阅读说明：本技术 一种炔雌醇药物共晶及其制备方法和应用 (Ethinylestradiol pharmaceutical co-crystal and preparation method and application thereof ) 是由 徐娟 宁丽峰 王慧萍 陈晓锋 李鹏 马进 于 2019-10-18 设计创作，主要内容包括：本发明公开了一种炔雌醇药物共晶,所述药物共晶是以炔雌醇为活性成分,以咪唑为共晶形成物,两者采用氢键相连,药物共晶的分子式为C-(23)H-(28)N-2O-2。该炔雌醇药物共晶具有好的水溶性及生物利用度。本发明还公开了该炔雌醇药物共晶的制备方法及应用。(The invention discloses ethinylestradiol pharmaceutical co-crystal which is prepared by taking ethinylestradiol as an active ingredient and imidazole as a co-crystal former, wherein the ethinylestradiol and the imidazole are connected by hydrogen bonds, and the molecular formula of the pharmaceutical co-crystal is C 23 H 28 N 2 O 2 . The ethinylestradiol pharmaceutical co-crystal has good water solubility and bioavailability. The invention also discloses a preparation method and application of the ethinylestradiol pharmaceutical co-crystal.)

1. The ethinylestradiol pharmaceutical co-crystal is characterized in that ethinylestradiol is used as an active ingredient of the pharmaceutical co-crystal, imidazole is used as a co-crystal former, the ethinylestradiol and the imidazole are connected by hydrogen bonds, and the molecular formula of the pharmaceutical co-crystal is C₂₃H₂₈N₂O₂。

2. The ethinylestradiol pharmaceutical co-crystal according to claim 1, wherein the pharmaceutical co-crystal is orthorhombic and has a space group of P2₁2₁2₁The unit cell parameters are:α ═ β ═ γ ═ 90 °, Z ═ 4, and unit cell volume

3. The pharmaceutical co-crystal of ethinylestradiol according to claim 1, characterized in that the X-ray powder diffraction at 2 Θ angles using Cu-ka radiation presents characteristic diffraction peaks at about 13.58 °, 14.09 °, 18.19 °.

4. The pharmaceutical co-crystal of ethinylestradiol according to claim 3, characterized in that the X-ray powder diffraction at 2 Θ angles using Cu-ka radiation further exhibits characteristic diffraction peaks at about 17.75 °, 20.96 °, 21.90 °, 22.69 °.

5. The ethinylestradiol pharmaceutical co-crystal of claim 1, wherein the molar ratio of ethinylestradiol to imidazole is 1: 1.

6. The method for preparing ethinylestradiol pharmaceutical co-crystals as claimed in any one of claims 1 to 5, comprising the steps of:

mixing ethinylestradiol and imidazole, and grinding to obtain mixed powder;

and dissolving the mixed powder in a solvent, and heating and refluxing to obtain a colorless block, namely the ethinylestradiol pharmaceutical co-crystal.

7. Use of ethinylestradiol pharmaceutical co-crystals according to any one of claims 1 to 5 for the preparation of a contraceptive medicament.

8. Use of ethinylestradiol pharmaceutical co-crystals according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of gynaecological disorders.

9. A pharmaceutical composition comprising the pharmaceutical co-crystal of ethinyl estradiol according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

Technical Field

The invention relates to the field of biomedicine. More particularly, relates to ethinylestradiol pharmaceutical co-crystal and a preparation method and application thereof.

