Etodolac-tetramethylpyrazine eutectic and preparation method thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and provides an etodolac-tetramethylpyrazine eutectic and a preparation method thereof.The etodolac-tetramethylpyrazine eutectic is characterized in that a basic unit of the eutectic is composed of two molecules of etodolac and one molecule of tetramethylpyrazine, Cu-K alpha radiation is used, and the etodolac-tetramethylpyrazine eutectic is obtained. An X-ray diffraction spectrum represented by 2theta has characteristic peaks at least at 9.4 + / -0.2 degrees, 13.7 + / -0.2 degrees, 14.6 + / -0.2 degrees, 18.8 + / -0.2 degrees, 27.3 + / -0.2 degrees and 27.7 + / -0.2 degrees. The prepared etodolac-tetramethylpyrazine eutectic is high in purity, has better chemical stability and solubility, and is beneficial to storage and transportation of products and application in preparation of preparations.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an etodolac-tetramethylpyrazine cocrystal and a preparation method thereof. Background Art

[0002] Etodolac, chemical name is 1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid, molecular formula is C 17 H 21 NO3, with a molecular weight of 287.35, is a white or off-white crystalline powder with the structural formula:

[0003]

[0004] Etodolac is a nonsteroidal anti-inflammatory drug of the indoleacetic acid class with a strong analgesic effect. It is widely used clinically to relieve the symptoms of rheumatoid arthritis and osteoarthritis, delay bone pathological changes caused by arthritis, and is also used to treat postoperative pain. The common mechanism of action of nonsteroidal anti-inflammatory drugs is to inhibit the activity of cyclooxygenase-2 (COX-2) and reduce the biosynthesis of prostaglandins at the site of inflammation, thereby controlling inflammation and relieving pain. Due to its poor water solubility and high permeability, etodolac belongs to the Biopharmaceutical Classification System (BCS) Class II drug. Researchers have attempted to improve the solubility of ETD through solid dispersions, self-emulsifying systems, and inclusion complexes with cyclodextrins. At present, the application scope of etodolac mostly stays on the selection and use of its monomers, which limits its broader application effects and application prospects.

[0005] Pharmaceutical cocrystal technology uses crystal engineering to co-crystallize two or more pure compounds to create new functional materials. The target molecule or ion is the active pharmaceutical ingredient (API), which is bound to the cocrystal precursor through hydrogen bonds. Pharmaceutical cocrystals are non-ionic supramolecular complexes that do not change the chemical composition of the active pharmaceutical ingredient API and can be used to improve physical and chemical properties such as solubility, stability and bioavailability during drug development.

[0006] Existing reports (Salts and Cocrystal of Etodolac: Advantage of Solubility, Dissolution and Permeability, Cryst. Growth Des. 2020, 20, 7, 4512–4522) provide crystallization of etodolac with five salts (i.e., isopropylamine = isoPA, n-hexylamine = nHA, cyclohexylamine = cycloHA, 2-phenylethylamine = phEA, piperazine = PPZ) and a cocrystal (isonicotinamide = INT), and experiments were conducted on the solubility, solubility and permeability of the cocrystal in pH 7.4 phosphate buffer solution. However, the stability and solubility of these cocrystals are still not ideal and need to be improved. The present invention explores that etodolac can form cocrystals with tetramethylpyrazine as a cocrystal former, which significantly improves the solubility, stability and permeability of etodolac in the drug development process, which also provides a basis for us to select drug-drug cocrystals in the future. Summary of the invention

[0007] In view of the deficiencies of the prior art, the present invention provides an etodolac-tetramethylpyrazine drug co-crystal, and characterizes and studies its structure. The co-crystal is composed of two molecules of etodolac and one molecule of tetramethylpyrazine as the basic structural unit of the co-crystal. The co-crystal of the present invention further improves the stability, solubility and permeability of etodolac. In addition, the present invention also provides a method for preparing the etodolac-tetramethylpyrazine co-crystal, which is simple, convenient and suitable for industrial production.

