CN108017596A - A kind of Vortioxetine and the new salt form of brufen and preparation method thereof - Google Patents
A kind of Vortioxetine and the new salt form of brufen and preparation method thereof Download PDFInfo
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- CN108017596A CN108017596A CN201810082558.7A CN201810082558A CN108017596A CN 108017596 A CN108017596 A CN 108017596A CN 201810082558 A CN201810082558 A CN 201810082558A CN 108017596 A CN108017596 A CN 108017596A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- 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
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Abstract
The invention discloses a kind of Vortioxetine and the new salt form of brufen, has the basic structural unit for being made up of R4 4 (12) tetramer synthon Hydrogenbond with two Vortioxetine molecules and two ibuprofen molecules, its space group is three oblique 1 crystallographic systems of P.The invention also discloses the Vortioxetine and the preparation method of the new salt form of brufen, Vortioxetine and brufen are dissolved in solvent by (1), are heated to reflux dissolving reaction；(2) after the completion of reacting, resulting solution stands, acquisition Vortioxetine and brufen new salt form complete to crystallization.This method is easy to operate, favorable reproducibility, new salt form Vortioxetine treatment severe adult's depression and the drug effect of the antipyretic throe anti-inflammatory of ibuprofen, and have good thermodynamic stability at the same time of preparation.
Description
Technical field
The present invention relates to a kind of new salt form of medicine and preparation method, more particularly to a kind of Vortioxetine and the new salt form of brufen
And preparation method thereof.
Background technology
The U.S. Food and Drug Administration of the first half of the year in 2017 (FDA) ratifies 23 new drugs, including 16 recruits altogether
Entity and 7 new biological products, have in this 16 chemicals 8 medicines (Parsabiv, Xermelo, Kisqali,
Xadago, Symproic, Zejula, Ingrezza, Baxdela) it is to list in a salt form.According to statistics, about 70-80%
Drug candidate due to final physicochemical property the defects of, cause research and development failure and cannot finally list, so improve medicine
Physicochemical property for new drug development tool be of great significance.The new salt form of medicine refers to introduce newly by proton translocation
Eutectic material (CCF), be self-assembly of under the active force of hydrogen bond with pharmaceutical activity active ingredient (API) with immobilization
Learn the supramolecular complex of metering ratio.The development phase before clinical drug, new drug development company would generally by pharmaceutical activity effectively into
Divide (API) by way of into salt to improve the solution degree of medicine, dissolution rate, permeability, hygroscopicity, stability and biology profit
Expenditure and some other physicochemical properties.When eutectic material (CCF) is selected, select medicine as binding partner oneself
Assembling forms the effect of new salt form not only saves two kinds of medicines each, and can be obviously improved the solubility of medicine, dissolution speed
Rate and bioavilability etc..Compared to nanocrystalline, solid dispersion and novel pharmaceutical formulation technology, medicine salt form is molten in improvement medicine
It is with the obvious advantage in terms of Xie Du, dissolution rate, permeability, hygroscopicity, stability and bioavilability, and the new salt form of medicine
The patent barrier of new drug can be broken by succeeding in developing.
Vortioxetine is by Lundbeck drugmaker of Denmark and the joint research and development exploitation of Japanese Takeda Pharmaceutical Company Limited, in 2013 9
The moon lists in the U.S., for treating severe adult's depression.The chemical name of Vortioxetine is 1- [2- (2,4- dimethyl benzene sulphur
Base) phenyl] piperazine, molecular formula C18H22N2S, its structural formula is as shown in formula a.Brufen has anti-inflammatory, analgesia, refrigeration function,
Chemical name is 2- methyl -4- (2- methyl-propyls) phenylacetic acid, molecular formula C13H18O2, its structural formula is as shown in formula b.
