Milrinone drug co-crystal and preparation method thereof

Abstract

This invention belongs to the technical field of medicinal chemistry and provides milrinone-drug cocrystals with a simple preparation method, an easily controllable crystallization process, and excellent reproducibility. The milrinone-chrysanthemum cocrystals, milrinone-emodin cocrystals, and milrinone-curcumin cocrystals all exhibit significantly enhanced solubility compared to the individual compounds, contributing to improved oral bioavailability.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a pharmaceutical cocrystal of milrinone, specifically a cocrystal of milrinone and a ketone compound, and a preparation method and application thereof. Background Art

[0002] Milrinone, chemical name is 1,6-dihydro-2-methyl-6-oxo-[3,4-bipyridine]-5-carbonitrile, molecular formula is C 12 H9N3O, with a molecular weight of 211.22, is a white or off-white crystalline powder with the structural formula:

[0003]

[0004] Milrinone was first developed by Sterling Pharmaceuticals in the United States as an anti-heart failure drug. It was first approved by the FDA in the United States in 1987, officially launched in the United States in 1992, and subsequently launched in the United Kingdom, France, Germany, the Netherlands, Belgium and other countries.

[0005] Milrinone is a phosphodiesterase inhibitor and a derivative of amrinone, with a mechanism of action similar to that of amrinone. It is effective both orally and intravenously, exhibiting both positive inotropic and vasodilatory effects. It is indicated for short-term treatment of patients with severe congestive heart failure who have failed conventional maintenance therapy. It is 10-30 times more effective than amrinone, has good tolerability, and offers minimal adverse reactions. Its positive inotropic effect is primarily achieved through phosphodiesterase inhibition, which increases cyclic adenosine monophosphate (CAMP) concentration in myocardial cells, increasing intracellular calcium, strengthening myocardial contractility, and increasing cardiac output. It is generally considered a highly effective, low-toxic, non-digitalis, non-sympathomimetic cardiotonic agent with significant efficacy for severe heart failure and pulmonary edema caused by ischemic heart disease and dilated cardiomyopathy. It is superior to dopamine-based agents, has fewer adverse reactions, and does not increase heart rate. Therefore, this drug has played an increasingly important role in the treatment of congestive heart failure (CHF) and peripheral vasodilation.

[0006] Chrysin is a natural flavonoid compound extracted from plants with a wide range of pharmacological activities. Studies have shown that it exhibits a wide range of pharmacological and physiological activities, including antioxidant, antitumor, anticancer, antiviral, antihypertensive, antidiabetic, antibacterial, antiallergic, antiplatelet, and antithrombotic properties. Furthermore, this compound is widely distributed in plants and has low toxicity, making it a very important resource for new drug development. Chrysin is soluble in alkali hydroxide solutions, slightly soluble in organic solvents such as ethanol and ether, and insoluble in water. These solubility properties significantly limit its development and use in pharmaceutical applications.

[0007] Emodin (EM), a hydroxyanthraquinone, is one of the main active ingredients in the traditional Chinese medicine rhubarb and the primary raw material for the synthesis of hypericin. Emodin exhibits a wide range of pharmacological activities, including antibacterial, anti-inflammatory, antiviral, antidiabetic, antitumor, hepatoprotective, and immunosuppressive effects. Recent studies have shown that emodin exhibits cytotoxicity against various tumor cells, possibly through inhibition of tumor cell proliferation and adhesion. Pure emodin can be used to treat tumors, primarily leukemia and gastric cancer, and is most commonly used for its antibacterial properties. In modern clinical practice, it is used in nearly every discipline, including the treatment of Japanese encephalitis, mumps, typhoid fever, dysentery, urinary tract infections, gonorrhea, pneumonia, cellulitis, suppurative skin diseases, otitis media, and vasculitis. It is also used in combination with other medications to treat acute and subacute appendicitis, burns, polio, eczema, and several fungal skin infections. It can also treat hepatitis, pinworms, stomatitis, oral lip ulcers, indigestion, hypertension, and arteriosclerosis. Recent studies have shown that low-dose emodin has an excitatory effect on isolated toad hearts, while high doses have an inhibitory effect and also have a hypotensive effect. Emodin is soluble in ethanol and alkaline solutions but nearly insoluble in water, a solubility characteristic that limits its application in drug development. This insolubility also significantly restricts its development and use in pharmaceutical applications.

