An apixaban-gallic acid eutectic solvate

Abstract

This invention belongs to the field of pharmaceutical cocrystal technology, specifically relating to an apixaban-gallic acid cocrystal solvate and its preparation method. The cocrystal solvate is formed by apixaban and gallic acid in a 1:1 molar ratio, simultaneously binding one molecule of acetone and one molecule of water. Its X-ray powder diffraction pattern exhibits characteristic peaks at 2θ values ​​of 8.3±0.2°, 11.3±0.2°, 12.7±0.2°, 13.8±0.2°, 16.8±0.2°, 18.3±0.2°, 22.0±0.2°, and 26.9±0.2°. The crystal form provided by this invention significantly improves the solubility of apixaban, resulting in tablets prepared with it as the active ingredient exhibiting high dissolution rate and high bioavailability, making it more suitable for oral formulations.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical cocrystallization technology, specifically relating to an apixaban-gallic acid cocrystallized solvate and its preparation method. Background Technology

[0002] Apixaban is a novel oral factor Xa inhibitor jointly developed by Bristol-Myers Squibb and Pfizer. It is a novel oral anticoagulant. By inhibiting an important coagulation factor Xa, it prevents thrombin formation and thrombus formation. Apixaban was first approved for marketing in the European Union on May 20, 2011, for the prevention of thrombosis in patients undergoing hip or knee replacement surgery, prevention of deep vein thrombosis (DVT), and prevention of stroke and systemic embolism in adults with nonvalvular atrial fibrillation (AF). Its Chinese chemical name is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazole[3,4-c]pyridine-3-carboxamide, and its molecular formula is C1. 25 H 25 N5O4, molecular weight: 459.50, structural formula is shown below:

[0003]

[0004] Among the currently reported literature, US20060160841 first disclosed the non-solvent crystalline form N-1 and the dihydrate crystalline form H2-2 of apixaban, and US20060069258 disclosed the specific crystal characterization parameters of crystalline forms N-1 and H2-2. In addition, the following crystalline forms of apixaban have been reported: patent WO2013119328 (types I, II, III, and DF-1); patent US20070203178 disclosed the crystalline form DMF-5 of the N,N-dimethylformamide solvate of apixaban and the crystalline form FA-2 of the formamide solvate; WO2012168364 disclosed the α-crystalline form of apixaban, which is a sesquihydrate; CN103360391 disclosed the β-crystalline form of apixaban; CN10 3539795 discloses a series of anhydrous polymorphs IV and amorphous forms of apixaban; CN103830199 discloses apixaban R form; EP275141A1 discloses an apixaban crystal form A and its preparation method; WO2014108919 discloses an apixaban crystal form M and a new intermediate for preparing apixaban. Among the above crystal forms, crystal form N-1 can be produced as a product. It is a thermodynamically stable anhydrous crystalline form, but it has the disadvantages of low water solubility (0.028 mg / mL at 24℃), slow dissolution rate, and low bioavailability, which have a certain impact on drug absorption.

[0005] Furthermore, patent CN106986868 discloses cocrystals formed by apixaban with oxalic acid, isonicotinic acid, 3-aminopyridine, and urea. While these cocrystals improve the solubility of apixaban, the solubility remains low. Moreover, the oxalic acid cocrystal of apixaban disclosed in this patent only shows high solubility initially, gradually decreasing thereafter. Other cocrystals contain small-molecule isonicotinic acid, 3-aminopyridine, and urea, which have certain side effects on the human body; for example, 3-aminopyridine is a potential genotoxic impurity. These unfavorable factors hinder the development of these cocrystals into safe oral formulations. Patent CN110922403B discloses cocrystals of apixaban with malonic acid, D-malic acid, maleic acid, L-tartaric acid, and L-proline. These cocrystals also improve the solubility of apixaban, but the solubility remains low, which is detrimental to the oral absorption of apixaban.