Research shows, monoamine (mainly including serotonin (5-HT), dopamine (DA) and can remove kidney at synapse
Upper parathyrine (NE)) elimination of neurotransmitter can trigger some thymopathies.Antidepressant is mainly by blocking presynaptic membrane
Transmission function between the intake of 5-HT, the 5-HT concentration for improving synaptic cleft, promotion cynapse, alleviates depression so as to reach
Effect.The monoamine that the antidepressants listed at present have wide spectrum mostly can act on, and with a series of adverse reaction, including dislike
Heart vomiting, abnormal heart rhythms, certain liver dysfunction etc..Vortioxetine has 5-HT3/7Receptor antagonist 5-HT1AAcceptor
Activator 5-HT1BThe multiple activities such as acceptor portion agonist and 5-HTT inhibitor, can effectively improve cynapse through a variety of ways
Gap location 5-HT concentration, and strengthen postsynaptic activity, its adverse reaction often shows as slight nausea and dizziness, in treatment weight
The significant effect in terms of depression is spent, the possibility that patient is recurred after healing is relatively low.But its active constituents of medicine (API) has
Water-soluble physicochemical drawbacks such as low (0.1mg/mL), stability difference, it is a kind of hydrogen of Vortioxetine to cause its product listed
Bromate, trade name Brintellix.
The content of the invention
It is an object of the invention to provide a kind of Vortioxetine and the new salt form of brufen.
Above-mentioned purpose of the present invention is achieved through the following technical solutions：A kind of Vortioxetine and the new salt form of brufen, have
R4 4 (12) tetramer is formed with two Vortioxetine molecules and two ibuprofen molecules by N-HO Hydrogenbonds to close
The basic structural unit of Cheng Zi, wherein, the O atom in ibuprofen molecule on carboxyl is as hydrogen-bond donating body, two Vortioxetines
N atoms in molecule on piperazine ring are as hydrogen bond receptor, its crystallographic features：Space group is three oblique P-1 crystallographic systems, and crystallographic system belongs to
Monoclinic system, a=7.9628 (6), b=11.7 485 (10), c=16.2216 (11), shaft angle are α=76.771 (7) °, β=
88.612 (6) °, γ=76.954 (7) °, V=1438.54 (19), Z=2.
The X- powder diffractograms of Vortioxetine and the new salt form of brufen are 5.58 ± 0.2,7.94 ± 0.2,11.26 in 2 θ
±0.2、 12.47±0.2、12.93±0.2、14.24±0.2、15.64±0.2、16.94±0.2、17.68±0.2、
18.84±0.2、19.74±0.2、 20.36±0.2、21.28±0.2、22.08±0.2、22.95±0.2、23.58±
0.2nd, 24.48 ± 0.2,25.64 ± 0.2,28.30 ± 0.2,29.60 ± 0.2,31.22 ± 0.2 have characteristic peak.
The fusing point of Vortioxetine and the new salt form of brufen is 122 DEG C.
The second object of the present invention is the preparation method for providing a kind of Vortioxetine and the new salt form of brufen.
Above-mentioned purpose of the present invention is achieved through the following technical solutions：A kind of preparation of Vortioxetine and the new salt form of brufen
Method, comprises the following steps：
(1) Vortioxetine and brufen are dissolved in solvent, are heated to reflux dissolving and react, obtain the Vortioxetine of heat
With the saturated solution of the new salt form of brufen；
(2) saturated solution is stood complete to crystallization, obtains Vortioxetine and the new salt form of brufen.
Vortioxetine and the molar ratio of brufen are 1 in the step (1):1~1:2.Solvent is in the step (1)
The mixed solution of alcohol and water, the volume ratio for being wherein alcohol and water are 10:1~1:3.Being heated to reflux the time in the step (1) is
0.5h~5h.
The usage amount of solvent meets that the hot solution that reaction obtains is Vortioxetine and the new salt form saturation of brufen in the present invention
Solution.Certainly, the usage amount of solvent is also required to be made choice according to the preparation amount of final product.One as the present invention
A embodiment, in the step (1), when Vortioxetine and the usage amount of brufen are less than 1g, solvent usage amount 4-8ml；
When Vortioxetine and the usage amount of brufen are higher than 1g, solvent usage amount is in more than 100ml, preferably 100-400ml.