Background

The pharmaceutical co-crystal is a supermolecule which is formed by acting force between molecules such as hydrogen bonds and the like between drug molecules and a co-crystal reagent and has a fixed composition and a single melting point. The existing research results show that the pharmaceutical cocrystal is formed by using a cocrystal reagent with better water solubility and an insoluble drug, so that the water solubility and the bioavailability of the insoluble drug can be obviously improved under the condition of not changing the molecular structure of the drug, and the cocrystal is the latest key technology for improving the physicochemical properties of the drug such as water solubility, permeability, stability and the like. The U.S. FDA has provided a guiding principle in the pharmaceutical co-crystal industry in 2013, and the pharmaceutical co-crystal is listed as a pharmaceutical excipient; the principle is revised in 2016, and the pharmaceutical co-crystal is further classified as a solid pharmaceutical solvate, so that a guiding principle is provided for approval and marketing of the co-crystal drug. In 2014, two eutectic drugs for treating diabetes, namely, farxiga and Suglat, were approved to be on the market, and in 2015, a heavy-pound eutectic drug for treating heart failure, namely, Nowa, is approved to be on the market, namely, LCZ 696.

Oral contraceptive is the most commonly used contraceptive and birth control measure for women of childbearing age, particularly unmarried and unintuitive women. Oral contraceptive drugs are mostly steroid hormone drugs, and excessive administration can cause abnormal ovulation and even infertility, thereby seriously affecting reproductive health of women of child-bearing age in China and threatening the number and quality of next generation population in China. Poor water solubility is a common problem for steroids, and ethinylestradiol requires large doses (0.02-1 mg/day) to be taken orally to achieve the necessary blood levels. The problems of improving the water solubility and bioavailability of steroid hormone medicaments and reducing the oral dose are to be solved urgently by the oral contraceptive in China at present.

In addition, ethinylestradiol has been reported to have an anhydrous crystal form and a 0.5 aqueous crystal form, and it has been proved that ethinylestradiol will be converted between the anhydrous crystal form and the 0.5 crystal form under dry or humid conditions, so that the crystal form stability and the crystal form purity of the ethinylestradiol product are difficult to guarantee.

Disclosure of Invention

Based on the facts, the first purpose of the invention is to provide ethinylestradiol pharmaceutical cocrystal to solve the problems of poor water solubility, low bioavailability, poor crystal form stability and the like of ethinylestradiol.

The second purpose of the invention is to provide a preparation method of ethinylestradiol pharmaceutical co-crystal.

The third purpose of the invention is to provide the application of the ethinylestradiol pharmaceutical co-crystal in preparing the contraceptive medicament.

The fourth purpose of the invention is to provide an application of the ethinylestradiol pharmaceutical co-crystal in preparing the medicine for treating the gynecological diseases.

A fifth object of the present invention is to provide a pharmaceutical composition.

In order to achieve the first purpose, the invention adopts the following technical scheme:

the ethinylestradiol pharmaceutical co-crystal is characterized in that ethinylestradiol is used as an active ingredient, imidazole is used as a co-crystal former, the ethinylestradiol and the imidazole are connected by adopting hydrogen bonds, and the molecular formula of the pharmaceutical co-crystal is C₂₃H₂₈N₂O₂。

It was found that different co-crystal formers have different effects on ethinyl estradiol, on whether or not co-crystals can be formed and on the properties of the co-crystals obtained. The invention discovers that the problems of water solubility, crystal form stability and the like of the ethinylestradiol pharmaceutical eutectic are obviously improved on the basis of not changing the structure of the ethinylestradiol by adopting imidazole as a eutectic formation substance.

Further, the pharmaceutical co-crystal is in an orthorhombic system, and the space group is P2₁2₁2₁The unit cell parameters are: α ═ β ═ γ ═ 90 °, Z ═ 4, and unit cell volume

Further, with Cu-K α radiation, X-ray powder diffraction at 2 θ angles has characteristic diffraction peaks at about 13.58 °, 14.09 °, 18.19 °.

Further, with Cu-K α radiation, X-ray powder diffraction at 2 θ also presents characteristic diffraction peaks at about 17.75 °, 20.96 °, 21.90 °, 22.69 °.

Further, with Cu-K α radiation, X-ray powder diffraction at 2 θ also has characteristic diffraction peaks at about 9.56 °, 10.90 °, 11.40 °, 14.93 °, 15.32 °, 19.84 °, 20.64 °, 23.49 °, 24.06 °, 27.16 °, 27.92 °, 29.12 °, 36.18 °.

