Oxaprozin-3-hydroxypyridine pharmaceutical salt and preparation method thereof

Abstract

The invention relates to an oxaprozin-3-hydroxypyridine pharmaceutical salt and a preparation method thereof. Mixing oxaprozin, 3-hydroxypyridine and an organic solvent or filtrate, and carrying out cooling crystallization or suspension crystallization to prepare oxaprozin-3-hydroxypyridine pharmaceutical salt; the structural formula of the pharmaceutical salt is shown in the specification, wherein the stoichiometric ratio of oxaprozin to 3-hydroxypyridine is 1: 1. According to the oxaprozin, the solubility of the oxaprozin is 0.180 + / -0.003 mg / mL and 0.930 + / -0.022 mg / mL in pure water at the temperature of 37 DEG C and a phosphate buffer solution with the pH of 6.8 at the temperature of 37 DEG C respectively, the inherent dissolution rate of the oxaprozin in the phosphate buffer solution with the temperature of 37 DEG C and the pH of 6.8 is 0.218 + / -0.004 mg / (cm < 2 >. Min), and the maximum dissolution concentration of 0.816 + / -0.005 mg / mL is achieved in 900 + / -1 min. Excellent wet stability and thermal stability are shown, and the solubilizing effect is remarkable. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of drug crystallization, and particularly to an oxaprozin-3-hydroxypyridine drug salt and a preparation method thereof. Background Art

[0002] Oxaprozin, with the chemical name of 4,5-diphenyl-2-oxazolepropionic acid, has the molecular formula of C 18 H 15 NO 3 , a relative molecular mass of 293.32, a melting point of 160.5 ± 1 °C, and a structural formula as shown in (I). Oxaprozin is one of the widely used non-steroidal anti-inflammatory drugs, used to relieve inflammation and joint pain associated with osteoarthritis and rheumatoid arthritis, and has good curative effects. According to the biopharmaceutics classification system, oxaprozin belongs to class II drugs, with poor water solubility. The literature (Wu H, Jiang YY, Shen C, et al. Measurement and Thermodynamic Modeling of Oxaprozin Solubilityin Polymers and Mixed Solutions[J]. Journal of Chemical&Engineering Data, 2024, 69(3):1273-1283. DOI:10.1021 / acs.jced.3c00564) reported that the mole fraction solubility of oxaprozin in ultrapure water at 30 °C was 6.006×10 -7 , equivalent to 0.01 mg / mL. Its limited water solubility and slow dissolution rate are not conducive to the curative effect and increase the risk of adverse cardiovascular or gastrointestinal diseases.

[0003]

[0004] During the process of designing solid forms of drugs, introducing guest molecules to modify the physicochemical properties of active pharmaceutical ingredients is an attractive method. Drug cocrystals, salts, and solvates refer to new solid forms formed by active pharmaceutical ingredients with guest molecules (cocrystal ligands, salt-forming agents, and solvents) through electrostatic interactions or hydrogen bond interactions. The difference between drug cocrystals and salts lies in whether proton transfer occurs during the formation process. Drug salts refer to solid forms formed by proton transfer between drugs and salt-forming agents, relying on electrostatic interactions, where individual components are presented in the form of anions or cations, and the overall form is neutral. Currently, two cocrystals and three salts of oxaprozin have been reported, namely two cocrystals formed by oxaprozin with 4,4'-bipyridine and 1,2-bis(4-pyridyl)ethane, and three salts formed by oxaprozin with piperazine, 2-amino-3-methylpyridine, and the anti-asthmatic drug salbutamol. All of them are from the research work of Srinivasulu et al. For details, see Aitipamula S, Wong ABH, Chow PS, et al., Novel solid forms of oxaprozin: cocrystals and an extended release drug–drug salt of salbutamol, RSC Advances, 2016, 6(41): 34110-34119 (DOI: 10.1039 / C6RA01802E). This literature reported the solubility of oxaprozin, oxaprozin-piperazine salt, and oxaprozin-salbutamol salt in a phosphate buffer solution at 37 °C and pH 7.4 with the cosolvent Tween 80 added. In contrast, the oxaprozin-piperazine salt and oxaprozin-salbutamol salt not only did not increase the solubility of oxaprozin, but instead decreased the solubility of oxaprozin from 2.30 mg / mL to 2.11 mg / mL and 2.02 mg / mL respectively, with the decrease rates being 8.26% and 12.17% respectively, indicating that forming salts with piperazine and salbutamol did not play a role in increasing the solubility of oxaprozin. In addition, among the three reported salts, salbutamol is expensive and easily decomposed, requiring storage at -20 °C, with high production costs; 2-amino-3-methylpyridine is a highly toxic chemical, and piperazine and 2-amino-3-methylpyridine belong to the dangerous category in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS), and ingestion will endanger human health, so they are not suitable as drug salt-forming agents.

[0005] Forming eutectics is also one of the methods to improve the physicochemical properties of active pharmaceutical ingredients. Patent Application CN116473975A and Patent Application CN116492349A disclose three binary eutectic mixtures formed by oxaprozin with isoniazid, pyrazinamide, and isoniazid respectively, and their preparation methods. In vitro dissolution experiments of oxaprozin, as well as three eutectic mixtures of oxaprozin + isoniazid, oxaprozin + pyrazinamide, and oxaprozin + isoniazid, were carried out under the condition of pure water at 37 °C, and the relationship diagram of the dissolution amount of oxaprozin vs. time was obtained, as shown in the appendix Figure 1 As shown, at 480 min, the dissolution amounts of oxaprozin in the three eutectic mixtures were increased from approximately 10 mg / 900 mL to approximately 14 mg / 900 mL, 16 mg / 900 mL, and 15 mg / 900 mL respectively. After converting the unit to mg / mL, it was increased from approximately 0.0111 mg / mL to approximately 0.0156 mg / mL, 0.0178 mg / mL, and 0.0167 mg / mL respectively, and the increase in the dissolution amount of oxaprozin was approximately 40%, 60%, and 50% respectively. Although forming eutectics improves the solubility of oxaprozin to a certain extent, binary eutectics are mixtures of two components. In eutectics, there is a strong cohesive force of the same structure, and there is also an adhesive force between different structures, but the cohesive force is greater than the adhesive force, resulting in eutectics being a discontinuous phase. It neither achieves a lattice-level uniform arrangement nor has a crystal structure different from the two pure components. Therefore, eutectics only have an apparent composition and do not have a definite internal structure. Currently, the means to confirm the formation of eutectics are single, and it can only be determined by thermal analysis methods. Compared with pharmaceutical eutectics, the advantages of pharmaceutical salts are more obvious. Pharmaceutical salts have a unique crystal structure different from the drug and the salt-forming agent and can be confirmed by various characterization means, such as X-ray powder diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, etc., and the drug quality is controllable. Moreover, pharmaceutical salts usually have advantages such as high solubility, fast release rate, and good stability, and are the preferred method to improve the physicochemical properties of drugs. In addition, the two methods for preparing eutectics disclosed in Patent CN116473975A and Patent CN116492349A have obvious defects. Among them, the solvent-mediated coprecipitation method requires a large amount of solvent, and the grinding method is a common method for preparing eutectics in the laboratory. It is very difficult to scale up to industrial production, and the practicability is poor.

