A topipusta-aminosulfonic acid eutectic

Abstract

This invention belongs to the field of medicinal chemistry, specifically relating to topiprostine-sulfamate cocrystal and its preparation method. The molar ratio of topiprostine to sulfamate in the topiprostine-sulfamate cocrystal provided by this invention is 1:1. The topiprostine-sulfamate cocrystal provided by this invention exhibits good stability and high solubility, which is of great significance for improving the bioavailability of topiprostine and the preparation of formulations.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to topipusta-aminosulfonic acid cocrystal and its preparation method. Background Technology

[0002] Topiroxostat, chemically named 4-[5-(pyridin-4-yl)-1H-[1,2,4]triazol-3-yl]pyridin-2-carboxynitrile, is a yellow crystalline powder. CAS number: 577778-58-6, its structural formula is shown in Formula I:

[0003]

[0004] Topiprolstat was jointly developed by Fuji Pharmaceutical Co., Ltd. and Sanwa Chemical Research Institute in Japan. A marketing application was submitted to the Japanese Ministry of Health, Labour and Welfare in June 2012, and topiprolstat tablets were approved on June 28, 2013. This product is a non-purine selective xanthine oxidase inhibitor used to treat gout and hyperuricemia.

[0005] Patent CN104411700 discloses two crystal forms and one hydrate of topirostat. The patent states that the solubility of crystal form I in water is 6.2 μg / ml, the solubility of crystal form II is 4.2 μg / ml, and the solubility of the hydrate is 1.9 μg / ml. This indicates that topirostat is a poorly soluble drug in water. Crystal form I has a higher solubility than crystal form II and the hydrate, making it the preferred crystal form for formulations. However, patent CN104042577 reports that crystal form I and crystal form II can interconvert during tableting. This crystal form conversion has a potential impact on the dissolution and stability of the drug formulation. These properties of topirostat pose a significant challenge in preparing solid formulations with good dissolution and / or stability.

[0006] Although numerous crystal forms of topipirostat have been published in existing literature, systematic research on these crystal forms still needs improvement, especially comprehensive studies on topipirostat cocrystal compounds. Novel drug cocrystal salts refer to supramolecular crystals with fixed stoichiometric ratios formed by the self-assembly of a new cocrystal material (CCF) with the active pharmaceutical ingredient (APT) under hydrogen bonding, introduced through proton transfer. Due to their potential advantages in dissolution, permeation, hygroscopicity, and stability, drug cocrystals have attracted increasing interest from researchers in the field of drug preparation. This invention provides a simple and easy-to-operate method for preparing topipirostat-sulfamate cocrystals, providing better evidence for the application of topipirostat in drug therapy, thereby more effectively utilizing the medicinal value of topipirostat. Summary of the Invention

[0007] In view of the shortcomings of the prior art, the present invention provides a topipsestat-aminosulfonic acid eutectic;

[0008] The specific technical content of this invention is as follows:

[0009] In a first aspect, the present invention provides a topipusta-sulfamic acid eutectic, wherein the eutectic molecular structure contains one molecule of topipusta and one molecule of sulfamic acid.

[0010] Preferably, the topipsestat-aminosulfonic acid eutectic, when subjected to Cu-Kα radiation, exhibits characteristic peaks at 8.25±0.2°, 16.48±0.2°, 24.79±0.2°, and 33.25±0.2° in its X-ray diffraction pattern expressed as 2θ.

[0011] Preferably, the topipsestat-aminosulfonic acid eutectic, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its 2θ X-ray diffraction pattern at 8.25±0.2°, 14.92±0.2°, 16.48±0.2°, 24.24±0.2°, 24.79±0.2°, 32.70±0.2°, 32.79±0.2°, 33.25±0.2°, and 41.90±0.2°.

[0012] Preferably, the topipsestat-aminosulfonic acid eutectic, when irradiated with Cu-Kα, exhibits characteristic peaks that conform to... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0013] Preferably, the topipsestat-aminosulfonic acid eutectic exhibits an endothermic peak in the differential scanning calorimetry (DSC) curve, corresponding to a temperature range of 245.27–281.29 °C, with a peak value of 267.02 °C.

