CN117069653A - Milrinone gallic acid eutectic - Google Patents

Milrinone gallic acid eutectic Download PDF

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CN117069653A
CN117069653A CN202211476745.6A CN202211476745A CN117069653A CN 117069653 A CN117069653 A CN 117069653A CN 202211476745 A CN202211476745 A CN 202211476745A CN 117069653 A CN117069653 A CN 117069653A
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milrinone
gallic acid
hemihydrate
eutectic
crystal
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翟立海
李玲
张明明
路来菊
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Shandong New Time Pharmaceutical Co Ltd
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Shandong New Time Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Hospice & Palliative Care (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a novel milrinone crystal form, in particular to a co-crystal of milrinone and gallic acid, and a preparation method and application thereof. The invention provides a novel milrinone crystal form with higher solubility and stability, namely milrinone gallic acid eutectic hemihydrate. In addition, the invention provides a method for preparing the milrinone gallic acid eutectic hemihydrate, which is simple, convenient and suitable for industrial production.

Description

Milrinone gallic acid eutectic
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a milrinone gallic acid eutectic crystal and a preparation method and application thereof.
Background
Milrinone (formula I) with chemical name of 1, 6-dihydro-2-methyl-6-oxo- [3, 4-bipyridine]-5-carbonitrile of formula C 12 H 9 N 3 O, molecular weight 211.22, is white or white-like crystalline powder, and has the structural formula:
milrinone was first developed by Sterling corporation in the united states to successfully produce an anti-heart failure drug, which was first approved by the FDA in the united states in 1987, formally marketed in the united states in 1992, and subsequently marketed in the united kingdom, france, germany, the netherlands, belgium, etc.
Milrinone is a phosphodiesterase inhibitor, is a derivative of amrinone, and has the same action mechanism as amrinone. It is effective for oral administration and intravenous injection, and has positive muscle strength and vasodilatation effects. Is suitable for short-term treatment of patients with severe congestive heart failure, the curative effect of which is 10-30 times stronger than that of amirinone, and has better tolerance and less adverse reaction. The positive inotropic effect of the product is mainly to increase the concentration of Cyclic Adenosine Monophosphate (CAMP) in myocardial cells, increase intracellular calcium, strengthen myocardial contractility and increase heart blood discharge by inhibiting phosphodiesterase. It is considered to be a high-efficiency, low-toxicity, non-digitalis and non-sympathomimetic cardiotonic, and has remarkable effects on severe heart failure and pulmonary edema caused by ischemic heart disease, dilated cardiomyopathy, etc., and is superior to dopamine, less in adverse reaction and not increasing heart rate. Therefore, the medicine plays an increasingly important role in treating Congestive Heart Failure (CHF), peripheral vascular dilation and the like.
In reality, due to the fact that milrinone is poor in water solubility and heavy in adverse reaction during oral administration, the crystal form of milrinone, which is good in solubility, high in stability and good in patent medicine prospect, is provided, and the problem to be solved by the person skilled in the art is solved urgently.
Gallic acid, also known as gallic acid or gallic acid, is an organic acid, and is found in plants such as gallnut, lacquer tree, tea, etc. Has antibacterial, antiviral, antioxidant, arteriosclerosis resisting, thrombosis resisting, vascular proliferation resisting, and antiinflammatory effects.
Drug co-crystallization refers to the incorporation of drug molecules into the same crystal lattice with other physiologically acceptable acid, base, salt, and non-ionic compound molecules by non-covalent bonding such as hydrogen bonding, pi-pi stacking, van der Waals forces, etc. On the premise of not damaging covalent bonds of the medicine, the formation of eutectic crystals can change physicochemical properties of the medicine, including stability, solubility, bioavailability and the like. When the two medicines form eutectic, the purpose of combined medication can be achieved while improving the physicochemical properties and the pharmacokinetic parameters of the two medicines.
Disclosure of Invention
Aiming at the defects of poor solubility and low stability of milrinone provided by the prior art, the invention aims to provide a novel crystal form of milrinone with higher solubility and stability, namely the milrinone gallic acid eutectic hemihydrate. In addition, the invention provides a method for preparing the milrinone gallic acid eutectic hemihydrate, which is simple, convenient and suitable for industrial production.