[0006] The existing oxaprozin salts have not been able to effectively improve the solubility of oxaprozin, and the salt-forming agent has high toxicity or poor stability. The oxaprozin eutectic disclosed in the patent has the defects of uncertain internal structure and insignificant effect of improving the solubility of oxaprozin. In summary, it is necessary to develop a solid form of oxaprozin drug salt with a precise structure, good stability, high increase in oxaprozin solubility, high dissolution rate, low toxicity of the salt-forming agent and not easy to decompose, and the preparation method thereof is simple, reproducible, consumes less solvent and is easy to industrialize. Summary of the invention

[0007] Currently, more than 60% of new drug molecules show poor water solubility due to their large molecular weight and good lipid solubility. These difficulties have further prompted researchers to seek new methods to develop and improve pharmaceutical products, such as obtaining new solid forms by drug salts or cocrystals, thereby adjusting the physicochemical properties of drugs, such as solubility, dissolution rate, hygroscopicity and stability, without changing their pharmacological properties. Drug saltization is a common method to improve their water solubility and bioavailability. In recent years, the pharmaceutical industry has increasingly used saltization to enhance the performance of drugs, and now more than 50% of drugs on the market are sold in the form of salts. By reducing the lattice energy or increasing the solvation energy, drug salts can promote the release of drug molecules from the lattice and increase the affinity of drugs with solvents, so that drug salts show good solubility advantages and higher bioavailability. Developing drug salts with high solubility and large dissolution rate is a technical solution to improve drug bioavailability.

[0008] The applicant has identified the potential sites of hydrogen bond donors and acceptors in the molecular structure of oxaprozin by conducting a full interaction analysis of oxaprozin. The dark red and blue areas show a higher tendency to form hydrogen bonds. Figure 2 As shown in the figure, the molecular structure of oxaprozin has a carboxyl group that can act as a proton donor, and a nitrogen atom on an oxazole ring that can act as a proton acceptor, which makes it possible for oxaprozin to form salts with salt-forming agents containing pyridine, pyrimidine and sulfonic acid groups. 3-Hydroxypyridine belongs to the pyridine salt-forming agent with a melting point of 126°C. It has a high melting point and good stability and is not easy to decompose. It has certain pharmacological activities and has anti-inflammatory and antioxidant effects. The GHS classification shows that its toxicity is lower than the salt-forming agents piperazine and 2-amino-3-methylpyridine reported in the literature (DOI: 10.1039 / C6RA01802E). In addition, 3-hydroxypyridine has a large solubility and can provide hydroxyl groups as hydrophilic groups. Making it into a salt agent is expected to increase the solubility of oxaprozin. The molecular electrostatic potential surface of oxaprozin and 3-hydroxypyridine was calculated by quantum chemical theory (see Appendix). Figure 3 and attached Figure 4) In the molecular structure of oxaprozin, the carboxylic acid proton has the largest positive electric potential with an electrostatic potential of 53.39 kcal / mol, and the 3-hydroxypyridine nitrogen atom has the largest negative electric potential with an electrostatic potential of -38.12 kcal / mol. The two are expected to form an oxaprozin salt through an N-H…O hydrogen bond. Additionally, the pK a value of oxaprozin is 4.3, and the pK a value of 3-hydroxypyridine is 8.75. ΔpK a = pK a (base) - pK a (acid) = 8.75 - 4.3 = 4.45. According to the ΔpK a rule, oxaprozin and 3-hydroxypyridine are expected to form a salt. The universal Easy Solvation Energy Evaluation solvent model was used to predict the solvation free energies of oxaprozin and the oxaprozin-3-hydroxypyridine salt, which are -10.785 kcal / mol and -16.938 kcal / mol, respectively. The solvation free energy can be used to indicate the strength of the solute-solvent interaction. The larger the absolute value, the easier it is for the solute to dissolve, the greater the solubility, and the faster the dissolution rate. Therefore, the increase in the solvation free energy of the oxaprozin-3-hydroxypyridine salt indicates that salification with 3-hydroxypyridine will increase the solubility of oxaprozin. The above analysis by the applicant shows that compared with single-component oxaprozin, the drug salt formed by the two components of oxaprozin and 3-hydroxypyridine may improve solubility and bioavailability due to synergistic effects.

[0009] The present invention discloses an oxaprozin-3-hydroxypyridine drug salt and its preparation method. The salt-forming agent used has low toxicity and is not easily decomposed. The prepared oxaprozin-3-hydroxypyridine drug salt is a colorless transparent flaky crystal with good stability, and the solubility of the drug salt in terms of oxaprozin is large, and the dissolution rate is large, thus contributing to the improvement of bioavailability. At the same time, the amount of solvent used is small, the method is simple to operate, and it is easy to repeat.

[0010] The technical solution of the present invention is as follows:

[0011] The present invention provides an oxaprozin-3-hydroxypyridine drug salt; the stoichiometric ratio of oxaprozin to 3-hydroxypyridine is 1:1, and the molecular formula is [C 18 H 14 NO 3 ·C 5 H 6 NO], and the structural formula is as follows,

[0012]

[0013] The oxaprozin-3-hydroxypyridine drug salt; the oxaprozin-3-hydroxypyridine drug salt is an orthorhombic system, the space group is Pbca, and the unit cell parameters are: α = 90°, β = 90°, γ = 90°, and the unit cell volume is Each unit cell contains 8 oxaprozin-3-hydroxypyridine molecules.

[0014] The oxaprozin-3-hydroxypyridine drug salt; the X-ray powder diffraction pattern of the oxaprozin-3-hydroxypyridine drug salt has characteristic peaks at diffraction angles 2θ = 3.45° ± 0.2°, 6.95° ± 0.2°, 10.49° ± 0.2°, 11.05° ± 0.2°, 14.14° ± 0.2°, 16.75° ± 0.2°, 17.38° ± 0.2°, 17.79° ± 0.2°, 19.99° ± 0.2°, 20.68° ± 0.2°, 21.52° ± 0.2°, 22.93° ± 0.2°, 24.43° ± 0.2°, 24.89° ± 0.2°, 25.95° ± 0.2°, 26.83° ± 0.2°.

[0015] The preparation method of the oxaprozin-3-hydroxypyridine drug salt of the present invention includes a cooling crystallization method or a suspension crystallization method.

[0016] The specific steps of the preparation method by cooling crystallization include:

[0017] (1) Add oxaprozin and 3-hydroxypyridine with a molar ratio of 1:1 to a liquid, and dissolve it clearly under stirring at 55 - 65°C;

[0018] (2) Cool the above-mentioned clear solution to 15 - 25°C at a cooling rate of 10 - 20°C / h under stirring, and maintain it for 1 - 2 h to obtain a crystal slurry;

[0019] (3) Filter the above-mentioned crystal slurry, and dry the filter cake at 40 - 60°C to obtain the oxaprozin-3-hydroxypyridine drug salt, and the filtrate can be recycled.

[0020] In the cooling crystallization step (1), the liquid is an organic solvent or the filtrate in step (3). When the liquid is an organic solvent, the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of the organic solvent is 0.02 - 0.06 g / mL; when the liquid is the filtrate in step (3), the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of the filtrate is 0.01 - 0.04 g / mL.

[0021] The preparation method by suspension crystallization, the specific steps include:

[0022] (1) Under the conditions of 15 - 28 °C and with stirring, oxaprozin and 3 - hydroxypyridine with a molar ratio of 1:1 are added to a liquid to form a solid - liquid two - phase mixture;

[0023] (2) At 15 - 28 °C, the above mixture is stirred at a constant temperature for 8 - 12 h to obtain a crystal slurry;

[0024] (3) The above crystal slurry is filtered, and the filter cake is dried at 40 - 60 °C to obtain the oxaprozin - 3 - hydroxypyridine drug salt, and the filtrate can be recycled.