[0008] Curcumin is a natural, fat-soluble phenolic substance extracted from the rhizomes of plants in the ginger family, including turmeric, zedoary turmeric, mustard, turmeric, and curry. It is a rare diketone pigment in the plant kingdom. Modern research has shown that curcumin exhibits a wide range of pharmacological activities, including anti-inflammatory, anti-tumor, anti-HIV, antioxidant, antibacterial, lipid-regulating, antiviral, anti-infective, anticoagulant, anti-hepatic fibrosis, and anti-atherosclerotic properties. It also exhibits low toxicity and a good safety profile.

[0009] Studies have shown that milrinone has poor water solubility, is practically insoluble, and exhibits severe adverse reactions upon oral administration. Therefore, providing a crystalline form of milrinone with good solubility, high stability, and promising drug development prospects has become a pressing challenge for those skilled in the art. Attempting to combine two active pharmaceutical ingredients through pharmaceutical cocrystal technology, with the goal of significantly improving the physicochemical properties of the active pharmaceutical ingredients and thus providing more options for clinical drug application, has become a pressing issue in pharmaceutical crystal form research. Summary of the Invention

[0010] Through research, the present invention discovered that milrinone and ketone compounds can form stable drug co-crystals, and the formed crystals have excellent physical and chemical properties that the two components do not have when they exist alone, such as significantly improved solubility and significantly improved stability.

[0011] The specific technical contents of the present invention are as follows:

[0012] The present invention provides a pharmaceutical co-crystal of milrinone and a ketone compound, wherein the ketone compound contains at least one hydroxyl group; wherein the pharmaceutical co-crystal is preferably a milrinone-chrysin co-crystal, a milrinone-emodin co-crystal, and a milrinone-curcumin co-crystal.

[0013] The milrinone-chrysanthemum cocrystal of the present invention has characteristic peaks at at least 7.9±0.2°, 8.3±0.2°, 9.6±0.2°, 12.0±0.2°, 12.6±0.2°, 20.7±0.2°, 34.2±0.2°, and 34.5±0.2° in an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0014] Preferably, the milrinone-chrysanthemum cocrystal has an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation, and has characteristic peaks at at least 7.9±0.2°, 8.3±0.2°, 9.3±0.2°, 9.6±0.2°, 12.0±0.2°, 12.6±0.2°, 14.6±0.2°, 16.4±0.2°, 20.7±0.2°, 26.6±0.2°, 34.2±0.2°, and 34.5±0.2°.

[0015] Preferably, the characteristic peaks of the milrinone-chrysin co-crystal, when irradiated with Cu-Kα, conform to Figure 1 The X-ray powder diffraction pattern is shown.

[0016] Preferably, the molecular formula of the milrinone-chrysin cocrystal is C 54 H 38 N6O 10 , the crystallographic parameters are: triclinic system, space group is P-1, unit cell parameters are: α=80.5680(10)°、β=68.472(2)°、γ=63.440(2)°,unit cell volume

[0017] The milrinone-emodin cocrystal of the present invention has characteristic peaks at least at 7.8±0.2°, 9.8±0.2°, 12.9±0.2°, 18.0±0.2°, and 25.7±0.2° in an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0018] Preferably, the milrinone-emodin cocrystal has an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation, and has characteristic peaks at at least 7.8±0.2°, 9.8±0.2°, 12.9±0.2°, 15.3±0.2°, 18.0±0.2°, 20.7±0.2°, 21.6±0.2°, 25.7±0.2°, 25.9±0.2°, 26.8±0.2°, and 27.7±0.2°.

[0019] Preferably, the characteristic peak of the milrinone-emodin co-crystal, when irradiated with Cu-Kα, meets Figure 2 The X-ray powder diffraction pattern is shown.

[0020] Preferably, the milrinone-emodin cocrystal has a molecular formula of C 27 H 19 N3O6, crystallographic parameters are: monoclinic system, space group is P21 / n, unit cell parameters are: α=90°、β=102.6510(10)°、γ=90°,unit cell volume

[0021] The milrinone-curcumin cocrystal of the present invention has characteristic peaks at least at 5.2±0.2°, 7.8±0.2°, 15.8±0.2°, 19.4±0.2°, 26.8±0.2°, and 27.9±0.2° in an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0022] Preferably, the milrinone-curcumin cocrystal has an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation, and has characteristic peaks at at least 5.2±0.2°, 7.8±0.2°, 14.3±0.2°, 15.8±0.2°, 19.4±0.2°, 26.8±0.2°, 27.9±0.2°, 29.3±0.2°, and 37.4±0.2°.

