CN116410167A - Icariin methanol solvate and preparation method thereof - Google Patents
Icariin methanol solvate and preparation method thereof Download PDFInfo
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 title claims abstract description 183
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- TZJALUIVHRYQQB-UHFFFAOYSA-N icariine Natural products C1=CC(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(C)O2)O)C(=O)C2=C(O)C=C(OC3C(C(O)C(O)C(CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-UHFFFAOYSA-N 0.000 title claims abstract description 94
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
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Abstract
The invention belongs to the field of drug crystal forms, and particularly relates to an icariin methanol solvate and a preparation method thereof. The invention provides an icariin methanol solvate and a preparation method thereof, cu-K alpha radiation is used, and an X-ray diffraction spectrum expressed by 2 theta has diffraction peaks at 6.03+/-0.2 degrees, 17.59 +/-0.2 degrees, 19.73+/-0.2 degrees, 24.86+/-0.2 degrees, 26.34+/-0.2 degrees and 30.14+/-0.2 degrees; the icariin methanol solvate provided by the invention has excellent properties, higher solubility and stability, provides a high-quality raw material selection for the preparation production of the icariin, and has the advantages of simple operation and easy control, thus being suitable for industrial amplification.
Description
Technical Field
The invention belongs to the field of drug crystal forms, and particularly relates to an icariin methanol solvate and a preparation method thereof.
Background
Icaritin (IT), also known as icaritin, is a polyhydroxy flavonoid monomer component in Epimedium plant of berberidaceae, and ITs structural formula is shown in formula (I):
pharmacological research shows that icariin has stronger anti-osteoporosis activity than other flavonoid glycoside compounds in epimedium, and has the functions of promoting osteoblast activity and inhibiting osteoclast activity in vitro. The traditional Chinese medicine epimedium has the effects of tonifying kidney, supporting yang, strengthening tendons and bones, dispelling wind, removing dampness, washing sore, killing parasites and relieving fatigue and pain. The icariin is taken as one of the main active ingredients, attracts attention of a plurality of scholars at home and abroad in recent years, and carries out intensive and extensive research on pharmacological actions of the icariin, and the results so far find that the main physiological activity of the icariin is in improving cardiovascular and cerebrovascular system functions, enhancing organism immunity and regulating endocrine, and has the effects of resisting tumor, resisting liver toxicity, resisting hypoxia reoxygenation, strengthening bones and the like.
Although icariin has a good clinical application prospect, the poor water solubility of the icariin greatly limits the clinical application of the icariin. At present, research on solving the solubility of icariin is mainly focused on two aspects, namely, research on preparing a new crystal form of the icariin or a derivative thereof and more conventional improvement on the solubility of the icariin by means of a preparation. For example Gu Dongsheng, the solubility of a raw material drug and a physical mixture is remarkably improved by preparing an icariin phospholipid complex (Gu Dongsheng, zhao Jiangli, shi Feng, etc.. Preparation of the icariin phospholipid complex and solid dispersion research [ J ]. Chinese herbal medicine, 2010,9 (41)), but the method has the problem that a dissolution medium may damage a drug structure or the dissolution medium evaporates; wang Jinyan the solubility of icariin is studied by a microemulsion technology (Jin Yan, chen Yan, zhang Zhenhai, etc. the preliminary study of the intestinal absorption characteristics of icariin from a microemulsion in Caco-2 cell model [ J ]. Chinese herbal medicine, 2012,3 (43)), although the solubility and absorption of icariin can be improved, a large amount of emulsifying agent and auxiliary emulsifying agent are used in the process, and a certain quality safety hazard exists.
In contrast, less studies have been reported on the raw material form of icariin, and patent CN101200743a reports that icariin is prepared in a crystalline form, but the dissolution characteristics thereof are not improved. Patent CN104860958A reports the crystalline form a and crystalline form B of anhydroicaritin, and the results of the study indicate that the solubility of anhydroicaritin is improved to some extent, but not significantly.
The related reports of the icariin at present mainly relate to the preparation, the physicochemical properties, the pharmacology and other properties of the icariin, but the solubility of the icariin is not improved significantly. Therefore, new crystal forms for obviously improving the solubility of the icariin are still required to be researched, the physicochemical properties of the icariin are effectively improved, the problem of the solubility of the icariin is fundamentally solved, the addition of auxiliary materials in the preparation production process is reduced as much as possible, and the hidden danger of medication is reduced as much as possible.
Disclosure of Invention
In view of the problems of poor solubility of the icariin in the prior art and defects of the existing improvement method, the invention successfully prepares the icariin methanol solvate crystal through a eutectic technology, and the crystal can remarkably improve the dissolution characteristic of the icariin and has good physicochemical stability.
