CN105330614A - vortioxetine hydrobromide crystal and preparation method thereof - Google Patents
vortioxetine hydrobromide crystal and preparation method thereof Download PDFInfo
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- CN105330614A CN105330614A CN201410376688.3A CN201410376688A CN105330614A CN 105330614 A CN105330614 A CN 105330614A CN 201410376688 A CN201410376688 A CN 201410376688A CN 105330614 A CN105330614 A CN 105330614A
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- hydrogen bromide
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Abstract
The invention discloses a vortioxetine hydrobromide crystal and a preparation method thereof. A powder X-ray diffraction pattern of the crystal shows characteristic peaks at the diffraction angle 2theta of 5.8+/-0.2, 6.9+/-0.2, 13.2+/-0.2, 14.1+/-0.2, 14.6+/-0.2, 16.2+/-0.2, 17+/-0.2, 18.2+/-0.2, 18.6+/-0.2, 19+/-0.2, 19.5+/-0.2, 20.7+/-0.2, 21.1+/-0.2, 21.6+/-0.2, 21.9+/-0.2, 22.3+/-0.2, 22.7+/-0.2, 23+/-0.2, 23.7+/-0.2, 24.4+/-0.2, 24.8+/-0.2, 25.4+/-0.2, 28.1+/-0.2, 28.5+/-0 2, and 30+/-0.2. The vortioxetine hydrobromide crystal provided by the invention has the advantages of high purity, simple preparation method, and low hygroscopicity. The crystal is not influenced by the change of environmental humidity in raw material preparation, weighing and storage, and maintains uniform and stable quality of the final product.
Description
Technical field
The present invention relates to field of medicaments, relate in particular to a kind of Hydrogen bromide fertile for western spit of fland crystal and preparation method thereof.
Background technology
Hydrogen bromide is fertile for Xi Ting (Vortioxetinehydrobromide), and chemistry 1-[2-(2,4-dimethylphenylsulfanyl) phenyl] piperazine by name, chemical structure is as shown in the formula shown in (I), and commodity are called BRINTELLIX
?.
formula (I)
Hydrogen bromide is fertile belongs to thymoleptic of new generation for Xi Ting.This medicine is played a role by combining of 2 kinds of mechanism of action: receptor active regulates and re-uptake suppresses.Research shows, Hydrogen bromide is fertile is 5-HT reuptake inhibitor for Xi Ting, is 5-HT simultaneously
3, 5-HT
7, 5-HT
1Dthe antagonist of acceptor, 5-HT
1Bthe partial agonist of acceptor, 5-HT
1Areceptor stimulant, plays antidepressant effect by regulating 5-HT.In body, non-clinical study has proved that it can increase the level of neurotransmitters seratonin, norepinephrine, Dopamine HCL, vagusstoff and histamine in brain specific region.
Hydrogen bromide is fertile is used for the treatment of major depressive disorder adult patient for Xi Ting.Major depressive disorder (MDD) is commonly called depression, is a kind of mental disorder, and be characterized in being in a bad mood change and other symptoms, can disturb the activity of the work capacity of a people, sleep, study, diet and enjoyment happiness.The outbreak usual all one's life with people of dysthymia disorders, although some people may only experience once.
Other S&S of MDD comprise daily routines are lost interest, body weight or diet generation considerable change, insomnia or drowsiness (hypersomnia), be on tenterhooks/stroll about (psychomotor agitation), tiredly to increase, compunction or petty and low sense, slowness of thinking or absent minded and introgression or suicidal thoughts.Not all MDD patient can experience identical symptom.
Polymorphism is the critical nature of compound, for most chemicals, generally all there is polymorphism, and different crystal-form substances has important impact for the stability of medicine, homogeneity, the aspect such as bioavailability and preparation.
Hydrogen bromide is irrigated has different crystal formations for Xi Ting, and document CN101472906 discloses Hydrogen bromide and irrigates three kinds of crystal formations for Xi Ting with α, β, γ, and the moisture absorption weightening finish under conditions of high humidity of these three kinds of crystal formations is respectively 0.3%, 0.6% and 2%.And prepare at raw material, weigh, transport and in preservation process, be usually difficult to guarantee that the humidity condition of environment is constant, if Hydrogen bromide is fertile cause content for Xi Ting due to moisture absorption weightening finish, final formulation products quality can be caused uneven.
Therefore research and develop a kind of agent of low hygroscopicity, highly purified medicinal crystal-form seems particularly necessity.
Summary of the invention
The invention provides a kind of Hydrogen bromide fertile for western spit of fland crystal formation and preparation method thereof, be intended to the defect making up the existence of above-mentioned prior art.
The invention provides a kind of Hydrogen bromide fertile for western spit of fland crystal formation.
