CN105111167A - Vortioxetine semi-hydrochloride, preparation method therefor, and pharmaceutical composition thereof - Google Patents
Vortioxetine semi-hydrochloride, preparation method therefor, and pharmaceutical composition thereof Download PDFInfo
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- CN105111167A CN105111167A CN201510477480.5A CN201510477480A CN105111167A CN 105111167 A CN105111167 A CN 105111167A CN 201510477480 A CN201510477480 A CN 201510477480A CN 105111167 A CN105111167 A CN 105111167A
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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 present invention discloses a vortioxetine semi-hydrochloride, a preparation method therefor, and a pharmaceutical composition thereof. The vortioxetine semi-hydrochloride is as shown in the formula I; a space group of the salt is a monoclinic system; two vortioxetine molecules share one proton; and a hydrogen bond N-H ... Cl- is combined with vortioxetine to form a basic structural unit. The vortioxetine semi-hydrochloride provided by the invention has a stable crystal form and high crystallinity; the preparation method is simple; and the crystal does not contain a solvent.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, relate to fertile for Xi Ting half hydrochloride and preparation method thereof in particular.
Background technology
Fertile for western spit of fland hydrobromate (vortioxetinehydrobromide), chemistry 1-[2-[(2 by name, 4-3,5-dimethylphenyl) sulfydryl] phenyl]-piperazine hydrobromide is by the medicine being used for the treatment of major depressive disorder and generalized anxiety disorder of military field (Takeda) drugmaker of Denmark Ling Bei (Lundbeck) drugmaker and Japan cooperative research and development.This medicine obtains U.S. FDA approval listing in September, 2013, trade(brand)name Brintellix.This medicine also obtains final approval on December 27th, 2013 in European Union.The fertile activeconstituents for western spit of fland hydrobromate replaces Xi Ting (vortioxetine) for fertile, it is the inhibitor of serotonin transporter, and Active Regulation is carried out to its acceptor simultaneously, also be 5-HT3A acceptor inhibitor, 5-HT7 acceptor inhibitor and part 5-HT1B receptor stimulant, regulate two kinds of mechanism to combine by re-uptake suppression and receptor active and play a role.The fertile CAS accession number for Xi Ting is 508233-74-7, and its chemistry is by name: 1-[2-(2,4-dimethylphenylsulfanyl) phenyl] piperazine, and chemical structural formula is as follows:
WO03029232 makes public for the first time fertile for Xi Ting, synthetic method and be applied to the treatment of dysthymia disorders.WO2007144005A1 and WO2008113359A2 discloses the fertile form for western spit of fland salt that can be medicinal, all disclose fertile for Xi Ting, fertile for western spit of fland hydrobromate, fertile for western spit of fland hydrobromate semihydrate, fertile for western spit of fland maleate, fertile for western spit of fland hydrochloride, fertile for western spit of fland hydrochloride hydrate, fertile for western spit of fland mesylate, fertile for western spit of fland bitartrate, fertile for western spit of fland hydrosulfate, fertile for western spit of fland dihydrogen phosphate, the fertile crystal formation for western spit of fland nitrate etc., wherein essentially disclosing fertilely has α, β, γ tri-kinds of crystalline forms for western spit of fland hydrobromate.
At present conventional fertilely have the crystal formation easily problem such as conversion, moisture absorption mutually for western spit of fland bromate, especially the fertile of different crystal forms has different solubleness for western spit of fland hydrobromate, calculate for western spit of fland alkali with fertile, the solubleness of α type is 2.0mg/mL, the solubleness of β type is 1.2mg/mL, and the conversion due to crystal formation may cause preparation to have obvious otherness in drug-eluting and bioavailability.The fertile western spit of fland hydrobromate that replaces easily forms solvate, and the existence of solvate usually causes the poor stability of medicine, is not suitable for the exploitation of preparation.