[0025] In step (1) of the suspension crystallization preparation method described above, the liquid is an organic solvent or the filtrate in step (3). When the liquid is an organic solvent, the ratio of the total mass of oxaprozin and 3 - hydroxypyridine to the volume of the organic solvent is 0.11 - 0.24 g / mL. When the liquid is the filtrate in step (3), the ratio of the total mass of oxaprozin and 3 - hydroxypyridine to the volume of the filtrate is 0.10 - 0.22 g / mL.

[0026] In the cooling crystallization method or the suspension crystallization method, the organic solvent is selected from one of methanol, ethanol, methyl acetate, isopropanol, acetone or acetonitrile.

[0027] The application of the oxaprozin - 3 - hydroxypyridine drug salt of the present invention in the preparation of an oxaprozin alternative drug.

[0028] Specific descriptions are as follows according to the attached drawings:

[0029] The molecular formula of the oxaprozin - 3 - hydroxypyridine drug salt of the present invention is [C 18 H 14 NO 3 ·C 5 H 6 NO], and the structural formula is as shown in II. The stoichiometric ratio of oxaprozin to 3 - hydroxypyridine is 1:1. This drug salt is an orthorhombic crystal system, the space group is Pbca, and the unit cell parameters are: α = 90°, β = 90°, γ = 90°, and the unit cell volume is Each unit cell contains 8 oxaprozin - 3 - hydroxypyridine molecules, as shown in the attached Figure 5 figure.

[0030]

[0031] The X-ray powder diffraction pattern of the oxaprozin-3-hydroxypyridine drug salt has characteristic peaks at diffraction angles 2θ = 3.45° ± 0.2°, 6.95° ± 0.2°, 10.49° ± 0.2°, 11.05° ± 0.2°, 14.14° ± 0.2°, 16.75° ± 0.2°, 17.38° ± 0.2°, 17.79° ± 0.2°, 19.99° ± 0.2°, 20.68° ± 0.2°, 21.52° ± 0.2°, 22.93° ± 0.2°, 24.43° ± 0.2°, 24.89° ± 0.2°, 25.95° ± 0.2°, 26.83° ± 0.2°. The X-ray powder diffraction pattern is shown in the attached Figure 6 as follows.

[0032] The differential scanning calorimetry (DSC) curve and thermogravimetric analysis (TGA) curve of the oxaprozin-3-hydroxypyridine drug salt are shown in the attached Figure 7 as follows. The DSC curve of this drug salt starts to absorb heat at 140 ± 1 °C, and the TGA curve starts to lose weight from 140 ± 1 °C, corresponding to the melting accompanied by decomposition process of the oxaprozin-3-hydroxypyridine drug salt.

[0033] There are two preparation methods for the oxaprozin-3-hydroxypyridine drug salt disclosed in the present invention, namely the cooling crystallization method and the suspension crystallization method.

[0034] A preparation method of an oxaprozin-3-hydroxypyridine drug salt of the present invention, wherein the specific steps of cooling crystallization include:

[0035] (1) Oxaprozin and 3-hydroxypyridine with a molar ratio of 1:1 are added to a liquid and dissolved clearly under stirring at 55 - 65 °C;

[0036] (2) The above-mentioned clear solution is cooled to 15 - 25 °C at a cooling rate of 10 - 20 °C / h under stirring and maintained for 1 - 2 h to obtain a crystal slurry;

[0037] (3) The above-mentioned crystal slurry is filtered, and the filter cake is dried at 40 - 60 °C to obtain the oxaprozin-3-hydroxypyridine drug salt, and the filtrate can be recycled.

[0038] In the cooling crystallization step (1) of the present invention, the liquid is an organic solvent or the filtrate in step (3). When the liquid is an organic solvent, the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of the organic solvent is 0.02 - 0.06 g / mL; when the liquid is the filtrate in step (3), the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of the filtrate is 0.01 - 0.04 g / mL.

[0039] A preparation method of an oxaprozin-3-hydroxypyridine drug salt of the present invention, wherein the specific steps of suspension crystallization include:

[0040] (1) Under the conditions of 15 - 28 °C and with stirring, oxaprozin and 3 - hydroxypyridine with a molar ratio of 1:1 are added to a liquid to form a solid - liquid two - phase mixture;

[0041] (2) At 15 - 28 °C, the above mixture is stirred at a constant temperature for 8 - 12 h to obtain a crystal slurry;

[0042] (3) The above crystal slurry is filtered, and the filter cake is dried at 40 - 60 °C to obtain the oxaprozin - 3 - hydroxypyridine drug salt, and the filtrate can be recycled.

[0043] In the suspension crystallization step (1) of the present invention, the liquid is an organic solvent or the filtrate in step (3). When the liquid is an organic solvent, the ratio of the total mass of oxaprozin and 3 - hydroxypyridine to the volume of the organic solvent is 0.11 - 0.24 g / mL. When the liquid is the filtrate in step (3), the ratio of the total mass of oxaprozin and 3 - hydroxypyridine to the volume of the filtrate is 0.10 - 0.22 g / mL.

[0044] The asymmetric unit of the oxaprozin - 3 - hydroxypyridine drug salt prepared by the present invention is as shown in Appendix Figure 8 (a). Each asymmetric unit consists of a deprotonated oxaprozin anion and a protonated 3 - hydroxypyridine cation. The proton on the oxaprozin carboxylic acid is transferred to the pyridine nitrogen atom of 3 - hydroxypyridine to form a charge - assisted N - H · …O hydrogen bond, as shown in Appendix Figure 8 (b). This fact is consistent with the prediction results based on the △pK a rule and the molecular electrostatic potential surface. Appendix Figure 9 shows the main crystal faces of oxaprozin and the crystal morphology predicted by the Attachment Energy (AE) model. Oxaprozin is a needle - shaped crystal, and the prediction result is consistent with the actual crystal morphology. Oxaprozin exposes the carboxyl group and the benzene ring on the main crystal faces (002) and (102) respectively. The carboxyl group belongs to a hydrophilic group, which is conducive to forming interactions with water, and the benzene ring belongs to a hydrophobic group, which is not conducive to dissolution. The drug salt prepared by the present invention is a colorless, transparent flaky crystal with a smooth surface and a complete morphology (Appendix Figure 10 ). The main particle size of the drug salt measured by a Malvern particle size analyzer is about 100 μm, as shown in Appendix Figure 11 . Appendix Figure 12The main crystal faces of the oxaprozin-3-hydroxypyridine drug salt and the crystal morphology predicted by the AE model are shown. The prediction results are consistent with the experimental results. The hydrophilic groups, namely the hydroxyl group and the pyridyl group, of the salt-forming agent 3-hydroxypyridine are exposed on the main crystal faces (002) and (102), respectively. Compared with single-component oxaprozin, the introduction of the salt-forming agent increases the hydration sites on the crystal faces, which helps water molecules interact with the crystal faces and promotes the dissolution of oxaprozin.

