CN108530382A - A kind of Febuxostat ligustrazine eutectic and its preparation method and application - Google Patents
A kind of Febuxostat ligustrazine eutectic and its preparation method and application Download PDFInfo
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- CN108530382A CN108530382A CN201810230116.2A CN201810230116A CN108530382A CN 108530382 A CN108530382 A CN 108530382A CN 201810230116 A CN201810230116 A CN 201810230116A CN 108530382 A CN108530382 A CN 108530382A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention provides a kind of Febuxostat ligustrazine eutectics and its preparation method and application, belong to field of medicaments.Febuxostat ligustrazine eutectic includes characteristic peak shown in the angles following 2 θ：4.18±0.2°、8.41±0.2°、11.75±0.2°、12.96±0.2°、14.25±0.2°、24.61±0.2°、25.86±0.2°、26.95°±0.2°.This eutectiferous stable crystal form of Febuxostat ligustrazine is good, and crystallinity is high, and its solubility is big, can prepare the drug for treating or preventing gout.
Description
Technical field
The present invention relates to field of medicaments, in particular to a kind of Febuxostat ligustrazine eutectic and preparation method thereof
And purposes.
Background technology
Gout is one group of different substantiality disease, underexcretion and (or) purine caused by being heredity and (or) being acquired
Dysbolism is that uric acid is excessive and the decline of kidney Scavenging activity, uric acid are accumulated to lead in vivo due to generating in vivo
Urate crystal is caused to be deposited in joint and each internal organs.Febuxostat (also known as：Febustat, structure are as follows), it is a kind of complete
A kind of new efficient non-purine type xanthine oxidoreductase enzyme (XOR, key enzyme for promoting uric acid to generate) selective depressant,
By acting on the oxidoreducing enzyme highly selectively, uric acid level is reduced in blood samples of patients to improve the disease of patient with gout
Shape achievees the purpose that treat gout.
There are a variety of crystal forms for Febuxostat, also there is many articles and patent report.The crystal form of Febuxostat is in different condition
Under (such as temperature, solvent, cooling rate etc.) can mutually convert, Crystal type stability is poor, makes it in preparation and crystal form quality
Control aspect has certain difficulty, therefore increases the technical difficulty of the product development.
Invention content
The purpose of the present invention is to provide a kind of Febuxostat ligustrazine eutectics and its preparation method and application, it is intended to carry
The stability of crystal form of high Febuxostat, to solve the body art problem that crystal form is uncontrollable in the prior art.
In order to realize that the above-mentioned purpose of the present invention, spy use following technical scheme：
Febuxostat ligustrazine eutectic shown in a kind of Formulas I：
Further, Febuxostat ligustrazine eutectic includes characteristic peak shown in the angles following 2 θ：4.18±0.2°、8.41
±0.2°、11.75±0.2°、12.96±0.2°、14.25±0.2°、24.61±0.2°、25.86±0.2°、26.95°±
0.2°。
Further, Febuxostat ligustrazine eutectic includes characteristic peak shown in the angles following 2 θ：12.68±0.2°、
16.27±0.2°、17.87±0.2°、22.53±0.2°、24.22±0.2°。
Further, the eutectiferous space group of Febuxostat ligustrazine is monoclinic system, axial length α=90 °, β=103.7 ± 0.2 °, γ=90 °.
Further, the eutectiferous decomposition temperature of Febuxostat ligustrazine is 166~171 DEG C.
A kind of above-mentioned eutectiferous preparation method of Febuxostat ligustrazine comprising：
Febuxostat solution and the mixing of ligustrazine solution in organic solvent, crystallization after concentration will be dissolved respectively.
Further, the molar ratio of the Febuxostat in Febuxostat solution and the ligustrazine in ligustrazine solution is 0.8
~1.2：1.
Further, organic solvent and the volume mass ratio of Febuxostat or ligustrazine are (3~30):1.
Further, organic solvent include at least one of alcohols, ethers, esters, ketone or nitrile of C1-C4 and its
Combination；
Preferably, the alcohols of C1-C4 includes at least one of methanol, ethyl alcohol, propyl alcohol, isopropanol or butanol；
Preferably, ethers includes at least one of ether, ethyl methyl ether or petroleum ether；
Preferably, esters include at least one of ethyl acetate, methyl acetate, propyl acetate or propyl formate；
Preferably, ketone is acetone or butanone and combinations thereof；
Preferably, nitrile is acetonitrile or propionitrile and combinations thereof.
A kind of pharmaceutical composition comprising above-mentioned Febuxostat ligustrazine eutectic and pharmaceutically acceptable carrier.