The specific technical content of the invention is as follows:
in one aspect, the invention provides a milrinone gallic acid eutectic hemihydrate, wherein in the eutectic, the molar ratio of milrinone, gallic acid and water is 2:2:1, and two molecules of milrinone, two molecules of gallic acid and one molecule of water form a basic unit of a crystal form.
Preferably, the milrinone gallic acid eutectic hemihydrate is characterized in that the Cu-ka radiation is used, and the X-ray diffraction pattern expressed in 2θ has characteristic peaks at least at 9.2±0.2°, 15.0±0.2°, 23.7±0.2°, and 27.0±0.2°.
Preferably, the milrinone gallic acid eutectic hemihydrate uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 9.2+/-0.2 degrees, 10.6+/-0.2 degrees, 15.0+/-0.2 degrees, 16.4+/-0.2 degrees, 22.3+/-0.2 degrees, 23.7+/-0.2 degrees, 24.9+/-0.2 degrees, 27.0+/-0.2 degrees, 28.0+/-0.2 degrees and 28.3+/-0.2 degrees.
Preferably, the milrinone gallic acid eutectic hemihydrate uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 1.
Preferably, the milrinone gallic acid eutectic hemihydrate has a molecular formula of C 38 H 32 N 6 O 13 The crystallographic parameters were: the triclinic system has a space group of P-1 and unit cell parameters of: a= 10.3716 (2), b= 11.1089 (2), c= 17.5817 (2), α= 80.4750 (10), β= 83.7000 (10), γ= 62.256 (2), unit cell volume v= 1766.87 (6).
In another aspect, the invention provides a method for preparing milrinone gallic acid eutectic hemihydrate, comprising the steps of:
dissolving milrinone and gallic acid in a mixed solvent, heating, stirring, filtering, cooling, crystallizing, filtering and drying to obtain the milrinone gallic acid eutectic hemihydrate.
Preferably, the solvent is selected from a mixed solvent of water and two organic solvents selected from methanol, ethanol, acetonitrile, acetone and trifluoroethanol, and particularly preferably a mixed solvent of trifluoroethanol, ethanol and water.
Preferably, the mass-volume ratio of the milrinone to the organic solvent is 21.1:3-6; preferably 21.1:4 to 5; wherein the mass of milrinone is calculated in mg, and the volume of the mixed solvent is calculated in ml.
Preferably, the molar ratio of milrinone to gallic acid is 1:0.8 to 1.2, preferably 1:1.
preferably, the heating temperature is 40 to 60 ℃, preferably 50 ℃.
The temperature of the cooling crystallization is 0-30 ℃, preferably 20-25 ℃.
The crystallization time is 16-72 hours, preferably 48-72 hours.
The drying temperature is 45-65 ℃ and the drying time is 8-12 hours.
The raw material milrinone used in the preparation method may be prepared according to any method in the prior art or purchased from commercial products.
Finally, the invention provides a pharmaceutical composition which contains the milrinone gallic acid eutectic hemihydrate and pharmaceutically viable components thereof.
Preferably, the pharmaceutically acceptable components thereof can be pharmaceutically active ingredients which can be combined and/or pharmaceutically acceptable auxiliary ingredients.
Confirmation of Crystal Structure
In the milrinone gallic acid eutectic hemihydrate test, X-ray crystal data are collected on a Japanese science XtaLAB Synergy model instrument, the test temperature 293 (2) K is radiated by Cu-Ka, and the data are collected in an omega scanning mode and are subjected to Lp correction. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
The crystallography data (shown in table 1) of the crystalline form of the milrinone gallic acid eutectic hemihydrate prepared by the invention is that the triclinic system, the space group is P-1, and the unit cell parameters are as follows: a= 10.3716 (2), b= 11.1089 (2), c= 17.5817 (2), α= 80.4750 (10), β= 83.7000 (10), γ= 62.256 (2), unit cell volume v= 1766.87 (6).