The physical state of Vortioxetine and the new salt form of brufen can be according to the preparation amount of Vortioxetine and the new salt form of brufen
Size have a different forms, when amount is few, obtain water white transparency bulk crystals；When measuring big, white powder is obtained.Therefore, when fertile
During for Xi Ting and few preparation amount of the new salt form of brufen, in the step (2), solution is transferred in teat glass, with sealing
Film seals test tube mouth, and 2-5 aperture is pricked on sealed membrane with pin, stands, and room temperature volatilization, it is block to separate out water white transparency after 2-3 days
Crystal.When the preparation amount of Vortioxetine and the new salt form of brufen is big, in the step (2), solution left standstill stays overnight crystallization, takes out
Filter, filter cake is vacuum dried to constant weight, obtains Vortioxetine and the new salt form of brufen.The vacuum drying temperature for 60~
70 DEG C, when processing time is 24~48 small.
The present invention has the following advantages：
It is depressed that 1. the new salt form of Vortioxetine and brufen prepared by the present invention is provided simultaneously with Vortioxetine treatment severe adult
Disease and the drug effect of the antipyretic throe anti-inflammatory of ibuprofen.
2. the new salt form fusing point of Vortioxetine and brufen prepared by the present invention is 122 DEG C, there is good Thermodynamically stable
Property.
3. easy to operate, favorable reproducibility of the invention.
4. the solvent selected is the aqueous solution of alcohol, the method used when preparation amount is few is organic for solvent room temperature volatility process
Solvent methanol or ethanol have volatility, and water is as anti-solvent, therefore Vortioxetine and the new salt form of brufen are waved in methanol or ethanol
Separated out during hair.
Brief description of the drawings
Fig. 1 is Vortioxetine and new 4 (12) tetramer synthon structure charts of salt form R4 of brufen；
Fig. 2 is the crystallographic data of Vortioxetine and the new salt form of brufen；
Fig. 3 is Vortioxetine and the theory of the new salt form of brufen and actual XRD comparison diagrams；
Fig. 4 is the DSC comparison diagrams of brufen, Vortioxetine and Vortioxetine and the new salt form of brufen.
Embodiment
Technical scheme is further described by the following examples.
Embodiment 1
(1) by 20.00mg Vortioxetines and 14.00mg brufens, i.e. molar ratio is 1:1 two kinds of medicines are dissolved in 4ml
The volume ratio of first alcohol and water is 1:In 1 mixed solution.0.5h is heated to reflux, solid drugs is completely dissolved and is reacted, is obtained
The saturated solution of the new salt form of Vortioxetine and brufen of heat.
(2) saturated solution in reaction vessel is transferred in teat glass, with ParafilmTM test tube mouth, is being sealed with pin
2-5 aperture is pricked on membrana oralis, is stood, room temperature volatilization, starts to separate out water white transparency bulk crystals after 2 days.
(3) crystal of precipitation is determined as Vortioxetine and the new salt form of brufen by single crystal diffraction：Fusing point is 122 DEG C.
R4 4 (12) tetramer is constituted by N-HO Hydrogenbonds with two Vortioxetine molecules and two ibuprofen molecules
The basic structural unit (Fig. 1) of synthon.Wherein, the O atom in ibuprofen molecule on carboxyl is as hydrogen-bond donating body, two
N atoms in Vortioxetine molecule on piperazine ring are as hydrogen bond receptor.For its crystallographic features referring to Fig. 2, space group is three oblique P-
1 crystallographic system, crystallographic system belong to monoclinic system, a=7.9628 (6), b=11.7 485 (10), c=16.2216 (11), shaft angle for α=
76.771 (7) °, β=88.612 (6) °, γ=76.954 (7) °, V=1438.54 (19), Z=2.As shown in figure 3, X- powder
Diffraction spectrogram 2 θ for 5.58 ± 0.2,7.94 ± 0.2,11.26 ± 0.2,12.47 ± 0.2,12.93 ± 0.2,14.24 ±
0.2、15.64±0.2、16.94±0.2、 17.68±0.2、18.84±0.2、19.74±0.2、20.36±0.2、21.28
±0.2、22.08±0.2、22.95±0.2、23.58±0.2、 24.48±0.2、25.64±0.2、28.30±0.2、
29.60 ± 0.2,31.22 ± 0.2 have characteristic peak.