[0014] Preferably, the crystallographic parameters of the topistat-sulfamic acid eutectic are: triclinic crystal system, space group P-1; and cell parameters are: α = 110.3360(10)°, β = 100.6170(10)°, γ = 100.5170(10)°, cell volume

[0015] A second aspect of the present invention provides a method for preparing a topipsestat-sulfamic acid eutectic, specifically comprising the following steps:

[0016] Topipusta was added to organic solvent 1, and aminosulfonic acid was added to water. The two were then ultrasonically mixed, and organic solvent 2 was added. The mixture was heated and stirred until completely dissolved. After the reaction was complete, the mixture was filtered and allowed to stand at room temperature to evaporate and crystallize. The crystals were then filtered and dried to obtain the topipusta-aminosulfonic acid eutectic.

[0017] Preferably, the molar ratio of topipsestat to aminosulfonic acid is 1:1 to 2.

[0018] More preferably, the molar ratio of topirostat to aminosulfonic acid is 1:1 to 1.5.

[0019] More preferably, the molar ratio of topiroxat to aminosulfonic acid is 1:1.

[0020] Preferably, the organic solvent 1 is selected from one or a combination of tetrahydrofuran, trifluoroethanol, n-propanol, isobutanol, isopropanol, and tert-butanol.

[0021] Preferably, the organic solvent 2 is selected from one or a combination of tetrahydrofuran, trifluoroethanol, methanol, ethanol, n-propanol, isobutanol, isopropanol, n-butanol, and tert-butanol.

[0022] More preferably, the organic solvent 1 is tetrahydrofuran and the solvent 2 is n-propanol.

[0023] Preferably, the heating temperature is 45–65°C.

[0024] More preferably, the heating temperature is 50°C.

[0025] Preferably, the heating and stirring time is 2 to 4 hours.

[0026] In the preparation method provided by the present invention, the crude topiprostat raw material is commercially available topiprostat or topiprostat prepared by the present invention according to the prior art.

[0027] The topicrol-aminosulfonate cocrystal described in this invention is used as an active ingredient in the preparation of drugs for treating gout and hyperuricemia.

[0028] A third aspect of the invention provides a pharmaceutical composition comprising the aforementioned topipista-sulfamic acid and other pharmaceutically acceptable components.

[0029] Preferably, the method for preparing the pharmaceutical composition is as follows: using standard and conventional techniques, the compound of the present invention is combined with a pharmaceutically acceptable solid or liquid carrier, and then arbitrarily combined with pharmaceutically acceptable excipients and formulation agents to prepare a usable dosage form.

[0030] Preferably, the available dosage form of the pharmaceutical composition is selected from one of the following: spray, tablet, capsule, powder for injection, liquid injection, lyophilized powder for injection, or other pharmaceutically available dosage forms.

[0031] Confirmation of crystal structure

[0032] The topistat-aminosulfonic acid eutectic provided by this invention was subjected to X-ray single-crystal diffraction analysis. The X-ray single-crystal diffraction instrument and testing conditions involved in this invention were: Rigaku XtaLAB Synergy X-ray single-crystal diffractometer, testing temperature 293(2)K, CuKa radiation, data collection in ω-scan mode and Lp correction. The structure was resolved by direct method, all non-hydrogen atoms were identified by difference Fourier method, all hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by least squares method.

[0033] The crystallographic data obtained from the testing and analysis of the topistat-sulfamic acid eutectic prepared in this invention are shown in Table 1: its crystallographic parameters are: triclinic system, space group P-1; cell parameters are: α = 110.3360(10)°, β = 100.6170(10)°, γ = 100.5170(10)°, cell volume

[0034] ORTEP diagram of the topistat-aminosulfonic acid eutectic of the present invention ( Figure 2 This indicates that one molecule of topipsestat is bound to one molecule of aminosulfonic acid.