Further, the molar ratio of the ethinyl estradiol to the imidazole is 1: 1.

In order to achieve the second purpose, the invention adopts the following technical scheme:

a preparation method of ethinylestradiol pharmaceutical co-crystal comprises the following steps:

mixing ethinylestradiol and imidazole, and grinding to obtain mixed powder;

and dissolving the mixed powder in a solvent, and heating and refluxing to obtain a colorless block, namely the ethinylestradiol pharmaceutical co-crystal.

Further, the above-mentioned polishing may be carried out in the presence of a solvent, and the amount of the solvent added is preferably an amount capable of functioning as an auxiliary polishing. Exemplary solvents include, but are not limited to, acetonitrile.

Further, the solvent for dissolving the mixed powder is selected from acetonitrile, and the amount added is preferably at least capable of dissolving the mixed powder.

Further, in the preparation method, the molar ratio of the ethinylestradiol to the imidazole is 1: 1.

In the preparation method, in the heating reflux process, the solvent is slowly volatilized, and the ethinylestradiol pharmaceutical co-crystal can be obtained after about one week.

In order to achieve the third object, the invention also provides the application of the ethinylestradiol pharmaceutical co-crystal in the preparation of the contraceptive medicament.

In order to achieve the fourth object, the invention also provides the application of the ethinylestradiol pharmaceutical co-crystal in the preparation of the medicament for treating gynecological diseases.

In order to achieve the fifth object, the invention provides a pharmaceutical composition, which comprises the ethinylestradiol pharmaceutical cocrystal as described in the first object and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers include, but are not limited to, diluents, binders, surfactants, humectants, adsorbent carriers, lubricants, fillers, disintegrating agents, and the appropriate form of the composition is determined by the mode of administration.

Pharmaceutical compositions prepared by mixing and suitable for oral, parenteral or topical administration may be in the form of tablets, oral liquid preparations, powders, lozenges, pastilles, reconstitutable powders, injectable and infusible solutions or suspensions, suppositories and transdermal devices. Orally administrable compositions are preferred, particularly oral compositions having a shape, as they are generally convenient to use.

Tablets and capsules for oral administration are generally unit dose and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, colorants, flavors and humectants. These tablets may be coated according to methods known in the art.

Fillers suitable for use include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

The solid oral composition can be prepared by conventional methods such as blending, filling, tabletting and the like. Repeated blending operations can be used to distribute the active agent throughout those compositions that use large amounts of filler. This is naturally convenient in the art.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or edible hydrogenated fats; emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated cocoa butter, oily esters such as esters of glycerol, propylene glycol or ethanol; preservatives, for example methyl or ethyl p-hydroxybenzoate, or sorbic acid, and, if desired, customary flavouring or colouring agents.

For parenteral administration, the compounds of the invention and a sterile carrier are formulated in fluid unit dosage forms. The compounds may be suspended or dissolved and parenteral solutions are generally prepared by dissolving the active compound in a carrier and filter sterilizing the solution before filling in a suitable vial or ampoule and sealing. It is also preferred that certain adjuvants such as local anesthetics, preservatives and buffering agents be dissolved in the carrier. To improve the stability of the pharmaceutical composition, it may be frozen after filling into vials and vacuum to remove water.

Parenteral suspensions are formulated in substantially the same manner except that the active compound is suspended in the vehicle without dissolution and sterilized by treatment with ethylene oxide prior to suspension in the sterile vehicle. Preferably, surfactants or wetting agents are added to the composition to facilitate uniform distribution of the active compound.

For topical administration, the composition may be in the form of a transdermal ointment or patch for systemic delivery of the compound, which may be prepared by conventional methods as described in standard textbooks, Pharmaceutical Formulations' -B.W.Barry (Drugs and Pharmaceutical Sciences-Ddkker) or Harrys cosmetics (Leonard Hill Books).

