CN105801517A - Novel crystal form of Vortioxetine hydrobromate and preparation method for novel crystal form of Vortioxetine hydrobromate - Google Patents
Novel crystal form of Vortioxetine hydrobromate and preparation method for novel crystal form of Vortioxetine hydrobromate Download PDFInfo
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- CN105801517A CN105801517A CN201410855479.7A CN201410855479A CN105801517A CN 105801517 A CN105801517 A CN 105801517A CN 201410855479 A CN201410855479 A CN 201410855479A CN 105801517 A CN105801517 A CN 105801517A
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Abstract
The invention relates to a novel crystal form of Vortioxetine hydrobromate and a preparation method for the novel crystal form of the Vortioxetine hydrobromate. The novel crystal form of the Vortioxetine hydrobromate is named a crystal form sigma, wherein in an X-ray powder diffraction atlas using Cu-K alpha radiation detection, the crystal form sigma has characteristic peaks when a 2[theta] angle is about 4.0 degrees, 11.5 degrees, 15.5 degrees, 17.7 degrees, 19.1 degrees, 20.8 degrees, 22.9 degrees, 27.2 degrees or 28.6 degrees. The invention also provides a method for preparing the novel crystal form sigma of the Vortioxetine hydrobromate. The method is simple and convenient and is good in reproducibility, and the obtained novel crystal form sigma of the Vortioxetine hydrobromate is high in purity and good in stability, so that the method is applicable to industrial production.
Description
Technical field
The present invention relates to fertile novel crystal forms for Xi Ting (1-[2-(2,4-methylphenyl-sulfanyl) phenyl] piperazine) hydrobromate and preparation method thereof.
Technical background
Fertile for western spit of fland chemistry 1-[2-(2,4-methylphenyl-sulfanyl) phenyl] piperazine by name, structural formula is such as shown in following formula I:
Fertile is developed jointly with Japan's force field (Takeda) pharmacy by Denmark Ling Bei (Lundbeck) pharmacy for Xi Ting, obtains FDA approval in JIUYUE, 2013, is used for treating severe adult's depression (MDD).Europe drug administration (EMA) subordinate people was used for treating Serious depression for Xi Ting issues Europe listing license with medicine committee (CHMP) suggestion was fertile October in the same year.
Fertile is that one has selectivity 5-hydroxy tryptamine reuptake inhibitor, 5-HT for Xi Ting3AAcceptor inhibitor, 5-HT7Acceptor inhibitor and part 5-HT1BThe newly-developed antidepressant of the multiple actions such as receptor stimulating agent, compared with existing antidepressants, has onset time, less toxic and side effects and better antidepressant activity faster.
Patent WO2007144005 discloses the fertile for western spit of fland salt (crystal free alkali, α/β/γ HBr salt, HBr semihydrate, ethyl acetate solvate and α HBr mixture, HCl salt, HCl salt monohydrate, mesylate, fumarate, maleate, mesotartaric acid salt, L/D-tartrate, sulfate, phosphate, nitrate) and preparation method thereof of crystal form.Wherein irrigate and disclose tri-kinds of solvent-free crystal forms of α, β, γ and a kind of HBr semihydrate for western spit of fland hydrobromate.The X ray diffracting characteristic peak position (° 2 θ) of alpha-crystal form is 5.85,9.30,17.49,18.58；The X ray diffracting characteristic peak position (° 2 θ) of beta crystal is 6.89,9.73,13.78,14.62；The X ray diffracting characteristic peak position (° 2 θ) of γ crystal formation is 11.82,16.01,17.22,18.84.
Patent WO2010094285 discloses a kind of fertile isopropanol solvate for western spit of fland hydrobromate, is used for removing impurity, and solvate itself cannot be applied to pharmacy as API.
In recent years, the polymorphism of drug molecule increasingly causes the extensive concern of people.Due to different polycrystalline kenels in stability, degree of dissociation, bioavailability is first-class very big difference, it is therefore desirable to drug molecule to be carried out polymorphic research as much as possible, guarantee to obtain likely obtaining different crystal forms, therefrom select the crystal formation that each side such as stability, dissolubility, dissolution and bioavailability are optimum, be applied to pharmaceutical production.
Summary of the invention
The invention discloses that a kind of good stability, purity is high, favorable reproducibility fertile for western spit of fland hydrobromate novel crystal forms δ and preparation method thereof.
The fertile western spit of fland hydrobromate novel crystal forms δ that replaces of the present invention, in the X-ray powder diffraction pattern of use Cu-K α radiation detection, has following characteristics peak, and its 2 θ angle value and relative intensity are as shown in the table:
| 2θ | Relative intensity |
| 4.0 | 100.00 |
| 11.5 | 15.4 |
| 15.5 | 1.8 |
| 17.7 | 5.3 |
| 19.1 | 14.9 |
| 20.8 | 11.3 |
| 22.9 | 12.0 |
| 27.2 | 10.7 |
| 28.6 | 10.5 |
Of the present invention irrigating has X powder diffraction collection of illustrative plates as shown in Figure 1 for western spit of fland hydrobromate novel crystal forms δ.