[0006] Therefore, it is necessary to develop a new crystal form of apixaban to improve its dissolution rate, making it dissolve quickly and stably, thereby increasing its bioavailability. Summary of the Invention

[0007] One of the objectives of this invention is to provide an apixaban-gallic acid co-crystal solvate.

[0008] The second objective of this invention is to provide a method for preparing an apixaban-gallic acid eutectic solvate.

[0009] A third objective of this invention is to provide a pharmaceutical composition comprising the above-mentioned gallic acid cocrystal solvate and a pharmaceutically acceptable carrier.

[0010] The specific technical content of this invention is as follows:

[0011] An apixaban-gallic acid cocrystal solvate, wherein the specific molecular structure contains one molecule of apixaban, one molecule of gallic acid, and one molecule of acetone and one molecule of water.

[0012] Preferably, the apixaban-gallic acid eutectic solvate exhibits characteristic peaks at 8.3±0.2°, 11.3±0.2°, 12.7±0.2°, 13.8±0.2°, 16.8±0.2°, 18.3±0.2°, 22.0±0.2°, and 26.9±0.2° in its 2θ X-ray diffraction pattern under Cu-Kα radiation.

[0013] Preferably, the apixaban-gallic acid eutectic solvate, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its 2θ X-ray diffraction pattern at 8.3±0.2°, 11.3±0.2°, 11.6±0.2°, 12.7±0.2°, 13.8±0.2°, 15.7±0.2°, 16.8±0.2°, 18.3±0.2°, 19.4±0.2°, 20.4±0.2°, 21.0±0.2°, 21.4±0.2°, 22.0±0.2°, 23.1±0.2°, 24.6±0.2°, 26.1±0.2°, and 26.9±0.2°.

[0014] Preferably, the apixaban / gallic acid eutectic solvate is subjected to Cu-Kα irradiation, and its characteristic peaks conform to the following... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0015] Preferably, the apixaban-gallic acid eutectic solvate has the molecular formula C0. 35 H 39 N5O 11 The crystallographic parameters are: triclinic crystal system, space group P-1, and unit cell parameters are: α = 90.7700(10)°, β = 101.2510(10)°, γ = 100.9500(10)°, cell volume

[0016] In a second aspect, the present invention provides a method for preparing an apixaban-gallic acid eutectic solvate, the specific steps of which include:

[0017] Apixaban and gallic acid were dissolved in a mixed solvent, heated and stirred, filtered, and the filtrate was cooled to crystallize. The resulting solid was filtered and dried to obtain an apixaban-gallic acid co-crystal solvate.

[0018] Preferably, the solvent is selected from a mixture of DMSO, acetone and water or a mixture of 2,2,2-trifluoroethanol, acetone and water; particularly preferred is a mixture of 2,2,2-trifluoroethanol, acetone and water.

[0019] Preferably, the volume ratio of 2,2,2-trifluoroethanol, acetone and water in the mixed solvent is 1:2 to 6:1, and particularly preferably 1:4:1; the volume ratio of DMSO, acetone and water in the mixed solvent is 1:2 to 6:1, and particularly preferably 1:4:1.

[0020] Preferably, the mass-to-volume ratio of apixaban to the mixed solvent is 55-115:1, wherein the mass is expressed in mg and the volume in mL.

[0021] Preferably, the molar ratio of apixaban to gallic acid is 1:0.8 to 1.20, more preferably 1:1.

[0022] Preferably, the heating temperature is 50°C and the stirring time is 1 to 3 hours.

[0023] Preferably, the crystallization temperature is 0–20°C; more preferably, it is 10–20°C.

[0024] Preferably, the crystallization time is 24–72 h.

[0025] Finally, the present invention provides a pharmaceutical composition comprising the apixaban and gallic acid cocrystal solvate of the present invention and other pharmaceutically acceptable components.

[0026] Preferably, the pharmaceutical composition is prepared using conventional techniques; the crystal form is combined with a pharmaceutically acceptable solid or liquid carrier, and optionally combined with pharmaceutically acceptable excipients and auxiliaries to prepare a usable dosage form.