The invention has the following beneficial effects:

the ethinylestradiol pharmaceutical co-crystal provided by the invention has a stable crystal form and high purity, and is good in water solubility and high in bioavailability. The ethinylestradiol pharmaceutical co-crystal can be well used for preparing contraceptive medicaments, medicaments for treating gynecological diseases and the like.

Drawings

The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.

FIG. 1 shows an infrared spectrum of ethinylestradiol pharmaceutical co-crystal prepared in example 1.

FIG. 2 shows the nuclear magnetic spectrum of ethinylestradiol pharmaceutical co-crystal prepared in example 1.

Fig. 3 shows a schematic structural diagram of the ethinylestradiol pharmaceutical co-crystal prepared in example 1.

Fig. 4 shows the actual and theoretical XRD patterns of ethinylestradiol pharmaceutical co-crystals prepared in example 1.

Fig. 5 shows a TG-DSC graph of ethinylestradiol pharmaceutical co-crystals prepared in example 1.

Fig. 6 shows stability curves of ethinylestradiol pharmaceutical co-crystals prepared in example 1 under different conditions.

FIGS. 7A to 7D are graphs showing HPLC test results of the ethinylestradiol pharmaceutical co-crystal prepared in example 1 in the original state, after standing at 60 ℃ for 30 days, at 25 ℃ for 30 days at 90% relative humidity, and under conditions of 4500 lx. + -. 500lx illumination for 30 days, respectively.

Fig. 8 shows solubility curves of ethinylestradiol pharmaceutical co-crystals, ethinylestradiol-nicotinamide co-crystals, and ethinylestradiol in water, which were prepared in example 1.

Fig. 9 shows a bioavailability curve of ethinylestradiol pharmaceutical co-crystals prepared in example 1 and ethinylestradiol.

Detailed Description

In order to more clearly illustrate the invention, the invention is further described below with reference to preferred embodiments and the accompanying drawings. Similar parts in the figures are denoted by the same reference numerals. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.

Example 1

Preparation of ethinylestradiol pharmaceutical co-crystal (EE-IZ)

The raw materials used are as follows:

ethinyl estradiol: (purity > 99%) Huarun black bamboo, pharmaceutical industries, Inc.;

imidazole: (purity > 99%) mecillin reagent;

acetonitrile: (analytically pure) Tianjin, Daloco chemical reagent plant.

The preparation method comprises the following steps:

powder sample: respectively adding 296.4mg (1.0mmol) of ethinylestradiol and 68.1mg (1.0mmol) of imidazole into a mortar, and carrying out auxiliary grinding for 1h by using an acetonitrile solvent to obtain a white powder sample;

single crystal cultivation: and (3) taking 150mg of the powder sample, adding 15ml of acetonitrile to dissolve, heating and refluxing for 3h, slowly volatilizing the solvent, and obtaining the colorless massive crystal after about 1 week.

Example 2

Infrared (IR) analysis of ethinylestradiol pharmaceutical co-crystals

The instrument model is as follows: bruker Vertex 70 infrared spectrometer of Bruker company

The sample preparation method comprises the following steps: and (5) tabletting potassium bromide.

And (3) measuring results: the infrared test results of the ethinylestradiol pharmaceutical co-crystal prepared in example 1 are shown in the following table 1 and fig. 1, respectively.

TABLE 1 Main Infrared absorption Peak data of ethinylestradiol pharmaceutical Co-crystals

Example 3

Pharmaceutical co-crystals of ethinylestradiol¹H-NMR nuclear magnetic resonance spectrum analysis

Instrument model and test conditions:

the instrument comprises the following steps: model AVANCE III HD 600MHz nuclear magnetic resonance spectrometer.