Active substance form has tremendous influence for pharmaceutical solid preparation, and medicine combines with acid and forms physico-chemical property and the bioavailability that salt can improve active constituents of medicine to a certain extent, expand active medicine raw material form scope, therefore developing the new pharmaceutically useful fertile new crystal for western spit of fland salt, crystal or known salts, is that current pharmaceutical industry is necessary.
Summary of the invention
Commercial goods Brintellix a kind ofly irrigates oral tablet for western spit of fland hydrobromate containing beta crystal.The first object of the present invention is for the existing fertile deficiency for western spit of fland medicine material form, provide a kind of can be medicinal fertile for Xi Ting half hydrochloride and crystal thereof.
Two of object of the present invention is to provide a kind of preparation simple to operate to irrigate method for Xi Ting half hydrochloric acid.
The fertile Xi Ting half hydrochloride chemical formula that replaces of the present invention is such as formula shown in I:
Described is fertile for Xi Ting half hydrochloride, and the spacer of its crystal is oblique system, axial length
α=90 °, β=92.63 ± 0.2 °, γ=90 °.
Described is fertile for Xi Ting half hydrochloride, uses Cu-k α radiation, in the Powder XRD pattern represented with 2 θ angles, has diffraction peak at 4.2 ± 0.2 °, 8.4 ± 0.2 °, 12.2 ± 0.2 °, 14.2 ± 0.2 °, 14.9 ± 0.2 ° places.
Further, described is fertile for Xi Ting half hydrochloride, use Cu-k α radiation, in the Powder XRD pattern represented with 2 θ angles, diffraction peak is had, as shown in Figure 2 at 4.2 ± 0.2 °, 8.4 ± 0.2 °, 12.2 ± 0.2 °, 14.2 ± 0.2 °, 14.9 ± 0.2 °, 16.7 ± 0.2 °, 17.4 ± 0.2 °, 19.1 ± 0.2 °, 21.8 ± 0.2 °, 23.0 ± 0.2 °, 24.4 ± 0.2 °, 25.2 ± 0.2 °, 29.3 ± 0.2 °, 31.3 ± 0.2 ° places.
Described is fertile for Xi Ting half hydrochloride, and in the structural unit of its crystal, two fertile atom N for western spit of fland molecule share a hydrogen ion, form NH
+n structure, two fertile for the hydrogen atom in the molecule atom N of western spit of fland and a Cl
-ion forms two N-HCl
-hydrogen bond, by the alternately arrangement of two kinds of patterns, fertile Xi Ting half hydrochloride that replaces defines one-dimensional catenary structure, as shown in Figure 1.
Described fertile for Xi Ting half hydrochloride crystal, start to decompose at 214 ± 2 DEG C, corresponding thermogravimetric analysis as shown in Figure 3.
Described fertile for Xi Ting half hydrochloride crystal, the infrared spectra that its KBr compressing tablet measures as shown in Figure 4.
The described fertile preparation method for Xi Ting half hydrochloride, comprises the steps:
(1) dissolve fertile in organic solvent for Xi Ting, form homogeneous phase solution;
(2) hydrogen chloride gas passed into or dilute hydrochloric acid solution be added drop-wise in above-mentioned solution, stirring, crystallization, obtaining fertile for Xi Ting half hydrochloride crystal; Described dilute hydrochloric acid solution is by concentrated hydrochloric acid alcohols or nitrile dilution.
Organic solvent described in step (1) and the fertile volume mass for Xi Ting are than being (5-50): 1, and described organic solvent is the low-carbon alcohol of C1-C4, ether, ethyl acetate or acetonitrile.
Organic solvent described in step (1) and the fertile volume mass for Xi Ting are than being (20-40): 1; The multiple of step (2) described dilution is 5-20 times.
Pass into the amount of hydrogen chloride gas to liquid no longer increases weight; Described dilute hydrochloric acid and the fertile mol ratio for Xi Ting are (0.3 ~ 0.5): 1.
Preferably, the recrystallization temperature described in step (2) is 0-50 DEG C, is more preferably room temperature.
