CN116410131A

CN116410131A - Mili pesticide co-crystal and preparation method thereof

Info

Publication number: CN116410131A
Application number: CN202111670690.8A
Authority: CN
Inventors: 翟立海; 李玲; 张明明; 路来菊
Original assignee: Shandong New Time Pharmaceutical Co Ltd
Current assignee: Shandong New Time Pharmaceutical Co Ltd
Priority date: 2021-12-31
Filing date: 2021-12-31
Publication date: 2023-07-11

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and provides a milriness pesticide co-crystal which is simple in preparation method operation, easy to control in crystallization process and good in reproducibility. The milrinone-chrysin eutectic, the milrinone-emodin eutectic and the milrinone curcumin eutectic have significantly enhanced solubility compared with the monomeric compound, and are beneficial to improving the oral bioavailability.

Description

Mili pesticide co-crystal and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a pharmaceutical co-crystal of milrinone, in particular to a co-crystal of milrinone and ketone compounds, and a preparation method and application thereof.

Background

Milrinone (milrinone) with chemical name 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 amirinone, and has the same action mechanism as amirinone. 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 amrinone, the tolerance is better, and the adverse reaction is less. The positive inotropic effect is mainly to increase the concentration of Cyclic Adenosine Monophosphate (CAMP) in myocardial cells by inhibiting phosphodiesterase, increase intracellular calcium, strengthen myocardial contractility and increase cardiac output. Is generally considered as an efficient, low-toxicity, non-digitalis and non-sympathomimetic cardiotonic, has obvious curative effects on serious heart failure and pulmonary edema caused by ischemic heart disease, dilated cardiomyopathy and the like, is superior to dopamine, has less adverse reaction and does not increase heart rate. Therefore, the medicine plays an increasingly important role in treating Congestive Heart Failure (CHF), peripheral vascular dilation and the like.

Chrysin is a natural flavonoid compound extracted from plants and has wide pharmacological activities such as antioxidation, anti-tumor, anticancer, antivirus, antihypertensive, antidiabetic, antibacterial, antiallergic, antiplatelet and antithrombotic, and the like, and the compound is widely distributed in the plants and has low toxicity, so that the chrysin is a very important resource in new medicine development and research. Chrysin is dissolved in alkaline hydroxide solution, slightly dissolved in organic solvents such as ethanol, diethyl ether and the like, and insoluble in water, and the dissolution property of chrysin greatly limits the development and the use of chrysin in the field of medicine application.

Emodin (EM) belongs to hydroxyanthraquinone, is one of main active ingredients of rheum officinale, and is a main raw material for synthesizing hypericin. The emodin has wide pharmacological activity, and has antibacterial, antiinflammatory, antiviral, antidiabetic, antitumor, liver protecting, and immunosuppression effects. Recent studies have found that emodin is cytotoxic to a variety of tumor cells, possibly by inhibiting tumor cell proliferation and adhesion. The pure emodin can be used for treating tumors, mainly for treating tumors such as leukemia and gastric cancer, and most commonly used emodin is used for bacteriostasis. It is used in almost every clinical department, such as treating Japanese encephalitis and parotitis, typhoid fever, dysentery, urinary tract infection, gonorrhea, pneumonia, cellulitis, suppurative dermatoses, otitis media, vasculitis, etc., and other medicines for treating acute and subacute appendicitis, burn, poliomyelitis, eczema and skin infection caused by several fungi, and can also treat hepatitis, enterobiasis, stomatitis, canker sore, dyspepsia, hypertension and arteriosclerosis. Recent studies have shown that emodin has an exciting effect on isolated toad hearts at small doses, while large doses have an inhibiting effect and also have a antihypertensive effect. Emodin is soluble in ethanol and alkali solutions and is almost insoluble in water, and its dissolution characteristics also limit its application in drug development. The water-insoluble nature of emodin also greatly limits its development and use in the field of pharmaceutical applications.

Curcumin is a natural liposoluble phenolic substance extracted from rhizome of Curcuma rhizome, curcumae rhizoma, mustard, radix Curcumae, curry, etc. of Zingiberaceae, and is a rare diketone pigment of plant kingdom. Modern researches have found that curcumin has wide pharmacological activities such as anti-inflammatory, anti-tumor, anti-HIV, antioxidant, antibacterial, lipid regulating, antiviral, anti-infective, anticoagulative, anti-hepatic fibrosis and anti-atherosclerosis, and has low toxicity and other various pharmacological activities, and good safety.