[0035] Table 1. Main crystallographic data of the topistat-sulfamate eutectic.

[0036]

[0037]

[0038] The X-ray powder diffraction test instrument and test conditions for the topistat-aminosulfonic acid eutectic test described in this invention are as follows: PANalytical Empyrean X-ray powder diffractometer; light source Cu target, flat sample stage, incident light path: BBHD, diffraction light path: PLXCEL, voltage 45KV, current 40mA, divergence slit 1 / 4°, anti-scattering slit 1°, Solar slit 0.04rad, counting time per step 0.5s, scanning range 3~50°.

[0039] Based on the above crystallographic data, the corresponding X-ray powder diffraction pattern (the characteristic peaks in the Cu-Kα powder diffraction pattern are detailed in the appendix) is shown in the appendix. Figure 1 And Table 2.

[0040] Table 2. Main PXRD peaks of topixistat-aminosulfonic acid cocrystal

[0041]

[0042] The thermal analysis test conditions for the topistat-aminosulfonic acid eutectic described in this invention using TGA / DSC are as follows: METTLETOLEDOTGA / DSC3+ thermal analyzer, dynamic temperature range: 30~350℃, heating rate: 10℃ / min, programmed gas N2, flow rate: 50ml / min, crucible: 40μl aluminum crucible.

[0043] The TGA / DSC test results of the topipirostat-aminosulfonic acid cocrystal described in this invention are as follows: Figure 3 As shown in the figure. The thermal differential analysis results show that the eutectic has an endothermic peak with a temperature range of 245.27 to 281.29℃ and a peak value of 267.02℃.

[0044] Compared with the prior art, the technical effects achieved by the present invention are as follows: the preparation of topipsestat-sulfamic acid cocrystal provided by the present invention has good chemical stability and high solubility; the preparation method provided by the present invention has good reproducibility and is easy to operate; and the solubility of the salt cocrystal prepared by the method is higher than that of conventional crystals composed of single drug components. Attached Figure Description

[0045] Figure 1 X-ray powder diffraction pattern of topipsestat-aminosulfonic acid eutectic.

[0046] Figure 2 ORTEP diagram of topipusta-aminosulfonic acid eutectic.

[0047] Figure 3 DSC-TGA image of topipsestat-aminosulfonic acid eutectic. Detailed Implementation

[0048] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0049] Example 1

[0050] 24.8 mg of topipusta was dissolved in 2 mL of tetrahydrofuran, and 9.7 mg of aminosulfonic acid was dissolved in 2 mL of H2O. The aminosulfonic acid solution was then added to the topipusta solution, and the two were ultrasonically mixed. 2 mL of n-propanol was then added, and the mixture was heated to 50 °C and stirred for 2 h. The mixture was filtered, placed in a small glass bottle, sealed with sealing film, and several holes were punched. The mixture was allowed to evaporate, crystallize, filter, and dry under reduced pressure to obtain a topipusta-aminosulfonic acid eutectic with a yield of 97.52% and a purity of 99.95%.

[0051] Example 2

[0052] 24.8 mg of topipusta was dissolved in 2 mL of tetrahydrofuran, and 19.4 mg of aminosulfonic acid was dissolved in 2 mL of H2O. The aminosulfonic acid solution was then added to the topipusta solution, and the two were sonicated and mixed. 2 mL of isopropanol was then added, and the mixture was heated to 45 °C and stirred for 3 h. The mixture was filtered, placed in a small glass bottle, sealed with sealing film, and several holes were punched. The mixture was allowed to evaporate, crystallize, filter, and dry under reduced pressure to obtain a topipusta-aminosulfonic acid eutectic with a yield of 97.01% and a purity of 99.91%.