[0027] Preferably, the other pharmaceutically acceptable components include other active ingredients that can be used in combination, diluents, binders, disintegrants, lubricants, etc.; more preferably, the diluent is selected from one or more of starch, sucrose, dextrin, lactose, microcrystalline cellulose, mannitol, and sorbitol; the binder is selected from one or more of methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, ethylcellulose, and povidone; the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and croscarmellose; and the lubricant is selected from one or more of magnesium stearate, micronized silica gel, talc, and sodium dodecyl sulfate.

[0028] Preferably, the pharmaceutical composition is in the form of tablets, capsules, granules, or pills.

[0029] Confirmation of crystal structure

[0030] The X-ray crystal data for the apixaban-gallic acid eutectic solvate assay described in this invention were collected using a Rigaku XtaLAB Synergy instrument at a test temperature of 293(2) K. Cu-Ka radiation was used, and data were collected via ω-scan and Lp correction was applied. The structure was resolved using a direct method, and all non-hydrogen atoms were identified using the difference Fourier method. Hydrogen atoms on all carbon and nitrogen atoms were obtained through theoretical hydrogenation. The structure was refined using the least squares method.

[0031] The crystallographic data (as shown in Table 1) for testing and analysis of the apixaban-gallic acid eutectic solvate prepared in this invention are as follows: its molecular formula is C 35 H 39 N5O 11The crystallographic parameters are: triclinic crystal system, space group P-1, and unit cell parameters are: α = 90.7700(10)°, β = 101.2510(10)°, γ = 100.9500(10)°, cell volume

[0032] Table 1. Main crystallographic data of the apixaban-gallic acid cocrystal solvate.

[0033]

[0034] The ORTEP diagram of the apixaban / gallic acid cocrystal solvate of the present invention shows that the crystalline form contains one molecule of apixaban and one molecule of gallic acid, bound to one molecule of acetone and one molecule of water, as shown in the attached diagram. Figure 3 As shown. The hydrogen bond diagram of the apixaban-gallic acid cocrystal solvate of the present invention is attached. Figure 4 As shown in the figure. Based on the above crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are shown in Table 2.

[0035] Table 2. PXRD peaks of the apixaban-gallic acid cocrystal solvate

[0036]

[0037] The TGA / DSC thermal analysis instrument and testing conditions in this invention: TGA / DSC thermal analyzer: METTLER TOLEDOTGA / DSC 3+ Dynamic temperature range: 30~300℃; heating rate: 10℃ / min; programmed gas N2; gas flow rate: 50mL / min; crucible: 40μl aluminum crucible.

[0038] The TGA / DSC test results of the apixaban / gallic acid cocrystal solvate prepared in this invention are as follows: Figure 2 As shown, the DSC spectrum shows an endothermic peak in the range of 123.22 to 161.95 °C, with the peak value of the corresponding endothermic peak being 148.91 °C. The TGA spectrum shows weight loss, indicating the loss of the binding solvent.

[0039] Compared with the prior art, the technical advantages of the present invention are:

[0040] The apixaban-gallic acid cocrystal solvate provided by this invention has good stability; the preparation method is simple to operate, the crystallization process is easy to control, and the reproducibility is good; it can significantly improve the solubility of apixaban, and tablets prepared with it as the active ingredient have high dissolution rate and fast dissolution speed; the oral bioavailability is higher than other existing crystal forms, making it more suitable for oral formulations. Attached Figure Description

[0041] Figure 1 PXRD pattern of the apixaban-gallic acid cocrystal solvate.

[0042] Figure 2 TGA / DSC plot of the apixaban-gallic acid cocrystal solvate.

[0043] Figure 3 ORTEP diagram of the apixaban-gallic acid cocrystal solvate.