Researches show that milrinone has poor water solubility, is almost insoluble in water and has heavier adverse reaction when being taken orally, so that the crystal form of milrinone with good solubility, high stability and good patent medicine prospect is provided, and the problem to be solved by the technicians in the field is solved urgently. And the two active ingredients of the medicine are combined through a pharmaceutical co-crystal technology so as to obviously improve the physicochemical properties of the active ingredients of the medicine, thereby providing more choices for clinical application of the medicine and becoming the problem to be solved in the research of the crystal forms of the medicine.

Disclosure of Invention

According to the invention, researches show that milrinone and ketone compounds can form stable drug co-crystals, and the formed crystals have excellent physicochemical properties such as significantly improved solubility, significantly improved stability and the like which are not possessed by the two components when the two components exist independently.

The specific technical content of the invention is as follows:

the invention provides a pharmaceutical co-crystal of milrinone and a ketone compound, wherein the ketone compound contains at least one hydroxyl; wherein the drug co-crystal is preferably milrinone-chrysin co-crystal, milrinone-emodin co-crystal and milrinone-curcumin co-crystal.

The milrinone-chrysin co-crystal adopts Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at least at 7.9+/-0.2 degrees, 8.3+/-0.2 degrees, 9.6+/-0.2 degrees, 12.0+/-0.2 degrees, 12.6+/-0.2 degrees, 20.7+/-0.2 degrees, 34.2+/-0.2 degrees and 34.5+/-0.2 degrees.

Preferably, the milrinone-chrysin co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 7.9+/-0.2 degrees, 8.3+/-0.2 degrees, 9.3+/-0.2 degrees, 9.6+/-0.2 degrees, 12.0+/-0.2 degrees, 12.6+/-0.2 degrees, 14.6+/-0.2 degrees, 16.4+/-0.2 degrees, 20.7+/-0.2 degrees, 26.6+/-0.2 degrees, 34.2+/-0.2 degrees and 34.5+/-0.2 degrees.

Preferably, the milrinone-chrysin co-crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 1.

Preferably, the milrinone-chrysin co-crystal has a molecular formula of C ₅₄ H ₃₈ N ₆ O ₁₀ The crystallographic parameters were: the triclinic system has a space group of P-1 and unit cell parameters of:

α= 80.5680 (10) °, β= 68.472 (2) °, γ= 63.440 (2) °, unit cell volume +.>

The milrinone-emodin co-crystal adopts Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at least at 7.8+/-0.2 degrees, 9.8+/-0.2 degrees, 12.9+/-0.2 degrees and 18.0+/-0.2 degrees and 25.7+/-0.2 degrees.

Preferably, the milrinone-emodin co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at least at 7.8+/-0.2 degrees, 9.8+/-0.2 degrees, 12.9+/-0.2 degrees, 15.3+/-0.2 degrees, 18.0+/-0.2 degrees, 20.7+/-0.2 degrees, 21.6+/-0.2 degrees, 25.7+/-0.2 degrees, 25.9+/-0.2 degrees, 26.8+/-0.2 degrees and 27.7+/-0.2 degrees.

Preferably, the milrinone-emodin co-crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 2.

Preferably, the milrinone-emodin co-crystal has a molecular formula of C ₂₇ H ₁₉ N ₃ O ₆ The crystallographic parameters were: monoclinic system, space group P21/n, unit cell parameters:

α=90 °, β= 102.6510 (10) °, γ=90°, unit cell volume +.>

The milrinone-curcumin co-crystal adopts Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at least at 5.2+/-0.2 degrees, 7.8+/-0.2 degrees, 15.8+/-0.2 degrees, 19.4+/-0.2 degrees, 26.8+/-0.2 degrees and 27.9+/-0.2 degrees.

Preferably, the milrinone-curcumin co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed in terms of 2 theta has characteristic peaks at least at 5.2+/-0.2 degrees, 7.8+/-0.2 degrees, 14.3+/-0.2 degrees, 15.8+/-0.2 degrees, 19.4+/-0.2 degrees, 26.8+/-0.2 degrees, 27.9+/-0.2 degrees, 29.3+/-0.2 degrees and 37.4+/-0.2 degrees.

Preferably, the milrinone-curcumin co-crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 3.

