pipemidic acid-salicylic acid molecules, see attached Figure 4 shown.

[0010]

[0011] The X-ray powder diffraction pattern of the pipemidic acid-salicylic acid drug-drug salt has characteristic peaks at diffraction angles 2θ=7.22°±0.2°, 8.02°±0.2°, 13.61°±0.2°, 14.93°±0.2°, 16.36°±0.2°, 17.41°±0.2°, 20.01°±0.2°, 20.53°±0.2°, 25.71°±0.2°, 26.72°±0.2°, and 29.74°±0.2°. The X-ray powder diffraction pattern is shown in the attached Figure 5 shown.

[0012] The differential scanning calorimetry (DSC) curve and thermogravimetric analysis (TGA) curve of the pipemidic acid-salicylic acid drug-drug salt are shown in the attached Figure 6 As shown, the DSC of the drug-drug salt begins to absorb heat at 240±1°C, and the TGA begins to lose weight from 244±1°C, corresponding to the melting decomposition process of the pipemidic acid-salicylic acid drug-drug salt.

[0013] The preparation method of the pipemidic acid-salicylic acid drug-drug salt disclosed in the present invention is a volatile solvent crystallization method, and the specific steps include:

[0014] (1) mixing pipemidic acid and salicylic acid in a molar ratio of 1:1, adding an organic solvent, and heating to 55-65° C. to form a clear solution;

[0015] (2) cooling the clarified solution to 20-45° C., and evaporating the solvent until the total evaporation amount of the solvent accounts for 80-90% of the initial volume of the organic solvent to obtain a slurry;

[0016] (3) Filter the above slurry and dry the filter cake at 40-60°C.

[0017] In the step (1), the total mass ratio of pipemidic acid and salicylic acid to the volume of the organic solvent is 0.011 to 0.016 g / mL.

[0018] The solvent volatilization method comprises the following steps: firstly volatilizing the solvent at a rate of 0.7-1.8% of the initial organic solvent volume per hour until the volatilized amount accounts for 35-40% of the initial organic solvent volume, precipitating colorless transparent prism crystals, and then continuing to volatilize the solvent at a rate of 8.0-20.0% of the initial organic solvent volume per hour until the total volatilized amount of the solvent accounts for 80-90% of the initial organic solvent volume.

[0019] The pipemidic acid is selected from pipemidic acid form A, pipemidic acid form B, pipemidic acid hydrate or a mixture thereof.

[0020] The organic solvent is selected from one of methanol, ethanol, isopropanol, acetone, butanone, acetonitrile or tetrahydrofuran.

[0021] The application of the pipemidic acid-salicylic acid drug-drug salt of the present invention in replacing the pipemidic acid drug.

[0022] At present, pipemidic acid and its salts have the problems of low dissolution rate, low maximum dissolution, easy hygroscopicity, and the salt-forming ligand cannot be used for medicine. The preparation method has the problems of many steps, low yield, high energy consumption, etc. The present invention develops a method with simple operation and low energy consumption to produce pipemidic acid-salicylic acid drug-drug salt which is pharmaceutically safe and reliable, has high maximum dissolution concentration and high dissolution rate.

[0023] The present invention adopts a volatile solvent crystallization method to prepare pipemidic acid-salicylic acid drug-drug salt. In order to obtain crystals with larger particle size, the initial solvent volatilization rate is slow and small. After the crystals are precipitated, the solvent volatilization rate is increased to improve efficiency. The yield of the pipemidic acid-salicylic acid drug-drug salt prepared by the present invention can reach 89%. The yield of pipemidic acid-m-hydroxybenzoate disclosed by Zhang et al. (DOI: 10.1039 / D1NJ03314J) is 58%. In comparison, the yield of the pipemidic acid-salicylic acid drug-drug salt of the present invention is higher and suitable for mass production.

[0024] The interactions in the crystal structure of the pipemidic acid-salicylic acid drug-drug salt prepared by the present invention are as follows: Figure 4As shown. In the crystal structure, the carboxyl proton of salicylic acid is transferred to the nitrogen atom of the piperidinium ring imino group of piperidinium acid, and an O1-H1···O2 intramolecular hydrogen bond is formed between the hydroxyl group and the carboxylate group of salicylic acid. Except for the charge-assisted hydrogen bond formed between the carboxyl group of salicylic acid and the piperidinium ring imino group of piperidinium acid, there is no other intermolecular interaction between the two. This fact is consistent with the prediction results based on △pKa and molecular electrostatic potential surface. The larger the lattice energy, the more energy is consumed to destroy its crystal structure, and the less conducive it is to release the molecule from the lattice. Molecular dynamics simulation was used to calculate the lattice energies of piperidinium acid-isohydroxybenzoate hydrate and piperidinium acid-salicylic acid drug-drug salt, which were -305.08 kcal / mol and -152.02 kcal / mol, respectively. In comparison, the lattice energy of the piperidinium acid-salicylic acid drug-drug salt disclosed in the present invention is lower, and piperidinium acid is more easily released from the lattice. As shown in the attached figure Figure 7 In the crystal structure of pipemidic acid-salicylic acid drug-drug salt, the main crystal face exposes hydrophilic groups such as carboxyl, carbonyl, and amino groups, which help water molecules diffuse into the crystal lattice and promote dissolution. In the crystal structure of pipemidic acid-m-hydroxybenzoate hydrate, the crystal face (001) is composed of lipophilic groups phenyl, and the crystal face (010) only exposes hydrophilic groups amino groups. The main crystal face exposes fewer hydrophilic groups and fewer solvation sites, which is not conducive to the solvation of pipemidic acid. The pipemidic acid-salicylic acid drug-drug salt disclosed in the present invention has low lattice energy, few intermolecular interactions in the crystal structure, and many exposed hydrophilic groups on the crystal face, which provide important structural support for improving the solubility and bioavailability of pipemidic acid.