A kind of purposes of above-mentioned Febuxostat ligustrazine eutectic in preparing the drug for treating or preventing gout.
Compared with prior art, beneficial effects of the present invention for example including：
The present invention provides a kind of medicinal co-crystal forms of new Febuxostat, this Febuxostat ligustrazine is eutectiferous
Stable crystal form is good, and crystallinity is high, and its solubility is big, can be used for developing, at several formulations, being used to prepare for treating or preventing
The drug of gout.
The eutectiferous preparation method of Febuxostat ligustrazine provided by the present invention, it is easy to operate, be not easy to form hydrate
And solvate.
Description of the drawings
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technology description to be briefly described.
Fig. 1 is Febuxostat ligustrazine crystal structure unit schematic diagram of the present invention.
Fig. 2 is the 1 eutectiferous powder xrd pattern of Febuxostat ligustrazine of embodiment.
Fig. 3 is the eutectiferous DSC figures of 1 Febuxostat ligustrazine of embodiment.
Fig. 4 is the eutectiferous powder xrd pattern of Febuxostat ligustrazine after 2 stability test of experimental example.
Specific implementation mode
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
Currently, (such as temperature, solvent, cooling rate etc.) can mutually convert the crystal form of Febuxostat at different conditions,
Crystal type stability is poor；Meanwhile solubility in water is very low, it is made to be difficult to develop into corresponding medicinal product.
In order to overcome drawbacks described above, inventor to provide a kind of Febuxostat ligustrazine eutectic, structure by research and development
Formula is as follows：
In the present invention, term " eutectic " refers to that " two kinds or more different moleculars, typically drug ingedient and eutectic are formed
Object, the crystallized stock formed in identical lattice ".According to this definition, pharmaceutical co-crystals can provide a kind of new conventional medicine
The solid-state form of object active component.Therefore, inventor is low and brilliant come the solubility for solving Febuxostat using pharmaceutical co-crystals technology
The problem of body stability difference, to improve the bioavilability and stability of Febuxostat so that Febuxostat is in production process
In more easily process.
Meanwhile ligustrazine, it is a kind of Pyrazine organic base, is commonly used for food additives or food stabilizer, it is acute
Toxicity (LD50) it is 00 mg/kg of Isosorbide-5-Nitrae (Mouse oral), 1,910 mg/kg (Oral Administration in Rats), 239 mg/kgs are (small
Mouse is injected), safety is good, and wherein Ligustrazine Phosphate Sodium Chloride Injection has been used as clinical medicine to use.In present embodiment,
Using ligustrazine and Febuxostat eutectic, securely and reliably, can solve that Febuxostat crystal form easily mutually converts, solubility is low etc. asks
Topic.
In Febuxostat ligustrazine eutectic, the molar ratio of Febuxostat and ligustrazine is 1:1.In its crystal structure list
In member, a nitrogen-atoms on the carboxyl and ligustrazine on a Febuxostat forms O=C-OHN hydrogen bond structures, brilliant
Solvent molecule is not contained in body structure.
Febuxostat ligustrazine eutectic has good stability and dissolubility, while being not easy to generate hydrate or molten
Object is closed in agent, this also can further promote promotion and application of the Febuxostat ligustrazine eutectic in medicinal and product development.
Further, Febuxostat ligustrazine eutectic includes characteristic peak shown in the angles following 2 θ：4.18±0.2°、8.41
±0.2°、11.75±0.2°、12.96±0.2°、14.25±0.2°、24.61±0.2°、25.86±0.2°、26.95°±
0.2°；Radiation source is Cu-K α.
Further, Febuxostat ligustrazine eutectic includes characteristic peak shown in the angles following 2 θ：12.68±0.2°、
16.27±0.2°、17.87±0.2°、22.53±0.2°、24.22±0.2°；Radiation source is Cu-K α.
Further, the eutectiferous space group of Febuxostat ligustrazine is monoclinic system, axial length a=α=90 °, β=103.7 ± 0.2 °, γ=90 °.
The eutectiferous preparation method of Febuxostat ligustrazine of the present invention is more convenient, is being closed with Febuxostat and ligustrazine
Reaction is prepared at eutectic in suitable organic solvent, is specifically comprised the following steps：
(1) Febuxostat and ligustrazine are dissolved separately in organic solvent, obtain Febuxostat solution and ligustrazine is molten
Liquid.
In step (1), it is preferable that the molar ratio of raw material Febuxostat and ligustrazine is 0.8~1.2：1；It is highly preferred that non-
Cloth sotan and the molar ratio of ligustrazine are 1:1.