Preferably, the milrinone-turmericA co-crystal of a formula C ₄₅ H ₄₀ N ₆ O ₉ The crystallographic parameters were: the triclinic system has a space group of P-1 and unit cell parameters of:

α= 105.9260 (10) °, β= 99.4120 (10) °, γ= 92.6650 (10) °, unit cell volume +.>

In another aspect, the invention provides a method of preparing the pharmaceutical co-crystal comprising the steps of:

dissolving milrinone and ketone compound in mixed solvent, heating and stirring, filtering, cooling, standing for crystallization, filtering and drying to obtain the drug co-crystal.

Preferably, the mixed solvent is selected from the group consisting of methanol, ethanol, acetonitrile, acetone, and trifluoroethanol.

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

Preferably, the ketone compounds are chrysin, emodin and curcumin.

Preferably, the heating temperature is 40-70 ℃.

Preferably, the temperature of the cooling crystallization is 0-30 ℃.

Preferably, the crystallization time is 1 to 72 hours.

Preferably, the drying temperature is 45-65 ℃ and the drying time is 8-12 hours.

Further preferably, the preparation method of the milrinone-chrysin co-crystal comprises the following steps:

dissolving milrinone and chrysin in mixed solvent, heating, stirring, filtering, cooling, standing for crystallization, filtering and drying to obtain milrinone-chrysin crystal.

Preferably, the mixed solvent is selected from the group consisting of methanol, ethanol, acetonitrile, acetone, and trifluoroethanol; particularly preferred are combinations of methanol, acetone, trifluoroethanol.

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

Preferably, the molar ratio of milrinone to chrysin is 1:0.8 to 1.6, preferably 1:1.

preferably, the heating temperature is 40 to 60 ℃, preferably 45 ℃.

Preferably, the temperature reduction crystallization temperature is 10-30 ℃, preferably 10-15 ℃.

Preferably, the crystallization time is 8-72 hours.

Further preferably, the preparation method of the milrinone-emodin co-crystal comprises the following steps:

dissolving milrinone and emodin in a mixed solvent, heating and stirring, filtering, cooling, standing for crystallization, filtering and drying to obtain milrinone-emodin crystals.

Preferably, the mixed solvent is selected from the group consisting of methanol, ethanol, acetonitrile, acetone, and trifluoroethanol; particularly preferred are combinations of methanol, ethanol, acetone.

Preferably, the mass-volume ratio of the milrinone to the mixed solvent is 1-2:1, the mass is in mg and the volume is in ml.

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

preferably, the heating temperature is 40 to 60 ℃, preferably 50 ℃.

Preferably, the temperature reduction crystallization temperature is 0-30 ℃, preferably 20-25 ℃.

Preferably, the crystallization time is 16-72 hours.

Further preferably, the preparation method of the milrinone-curcumin co-crystal comprises the following steps:

and dissolving milrinone and curcumin in the mixed solvent, heating, stirring, filtering, cooling, standing, crystallizing, filtering and drying to obtain milrinone-curcumin crystals.

Preferably, the mixed solvent is selected from the group consisting of methanol, ethanol, acetonitrile, acetone, and trifluoroethanol; particularly preferred are combinations of methanol, ethanol, acetone or trifluoroethanol.

Further preferably, the solvent selected from the mixed solvent is not an anhydrous solvent; preferably, the solvent selected contains at least 0.05% (by volume) water.

Preferably, the mass-volume ratio of the milrinone to the mixed solvent is 4-11:1, the mass is calculated in mg, and the volume is calculated in ml; preferably 5-7:1, mass in mg and volume in ml.

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

preferably, the heating temperature is 50 to 70 ℃, preferably 60 ℃.

Preferably, the temperature reduction crystallization temperature is 0-30 ℃, preferably 10-15 ℃.

Preferably, the crystallization time is 8-72 hours.

Confirmation of Crystal Structure

In the Mili pesticide co-crystal test, X-ray crystal data are collected on a Japan XtaLAB Synergy model instrument, the test temperature 293 (2) K is measured, cu-Ka radiation is used, and 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.