[0023] Preferably, the milrinone-curcumin co-crystal, when subjected to Cu-Kα radiation, has a characteristic peak that meets Figure 3 The X-ray powder diffraction pattern is shown.

[0024] Preferably, the milrinone-curcumin co-crystal has a molecular formula of C 45 H 40 N6O9, crystallographic parameters are: triclinic system, space group is P-1, unit cell parameters are: α=105.9260(10)°、β=99.4120(10)°、γ=92.6650(10)°,unit cell volume

[0025] In another aspect, the present invention provides a method for preparing the pharmaceutical co-crystal, comprising the steps of:

[0026] The milrinone and ketone compound are dissolved in a mixed solvent, heated and stirred, filtered, cooled and allowed to stand for crystallization, filtered and dried to obtain a drug co-crystal.

[0027] Preferably, the mixed solvent is selected from a combination of methanol, ethanol, acetonitrile, acetone or trifluoroethanol.

[0028] Preferably, the molar ratio of milrinone to ketone compound is 1:0.5-1.6.

[0029] Preferably, the ketone compounds are chrysanthemumin, emodin and curcumin.

[0030] Preferably, the heating temperature is 40-70°C.

[0031] Preferably, the cooling and crystallization temperature is 0-30°C.

[0032] Preferably, the crystallization time is 1 to 72 hours.

[0033] Preferably, the drying temperature is 45-65° C., and the drying time is 8-12 hours.

[0034] Further preferably, the method for preparing the milrinone-chrysanthemum co-crystal comprises the following steps:

[0035] Milrinone and chrysin are dissolved in a mixed solvent, heated and stirred, filtered, cooled and allowed to stand for crystallization, filtered and dried to obtain milrinone-chrysin crystals.

[0036] Preferably, the mixed solvent is selected from a combination of methanol, ethanol, acetonitrile, acetone or trifluoroethanol; particularly preferably, the combination of methanol, acetone and trifluoroethanol.

[0037] Preferably, the mass-to-volume ratio of milrinone to the mixed solvent is 4-11:1, with the mass being measured in mg and the volume being measured in ml; preferably 5-7:1, with the mass being measured in mg and the volume being measured in ml.

[0038] Preferably, the molar ratio of milrinone to chrysanthemum is 1:0.8-1.6, preferably 1:1.

[0039] Preferably, the heating temperature is 40-60°C, preferably 45°C.

[0040] Preferably, the cooling and crystallization temperature is 10-30°C, preferably, the cooling and crystallization temperature is 10-15°C.

[0041] Preferably, the crystallization time is 8 to 72 hours.

[0042] Preferably, the drying temperature is 45-65° C., and the drying time is 8-12 hours.

[0043] Further preferably, the method for preparing the milrinone-emodin cocrystal comprises the following steps:

[0044] Milrinone and emodin are dissolved in a mixed solvent, heated and stirred, filtered, cooled and allowed to stand for crystallization, filtered and dried to obtain milrinone-emodin crystals.

[0045] Preferably, the mixed solvent is selected from a combination of methanol, ethanol, acetonitrile, acetone or trifluoroethanol; particularly preferably, the combination of methanol, ethanol and acetone.

[0046] Preferably, the mass-to-volume ratio of milrinone to the mixed solvent is 1-2:1, with the mass being measured in mg and the volume being measured in ml.

[0047] Preferably, the molar ratio of milrinone to emodin is 1:0.5-1.2, preferably 1:1.

[0048] Preferably, the heating temperature is 40-60°C, preferably 50°C.

[0049] Preferably, the cooling and crystallization temperature is 0-30°C, preferably, the cooling and crystallization temperature is 20-25°C.

[0050] Preferably, the crystallization time is 16 to 72 hours.

[0051] Preferably, the drying temperature is 45-65° C., and the drying time is 8-12 hours.

[0052] Further preferably, the method for preparing the milrinone-curcumin co-crystal comprises the following steps:

[0053] Milrinone and curcumin are dissolved in a mixed solvent, heated and stirred, filtered, cooled and allowed to stand for crystallization, filtered and dried to obtain milrinone-curcumin crystals.