The specific technical content of the invention is as follows:
in a first aspect of the present invention, there is provided a methanol solvate of icariin, characterized in that the molar ratio of icariin to methanol in the crystal unit structure is 1:1.
Preferably, the icariin methanol solvate uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed in 2 theta has characteristic peaks at 6.03+/-0.2 degrees, 17.59 +/-0.2 degrees, 19.73+/-0.2 degrees, 24.86+/-0.2 degrees, 26.34+/-0.2 degrees and 30.14+/-0.2 degrees.
Preferably, the icariin methanol solvate uses Cu-ka radiation, and its main crystallographic parameters are: triclinic crystal system, the space group is P-1; the unit cell parameters are:
α= 93.3430 (10) °, β= 93.3430 (10) °, γ= 91.8490 (10) °, unit cell volume +.>
Preferably, the icariin methanol solvate uses Cu-ka radiation, and its characteristic peak has an X-ray powder diffraction pattern shown in fig. 1.
In a second aspect of the present invention, there is provided a method for preparing a methanol solvate of icariin, comprising the steps of: dissolving icariin in the mixed solvent of methanol and organic solvent A, heating, stirring, cooling, crystallizing, filtering, and drying to obtain icariin methanol solvate.
Preferably, the organic solvent A is selected from one or more of acetonitrile, tetrahydrofuran, acetone and isopropanol, more preferably one or two of tetrahydrofuran and isopropanol.
Preferably, the mass volume ratio of the icariin to the methanol is 11-20: 1, mg/mL; preferably 14-17:1, mg/mL.
Preferably, the volume ratio of the methanol to the organic solvent A is 5-7: 1.
preferably, the temperature of the heating and stirring is 45-65 ℃, preferably 50-55 ℃.
Preferably, the temperature reduction crystallization temperature is 0-15 ℃; preferably 5 to 10 ℃.
Preferably, the crystallization time is 25 to 72 hours.
The drying is a conventional drying means in the art, such as vacuum drying at 50-60 ℃.
Preferably, the preparation method of the icariin methanol solvate comprises the following specific steps: dissolving the icariin in the mixed solvent of methanol/organic solvent A, heating and stirring at 45-65 ℃ until the icariin is completely dissolved, cooling to 0-15 ℃ for crystallization for 25-72 hours, filtering, and drying a filter cake to obtain the icariin methanol solvate.
In a third aspect, the invention provides a pharmaceutical composition, which contains the icariin methanol solvate and other pharmaceutically acceptable components.
Preferably, the preparation method of the pharmaceutical composition comprises the following steps: the icariin methanol solvate is combined with a pharmaceutically acceptable solid or liquid carrier, and optionally with pharmaceutically acceptable adjuvants and excipients, using standard and conventional techniques, to prepare a pharmaceutical dosage form.
Preferably, the pharmaceutically acceptable additional components include, but are not limited to, pharmaceutically active ingredients, excipients, fillers, and the like, which may be used in combination.
Preferably, the dosage form of the pharmaceutical composition includes, but is not limited to, spray, tablet, capsule, powder injection, injection and the like.
In a fourth aspect, the invention provides an application of a icariin methanol solvate serving as an active ingredient in preparing medicines for treating liver injury, liver fibrosis, tumor and the like.
Confirmation of crystal structure:
the X-ray crystal data of the present invention were collected on a Japanese national institute model XtaLAB Synergy instrument, tested for temperature 293 (2) K, and data were collected and Lp corrected in an omega scan using CuKa radiation. The crystal structure is obtained by calculation through a ShellXT program in 01ex2 software, structural parameters and atomic types are corrected through a least square method by adopting the ShellXL program, all hydrogen atom positions are obtained through a geometric calculation method and a difference Fourier method, and the fitting degree (goof value) is 1.019 and is close to 1.0, so that the weight scheme is proper, and the structure is accurate. The data of the crystallography obtained by testing and analyzing the icariin methanol solvate prepared by the invention are shown in table 1. The ORTEP diagram of the epimedium aglycone methanol solvate is shown in figure 2, which shows that the epimedium aglycone and the methanol are connected through an intramolecular hydrogen bond; the crystal stacking diagram of icariin methanol solvate is shown in figure 3.
TABLE 1 icariin methanol solvate principal crystallographic data
In the invention, an X-ray powder diffraction test instrument and test conditions are as follows: the X-ray powder diffractometer is PANalytical EMPYREAN; cu-K alpha; sample stage: a flat plate; the incident light path is BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40mA; 1/4 of the divergent slit; an anti-scattering slit 1; a cable pull slit of 0.04rad; step size: 0.5s; scanning range: 3-50 deg. According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in the accompanying figure 1 and the table 2.