Testing and analysis of the crystallographic data (Table 1) of the crystalline form of the milrinone-chrysin co-crystal prepared according to the invention are that the triclinic system, the space group being P-1, the unit cell parameters being:

α= 80.5680 (10) °, β= 68.472 (2) °, γ= 63.440 (2) °, unit cell volume +.>

TABLE 1 data on principle crystallography of milrinone-chrysin cocrystal

The ORTEP diagram of the milrinone-chrysin co-crystal of the invention shows (FIG. 4) that one molecule of milrinone binds one molecule of chrysin in the crystalline form. The hydrogen bond diagram of the milrinone-chrysin eutectic is shown in figure 7. 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 peaks for milrinone-chrysin cocrystal

Testing and resolving the crystallographic data of the crystalline form of the milrinone-emodin co-crystal prepared according to the invention (Table 3) is monoclinic system, space group P2 ₁ And/n, the unit cell parameters are:

α=90 °, β= 102.6510 (10) °, γ=90°, unit cell volume +.>

TABLE 3 data on major crystallography of milrinone-emodin co-crystals

The ORTEP diagram of the milrinone-emodin co-crystal of the present invention shows (shown in figure 5) that one molecule of milrinone binds one molecule of emodin in this crystalline form. The hydrogen bond diagram of the milrinone-emodin eutectic is shown in figure 8. Based on the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in FIG. 2 and Table 4.

TABLE 4 PXRD peak of milrinone-emodin co-crystal

Testing and analysis of the crystallographic data (Table 5) of the crystalline form of the milrinone-curcumin co-crystal prepared according to the invention are that the triclinic system, the space group being P-1, the unit cell parameters being:

TABLE 5 Milrinon-curcumin co-crystal primary crystallographic data

The ORTEP diagram of the milrinone-curcumin co-crystal of the present invention shows (shown in fig. 6) that two molecules of milrinone bind one molecule of curcumin and one molecule of water in the crystalline form. The hydrogen bond diagram of the milrinone-curcumin eutectic is shown in figure 9. Based on the above-mentioned crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in FIG. 3 and Table 6.

TABLE 6 PXRD peak of milrinone-curcumin co-crystal

Compared with the prior art, the invention has the technical effects that:

the preparation method of the milriness pesticide co-crystal provided by the invention is simple to operate, the crystallization process is easy to control, and the repeatability is good. The milrinone-chrysin eutectic, the milrinone-emodin eutectic and the milrinone curcumin eutectic have significantly enhanced solubility compared with the monomeric compound, and are beneficial to improving the oral bioavailability. The pharmaceutical co-crystal provided by the invention contains two pharmaceutical active ingredients, provides better pharmaceutical raw materials for treating one or more diseases by combined medication in clinic, and has higher clinical research and development values.

Drawings

FIG. 1 PXRD spectra of milrinone-chrysin co-crystals.

FIG. 2 PXRD spectra of milrinone-emodin co-crystals.

Fig. 3 PXRD pattern of milrinone-curcumin co-crystal.

FIG. 4 ORTEP diagram of milrinone-chrysin co-crystal.

FIG. 5 ORTEP diagram of milrinone-emodin co-crystal.

FIG. 6 ORTEP diagram of milrinone-curcumin co-crystal.

FIG. 7 shows a hydrogen bonding diagram of the milrinone-chrysin co-crystal.

FIG. 8 hydrogen bonding diagram of milrinone-emodin co-crystal.

Fig. 9 is a hydrogen bonding diagram of milrinone-curcumin co-crystal.

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

Milrinone (180 mg) and chrysin (217 mg) are added into a mixed solvent of methanol (15 mL) and acetone (15 mL), heated in a water bath at 45 ℃ and stirred until the mixture is completely dissolved, filtered, stood and crystallized for 24 hours at 10 ℃, filtered and dried for 12 hours at 50 ℃ to obtain the milrinone-chrysin eutectic. Yield: 90%, purity: 99.93%.

Example 2

Milrinone (200 mg) and chrysin (241 mg) are added into a mixed solvent of trifluoroethanol (20 mL) and acetone (20 mL), heated and stirred in a water bath at 45 ℃ until the mixture is completely dissolved, filtered, stood and crystallized for 36h at 10 ℃, filtered and dried for 12h at 50 ℃ to obtain the milrinone-chrysin eutectic. Yield: 89%, purity: 99.93%.

Example 3

Milrinone (210 mg) and chrysin (253 mg) are added into a mixed solvent of methanol (15 mL) and acetone (15 mL), heated in a water bath at 45 ℃ and stirred until the mixture is completely dissolved, filtered, stood and crystallized for 24 hours at 15 ℃, filtered and dried for 12 hours at 50 ℃ to obtain the milrinone-chrysin eutectic. Yield: 90%, purity: 99.89%.

