Icariin co-crystal

Abstract

The application provides a icariin-1,2-dipyridyl ethane co-crystal, and relates to the technical field of crystal drug molecules. The co-crystal uses Cu-K alpha radiation, and the X-ray diffraction spectrum expressed by 2theta has characteristic peaks at 5.00+ / -0.2 degrees, 10.09+ / -0.2 degrees, 10.28+ / -0.2 degrees, 12.41+ / -0.2 degrees, 17.14+ / -0.2 degrees, 23.01+ / -0.2 degrees, 24.43+ / -0.2 degrees, 26.88+ / -0.2 degrees, 27.53+ / -0.2 degrees and 27.60+ / -0.2 degrees. The crystallographic measurement parameters are as follows: triclinic crystal system, space group P-1, cell parameters alpha=104.080(2) degrees, beta=92.0920(10) degrees, gamma=90.1980(10) degrees, cell volume V=0.5937(5) nm3, Z=2, Dc=1.406 g / cm3, F(000)=288, mu=0.152 mm-1, Rint=0.038, R=0.038, wR=0.093, S=1.03, and the related preparation method and application are provided. The icariin-1,2-dipyridyl ethane co-crystal of the application has achieved great improvement in stability and bioavailability.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of crystal form drugs, in particular to the technical field of icariin organic drug co-crystals, and specifically to a drug co-crystal of icariin and 1,2-dipyridylethane, a preparation method and application thereof. BACKGROUND

[0002] Icaritin is also known as icariin, with a molecular formula of C 21 H 20 O6 and a relative molecular mass of 368.126, and a structure as shown below:

[0003]

[0004] Icaritin is a main pharmacodynamic monomer component in Epimedium, and belongs to flavonoids. The basic mother nucleus of flavonoids is a kind of polyphenol compounds of benzopyrone (C6-C3-C6), which exists in a variety of plants in the form of free or glycoside, and has multiple pharmacological activities such as anti-oxidation, anti-tumor, anti-virus, neuroprotection, free radical scavenging, anti-inflammation, cardiovascular protection, and α-glucosidase inhibition. For example, it is disclosed in Chinese Experimental Prescriptions, Vol. 18, No. 14, 2012 that “Effect of Icaritin on Estrogen-dependent Breast Cancer MCF-7 Cells”, and it is revealed through research that icaritin has the effect of inhibiting the proliferation of E2-induced human breast cancer MCF-7 cells in combination with estradiol. It is disclosed in Chinese Journal of Comparative Medicine, No. 6, 2011 that “Icaritin in vitro Anti-lymphoma Cell Proliferation Effect”, and it is revealed that icaritin has the effect of inhibiting tumor cell proliferation. Although icaritin has good clinical application prospects, its poor water solubility greatly limits its clinical application. Icaritin is slightly soluble in water, and its poor water solubility leads to poor oral absorption and low bioavailability. According to statistics, more than 40% of candidate drugs in the drug research and development process cannot enter clinical research due to poor water solubility, poor permeability, and low bioavailability, which makes some candidate drugs with potential clinical value unable to enter clinical research.

[0005] In recent years, it has been found that different drug crystal forms can change the physicochemical properties (density, hardness, solubility, stability, optical and electrical properties, etc.), dissolution rate, and biological effects, and therefore, the research on drug crystal forms has important value in medicine.

[0006] The reported icariin, icariin, and anhydrous icariin all have the problems of poor water solubility and low bioavailability. In view of the IV class of low solubility and low permeability icariin, the literature “Study on Polymorphism of Icariin and Crystallization Induced Asymmetric Transformation of Sanguinarine Methanol Compounds” (Nanchang University, Jia Lina) prepared a series of icariin hydrates and anhydrous crystal forms; the patent CN104844668A discloses the preparation of an anhydrous alpha crystal form of icariin, and the patents CN104829667A and CN104804053A further prepare icariin hydrate crystal forms H1 and H2 with slightly improved dissolution rate through crystal form research. The literature “Transformation History of Material Basis in the Processing of Epimedium” reports three crystal forms A, B and C of anhydrous icariin and crystal form D of icariin. The patent CN103936705A discloses four icariin solvates and one anhydrous crystal form B, and reports that the solvate crystal forms are unstable and easily transform into anhydrous crystal form B. The patents CN104230870A and CN104945364A disclose two icariin hydrate crystal forms and study the light stability of icariin hydrate crystal form and anhydrous crystal form B, and report that the anhydrous crystal form B is not stable under light, and the hydrate crystal form has improved light stability to a certain extent. The patent CN112294765A discloses an icariin amorphous form, which has improved solubility and bioavailability compared with icariin crystal form, but the amorphous form generally has poor stability, which is not conducive to its application in drugs.

