Icaritin and 1,2-dipyridyl ethylene co-crystal

Abstract

The application provides a icariin-1,2-dipyridyl ethylene 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 in 2theta has characteristic peaks at 7.54+ / -0.2 degrees, 8.96+ / -0.2 degrees, 9.38+ / -0.2 degrees, 9.67+ / -0.2 degrees, 12.51+ / -0.2 degrees, 14.36+ / -0.2 degrees, 15.08+ / -0.2 degrees, 15.32+ / -0.2 degrees, 17.55+ / -0.2 degrees, 25.08+ / -0.2 degrees, 25.41+ / -0.2 degrees and 25.95+ / -0.2 degrees. The crystallographic measurement parameters are as follows: monoclinic crystal system, space group C2 / c; cell parameters: alpha=90 degrees, beta=95.5870(10) degrees, gamma=90 degrees, cell volume V=1, 1, 1, and the related preparation method and application are provided. The icariin-1,2-dipyridyl ethylene co-crystal of the application has achieved great improvement in stability, bioavailability and the like.

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-dipyridyl ethylene, a preparation method and application thereof. BACKGROUND

[0002] Icaritin is also known as icariin, with a molecular formula of C 21 H 20 O6, 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 dehydrated 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 "Research on Polymorphs of Icariin and Crystallization Induced Asymmetric Transformation of Sanguinarine Methanolate" (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 dehydrated icariin and icariin crystal form D. 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.

[0007] The reported icariin, icariin, and dehydrated 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 "Research on Polymorphs of Icariin and Crystallization Induced Asymmetric Transformation of Sanguinarine Methanolate" (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 dehydrated icariin and icariin crystal form D. 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. SUMMARY

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

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

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

[0011]

[0012] Preferably, the icariin-1,2-dipyridyl ethylene co-crystal has an X-ray diffraction pattern, expressed in terms of 2-theta, using Cu-Kalpha radiation, with characteristic peaks at 7.54±0.2°, 8.96±0.2°, 9.67±0.2°, 17.55±0.2°, 25.08±0.2°, 25.41±0.2°.

[0013] Preferably, the icariin-1,2-dipyridyl ethylene co-crystal has an X-ray diffraction pattern, expressed in terms of 2-theta, using Cu-Kalpha radiation, with characteristic peaks at 7.54±0.2°, 8.96±0.2°, 9.38±0.2°, 9.67±0.2°, 12.51±0.2°, 14.36±0.2°, 15.08±0.2°, 15.32±0.2°, 17.55±0.2°, 25.08±0.2°, 25.41±0.2°, 25.95±0.2°.

[0014] Preferably, the icariin-1,2-dipyridyl ethylene co-crystal has an X-ray powder diffraction pattern with characteristic peaks corresponding to the X-ray powder diffraction pattern as shown in Figure 1 Preferably, the icariin-1,2-dipyridyl ethylene co-crystal has an X-ray powder diffraction pattern with characteristic peaks corresponding to the X-ray powder diffraction pattern as shown in

[0015] Preferably, the icariin-1,2-dipyridyl ethylene co-crystal has the following crystallographic parameters: monoclinic crystal system, space group C2 / c; cell parameters are: α = 90°, β = 95.5870(10)°, γ = 90°, cell volume V = 1 1 1 1. 1 (2) A3.

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

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

[0018] Preferably, the molar ratio of icariin to 1,2-dipyridyl ethylene is 1:0.5-1, preferably 1:0.8.

[0019] Preferably, the organic solvent is one or two of acetonitrile, acetone, tetrahydrofuran, methanol, ethanol, isopropanol; further preferably, it is one or a combination of acetonitrile and 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, wherein the mass is in mg and the volume is in mL.

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

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

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

[0024] In a third aspect, the present application provides a pharmaceutical composition comprising the icariin-1,2-dipyridyl ethylene 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 by using standard and conventional techniques to combine the compound of the present application with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable adjuvants and excipients to prepare a dosage form.

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

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

[0029] Advantages of the present application:

[0030] The icariin-1,2-dipyridyl ethylene co-crystal prepared by the present application has great improvement in stability and bioavailability. The preparation method of the icariin-1,2-dipyridyl ethylene 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-dipyridyl ethylene co-crystal.

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

[0033] Figure 3 : Packing diagram of icariin-1,2-dipyridylethylene eutectic.