[0008] The specific technical contents of the present invention are as follows:

[0009] On the one hand, the present invention provides a high-purity etodolac-tetramethylpyrazine cocrystal, wherein the basic unit is composed of two molecules of etodolac and one molecule of tetramethylpyrazine, and the cocrystal is characterized in that, using Cu-Kα radiation, the X-ray diffraction spectrum represented by 2θ has characteristic peaks at least at 9.4±0.2°, 13.7±0.2°, 14.6±0.2°, 18.8±0.2°, 27.3±0.2°, and 27.7±0.2°.

[0010] Preferably, the etodolac-tetramethylpyrazine cocrystal has characteristic peaks at least at 9.4±0.2°, 10.6±0.2°, 13.7±0.2°, 14.3±0.2°, 16.7±0.2°, 18.5±0.2°, 18.8±0.2°, 23.1±0.2°, 24.4±0.2°, 27.3±0.2°, 27.7±0.2°, and 33.6±0.2° in an X-ray diffraction spectrum expressed as 2θ using Cu-Kα radiation.

[0011] Preferably, the characteristic peaks of the etodolac-tetramethylpyrazine cocrystal using Cu-Kα radiation conform to the following Figure 1 The X-ray powder diffraction spectrum is shown.

[0012] Preferably, the etodolac-tetramethylpyrazine cocrystal has a molecular formula of C 42 H 54 N4O6, crystallographic parameters are: triclinic system, space group is P-1, unit cell parameters are: a=9.4009(5), b=10.4082(7), c=10.6835(5), α=75.153(5), β=88.641(4), γ=76.067(5), unit cell volume V=979.91(10).

[0013] In another aspect, the present invention provides a method for preparing the etodolac-tetramethylpyrazine cocrystal, comprising the following steps:

[0014] Etodolac and tetramethylpyrazine are dissolved in a mixed solvent, heated and stirred, filtered, cooled and allowed to stand for evaporation and crystallization, filtered and dried to obtain etodolac-tetramethylpyrazine cocrystals.

[0015] Preferably, the solvent is selected from a mixed solvent of one of methanol, ethanol, acetone and water, preferably ethanol and water.

[0016] Preferably, the mass-to-volume ratio of etodolac to the mixed solvent is 86:1-5; preferably 86:2-3, wherein the mass is measured in mg and the volume is measured in mL.

[0017] Preferably, the volume ratio of the organic solvent to water is 2:0.5-1.5; preferably 2:1-1.2.

[0018] Preferably, the molar ratio of etodolac to tetramethylpyrazine is 1:0.8-1.2, preferably 1:1.

[0019] Preferably, the heating temperature is 40-60°C, preferably 45°C.

[0020] The cooling and crystallization temperature is 10-30°C, preferably, the cooling and crystallization temperature is 10-15°C.

[0021] The crystallization time is 8 to 72 hours.

[0022] The drying temperature is 45 to 65° C., and the drying time is 8 to 12 hours.

[0023] In yet another aspect, the present invention provides a pharmaceutical composition comprising the etodolac-tetramethylpyrazine cocrystal of the present invention and other pharmaceutically acceptable components.

[0024] Preferably, the other pharmaceutically acceptable components may be active pharmaceutical ingredients that can be used in combination and / or pharmaceutically acceptable auxiliary ingredients.

[0025] Confirmation of crystal structure

[0026] The X-ray crystal data in the test of the etodolac and tetramethylpyrazine cocrystal of the present invention were collected on a Rigaku XtaLAB Synergy instrument of Japan, with a test temperature of 293 (2) K, using Cu-Ka radiation, collecting data in ω scanning mode and performing Lp correction. The structure was analyzed by the direct method, all non-hydrogen atoms were found by the difference Fourier method, all hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation, and the structure was refined by the least square method.