[0025] The literature reports the maximum dissolution concentration of pipemidic acid-m-hydroxybenzoate hydrate in pure water at 37°C and pH 5.6. max The dissolution rate is 0.252 mg / mL, and the dissolution rate is less than 0.001 mg / mL / min (Zhang et al., DOI: 10.1039 / D1NJ03314J). In order to compare with pipemidic acid-m-hydroxybenzoate hydrate, the applicant measured the dissolution curves of pipemidic acid trihydrate and pipemidic acid-salicylic acid drug-drug salt prepared by the present invention in pure water at 37°C and pH 5.6. The pipemidic acid concentration in the pipemidic acid trihydrate aqueous solution and the pipemidic acid-salicylic acid drug-drug salt aqueous solution reached the maximum at 20±1min and 90±1min, respectively, and maintained the maximum dissolution concentration. max The dissolution rates were 0.022±0.003mg / mL / min and 0.066±0.002mg / mL / min, respectively. The dissolution experiment showed that the maximum dissolution concentration C of the pipemidic acid-salicylic acid drug-drug salt disclosed in the present invention was 0.441±0.06mg / mL and 5.953±0.15mg / mL, respectively. The dissolution rates were 0.022±0.003mg / mL / min and 0.066±0.002mg / mL / min, respectively. max The dissolution rate is greater than that of the currently used pharmaceutical form of pipemidic acid trihydrate, and much greater than that of pipemidic acid-m-hydroxybenzoate hydrate.

[0026] In order to compare the wet stability of pipemidic acid-hydrochloride and pipemidic acid-salicylic acid drug-drug salt prepared by the present invention, the adsorption / desorption isotherms of the two at 25°C were determined. For pipemidic acid-salicylic acid drug-drug salt, the relative humidity increased from 0% to 95±0.5%, and the sample mass increased by 0.25±0.01%, and when the relative humidity decreased to 0%, the sample mass returned to the initial mass. For pipemidic acid-hydrochloride, when the relative humidity was steadily increased to 95±0.5%, pipemidic acid-hydrochloride showed a mass increase of 1.5±0.01%, which is about 6 times that of the pipemidic acid-salicylic acid drug-drug salt disclosed in the present application. The results show that compared with pipemidic acid-hydrochloride, the pipemidic acid-salicylic acid drug-drug salt provided by the present invention shows excellent wet stability.

[0027] The pipemidic acid-salicylic acid drug-drug salt prepared by the present invention was subjected to an accelerated stability test. The drug was stored at a temperature of 40° C. and a relative humidity of 75±5% for 8 weeks, and samples were taken at 0 days, 2 weeks, 4 weeks, and 8 weeks, respectively, and X-ray powder diffraction analysis was performed. The results showed that the X-ray powder diffraction pattern remained unchanged, indicating that the crystal structure did not change and the thermal stability was good.