[0054] Preferably, the mixed solvent is selected from a combination of methanol, ethanol, acetonitrile, acetone or trifluoroethanol; particularly preferably, a combination of methanol, ethanol, acetone or trifluoroethanol.

[0055] Further preferably, the solvent selected in the mixed solvent is not an anhydrous solvent; preferably, the selected solvent contains at least 0.05% (by volume) of water.

[0056] Preferably, the mass-to-volume ratio of milrinone to the mixed solvent is 4-11:1, with the mass being measured in mg and the volume being measured in ml; preferably 5-7:1, with the mass being measured in mg and the volume being measured in ml.

[0057] Preferably, the molar ratio of milrinone to curcumin is 1:0.8-1.5, preferably 1:1.

[0058] Preferably, the heating temperature is 50-70°C, preferably 60°C.

[0059] Preferably, the cooling and crystallization temperature is 0-30°C, preferably, the cooling and crystallization temperature is 10-15°C.

[0060] Preferably, the crystallization time is 8 to 72 hours.

[0061] Preferably, the drying temperature is 45 to 65° C., and the drying time is 8 to 12 hours.

[0062] Confirmation of crystal structure

[0063] X-ray crystallographic data for the milrinone co-crystal analysis described herein were collected on a Rigaku XtaLAB Synergy instrument at a temperature of 293(2)K using Cu-Ka radiation and ω scanning with Lp correction. The structure was solved using a direct method, with the difference Fourier transform method identifying all non-hydrogen atoms. All hydrogen atoms on carbon and nitrogen were obtained using theoretical hydrogenation, and the structure was refined using the least squares method.

[0064] The crystallographic data (Table 1) of the milrinone-chrysin co-crystal prepared by the present invention are as follows: triclinic system, space group P-1, unit cell parameters: α=80.5680(10)°、β=68.472(2)°、γ=63.440(2)°,unit cell volume

[0065] Table 1 Main crystallographic data of milrinone-chrysin cocrystal

[0066]

[0067]

[0068] The ORTEP diagram of the milrinone-chrysanthemum co-crystal of the present invention shows that ( Figure 4 The hydrogen bond diagram of the milrinone-chrysin co-crystal of the present invention is shown in the attached figure. Figure 7 According to the above crystallographic data, the corresponding characteristic peaks in the X-ray powder diffraction pattern (Cu-Kα) are shown in the attached Figure 1 And Table 2.

[0069] Table 2 PXRD peaks of milrinone-chrysin cocrystal

[0070]

[0071]

[0072] The crystallographic data (Table 3) of the milrinone-emodin co-crystal prepared by the present invention are as follows: monoclinic system, space group P21 / n, unit cell parameters: α=90°、β=102.6510(10)°、γ=90°,unit cell volume

[0073] Table 3 Main crystallographic data of milrinone-emodin cocrystal

[0074]

[0075] The ORTEP diagram of the milrinone-emodin cocrystal of the present invention shows that ( Figure 5 The hydrogen bond diagram of the milrinone-emodin co-crystal of the present invention is shown in the attached figure. Figure 8 According to the above crystallographic data, the corresponding characteristic peaks in the X-ray powder diffraction pattern (Cu-Kα) are shown in the attached Figure 2 and Table 4.

[0076] Table 4 PXRD peaks of milrinone-emodin cocrystal

[0077]

[0078] The crystallographic data (Table 5) of the milrinone-curcumin co-crystal prepared by the present invention are as follows: triclinic system, space group P-1, unit cell parameters are: α=105.9260(10)°、β=99.4120(10)°、γ=92.6650(10)°,unit cell volume

[0079] Table 5 Main crystallographic data of milrinone-curcumin co-crystal

[0080]

[0081]

[0082] The ORTEP diagram of the milrinone-curcumin co-crystal of the present invention shows that ( Figure 6 In this crystalline form, two molecules of milrinone are bound to one molecule of curcumin and one molecule of water. The hydrogen bond diagram of the milrinone-curcumin co-crystal of the present invention is shown in the attached figure. Figure 9 According to the above crystallographic data, the corresponding characteristic peaks in the X-ray powder diffraction pattern (Cu-Kα) are shown in the attached Figure 3 and Table 6.