[0044] Figure 4 Hydrogen bond diagram of the apixaban-gallic acid cocrystal solvate. Detailed Implementation

[0045] To facilitate understanding of the present invention, the technical solutions described below are further explained in conjunction with specific embodiments; however, the present invention is not limited thereto. The raw material apixaban used in the embodiments of the present invention can be prepared according to any method in the prior art or purchased from commercially available products.

[0046] Example 1

[0047] 4.59 g of apixaban and 1.70 g of gallic acid were dissolved in a mixed solvent consisting of 10 mL of 2,2,2-trifluoroethanol, 40 mL of acetone, and 10 mL of water. The mixture was heated and stirred in a water bath at 50 °C for 2 h, filtered, and then cooled to 10–20 °C to crystallize for 48 h. After filtration and drying, the apixaban-gallic acid cocrystal solvate was obtained. The yield was 93.5%, and the purity was 99.92%.

[0048] Example 2

[0049] 4.59 g of apixaban and 1.36 g of gallic acid were dissolved in a mixed solvent consisting of 10 mL DMSO, 40 mL acetone, and 10 mL water. The mixture was heated and stirred in a water bath at 50 °C for 1 h. After filtration, the mixture was cooled to 10–20 °C to crystallize for 48 h. After filtration and drying, the apixaban-gallic acid cocrystal solvate was obtained. Yield: 89.2%, Purity: 99.87%.

[0050] Example 3

[0051] 4.59 g of apixaban and 2.04 g of gallic acid were dissolved in a mixed solvent of 10 mL of 2,2,2-trifluoroethanol, 60 mL of acetone, and 10 mL of water. The mixture was heated and stirred in a water bath at 50 °C for 1 h, filtered, and then cooled to 10–20 °C to crystallize for 72 h. After filtration and drying, the apixaban-gallic acid cocrystal solvate was obtained. Yield: 90.0%, Purity: 99.90%.

[0052] Example 4

[0053] 4.59 g of apixaban and 1.70 g of gallic acid were dissolved in a mixed solvent consisting of 15 mL of 2,2,2-trifluoroethanol, 40 mL of acetone, and 10 mL of water. The mixture was heated and stirred in a water bath at 60 °C for 1 h, filtered, and allowed to stand at room temperature for 24 h to evaporate and crystallize. The solution was then filtered and dried to obtain a eutectic solvate of apixaban and gallic acid. The yield was 80.8%, and the purity was 99.73%.

[0054] Example 5

[0055] 4.59 g of apixaban and 1.19 g of gallic acid were dissolved in a mixed solvent consisting of 10 mL of 2,2,2-trifluoroethanol, 40 mL of acetone, and 10 mL of water. The mixture was heated and stirred in a water bath at 35 °C for 1 h, filtered, and then cooled to 0-5 °C to crystallize for 5 h. After filtration and drying, the apixaban-gallic acid cocrystalline solvate was obtained. The yield was 83.5%, and the purity was 99.80%.

[0056] Comparative Example 1

[0057] 0.182 g of nicotinic acid and 0.68 g of apixaban were added to 7 mL of 0.5% aqueous trifluoroethanol. After stirring at 30 °C for 24 h, 15 mL of ethyl acetate was added dropwise. The mixture was stirred at the same temperature for 30 min and then filtered to obtain white crystals. The crystals were then placed in a drying oven and dried under vacuum at 40 °C for 4 h to obtain white crystals.

[0058] Comparative Example 2

[0059] 4.59 g of apixaban and 1.10 g of hydroquinone were dissolved in a mixed solvent of 10 mL of 2,2,2-trifluoroethanol, 40 mL of acetonitrile and 10 mL of water. The mixture was heated and stirred in a water bath at 50 °C for 1 h. After filtration, the mixture was allowed to stand at room temperature to volatilize and crystallize, yielding a eutectic of apixaban and hydroquinone.