[0028] The applicant used the Kirby Bauer agar diffusion method to determine the antibacterial activity of pipemidic acid trihydrate, pipemidic acid-salicylic acid drug-drug salt prepared by the present invention, and salicylic acid. Weigh 2.5g of Luria-Bertani broth medium and 1.5g of agar powder respectively, add 100mL of distilled water, and sterilize with high-temperature and high-pressure steam. After cooling to 40-50°C, draw 15mL and pour it into a disposable sterile culture dish to obtain Luria-Bertani solid culture medium at room temperature for standby use. Add Escherichia coli to the broth and culture it in an incubator at 37°C for 15 hours. Dilute the Escherichia coli culture solution to 10 with sterile phosphate buffer solution. 6CFU / mL (the number of bacteria or fungi per unit volume, Colony forming unit means colony forming unit), take 100 μL of the dilution and evenly spread it on the Luria-Bertani solid medium. A sterile filter paper with a diameter of 8 mm was immersed in 14 mmol / L dimethyl sulfoxide solution of pipemidic acid trihydrate, pipemidic acid-salicylic acid drug-drug salt, and salicylic acid, respectively. Another sterile filter paper was immersed in dimethyl sulfoxide as a control group. The treated sterile filter paper was sandwiched in the Luria-Bertani solid culture medium, gently pressed, and the culture dish was placed in a 37°C constant temperature incubator for standing. The culture dishes containing sterile filter paper immersed in dimethyl sulfoxide solution of pipemidic acid trihydrate, pipemidic acid-salicylic acid drug-drug salt, and salicylic acid were recorded as groups 1, 2, and 3, respectively, and the culture dish containing sterile filter paper immersed in dimethyl sulfoxide was recorded as group 4. After 24 hours, the diameters of the inhibition zones around the filter paper in groups 1, 2, 3, and 4 were measured and recorded as d1, d2, d3, and d4, respectively. The results show that compared with pipemidic acid trihydrate and salicylic acid, the diameter d2 of the inhibition zone of the pipemidic acid-salicylic acid drug salt prepared by the present invention is the largest. The antibacterial activity was reflected by the diameter of the inhibition zone against Escherichia coli. The obtained pipemidic acid-salicylic acid drug-drug salt had the strongest antibacterial activity, and d2>d1+d3, indicating that the synergistic effect of salicylic acid and pipemidic acid improved the antibacterial activity of pipemidic acid, achieving an antibacterial effect of 1+1>2.

[0029] In summary, the present invention provides a pipemidic acid-salicylic acid drug-drug salt and a preparation method thereof. The method is simple to operate, has low energy consumption, low solvent usage, and good product reproducibility. The pipemidic acid-salicylic acid drug-drug salt provided by the present invention improves the maximum dissolution concentration and dissolution rate of pipemidic acid, and the drug salt has good moisture resistance and thermal stability. The pipemidic acid-salicylic acid drug-drug salt provided by the present invention not only improves the dissolution properties of pipemidic acid, but also improves the antibacterial performance due to the synergistic antibacterial effect of the ligand and pipemidic acid, showing an antibacterial effect of 1+1>2, and therefore can be used as a potential substitute for pipemidic acid, which is of great significance for improving bioavailability and enhancing efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is the dissolution curve of pipemidic acid-2,3-dihydroxybenzoate hydrate and pipemidic acid-m-hydroxybenzoate hydrate in pure water at 37°C and pH 5.6.

[0031] Figure 2 is the molecular surface electrostatic potential diagram of pipemidic acid (in kcal / mol)

[0032] Figure 3 is the molecular surface electrostatic potential diagram of salicylic acid (in kcal / mol)

[0033] Figure 4 The crystal cell diagram of the pipemidic acid-salicylic acid drug-drug salt prepared by the present invention is

[0034] Figure 5 The X-ray powder diffraction pattern of the pipemidic acid-salicylic acid drug-drug salt prepared by the present invention is

[0035] Figure 6 The differential scanning calorimetry curve and thermogravimetric analysis curve of the pipemidic acid-salicylic acid drug-drug salt prepared by the present invention are

[0036] Figure 7 The main crystal faces of pipemidic acid-m-hydroxybenzoate hydrate and pipemidic acid-salicylic acid drug-drug salt prepared by the present invention and the crystal morphology predicted based on the BFDH model

[0037] Figure 8 The dissolution curve of pipemidic acid trihydrate and pipemidic acid-salicylic acid drug-drug salt prepared by the present invention in pure water at 37°C and pH 5.6 is shown in FIG.

[0038] Fig. 9 The adsorption / desorption isotherms of pipemidic acid hydrochloride and pipemidic acid-salicylic acid drug-drug salt prepared by the present invention at 25°C are

[0039] Fig.10 The X-ray powder diffraction pattern of the pipemidic acid-salicylic acid drug-drug salt accelerated stability test prepared by the present invention is

[0040] Fig.11 The antibacterial test results of pipemidic acid trihydrate, salicylic acid and pipemidic acid-salicylic acid drug-drug salt prepared by the present invention on Escherichia coli are as follows DETAILED DESCRIPTION

[0041] The above contents of the present invention will be further described in detail below through specific implementation methods in the form of embodiments, but this should not be understood as the scope of the above subject of the present invention being limited to the following embodiments.

[0042] Embodiment 1:

[0043] The volatile solvent crystallization method is used to prepare the pipemidic acid-salicylic acid drug-drug salt, and the specific steps are as follows:

[0044] (1) 3.57 g of pipemidic acid trihydrate and 1.38 g of salicylic acid were added to 310 mL of methanol and heated to 65° C. to form a clear solution, wherein the total mass ratio of pipemidic acid and salicylic acid to the volume of methanol solvent was 0.016 g / mL;

[0045] (2) cooling the clear solution to 25° C., first volatilizing the solvent methanol at a rate of 5.6 mL / h until the volatilization amount is 124 mL (i.e., volatilizing the solvent at a rate of 1.8% of the initial organic solvent volume per hour until the volatilization amount accounts for 40% of the initial organic solvent volume), precipitating colorless transparent prismatic crystals, and then continuing to volatilize the solvent methanol at a rate of 62.0 mL / h until the total volatilization amount of the solvent is 279 mL (i.e., continuing to volatilize the solvent at a rate of 20% of the initial organic solvent volume per hour until the total volatilization amount of the solvent accounts for 90% of the initial organic solvent volume), to obtain a crystal slurry;

[0046] (3) The above slurry was filtered and the filter cake was dried at 60°C.