Meanwhile in step (1), it is preferable that the volume mass ratio of organic solvent and Febuxostat or ligustrazine be (3~
30):1；Or it is (10~20)：1；It is highly preferred that organic solvent is (5 with the volume mass ratio of Febuxostat or ligustrazine
~15):1；
Meanwhile low-carbon alcohols, ethers, esters, ketone or one kind or several in nitrile that the organic solvent is C1-C4
Mixed organic solvents；
Preferably, the alcohols solvent is methanol, ethyl alcohol, propyl alcohol, isopropanol, butanol；Ethers has ether, ethyl methyl ether, stone
Oily ether；Esters have ethyl acetate, methyl acetate, propyl acetate, propyl formate；Ketone has acetone, butanone；Nitrile has acetonitrile, third
Nitrile；Thus, further, in the present invention solvent for use be one kind in above-mentioned specific solvent or two kinds, three kinds even more
The mixed organic solvents of multi-solvents；
(2) Febuxostat solution is mixed with ligustrazine solution, crystallization after concentration.
Preferably, in step (2), the temperature of the crystallization is 0-50 DEG C, it is furthermore preferred that the temperature of crystallization is 10-25 DEG C.
Present embodiment also provides a kind of pharmaceutical composition comprising Febuxostat ligustrazine eutectic, and pharmaceutically
Acceptable carrier.
In order to make the pharmaceutical composition discharge active component, medicine of the invention rapidly, continuously and in a very long time
Compositions can be manufactured according to those conventional methods in the art are disclosed in.The administration of the pharmaceutical composition of the present invention
Approach is oral, nasal inhalation or parenteral administration.The preparation of the pharmaceutical composition can be powder, particle, tablet, emulsion, sugar
Slurry, aerosol, soft capsule, hard capsule, sterile injectable preparation and sterilized powder etc..
Herein, it is that can physiologically connect that term " pharmaceutically acceptable ", which refers to the compound when compound is to human administration,
It receives, and the allergic reactions such as gastrointestinal disturbance, dizziness or these similar anaphylactoid systemic anaphylaxis will not occur.
In the present invention, " pharmaceutically acceptable carrier " includes but not limited to：Adhesive (such as microcrystalline cellulose, algae
Hydrochlorate, gelatin and polyvinylpyrrolidone), filler (such as starch, sucrose, glucose and anhydrous lactic acid), disintegrant (as be crosslinked
PVP, crosslinked carboxymethyl fecula sodium, croscarmellose sodium and low-substituted hydroxypropyl cellulose), lubricant (stearic acid
Magnesium, aluminum stearate, talcum, polyethylene glycol, sodium benzoate), wetting agent (such as glycerine), surfactant (such as hexadecanol) and
Sorbefacient, corrigent, sweetener, diluent, coating agent etc..
Used test instrument of the present invention specifically refers to as follows：
Crystal structure is measured by X-ray single crystal diffractometer, and full name is：Agilent Gemini E single crystal diffractometers；
Model X ' the Pert that Powder XRD pattern is produced using PANalytical companies of Holland3Powder diffractometers are surveyed
It is fixed；
Thermogravimetric analysis is measured using NETZSCH companies of Germany STA4 49C synchronous solvings, using nitrogen atmosphere, heating
10 DEG C/min of speed；
Infrared spectrum is measured using PerkinElmer companies of U.S. Spectrum Two infrared spectrum instruments；
Nuclear magnetic spectrogram is collected using the 400MHz rubrum nuclear magnetic resonance spectrometers of Bruker companies of Germany production.
Embodiment 1
The present embodiment provides a kind of Febuxostat ligustrazine eutectic, preparation method is：
1.01 grams of Febuxostats are taken to be dissolved in 15mL methanol；0.43 gram of ligustrazine is taken to be dissolved in 5mL methanol, by gained
Two kinds of solution concentrate after being mixed, and are cooled to room temperature crystallization, 0.88 gram of clear crystal is obtained by filtration.
The crystal1H NMR are shown：δ:13.43 (s, 1H), 8.30 (d, J=2.2Hz, 1H), 8.23 (dd, J=8.9,
2.2Hz, 1H), 7.38 (d, J=9.0Hz, 1H), 4.01 (d, J=6.5Hz, 2H), 2.66 (s, 3H), 2.38 (s, 12H),
2.05-2.14 (m, 1H), 1.02 (d, J=6.7Hz, 6H)
The infrared spectrum of crystal is in 2231 ± 2cm-1、1683±2cm-1、1606±2cm-1、1434±2cm-1、1377±
2cm-1、1294±2cm-1、1254±2cm-1、1010±2cm-1、1175±2cm-1、825±2cm-1There is absorption peak at place.