TABLE 1 data on major crystallography of milrinone gallic acid eutectic hemihydrate
The ORTEP diagram of the milrinone gallic acid eutectic hemihydrate of the invention shows that the crystal form contains two molecules of milrinone, two molecules of gallic acid and one molecule of water, and is shown in figure 2. The stacking diagram of the milrinone gallic acid eutectic hemihydrate is shown in figure 3. According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in the accompanying figures 1 and 2.
TABLE 2 PXRD peak of milrinone gallic acid eutectic hemihydrate
Compared with the prior art, the invention has the technical effects that:
the invention provides a novel milrinone gallic acid eutectic hemihydrate, the preparation method is simple to operate, the crystallization process is easy to control, and the reproducibility is good. After the two are formed into eutectic, the dissolubility of milrinone can be obviously enhanced, the oral bioavailability is improved, and the pharmaceutical value is very high.
Drawings
FIG. 1 PXRD spectra of milrinone gallic acid eutectic hemihydrate.
FIG. 2 ORTEP diagram of milrinone gallic acid eutectic hemihydrate.
FIG. 3 is a plot of the packing of the milrinone gallic acid eutectic hemihydrate.
FIG. 4 comparative example 1 Crystal form ORTEP diagram and main crystallographic data
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
Example 1
Dissolving 21.2mg milrinone and 17.2mg gallic acid in a mixed solvent of 2mL trifluoroethanol, 2mL ethanol and 0.5mL water, heating and stirring in a water bath at 50 ℃ until the mixture is completely dissolved, filtering, cooling to 20-25 ℃, standing for crystallization, and after crystallization, filtering and drying to obtain milrinone gallic acid eutectic hemihydrate, wherein the yield is: 95%, purity: 99.93%.
Example 2
21.3mg milrinone and 17.0mg gallic acid are dissolved in a mixed solvent of 3mL trifluoroethanol, 2mL methanol and 1mL water, heated and stirred in a water bath at 40 ℃ until the mixture is completely dissolved, filtered, cooled to 0-10 ℃ for standing crystallization, after crystallization, the milrinone gallic acid eutectic hemihydrate is obtained by filtering and drying, and the yield is: 92%, purity: 99.88%.
Example 3
21.2mg milrinone and 17.2mg gallic acid are dissolved in a mixed solvent of 2mL trifluoroethanol, 1.5mL ethanol and 0.5mL water, heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, cooled to 10-15 ℃, stood for crystallization, and filtered and dried after crystallization, thus obtaining the milrinone gallic acid eutectic hemihydrate with yield: 91%, purity: 99.89%.
Example 4
21.2mg milrinone and 17.1mg gallic acid are dissolved in a mixed solvent of 2mL methanol, 2mL acetonitrile and 0.5mL water, heated and stirred in a water bath at 50 ℃ until the mixture is completely dissolved, filtered, cooled to 25-30 ℃, stood for crystallization, and after crystallization, filtered and dried to obtain milrinone gallic acid eutectic hemihydrate, the yield is: 93%, purity: 99.83%.
Example 5
21.0mg milrinone and 17.2mg gallic acid are dissolved in a mixed solvent of 2mL acetone, 2mL ethanol and 0.5mL water, heated and stirred in a water bath at 50 ℃ until the mixture is completely dissolved, filtered, cooled to 20-25 ℃, stood for crystallization, and filtered and dried after crystallization, thus obtaining the milrinone gallic acid eutectic hemihydrate with the yield: 94%, purity: 99.86%.
Example 6
21.2mg milrinone and 17.2mg gallic acid are dissolved in a mixed solvent of 2mL trifluoroethanol, 2mL methanol and 0.5mL water, the mixture is heated and stirred in a water bath at 50 ℃ until the mixture is completely dissolved, the mixture is filtered, the temperature is reduced to 10-20 ℃, standing and crystallization are carried out, after crystallization, the mixture is filtered and dried to obtain milrinone gallic acid eutectic hemihydrate, and the yield is: 91%, purity: 99.82%.