Solvent: CD (compact disc)₃OD (TMS internal standard);

the nuclear magnetic test spectrum of the ethinylestradiol pharmaceutical co-crystal prepared in example 1 is shown in fig. 2. The shift of the nuclear magnetic resonance hydrogen spectrum is as follows:¹H NMR(600MHz,Methanol-d₄)δ7.67(s,1H),7.08(d,J＝8.5Hz,1H),7.05(s,2H),6.54(dd,J＝8.5,2.7Hz,1H),6.47(d,J＝2.6Hz,1H),2.89(s,1H),2.84-2.71(m,2H),2.37-2.30(m,1H),2.29-2.22(m,1H),2.12(td,J＝11.3,4.2Hz,1H),2.01-1.90(m,2H),1.90-1.83(m,1H),1.80-1.70(m,3H),1.46-1.26(m,4H),0.86(s,3H).

example 4

X-ray single crystal diffraction (SXRD) detection of ethinylestradiol drug cocrystal

The instrument model is as follows: agilent Gemini E type X-ray single crystal diffractometer manufactured by Agilent

The detection method comprises the following steps: selecting colorless crystals with size of 0.27mm × 0.32mm × 0.34mm, adopting graphite monochromatized Mo-K ray, and radiating with wavelengthMeasuring temperature: 298(10) K. The structure resolution and refinement are done using the SHELL XT-14 and Olex2 programs. The atomic position is determined by a direct method, then all non-hydrogen atomic coordinates are obtained by a difference function method and a least square method, and the structure is corrected by the least square method.

The structural schematic diagram of the ethinylestradiol pharmaceutical co-crystal prepared in example 1 is shown in fig. 3, the SXRD parameters are shown in table 2 below, specific non-hydrogen atom coordinates are shown in table 3, bond length data are shown in table 4, and bond angle data are shown in table 5.

TABLE 2 Crystal Structure and refinement parameters thereof

TABLE 3 non-Hydrogen atom coordinates

TABLE 4 bond Length

Key with a key body	Length of the bond	Key with a key body	Length of the bond
				C1-C2	1.169(4)	C11-C16	1.522(4)
O1-C3	1.434(3)	C12-C13	1.523(3)
				C2-C3	1.468(4)	C13-C14	1.520(4)
O2-C19	1.375(3)	C14-C15	1.507(4)
				C3-C4	1.550(4)	C15-C16	1.397(3)
C3-C7	1.555(4)	C15-C20	1.390(3)
				C4-C5	1.544(4)	C16-C17	1.391(4)
C5-C6	1.526(4)	C17-C18	1.382(4)
				C6-C7	1.532(4)	C18-C19	1.382(4)
C6-C12	1.522(3)	C19-C20	1.370(4)
				C7-C8	1.535(3)	N1-C21	1.286(5)
C7-C9	1.530(4)	N1-C23	1.358(5)
				C9-C10	1.538(4)	N2-C21	1.320(5)
C10-C11	1.540(4)	N2-C22	1.342(5)
				C11-C12	1.530(4)	C22-C23	1.338(7)

TABLE 5 Key Angle (°)

Key with a key body	Key angle	Key with a key body	Key angle
				C1-C2-C3	177.5(4)	C6-C12-C11	109.5(2)
O1-C3-C2	108.3(2)	C6-C12-C13	114.4(2)
				O1-C3-C4	108.7(2)	C13-C12-C11	109.4(2)
O1-C3-C7	114.1(2)	C14-C13-C12	109.4(2)
				C2-C3-C4	111.2(3)	C15-C14-C13	112.6(2)
C2-C3-C7	111.2(2)	C16-C15-C14	122.3(2)
				C4-C3-C7	103.3(2)	C20-C15-C14	117.9(2)
C5-C4-C3	107.1(2)	C20-C15-C16	119.8(2)
				C6-C5-C4	103.7(2)	C15-C16-C11	121.2(2)
C5-C6-C7	104.4(2)	C17-C16-C11	121.2(2)
				C12-C6-C5	119.4(2)	C17-C16-C15	117.5(2)
C12-C6-C7	113.1(2)	C18-C17-C16	122.5(3)
				C6-C7-C3	100.2(2)	C17-C18-C19	119.0(3)
C6-C7-C8	112.3(2)	O2-C19-C18	117.9(3)
				C8-C7-C3	108.0(2)	C20-C19-O2	122.5(3)
C9-C7-C3	117.6(2)	C20-C19-C18	119.6(2)
				C9-C7-C6	109.2(2)	C19-C20-C15	121.4(2)
C9-C7-C8	109.3(2)	C21-N1-C23	104.4(4)
				C7-C9-C10	111.4(2)	C21-N2-C22	107.4(4)
C9-C10-C11	112.5(2)	N1-C21-N2	112.5(4)
				C12-C11-C10	110.9(2)	C23-C22-N2	105.2(4)
C16-C11-C10	114.0(2)	C22-C23-N1	110.5(4)
				C16-C11-C12	111.5(2)