[0045] The applicant measured the solubility of oxaprozin and oxaprozin-3-hydroxypyridine salt in pure water at 37 °C (body temperature) and pH 6.8 phosphate buffer (simulating the small intestine environment) using the shake flask method (excess powder sample was placed in a vial containing 10 mL of buffer solution and shaken for 24 h to reach the equilibrium saturation state). The buffer solution was prepared according to the Chinese Pharmacopoeia (2020 Edition). As attached Figure 13As shown, the solubilities of oxaprozin under two conditions are 0.013±0.002 mg / mL and 0.832±0.001 mg / mL respectively. For the oxaprozin-3-hydroxypyridine drug salt provided by the present invention, the solubilities calculated as oxaprozin are 0.180±0.003 mg / mL and 0.930±0.022 mg / mL respectively, which are 12.85 times and 11.78% higher than the solubility of oxaprozin respectively. The solubilities of three eutectics of oxaprozin in pure water at 37°C disclosed in patent application CN116473975A and patent application CN116492349A are increased by about 40%, 60% and 50% respectively. In contrast, the oxaprozin-3-hydroxypyridine drug salt prepared by the present invention obviously has a better solubilization effect. Further, the applicant measured the solubilities of the three eutectics prepared according to the methods of patent application CN116473975A and patent application CN116492349A in phosphate buffer at 37°C and pH 6.8. The data are shown in Table 1. Calculated as oxaprozin, the solubilities of the three eutectics are lower than that of oxaprozin, and the effect of solubilizing oxaprozin is not achieved. Similarly, the applicant prepared the oxaprozin-4,4'-bipyridine cocrystal, oxaprozin-1,2-bis(4-pyridyl)ethane cocrystal and oxaprozin-2-amino-3-methylpyridine salt whose solubilities were not measured in the literature (DOI: 10.1039 / C6RA01802E), and measured their solubilities in phosphate buffer at 37°C and pH 6.8. Calculated as oxaprozin, they are 0.588±0.003 mg / mL, 0.644±0.002 mg / mL and 0.757±0.002 mg / mL respectively, while the solubility of oxaprozin under the same conditions is 0.832±0.001 mg / mL. In contrast, these two cocrystals and one salt do not increase the solubility of oxaprozin, but decrease it by 29.33%, 22.60% and 9.01% respectively. The data are shown in Table 1. In addition, for comparison, the applicant also measured the solubility of the oxaprozin-3-hydroxypyridine drug salt disclosed in the present application in phosphate buffer at 37°C and pH 7.4 (containing 0.5% Tween 80 as a cosolvent) according to the solubility test method described in this literature. Calculated as oxaprozin, it is 3.07±0.004 mg / mL. Compared with the solubility of oxaprozin of 2.30 mg / mL under the same test conditions reported in this literature, the oxaprozin-3-hydroxypyridine drug salt of the present application increased the solubility of oxaprozin by 33.48%. The solubilities of the oxaprozin-piperazine salt and oxaprozin-salbutamol salt reported in this literature are only 2.11 mg / mL and 2.02 mg / mL, which are significantly lower than the solubility of the oxaprozin-3-hydroxypyridine drug salt of the present application, and decrease the solubility of oxaprozin by 8.26% and 12.17% respectively.For the convenience of comparison, the applicant summarizes the solubilities of oxaprozin, oxaprozin eutectic, oxaprozin co-crystal, and oxaprozin salt mentioned under the above conditions in Table 1. In summary, the oxaprozin-3-hydroxypyridine drug salt provided by the present invention significantly improves the solubility of oxaprozin in pure water at 37 °C, in phosphate buffer at 37 °C and pH 6.8, and in phosphate buffer at 37 °C and pH 7.4 (containing 0.5% Tween 80 co-solvent), which is consistent with the results of solvation free energy and crystal plane analysis. In short, the reported oxaprozin co-crystals or salts currently have problems such as low solubility of oxaprozin, high toxicity of salt-forming agents, or poor stability. The oxaprozin eutectic disclosed in the patent has defects such as uncertain internal structure and insignificant effect of improving the solubility of oxaprozin. The present invention provides an oxaprozin-3-hydroxypyridine drug salt, which has a crystal structure different from that of oxaprozin and 3-hydroxypyridine. There are various means to confirm its crystal structure, and the absolute molecular configuration is clear, meeting the basic requirements for the active ingredient of chemical drugs in the approval process. Moreover, the oxaprozin-3-hydroxypyridine drug salt provided by the present invention significantly improves the solubility of oxaprozin.

[0046] Generally, the higher the melting point of a crystal, the greater the lattice strength, and the greater the absolute value of the solvation free energy, the easier it is to dissolve. The melting point of oxaprozin-salbutamol salt is 172.7 °C, which is higher than that of oxaprozin (160.5 ± 1 °C) and oxaprozin-3-hydroxypyridine salt (140 ± 1 °C). The applicant calculated the lattice energies of oxaprozin and oxaprozin-salbutamol salt. The larger the absolute value of the lattice energy, the greater the lattice strength. The lattice energy of oxaprozin-salbutamol salt is -132.98 kcal / mol, and the lattice energy of oxaprozin is -72.69 kcal / mol. The melting point and lattice energy data both indicate that oxaprozin-salbutamol salt is not conducive to the release and dissolution of oxaprozin molecules from the lattice. The applicant calculated the solvation free energies of oxaprozin-piperazine salt and oxaprozin-2-amino-3-methylpyridine salt, which are -8.213 and -13.927 kcal / mol respectively, and their absolute values are lower than that of oxaprozin-3-hydroxypyridine drug salt (-16.938 kcal / mol), indicating that oxaprozin-piperazine salt and oxaprozin-2-amino-3-methylpyridine salt are more difficult to dissolve than oxaprozin-3-hydroxypyridine drug salt. The above analysis provides a theoretical basis for the fact that the solubilities of oxaprozin-salbutamol salt, oxaprozin-piperazine salt, and oxaprozin-2-amino-3-methylpyridine salt are lower than that of oxaprozin. In addition, it should be noted that salbutamol has poor stability and needs to be stored at -20 °C; in the classification of the Globally Harmonized System of Classification and Labelling of Chemicals (GHS), piperazine and 2-amino-3-methylpyridine belong to the dangerous category, and ingestion will endanger human health. The safety and practicability of these three salt-forming agents are also inferior to the salt-forming agent 3-hydroxypyridine selected in the present invention.

[0047] Table 1 Solubility of Oxaprozin, Oxaprozin Eutectic and Oxaprozin Salt under Two Conditions, Calculated as Oxaprozin, Unit: mg / mL

[0048]

[0049] Note: a The data were measured by the inventors of this application. b The data were reported in the literature (DOI: 10.1039 / C6RA01802E); the percentage increase or decrease in the table = (x - x OXA ) / x OXA , where x is the solubility of Oxaprozin Eutectic, Oxaprozin Cocrystal or Salt, and x OXA is the solubility of Oxaprozin under the same conditions.

[0050] The applicant measured the dissolution curves of Oxaprozin and Oxaprozin-3-hydroxypyridine salt in phosphate buffer at pH 6.8 and 37 °C according to the method described in "APPARENT INTRINSIC DISSOLUTION" in the United States Pharmacopeia USP46-NF41. In the test, a powder sample with a particle size of 100 to 140 mesh was compressed at 8 MPa for 3 min to obtain a disk with a diameter of 13 mm. The outer surface of the disk was covered with paraffin, and one circular surface was exposed.