[0047] The stoichiometric ratio of pipemidic acid to salicylic acid in the obtained pipemidic acid-salicylic acid drug-drug salt is 1:1. The X-ray powder diffraction pattern of the drug-drug salt is shown in the attached Figure 5 As shown, there are characteristic peaks at diffraction angles 2θ = 7.22°, 8.02°, 13.61°, 14.93°, 16.36°, 17.41°, 20.01°, 20.53°, 25.71°, 26.72°, and 29.74°; its DSC curve and TGA curve are attached Figure 6 As shown, the DSC of the drug-drug salt begins to absorb heat at 240.0°C, and the TGA begins to lose weight from 244.0°C.

[0048] The dissolution curves of the obtained pipemidic acid-salicylic acid drug-drug salt and pipemidic acid trihydrate in pure water at 37°C and pH 5.6 are shown in the attached figure. Figure 8 As shown, the maximum dissolution concentration of the obtained pipemidic acid-salicylic acid drug-drug salt is 5.953 mg / mL (based on pipemidic acid), the dissolution rate is 0.066 mg / mL / min, and the maximum dissolution concentration C max The dissolution rate is greater than that of the currently used pharmaceutical form of pipemidic acid trihydrate and much greater than that of pipemidic acid-m-hydroxybenzoate hydrate. The isothermal adsorption / desorption test results at 25°C are shown in the attached Fig. 9 As shown in Table 1, when the relative humidity increased from 0% to 95%, the mass of the obtained pipemidic acid-salicylic acid drug-drug salt increased by 0.24%, and when the relative humidity decreased to 0%, the mass reversibly recovered to the initial weight; for pipemidic acid-hydrochloride, when the relative humidity increased to 95%, the pipemidic acid-hydrochloride showed a mass increase of 1.5%. The obtained pipemidic acid-salicylic acid drug-drug salt was subjected to an accelerated stability test using a constant temperature and humidity chamber. It was stored at a temperature of 40°C and a relative humidity of 75% for 8 weeks, and samples were taken at 0 days, 2 weeks, 4 weeks, and 8 weeks for X-ray powder diffraction analysis. As shown in the attached Fig.10 As shown, the X-ray powder diffraction pattern remains unchanged, indicating that the crystal structure has not changed and its thermal stability is good.

[0049] Table 1 The mass and mass increase percentage of pipemidic acid-salicylic acid drug-drug salt and pipemidic acid-hydrochloride during adsorption / desorption at 25 °C

[0050]

[0051]

[0052] The applicant used the Kirby Bauer agar diffusion method to determine the antibacterial activity of pipemidic acid trihydrate, the obtained pipemidic acid-salicylic acid drug-drug salt and salicylic acid. The results are shown in Table 2 and Attached Fig.11 As shown (attached Fig.11 Samples 1, 2, and 3 are pipemidic acid trihydrate, the obtained pipemidic acid-salicylic acid drug-drug salt, and salicylic acid experimental group, respectively, and sample 4 is a dimethyl sulfoxide control group). The diameters of the inhibition zones d1, d2, d3, and d4 of pipemidic acid trihydrate, the obtained pipemidic acid-salicylic acid drug-drug salt, salicylic acid, and dimethyl sulfoxide against Escherichia coli are 27.8±0.5 mm, 32.0±0.5 mm, 1.5±0.5 mm, and 0±0.5 mm, respectively. The pipemidic acid-salicylic acid drug salt has the largest inhibition zone diameter and the strongest antibacterial activity, and d2>d1+d3. Due to the synergistic effect of salicylic acid and pipemidic acid, the obtained pipemidic acid-salicylic acid drug-drug salt achieves an antibacterial effect of 1+1>2.

[0053] Table 2 Inhibition zone diameters of pipemidic acid trihydrate, pipemidic acid-salicylic acid drug-drug salt, salicylic acid and dimethyl sulfoxide against Escherichia coli (d1, d2, d3 and d4, respectively)

[0054]

[0055]

[0056] Embodiment 2:

[0057] The volatile solvent crystallization method is used to prepare the pipemidic acid-salicylic acid drug-drug salt, and the specific steps are as follows:

[0058] (1) 3.03 g of Form A pipemidic acid and 1.38 g of salicylic acid were added to 315 mL of ethanol and heated to 60° C. to form a clear solution, wherein the total mass ratio of pipemidic acid and salicylic acid to the volume of ethanol solvent was 0.014 g / mL;

[0059] (2) cooling the clear solution to 30° C., first volatilizing the solvent ethanol at a rate of 4.1 mL / h until the volatilization amount is 120 mL (i.e., volatilizing the solvent at a rate of 1.3% of the initial organic solvent volume per hour until the volatilization amount accounts for 38% of the initial organic solvent volume), precipitating colorless transparent prismatic crystals, and then continuing to volatilize the solvent ethanol at a rate of 44.1 mL / h until the total volatilization amount of the solvent is 268 mL (i.e., continuing to volatilize the solvent at a rate of 14% of the initial organic solvent volume per hour until the total volatilization amount of the solvent accounts for 85% of the initial organic solvent volume), to obtain crystal slurry;

[0060] (3) The above slurry was filtered and the filter cake was dried at 50°C.