Concrete technical scheme is as follows:
A kind of Hydrogen bromide is fertile for western spit of fland crystal, using in the powder x-ray diffraction collection of illustrative plates that source of radiation is Cu-K α, in diffraction angle 2 θ=5.8 ± 0.2, 6.9 ± 0.2, 13.2 ± 0.2, 14.1 ± 0.2, 14.6 ± 0.2, 16.2 ± 0.2, 17.0 ± 0.2, 18.2 ± 0.2, 18.6 ± 0.2, 19.0 ± 0.2, 19.5 ± 0.2, 20.7 ± 0.2, 21.1 ± 0.2, 21.6 ± 0.2, 21.9 ± 0.2, 22.3 ± 0.2, 22.7 ± 0.2, 23.0 ± 0.2, 23.7 ± 0.2, 24.4 ± 0.2, 24.8 ± 0.2, 25.4 ± 0.2, 28.1 ± 0.2, 28.5 ± 0.2, there is characteristic peak at 30.0 ± 0.2 degree of places, the relative intensity of corresponding characteristic peak is as shown in table 1 below:
| 2θ（°） | Relative intensity | 2θ（°） | Relative intensity |
| 5.8±0.2 | 47.4 | 21.6±0.2 | 38.5 |
| 6.9±0.2 | 72.8 | 21.9±0.2 | 41.3 |
| 13.2±0.2 | 41.2 | 22.3±0.2 | 34.1 |
| 14.1±0.2 | 67.5 | 22.7±0.2 | 72.4 |
| 14.6±0.2 | 75.9 | 23.0±0.2 | 100.0 |
| 16.2±0.2 | 42.3 | 23.7±0.2 | 54.7 |
| 17.0±0.2 | 40.7 | 24.4±0.2 | 37.5 |
| 18.2±0.2 | 69.2 | 24.8±0.2 | 38.2 |
| 18.6±0.2 | 54.1 | 25.4±0.2 | 36.7 |
| 19.0±0.2 | 45.8 | 28.1±0.2 | 38.1 |
| 19.5±0.2 | 39.0 | 28.5±0.2 | 30.7 |
| 20.7±0.2 | 72.0 | 30.0±0.2 | 53.2 |
| 21.1±0.2 | 39.9 |
Table 1
Present invention also offers a kind of above-mentioned Hydrogen bromide and irrigate preparation method for western spit of fland crystal.
Concrete technical scheme is as follows:
A preparation method for western spit of fland crystal is irrigated to Hydrogen bromide described in claim 1, comprises the steps:
Step one: fertile for the existing Hydrogen bromide Xi Ting of replacing is dissolved in isopropanol water solution and obtains mixed solution;
Step 2: step one gained mixed solution is heated to backflow clarification;
Step 3: filter after the mixed solution cooling of step 2 gained backflow clarification, solid is carried out vacuum drying, obtain Hydrogen bromide fertile for western spit of fland crystal.
Preferably, existing Hydrogen bromide described in step one is irrigated for Xi Ting is one or more in α, β, γ tri-kinds of crystal formations.
Preferably, the volume percent of isopropanol water solution described in step one is 20%-40%.
Further, the volume percent of isopropanol water solution described in step one is 30%.
Preferably, the temperature of vacuum drying described in step 3 is 45-100 DEG C.
Further, the temperature of vacuum drying described in step 3 is 70 DEG C.
Preferably, the volume mass ratio for Xi Ting irrigated by isopropanol water solution described in step one and described existing Hydrogen bromide is 3 ~ 100ml/g.
Further, the volume mass ratio for Xi Ting irrigated by isopropanol water solution described in step one and described existing Hydrogen bromide is 10ml/g.
Compared with prior art, Hydrogen bromide of the present invention irrigates that purity for western spit of fland crystal is high, preparation method is easy, and water absorbability is low.Prepare, weigh, transport and be not subject in preservation process the impact of ambient moisture change at raw material, maintain final formulation products uniform quality and stablize.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that Hydrogen bromide that embodiment 1-3 obtains irrigates for western spit of fland crystal;
Fig. 2 is that in comparative example, the X-ray powder diffraction for western spit of fland beta crystal irrigated by Hydrogen bromide;
Fig. 3 is the comparison diagram of Fig. 1 and Fig. 2.
Embodiment
Below in conjunction with accompanying drawing and embodiment, the present invention will be further described.
Embodiment 1:
By fertile for 1g Hydrogen bromide for Xi Ting add 10ml volume percent be 30% methyl alcohol water-soluble in, reflux molten clear after be down to stirring at room temperature and filter, filter rear 70 DEG C of vacuum dryings and obtain 0.79g crystal, it is 99.88% that HPLC shows purity.
Embodiment 2:
By fertile for 0.7g Hydrogen bromide for Xi Ting add 50ml volume percent be 40% methyl alcohol water-soluble in, reflux molten clear after be down to stirring at room temperature and filter, filter rear 90 DEG C of vacuum and dry to obtain dry 0.65g crystal, it is 99.80% that HPLC shows purity.