The powder xrd pattern of crystal as shown in Fig. 2, as shown in Figure 2, gained crystal 2 θ angles be 4.18 °, 8.41 °,
There is apparent diffraction maximum at 11.75 °, 12.96 °, 14.25 °, 24.22 °, 24.61 °, 25.86 ° and 26.95 °；
The DSC of crystal is as shown in Figure 3；Eutectiferous decomposition temperature is 168.7 ± 2 DEG C as shown in Figure 3.
By filtered solution slow evaporation at room temperature, the monocrystalline of Febuxostat ligustrazine, the structure of the crystal are obtained
Cell schematics are as shown in Figure 1.
Embodiment 2
The present embodiment provides a kind of Febuxostat ligustrazine eutectic, preparation method is：
It takes 35.0 grams of Febuxostats to be dissolved in 400mL acetonitriles, 15.1 grams of ligustrazines is taken to be dissolved in 150mL acetonitriles, it will
Two kinds of solution of gained concentrate after being mixed, and are cooled to 5 DEG C of crystallizations, 38.2 grams of clear crystal is obtained after filtering.
Nuclear-magnetism, powder X-ray RD diffraction and the examination of infrared spectrum of crystal obtained by the present embodiment with result one in embodiment 1
It causes, decomposition temperature is 169.3 DEG C.
Embodiment 3
The present embodiment provides a kind of Febuxostat ligustrazine eutectic, preparation method is：
It takes 5.0 grams of Febuxostats to be dissolved in 80mL acetone, takes 2.2 grams of ligustrazines to be dissolved in 30mL acetone, by gained
Two kinds of solution concentrate after being mixed, and are cooled to 15 DEG C of crystallizations, obtain 4.4 grams of clear crystal.
Nuclear-magnetism, powder X-ray RD diffraction and the examination of infrared spectrum of 3 gained crystal of embodiment with result one in embodiment 1
It causes, decomposition temperature is 168.9 DEG C.
Embodiment 4
The present embodiment provides a kind of Febuxostat ligustrazine eutectic, preparation method is：
It takes 10.0 grams of Febuxostats to be dissolved in 250mL ethyl acetate, 4.3 grams of ligustrazines is taken to be dissolved in 100mL acetic acid second
In ester, is concentrated after two solution are mixed, be cooled to 20 DEG C of crystallizations, obtain 9.1 grams of clear crystal.
Nuclear-magnetism, powder X-ray RD diffraction and the examination of infrared spectrum of 4 gained crystal of embodiment with result one in embodiment 1
It causes, decomposition temperature is 169.3 DEG C.
Experimental example 1
Febuxostat ligustrazine eutectic accelerated stability test one：
Appropriate (about 6g) is taken by the Febuxostat ligustrazine eutectic crystal obtained by 2 method of embodiment, is divided into 3 parts, and
It is placed in the plane ware that number is 1,2 and 3, three plane wares is then respectively placed in following conditions (storage condition 1：4500±
500lx illumination；Storage condition 2：60 DEG C of high temperature；Storage condition 3：92.5 high humidity of relative humidity) carry out stability test.Test knot
Fruit is as shown in table 1：
1 Febuxostat ligustrazine eutectic stability experiment of table
By experimental result it is found that with experiment start sample compared with, entirely test during, Febuxostat ligustrazine eutectic
The crystal form of body does not convert, it can be seen that, Febuxostat ligustrazine eutectic crystalline structure of the invention is stablized, and is suitble to long-term
Storage.
Experimental example 2
Febuxostat ligustrazine eutectic accelerated stability test one：
6.0 grams of the Febuxostat ligustrazine eutectic that Example 2 obtains, is added in 25mL water, 37 DEG C of insulated and stirreds
It filters afterwards for 24 hours, obtains 2.6 grams of samples, gained sample is subjected to powder X-ray RD diffraction analysis, test results are shown in figure 4.
Febuxostat ligustrazine eutectic powder XRD pattern and Fei Busuo after experiment shown in Fig. 4 before testing as shown in Figure 1
It is found that after experiment, Febuxostat ligustrazine of the present invention is eutectiferous for the comparison of smooth ligustrazine eutectic powder XRD pattern
Crystal form does not change, it can be seen that, Febuxostat ligustrazine eutectic of the present invention has good structural stability, does not have
Form hydrate.