[0051] As shown in the appendix Figure 14 , the intrinsic dissolution rate measured based on the dissolution curve of Oxaprozin in the first 30 min was 0.179 ± 0.003 mg / (cm 2 ·min). The intrinsic dissolution rate of the Oxaprozin-3-hydroxypyridine drug salt provided by the present invention, calculated as Oxaprozin, was 0.218 ± 0.004 mg / (cm 2 ·min), and the intrinsic dissolution rate of Oxaprozin increased by 21.79%. The concentration of Oxaprozin at 900 ± 1 min of dissolution was defined as the maximum dissolution concentration. Then, the maximum dissolution concentration of Oxaprozin was 0.623 ± 0.002 mg / mL, and the maximum dissolution concentration of Oxaprozin in the Oxaprozin-3-hydroxypyridine drug salt was 0.816 ± 0.005 mg / mL. Compared with the former, the maximum dissolution concentration increased by 30.98%, which was consistent with the trend that the Oxaprozin-3-hydroxypyridine drug salt significantly increased the solubility of Oxaprozin. Therefore, the Oxaprozin-3-hydroxypyridine drug salt disclosed in the present invention has higher solubility and faster dissolution rate, which is beneficial to the improvement of the bioavailability of Oxaprozin.

[0052] An accelerated stability experiment was conducted on the oxaprozin-3-hydroxypyridine drug salt prepared by the method of the present invention. It was stored for 8 weeks at a temperature of 40 °C and a relative humidity of 75 ± 5%. Samples were taken at 0 week, 2 weeks, 4 weeks, and 8 weeks respectively to measure the X-ray powder diffraction pattern, as shown in the appendix Figure 15 As shown, its X-ray powder diffraction Figure 1 remained unchanged, indicating that the crystal structure of the drug salt did not change and its hygrothermal stability was good.

[0053] The present invention provides an oxaprozin-3-hydroxypyridine drug salt and a preparation method thereof. This method consumes less solvent. The oxaprozin-3-hydroxypyridine salt is prepared by the cooling method and the suspension crystallization method, and the consumption of organic solvents is 0.02 - 0.1 m 3 / kg and 0.004 - 0.009 m 3 / kg respectively based on oxaprozin, and the filtrate can be recycled and reused. Solution crystallization or suspension crystallization can be carried out in a stirred tank, and the liquid is transported through pipelines and pumps, making the production operation convenient. Among the two methods for preparing the oxaprozin eutectic disclosed in Patent Application CN116473975A and Patent Application CN116492349A, the grinding method is usually carried out in a mortar or a ball mill, and the solid transportation usually uses manual labor. The equipment used is bulky. Compared with solution crystallization or suspension crystallization, this method is not easy to industrialize and has poor practicability; the solvent-mediated coprecipitation method consumes 0.06 - 0.25 m 3 / kg of ethanol based on oxaprozin, with a large solvent consumption and high cost. The preparation method of the oxaprozin-3-hydroxypyridine salt provided by the present invention is simple in operation, only requiring three steps, and the product quality is stable and the reproducibility is good. More importantly, the solubility and intrinsic dissolution rate of the oxaprozin-3-hydroxypyridine drug salt are both higher than those of oxaprozin and it has good stability, is easy to produce and apply, and has good prospects. Description of the Drawings

[0054] Figure 1 are the dissolution curves of oxaprozin (OXA), oxaprozin-isonicotinamide eutectic (OXA-iNAM), oxaprozin-pyrazinamide eutectic (OXA-PZA), and oxaprozin-isoniazid eutectic (OXA-INH) in pure water at 37 °C in the reported patents. (a) Appendix in Patent Application CN116473975A Figure 5 ; (b) Appendix in Patent Application CN116492349A Figure 4

[0055] Figure 2 is the full interaction diagram of oxaprozin

[0056] Figure 3 is the molecular surface electrostatic potential diagram of oxaprozin

[0057] Figure 4 is the molecular surface electrostatic potential map of 3-hydroxypyridine

[0058] Figure 5 is the unit cell diagram of the oxaprozin-3-hydroxypyridine drug salt prepared by the present invention

[0059] Figure 6 is the X-ray powder diffraction pattern of the oxaprozin-3-hydroxypyridine drug salt prepared by the present invention

[0060] Figure 7 is the DSC curve and TGA curve diagram of the oxaprozin-3-hydroxypyridine drug salt prepared by the present invention

[0061] Figure 8 is the crystal structure of the oxaprozin-3-hydroxypyridine drug salt prepared by the present invention: (a) asymmetric unit diagram; (b) hydrogen bond interaction diagram

[0062] Figure 9 are the main crystal faces of oxaprozin and the predicted crystal morphology under the AE model

[0063] Figure 10 is the optical microscope image of the oxaprozin-3-hydroxypyridine drug salt prepared by the present invention

[0064] Figure 11 is the particle size distribution diagram of the oxaprozin-3-hydroxypyridine drug salt prepared by the present invention

[0065] Figure 12 are the main crystal faces of the oxaprozin-3-hydroxypyridine drug salt prepared by the present invention and the predicted crystal morphology under the AE model

[0066] Figure 13 are the solubility diagrams of oxaprozin and the oxaprozin-3-hydroxypyridine drug salt prepared by the present invention in pure water and pH 6.8 phosphate buffer at 37°C

[0067] Figure 14 is the dissolution curve diagram of oxaprozin and the oxaprozin-3-hydroxypyridine drug salt prepared by the present invention in pH 6.8 phosphate buffer at 37°C

[0068] Figure 15 is the X-ray powder diffraction pattern of the accelerated stability test of the oxaprozin-3-hydroxypyridine drug salt prepared by the present invention Detailed implementation manners

[0069] The above content of the present invention will be further described in detail below in the form of specific embodiments by way of examples, but it should not be understood that the scope of the above main body of the present invention is limited only to the following examples.

[0070] Example 1:

[0071] The oxaprozin-3-hydroxypyridine drug salt is prepared by the method of cooling crystallization, and the specific steps are as follows:

[0072] (1) 0.88 g of oxaprozin and 0.286 g of 3-hydroxypyridine are added to 19.3 mL of acetonitrile, and the mixture is heated to 55 °C with stirring to form a clear solution. Among them, the molar ratio of oxaprozin to 3-hydroxypyridine is 1:1, and the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of acetonitrile is 0.060 g / mL;

[0073] (2) The above-mentioned clear solution is cooled to 15 °C at a cooling rate of 10 °C / h with stirring and maintained for 1 h to obtain a crystal slurry;

[0074] (3) The above-mentioned crystal slurry is filtered, and the filter cake is dried at 40 °C, and the filtrate can be recycled.

[0075] In the obtained oxaprozin-3-hydroxypyridine drug salt, the stoichiometric ratio of oxaprozin to 3-hydroxypyridine is 1:1. The X-ray powder diffraction pattern of this drug salt is shown in the appendix Figure 6 As shown, characteristic peaks are present at diffraction angles 2θ = 3.47°, 6.93°, 10.47°, 11.07°, 14.12°, 16.77°, 17.37°, 17.81°, 19.97°, 20.66°, 21.51°, 22.91°, 24.43°, 24.87°, 25.93°, 26.81°; its DSC curve and TGA curve are shown in the appendix Figure 7 As shown, the DSC curve of this drug salt starts to absorb heat at 140.5 °C, and the TGA curve starts to lose weight from 140.8 °C.