Comparative example 1
Mirinone (169.0 mg) and gallic acid (136.1 mg) were mixed uniformly in equimolar ratio, 50. Mu.l of water was gradually added and sufficiently ground in mortar for 45 minutes. Dissolving the ground powder sample in a minimum amount of methanol/acetonitrile/H 2 In the mixed solvent of O, the volume ratio of methanol, acetonitrile and water is 2:1:1, and the mixed solvent is rapidly and vigorously stirred for about 3 hours at 60 ℃. After cooling to room temperature, the resulting reaction mixture was filtered. The above powder sample was added to the filtrate as seed crystal, and the solution was allowed to stand for slow evaporation for 1 day to obtain colorless crystals. Yield 83.5% and purity 99.90%.
Comparative example 2
Mixing the milrinone crude product, ethanol, acetone and water according to the mass volume ratio of 7g:83ml:57ml:105ml of the mixture is dissolved, slowly heated to 94 ℃, fully stirred and dissolved uniformly; then adding activated carbon for decoloring for 4.5 hours, wherein the mass of the activated carbon is 8% of that of the milrinone crude product, and filtering while the activated carbon is hot to remove the activated carbon; stirring the solution obtained by suction filtration at a stirring rate of 6 revolutions per minute, cooling to 34 ℃, wherein the cooling rate is 2 ℃/min, and dropwise adding deionized water into the filtrate under an ultrasonic field until crystals are separated out when the filtrate is cooled to room temperature; closing an ultrasonic field, standing for 27 hours, filtering, washing with ethanol, and drying to obtain the milrinone crystal. The yield was 87.5% and the purity was 99.88%.
Comparative example 3
Placing 10g milrinone in a 500ml beaker, dropwise adding 0.1N hydrochloric acid solution, stirring to dissolve the solution to enable the pH value of the solution to be 4-4.5, adding acetone with the volume being 5 times of the solution, cooling, precipitating white precipitate, filtering, washing a filter cake with acetone for 2 times, airing, and then drying at 105 ℃ for 2 hours to obtain 12g milrinone hydrochloride with the yield of 93% and the purity of 99.90%.
Comparative example 4
Placing 10g milrinone in a 500ml beaker, dropwise adding 0.1N sulfuric acid solution, stirring to dissolve the solution, enabling the pH value of the solution to be 4-5, adding acetone with the volume of 5 times of the solution, cooling, precipitating white precipitate, filtering, washing a filter cake with acetone for 2 times, airing, and then drying at 105 ℃ for 2 hours to obtain 14.3g milrinone sulfate with the yield of 97% and the purity of 99.89%.
Comparative example 5
10g milrinone is placed in a 500ml beaker, 0.1N methanesulfonic acid solution is added dropwise and stirred to be dissolved, the pH value of the solution is 4-5, acetone with the volume being 5 times of that of the solution is added, the solution is cooled, white precipitate is separated out, the solution is filtered, a filter cake is washed with acetone for 2 times and dried in the air, and then the solution is dried at 105 ℃ for 2 hours, so that 14.0g milrinone methanesulfonate is obtained, the yield is 96.2%, and the purity is 99.91%.
Stability test
The specific stability test method is carried out by referring to the guidance method related to stability investigation in the fourth section of Chinese pharmacopoeia, the purity detection is carried out by using an HPLC method, and the specific detection result is shown in Table 3.
TABLE 3 stability test results of different milrinone crystals under light, high temperature and high humidity conditions
Experimental results show that the milrinone gallic acid eutectic hemihydrate prepared by the embodiment of the invention has high purity, small sample purity change under high temperature, high humidity and strong light conditions and good stability. Examples 1 to 6 were examined and found to have similar stability test results.
Solubility experiment
The method comprises the following steps: respectively weighing 10ml of medium (water and 0.01mol/L HCl solution) in a penicillin bottle, adding excessive sample to be tested, sealing the penicillin bottle, placing in a constant-temperature water bath at 25 ℃ for stirring for 1 hour, filtering by a filter membrane, and taking filtrate; the absorbance was measured at a wavelength of 270nm, and the solubility was calculated by measuring the absorbance of the standard control.
TABLE 4 solubility of different milrinone crystals in different media
The test result shows that the solubility of the milrinone gallic acid eutectic hemihydrate in 0.01mol/L HCl and water is obviously improved compared with other crystal forms of milrinone, and the bioavailability is improved. Examples 1 to 6 were examined and found to have similar solubility test results.