[0027] The crystallographic data (as shown in Table 1) of the crystal form of the etodolac-tetramethylpyrazine cocrystal prepared by the present invention are tested and analyzed: triclinic system, space group is P-1, unit cell parameters are: a=9.4009(5), b=10.4082(7), c=10.6835(5), α=75.153(5), β=88.641(4), γ=76.067(5), unit cell volume V=979.91(10).

[0028] Table 1 Main crystallographic data of etodolac-tetramethylpyrazine cocrystal

[0029]

[0030] The ORTEP diagram of the etodolac-tetramethylpyrazine cocrystal of the present invention shows that the crystalline form contains two molecules of etodolac and one molecule of tetramethylpyrazine. Figure 2 The hydrogen bond diagram of the etodolac-tetramethylpyrazine cocrystal of the present invention is shown in the attached Figure 3 According to the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are shown in the attached Figure 1 And Table 2.

[0031] Table 2 PXRD peaks of etodolac-tetramethylpyrazine cocrystal

[0032]

[0033]

[0034] In the specific embodiments of the present invention, the etodolac-tetramethylpyrazine cocrystal samples prepared in Examples 1-4 all have the same crystallographic parameters and X-ray powder diffraction spectra as described above.

[0035] Compared with the prior art, the technical effects achieved by the present invention are:

[0036] (1) The method for preparing etodolac-tetramethylpyrazine cocrystal is simple to operate;

[0037] (2) The yield of the prepared etodolac-tetramethylpyrazine co-crystal is as high as 90% or more, and the purity of the prepared co-crystal is as high as 99.90% or more;

[0038] (3) The prepared etodolac-tetramethylpyrazine cocrystal has good chemical stability, good solubility in different media, and enhanced bioavailability and absorption properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 : PXRD pattern of etodolac-tetramethylpyrazine cocrystal.

[0040] Figure 2 : ORTEP diagram of etodolac-tetramethylpyrazine cocrystal.

[0041] Figure 3 : Hydrogen bond diagram of etodolac-tetramethylpyrazine cocrystal. DETAILED DESCRIPTION

[0042] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention are all within the scope of protection claimed by the present invention.

[0043] Example 1

[0044] Etodolac (86.1 mg) and tetramethylpyrazine (40.8 mg) were dissolved in a mixed solvent of ethanol (2 mL) and water (1.0 mL), heated in a water bath at 45°C with stirring until completely dissolved, filtered, cooled to 15°C, allowed to stand for crystallization, filtered, and vacuum dried at 50°C for 10 h to obtain a cocrystal of etodolac-tetramethylpyrazine with a yield of 97% and a purity of 99.95%.

[0045] Example 2

[0046] Etodolac (86.0 mg) and tetramethylpyrazine (40.6 mg) were dissolved in a mixed solvent of ethanol (2 mL) and water (1.2 mL), heated in a water bath at 45° C. with stirring until completely dissolved, filtered, cooled to 10° C., allowed to stand for crystallization, filtered, and vacuum dried at 45° C. for 12 h to obtain a cocrystal of etodolac-tetramethylpyrazine with a yield of 95% and a purity of 99.94%.

[0047] Example 3

[0048] Etodolac (86.0 mg) and tetramethylpyrazine (32.7 mg) were dissolved in a mixed solvent of methanol (4 mL) and water (1 mL), heated in a water bath at 45°C with stirring until completely dissolved, filtered, cooled to 30°C, allowed to stand for crystallization, filtered, and vacuum dried at 65°C for 8 h to obtain etodolac-tetramethylpyrazine cocrystals with a yield of 92% and a purity of 99.92%.

[0049] Example 4

[0050] Etodolac (86.2 mg) and tetramethylpyrazine (49.0 mg) were dissolved in a mixed solvent of acetone (2 mL) and water (1.5 mL), heated in a water bath at 45° C. with stirring until completely dissolved, filtered, cooled to 15° C., allowed to stand for crystallization, filtered, and vacuum dried at 55° C. for 10 h to obtain a cocrystal of etodolac-tetramethylpyrazine with a yield of 90% and a purity of 99.93%.