Embodiment 3:
By fertile for 1.0g Hydrogen bromide for Xi Ting add 5ml volume percent be 70% methyl alcohol water-soluble in, reflux molten clear after be down to stirring at room temperature and filter, filter rear 80 DEG C of vacuum and dry to obtain dry 0.83g crystal, it is 99.85% that HPLC shows purity.
Comparative example 1:
Add 10ml methyl alcohol by fertile for 1g Hydrogen bromide for Xi Ting, stir after being heated to reflux and be cooled to 25 DEG C.After filtering, solid vacuum drying obtains 0.6g beta crystal solid.It is 99.78% that HPLC shows purity.
Comparative example 2:
Add 10ml water by fertile for 1g Hydrogen bromide in western spit of fland, stir after being heated to reflux and be cooled to 25 DEG C.After filtering, solid vacuum drying obtains 0.47g beta crystal solid.It is 99.68% that HPLC shows purity.
By embodiment 1,2,3 gained Hydrogen bromides are fertile carries out powder x-ray diffraction respectively for western spit of fland crystal and the fertile western spit of fland β crystal that replaces of comparative example 1,2 gained Hydrogen bromide, and source of radiation is Cu-K α.
Fig. 1 is embodiment 1, and the X-ray diffracting spectrum for western spit of fland crystal irrigated by 2,3 gained Hydrogen bromides.
Fig. 2 is comparative example 1, and the X-ray diffracting spectrum for western spit of fland β crystal irrigated by 2 gained Hydrogen bromides.
Fig. 3 is the comparison diagram of Fig. 1, Fig. 2.
Getting dry tool plug glass weighing bottle is placed in growth cabinet in test the day before yesterday, (design temperature is 25 DEG C ± 1 DEG C, relative humidity 80% ± 2%).Accurately weighed weight is m1.Example 1-3 gained Hydrogen bromide is fertile for western spit of fland crystal respectively, and comparative example 1-2 gained Hydrogen bromide is fertile appropriate for western spit of fland β crystal, is laid in above-mentioned weighing bottle, accurately weighed quality m2.Weighing bottle is uncovered, and with bottle cap with being placed in 24h under above-mentioned fixed temperature and humidity condition.Build weighing bottle lid, accurately weighed weight m3.Calculate percentage weight increase, result is as shown in table 2 below.
| m 1（g） | m2（g） | m3（g） | Percentage weight increase | |
| Embodiment 1 | 19.5594 | 20.6378 | 20.6397 | 0.18% |
| Embodiment 2 | 20.0223 | 21.2338 | 21.2358 | 0.17% |
| Embodiment 3 | 19.2364 | 20.3219 | 20.324 | 0.19% |
| Comparative example 1 | 19.6894 | 20.7786 | 20.7855 | 0.63% |
| Comparative example 2 | 20.2346 | 21.3452 | 21.3516 | 0.58% |
Table 2
Observation table 2 can be reached a conclusion, Hydrogen bromide provided by the invention is fertile fertile far below existing Hydrogen bromide for western spit of fland crystal formation hydroscopicity for western spit of fland crystal hydroscopicity, can prepare, weigh, transport and not be subject in preservation process the impact of ambient moisture change at raw material, maintain the uniform and stable of final formulation products quality.And purity is higher.
The above, be only a few embodiments of the present invention, the present invention is not limited to the restriction of above-described embodiment, all above-described embodiment is done according to technical spirit of the present invention similar amendment, change and replacement, still belong in the scope of technical solution of the present invention.Protection scope of the present invention is only defined by claims.
Claims (9)
1. a Hydrogen bromide is fertile for western spit of fland crystal, it is characterized in that: using in the powder x-ray diffraction collection of illustrative plates that source of radiation is Cu-K α, in diffraction angle 2 θ=5.8 ± 0.2, 6.9 ± 0.2, 13.2 ± 0.2, 14.1 ± 0.2, 14.6 ± 0.2, 16.2 ± 0.2, 17.0 ± 0.2, 18.2 ± 0.2, 18.6 ± 0.2, 19.0 ± 0.2, 19.5 ± 0.2, 20.7 ± 0.2, 21.1 ± 0.2, 21.6 ± 0.2, 21.9 ± 0.2, 22.3 ± 0.2, 22.7 ± 0.2, 23.0 ± 0.2, 23.7 ± 0.2, 24.4 ± 0.2, 24.8 ± 0.2, 25.4 ± 0.2, 28.1 ± 0.2, 28.5 ± 0.2, there is characteristic peak at 30.0 ± 0.2 degree of places, the relative intensity of corresponding characteristic peak is respectively: 47.4,72.8,41.2,67.5,75.9,42.3,40.7,69.2,54.1,45.8,39.0,72.0,39.9,38.5,41.3,34.1,72.4,100.0,54.7,37.5,38.2,36.7,38.1,30.7,53.2.