Pharmacokinetic parameters of milrinone and its co-crystal
The method comprises the following steps: in vivo PK test was carried out by single dose oral administration, male SD rats (220-260 g) were fed in a quiet atmosphere of 0% -60% constant humidity at 25+ -1deg.C, with rhythmic light from 7 in the morning to 7 in the evening. PK experiments were strictly performed according to the laboratory management guidelines issued by the chinese institute of technology. Prior to the experiment, the rats tested were randomly divided into three groups (n=5 per group) and allowed to drink water freely, and fasted overnight. All samples tested were suspended in vegetable oil and then orally administered in a single dose of 10mg/kg milrinone or its equivalent. After administration, 0.5mL blood samples were collected at the designed time points according to the administration conditions, and the blood concentration of milrinone was measured, and the results are shown in table 5.
TABLE 5 pharmacokinetic study results for different milrinone crystals
These results indicate that milrinone gallic acid eutectic hemihydrate has better bioavailability than milrinone other crystals.

Claims (10)

1. The milrinone gallic acid eutectic hemihydrate is characterized in that the eutectic consists of active pharmaceutical ingredients of milrinone and a eutectic ligand gallic acid, and the molar ratio of the milrinone, the gallic acid and water in the eutectic is 2:2:1.
2. The milrinone gallic acid eutectic hemihydrate of claim 1, wherein the eutectic base unit is composed of two molecules of milrinone, two molecules of gallic acid, and one molecule of water, and the crystallographic parameters are: the triclinic system has a space group of P-1 and unit cell parameters of: a= 10.3716 (2), b= 11.1089 (2), c= 17.5817 (2), α= 80.4750 (10), β= 83.7000 (10), γ= 62.256 (2), unit cell volume v= 1766.87 (6).
3. The milrinone gallic acid co-crystal hemihydrate according to claim 1, wherein the co-crystal has characteristic peaks in the X-ray diffraction pattern expressed in 2Θ of at least 9.2 ± 0.2 °, 15.0 ± 0.2 °, 23.7 ± 0.2 °, 27.0 ± 0.2 ° using Cu-ka radiation.
4. The milrinone gallic acid co-crystal hemihydrate according to claim 1, wherein the co-crystal has characteristic peaks at least at 9.2±0.2°, 10.6±0.2°, 15.0±0.2°, 16.4±0.2°, 22.3±0.2°, 23.7±0.2°, 24.9±0.2°, 27.0±0.2°, 28.0±0.2°, 28.3±0.2° using an X-ray diffraction pattern expressed in 2Θ of Cu-ka radiation.
5. The milrinone gallic acid co-crystal hemihydrate of claim 1, wherein the co-crystal has an X-ray powder diffraction pattern as shown in figure 1.
6. A process for preparing the milrinone gallic acid co-crystal hemihydrate according to any one of claims 1 to 5, characterized in that it comprises the following steps:
dissolving milrinone and gallic acid in a mixed solvent, heating, stirring, filtering, cooling, crystallizing, filtering and drying to obtain the milrinone gallic acid eutectic hemihydrate.
7. The method for preparing milrinone gallic acid eutectic hemihydrate according to claim 6, wherein the solvent is a mixed solvent of water and two organic solvents selected from methanol, ethanol, acetonitrile, acetone and trifluoroethanol, and particularly preferably a mixed solvent of trifluoroethanol, ethanol and water.
8. The method for preparing milrinone gallic acid eutectic hemihydrate according to claim 6, wherein the molar ratio of milrinone to gallic acid is 1:0.8 to 1.2, preferably 1:1.
9. the method for preparing milrinone gallic acid eutectic hemihydrate according to claim 6, wherein the temperature reduction crystallization temperature is 0-30 ℃.
10. Use of the milrinone gallic acid co-crystal hemihydrate according to any one of claims 1-5 for the preparation of a medicament for the treatment of Congestive Heart Failure (CHF) and peripheral vascular disease.
CN202211476745.6A 2022-11-23 2022-11-23 Milrinone gallic acid eutectic Pending CN117069653A (en)

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