Of the present invention fertile for western spit of fland hydrobromate novel crystal forms δ, thermogravimetric analysis shows that it has 4.43% thermal weight loss, differential scanning calorimetry is analyzed collection of illustrative plates and is shown in about 70～90 DEG C and has endothermic peak, and there is exothermic peak at 145 DEG C of places, and there is melted endothermic peak at 226～230 DEG C and 232～234 DEG C of places.
The fertile western spit of fland hydrobromate novel crystal forms δ of replacing of the present invention has thermogravimetric analysis collection of illustrative plates as shown in Figure 2 and differential scanning calorimetry analyzes collection of illustrative plates.
Recording water content by determination of water is 4.4, identical in quality with thermal weight loss loss, it was shown that fertile is monohydrate for western spit of fland hydrobromate novel crystal forms δ.
Present invention simultaneously provides and irrigate the method for western spit of fland hydrobromate novel crystal forms δ a kind of preparation, the method includes:
Fertile will mix with aprotic solvent for western spit of fland hydrobromate under (a) room temperature, be configured to suspension；
B suspension described in step (a) is heated to being completely dissolved and filtering by ()；
C the filtrate of (b) is added the polar solvent after cooling by (), continue stirring after precipitating out solid, and filtration drying obtains fertile for western spit of fland hydrobromate novel crystal forms δ.
Preparation method of the present invention, the aprotic solvent that step (a) uses includes acetonitrile, DMF, N,N-dimethylacetamide, dimethyl sulfoxide, dimethyl sulfone.Preferred N,N-dimethylformamide.
Preparation method of the present invention, what step (c) used polar solvent includes water, methanol, ethanol, isopropanol and arbitrary proportion mixed solvent thereof.Preferred water.
Preparation method of the present invention, the chilling temperature described in step (c) is 0 DEG C to 10 DEG C, it is preferable that 1.8-3.5 DEG C.
Preparation method of the present invention, the quantity of solvent volume ratio that the quantity of solvent that step (c) uses and step (a) use is 5:1～15:1, it is preferable that 8:1～10:1.
The method for western spit of fland hydrobromate novel crystal forms δ, simple to operate, favorable reproducibility are irrigated in preparation provided by the present invention, obtain product purity height, good stability, can meet large-scale industrial production.
Accompanying drawing explanation
Accompanying drawing 1 is 1 fertile X-ray powder diffraction (XRPD) collection of illustrative plates for western spit of fland hydrobromate novel crystal forms δ obtained according to embodiments of the present invention.
Accompanying drawing 2 is the 1 fertile thermogravimetric analysis (TGA) for western spit of fland hydrobromate novel crystal forms δ obtained according to embodiments of the present invention.
The accompanying drawing 31 fertile differential scanning calorimetry for western spit of fland hydrobromate novel crystal forms δ obtained according to embodiments of the present invention analyzes collection of illustrative plates (DSC).
Detailed description of the invention
Below example is in that to describe the present invention, and the unrestricted present invention in detail.
The analysis testing conditions of the present invention is as follows:
1, X-ray powder diffraction data is that the BRUKERD8Advance using Brooker company of Germany measures, voltage x current: 40kV, 40mA；Clinometer: vertical clinometer, radius 280mm；Slit: DS=2 °, SS=1/2 °, mask=15mm, RS=5.0mm；Detector: LYNXEYE detector；Scan pattern: scan continuously；Sweep limits: 3 °-40 °；Often walk gate time: 0.2s；Scanning total time: 390s.
2, TGA is measured by the SDTQ600 of TA company of the U.S., and test condition is 120ml/minN2,10 DEG C/min of programming rate.
3, DSC is measured by the NETZSCHDSC200F3Maia of Nai Chi company of Germany, and test condition is 120ml/minN2,10 DEG C/min of programming rate.
Embodiment 1
Under room temperature, weigh 1g and irrigate for western spit of fland hydrobromate, join in the DMF of 6ml, be warming up to 75 DEG C so as to be completely dissolved, filter.Filtrate is added in the 50ml water being cooled to 2 DEG C, precipitate out solid, after continuing stirring 10min, be pumped through filter, dry and obtain the fertile for western spit of fland hydrobromate novel crystal forms δ of off-white color.