[0083] Table 6 PXRD peaks of milrinone-curcumin cocrystals

[0084]

[0085] Compared with the prior art, the technical effects achieved by the present invention are:

[0086] The milrinone drug co-crystals provided herein have a simple preparation method, an easily controllable crystallization process, and excellent reproducibility. Milrinone-chrysin co-crystals, milrinone-emodin co-crystals, and milrinone-curcumin co-crystals all exhibit significantly enhanced solubility compared to the individual compounds, contributing to improved oral bioavailability. The drug co-crystals provided herein contain two active pharmaceutical ingredients, providing a promising pharmaceutical raw material for combined clinical treatment of one or more diseases, and possessing high clinical research and development value. BRIEF DESCRIPTION OF THE DRAWINGS

[0087] Figure 1 .PXRD pattern of milrinone-chrysanthemum cocrystal.

[0088] Figure 2 .PXRD pattern of milrinone-emodin cocrystal.

[0089] Figure 3 .PXRD pattern of milrinone-curcumin co-crystal.

[0090] Figure 4 .ORTEP diagram of milrinone-chrysin cocrystal.

[0091] Figure 5 .ORTEP diagram of milrinone-emodin cocrystal.

[0092] Figure 6 .ORTEP diagram of milrinone-curcumin cocrystal.

[0093] Figure 7 .Hydrogen bond diagram of milrinone-chrysanthemum cocrystal.

[0094] Figure 8 .Hydrogen bond diagram of milrinone-emodin cocrystal.

[0095] Figure 9 .Hydrogen bond diagram of milrinone-curcumin cocrystal. DETAILED DESCRIPTION

[0096] The present invention is further illustrated by the following examples. It should be understood that the examples of the present invention are merely for illustrating the present invention, rather than for limiting the present invention. Therefore, simple improvements to the present invention based on the method of the present invention fall within the scope of protection claimed by the present invention.

[0097] Example 1

[0098] Milrinone (180 mg) and chrysin (217 mg) were added to a mixture of methanol (15 mL) and acetone (15 mL). The mixture was heated in a 45°C water bath with stirring until completely dissolved. The mixture was filtered and allowed to stand at 10°C for 24 hours to crystallize. The mixture was then filtered and dried at 50°C for 12 hours to obtain milrinone-chrysin cocrystals. Yield: 90%, purity: 99.93%.

[0099] Example 2

[0100] Milrinone (200 mg) and chrysin (241 mg) were added to a mixture of trifluoroethanol (20 mL) and acetone (20 mL). The mixture was heated in a 45°C water bath with stirring until completely dissolved. The mixture was filtered and allowed to stand at 10°C for 36 hours to crystallize. The mixture was then filtered and dried at 50°C for 12 hours to obtain milrinone-chrysin cocrystals. Yield: 89%, purity: 99.93%.

[0101] Example 3

[0102] Milrinone (210 mg) and chrysin (253 mg) were added to a mixture of methanol (15 mL) and acetone (15 mL). The mixture was heated in a 45°C water bath with stirring until completely dissolved. The mixture was filtered and allowed to stand at 15°C for 24 hours to crystallize. The mixture was then filtered and dried at 50°C for 12 hours to obtain milrinone-chrysin cocrystals. Yield: 90%, purity: 99.89%.

[0103] Example 4

[0104] Milrinone (211 mg) and chrysin (304 mg) were added to a mixture of ethanol (26 mL) and acetone (26 mL). The mixture was heated in a 40°C water bath with stirring until completely dissolved. The mixture was filtered and allowed to stand at 15°C for 48 hours to crystallize. The mixture was then filtered and dried at 50°C for 12 hours to obtain milrinone-chrysin cocrystals. Yield: 85%, purity: 99.91%.

[0105] Example 5

[0106] Milrinone (330 mg) and chrysin (636 mg) were added to a mixture of trifluoroethanol (20 mL) and acetonitrile (10 mL). The mixture was heated in a 60°C water bath with stirring until completely dissolved. The mixture was filtered and allowed to stand at 20°C for 48 hours to crystallize. The mixture was then filtered and dried at 50°C for 12 hours to obtain milrinone-chrysin cocrystals. Yield: 82%, purity: 99.87%.

[0107] Example 6

[0108] Milrinone (240 mg) and chrysin (289 mg) were added to a mixture of ethanol (10 mL) and acetonitrile (10 mL). The mixture was heated in a 45°C water bath with stirring until completely dissolved. The mixture was filtered and allowed to stand at 30°C for 48 hours to crystallize. The mixture was then filtered and dried at 50°C for 12 hours to obtain milrinone-chrysin cocrystals. Yield: 79%, purity: 99.83%.