[0053] Example 3

[0054] 24.8 mg of topipirostat was dissolved in 2 mL of trifluoroethanol, and 8.7 mg of aminosulfonic acid was dissolved in 2 mL of H2O. The aminosulfonic acid solution was then added to the topipirostat solution, and the two were ultrasonically mixed. 4 mL of tert-butanol was then added, and the mixture was heated to 65 °C and stirred for 4 h. The mixture was filtered, placed in a small glass bottle, sealed with sealing film, and several holes were punched. The mixture was allowed to evaporate, crystallize, filter, and dry under reduced pressure to obtain a topipirostat-aminosulfonic acid eutectic with a yield of 97.26% and a purity of 99.92%.

[0055] Example 4

[0056] 24.8 mg of topipirostat was dissolved in 4 mL of tetrahydrofuran, and 9.7 mg of aminosulfonic acid was dissolved in 2 mL of H2O. The aminosulfonic acid solution was then added to the topipirostat solution, and the two were sonicated and mixed. 6 mL of n-propanol was then added, and the mixture was heated to 60 °C and stirred for 2 h. The mixture was filtered, placed in a small glass bottle, sealed with sealing film, and several holes were punched. The mixture was allowed to evaporate, crystallize, filter, and dry under reduced pressure to obtain a topipirostat-aminosulfonic acid eutectic with a yield of 96.93% and a purity of 99.92%.

[0057] Example 5

[0058] 24.8 mg of topipirostat was dissolved in 2 mL of tetrahydrofuran, and 21.3 mg of aminosulfonic acid was dissolved in 2 mL of H2O. The aminosulfonic acid solution was then added to the topipirostat solution, and the two were ultrasonically mixed. 2 mL of n-propanol was then added, and the mixture was heated to 50 °C and stirred for 2 h. The mixture was filtered, placed in a small glass bottle, sealed with sealing film, and several holes were punched. The mixture was allowed to evaporate, crystallize, filter, and dry under reduced pressure to obtain a topipirostat-aminosulfonic acid eutectic with a yield of 95.28% and a purity of 99.87%.

[0059] Example 6

[0060] 24.8 mg of topipirostat was dissolved in 2 mL of tetrahydrofuran, and 9.2 mg of aminosulfonic acid was dissolved in 2 mL of H2O. The aminosulfonic acid solution was then added to the topipirostat solution, and the two were ultrasonically mixed. 4 mL of n-propanol was then added, and the mixture was heated to 50 °C and stirred for 2 h. The mixture was filtered, placed in a small glass bottle, sealed with sealing film, and several holes were punched. The mixture was allowed to evaporate, crystallize, filter, and dry under reduced pressure to obtain a topipirostat-aminosulfonic acid eutectic with a yield of 91.50% and a purity of 99.82%.

[0061] The topipsestat-aminosulfonate cocrystals obtained in the above examples have the same crystal form. Topipsestat-aminosulfonate cocrystals were prepared according to Examples 1 to 6, and their stability and solubility were studied.

[0062] Comparative Example 1

[0063] Add 5g of crude topipustae to a reaction vessel, add 40mL of acetic acid and 40mL of water to the reaction vessel, heat the reaction system to reflux, keep it warm and stir for 30 minutes, cool it naturally to room temperature, filter it, and dry it at room temperature overnight to obtain a white crystalline powder (C crystals), with a yield of 83.31% and a purity of 99.89%.

[0064] Comparative Example 2

[0065] 7.4 mg of topipsestat free base was dissolved in 0.18 mL of 1-methylpyrrolidone, the solution was stirred, and 2.0 mL of acetonitrile was added dropwise to the solution. The mixture was stirred for 1 hour at room temperature, filtered, and crystal form A was obtained with a yield of 85.42% and a purity of 99.76%.

[0066] Stability test

[0067] The specific stability test methods were carried out in accordance with the guidelines for stability studies in Part IV of the 2015 edition of the Chinese Pharmacopoeia. Purity was determined by HPLC. The specific test results are shown in Table 3.

[0068] Table 3. Stability tests of topipsestat crystal forms under light, high temperature, and high humidity conditions.