Embodiment 2
Under room temperature, weigh 1g and irrigate for western spit of fland hydrobromate, join in the DMF of 6ml, be warming up to 75 DEG C so as to be completely dissolved, filter.Filtrate is added in the 50ml water being cooled to 5 DEG C, precipitate out solid, after continuing stirring 20min, be pumped through filter, dry and obtain the fertile for western spit of fland hydrobromate novel crystal forms δ of off-white color.
Embodiment 3
Under room temperature, weigh 100g and irrigate for western spit of fland hydrobromate, join in the DMF of 600ml, be warming up to 75 DEG C so as to be completely dissolved, filter.Filtrate is added in the 5L water being cooled to 2.5 DEG C, precipitate out solid, after continuing stirring 2h, be pumped through filter, dry and obtain the fertile for western spit of fland hydrobromate novel crystal forms δ of off-white color.
Claims (8)
1. a fertile crystal formation δ for western spit of fland hydrobromate compound (Formulas I), it is characterized in that the X-ray powder diffraction pattern of described crystal formation δ includes the characteristic peak (± 0.2 °) shown in following 2 θ angles: 4.0 °, 11.5 °, 15.5 °, 17.7 °, 19.1 °, 20.8 °, 22.9 °, 27.2 °, 28.6 °.
2. as claimed in claim 1 fertile for western spit of fland hydrobromate novel crystal forms δ, it is characterized in that described crystal formation δ has 4.43% thermal weight loss, differential scanning calorimetry analysis collection of illustrative plates is shown in about 70～90 DEG C endothermic peak, there is exothermic peak at 145 DEG C of places, and there is melted endothermic peak at 226～230 DEG C and 232～234 DEG C of places.
3. as claimed in claim 1 fertile for western spit of fland hydrobromate novel crystal forms δ, it is characterised in that water content is 4.4%, for monohydrate.
4. the method preparing formula described in claim 1 (I) compound novel crystal forms δ, including: following steps
Fertile will mix with aprotic solvent for western spit of fland hydrobromate under (a) room temperature, be configured to suspension；
B suspension described in step (a) is heated to being completely dissolved and filtering by ()；
C the filtrate of (b) is added the polar solvent after cooling by (), continue stirring after precipitating out solid, and filtration drying obtains fertile for western spit of fland hydrobromate novel crystal forms δ.
5. method as claimed in claim 4, the aprotic solvent described in step (a) is selected from: acetonitrile, DMF, N,N-dimethylacetamide, dimethyl sulfoxide, dimethyl sulfone.
6. method as claimed in claim 4, the polar solvent described in step (c) is selected from: water, methanol, ethanol, isopropanol and arbitrary proportion mixed solvent thereof.Preferred water.
7. method as claimed in claim 4, the chilling temperature described in step (c) is 0 DEG C to 10 DEG C, it is preferable that 1.8-3.5 DEG C.
8. method as claimed in claim 4, the quantity of solvent volume ratio that the quantity of solvent that step (c) uses and step (a) use is 5:1～15:1, it is preferable that 8:1～10:1.
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| CN201410855479.7A CN105801517A (en) | 2014-12-30 | 2014-12-30 | Novel crystal form of Vortioxetine hydrobromate and preparation method for novel crystal form of Vortioxetine hydrobromate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109928941A (en) * | 2017-12-19 | 2019-06-25 | 成都弘达药业有限公司 | A kind of crystalline compounds and preparation method thereof of hydrobromic acid Vortioxetine |
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 |
| CN102317272A (en) * | 2009-02-17 | 2012-01-11 | H.隆德贝克有限公司 | Purification of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine |
| WO2014044721A1 (en) * | 2012-09-19 | 2014-03-27 | Sandoz Ag | Novel crystalline form of vortioxetine hydrobromide |
| CN104098530A (en) * | 2014-08-07 | 2014-10-15 | 段希福 | Preparation method of Vortioxetine |
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2014
- 2014-12-30 CN CN201410855479.7A patent/CN105801517A/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 |
| CN102317272A (en) * | 2009-02-17 | 2012-01-11 | H.隆德贝克有限公司 | Purification of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine |
| WO2014044721A1 (en) * | 2012-09-19 | 2014-03-27 | Sandoz Ag | Novel crystalline form of vortioxetine hydrobromide |
| CN104098530A (en) * | 2014-08-07 | 2014-10-15 | 段希福 | Preparation method of Vortioxetine |
Non-Patent Citations (2)
| Title |
|---|
| 叶彦春、郭燕文、黄学斌主编: "《有机化学实验（第2版）》", 28 February 2014, 北京理工大学出版社 * |
| 林友文主编: "《有机化学实验指导》", 30 November 2013, 厦门大学出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109928941A (en) * | 2017-12-19 | 2019-06-25 | 成都弘达药业有限公司 | A kind of crystalline compounds and preparation method thereof of hydrobromic acid Vortioxetine |
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