[0061] The stoichiometric ratio of pipemidic acid to salicylic acid in the obtained pipemidic acid-salicylic acid drug-drug salt is 1:1, and the X-ray powder diffraction pattern of the drug-drug salt has characteristic peaks at diffraction angles of 2θ=7.42°, 8.22°, 13.79°, 15.13°, 16.55°, 17.61°, 20.19°, 20.70°, 25.89°, 26.90°, and 29.91°; the DSC of the drug-drug salt begins to absorb heat at 241.0°C, and the TGA begins to lose weight from 244.8°C.

[0062] The maximum dissolution concentration of the obtained pipemidic acid-salicylic acid drug-drug salt in pure water at 37°C and pH 5.6 was 5.960 mg / mL (in terms of pipemidic acid), and the dissolution rate was 0.067 mg / mL / min. In the isothermal adsorption / desorption experiment at 25°C, the relative humidity increased from 0% to 95%, and the mass of the obtained pipemidic acid-salicylic acid drug-drug salt increased by 0.25%. When the relative humidity decreased to 0%, the mass reversibly recovered to the initial weight. The obtained pipemidic acid-salicylic acid drug-drug salt was stored for 8 weeks at a temperature of 40°C and a relative humidity of 75%, and the X-ray powder diffraction pattern remained unchanged. The Kirby Bauer agar diffusion method was used to determine the antibacterial activity of pipemidic acid trihydrate, the obtained pipemidic acid-salicylic acid drug-drug salt and salicylic acid. The results showed that the pipemidic acid-salicylic acid drug salt had the largest inhibition zone diameter and the strongest antibacterial activity, and the antibacterial effect of 1+1>2 was achieved due to the synergistic effect of salicylic acid and pipemidic acid.

[0063] Embodiment 3:

[0064] The volatile solvent crystallization method is used to prepare the pipemidic acid-salicylic acid drug-drug salt, and the specific steps are as follows:

[0065] (1) adding 3.03 g of Form B pipemidic acid and 1.38 g of salicylic acid to 400 mL of isopropanol and heating to 55° C. to form a clear solution, wherein the total mass ratio of pipemidic acid and salicylic acid to the volume ratio of isopropanol solvent is 0.011 g / mL;

[0066] (2) cooling the clear solution to 45° C., first evaporating the isopropanol solvent at a rate of 2.8 mL / h until the evaporation amount is 140 mL, precipitating colorless transparent prismatic crystals, and then continuing to evaporate the isopropanol solvent at a rate of 32.0 mL / h until the total evaporation amount of the solvent is 320 mL, thereby obtaining a crystal slurry;

[0067] (3) The above slurry was filtered and the filter cake was dried at 40°C.

[0068] The stoichiometric ratio of pipemidic acid to salicylic acid in the obtained pipemidic acid-salicylic acid drug-drug salt is 1:1, and the X-ray powder diffraction pattern of the drug-drug salt has characteristic peaks at diffraction angles 2θ=7.02°, 7.84°, 13.43°, 14.73°, 16.17°, 17.21°, 19.83°, 20.36°, 25.53°, 26.54°, and 29.57°; the DSC of the drug-drug salt begins to absorb heat at 239.2°C, and the TGA begins to lose weight from 243.0°C.

[0069] The maximum dissolution concentration of the obtained pipemidic acid-salicylic acid drug-drug salt in pure water at 37°C and pH 5.6 was 5.803 mg / mL (in terms of pipemidic acid), and the dissolution rate was 0.064 mg / mL / min. In the isothermal adsorption / desorption experiment at 25°C, the relative humidity increased from 0% to 95%, and the mass of the obtained pipemidic acid-salicylic acid drug-drug salt increased by 0.24%. When the relative humidity decreased to 0%, the mass reversibly recovered to the initial weight. The obtained pipemidic acid-salicylic acid drug-drug salt was stored for 8 weeks at a temperature of 40°C and a relative humidity of 75%, and the X-ray powder diffraction pattern remained unchanged. The Kirby Bauer agar diffusion method was used to determine the antibacterial activity of pipemidic acid trihydrate, the obtained pipemidic acid-salicylic acid drug-drug salt and salicylic acid. The results showed that the pipemidic acid-salicylic acid drug salt had the largest inhibition zone diameter and the strongest antibacterial activity, and the antibacterial effect of 1+1>2 was achieved due to the synergistic effect of salicylic acid and pipemidic acid.