A kind of pharmaceutical composition, comprises described irrigating for Xi Ting half hydrochloride.
It is in suitable organic solvent, react salify for Xi Ting with hydrogen chloride gas or dilute hydrochloric acid prepare with fertile that the present invention irrigates for Xi Ting half hydrochloride crystal, and replace compared with the salt of western spit of fland with existing irrigating, tool of the present invention has the following advantages:
(1) the invention provides a kind of newly fertile for Xi Ting half hydrochloride medicinal forms;
(2) provided by the present invention fertile for Xi Ting half hydrochloric acid stable crystal form, degree of crystallinity is high;
(3) the fertile preparation method for Xi Ting half hydrochloric acid provided by the present invention is simple to operate, not containing solvent in crystal;
(4) one provided by the invention is described fertile for Xi Ting half hydrochloride crystal, be place 24 hours under the environment of 80% in relative humidity, water regain is less than 0.3%, is conducive to the accurate quantitative analysis in production process and resists the content caused because of environmental factors uneven.
Accompanying drawing explanation
Fig. 1 is that the present invention is fertile for Xi Ting half hydrochloric acid crystalline structure cell schematics.
Fig. 2 is that the fertile powder X-ray RD for Xi Ting half hydrochloride of embodiment 1 schemes.
Fig. 3 is that the fertile TG for Xi Ting half hydrochloride of embodiment 1 schemes.
Fig. 4 is that the fertile IR for Xi Ting half hydrochloride of embodiment 1 schemes.
Fig. 5 is that embodiment 1 is fertile for Xi Ting half hydrochloride
1h-NMR schemes.
Fig. 6 is that the fertile powder X-ray RD for Xi Ting half hydrochloride of embodiment 3 schemes.
Embodiment
Below in conjunction with specific embodiment, the present invention is more specifically described in detail, but embodiments of the present invention are not limited thereto, for the parameter do not indicated especially, can refer to routine techniques and carry out.
Crystalline structure is measured by X-ray single crystal diffractometer, and full name is: BrukerApexIICCD single crystal diffractometer.
Nuclear-magnetism spectrum adopts Switzerland Bruker company AvanceIII400MHz nmr determination, and deuterated dimethyl sulfoxide makees solvent.
Powder XRD pattern is that D8ADVANCE diffractometer measures by the model adopting German Bruker company to produce.
Thermogravimetric analysis adopts German NETZSCH company STA449F3 synchronous solving to measure, and adopts nitrogen atmosphere, heat-up rate 10 DEG C/min.
Infrared spectra adopts German Bruker company VERTEX33FT-IR Instrument measuring, KBr compressing tablet.
Embodiment 1
Add in the side of the H pipe of intercommunication and irrigate ethanolic soln 4mL for Xi Ting containing 0.1g; H pipe opposite side adds massfraction 38% concentrated hydrochloric acid 1mL, continues to add ethanol 3mL.Close H pipe and make hydrogen chloride gas slowly diffusion in H pipe, after 72 hours, obtain white crystal.
As shown in Figure 1, as shown in Figure 2, as shown in Figure 3, IR schemes as shown in Figure 4 TG figure powder X-ray RD figure the structural unit schematic diagram of this crystal,
1h-NMR is (* represents the characteristic peak of solvent) as shown in Figure 5.
Embodiment 2
Getting the fertile Xi Ting that replaces of 10g adds in 350mL acetonitrile, heated and stirred makes it dissolve completely, in container, hydrogen chloride gas is passed into again to no longer increasing weight under stirring, suction filtration solids under room temperature, be dried to constant weight with 10mL acetonitrile wash, must irrigate for Xi Ting half hydrochloride salt as white powder 9.8g, the powdery diffractometry of this solid is fertile consistent for Xi Ting half hydrochloride with formula (I).