TABLE 2 major PXRD peaks of icariin methanol solvate
The samples prepared in examples 1 to 5 all conform to the X-ray powder diffraction patterns.
The invention has the beneficial effects that:
the icariin methanol solvate provided by the invention has better stability in a solid state or a solution state, obviously improves the solubility of the icariin, and provides a high-quality raw material selection for the preparation production of the icariin; the preparation method is simple and convenient to operate, the crystallization process is easy to control, the reproducibility is good, and the prepared crystal is high in purity and suitable for industrial production.
Drawings
Fig. 1: x-ray powder diffraction pattern of icariin methanol solvate.
Fig. 2: ORTEP figure of icariin methanol solvate
Fig. 3: a pile-up diagram of icariin methanol solvate.
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.
The raw material icariin can be prepared according to any method in the prior art or purchased from a commercial product (the purity is more than or equal to 98%), and the rest reagent materials are commercially available.
1. Preparation of crystalline forms
Example 1
Dissolving 368.4mg of icariin in a mixed solvent of 24mL of methanol and 4mL of tetrahydrofuran, stirring at 50-55 ℃ until the icariin is completely dissolved, slowly cooling to 5-10 ℃, standing for 48 hours for crystallization, filtering, and vacuum drying a filter cake at 60 ℃ to obtain the icariin methanol solvate, wherein the yield is as follows: 97.6%, purity: 99.97%.
Example 2
Dissolving 368.5mg of icariin in a mixed solvent of 26.3mL of methanol and 5.3mL of isopropanol, stirring at 55-60 ℃ until the icariin is completely dissolved, slowly cooling to 10-15 ℃, standing for 72 hours, crystallizing, filtering, and vacuum drying a filter cake at 50 ℃ to obtain the icariin methanol solvate, wherein the yield is: 96.0% purity: 99.96%.
Example 3
Dissolving 368.4mg of icariin in a mixed solvent of 21.7mL of methanol and 3mL of acetonitrile, stirring at 60-65 ℃ until the icariin is completely dissolved, slowly cooling to 0-5 ℃ and standing for 25 hours for crystallization, filtering, and vacuum drying a filter cake at 60 ℃ to obtain the icariin methanol solvate, wherein the yield is: 96.5%, purity: 99.94%.
Example 4
Dissolving 368.4mg of icariin in a mixed solvent of 18.5mL of methanol and 3.7mL of acetone, stirring at 45-50 ℃ until the icariin is completely dissolved, slowly cooling to 5-10 ℃, standing for about two days for crystallization, filtering, and vacuum drying a filter cake at 60 ℃ to obtain the icariin methanol solvate, wherein the yield is: 95.2%, purity: 99.92%.
Example 5
Dissolving 368.5mg of icariin in a mixed solvent of 33.5mL of methanol, 3mL of tetrahydrofuran and 3.5mL of isopropanol, stirring at 50-55 ℃ until the icariin is completely dissolved, slowly cooling to 5-10 ℃ and standing for about two days for crystallization, filtering, and vacuum drying a filter cake at 50 ℃ to obtain the icariin methanol solvate with the yield: 95.6%, purity: 99.94%.
Comparative example 1
368.4mg icariin was dissolved in 30mL acetone, filtered, and about 15mL distilled water was added to the filtrate, dissolved at 75℃under reflux, and left to crystallize at 20 ℃. After crystallization for 24 hours, light yellow crystals were obtained by filtration. The obtained crystals were continuously dried at 80℃until no change in the weight of the crystals occurred, to obtain icariin crystals in 91.5% yield and 99.88% purity.
Comparative example 2
15mg of the icariin crystals prepared in comparative example 1 were dissolved in 1.2mL of methanol solvent to obtain a suspension. The suspension is stirred for 4 days at 20 ℃, centrifuged, and the obtained crystals are collected as 1/3 methanol solvate of icariin, the yield is 88.6%, and the purity is 99.84%.
Comparative example 3
15mg of the crystals obtained in comparative example 1 were weighed into a 3mL vial, 20mL of the vial was taken and 4mL of methanol solvent was added thereto, the 3mL vial was placed into the 20mL vial, the vial was sealed, and the mixture was allowed to stand at 20℃for 5 days, and the obtained crystals were collected as icariin methanol solvate, with a yield of 90.3% and a purity of 99.85%.
2. Verification embodiment
1. Stability test
The stability test method of the invention is carried out by referring to the guidance method of the fourth part of the Chinese pharmacopoeia (2020 edition) on stability investigation, and the high-temperature test conditions are as follows: 60 ℃, strong light irradiation test conditions: 4500lx±500lx, high humidity test conditions: 92.5%. Purity detection the purity was detected by HPLC, 3 replicates were run and the results averaged. The specific detection results are shown in Table 3.