[0060] Comparative Example 3

[0061] 0.05 g of oxalic acid was added to 1 mL of acetone and stirred to obtain a clear solution. Then, 0.34 g of apixaban was added, followed by 2 mL of trifluoroethanol. The mixture was suspended and stirred at room temperature for 24 hours. The solution was filtered to obtain a white solid, which was then dried under vacuum at room temperature in a drying oven to obtain white crystals.

[0062] Verification of Examples

[0063] 1. Stability Study of Apixaban-Gallic Acid Cocrystal Solvate

[0064] The specific stability test methods were carried out in accordance with the guidelines for stability testing of active pharmaceutical ingredients and preparations in Part IV of the 2020 edition of the Chinese Pharmacopoeia. Purity was detected by HPLC, and the results are shown in Table 3.

[0065] Table 3. Results of stability study of the apixaban-gallic acid cocrystal solvate.

[0066]

[0067] Note: The apixaban-gallic acid cocrystal solvate prepared in the embodiments of the present invention has the same stability as the crystal form in Example 1.

[0068] The experimental results show that the apixaban-gallic acid cocrystal solvate prepared in this invention exhibits almost no change in content under high temperature, high humidity, and strong light conditions, demonstrating good stability.

[0069] 2. Solubility test

[0070] The specific procedure for the solubility experiment is as follows:

[0071] Excess amounts of the apixaban-gallic acid cocrystal solvate prepared in Example 1 of this invention, crystal forms of Comparative Example 1, Comparative Example 2, Comparative Example 3, and apixaban N-1 crystal form were placed in a constant temperature medium (pH 1.0 HCl and pH 6.8 phosphate buffer) at 37°C and stirred for 24 h to dissolve. The saturated solution was filtered, and the filtrate was measured. The concentration of the saturated solution was calculated using the external standard method. The results are shown in Table 4.

[0072] Table 4. Solubility Study Results of Apixaban Crystal Forms

[0073]

[0074] Note: The apixaban-gallic acid eutectic solvate prepared in the embodiments of the present invention has the same solubility properties as the crystal form in Example 1.

[0075] Experimental results show that the apixaban-gallic acid cocrystal solvate provided by this invention has significantly higher solubility in pH 1.0 hydrochloric acid solution and pH 6.8 phosphate buffer than the existing crystal form of apixaban, which helps to improve its bioavailability.

[0076] 3. Dissolution test of the formulation

[0077] Using the apixaban-gallic acid cocrystal solvate obtained in Example 1, the crystal forms of Comparative Example 1, Comparative Example 2, Comparative Example 3, and apixaban N-1 as active ingredients, 1000 tablets (2.5 mg / tablet) were prepared according to the following method:

[0078] Components by weight (%): 2.5g active ingredient, 45.0g cellulose lactose, 45.0g microcrystalline cellulose, 4.5g croscarmellose sodium, 2.0g sodium dodecyl sulfate, 1.0g magnesium stearate.

[0079] Preparation method: Sodium dodecyl sulfate is dissolved in water to form a granulation solution; active ingredients, cellulose lactose, microcrystalline cellulose and croscarmellose sodium are added to a fluidized bed and granulated by top spraying with the granulation solution; after granulation, magnesium stearate is added, mixed evenly and then compressed into tablets.

[0080] Following the FDA's dissolution test method and sampling time, a 0.05M sodium phosphate buffer solution (pH 6.8) containing 0.05% SLS was used as the dissolution medium. The dissolution test was conducted at 37°C and a rotation speed of 75 rpm. Samples were removed at 5, 10, 20, 30, and 45 minutes after the start of the test, and the concentration was determined by HPLC. The test results are shown in Table 5.

[0081] Table 5 Results of tablet dissolution test

[0082]

[0083] Experimental results show that, compared with other crystal forms, tablets prepared using the apixaban and gallic acid cocrystal solvate provided by this invention as the active ingredient dissolve faster and have a higher dissolution rate. The cocrystal solvate provided by this invention is more suitable for oral formulations.