1H-NMR(d
6-DMSO,δppm):7.33(d,1H),7.24(s,1H),7.07-7.14(m,3H),6.87-7.01(m,1H),6.40(d,1H),3.04(s,8H),2.32(s,3H),2.24(s,3H)。
Embodiment 3
Getting the fertile Xi Ting that replaces of 10g adds in 250mL methyl alcohol, stirring makes it dissolve completely, in container, hydrogen chloride gas is passed into again to no longer increasing weight under stirring, suction filtration solids under room temperature, be dried to constant weight by 10mL methanol wash, must irrigate for Xi Ting half hydrochloride salt as white powder 9.3g, the powdery diffractometry of this solid is fertile consistent for Xi Ting half hydrochloride with thermogravimetric analysis and formula (I).
Embodiment 4
The preparation of dilute hydrochloric acid ethanolic soln: get massfraction 38% concentrated hydrochloric acid 10mL, become 100mL with alcohol dilution, be referred to as dilute hydrochloric acid ethanolic soln.
Getting the fertile Xi Ting that replaces of 10g adds in 300mL ethyl acetate, heating makes it dissolve completely, 13mL dilute hydrochloric acid ethanolic soln is dripped wherein again under stirring, separate out fertile for Xi Ting half hydrochloride salt as white powder, stir suction filtration solids after 40 minutes, also dry with the washing of 10mL ethyl acetate, must irrigate for Xi Ting half hydrochloride salt as white powder 8.4g.The infrared spectrogram of this solid is fertile consistent for Xi Ting half hydrochloride with formula (I).
Ultimate analysis (the fertile molecular weight for Xi Ting half hydrochloride calculates according to 316.7): Cl:5.58 (calculated value: 5.61).
Embodiment 5
Getting the fertile Xi Ting that replaces of 10g adds in 450mL ether, stirring makes it dissolve completely, 10mL dilute hydrochloric acid ethanolic soln is dripped wherein again under stirring, separate out fertile for Xi Ting half hydrochloride salt as white powder, stir suction filtration solids after 30 minutes, drain with 20mL washed with diethylether, must irrigate for Xi Ting half hydrochloride salt as white powder 7.4g.The powdery diffractometry of this solid is fertile consistent for Xi Ting half hydrochloride with thermogravimetric analysis and formula (I).
Embodiment 6
Getting the fertile Xi Ting that replaces of 10g adds in 450mL ether, stirring makes it dissolve completely, in container, hydrogen chloride gas is passed into again to no longer increasing weight under stirring, suction filtration solids under room temperature, be dried to constant weight with 20mL washed with diethylether, must irrigate for Xi Ting half hydrochloride salt as white powder 10.2g, the powdery diffractometry of this solid is fertile consistent for Xi Ting half hydrochloride with infrared spectra and formula (I).
Embodiment 7
Stability test
The fertile of Example 3 replaces Xi Ting half hydrochloride crystal, gets appropriate in the plane ware being numbered 1,2 and 3 respectively, is placed in (storage condition 1:4500 ± 500lx the illumination of following condition respectively; Storage condition 2:60 DEG C high temperature; Storage condition 3: relative humidity 92.5 high humidity) carry out stability test.Test result is as shown in table 1.
Table 1 is fertile for Xi Ting half hydrochloride study on the stability
Compared with the sample started with experiment, at whole experimental session, the fertile content for Xi Ting half hydrochloride and maximum list content of mixing does not change, and fertilely for Xi Ting half hydrochloride, transformation of crystal does not occur, prove that of the present invention irrigating replaces Xi Ting half hydrochloride to be quite stable, be applicable to prolonged storage.Powder XRD analysis shows, fertile Xi Ting half hydrochloride Form that replaces is stablized, and transformation of crystal does not occur.
Embodiment 8
The fertile prescription for Xi Ting half hydrochloride sheet (containing fertile for western spit of fland 10mg):
The mensuration of the fertile dissolution rate for Xi Ting half hydrochloride sheet: get 6, tablet, measure according to dissolution method [Chinese Pharmacopoeia version in 2010 two annex XC second methods].Measure medium: pH7.0 phosphate buffer solution; Slurry processes; Rotating speed 50rpm, operates in accordance with the law.Respectively at 5,10,15,20,30,40,60min sampling, adopt high-performance liquid chromatography method, the results are shown in Table 2.