From the above single crystal structure analysis, it was found that the ethinylestradiol pharmaceutical cocrystal does not contain solvent molecules in the crystal structure, and ethinylestradiol and imidazole are linked by hydrogen bonds. The ratio between the two is 1: 1.

Example 5

X-ray diffraction spectrum (PXRD) detection of ethinylestradiol drug cocrystal

Methods and samples:

the instrument model is as follows: x-ray powder apparatus model D8 ADVANCE of Bruker, germany.

The measurement conditions were as follows: copper target, 40KV/40mA, initial angle 3 deg., end angle 60 deg., step width 0.02, scanning speed 17.7 s/step, wavelengthA graphite monochromator.

And (3) determining a sample: ethinylestradiol pharmaceutical co-crystal sample obtained in example 1

Theoretical spectrogram: the theoretical spectrogram is obtained by simulation by Mercury software. The software may be downloaded at a website: https:// www.ccdc.cam.ac.uk/solutions/csd-system/components/mercure-

The test results are shown in fig. 4 and table 6 below. It can be seen that the theoretical values of the resolution of the eutectic prepared in example 1 and the single crystal are consistent in the intensity and position of the peak, which indicates that the eutectic has the same spatial structure and the crystal form as the EE-IZ single crystal.

TABLE 6 EE-IZ samples X-powder diffraction Spectroscopy absorption peaks

Example 6

Thermal analysis (TG-DSC) of ethinylestradiol pharmaceutical co-crystals

The experimental conditions are as follows:

TGA instrument model: NETZSCH TG209F 1;

DSC instrument model: rigaku DSC 8231;

the heating rate is as follows: 10 ℃/min;

temperature range: 40-400 deg.C (TG), 40-200 Deg.C (DSC);

gas atmosphere: nitrogen gas;

the experimental results are as follows:

the results of the experiment are shown in FIG. 5. Wherein the content of the first and second substances,

differential Scanning Calorimeter (DSC) shows: no melting point was observed for the eutectic samples prepared in example 1 over the temperature range tested.

Thermogravimetric analysis (TGA) shows: the co-crystal sample EE-IZ prepared in example 1 melts at 155.6 ℃ and decomposes thereafter, before which the TGA curve shows no weight loss, indicating that the drug does not contain water of crystallization.

Comparative example 1

Example 1 was repeated, except that the same mass of L-proline was used instead of imidazole, and the remaining conditions were not changed, so that no cocrystal could be obtained.

Example 7

Stability study of prepared eutectic sample EE-IZ

The following tests were carried out on the eutectic sample EE-IZ prepared in example 1, and samples were taken for XRPD testing.

High-temperature test: the eutectic sample EE-IZ was placed in a clean beaker at 60 ℃ ± 2 ℃ for 10 days and sampled at day 0, day 5, day 10 and day 30.

High humidity test: the eutectic sample EE-IZ was placed in a clean beaker at 25 ℃ under relative humidity 90% ± 5% for 10 days, and sampled at day 0, day 5, day 10 and day 30.

And (3) illumination test: the eutectic sample EE-IZ was placed in a clean beaker, placed in a light box with a fluorescent lamp under an illumination of 4500 lx. + -. 500lx for 10 days, and sampled on days 0, 5, 10 and 30.