[0007] The reported icariin crystal forms have unsatisfactory improvement in drug effect. For example, the anhydrous crystal form B has certain improvement in physical stability, but has poor chemical stability, especially light stability and bioavailability; the amorphous icariin has certain improvement in solubility and bioavailability, but has poor stability. In view of the above problems, further research and development of icariin crystal forms suitable for drugs is still a problem to be solved. SUMMARY

[0008] In view of the problems in the prior art, the present application provides an icariin-1,2-dipyridyl ethane co-crystal, which has exact crystallographic main parameters and atomic spatial positions; the present application further provides a preparation method of the icariin-1,2-dipyridyl ethane co-crystal.

[0009] The specific technical solutions of the present application are as follows:

[0010] In a first aspect, the present application provides a icariin-1,2-dipyridylethane co-crystal, wherein the molar ratio of icariin to 1,2-dipyridylethane in the co-crystal is 2:1, one molecule of icariin and two molecules of 1,2-dipyridylethane constitute a basic unit of the crystal form, and the specific structure is shown as formula I:

[0011]

[0012] Preferably, the icariin-1,2-dipyridylethane co-crystal has characteristic peaks at 5.00±0.2°, 10.09±0.2°, 10.28±0.2°, 27.53±0.2°, 27.60±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0013] Preferably, the icariin-1,2-dipyridylethane co-crystal has characteristic peaks at 5.00±0.2°, 10.09±0.2°, 10.28±0.2°, 12.41±0.2°, 17.14±0.2°, 23.01±0.2°, 24.43±0.2°, 26.88±0.2°, 27.53±0.2°, 27.60±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0014] Preferably, the icariin-1,2-dipyridylethane co-crystal has characteristic peaks in the X-ray powder diffraction spectrum expressed as shown in Figure 1 Preferably, the icariin-1,2-dipyridylethane co-crystal has characteristic peaks in the X-ray powder diffraction spectrum expressed as shown in

[0015] Preferably, the icariin-1,2-dipyridylethane co-crystal has the following crystallographic parameters: triclinic crystal system, space group P-1; cell parameters are as follows: α=104.080(2)°, β=92.0920(10)°, γ=90.1980(10)°, cell volume V= 1.030(2) nm3, Z=2, Dc=1.352 g / cm3, F(000)= 448, μ=0.141 mm-1, Rint=0.035, R=0.038, ωR=0.082.

[0016] In a second aspect, the present application provides a preparation method of icariin-1,2-dipyridylethane co-crystal, comprising the following steps:

[0017] The icariin and 1,2-dipyridylethane are placed in an organic solvent, heated and stirred, cooled and crystallized, filtered, washed, and dried to obtain the icariin-1,2-dipyridylethane co-crystal.

[0018] Preferably, the molar ratio of the icariin to 1,2-dipyridylethane is 1:0.6-1.2, preferably 1:1.

[0019] Preferably, the organic solvent is one or two of acetonitrile, acetone, tetrahydrofuran, methanol, ethanol, isopropanol; further preferably one or a combination of acetonitrile, acetone; if the organic solvent is a mixture of two solvents, the volume ratio of the less polar solvent to the more polar solvent is preferably 1:1.5-2.

[0020] Preferably, the mass-volume ratio of the icariin to the organic solvent is 5-7:1, where the mass is in mg and the volume is in mL.

[0021] Preferably, the heating temperature is 50-80℃; the heating and stirring time is 3-8 hours.

[0022] Preferably, the cooling and crystallization temperature is 0-15℃; preferably 5-10℃.

[0023] Preferably, the washing solvent is one or two of ethanol, acetone, acetonitrile.

[0024] In a third aspect, the present application provides a pharmaceutical composition comprising the icariin-1,2-dipyridyl ethane co-crystal of the present application and other pharmaceutically acceptable components.

[0025] Preferably, the other pharmaceutically acceptable components include other active ingredients, excipients, fillers, etc. that can be used in combination.