The fertile dissolution determination (n=6) for Xi Ting half hydrochloride sheet of table 2
Result illustrates: irrigate and replace Xi Ting half hydrochloride sheet through 15min dissolution rate more than 80%, complete stripping in 60min.With fertile for compared with the hydrobromate sheet of western spit of fland, be 62.6% containing the present invention's preparation accumulation dissolution rate 10 minutes time that to irrigate for Xi Ting half hydrochloride be raw material, replace 73% of the accumulation dissolution rate of the preparation that western spit of fland hydrobromate is raw material with fertile, basically identical both 40 minutes time, illustrate and of the present inventionly fertile can avoid prominently releasing phenomenon for the Xi Ting half hydrochloride preparation that is raw material, good drug level can be kept again, be suitable for exploitation and the manufacture of medicament.
Claims (10)
1. fertile for Xi Ting half hydrochloride, it is characterized in that, its chemical formula is as shown in I:
2. according to claim 1 fertile for Xi Ting half hydrochloride, it is characterized in that, the spacer of its crystal is oblique system, axial length
α=90 °, β=92.63 ± 0.2 °, γ=90 °.
3. according to claim 2 fertile for Xi Ting half hydrochloride, it is characterized in that, use Cu-k α radiation, in the Powder XRD pattern represented with 2 θ angles, have diffraction peak at 4.2 ± 0.2 °, 8.4 ± 0.2 °, 12.2 ± 0.2 °, 14.2 ± 0.2 °, 14.9 ± 0.2 ° places; Further, use Cu-k α radiation, in the Powder XRD pattern represented with 2 θ angles, there is diffraction peak at 4.2 ± 0.2 °, 8.4 ± 0.2 °, 12.2 ± 0.2 °, 14.2 ± 0.2 °, 14.9 ± 0.2 °, 16.7 ± 0.2 °, 17.4 ± 0.2 °, 19.1 ± 0.2 °, 21.8 ± 0.2 °, 23.0 ± 0.2 °, 24.4 ± 0.2 °, 25.2 ± 0.2 °, 29.3 ± 0.2 °, 31.3 ± 0.2 ° places.
4. irrigating for Xi Ting half hydrochloride according to claim 1 or 2 or 3, is characterized in that, in the structural unit of its crystal, two fertile atom N for western spit of fland molecule share hydrogen ions, formation NH
+n structure, two fertile for the hydrogen atom in the molecule atom N of western spit of fland and a Cl
-ion forms two N-HCl
-hydrogen bond, by the alternately arrangement of two kinds of patterns, fertile Xi Ting half hydrochloride that replaces defines one-dimensional catenary structure.
5. irrigating for Xi Ting half hydrochloride according to claim 1 or 2 or 3 or 4, is characterized in that, its crystal starts to decompose at 214 ± 2 DEG C; The infrared spectra that its KBr compressing tablet measures as shown in Figure 4.
6. the fertile preparation method for Xi Ting half hydrochloride described in any one of Claims 1 to 5, is characterized in that, comprise the steps:
(1) dissolve fertile in organic solvent for Xi Ting, form homogeneous phase solution;
(2) hydrogen chloride gas passed into or dilute hydrochloric acid solution be added drop-wise in above-mentioned solution, stirring, crystallization, obtaining fertile for Xi Ting half hydrochloride crystal; Described dilute hydrochloric acid solution is by concentrated hydrochloric acid alcohols or nitrile dilution.
7. preparation method according to claim 6, it is characterized in that, organic solvent described in step (1) and the fertile volume mass for Xi Ting are than being (5-50): 1, and described organic solvent is the low-carbon alcohol of C1-C4, ether, ethyl acetate or acetonitrile.