[0034] Figure 4 DSC-TGA image of icariin-1,2-dipyridylethylene eutectic. Detailed Implementation

[0035] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the invention and not for limiting the invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention are all within the scope of protection of the present invention.

[0036] Materials used in the experiment: Icariin can be purchased or prepared according to existing methods. The icariin crystal form required for the comparative experiment can be prepared according to existing techniques; other materials used in this experiment without specified source and specifications are all commercially available analytical grade or chemically pure.

[0037] Example 1

[0038] Approximately 3.7 g of icariin and 1.46 g of 1,2-dipyridylethylene were placed in 600 ml of acetone, heated to 50 °C and stirred for 6 hours. The mixture was then slowly cooled to 5–10 °C to allow crystallization. After crystallization, the mixture was filtered, and the filter cake was washed with acetone and dried to obtain icariin-1,2-dipyridylethylene eutectic with a yield of 93.2% and a purity of 99.92%.

[0039] Example 2

[0040] Approximately 3.7 g of icariin and 0.9 g of 1,2-dipyridylethylene were placed in 550 ml of acetone / methanol (V 丙酮 :V 甲醇 In a mixed solvent of 1:1.5, the mixture was heated to 60°C and stirred for 5 hours. Then, the temperature was slowly lowered to 0-5°C to allow crystallization. After crystallization, the mixture was filtered, the filter cake was washed with acetone and dried to obtain icariin-1,2-dipyridylethylene eutectic with a yield of 90.5% and a purity of 99.87%.

[0041] Example 3

[0042] Approximately 3.7g of icariin and 1.82g of 1,2-dipyridylethylene were placed in 750ml of isopropanol / acetonitrile (V 异丙醇 V 乙腈 In a mixed solvent of 1:1.8, the mixture was heated to 75°C and stirred for 3 hours. Then, the temperature was slowly lowered to 10-15°C to allow crystallization. After crystallization, the mixture was filtered, and the filter cake was washed with acetonitrile and dried to obtain icariin-1,2-dipyridylethylene eutectic with a yield of 91.4% and a purity of 99.84%.

[0043] Example 4

[0044] About 3.7 g of icariin, 1.52 g of 1,2-dipyridyl ethylene were placed in 700 ml of ethanol / acetonitrile (V 乙醇 :V 乙腈 = 1:2), heated to 80°C, stirred for 5 hours, slowly cooled to 0-5°C, temperature controlled crystallization, after crystallization, filtered, the filter cake was washed with ethanol, dried, to obtain icariin-1,2-dipyridyl ethylene co-crystal, yield 90.8%, purity 99.85%.

[0045] Example 5

[0046] About 3.7 g of icariin, 1.25 g of 1,2-dipyridyl ethylene were placed in 750 ml of tetrahydrofuran, heated to 60°C, stirred for 8 hours, slowly cooled to 5-10°C, temperature controlled crystallization, after crystallization, filtered, the filter cake was washed with ethanol, dried, to obtain icariin-1,2-dipyridyl ethylene co-crystal, yield 91.6%, purity 99.91%.

[0047] Example 6

[0048] About 3.7 g of icariin, 1.15 g of 1,2-dipyridyl ethylene were placed in 650 ml of acetonitrile, heated to 70°C, stirred for 5 hours, slowly cooled to 5-10°C, temperature controlled crystallization, after crystallization, filtered, the filter cake was washed with acetonitrile, dried, to obtain icariin-1,2-dipyridyl ethylene co-crystal, yield 90.7%, purity 99.82%.

[0049] Characterization of icariin-1,2-dipyridyl ethylene co-crystal

[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-Ka; sample table: flat plate; incident light path: BBHD; diffracted light path: PLXCEL; voltage: 45kv, current: 40mA; divergence slit: 1 / 4; anti-scattering slit: 1; soller slit: 0.04 rad; step length: 0.5s; scanning range: 3-50°. The corresponding characteristic peaks in the X-ray diffraction pattern (Cu-Ka) are shown in the attached Figure 1 and Table 1.

[0051] Table 1 PXRD peaks of icariin-1,2-dipyridyl ethylene co-crystal

[0052]

[0053]

[0054] The icariin-1,2-dipyridyl ethylene 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 diffraction instrument 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, all hydrogen atoms on carbon and nitrogen are obtained by theoretical hydrogenation, and the structure is refined by least square method.