The powder X-ray diffraction analysis was carried out on the samples subjected to the high temperature, high humidity and light test on day 0 (i.e., the starting sample), day 5, day 10 and day 30, respectively, and the results are shown in FIG. 6. It is known that under these conditions, the eutectic sample EE-IZ has good high-temperature stability, high-humidity stability and light stability.

The HPLC of the samples at day 0 (i.e., the starting sample), 30 days under high temperature, high humidity, light test, respectively, was tested.

The test conditions were as follows:

the instrument comprises the following steps: shimadzu LC2010 AHT;

chromatographic column Xbridge C182.1 × 50mm, 3.5 um;

mobile phase A-Water (0.05% TFA); b-acetonitril (0.05% TFA);

gradient elution is shown in table 7 below:

TABLE 7 gradient elution conditions

Time (min)	A(％)	B(％)
			0.0	90	10
7.0	0	100
			8.0	0	100
8.01	90	10
			10	90	10

The flow rate is 0.8 mL/min;

the wavelength is 214 nm; 254 nm;

the column temperature was 45 ℃.

In which the HPLC test results of the starting sample, the sample placed at 60 ℃ for 30 days, the sample placed at 25 ℃ at 90% relative humidity for 30 days, and the sample placed at an illumination of 4500 lx. + -. 500lx for 30 days are shown in FIGS. 7A to 7D, in this order. It is also known that the sample has good stability under these conditions.

Example 8

Water solubility research of prepared eutectic sample EE-IZ

Dissolution conditions:

the device comprises the following steps: a paddle method;

volume: 1000 ml;

temperature: 37 ℃;

rotating speed: 100 rpm;

dissolution medium: water: deionized water is adopted, and degassing is carried out for standby.

Sample preparation: ethinylestradiol-imidazole cocrystal EE-IZ prepared in example 1; and for comparison, ethinylestradiol-nicotinamide eutectic crystal (the preparation method comprises the steps of adding 296.4mg of ethinylestradiol and 122.1mg of nicotinamide into a mortar respectively, and carrying out auxiliary grinding for 1h by using an acetonitrile solvent to obtain ethinylestradiol-nicotinamide eutectic crystal EE-NA) and pure ethinylestradiol EE.

The test method comprises the following steps:

respectively taking 20mg of ethinylestradiol-imidazole eutectic, ethinylestradiol-nicotinamide eutectic and ethinylestradiol respectively, placing in a dissolution instrument, performing solubility evaluation according to the conditions, sampling 10ml at 10min, 20min, 30min, 45min, 60min, 90min and 120min respectively, supplementing 10ml of solution, filtering by using a 0.45 mu m membrane, measuring an absorption value at 295nm, and calculating the cumulative dissolution rate.

The results are shown in FIG. 8: when water is used as a dissolving medium, 20% of ethinylestradiol-imidazole eutectic is dissolved out within 120min, only 7% of ethinylestradiol-nicotinamide eutectic and ethinylestradiol are dissolved out, the dissolving behaviors of the compounds are basically consistent, and the dissolving rate of the ethinylestradiol-imidazole eutectic is faster than that of the ethinylestradiol-nicotinamide eutectic and the ethinylestradiol.

Example 9

Bioavailability study of prepared eutectic sample EE-IZ

And (3) testing conditions are as follows:

animals: female SD rats (250-280g), 3/group;

the administration route is as follows: performing intragastric administration;

blood sampling points: 0,0.25,0.5,1,1.5,2,3,5,7,12 and 24 hours;

sample analysis: LC-MS/MS;

PK analysis: winnolin.

The test results of the test using the eutectic sample EE-IZ and ethinylestradiol prepared in example 1 as the drugs are shown in fig. 9. It can be seen that the bioavailability of the EE-IZ co-crystal is superior to that of ethinylestradiol.

It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention, and it will be obvious to those skilled in the art that other variations or modifications may be made on the basis of the above description, and all embodiments may not be exhaustive, and all obvious variations or modifications may be included within the scope of the present invention.