8. preparation method according to claim 7, is characterized in that, organic solvent described in step (1) and the fertile volume mass for Xi Ting are than being (20-40): 1; The multiple of step (2) described dilution is 5-20 times.
9. the preparation method according to claim 6 or 7 or 8, is characterized in that, passes into the amount of hydrogen chloride gas to liquid no longer increases weight; Described dilute hydrochloric acid and the fertile mol ratio for Xi Ting are (0.3 ~ 0.5): 1.
10. a pharmaceutical composition, is characterized in that, comprises irrigating for Xi Ting half hydrochloride described in any one of Claims 1 to 5.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105380921A (en) * | 2015-12-15 | 2016-03-09 | 中山万汉医药科技有限公司 | Preparation method of vortioxetine hydrobromide tablet |
| CN106596798A (en) * | 2017-01-23 | 2017-04-26 | 合肥创新医药技术有限公司 | Method for analyzing related substances in vortioxetine hydrobromide |
| CN106674153A (en) * | 2015-11-05 | 2017-05-17 | 浙江京新药业股份有限公司 | Vortioxetine hemihydrochloride crystal and composition, preparation and application thereof |
| CN107011289A (en) * | 2017-03-10 | 2017-08-04 | 万全万特制药（厦门）有限公司 | The preparation method of Vortioxetine beta crystal |
| CN112438979A (en) * | 2019-09-04 | 2021-03-05 | 普济生物科技（台州）有限公司 | Vortioxetine hydrobromide-containing coated particles, solid dispersions and formulations for oral taste masking |
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| CN102617513A (en) * | 2006-06-16 | 2012-08-01 | H.隆德贝克有限公司 | 1- [2- (2,4-dimethylphenylsulfanyl)-phenyl] piperazine as a compound with combined serotonin reuptake, 5-HT3 AND 5-HT1A activity for the treatment of cognitive impairment |
| WO2015035802A1 (en) * | 2013-09-12 | 2015-03-19 | 杭州普晒医药科技有限公司 | Vortioxetine salt and crystal thereof, their preparation method, pharmaceutical compositions and usage |
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2015
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102617513A (en) * | 2006-06-16 | 2012-08-01 | H.隆德贝克有限公司 | 1- [2- (2,4-dimethylphenylsulfanyl)-phenyl] piperazine as a compound with combined serotonin reuptake, 5-HT3 AND 5-HT1A activity for the treatment of cognitive impairment |
| WO2015035802A1 (en) * | 2013-09-12 | 2015-03-19 | 杭州普晒医药科技有限公司 | Vortioxetine salt and crystal thereof, their preparation method, pharmaceutical compositions and usage |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106674153A (en) * | 2015-11-05 | 2017-05-17 | 浙江京新药业股份有限公司 | Vortioxetine hemihydrochloride crystal and composition, preparation and application thereof |
| CN105380921A (en) * | 2015-12-15 | 2016-03-09 | 中山万汉医药科技有限公司 | Preparation method of vortioxetine hydrobromide tablet |
| CN105380921B (en) * | 2015-12-15 | 2017-06-09 | 中山万汉制药有限公司 | A kind of preparation method of hydrobromic acid Vortioxetine piece |
| CN106596798A (en) * | 2017-01-23 | 2017-04-26 | 合肥创新医药技术有限公司 | Method for analyzing related substances in vortioxetine hydrobromide |
| CN106596798B (en) * | 2017-01-23 | 2020-06-26 | 合肥创新医药技术有限公司 | Analysis method of related substances in vortioxetine hydrobromide |
| CN107011289A (en) * | 2017-03-10 | 2017-08-04 | 万全万特制药（厦门）有限公司 | The preparation method of Vortioxetine beta crystal |
| CN112438979A (en) * | 2019-09-04 | 2021-03-05 | 普济生物科技（台州）有限公司 | Vortioxetine hydrobromide-containing coated particles, solid dispersions and formulations for oral taste masking |
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Application publication date: 20151202 |