[0055] The crystallographic parameters of the icariin-1,2-dipyridyl ethylene co-crystal prepared in the present application are as follows: monoclinic crystal system, space group C2 / c, cell parameters are as follows: α = 90°, β = 95.5870(10)°, γ = 90°, cell volume V = 1 1 1 1. 1 (2) A3 The ORTEP of the icariin-1,2-dipyridyl ethylene co-crystal of the present application is as shown in the following figure: Figure 2 It is shown that two molecules of icariin and one molecule of 1,2-dipyridyl ethylene are combined to form a co-crystal. The packing diagram of the icariin-1,2-dipyridyl ethylene co-crystal of the present application is as shown in the following figure: Figure 3

[0056] Table 2 Main crystallographic data of icariin-1,2-dipyridyl ethylene co-crystal

[0057]

[0058] 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℃; heating rate: 10℃ / 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) diagram are as shown in the following figure: Figure 4

[0059] 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) diagram.

[0060] Comparative example 1

[0061] 6.5 g of icariin is added into 200 ml of acetone to be dissolved, filtered, 100 ml of distilled water is added into the filtrate, dissolved under reflux at 75℃, placed at 20℃ for 24 hours for crystallization, filtered, and continuously dried at 80℃ until the weight is not changed, to obtain icariin crystal form B, with a yield of 90.3% and a purity of 99.86%. ​​

[0062] Comparative Example 2

[0063] Take about 1g of icariin, add a mixed solvent of chloroform / methanol (V 氯仿 :V 甲醇 =1:1) to completely dissolve, and then place in an environment with a temperature of 30℃ and a relative humidity of 90% to volatilize and crystallize. After crystallization is complete, filter to obtain icariin crystal form D with a yield of 82.4% and a purity of 99.83%.

[0064] Comparative Example 3

[0065] Take 10g of icariin and 700ml of acetone, and place in a 5.0L flask. Stir and dissolve in a warm water bath, then quickly add 4L of purified water while stirring. Continue stirring for 10min, then crystallize. After the solution is cooled to room temperature, filter, and then place the filter cake in a 25℃ air-drying oven to dry for 48 hours to obtain icariin monohydrate with a yield of 92.8% and a purity of 99.88%.

[0066] Comparative Example 4

[0067] Take 10g of icariin and 700ml of acetone, and place in a 1L beaker. Stir and dissolve in a warm water bath, then quickly add the icariin acetone solution to a flask containing 4L of purified water at room temperature, and stir vigorously for 10min. Crystallize, then filter after the solution is cooled to room temperature. Place the filter cake in a 25℃ air-drying oven to dry for 48 hours to obtain icariin hemihydrate with a yield of 90% and a purity of 99.85%.

[0068] Comparative Example 5

[0069] Take 2.4g of icariin and place 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 place 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 control the stirring speed at 1000r / min for 20min. Filter, collect the precipitate, and then pre-freeze at -40℃ and freeze dry for 24 hours to obtain icariin amorphous particles with a yield of 73.2% and a purity of 99.80%.

[0070] Verification Example

[0071] The icariin crystal form prepared above is investigated in terms of stability, bioavailability, etc., and the specific implementation content is as follows:

[0072] Stability Test

[0073] 1. Light test: According to the “Guidelines for Stability Test of Raw Materials and Preparations in Chinese Pharmacopoeia 2020 Volume 4-9001”, an appropriate amount of icariin crystal form of Example 1 and Comparative Examples 1-5 was 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, and the purity was detected on the 0th day, 5th day, 10th day and 30th day.

[0074] 2. High temperature test: According to the “Guidelines for Stability Test of Raw Materials and Preparations in Chinese Pharmacopoeia 2020 Volume 4-9001”, an appropriate amount of icariin crystal form of Example 1 and Comparative Examples 1-5 was taken and placed in a 60°C closed thermostat, and the purity was detected on the 0th day, 5th day, 10th day and 30th day.

[0075] Table 3 Results of light stability test of icariin crystal form

[0076]

[0077] The results of light and high temperature stability tests 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-dipyridyl ethylene co-crystal prepared by the present application has good stability under light and high temperature conditions. It is found that Examples 1-6 have similar stability test results.

[0078] Comparison of relative humidity (RH) and high temperature stability

[0079] The icariin crystal forms prepared from Example 1 and Comparative Examples 1-5 were respectively taken, and the PXRD detection was carried out after being stored at 40°C, 75% RH and 80°C for 1 week, to test the relative humidity and high temperature stability of each crystal form, and the results are shown in Table 4.