[0070] Embodiment 4:

[0071] The volatile solvent crystallization method is used to prepare the pipemidic acid-salicylic acid drug-drug salt, and the specific steps are as follows:

[0072] (1) adding a mixture of 1.01 g of Form A pipemidic acid and 2.02 g of Form B pipemidic acid and 1.38 g of salicylic acid to 280 mL of acetone, and heating to 65° C. to form a clear solution, wherein the total mass ratio of pipemidic acid and salicylic acid to the volume of acetone solvent is 0.016 g / mL;

[0073] (2) cooling the clear solution to 20° C., first evaporating the solvent acetone at a rate of 5.0 mL / h until the evaporation amount is 112 mL, precipitating colorless transparent prismatic crystals, and then continuing to evaporate the solvent acetone at a rate of 22.4 mL / h until the total evaporation amount of the solvent is 224 mL, to obtain a crystal slurry;

[0074] (3) The above slurry was filtered and the filter cake was dried at 60°C.

[0075] The stoichiometric ratio of pipemidic acid to salicylic acid in the obtained pipemidic acid-salicylic acid drug-drug salt is 1:1, and the X-ray powder diffraction spectrum of the drug-drug salt has characteristic peaks at diffraction angles 2θ=7.32°, 8.11°, 13.68°, 15.01°, 16.44°, 17.51°, 20.10°, 20.61°, 25.78°, 26.80°, and 29.81°; the DSC of the drug-drug salt begins to absorb heat at 240.5°C, and the TGA begins to lose weight from 244.4°C.

[0076] The maximum dissolution concentration of the obtained pipemidic acid-salicylic acid drug-drug salt in pure water at 37°C and pH 5.6 was 5.850 mg / mL (in terms of pipemidic acid), and the dissolution rate was 0.065 mg / mL / min. In the isothermal adsorption / desorption experiment at 25°C, the relative humidity increased from 0% to 95%, and the mass of the obtained pipemidic acid-salicylic acid drug-drug salt increased by 0.26%. When the relative humidity decreased to 0%, the mass reversibly recovered to the initial weight. The obtained pipemidic acid-salicylic acid drug-drug salt was stored for 8 weeks at a temperature of 40°C and a relative humidity of 75%, and the X-ray powder diffraction pattern remained unchanged. The Kirby Bauer agar diffusion method was used to determine the antibacterial activity of pipemidic acid trihydrate, the obtained pipemidic acid-salicylic acid drug-drug salt and salicylic acid. The results showed that the pipemidic acid-salicylic acid drug salt had the largest inhibition zone diameter and the strongest antibacterial activity, and the antibacterial effect of 1+1>2 was achieved due to the synergistic effect of salicylic acid and pipemidic acid.

[0077] Embodiment 5:

[0078] The volatile solvent crystallization method is used to prepare the pipemidic acid-salicylic acid drug-drug salt, and the specific steps are as follows:

[0079] (1) adding a mixture of 1.79 g of pipemidic acid trihydrate and 1.52 g of Form A pipemidic acid and 1.38 g of salicylic acid to 335 mL of butanone, and heating to 60° C. to form a clear solution, wherein the total mass ratio of pipemidic acid and salicylic acid to the volume ratio of butanone solvent is 0.014 g / mL;

[0080] (2) cooling the clear solution to 45° C., first evaporating the solvent butanone at a rate of 4.3 mL / h until the evaporation amount is 127 mL, precipitating colorless transparent prismatic crystals, and then continuing to evaporate the solvent butanone at a rate of 47.1 mL / h until the total evaporation amount of the solvent is 285 mL, to obtain a crystal slurry;

[0081] (3) The above slurry was filtered and the filter cake was dried at 50°C.

[0082] The stoichiometric ratio of pipemidic acid to salicylic acid in the obtained pipemidic acid-salicylic acid drug-drug salt is 1:1, and the X-ray powder diffraction spectrum of the drug-drug salt has characteristic peaks at diffraction angles 2θ=7.12°, 7.94°, 13.53°, 14.86°, 16.27°, 17.31°, 19.93°, 20.46°, 25.64°, 26.65°, and 29.67°; the DSC of the drug-drug salt begins to absorb heat at 239.4°C, and the TGA begins to lose weight from 243.5°C.