[0026] Preferably, the pharmaceutical composition of the present application can be prepared using the following method: using standard and conventional techniques, the compound of the present application is combined with pharmaceutically acceptable solid or liquid carriers, and optionally combined with pharmaceutically acceptable adjuvants and excipients to prepare a dosage form.

[0027] Preferably, the pharmaceutical composition is a spray, tablet, capsule, powder injection, liquid injection, etc.

[0028] In a fourth aspect, the present application provides the use of icariin-1,2-dipyridyl ethane co-crystal as an active ingredient to prepare an anti-tumor drug and as an active ingredient to prepare an α-glucosidase inhibitor drug.

[0029] Advantages of the present application:

[0030] The icariin-1,2-dipyridyl ethane co-crystal prepared by the present application has greatly improved stability and bioavailability. The preparation method of the icariin-1,2-dipyridyl ethane co-crystal is simple and suitable for industrial production; the obtained co-crystal has regular crystal form and uniform particle size, has clear crystallographic main parameters and exact atomic spatial position, and is suitable for large-scale popularization and application. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 X-ray powder diffraction pattern of icariin-1,2-dipyridylethane co-crystal.

[0032] Figure 2 ORTEP diagram of icariin-1,2-dipyridylethane co-crystal.

[0033] Figure 3 Stacking diagram of icariin-1,2-dipyridylethane co-crystal.

[0034] Figure 4 DSC-TGA diagram of icariin-1,2-dipyridylethane co-crystal. DETAILED DESCRIPTION

[0035] The present application will be further described by the following examples. It should be understood that the examples of the present application are only used to illustrate the present application, but not to limit the present application, so, simple improvement of the present application under the method of the present application is within the scope of the present application.

[0036] Materials used in the experiment: icariin can be purchased, or prepared according to the method disclosed in the prior art. Icariin crystal form required in the comparative experiment can be prepared according to the prior art; the materials used in other experiments not marked with source and specification are commercially available analytical or chemical pure.

[0037] Example 1

[0038] About 3.7 g of icariin and 1.84 g of 1,2-dipyridylethane were placed in 700 ml of isopropanol, heated to 60°C, stirred for 7 hours, then slowly cooled to 5-10°C, temperature controlled crystallization, after the completion of crystallization, filtered, the filter cake was washed with ethanol, and dried to obtain icariin-1,2-dipyridylethane co-crystal, with a yield of 94.1% and a purity of 99.94%.

[0039] Example 2

[0040] About 3.7 g of icariin and 1.12 g of 1,2-dipyridylethane were placed in 550 ml of acetonitrile, heated to 75°C, stirred for 3 hours, then slowly cooled to 0-5°C, temperature controlled crystallization, after the completion of crystallization, filtered, the filter cake was washed with acetonitrile, and dried to obtain icariin-1,2-dipyridylethane co-crystal, with a yield of 92.5% and a purity of 99.88%.

[0041] Example 3

[0042] About 3.7g of icariin, 2.21g of 1,2-dipyridylethane was placed in 750ml of ethanol, heated to 70℃, stirred for 5 hours, slowly cooled to 10-15℃, temperature control crystallization, after crystallization, filtration, filter cake was washed with acetonitrile, dried, icariin-1,2-dipyridylethane eutectic was obtained, the yield was 91.1%, and the purity was 99.90%.

[0043] Example 4

[0044] About 3.7g of icariin, 1.65g of 1,2-dipyridylethane was placed in 600ml of acetone, heated to 50℃, stirred for 5 hours, slowly cooled to 0-5℃, temperature control crystallization, after crystallization, filtration, filter cake was washed with acetone, dried, icariin-1,2-dipyridylethane eutectic was obtained, the yield was 90.7%, and the purity was 99.85%.

[0045] Example 5

[0046] About 3.7g of icariin, 1.84g of 1,2-dipyridylethane was placed in 750ml of methanol, heated to 60℃, stirred for 8 hours, slowly cooled to 5-10℃, temperature control crystallization, after crystallization, filtration, filter cake was washed with ethanol, dried, icariin-1,2-dipyridylethane eutectic was obtained, the yield was 91.6%, and the purity was 99.89%.