[0084] 4. Pharmacokinetic study of apixaban in rats

[0085] Drugs: Crystal form of Example 1, crystal form of Comparative Example 1, crystal form of Comparative Example 2, crystal form of Comparative Example 3, and crystal form of Apixaban N-1.

[0086] Animals: Male SD rats, weighing 180–220g.

[0087] Methods: Thirty male SD rats were randomly divided into six groups. They were fasted overnight but had free access to water. The apixaban crystal forms were dissolved in DMSO:propylene glycol:physiological saline (1:1:8) and administered by gavage at a concentration of 0.2 mg / mL, with a volume of 10 mL / kg. Blood samples were collected from the retro-orbital vein at 0.25, 0.50, 1, 2, 4, 6, 8, and 24 hours after gavage administration, and plasma drug concentrations were determined using UPLC-MS / MS. The mean pharmacokinetic parameters of each apixaban crystal form are summarized in Table 6.

[0088] Table 6. Pharmacokinetic parameters

[0089]

[0090] The results showed that the bioavailability of the apixaban cocrystal solvate with gallic acid was 3.2 times that of the apixaban N-1 crystal form, and it also had better oral bioavailability compared to other existing apixaban crystal forms.

Claims

1. A co-crystal solvate of Apixaban and Gallic acid characterized by, The eutectic solvate contains one molecule of apixaban, one molecule of gallic acid, and is also bound to one molecule of acetone and one molecule of water. The X-ray powder diffraction pattern of the eutectic solvate, measured by Cu-Kα rays, shows characteristic peaks at 2θ values ​​of 8.3±0.2°, 11.3±0.2°, 12.7±0.2°, 13.8±0.2°, 16.8±0.2°, 18.3±0.2°, 22.0±0.2°, and 26.9±0.2°.

2. The apixaban / gallic acid eutectic solvate according to claim 1, characterized in that, The X-ray powder diffraction pattern of the eutectic solvate, measured by Cu-Kα rays, shows characteristic peaks at 2θ values ​​of 8.3±0.2°, 11.3±0.2°, 11.6±0.2°, 12.7±0.2°, 13.8±0.2°, 15.7±0.2°, 16.8±0.2°, 18.3±0.2°, 19.4±0.2°, 20.4±0.2°, 21.0±0.2°, 21.4±0.2°, 22.0±0.2°, 23.1±0.2°, 24.6±0.2°, 26.1±0.2°, and 26.9±0.2°.

3. The apixaban / gallic acid eutectic solvate according to claim 1, characterized in that, The characteristic peaks of the eutectic solvate conform to the X-ray powder diffraction pattern shown in Figure 1.

4. A method for preparing the apixaban / gallic acid eutectic solvate according to any one of claims 1-3, comprising the following steps: Apixaban and gallic acid are dissolved in a mixed solvent, heated and stirred, filtered, and the filtrate is cooled to crystallize. The resulting solid is filtered and dried to obtain an apixaban-gallic acid eutectic solvate. The mixed solvent is a mixture of DMSO, acetone and water or a mixture of 2,2,2-trifluoroethanol, acetone and water.

5. The preparation method according to claim 4, characterized in that, The volume ratio of DMSO, acetone and water in the mixed solvent is 1:2 to 6:1; the volume ratio of 2,2,2-trifluoroethanol, acetone and water in the mixed solvent is 1:2 to 6:

1.

6. The preparation method according to claim 4, characterized in that, The molar ratio of apixaban to gallic acid is 1:0.8 to 1.

20.

7. The preparation method according to claim 4, characterized in that, The mass-to-volume ratio of apixaban to the mixed solvent is 55–115:1, where mass is expressed in mg and volume in mL.

8. The preparation method according to claim 4, characterized in that, The crystallization temperature is 0–20°C, and the crystallization time is 24–72 h.

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the apixaban and gallic acid cocrystal solvate as described in any one of claims 1-3 and other pharmaceutically acceptable components.

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