[0083] The maximum dissolution concentration of the obtained pipemidic acid-salicylic acid drug-drug salt in pure water at 37°C and pH 5.6 was 6.000 mg / mL (in terms of pipemidic acid), and the dissolution rate was 0.067 mg / mL / min. In the isothermal adsorption / desorption experiment at 25°C, the mass of the obtained pipemidic acid-salicylic acid drug-drug salt increased by 0.25% when the relative humidity increased from 0% to 95%, and the mass reversibly recovered to the initial weight when the relative humidity decreased to 0%. The obtained pipemidic acid-salicylic acid drug-drug salt was stored for 8 weeks at a temperature of 40°C and a relative humidity of 75%, and the X-ray powder diffraction pattern remained unchanged. The Kirby Bauer agar diffusion method was used to determine the antibacterial activity of pipemidic acid trihydrate, the obtained pipemidic acid-salicylic acid drug-drug salt and salicylic acid. The results showed that the pipemidic acid-salicylic acid drug salt had the largest inhibition zone diameter and the strongest antibacterial activity, and the antibacterial effect of 1+1>2 was achieved due to the synergistic effect of salicylic acid and pipemidic acid.

[0084] Embodiment 6:

[0085] (1) 3.57 g of pipemidic acid trihydrate and 1.38 g of salicylic acid were added to 310 mL of acetonitrile and heated to 65° C. to form a clear solution, wherein the total mass ratio of pipemidic acid and salicylic acid to the volume of acetonitrile solvent was 0.016 g / mL;

[0086] (2) cooling the clear solution to 40° C., first evaporating the solvent acetonitrile at a rate of 5.6 mL / h until the evaporation amount is 124 mL, precipitating colorless transparent prismatic crystals, and then continuing to evaporate the solvent acetonitrile at a rate of 24.8 mL / h until the total evaporation amount of the solvent is 248 mL, to obtain a crystal slurry;

[0087] (3) The above slurry was filtered and the filter cake was dried at 60°C.

[0088] The stoichiometric ratio of pipemidic acid to salicylic acid in the obtained pipemidic acid-salicylic acid drug-drug salt is 1:1, and the X-ray powder diffraction spectrum of the drug-drug salt has characteristic peaks at diffraction angles 2θ=7.37°, 8.15°, 13.73°, 15.06°, 16.50°, 17.56°, 20.14°, 20.66°, 25.83°, 26.84°, and 29.86°; the DSC of the drug-drug salt begins to absorb heat at 240.9°C, and the TGA begins to lose weight from 245.0°C.

[0089] The maximum dissolution concentration of the obtained pipemidic acid-salicylic acid drug-drug salt in pure water at 37°C and pH 5.6 was 6.053 mg / mL (in terms of pipemidic acid), and the dissolution rate was 0.067 mg / mL / min. In the isothermal adsorption / desorption experiment at 25°C, the mass of the obtained pipemidic acid-salicylic acid drug-drug salt increased by 0.24% when the relative humidity increased from 0% to 95%, and the mass reversibly recovered to the initial weight when the relative humidity decreased to 0%. The obtained pipemidic acid-salicylic acid drug-drug salt was stored for 8 weeks at a temperature of 40°C and a relative humidity of 75%, and the X-ray powder diffraction pattern remained unchanged. The Kirby Bauer agar diffusion method was used to determine the antibacterial activity of pipemidic acid trihydrate, the obtained pipemidic acid-salicylic acid drug-drug salt and salicylic acid. The results showed that the pipemidic acid-salicylic acid drug salt had the largest inhibition zone diameter and the strongest antibacterial activity, and the antibacterial effect of 1+1>2 was achieved due to the synergistic effect of salicylic acid and pipemidic acid.

[0090] Embodiment 7:

[0091] The volatile solvent crystallization method is used to prepare the pipemidic acid-salicylic acid drug-drug salt, and the specific steps are as follows:

[0092] (1) adding a mixture of 1.79 g of pipemidic acid trihydrate and 1.52 g of Form B pipemidic acid and 1.38 g of salicylic acid to 426 mL of tetrahydrofuran, and heating to 55° C. to form a clear solution, wherein the total mass ratio of pipemidic acid and salicylic acid to the volume ratio of tetrahydrofuran solvent is 0.011 g / mL;

[0093] (2) cooling the clear solution to 30° C., first evaporating the solvent tetrahydrofuran at a rate of 3.0 mL / h until the evaporation amount is 170 mL, and precipitating colorless transparent prismatic crystals; then continuing to evaporate the solvent tetrahydrofuran at a rate of 34.2 mL / h until the total evaporation amount of the solvent is 341 mL, and obtaining a crystal slurry;

[0094] (3) The above slurry was filtered and the filter cake was dried at 40°C.

[0095] The stoichiometric ratio of pipemidic acid to salicylic acid in the obtained pipemidic acid-salicylic acid drug-drug salt is 1:1, and the X-ray powder diffraction spectrum of the drug-drug salt has characteristic peaks at diffraction angles of 2θ=7.27°, 8.07°, 13.65°, 4.96°, 16.40°, 17.46°, 20.06°, 20.57°, 25.74°, 26.76°, and 29.78°; the DSC of the drug-drug salt begins to absorb heat at 240.5°C, and the TGA begins to lose weight from 244.4°C.