Example 4

Milrinone (211 mg) and chrysin (304 mg) are added into a mixed solvent of ethanol (26 mL) and acetone (26 mL), heated in a water bath at 40 ℃ and stirred until the mixture is completely dissolved, filtered, stood and crystallized for 48 hours at 15 ℃, filtered and dried for 12 hours at 50 ℃ to obtain the milrinone-chrysin eutectic. Yield: 85%, purity: 99.91%.

Example 5

Milrinone (330 mg) and chrysin (636 mg) are added into a mixed solvent of trifluoroethanol (20 mL) and acetonitrile (10 mL), heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, and subjected to standing crystallization for 48h at 20 ℃, filtered and dried at 50 ℃ for 12h to obtain the milrinone-chrysin eutectic. Yield: 82%, purity: 99.87%.

Example 6

Milrinone (240 mg) and chrysin (289 mg) are added into a mixed solvent of ethanol (10 mL) and acetonitrile (10 mL), heated and stirred in a water bath at 45 ℃ until the mixture is completely dissolved, filtered, and subjected to standing crystallization for 48h at 30 ℃, filtered and dried at 50 ℃ for 12h to obtain the milrinone-chrysin eutectic. Yield: 79%, purity: 99.83%.

Example 7

Milrinone (30 mg) and emodin (38 mg) are added into a mixed solvent of methanol (10 mL) and acetone (10 mL), heated in a water bath at 50 ℃ and stirred until the mixture is completely dissolved, filtered, and subjected to standing crystallization at room temperature (20-25 ℃) for 24 hours, filtered and dried at 60 ℃ for 12 hours to obtain milrinone-emodin eutectic, and the yield is: 90%, purity: 99.92%.

Example 8

Milrinone (20 mg) and emodin (26 mg) are added into a mixed solvent of ethanol (10 mL) and acetone (10 mL), water bath heating and stirring are carried out at 50 ℃ until complete dissolution, filtration is carried out, standing and crystallization are carried out at room temperature (20-25 ℃) for 36h, filtration is carried out, drying is carried out at 60 ℃ for 12h, milrinone-emodin eutectic is obtained, and the yield is: 89%, purity: 99.92%.

Example 9

Milrinone (40 mg) and emodin (51 mg) are added into a mixed solvent of ethanol (10 mL) and acetone (10 mL), water bath heating and stirring are carried out at 50 ℃ until complete dissolution, filtration is carried out, standing and crystallization are carried out at room temperature (20-25 ℃) for 48h, filtration is carried out, drying is carried out at 60 ℃ for 12h, milrinone-emodin eutectic is obtained, and the yield is: 87%, purity: 99.90%.

Example 10

Milrinone (90 mg) and emodin (161 mg) are added into a mixed solvent of acetonitrile (20 mL) and trifluoroethanol (10 mL), heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, and subjected to standing crystallization at room temperature (20-25 ℃) for 72h, filtered and dried at 60 ℃ for 12h to obtain milrinone-emodin eutectic, and the yield is: 81%, purity: 99.88%.

Example 11

Milrinone (200 mg) and curcumin (349 mg) are dissolved in a mixed solvent of methanol (20 mL, AR analytical grade) and ethanol (20 mL, AR analytical grade), heated and stirred in a water bath at 60 ℃ until the milrinone and curcumin are completely dissolved, filtered, kept stand, volatilized and crystallized for 48 hours in an environment at 10-15 ℃, filtered, dried at 60 ℃ for 12 hours to obtain milrinone-curcumin eutectic, and the yield is: 87%, purity: 99.89%.

Example 12

Milrinone (210 mg) and curcumin (363 mg) are dissolved in a mixed solvent of methanol (15 mL, AR analytical grade) and ethanol (15 mL, AR analytical grade), heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, subjected to standing, volatilizing and crystallizing for 48 hours in an environment at 10-15 ℃, filtered, and dried at 60 ℃ for 12 hours to obtain milrinone-curcumin eutectic, and the yield is: 85%, purity: 99.88%.