Embodiment 2
(1) by 20.00mg Vortioxetines and 14.00mg brufens, i.e. molar ratio is 1:1 two kinds of medicines are dissolved in 4ml
The volume ratio of second alcohol and water is 1:In 1 mixed solution.0.5h is heated to reflux, solid drugs is completely dissolved and is reacted, is obtained
The saturated solution of the new salt form of Vortioxetine and brufen of heat.
(2) saturated solution in reaction vessel is transferred in teat glass, with ParafilmTM test tube mouth, is being sealed with pin
2-5 aperture is pricked on membrana oralis, is stood, room temperature volatilization, starts to separate out water white transparency bulk crystals after 2 days.
(3) crystal of precipitation is determined as Vortioxetine and the new salt form of brufen by single crystal diffraction.Its fusing point is 122
℃.R4 4 (12) four is constituted by N-HO Hydrogenbonds with two Vortioxetine molecules and two ibuprofen molecules
The basic structural unit (Fig. 1) of aggressiveness synthon, its space group are three oblique P-1 crystallographic systems.Wherein, in ibuprofen molecule on carboxyl
O atom as hydrogen-bond donating body, the N atoms in two Vortioxetine molecules on piperazine ring are as hydrogen bond receptor.Crystallography is special
X- powder diffractograms of seeking peace are identical with embodiment one.
Embodiment 3
(1) by 2.00g Vortioxetines and 1.40g brufens, i.e. molar ratio is 1:1 two kinds of medicines are dissolved in 180ml first
The volume ratio of alcohol and water is 1:In 2 mixed solution.1h is heated to reflux, solid drugs is completely dissolved and is reacted, obtains heat
The saturated solution of Vortioxetine and the new salt form of brufen.
(2) saturated solution in reaction vessel is transferred in teat glass, with ParafilmTM test tube mouth, is being sealed with pin
2-5 aperture is pricked on membrana oralis, stands volatilization, starts to separate out water white transparency bulk crystals after 3 days.
(3) crystal of precipitation is determined as Vortioxetine and the new salt form of brufen by single crystal diffraction.Its fusing point is 122
℃.R4 4 (12) four is constituted by N-HO Hydrogenbonds with two Vortioxetine molecules and two ibuprofen molecules
The basic structural unit (Fig. 1) of aggressiveness synthon, its space group are three oblique P-1 crystallographic systems.Wherein, in ibuprofen molecule on carboxyl
O atom as hydrogen-bond donating body, the N atoms in two Vortioxetine molecules on piperazine ring are as hydrogen bond receptor.Crystallography is special
X- powder diffractograms of seeking peace are identical with embodiment one.
Embodiment 4
(1) by 2.00g Vortioxetines and 1.40g brufens, i.e. molar ratio is 1:1 two kinds of medicines are dissolved in 180ml second
The volume ratio of alcohol and water is 1:In 2 mixed solution.1h is heated to reflux, solid drugs is completely dissolved and is reacted, obtains heat
The saturated solution of Vortioxetine and the new salt form of brufen.
(2) saturated solution in reaction vessel is transferred in teat glass, with ParafilmTM test tube mouth, is being sealed with pin
2-5 aperture is pricked on membrana oralis, stands volatilization, starts to separate out water white transparency bulk crystals after 3 days.