[0076] Example 2:

[0077] The oxaprozin-3-hydroxypyridine drug salt is prepared by the method of cooling crystallization, and the specific steps are as follows:

[0078] (1) 0.66 g of oxaprozin and 0.214 g of 3-hydroxypyridine are added to 42 mL of acetone, and the mixture is heated to 58 °C with stirring to form a clear solution. Among them, the molar ratio of oxaprozin to 3-hydroxypyridine is 1:1, and the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of acetone is 0.020 g / mL;

[0079] (2) The above-mentioned clear solution is cooled to 20 °C at a cooling rate of 15 °C / h and maintained for 1.5 h to obtain a crystal slurry;

[0080] (3) The above-mentioned crystal slurry is filtered, and the filter cake is dried at 50 °C, and the filtrate can be recycled.

[0081] The stoichiometric ratio of oxaprozin to 3-hydroxypyridine in the obtained oxaprozin-3-hydroxypyridine drug salt is 1:1. The X-ray powder diffraction pattern of this drug salt has characteristic peaks at diffraction angles 2θ = 3.46°, 6.94°, 10.48°, 11.06°, 14.13°, 16.76°, 17.39°, 17.80°, 19.98°, 20.67°, 21.53°, 22.92°, 24.44°, 24.88°, 25.94°, 26.82°. The DSC curve of this drug salt starts to absorb heat at 140.3 °C, and the TGA curve starts to lose weight from 140.5 °C.

[0082] Example 3:

[0083] The oxaprozin-3-hydroxypyridine drug salt was prepared by the cooling crystallization method. The specific steps are as follows:

[0084] (1) 0.44 g of oxaprozin and 0.143 g of 3-hydroxypyridine were added to 20 mL of isopropanol, and the mixture was heated to 65 °C with stirring to form a clear solution. Among them, the molar ratio of oxaprozin to 3-hydroxypyridine is 1:1, and the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of isopropanol is 0.029 g / mL.

[0085] (2) The above clear solution was cooled to 25 °C at a rate of 20 °C / h and maintained for 2 h to obtain a crystal slurry.

[0086] (3) The above crystal slurry was filtered, and the filter cake was dried at 60 °C. The filtrate can be recycled.

[0087] The stoichiometric ratio of oxaprozin to 3-hydroxypyridine in the obtained oxaprozin-3-hydroxypyridine drug salt is 1:1. The X-ray powder diffraction pattern of this drug salt has characteristic peaks at diffraction angles 2θ = 3.47°, 6.94°, 10.48°, 11.07°, 14.13°, 16.77°, 17.39°, 17.80°, 19.98°, 20.66°, 21.53°, 22.92°, 24.44°, 24.87°, 25.94°, 26.82°. The DSC curve of this drug salt starts to absorb heat at 140.1 °C, and the TGA curve starts to lose weight from 140.5 °C.

[0088] Example 4:

[0089] The oxaprozin-3-hydroxypyridine drug salt was prepared by the cooling crystallization method. The specific steps are as follows:

[0090] (1) Add 0.77 g of oxaprozin and 0.25 g of 3-hydroxypyridine to 25.5 mL of the recycled filtrate, and heat it to 55 °C with stirring to form a clear solution. Among them, the molar ratio of oxaprozin to 3-hydroxypyridine is 1:1, and the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the filtrate volume is 0.040 g / mL;

[0091] (2) Cool the above-mentioned clear solution to 20 °C at 15 °C / h and maintain it for 2 h to obtain a crystal slurry;

[0092] (3) Filter the above-mentioned crystal slurry, dry the filter cake at 60 °C, and the filtrate can be recycled.

[0093] In the obtained oxaprozin-3-hydroxypyridine drug salt, the stoichiometric ratio of oxaprozin to 3-hydroxypyridine is 1:1. The X-ray powder diffraction pattern of this drug salt has characteristic peaks at diffraction angles 2θ = 3.45°, 6.95°, 10.47°, 11.05°, 14.13°, 16.77°, 17.39°, 17.80°, 19.98°, 20.66°, 21.53°, 22.92°, 24.45°, 24.87°, 25.94°, 26.82°. The DSC curve of this drug salt starts to absorb heat at 140.2 °C, and the TGA curve starts to lose weight from 140.5 °C.

[0094] Example 5:

[0095] The cooling crystallization method is adopted to prepare the oxaprozin-3-hydroxypyridine drug salt, and the specific steps are as follows:

[0096] (1) Add 0.33 g of oxaprozin and 0.107 g of 3-hydroxypyridine to 42 mL of the recycled filtrate, and heat it to 60 °C with stirring to form a clear solution. Among them, the molar ratio of oxaprozin to 3-hydroxypyridine is 1:1, and the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the filtrate volume is 0.010 g / mL;

[0097] (2) Cool the above-mentioned clear solution to 25 °C at 20 °C / h and maintain it for 1.5 h to obtain a crystal slurry;

[0098] (3) Filter the above-mentioned crystal slurry, dry the filter cake at 40 °C, and the filtrate can be recycled.

[0099] The stoichiometric ratio of oxaprozin to 3-hydroxypyridine in the obtained oxaprozin-3-hydroxypyridine drug salt is 1:1. The X-ray powder diffraction pattern of this drug salt has characteristic peaks at diffraction angles 2θ = 3.44°, 6.94°, 10.48°, 11.07°, 14.13°, 16.75°, 17.39°, 17.80°, 19.98°, 20.66°, 21.52°, 22.92°, 24.44°, 24.87°, 25.94°, 26.82°; the DSC curve of this drug salt starts to absorb heat at 140.1 °C, and the TGA curve starts to lose weight from 140.6 °C.

[0100] Example 6:

[0101] The oxaprozin-3-hydroxypyridine drug salt was prepared by the cooling crystallization method, and the specific steps are as follows:

[0102] (1) 0.55 g of oxaprozin and 0.178 g of 3-hydroxypyridine were added to 30 mL of the recycled filtrate, and the mixture was heated to 65 °C with stirring to form a clear solution. Among them, the molar ratio of oxaprozin to 3-hydroxypyridine is 1:1, and the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the filtrate volume is 0.024 g / mL;

[0103] (2) The above clear solution was cooled to 15 °C at 10 °C / h and maintained for 1 h to obtain a crystal slurry;

[0104] (3) The above crystal slurry was filtered, and the filter cake was dried at 50 °C, and the filtrate could be recycled.

[0105] The stoichiometric ratio of oxaprozin to 3-hydroxypyridine in the obtained oxaprozin-3-hydroxypyridine drug salt is 1:1. The X-ray powder diffraction pattern of this drug salt has characteristic peaks at diffraction angles 2θ = 3.47°, 6.94°, 10.48°, 11.05°, 14.13°, 16.77°, 17.39°, 17.78°, 19.99°, 20.66°, 21.53°, 22.92°, 24.44°, 24.87°, 25.94°, 26.82°; the DSC curve of this drug salt starts to absorb heat at 140.5 °C, and the TGA curve starts to lose weight from 140.5 °C.

[0106] Example 7:

[0107] The oxaprozin-3-hydroxypyridine drug salt was prepared by the suspension crystallization method, and the specific steps are as follows:

[0108] (1) At 15 °C with stirring, 1.00 g of oxaprozin and 0.324 g of 3-hydroxypyridine were added to 12 mL of methanol to form a solid-liquid two-phase mixture. Among them, the molar ratio of oxaprozin to 3-hydroxypyridine was 1:1, and the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of methanol was 0.11 g / mL;

[0109] (2) At 15 °C, the above mixture was stirred at a constant temperature for 8 h to obtain a crystal slurry;

[0110] (3) The above crystal slurry was filtered, and the filter cake was dried at 40 °C, and the filtrate could be recycled.