[0051] Comparative Example 1

[0052] 10 drops of methanol were added to etodolac (1.0 g, 3.48 mmol) and piperazine (150.05 mg, 1.74 mmol), and the mixture was mixed and ground for about 30 min. Acetonitrile (35 mL) was added to the mixture, and the mixture was heated to 80 ° C to dissolve. The solvent was slowly evaporated at room temperature to obtain etodolac-piperazine salt with a yield of 48.9% and a purity of 99.78%.

[0053] Comparative Example 2

[0054] 10 drops of methanol were added to etodolac (1.0 g, 3.48 mmol) and isoniazid (425.10 mg, 3.48 mmol), and the mixture was mixed and ground for about 30 min. Acetonitrile (35 mL) was added to the mixture, and the mixture was heated to 80 ° C for dissolution. The solvent was slowly evaporated at room temperature to obtain etodolac-isonicotinamide cocrystals with a yield of 43.3% and a purity of 99.80%.

[0055] Comparative Example 3

[0056] Etodolac (1.0 g, 3.48 mmol) was dissolved in acetonitrile (30 mL), and then isopropylamine (342 μL, 4.18 mmol) was added to the stirred solution at room temperature to prepare an amine salt, and the stirring was continued for 10 minutes. The uniformly stirred solution was slowly evaporated from the solvent at room temperature to obtain etodolac-isopropylamine salt, with a yield of 58.6% and a purity of 99.71%.

[0057] Stability test

[0058] The specific stability test method is carried out in accordance with the guidance methods for stability investigation in Part 4 of the Chinese Pharmacopoeia.

[0059] High temperature test: Place the test sample in a suitable clean container with its opening opened and place it at 60°C for 10 days. Take samples on the 5th and 10th days and use HPLC to test the purity.

[0060] High humidity test: Place the test sample in a closed constant humidity container with its opening opened, and place it at 25°C and relative humidity of 90%±5% for 10 days. Take samples on the 5th and 10th days, and perform purity test using HPLC.

[0061] Strong light irradiation test: The opening of the test sample is placed in a lighting device equipped with a fluorescent lamp and placed under an illumination of 4500lx±500lx for 10 days. Samples are taken on the 5th and 10th days, and the purity is tested by HPLC.

[0062] Table 3 Stability test results of etodolac-tetramethylpyrazine cocrystal

[0063]

[0064]

[0065] The experimental results show that the etodolac-tetramethylpyrazine eutectic prepared in the embodiment of the present invention has high purity, and the purity of the sample changes little under high temperature, high humidity and strong light conditions, and has good stability.

[0066] Solubility test

[0067] Method: 10 ml of medium (pH = 7.4 phosphate buffer solution) was measured in vials, and an excess of the sample to be tested was added. The vials were sealed and placed in a 25°C constant temperature water bath for stirring for 24 hours. The samples were filtered through a membrane and the filtrate was taken. The absorbance was measured at a wavelength of 270 nm, and the solubility was calculated by testing the absorbance of the standard reference substance.

[0068] Table 4 Solubility test results of etodolac-tetramethylpyrazine cocrystal and its salt

[0069]

[0070] The test results show that the solubility of the etodolac-tetramethylpyrazine cocrystals prepared in Examples 1 to 4 of the present invention in a phosphate buffer solution at pH = 7.4 is lower than that of the etodolac-isopropylamine salt (Comparative Example 3), and the solubility and dissolution rate are significantly higher than those of Comparative Examples 1 to 2, and have higher solubility than the prior art crystalline form.

[0071] Permeability test

[0072] Test conditions: The permeability test was carried out using the Franz diffusion cell method at a water temperature of (37±0.5)℃.