Experimental example 3
Solubility test in Febuxostat ligustrazine eutectic pure water
Gained Febuxostat ligustrazine eutectic after taking the saturated solution of 37 DEG C of Febuxostat and experimental example 2 to filter respectively
Liquid solution measures its solubility in water；
The result shows that：The solubility of Febuxostat is 0.012mg/mL；The eutectiferous solubility of Febuxostat ligustrazine is
0.150mg/mL.Illustrate Febuxostat and ligustrazine into the solubility for greatly improving Febuxostat after eutectic, it is about non-
13 times of cloth sotan.
Febuxostat ligustrazine eutectic provided by the present invention is with good stability, can long term storage, even if
After re-dissolving crystallization, crystal structure will not change；Meanwhile Febuxostat ligustrazine eutectic of the present invention also has
Good dissolubility, and these all provide new thinking for the exploitation of Febuxostat product.Further, Fei Busuo of the present invention
Smooth ligustrazine eutectic preparation is easy, and this is but also it is suitable for production and preparation of large-scale industrialization.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from the present invention's
Many other change and modification can be made in the case of spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. Febuxostat ligustrazine eutectic shown in a kind of Formulas I：
2. Febuxostat ligustrazine eutectic according to claim 1, which is characterized in that the Febuxostat ligustrazine is total
Crystal includes characteristic peak shown in the angles following 2 θ：4.18±0.2°、8.41±0.2°、11.75±0.2°、12.96±0.2°、
14.25±0.2°、24.61±0.2°、25.86±0.2°、26.95°±0.2°。
3. Febuxostat ligustrazine eutectic according to claim 2, which is characterized in that the Febuxostat ligustrazine is total
Crystal includes characteristic peak shown in the angles following 2 θ：12.68±0.2°、16.27±0.2°、17.87±0.2°、22.53±0.2°、
24.22±0.2°。
4. Febuxostat ligustrazine eutectic according to claim 1, which is characterized in that the Febuxostat ligustrazine is total
The space group of crystal is monoclinic system, axial length
α=90 °, β=103.7 ± 0.2 °, γ=90 °.
5. Febuxostat ligustrazine eutectic according to claim 1, which is characterized in that the Febuxostat ligustrazine is total
The decomposition temperature of crystal is 166~171 DEG C.
6. a kind of eutectiferous preparation method of Febuxostat ligustrazine, feature as described in any one of Claims 1 to 5 exists
In comprising：
Febuxostat solution and the mixing of ligustrazine solution in organic solvent, crystallization after concentration will be dissolved respectively.
7. the eutectiferous preparation method of Febuxostat ligustrazine according to claim 6, which is characterized in that the Fei Busuo
The molar ratio of Febuxostat in smooth solution and the ligustrazine in the ligustrazine solution is 0.8~1.2：1.
8. the eutectiferous preparation method of Febuxostat ligustrazine according to claim 6, which is characterized in that described organic molten
Agent includes at least one of alcohols, ethers, esters, ketone or nitrile of C1-C4 and combinations thereof；
Preferably, the alcohols of the C1-C4 includes at least one of methanol, ethyl alcohol, propyl alcohol, isopropanol or butanol；
Preferably, the ethers includes at least one of ether, ethyl methyl ether or petroleum ether；
Preferably, the esters include at least one of ethyl acetate, methyl acetate, propyl acetate or propyl formate；
Preferably, the ketone is acetone or butanone and combinations thereof；
Preferably, the nitrile is acetonitrile or propionitrile and combinations thereof.
9. a kind of pharmaceutical composition, which is characterized in that it includes such as Claims 1 to 5 any one of them Febuxostat Rhizoma Chuanxiong
Piperazine eutectic and pharmaceutically acceptable carrier.
10. a kind of as Claims 1 to 5 any one of them Febuxostat ligustrazine eutectic is being prepared for treating or preventing
Purposes in the drug of gout.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110003122A (en) * | 2019-05-08 | 2019-07-12 | 国家卫生健康委科学技术研究所 | The pharmaceutical co-crystals body and its application of ethinyloestradiol and ligustrazine |
| CN111714479A (en) * | 2019-03-23 | 2020-09-29 | 中国医学科学院药物研究所 | Medicine composition containing Bexarotene |
| CN111718257A (en) * | 2019-03-23 | 2020-09-29 | 中国医学科学院药物研究所 | Bexarotene and ligustrazine eutectic compound, preparation method, composition and application thereof |
| CN113402390A (en) * | 2021-07-21 | 2021-09-17 | 河北农业大学 | Aspirin medicine eutectic and preparation method and application thereof |
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| CN113402390B (en) * | 2021-07-21 | 2022-12-06 | 河北农业大学 | Aspirin medicine eutectic and preparation method and application thereof |
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