[0080] Table 4 Results of relative humidity stability of icariin crystal form

[0081]

[0082] Note: √ indicates stability under this storage condition, and the PXRD pattern is unchanged; ╳ indicates instability under this storage condition.

[0083] The comparison results of relative humidity (RH) stability show that the icariin-1,2-dipyridyl ethylene co-crystal prepared by the present application has good stability under high humidity and high temperature environment, and the crystal form does not change.

[0084] Beagle dog pharmacokinetic test

[0085] 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. The dogs were fasted for 24 hours before administration. The icariin-1,2-dipyridyl ethylene co-crystal of Example 1, the icariin crystal forms of Comparative Examples 1-5, and the control product (icariin nanocrystal from Shandong New Era Pharmaceutical Co., Ltd.) were orally administered 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 before and after administration. The blood samples were centrifuged at 3000 r / min for 10 min after collection, and the plasma was separated and stored at -20°C for testing.

[0086] Fifty μL of the plasma sample was taken, 150 μL of 0.05 mol / L ammonium dihydrogen phosphate aqueous solution was added, and vortexed for 1 min. Thirty μL of the sample was added to 125 μL of 200 U β-glucuronidase, mixed, and incubated at 37°C for 1 h. Fifty μL of the internal standard wogonoside methanol solution was added, 1.2 mL of methyl tert-butyl ether-n-hexane (2:1) was added, vortexed for 2 min, centrifuged at 12000 r / min for 5 min at 4°C, and 960 μL of the upper organic phase was taken into a glass test tube. Nitrogen was blown to dryness in a 40°C water bath, 100 μL of 70% methanol aqueous solution was added, vortexed to dissolve, and vortexed to dissolve. After vortexing, the sample was centrifuged at 12000 r / min for 10 min at 4°C, and 50 μL of the supernatant was subjected to LC-MS / MS quantitative analysis.

[0087] Table 5 Pharmacokinetic parameters of beagle dogs after oral administration

[0088]

[0089] Mouse glucose tolerance test

[0090] Eighty mice were randomly divided into 8 groups, 10 mice in each group. The icariin crystal forms of Example 1 and Comparative Examples 1-5 were administered at a dose of 50 mg / kg. A negative control group and a positive control group were set up. The negative control group was administered with normal saline, and the positive control group was administered with Acarbose at a dose of 50 mg / kg. The administration was continued for 7 days. The mice were fasted for 8 hours before the last administration, and 5 g / kg of starch was administered 1 hour after the administration. Blood samples were collected from the orbital venous sinus at 0 hour, 0.5 hour, 1 hour, 2 hours, 3 hours after the starch administration, and the blood glucose value was determined using glucose oxidase test paper, with the unit being mmol / L. The results are shown in Table 6.

[0091] Table 6 Results of the mouse glucose tolerance test of the icariin crystal form

[0092]

[0093] In addition, in vitro cell tests found that the icariin-1,2-dipyridyl ethylene co-crystal of the present application has inhibitory effect on a series of tumor cells, such as liver cancer Huh-7 cells (IC50=4.8 μM), breast cancer MCF-7 cells (IC50=1.4 μM), and acute myeloid leukemia MV-4-11 cells (IC50=5.5 μM), all of which show good inhibitory effect.

[0094] The icariin-1,2-dipyridyl ethylene co-crystal prepared by the present application has achieved beneficial effects in stability, bioavailability, etc., and the comprehensive performance has made a more significant progress compared to the icariin crystal form reported in the prior art.

Claims

1. A icariin-1,2-dipyridyl ethylene co-crystal, characterized in that, The co-crystal is composed of an active pharmaceutical ingredient icariin and a co-crystal ligand 1,2-dipyridyl ethylene; the molar ratio of icariin to 1,2-dipyridyl ethylene 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 ethene co-crystal of claim 1, wherein, The co-crystal basic unit is composed of two molecules of icariin and one molecule of 1,2-dipyridyl ethylene, and the crystallographic parameters are as follows: monoclinic crystal system, space group C2 / c; cell parameters are as follows: a = 19.0854(2) Å, b = 11.16810(10) Å, c = 22.8794(2) Å, α = 90°, β = 95.5870(10)°, γ = 90°, and the cell volume structure is as shown in the following: V = 4853.52(8) Å 3 .

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

4. The method for preparing icariin-1,2-dipyridylethylene eutectic according to claim 3, characterized in that, The molar ratio of icariin to 1,2-dipyridyl ethylene is 1:0.5-1.0; 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 ethylene 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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