[0109] Example 7

[0110] Milrinone (30 mg) and emodin (38 mg) were added to a mixed solvent of methanol (10 mL) and acetone (10 mL), heated in a 50°C water bath with stirring until completely dissolved, filtered, and allowed to stand at room temperature (20-25°C) for 24 h to crystallize, filtered, and dried at 60°C for 12 h to obtain milrinone-emodin cocrystals with a yield of 90% and a purity of 99.92%.

[0111] Example 8

[0112] Milrinone (20 mg) and emodin (26 mg) were added to a mixed solvent of ethanol (10 mL) and acetone (10 mL), heated in a 50°C water bath with stirring until completely dissolved, filtered, and allowed to stand at room temperature (20-25°C) for 36 h to crystallize, filtered, and dried at 60°C for 12 h to obtain milrinone-emodin cocrystals with a yield of 89% and a purity of 99.92%.

[0113] Example 9

[0114] Milrinone (40 mg) and emodin (51 mg) were added to a mixed solvent of ethanol (10 mL) and acetone (10 mL), heated in a 50°C water bath with stirring until completely dissolved, filtered, and allowed to stand at room temperature (20-25°C) for 48 h to crystallize, filtered, and dried at 60°C for 12 h to obtain milrinone-emodin cocrystals with a yield of 87% and a purity of 99.90%.

[0115] Example 10

[0116] Milrinone (90 mg) and emodin (161 mg) were added to a mixed solvent of acetonitrile (20 mL) and trifluoroethanol (10 mL), heated in a 60°C water bath with stirring until completely dissolved, filtered, and allowed to stand at room temperature (20-25°C) for 72 h to crystallize, filtered, and dried at 60°C for 12 h to obtain milrinone-emodin cocrystals with a yield of 81% and a purity of 99.88%.

[0117] Example 11

[0118] Milrinone (200 mg) and curcumin (349 mg) were dissolved in a mixed solvent of methanol (20 mL, AR analytical grade) and ethanol (20 mL, AR analytical grade), heated in a 60°C water bath with stirring until completely dissolved, filtered, allowed to stand at 10-15°C for 48 h to evaporate and crystallize, filtered, and dried at 60°C for 12 h to obtain milrinone-curcumin cocrystals with a yield of 87% and a purity of 99.89%.

[0119] Example 12

[0120] Milrinone (210 mg) and curcumin (363 mg) were dissolved in a mixed solvent of methanol (15 mL, AR analytical grade) and ethanol (15 mL, AR analytical grade), heated in a 60°C water bath with stirring until completely dissolved, filtered, allowed to stand at 10-15°C for 48 h to evaporate and crystallize, filtered, and dried at 60°C for 12 h to obtain milrinone-curcumin cocrystals with a yield of 85% and a purity of 99.88%.

[0121] Example 13

[0122] Milrinone (160 mg) and curcumin (279 mg) were dissolved in a mixed solvent of methanol (20 mL, AR analytical grade) and acetone (20 mL, AR analytical grade), heated in a 60°C water bath with stirring until completely dissolved, filtered, allowed to stand at 10-15°C for 48 h to evaporate and crystallize, filtered, and dried at 60°C for 12 h to obtain milrinone-curcumin cocrystals with a yield of 85% and a purity of 99.89%.

[0123] Example 14

[0124] Milrinone (90 mg) and curcumin (126 mg) were dissolved in a mixed solvent of methanol (20 mL, AR analytical grade) and trifluoroethanol (10 mL, AR analytical grade), heated in a 70°C water bath with stirring until completely dissolved, filtered, and allowed to stand at 20-25°C for 72 h to evaporate and crystallize. The mixture was filtered and dried at 60°C for 12 h to obtain milrinone-curcumin cocrystals with a yield of 81% and a purity of 99.87%.

[0125] Stability test

[0126] The specific stability test method is carried out in accordance with the guidance method for stability investigation in Part IV of the Chinese Pharmacopoeia.

[0127] High temperature test: Place the test sample in a suitable clean container with the opening opened and place it at 60℃ for 10 days. Take samples on the 5th and 10th days and test the purity by HPLC.

[0128] High humidity test: Place the test sample in a sealed 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 by HPLC.