[0111] In the obtained oxaprozin-3-hydroxypyridine drug salt, the stoichiometric ratio of oxaprozin to 3-hydroxypyridine was 1:1. The X-ray powder diffraction pattern of this drug salt had characteristic peaks at diffraction angles 2θ = 3.43°, 6.93°, 10.51°, 11.07°, 14.16°, 16.73°, 17.36°, 17.81°, 19.99°, 20.66°, 21.50°, 22.91°, 24.41°, 24.87°, 25.93°, 26.81°. The DSC curve of this drug salt started to absorb heat at 140.5 °C, and the TGA curve started to lose weight from 140.6 °C.

[0112] Example 8:

[0113] The suspension crystallization method was used to prepare the oxaprozin-3-hydroxypyridine drug salt, and the specific steps were as follows:

[0114] (1) At 20 °C with stirring, 1.20 g of oxaprozin and 0.390 g of 3-hydroxypyridine were added to 6.5 mL of ethanol to form a solid-liquid two-phase mixture. Among them, the molar ratio of oxaprozin to 3-hydroxypyridine was 1:1, and the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of ethanol was 0.24 g / mL;

[0115] (2) At 20 °C, the above mixture was stirred at a constant temperature for 10 h to obtain a crystal slurry;

[0116] (3) The above crystal slurry was filtered, and the filter cake was dried at 55 °C, and the filtrate could be recycled.

[0117] The stoichiometric ratio of oxaprozin to 3-hydroxypyridine in the obtained oxaprozin-3-hydroxypyridine drug salt is 1:1. The X-ray powder diffraction pattern of this drug salt has characteristic peaks at diffraction angles 2θ = 3.47°, 6.95°, 10.50°, 11.05°, 14.15°, 16.74°, 17.39°, 17.81°, 19.97°, 20.67°, 21.51°, 22.94°, 24.42°, 24.88°, 25.94°, 26.82°. The DSC curve of this drug salt starts to absorb heat at 140.2 °C, and the TGA curve starts to lose weight from 140.8 °C.

[0118] Example 9:

[0119] The oxaprozin-3-hydroxypyridine drug salt was prepared by the suspension crystallization method, and the specific steps are as follows:

[0120] (1) At 28 °C with stirring, 1.1 g of oxaprozin and 0.357 g of 3-hydroxypyridine were added to 8 mL of methyl acetate to form a solid-liquid two-phase mixture. Among them, the molar ratio of oxaprozin to 3-hydroxypyridine is 1:1, and the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of methyl acetate is 0.18 g / mL;

[0121] (2) At 28 °C, the above mixture was stirred at a constant temperature for 12 h to obtain a crystal slurry;

[0122] (3) The above crystal slurry was filtered, and the filter cake was dried at 60 °C. The filtrate can be recycled.

[0123] The stoichiometric ratio of oxaprozin to 3-hydroxypyridine in the obtained oxaprozin-3-hydroxypyridine drug salt is 1:1. The X-ray powder diffraction pattern of this drug salt has characteristic peaks at diffraction angles 2θ = 3.44°, 6.95°, 10.50°, 11.05°, 14.12°, 16.74°, 17.39°, 17.77°, 19.97°, 20.67°, 21.50°, 22.94°, 24.42°, 24.88°, 25.94°, 26.85°. The DSC curve of this drug salt starts to absorb heat at 140.3 °C, and the TGA curve starts to lose weight from 140.4 °C.

[0124] Example 10:

[0125] The oxaprozin-3-hydroxypyridine drug salt was prepared by the suspension crystallization method, and the specific steps are as follows:

[0126] (1) Under the condition of 25 °C and stirring, 1.3 g of oxaprozin and 0.421 g of 3-hydroxypyridine were added to 7.8 mL of the recycled filtrate to form a solid-liquid two-phase mixture. Among them, the molar ratio of oxaprozin to 3-hydroxypyridine is 1:1, and the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the filtrate volume is 0.22 g / mL;

[0127] (2) At 25 °C, the above mixture was stirred at a constant temperature for 12 h to obtain a crystal slurry;

[0128] (3) The above crystal slurry was filtered, and the filter cake was dried at 50 °C. The filtrate can be recycled.

[0129] In the obtained oxaprozin-3-hydroxypyridine drug salt, the stoichiometric ratio of oxaprozin to 3-hydroxypyridine is 1:1. The X-ray powder diffraction pattern of this drug salt has characteristic peaks at diffraction angles 2θ = 3.43°, 6.96°, 10.50°, 11.05°, 14.14°, 16.74°, 17.39°, 17.77°, 19.99°, 20.67°, 21.50°, 22.93°, 24.42°, 24.88°, 25.94°, 26.83°. The DSC curve of this drug salt starts to absorb heat at 140.3 °C, and the TGA curve starts to lose weight from 140.7 °C.

[0130] Example 11:

[0131] The suspension crystallization method was used to prepare the oxaprozin-3-hydroxypyridine drug salt. The specific steps are as follows:

[0132] (1) Under the condition of 15 °C and stirring, 0.9 g of oxaprozin and 0.292 g of 3-hydroxypyridine were added to 11.5 mL of the recycled filtrate to form a solid-liquid two-phase mixture. Among them, the molar ratio of oxaprozin to 3-hydroxypyridine is 1:1, and the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the filtrate volume is 0.10 g / mL;

[0133] (2) At 15 °C, the above mixture was stirred at a constant temperature for 10 h to obtain a crystal slurry;

[0134] (3) The above crystal slurry was filtered, and the filter cake was dried at 40 °C. The filtrate can be recycled.

[0135] The stoichiometric ratio of oxaprozin to 3 - hydroxypyridine in the obtained oxaprozin - 3 - hydroxypyridine drug salt is 1:1. The X - ray powder diffraction pattern of this drug salt has characteristic peaks at diffraction angles 2θ = 3.44°, 6.95°, 10.50°, 11.05°, 14.12°, 16.74°, 17.39°, 17.77°, 19.97°, 20.67°, 21.50°, 22.94°, 24.42°, 24.88°, 25.94°, 26.82°. The DSC curve of this drug salt starts to absorb heat at 140.4 °C, and the TGA curve starts to lose weight from 140.4 °C.

[0136] Example 12:

[0137] The oxaprozin - 3 - hydroxypyridine drug salt was prepared by the suspension crystallization method, and the specific steps are as follows:

[0138] (1) At 28 °C with stirring, 1.05 g of oxaprozin and 0.34 g of 3 - hydroxypyridine were added to 9 mL of the recycled filtrate to form a solid - liquid two - phase mixture. Among them, the molar ratio of oxaprozin to 3 - hydroxypyridine is 1:1, and the ratio of the total mass of oxaprozin and 3 - hydroxypyridine to the filtrate volume is 0.15 g / mL.

[0139] (2) At 28 °C, the above - mentioned mixture was stirred at a constant temperature for 8 h to obtain a crystal slurry.

[0140] (3) The above - mentioned crystal slurry was filtered, and the filter cake was dried at 60 °C, and the filtrate could be recycled.