[0047] Example 6

[0048] About 3.7g of icariin, 1.15g of 1,2-dipyridylethane was placed in 700ml of tetrahydrofuran / isopropanol (V 四氢呋喃 :V 异丙醇 =1:2), heated to 60℃, stirred for 4 hours, slowly cooled to 0-5℃, temperature control crystallization, after crystallization, filtration, filter cake was washed with ethanol, dried, icariin-1,2-dipyridylethane eutectic was obtained, the yield was 90.3%, and the purity was 99.83%.

[0049] Characterization of icariin-1,2-dipyridylethane eutectic

[0050] The X-ray powder diffraction tester and test conditions involved in the present application are as follows: X-ray powder diffractometer: PANalytical EMPYREA; Cu-Kα; sample table: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage: 45kv, current: 40mA; divergence slit: 1 / 4; anti-scattering slit: 1; soller slit: 0.04rad; step length: 0.5s; scanning range: 3-50°. The corresponding characteristic peaks in the X-ray diffraction pattern (Cu-Kα) are shown in the attached Figure 1 and Table 1.

[0051] Table 1. Icaritin-1,2-dipyridylethane co-crystal PXRD peaks

[0052]

[0053]

[0054] The icaritin-1,2-dipyridylethane co-crystal provided by the present application is subjected to X-ray single crystal diffraction test analysis. The X-ray single crystal diffraction instrument and test conditions involved in the present application are as follows: XtaLAB Synergy X-ray single crystal diffractometer of Rigaku, test temperature 293(2) K, CuKa radiation, data collection by ω scanning mode and Lp correction. The structure is analyzed by direct method, all non-hydrogen atoms are found by difference Fourier method, and hydrogen atoms on all carbon and nitrogen are obtained by theoretical hydrogenation. The structure is refined by least squares method.

[0055] The crystallographic parameters of the icaritin-1,2-dipyridylethane co-crystal prepared by the present application are as follows: triclinic crystal system, space group P-1; cell parameters are as follows: α = 104.080(2) °, β = 92.0920(10) °, γ = 90.1980(10) °. The ORTEP of the icaritin-1,2-dipyridylethane co-crystal of the present application Figure 2 indicates that two molecules of icaritin and one molecule of 1,2-dipyridylethane are combined to form a co-crystal. The packing diagram of the icaritin-1,2-dipyridylethane co-crystal of the present application is shown in Figure 3 .

[0056] Table 2. Main crystallographic data of icaritin-1,2-dipyridylethane co-crystal

[0057]

[0058]

[0059] The TGA / DSC thermal analysis tester and test conditions in the present application are as follows: TGA / DSC thermal analyzer: METTLER TOLEDO TGA / DSC3+; dynamic temperature section: 30-300 °C; heating rate: 10 °C / min; program section gas: N2; gas flow: 50 mL / min; crucible: aluminum crucible 40 μl. The differential scanning calorimetry curve and thermal gravimetric analysis (DSC / TGA) graph are shown in Figure 4 .

[0060] The samples of Examples 1-6 all meet the X-ray powder diffraction pattern, crystallographic parameters, differential scanning calorimetry curve and thermal gravimetric analysis (DSC / TGA) graph.

[0061] Comparative Example 1

[0062] Take 6.5g of icariin and dissolve it in 200ml of acetone. Filter the solution and add 100ml of distilled water to the filtrate. Dissolve the solution at 75℃ and then let it stand at 20℃ for 24 hours to crystallize. Filter the solution and dry the filter cake at 80℃ until the weight is constant. Icariin crystal form B is obtained with a yield of 90.3% and a purity of 99.86%.

[0063] Comparative Example 2

[0064] Take about 1g of icariin and add a mixed solvent of chloroform / methanol (V 氯仿 :V 甲醇 =1:1) to it until it is completely dissolved. Then let it stand in an environment with a temperature of 30℃ and a relative humidity of 90% to volatilize and crystallize. After the crystallization is complete, filter the solution to obtain icariin crystal form D with a yield of 82.4% and a purity of 99.83%.

[0065] Comparative Example 3

[0066] Take 10g of icariin and 700ml of acetone and put them in a 5.0L flask. Dissolve the solution in a warm water bath and then quickly add 4L of purified water while stirring. Continue stirring for 10 minutes to crystallize. Filter the solution after it cools to room temperature. Dry the filter cake in a 25℃ air-drying oven for 48 hours to obtain icariin monohydrate with a yield of 92.8% and a purity of 99.88%.