(3) crystal of precipitation is determined as Vortioxetine and the new salt form of brufen by single crystal diffraction.Its fusing point is 122
℃.R4 4 (12) four is constituted by N-HO Hydrogenbonds with two Vortioxetine molecules and two ibuprofen molecules
The basic structural unit (Fig. 1) of aggressiveness synthon, its space group are three oblique P-1 crystallographic systems.Wherein, in ibuprofen molecule on carboxyl
O atom as hydrogen-bond donating body, the N atoms in two Vortioxetine molecules on piperazine ring are as hydrogen bond receptor.Crystallography is special
X- powder diffractograms of seeking peace are identical with embodiment one.
Embodiment 5
(1) by 20.00g Vortioxetines and 14.00g brufens, i.e. molar ratio is 1:1 two kinds of medicines are dissolved in 300ml
The volume ratio of first alcohol and water is 1:In 2 mixed solution.1h is heated to reflux, solid drugs is completely dissolved and is reacted, obtains heat
Vortioxetine and the new salt form of brufen saturated solution.
(2) saturated solution slow cooling stands overnight crystallization to room temperature.Filter, filtrate is filtered and is removed, filter cake is positioned over
In 60 DEG C of vacuum drying chamber, dry 48h obtains new salt form sample 18g to constant weight.
(3) crystal of precipitation is determined as Vortioxetine and the new salt form of brufen by single crystal diffraction.Its fusing point is 122
℃.R4 4 (12) four is constituted by N-HO Hydrogenbonds with two Vortioxetine molecules and two ibuprofen molecules
The basic structural unit (Fig. 1) of aggressiveness synthon, its space group are three oblique P-1 crystallographic systems.Wherein, in ibuprofen molecule on carboxyl
O atom as hydrogen-bond donating body, the N atoms in two Vortioxetine molecules on piperazine ring are as hydrogen bond receptor.Crystallography is special
X- powder diffractograms of seeking peace are identical with embodiment one.
Embodiment 6
(1) by 20.00g Vortioxetines and 14.00g brufens, i.e. molar ratio is 1:1 two kinds of medicines are dissolved in 300ml
The volume ratio of second alcohol and water is 1:In 2 mixed solution.1h is heated to reflux, solid drugs is completely dissolved and is reacted, obtains heat
Vortioxetine and the new salt form of brufen saturated solution.
(2) saturated solution slow cooling stands overnight crystallization to room temperature., filter, filtrate filtered and is removed, filter cake is placed
In 60 DEG C of vacuum drying chamber, dry 48h obtains new salt form sample 22g to constant weight.
(3) crystal of precipitation is determined as Vortioxetine and the new salt form of brufen by single crystal diffraction.Its fusing point is 122
℃.R4 4 (12) four is constituted by N-HO Hydrogenbonds with two Vortioxetine molecules and two ibuprofen molecules
The basic structural unit (Fig. 1) of aggressiveness synthon, its space group are three oblique P-1 crystallographic systems.Wherein, in ibuprofen molecule on carboxyl
O atom as hydrogen-bond donating body, the N atoms in two Vortioxetine molecules on piperazine ring are as hydrogen bond receptor.Crystallography is special
X- powder diffractograms of seeking peace are identical with embodiment one.
Claims (10)
1. a kind of Vortioxetine and the new salt form of brufen, it is characterised in that have with two Vortioxetine molecules and two cloth Lip rivers
Fragrant molecule is made up of the basic structural unit of R4 4 (12) tetramer synthon Hydrogenbond, wherein, carboxylic in ibuprofen molecule
O atom on base is as hydrogen-bond donating body, and for the N atoms in two Vortioxetine molecules on piperazine ring as hydrogen bond receptor, it is brilliant
Body feature：Space group is three oblique P-1 crystallographic systems, and crystallographic system belongs to monoclinic system, a=7.9628 (6), b=11.7 485 (10), c
=16.2216 (11), shaft angle are α=76.771 (7) °, β=88.612 (6) °, γ=76.954 (7) °, V=1438.54
(19), Z=2.