[0069]

[0070]

[0071] Stability test results show that the topipsestat-aminosulfonate eutectic prepared in this invention has good stability. Further investigation revealed similar stability test results for Examples 1-6.

[0072] Solubility test

[0073] Following the pharmacopoeia method, the dosage was proportionally reduced to save materials. Acetate buffer solution (pH 4.5), hydrochloric acid solution (pH 1.0), and water were prepared separately. Appropriate amounts of topiprexate crystals prepared in Example 1 and Comparative Examples 1-2 were sequentially placed into stoppered test tubes containing the respective pH 4.5 acetate buffer solution, pH 1.0 hydrochloric acid solution, and water. The samples were placed in a water bath at 37°C and 200 rpm for 24 hours to equilibrate. Samples were then taken, filtered through a 0.45 μm microporous membrane, and the filtrate was diluted with water to the linear range. Using the aqueous solution as a blank, the solubility was calculated by measuring absorbance. The results are shown in Table 4.

[0074] Table 4. Solubility (μg / ml) in aqueous solution at pH 7

[0075]

[0076] Solubility test results show that the solubility of the topipsestat-aminosulfonate eutectic phase prepared in this invention is significantly improved compared to the crystal form disclosed in the prior art. Further investigation revealed similar solubility test results for Examples 1-6.

Claims

1. A topiroxostat-sulfamic acid co-crystal, characterized in that, X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation has characteristic peaks at 8.25±0.2°, 16.48±0.2°, 24.79±0.2°, 33.25±0.2°.

2. The topiroxostat-sulfamic acid co-crystal according to claim 1, characterized in that, X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation has characteristic peaks at 8.25±0.2°, 14.92±0.2°, 16.48±0.2°, 24.24±0.2°, 24.79±0.2°, 32.70±0.2°, 32.79±0.2°, 33.25±0.2°, 41.90±0.2°.

3. The topiroxostat-sulfamic acid co-crystal according to claim 1, wherein The molecular formula is C 13 H 11 N7O3S, crystallographic parameters are: triclinic system, space group P-1; cell parameters are: a =4.957Å, b =12.78890(10)Å, c =13.24120(10)Å, α=110.3360(10)°, β=100.6170(10)°, γ=100.5170(10)°, cell volume V =745.367(10)Å 3 .

4. The topiroxostat-sulfamic acid co-crystal of claim 1, wherein, The characteristic peaks thereof match the X-ray powder diffraction spectrum as shown in Figure 1.

5. A process for the preparation of a topiroxostat-sulfamic acid co-crystal according to any one of claims 1 to 4, characterized in that, The specific preparation method comprises: adding topiroxostat into organic solvent 1, adding aminosulfonic acid into water, then ultrasonically mixing the two, adding organic solvent 2, heating and stirring until completely dissolved, filtering, standing at room temperature to volatilize and crystallize, filtering and drying to obtain topiroxostat-aminosulfonic acid co-crystal; wherein the organic solvent 1 is selected from one or combination of tetrahydrofuran, trifluoroethanol, n-propanol, isobutyl alcohol, isopropyl alcohol and tert-butyl alcohol; the organic solvent 2 is selected from one or combination of tetrahydrofuran, trifluoroethanol, methanol, ethanol, n-propanol, isobutyl alcohol, isopropyl alcohol, n-butyl alcohol and tert-butyl alcohol.

6. The production method according to claim 5, wherein The molar ratio of topiroxostat to aminosulfonic acid is 1:1-2.

7. The production method according to claim 6, wherein The molar ratio of topiroxostat to aminosulfonic acid is 1:1-1.

5.

8. The production method according to claim 5, wherein The organic solvent 1 is tetrahydrofuran, and the organic solvent 2 is n-propanol.

9. The production method according to claim 5, wherein The heating temperature is 45-65℃.

10. A pharmaceutical composition, characterized by, The composition comprises the topiroxostat-aminosulfonic acid co-crystal according to any one of claims 1-4 and other pharmaceutically acceptable ingredients.

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