[0067] Comparative Example 4

[0068] Take 10g of icariin and 700ml of acetone and put them in a 1L beaker. Dissolve the solution in a warm water bath and then quickly add the icariin acetone solution to a flask containing 4L of purified water at room temperature while stirring vigorously. Continue stirring for 10 minutes to crystallize. Filter the solution after it cools to room temperature. Dry the filter cake in a 25℃ air-drying oven for 48 hours to obtain icariin hemihydrate with a yield of 90% and a purity of 99.85%.

[0069] Comparative Example 5

[0070] Take 2.4g of icariin and put it in 120ml of sodium hydroxide aqueous solution (0.2mol / L) and stir to dissolve to obtain an icariin base solution. Take 3.84g of polymer Soluplus and put it in 480ml of hydrochloric acid aqueous solution (0.05mol / L) and stir to dissolve to obtain a polymer Soluplus hydrochloric acid aqueous solution. Use a peristaltic pump to add the icariin base solution to the hydrochloric acid aqueous solution and stir at a speed of 1000r / min for 20 minutes. Filter and collect the precipitate and then pre-freeze it at -40℃ and freeze-dry it for 24 hours to obtain icariin amorphous particles with a yield of 73.2% and a purity of 99.80%.

[0071] Verification Example:

[0072] The icariin crystal form prepared above is investigated in terms of stability, bioavailability, etc., and the specific implementation content is as follows:

[0073] Stability test

[0074] 1. Light test: According to the “Guidelines for Stability Test of Raw Materials and Preparations in Chinese Pharmacopoeia 2020 Volume IV-9001”, an appropriate amount of icariin crystal form of Example 1 and Comparative Examples 1-5 was respectively taken and placed in an open container (thickness not more than 3 mm), and then placed in a light box for testing under the condition of illumination of 4500 lx ± 500 lx. The purity was detected by sampling at 0 day, 5 days, 10 days and 30 days, respectively.

[0075] 2. High temperature test: According to the “Guidelines for Stability Test of Raw Materials and Preparations in Chinese Pharmacopoeia 2020 Volume IV-9001”, an appropriate amount of icariin crystal form of Example 1 and Comparative Examples 1-5 was respectively taken and placed in a 60°C closed thermostat. The purity was detected by sampling at 0 day, 5 days, 10 days and 30 days, respectively.

[0076] Table 3 Results of light stability test of icariin crystal form

[0077]

[0078]

[0079] The results of light and high temperature stability test show that the stability of icariin amorphous form is poor, and it is significantly degraded after light and high temperature investigation. The light stability of icariin crystal form B and crystal form D is poor, and it is significantly degraded after light stability investigation. The icariin-1,2-dipyridylethane co-crystal prepared by the present application is stable under light and high temperature conditions. It is found that Examples 1-6 have similar stability test results.

[0080] Relative humidity (RH) and high temperature stability comparison

[0081] The icariin crystal forms prepared from Example 1 and Comparative Examples 1-5 were respectively taken and stored under the conditions of 40°C, 75% RH and 80°C for 1 week, and then subjected to PXRD detection to test the relative humidity and high temperature stability of each crystal form. The results are shown in Table 4.

[0082] Table 4 Results of relative humidity stability of icariin crystal form

[0083]

[0084] Note: √ indicates stability under this storage condition, and the PXRD spectrum is unchanged; ╳ indicates instability under this storage condition.

[0085] The relative humidity (RH) stability comparison results show that the icariin-1,2-dipyridyl ethane co-crystal prepared in the application has good stability under high humidity and high temperature environment, and the crystal form does not change.

[0086] Beagle dog pharmacokinetic test

[0087] Healthy male beagle dogs (weight 6-8 kg, age 1-2 years) were placed in the same environment and allowed to eat and drink freely. Before administration, the dogs were fasted for 24 hours, and then orally administered with the icariin-1,2-dipyridyl ethane co-crystal of Example 1, the icariin crystal of Comparative Examples 1-5, and the control product (icariin nanocrystal from Shandong New Era Pharmaceutical Co., Ltd.), at a dose of 10 mg / kg (calculated as icariin). Blood samples were collected from the peripheral vein at 10 min, 30 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6 h, 8 h, 10 h, 12 h, and 24 h after administration. After blood collection, the samples were centrifuged for 10 min (3000 r / min) to separate the plasma, which was stored at -20°C for testing.