[0129] Strong light irradiation test: Place the opening of the test sample in a light box equipped with a fluorescent lamp or other suitable lighting device, and place it under the condition of illumination of 4500lx±500lx for 10 days. Take samples on the 5th and 10th days, and test the purity by HPLC.

[0130] Table 7 Stability test results of cocrystals

[0131]

[0132]

[0133] Solubility test

[0134] Method: 10 ml of medium (water, 0.01 mol / L HCl solution) was measured and placed in a vial, and an excess of the sample to be tested was added. The vial was sealed and placed in a 25°C constant temperature water bath with stirring for 1 hour. The solution was filtered through a filter membrane and the filtrate was collected. The HPLC test was performed and the concentration of the saturated solution was calculated according to the external standard method.

[0135] Table 8 Solubility of cocrystals in different media (mg / mL)

[0136]

Claims

1. A pharmaceutical co-crystal of milrinone, characterized in that The drug co-crystal contains two drug components, milrinone and a ketone compound, specifically a milrinone-chrysin co-crystal, a milrinone-emodin co-crystal or a milrinone-curcumin co-crystal. The molecular formula of the milrinone-chrysin co-crystal is C 54 H 38 N6O 10 The crystallographic parameters are: triclinic system, space group is P-1, unit cell parameters are: a=12.8543(3)Å, b=14.0049(3)Å, c=15.0414(2)Å, α=80.5680(10)°, β=68.472(2)°, γ=63.440(2)°, unit cell volume V=2253.07(9)Å 3 The milrinone-emodin cocrystal has a molecular formula of C 27 H 19 N3O6, crystallographic parameters are: monoclinic system, space group is P21 / n, unit cell parameters are, a=14.07360(10)Å, b=10.70780(10)Å, c=14.94630(10)Å, α=90°, β=102.6510(10)°, γ=90°, unit cell volume V=2197.68(3)Å 3 The milrinone-curcumin cocrystal has a molecular formula of C 45 H 40 N6O9, crystallographic parameters are: triclinic system, space group is P-1, unit cell parameters are: a=8.04530(10)Å, b=14.1146(2)Å, c=22.8566(3)Å, α=105.9260(10)°, β=99.4120(10)°, γ=92.6650(10)°, unit cell volume V=2450.84(6)Å 3 .

2. The pharmaceutical co-crystal according to claim 1, wherein The milrinone-chrysanthemum eutectic has characteristic peaks at least at 7.9±0.2°, 8.3±0.2°, 9.6±0.2°, 12.0±0.2°, 12.6±0.2°, 20.7±0.2°, 34.2±0.2°, and 34.5±0.2° in an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

3. The pharmaceutical co-crystal according to claim 1, wherein The characteristic peaks of the milrinone-chrysin co-crystal conform to the X-ray powder diffraction pattern shown in FIG1 using Cu-Kα radiation.

4. The pharmaceutical co-crystal according to claim 1, wherein The milrinone-emodin cocrystal uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at at least 7.8±0.2°, 9.8±0.2°, 12.9±0.2°, 18.0±0.2°, and 25.7±0.2°.

5. The pharmaceutical co-crystal according to claim 1, wherein The characteristic peaks of the milrinone-emodin co-crystal conform to the X-ray powder diffraction pattern shown in FIG2 using Cu-Kα radiation.

6. The pharmaceutical co-crystal according to claim 1, wherein The milrinone-curcumin co-crystal uses Cu-Kα radiation, and the X-ray diffraction spectrum expressed in 2θ has characteristic peaks at at least 5.2±0.2°, 7.8±0.2°, 15.8±0.2°, 19.4±0.2°, 26.8±0.2°, and 27.9±0.2°.

7. The pharmaceutical co-crystal according to claim 1, wherein The characteristic peaks of the milrinone-curcumin co-crystal using Cu-Kα radiation conform to the X-ray powder diffraction pattern shown in FIG3 .

8. The method for preparing the pharmaceutical co-crystal according to claim 1, characterized in that: The steps include: Milrinone and a ketone compound are dissolved in a mixed solvent, heated and stirred, filtered, cooled and allowed to stand for crystallization, filtered and dried to obtain a drug co-crystal, wherein the ketone compound is chrysin, emodin or curcumin.

9. The preparation method according to claim 8, wherein The mixed solvent is selected from a combination of methanol, ethanol, acetonitrile, acetone or trifluoroethanol.

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