[0141] The stoichiometric ratio of oxaprozin to 3 - hydroxypyridine in the obtained oxaprozin - 3 - hydroxypyridine drug salt is 1:1. The X - ray powder diffraction pattern of this drug salt has characteristic peaks at diffraction angles 2θ = 3.44°, 6.95°, 10.50°, 11.05°, 14.12°, 16.74°, 17.39°, 17.77°, 19.97°, 20.67°, 21.50°, 22.94°, 24.42°, 24.88°, 25.94°, 26.81°. The DSC curve of this drug salt starts to absorb heat at 140.7 °C, and the TGA curve starts to lose weight from 140.8 °C.

[0142] The applicant measured the solubility of oxaprozin and the oxaprozin - 3 - hydroxypyridine drug salt prepared in the examples of the present invention in pure water and pH 6.8 phosphate buffer at 37 °C, as shown in the appendix Figure 13As shown. The solubility of oxaprozin under two conditions is 0.013±0.002mg / mL and 0.832±0.001mg / mL respectively. The oxaprozin-3-hydroxypyridine drug salt provided by the present invention increases the solubility of oxaprozin to 0.180±0.003mg / mL and 0.930±0.022mg / mL respectively, which is 12.85 times and 11.78% higher year-on-year. The applicant measured the dissolution curves of oxaprozin and the oxaprozin-3-hydroxypyridine drug salt prepared in the examples in 37°C, pH 6.8 phosphate buffer solution, as shown in the appendix Figure 14 As shown. The intrinsic dissolution rate of oxaprozin is 0.179±0.003mg / (cm 2 ·min). The intrinsic dissolution rate of the oxaprozin-3-hydroxypyridine drug salt provided by the present invention is 0.218±0.004mg / (cm 2 ·min) in terms of oxaprozin, and the intrinsic dissolution rate increases by 21.79%. In the dissolution curve graph, the dissolution concentrations of oxaprozin and the oxaprozin-3-hydroxypyridine drug salt both reach the maximum at 900±1min, which are 0.623±0.002mg / mL and 0.816±0.005mg / mL respectively. The dissolution experiment shows that the maximum dissolution concentration and the intrinsic dissolution rate of the oxaprozin-3-hydroxypyridine drug salt disclosed by the present invention are both greater than those of oxaprozin.

[0143] An accelerated stability experiment was carried out using the oxaprozin-3-hydroxypyridine drug salt prepared in the examples of the present invention. It was stored for 8 weeks under the conditions of a temperature of 40°C and a relative humidity of 75±5%, and samples were taken at 0 week, 2 weeks, 4 weeks, and 8 weeks respectively for X-ray powder diffraction analysis. The results show that the X-ray powder diffraction pattern remains unchanged, indicating that the crystal structure has not changed and its hydrothermal stability is good. As shown in the appendix Figure 15 The X-ray powder diffraction pattern of the accelerated stability experiment of the oxaprozin-3-hydroxypyridine drug salt prepared in Example 1 of the present invention is shown as follows.

[0144] In summary, the present invention provides an oxaprozin-3-hydroxypyridine drug salt and a preparation method thereof. This method consumes less solvent, is convenient and simple to operate, has good practicability, stable product quality, and good reproducibility. The oxaprozin-3-hydroxypyridine drug salt provided by the present invention improves the solubility and dissolution rate of oxaprozin, and the drug salt has good thermal stability, which is of great significance for improving bioavailability.

[0145] For the technical solutions disclosed and proposed in the present invention, those skilled in the art can achieve them by referring to the content herein and appropriately changing conditions, routes and other aspects. Although the methods and preparation techniques of the present invention have been described through preferred embodiments, it is obvious that relevant technicians can make changes or re-combinations to the methods and technical routes described herein without departing from the content, spirit and scope of the present invention to achieve the final preparation technique. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all regarded as being included in the spirit, scope and content of the present invention. Matters not covered by the present invention belong to well-known techniques.

Claims

1. An oxaprozin-3-hydroxypyridine drug salt; characterized in that: The stoichiometric ratio of oxaprozin to 3-hydroxypyridine is 1:1, and the molecular formula is [C 18 H 14 NO3·C5H6NO], the structural formula is as follows, 2. The oxaprozin-3-hydroxypyridine drug salt according to claim 1, characterized in that: Oxaprozin-3-hydroxypyridine drug salt is an orthorhombic crystal system with a space group of Pbca and unit cell parameters of: α=90°,β=90°,γ=90°,the unit cell volume is Each unit cell contains 8 molecules of oxaprozin-3-hydroxypyridine.

3. The oxaprozin-3-hydroxypyridine drug salt according to claim 1, characterized in that: The X-ray powder diffraction pattern of oxaprozin-3-hydroxypyridine drug salt has characteristic peaks at diffraction angles 2θ=3.45°±0.2°, 6.95°±0.2°, 10.49°±0.2°, 11.05°±0.2°, 14.14°±0.2°, 16.75°±0.2°, 17.38°±0.2°, 17.79°±0.2°, 19.99°±0.2°, 20.68°±0.2°, 21.52°±0.2°, 22.93°±0.2°, 24.43°±0.2°, 24.89°±0.2°, 25.95°±0.2°, and 26.83°±0.2°.

4. The method for preparing the drug salt of oxaprozin-3-hydroxypyridine according to claim 1, characterized in that: Including cooling crystallization or suspension crystallization.

5. The preparation method according to claim 4, characterized in that: The specific steps of cooling crystallization include: (1) adding oxaprozin and 3-hydroxypyridine in a molar ratio of 1:1 into a liquid, and dissolving them at 55 to 65° C. under stirring; (2) cooling the clarified solution to 15-25° C. at a cooling rate of 10-20° C. / h under stirring, and maintaining the temperature for 1-2 h to obtain a slurry; (3) Filter the above slurry, and dry the filter cake at 40-60° C. to obtain oxaprozin-3-hydroxypyridine drug salt. The filtrate can be recycled.

6. The preparation method according to claim 5, characterized in that: In step (1), the liquid is an organic solvent or the filtrate in step (3). When the liquid is an organic solvent, the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of the organic solvent is 0.02 to 0.06 g / mL; when the liquid is the filtrate in step (3), the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of the filtrate is 0.01 to 0.04 g / mL.

7. The preparation method according to claim 4, characterized in that: The specific steps of suspension crystallization include: (1) adding oxaprozin and 3-hydroxypyridine in a molar ratio of 1:1 to a liquid under stirring at 15 to 28° C. to form a solid-liquid two-phase mixture; (2) stirring the mixture at a constant temperature of 15 to 28° C. for 8 to 12 hours to obtain a slurry; (3) Filter the above slurry, and dry the filter cake at 40-60° C. to obtain oxaprozin-3-hydroxypyridine drug salt. The filtrate can be recycled.

8. The preparation method according to claim 7, characterized in that: In step (1), the liquid is an organic solvent or the filtrate in step (3). When the liquid is an organic solvent, the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of the organic solvent is 0.11 to 0.24 g / mL. When the liquid is the filtrate in step (3), the ratio of the total mass of oxaprozin and 3-hydroxypyridine to the volume of the filtrate is 0.10 to 0.22 g / mL.

9. The preparation method according to claim 6 or 8, characterized in that: The organic solvent is selected from one of methanol, ethanol, methyl acetate, isopropanol, acetone or acetonitrile.

10. Use of the oxaprozin-3-hydroxypyridine drug salt of claim 1 for preparing an oxaprozin substitute drug.

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