Example 13

Milrinone (160 mg) and curcumin (279 mg) are dissolved in a mixed solvent of methanol (20 mL, AR analytical grade) and acetone (20 mL, AR analytical grade), heated and stirred in a water bath at 60 ℃ until the mixture is completely dissolved, filtered, and subjected to standing, volatilizing and crystallization for 48 hours in an environment at 10-15 ℃, filtered and dried at 60 ℃ for 12 hours to obtain milrinone-curcumin eutectic, and the yield is: 85%, purity: 99.89%.

Example 14

Milrinone (90 mg) and curcumin (126 mg) are dissolved in a mixed solvent of methanol (20 mL, AR analytical grade) and trifluoroethanol (10 mL, AR analytical grade), heated and stirred in a water bath at 70 ℃ until the mixture is completely dissolved, filtered, subjected to standing, volatilizing and crystallizing for 72 hours in an environment at 20-25 ℃, filtered and dried at 60 ℃ for 12 hours to obtain milrinone-curcumin eutectic, and the yield is: 81%, purity: 99.87%.

Stability test

The specific stability test method is carried out by referring to the guidance method of the fourth section of the Chinese pharmacopoeia on stability investigation.

High temperature test: the sample is placed in a clean container with proper opening, placed at 60 ℃ for 10 days, sampled on the 5 th day and the 10 th day, and the purity is detected by an HPLC method.

High humidity test: the sample is placed in a constant humidity closed container at 25 ℃ under the condition of 90% of relative humidity and 5% of relative humidity for 10 days, sampling is carried out on the 5 th day and the 10 th day, and the purity detection is carried out by an HPLC method.

Strong light irradiation test: the sample is placed in a light box or other suitable light device with fluorescent lamp, and placed under the condition of 4500lx and 500lx for 10 days, sampled on the 5 th day and the 10 th day, and purity is detected by HPLC.

TABLE 7 stability test results of Co-crystals

Solubility test

The method comprises the following steps: respectively weighing 10ml of medium (water, 0.01mol/LHCl 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; HPLC detection and calculation of the concentration of saturated solution according to external standard method.

Table 8 solubility of Co-crystals in different media (mg/mL)

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Claims

1. The pharmaceutical co-crystal of milrinone is characterized by comprising two pharmaceutical components of milrinone and ketone compounds, and specifically comprises a milrinone-chrysin co-crystal, a milrinone-emodin co-crystal or a milrinone-curcumin co-crystal.

2. The pharmaceutical co-crystal according to claim 1, wherein the milrinone-chrysin co-crystal has characteristic peaks in X-ray diffraction pattern expressed in 2Θ of 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 °, 34.5 ± 0.2 ° using Cu-ka radiation.

3. The pharmaceutical co-crystal according to claim 1, wherein said milrinone-chrysin co-crystal is irradiated with Cu-ka radiation and has a characteristic peak corresponding to the X-ray powder diffraction pattern shown in figure 1.

4. The pharmaceutical co-crystal according to claim 1, wherein said milrinone-emodin co-crystal has characteristic peaks in X-ray diffraction pattern expressed in 2Θ of at least 7.8 ± 0.2 °, 9.8 ± 0.2 °, 12.9 ± 0.2 °, 18.0 ± 0.2 °, 25.7 ± 0.2 ° using Cu-ka radiation.

5. The pharmaceutical co-crystal according to claim 1, wherein said milrinone-emodin co-crystal uses Cu-ka radiation and has characteristic peaks corresponding to the X-ray powder diffraction pattern shown in figure 2.

6. The pharmaceutical co-crystal according to claim 1, wherein the milrinone-curcumin co-crystal has characteristic peaks in X-ray diffraction pattern expressed in 2Θ of at least 5.2 ± 0.2 °, 7.8 ± 0.2 °, 15.8 ± 0.2 °, 19.4 ± 0.2 °, 26.8 ± 0.2 °, 27.9 ± 0.2 ° using Cu-ka radiation.

7. The pharmaceutical co-crystal according to claim 1, wherein the milrinone-curcumin co-crystal has a characteristic peak corresponding to the X-ray powder diffraction pattern shown in fig. 3 using Cu-ka radiation.

8. A method of preparing the pharmaceutical co-crystal of claim 1, comprising the steps of:

9. The method of claim 8, wherein the mixed solvent is selected from the group consisting of methanol, ethanol, acetonitrile, acetone, and trifluoroethanol.

10. The method of claim 8, wherein the ketone compound is chrysin, emodin or curcumin.