[0096] The maximum dissolution concentration of the obtained pipemidic acid-salicylic acid drug-drug salt in pure water at 37°C and pH 5.6 was 6.103 mg / mL (in terms of pipemidic acid), and the dissolution rate was 0.068 mg / mL / min. In the isothermal adsorption / desorption experiment at 25°C, the relative humidity increased from 0% to 95%, and the mass of the obtained pipemidic acid-salicylic acid drug-drug salt increased by 0.26%. When the relative humidity decreased to 0%, the mass reversibly recovered to the initial weight. The obtained pipemidic acid-salicylic acid drug-drug salt was stored for 8 weeks at a temperature of 40°C and a relative humidity of 75%, and the X-ray powder diffraction pattern remained unchanged. The Kirby Bauer agar diffusion method was used to determine the antibacterial activity of pipemidic acid trihydrate, the obtained pipemidic acid-salicylic acid drug-drug salt and salicylic acid. The results showed that the pipemidic acid-salicylic acid drug salt had the largest inhibition zone diameter and the strongest antibacterial activity, and the antibacterial effect of 1+1>2 was achieved due to the synergistic effect of salicylic acid and pipemidic acid.

[0097] The technical solutions disclosed and proposed by the present invention can be realized by those skilled in the art by referring to the contents of this article and appropriately changing the conditions, routes and other links. Although the methods and preparation techniques of the present invention have been described through preferred embodiments, relevant technicians can obviously modify or re-combine the methods and technical routes described herein without departing from the content, spirit and scope of the present invention to achieve the final preparation technology. It is particularly important to point out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the spirit, scope and content of the present invention. Matters not covered in the present invention belong to the known technology.

Claims

1. A pipemidic acid-salicylic acid drug-drug salt, characterized in that: The molecular formula of the pipemidic acid-salicylic acid drug-drug salt is: 14 H 18 N5O3·C7H5O3], the stoichiometric ratio of pipemidic acid to salicylic acid is 1:1, and its structural formula is as follows:

2. The pipemidic acid-salicylic acid drug-drug salt according to claim 1, characterized in that: The pipemidic acid-salicylic acid drug-drug salt is a monoclinic crystal system with a space group of P21 / n and unit cell parameters of: α=90°,β=98.019(5)°,γ=90°,the unit cell volume is Each unit cell contains 4 pipemidic acid-salicylic acid molecules.

3. The pipemidic acid-salicylic acid drug-drug salt according to claim 1, characterized in that: The X-ray powder diffraction pattern of the pipemidic acid-salicylic acid drug-drug salt has characteristic peaks at diffraction angles 2θ=7.22°±0.2°, 8.02°±0.2°, 13.61°±0.2°, 14.93°±0.2°, 16.36°±0.2°, 17.41°±0.2°, 20.01°±0.2°, 20.53°±0.2°, 25.71°±0.2°, 26.72°±0.2°, and 29.74°±0.2°.

4. The pipemidic acid-salicylic acid drug-drug salt according to claim 1, characterized in that: The differential scanning calorimetry curve of the pipemidic acid-salicylic acid drug-drug salt begins to absorb heat at 240±1°C, and the thermogravimetric analysis curve begins to lose weight at 244±1°C.

5. The method for preparing the pipemidic acid-salicylic acid drug-drug salt according to claim 1, characterized in that The solvent evaporation crystallization method is adopted, which specifically comprises the following steps: (1) mixing pipemidic acid and salicylic acid in a molar ratio of 1:1, adding an organic solvent, and heating to 55-65° C. to form a clear solution, wherein the organic solvent is selected from one of methanol, ethanol, isopropanol, acetone, butanone, acetonitrile or tetrahydrofuran; (2) cooling the clear solution to 20-45° C., and evaporating the solvent until the total evaporation amount of the solvent accounts for 80-90% of the initial volume of the organic solvent to obtain a slurry; (3) Filter the above slurry and dry the filter cake at 40-60°C.

6. The method for crystallizing the pipemidic acid-salicylic acid drug-drug salt according to claim 5, characterized in that: In step (1), the total mass ratio of pipemidic acid and salicylic acid to the volume of the organic solvent is 0.011 to 0.016 g / mL.

7. The method for crystallizing the pipemidic acid-salicylic acid drug-drug salt according to claim 5, characterized in that: The volatilization of the solvent is first performed at a rate of 0.7 to 1.8% of the initial volume of the organic solvent per hour until the volatilized amount accounts for 35 to 40% of the initial volume of the organic solvent, and colorless transparent prism crystals are precipitated. Then, the volatilization of the solvent is continued at a rate of 8.0 to 20.0% of the initial volume of the organic solvent per hour until the total volatilized amount of the solvent accounts for 80 to 90% of the initial volume of the organic solvent.

8. The method for crystallizing the pipemidic acid-salicylic acid drug-drug salt according to claim 5, characterized in that: The pipemidic acid is selected from pipemidic acid form A, pipemidic acid form B, pipemidic acid hydrate or a mixture thereof.

9. Use of the pipemidic acid-salicylic acid drug-drug salt according to claim 1 for preparing a pipemidic acid substitute drug.

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