[0088] 50 μL of the blood plasma sample was added with 150 μL of 0.05 mol / L ammonium dihydrogen phosphate aqueous solution, vortexed for 1 min, and then 30 μL of the sample was added with 125 μL of 200 U β-glucuronidase, mixed, incubated at 37°C for 1 hour, added with 50 μL of the internal standard wogonoside methanol solution, 1.2 mL of methyl tert-butyl ether-n-hexane (2:1), vortexed for 2 min, centrifuged at 4°C and 12000 r / min for 5 min, and 960 μL of the upper organic phase was taken into a glass test tube, dried by nitrogen blowing in a 40°C water bath, added with 100 μL of 70% methanol aqueous solution, vortexed for redissolution, and after redissolution, the sample was centrifuged at 4°C and 12000 r / min for 10 min, and 50 μL of the supernatant was subjected to LC-MS / MS quantitative analysis.

[0089] Table 5 Pharmacokinetic parameters of beagle dogs after oral administration (n=3)

[0090]

[0091] Mouse glucose tolerance test

[0092] Take 80 mice, and randomly divide into 8 groups, 10 mice in each group. Respectively take the icariin crystal form of example 1, comparative example 1~5 according to the dose of 50mg / kg, and give them by gavage. Set up negative control group, positive control group, the negative control group is given normal saline, and the positive control group is given by gavage with acarbose 50mg / kg. Continuous administration for 7 days, 8 hours before the last administration, and give them by gavage with starch 5g / kg after 1 hour of administration, and take blood from the venous sinus of the eye at 0 hour, 0.5 hour, 1 hour, 2 hours, 3 hours after the starch is given, and determine the blood glucose value by using glucose oxidase test paper, unit mmol / L, and the results are shown in table 6:

[0093] Table 6: Results of icariin crystal form in mice glucose tolerance test

[0094]

[0095]

[0096] In addition, in vitro cell tests find that the icariin-1,2-dipyridyl ethane co-crystal of the application has inhibitory effect on a series of tumor cells, such as the inhibition of hepatocarcinoma Huh-7 cells (IC50=4.3μM), the inhibition of breast cancer MCF-7 cells (IC50=2.8μM), and the inhibition of acute myeloid leukemia MV-4-11 cells (IC50=1.6μM), all of which show good inhibitory effect.

[0097] The icariin-1,2-dipyridyl ethane co-crystal prepared by the application has achieved beneficial effects in stability, bioavailability, etc., and the comprehensive performance has made a more significant progress compared with the icariin crystal form reported in the prior art.

Claims

1. A icariin-1,2-dipyridyl ethane co-crystal, characterized in that, The co-crystal is composed of an active pharmaceutical ingredient icariin and a co-crystal ligand 1,2-dipyridyl ethane; the molar ratio of icariin to 1,2-dipyridyl ethane in the co-crystal is 2:1; the co-crystal has an X-ray powder diffraction pattern as shown in Figure 1; and the structure is as shown below: 。 2. The icariin-1,2-dipyridyl ethane cocrystal of claim 1, wherein, The crystallographic parameters of the co-crystal are: triclinic system, space group P-1; cell parameters are: a = 7.83750(10) A, b = 8.72060(10) A, c = 17.8286(3) A, a = 104.080(2) °, b = 92.0920(10) °, g = 90.1980(10) °, cell volume V = 1181.05(3) A 3 .

3. A process for the preparation of a icariin-1,2-dipyridyl ethane co-crystal as claimed in any one of claims 1 to 2, characterized in that, The method comprises the following steps: placing icariin and 1,2-dipyridyl ethane in an organic solvent, heating and stirring, cooling and crystallizing, filtering, washing, and drying to obtain icariin-1,2-dipyridyl ethane co-crystal, wherein the organic solvent is one or two of acetonitrile, acetone, tetrahydrofuran, methanol, ethanol, and isopropanol.

4. The method of claim 3, wherein the icariin-1,2-dipyridyl ethane cocrystal is prepared by, The molar ratio of icariin to 1,2-dipyridyl ethane is 1:0.6-1.2; and the mass-volume ratio of icariin to the organic solvent is 5-7:1, wherein the mass is in mg and the volume is in mL.

5. Use of icariin-1,2-dipyridyl ethane co-crystal according to any one of claims 1-2 in the preparation of a medicament for resisting liver cancer, breast cancer, and acute myeloid leukemia.

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