TABLE 3 stability test results of icariin methanol solvate under light, high temperature and high humidity conditions
Meanwhile, the test results of the stability test similar to those of examples 1 to 5 of the present application were found.
2. Solubility experiment
The method comprises the following steps: respectively weighing 10ml of medium (water and 0.01mol/L HCl solution) in a penicillin bottle, adding excessive sample to be tested, sealing the penicillin bottle, placing in a constant-temperature water bath at 25 ℃ for stirring for 1 hour, filtering by a filter membrane, and taking filtrate; the absorbance was measured at a wavelength of 270nm and the solubility was calculated by testing the absorbance of the standard control.
TABLE 4 solubility of icariin methanol solvate in different Medium (μg/mL)
Meanwhile, the test results of the solubility test similar to those of examples 1 to 5 of the present application were found.
3. Biological Activity assay
1. Material
1.1 pharmaceutical products
Example 1 and comparative examples 1-3 self-prepared crystalline forms.
1.2 animals
Beagle experimental dogs were 30, male and female halves, and had body weights (12-15 kg) supplied by Guangzhou medical research institute, inc.
In vivo pharmacokinetic experiments in beagle experimental dogs
After 30 Beagle dogs were adaptively bred for two weeks and quarantined, 24 healthy and normal animals were selected and administered in 4 groups to form 1 of example 1 and form 1 of comparative example 1-3, respectively, and 15mg/kg of the mixture was orally administered, blood was collected from peripheral veins at 0, 0.5, 1, 2, 4, 6, 8 and 12 hours, and plasma was obtained by centrifugation at 2-8℃for 10 minutes. Icariin concentration in Beagle canine plasma was determined using beta-glucuronidase hydrolysis, LC-MS/MS (see Huang Ying, liu Yanju, hu Lei, et al LC-MS/MS for determination of the concentration of acibenzodine in Beagle plasma [ C ]]The seventh national toxicology institute of the Chinese society and the eighth Hubei scientific forum discussion.2015.). The pharmacokinetic parameters measured are shown in Table 5, where the area under the plasma concentration-time curve (AUC) was calculated using the trapezoidal method, elimination half-life (t 1/2 ) The peak concentration (C) was calculated by Best Fit method max ) Peak time of arrival (T) max ) Actual measurement values were used.
TABLE 5 pharmacokinetic parameters following oral administration in Beagle dogs [ ]
n＝6)
Note that: group 1 dosing example 1; comparative example 1 was administered in group 2; group 3 dosing comparative example 2; comparative example 3 was administered to group 4.
Claims (10)
1. A methanol solvate of icariin is characterized in that Cu-K alpha radiation is used, an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 6.03+/-0.2 degrees, 17.59 +/-0.2 degrees, 19.73+/-0.2 degrees, 24.86+/-0.2 degrees, 26.34+/-0.2 degrees and 30.14+/-0.2 degrees, and the molar ratio of the icariin to methanol in a crystal unit structure is 1:1.
2. The icariin methanol solvate of claim 1, wherein Cu-ka radiation is used with main crystallographic parameters: triclinic crystal system, the space group is P-1; the unit cell parameters are:
α= 93.3430 (10) °, β= 93.3430 (10) °, γ= 91.8490 (10) °, unit cell volume +.>
3. The methanol solvate of icariin according to claim 1, wherein the characteristic peak has an X-ray powder diffraction pattern as shown in fig. 1.
4. A process for the preparation of the epimedium aglycone methanol solvate of any one of claims 1 to 3, comprising the steps of: dissolving icariin in the mixed solvent of methanol and organic solvent A, heating, stirring, cooling, crystallizing, filtering, and drying to obtain icariin methanol solvate.
5. The preparation method according to claim 4, wherein the organic solvent A is one or more selected from acetonitrile, tetrahydrofuran, acetone and isopropanol.
6. The preparation method of claim 4, wherein the mass-to-volume ratio of the icariin to the methanol is 11-20: 1, mg/mL.
7. The method according to claim 4, wherein the volume ratio of the methanol to the organic solvent A is 5-7: 1.
8. the method according to claim 4, wherein the temperature of the heating and stirring is 45 to 65 ℃.
9. The preparation method according to claim 4, wherein the specific steps are as follows: dissolving the icariin in a mixed solvent of methanol and an organic solvent A, heating and stirring the mixture at 45-65 ℃ until the icariin is completely dissolved, cooling the mixture to 0-15 ℃ for crystallization for 25-72 hours, filtering the mixture, and drying a filter cake to obtain the icariin methanol solvate.
10. An application of icariin methanol solvate as active component in preparing medicine for treating liver injury, liver fibrosis, tumor, etc.
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