[0073] Dialysis membrane (model: MW 14000Da, Himedia, India): treated with 10% sodium bicarbonate solution, 10MmEDTA solution and deionized water at 0°C for 20 min respectively; the treated dialysis membrane was loaded into a diffusion cell (20 mL); etodolac, etodolac acid salts prepared in Example 1 and Comparative Examples 1 to 3 and cocrystals (based on etodolac amount, 100 mg) were suspended in 2 ml of distilled water in the donor chamber; phosphate buffer (pH = 7.0) was filled in the receptor chamber, maintained at room temperature, bubbles were removed, and magnetic stirring was performed at 45 ± 5 RPM; after 3 hours, the cumulative permeation amount was tested.

[0074] Table 5 Cumulative permeation amount of etodolac-tetramethylpyrazine cocrystal (mg / 20mL)

[0075]

[0076] It can be seen from the above permeability test results that the etodolac-tetramethylpyrazine cocrystal of the present invention has good permeability.

[0077] The etodolac-tetramethylpyrazine cocrystal prepared by the present invention has achieved beneficial effects in terms of stability, solubility and permeability, and its comprehensive performance has achieved significant improvement compared with the etodolac acid salt and crystal form reported in the prior art, and is more suitable for use in pharmaceutical preparations.

Claims

1. An etodolac-tetramethylpyrazine cocrystal, characterized in that: Using Cu-Kα radiation, the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 9.4±0.2°, 13.7±0.2°, 14.6±0.2°, 18.8±0.2°, 27.3±0.2°, and 27.7±0.2°.

2. The etodolac-tetramethylpyrazine cocrystal according to claim 1, characterized in that: Using Cu-Kα radiation, the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at 9.4±0.2°, 10.6±0.2°, 13.7±0.2°, 14.3±0.2°, 16.7±0.2°, 18.5±0.2°, 18.8±0.2°, 23.1±0.2°, 24.4±0.2°, 27.3±0.2°, 27.7±0.2°, and 33.6±0.2°.

3. The etodolac-tetramethylpyrazine cocrystal according to claim 1, characterized in that: Using Cu-Kα radiation, its characteristic peak has an X-ray powder diffraction spectrum as shown in FIG1 .

4. A method for preparing etodolac-tetramethylpyrazine cocrystal, characterized in that: The specific preparation steps include: dissolving etodolac and tetramethylpyrazine in a mixed solvent, heating and stirring, filtering, cooling and standing for volatilization and crystallization, filtering and drying to obtain etodolac-tetramethylpyrazine cocrystals.

5. The method for preparing the etodolac-tetramethylpyrazine cocrystal according to claim 4, characterized in that: The mixed solvent is selected from a mixed solvent of one of methanol, ethanol, acetone and water, preferably ethanol and water; wherein the volume ratio of the organic solvent to water is 2:0.5-1.5; preferably 2:1-1.

2.

6. The method for preparing the etodolac-tetramethylpyrazine cocrystal according to claim 4, characterized in that: The mass-to-volume ratio of etodolac to the mixed solvent is 86:2-5, preferably 86:2-3, wherein the mass is measured in mg and the volume is measured in mL.

7. The method for preparing the etodolac-tetramethylpyrazine cocrystal according to claim 4, characterized in that: The molar ratio of etodolac to tetramethylpyrazine is 1:0.8-1.2, preferably 1:

1.

8. The method for preparing the etodolac-tetramethylpyrazine cocrystal according to claim 4, characterized in that: The cooling and crystallization temperature is 10-30°C, preferably 10-15°C.

9. The method for preparing the etodolac-tetramethylpyrazine cocrystal according to claim 4, characterized in that: The drying temperature is 45-65° C., and the drying time is 8-12 hours.

10. A pharmaceutical composition, characterized in that The composition contains the etodolac-tetramethylpyrazine cocrystal according to any one of claims 1 to 4, and is mixed with other components.

Images