2. Vortioxetine according to claim 1 and the new salt form of brufen, it is characterised in that the X- of the new salt form of medicine
Powder diffractogram is 5.58 ± 0.2,7.94 ± 0.2,11.26 ± 0.2,12.47 ± 0.2,12.93 ± 0.2,14.24 in 2 θ
± 0.2,15.64 ± 0.2,16.94 ± 0.2,17.68 ± 0.2,18.84 ± 0.2,19.74 ± 0.2,20.36 ± 0.2,21.28
± 0.2,22.08 ± 0.2,22.95 ± 0.2,23.58 ± 0.2,24.48 ± 0.2,25.64 ± 0.2,28.30 ± 0.2,29.60
± 0.2 and 31.22 ± 0.2 have characteristic peak.
3. Vortioxetine according to claim 1 and the new salt form of brufen, it is characterised in that the Vortioxetine and Bu Luo
The fusing point of fragrant new salt form is 122 DEG C.
4. the preparation method of the new salt form of Vortioxetine and brufen described in claim 1, it is characterised in that including following step
Suddenly：
(1) Vortioxetine and brufen are dissolved in solvent, are heated to reflux dissolving reaction, obtain the Vortioxetine and Bu Luo of heat
The saturated solution of fragrant new salt form；
(2) saturated solution is stood complete to crystallization, obtains Vortioxetine and the new salt form of brufen.
5. the preparation method of Vortioxetine according to claim 4 and the new salt form of brufen, it is characterised in that the step
(1) Vortioxetine and the molar ratio of brufen are 1 in:1~1:2.
6. the preparation method of Vortioxetine according to claim 4 and the new salt form of brufen, it is characterised in that the step
(1) solvent is alcohol and the mixed solution of water in, and the wherein volume ratio of alcohol and water is 10:1~1:3.
7. the preparation method of Vortioxetine according to claim 6 and the new salt form of brufen, it is characterised in that the step
(1) in, when Vortioxetine and the usage amount of brufen are less than 1g, solvent usage amount 4-8ml；When Vortioxetine and brufen
Usage amount when being higher than 1g, solvent usage amount is in more than 100ml.
8. the preparation method of Vortioxetine according to claim 4 and the new salt form of brufen, it is characterised in that the step
(2) in, solution is transferred in teat glass, with ParafilmTM test tube mouth, 2-5 aperture is pricked on sealed membrane with pin, it is quiet
Put, room temperature volatilization, separates out water white transparency bulk crystals after 2-3 days.
9. the preparation method of Vortioxetine according to claim 4 and the new salt form of brufen, it is characterised in that the step
(2) in, solution left standstill stays overnight crystallization, filters, filter cake is vacuum dried to constant weight, obtains Vortioxetine and the new salt form of brufen.
10. the preparation method of Vortioxetine according to claim 9 and the new salt form of brufen, it is characterised in that described true
The dry temperature of sky is 60~70 DEG C, when processing time is 24-48 small.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104610195A (en) * | 2015-01-30 | 2015-05-13 | 上虞京新药业有限公司 | Aspartate of vortioxetine or hydrate thereof as well as preparation method and application thereof |
| CN104628677A (en) * | 2015-03-16 | 2015-05-20 | 浙江大学 | Crystal forms of vortioxetine organic acid salt and preparation method thereof |
-
2018
- 2018-01-29 CN CN201810082558.7A patent/CN108017596A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104610195A (en) * | 2015-01-30 | 2015-05-13 | 上虞京新药业有限公司 | Aspartate of vortioxetine or hydrate thereof as well as preparation method and application thereof |
| CN104628677A (en) * | 2015-03-16 | 2015-05-20 | 浙江大学 | Crystal forms of vortioxetine organic acid salt and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 何赛飞: "沃替西汀新盐：设计、制备、表征及性质研究", 《中国优秀硕士学位论文 全文数据库 医药卫生科技辑》 * |
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Application publication date: 20180511 |