2. the preparation method for western spit of fland crystal is irrigated to Hydrogen bromide described in claim 1, it is characterized in that: comprise the steps:
Step one: fertile for the existing Hydrogen bromide Xi Ting of replacing is dissolved in isopropanol water solution and obtains mixed solution;
Step 2: step one gained mixed solution is heated to backflow clarification;
Step 3: filter after the mixed solution cooling of step 2 gained backflow clarification, solid is carried out vacuum drying, obtain Hydrogen bromide fertile for western spit of fland crystal.
3. the preparation method for western spit of fland crystal irrigated by Hydrogen bromide as claimed in claim 2, it is characterized in that: it is one or more in α, β, γ tri-kinds of crystal formations that existing Hydrogen bromide described in step one is irrigated for Xi Ting.
4. the preparation method for western spit of fland crystal irrigated by Hydrogen bromide as claimed in claim 2, it is characterized in that: the volume percent of isopropanol water solution described in step one is 20%-40%.
5. the preparation method for western spit of fland crystal irrigated by Hydrogen bromide as claimed in claim 4, it is characterized in that: the volume percent of isopropanol water solution described in step one is 30%.
6. the preparation method for western spit of fland crystal irrigated by Hydrogen bromide as claimed in claim 2, it is characterized in that: the temperature of vacuum drying described in step 3 is 45-100 DEG C.
7. the preparation method for western spit of fland crystal irrigated by Hydrogen bromide as claimed in claim, it is characterized in that: the temperature of vacuum drying described in step 3 is 70 DEG C.
8. as described in any one of claim 2-7, the preparation method for western spit of fland crystal irrigated by Hydrogen bromide, it is characterized in that: the volume mass ratio that isopropanol water solution described in step one and described existing Hydrogen bromide are irrigated for Xi Ting is 3 ~ 100ml/g.
9. the preparation method for western spit of fland crystal irrigated by Hydrogen bromide as claimed in claim 8, it is characterized in that: the volume mass ratio that isopropanol water solution described in step one and described existing Hydrogen bromide are irrigated for Xi Ting is 10ml/g.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108069924A (en) * | 2016-11-11 | 2018-05-25 | 浙江京新药业股份有限公司 | The preparation method of Vortioxetine hydrobromate alpha-crystal form |
| CN108069925A (en) * | 2016-11-16 | 2018-05-25 | 浙江京新药业股份有限公司 | Vortioxetine hydrobromate anhydrous crystal forms I and its preparation method and application |
| CN110156720A (en) * | 2018-02-12 | 2019-08-23 | 成都弘达药业有限公司 | A kind of crystallite and preparation method thereof of hydrobromic acid Vortioxetine |
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| CN101472906A (en) * | 2006-06-16 | 2009-07-01 | 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 |
| WO2014044721A1 (en) * | 2012-09-19 | 2014-03-27 | Sandoz Ag | Novel crystalline form of vortioxetine hydrobromide |
| CN104130212A (en) * | 2014-07-01 | 2014-11-05 | 安徽省逸欣铭医药科技有限公司 | Synthesis method suitable for industrialized production of vortioxetine hydrobromide |
| CN105198837A (en) * | 2014-06-09 | 2015-12-30 | 上海医药工业研究院 | Vortioxetine hydrobromide crystal and preparing method thereof |
-
2014
- 2014-08-04 CN CN201410376688.3A patent/CN105330614A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101472906A (en) * | 2006-06-16 | 2009-07-01 | 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 |
| WO2014044721A1 (en) * | 2012-09-19 | 2014-03-27 | Sandoz Ag | Novel crystalline form of vortioxetine hydrobromide |
| CN105198837A (en) * | 2014-06-09 | 2015-12-30 | 上海医药工业研究院 | Vortioxetine hydrobromide crystal and preparing method thereof |
| CN104130212A (en) * | 2014-07-01 | 2014-11-05 | 安徽省逸欣铭医药科技有限公司 | Synthesis method suitable for industrialized production of vortioxetine hydrobromide |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108069924A (en) * | 2016-11-11 | 2018-05-25 | 浙江京新药业股份有限公司 | The preparation method of Vortioxetine hydrobromate alpha-crystal form |
| CN108069925A (en) * | 2016-11-16 | 2018-05-25 | 浙江京新药业股份有限公司 | Vortioxetine hydrobromate anhydrous crystal forms I and its preparation method and application |
| CN110156720A (en) * | 2018-02-12 | 2019-08-23 | 成都弘达药业有限公司 | A kind of crystallite and preparation method thereof of hydrobromic acid Vortioxetine |
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Application publication date: 20160217 |