CN107954947A - Vortioxetine hydrobromate crystal form C and preparation method thereof - Google Patents

Vortioxetine hydrobromate crystal form C and preparation method thereof Download PDF

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Publication number
CN107954947A
CN107954947A CN201610901186.7A CN201610901186A CN107954947A CN 107954947 A CN107954947 A CN 107954947A CN 201610901186 A CN201610901186 A CN 201610901186A CN 107954947 A CN107954947 A CN 107954947A
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Prior art keywords
crystal form
vortioxetine
formula
vortioxetine hydrobromate
semihydrate
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张小波
崔东冬
张玉良
方拥军
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BEIJING LUNARSUN MEDICAL TECHNOLOGY Co Ltd
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BEIJING LUNARSUN MEDICAL TECHNOLOGY Co Ltd
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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
    • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses the novel crystal forms C of Vortioxetine hydrobromate semihydrate, and disclose its preparation method and pharmaceutical composition.The powder diffraction spectrum of the novel crystal forms C of Vortioxetine hydrobromate semihydrate is comprising 2 θ ± 0.20o：4.50,6.10,7.74,11.10,12.20,19.08,25.20,27.62 characteristic peak.Novel crystal forms solubility is good, and physicochemical properties are stablized, suitable for various forms preparation.Crystal form preparation process is simple, is easy to convert industry size, is adapted to industrialized production.

Description

Vortioxetine hydrobromate crystal form C and preparation method thereof
Technical field
The present invention relates to medicinal chemistry arts, and in particular to Vortioxetine hydrobromate crystal form C, its preparation method and contains The pharmaceutical composition and its pharmaceutical applications of the compound of therapeutically effective amount.
Background technology
Vortioxetine hydrobromate (Vortioxetine Hydrobromide, Brintellix), the entitled 1- [2- of chemistry (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide, CAS：960203-27-4, structural formula such as formula（I）It is described：
（Ι）.
Vortioxetine hydrobromate is the inhibitor of serotonin transporter, and carries out Active Regulation to its acceptor, by Lundbeck (Lundbeck) and military field (Takeda) are developed jointly.In September, 2013 obtains FDA (Food and Drug Adminstration) (FDA) approval For treating major depressive disorder adult patient, European drug administration is obtained December in the same year（EMA）Listing license.Vortioxetine with Existing antidepressant is compared, and has faster onset time, the toxic side effect of smaller and more preferable antidepressant activity.
Patent WO2003/029232 discloses compound 1- [2-（2,4- 3,5-dimethylphenyls-sulfanyl）Phenyl] piperazine is (fertile For Xi Ting) as with suppression serotonin transporter（SERT）The compound of activation.
The hydrobromate, hydrochloride, hydrochloride one that WO2007/144005 discloses the Vortioxetine in crystal habit are hydrated Thing, mesylate, fumarate, maleate, mesotartaric acid salt, L-（+）- tartrate, D-（-）- tartrate, sulphur Hydrochlorate, phosphate, nitrate and their preparation method and characterization.It discloses the crystal of a variety of Vortioxetine hydrobromates Form, including alpha-crystal form, beta crystal, γ crystal forms, semihydrate and ethyl acetate solvate.The α of Vortioxetine hydrobromate is brilliant Type, beta crystal are obtained via being crystallized from ethyl acetate.Vortioxetine hydrobromate γ crystal forms and semihydrate are via water Crystallize and obtain.WO2010/094285 discloses the isopropanol solvate of Vortioxetine hydrobromate and for purifying The method of Vortioxetine and pharmaceutical salts.
It is comprising 2 θ ± 0.20 ° in the XRPD collection of illustrative plates of alpha-crystal form：5.81,7.03,9.24,12.83,14.05,16.25, 17.44,18.19,18.52,19.34,20.40,21.14,22.95,27.93,29.25.
It is comprising 2 θ ± 0.20 ° in the XRPD collection of illustrative plates of beta crystal：6.83,8.37,9.24,11.84,13.16,13.71, 15.54,15.25,15.63,16.07,16.91,17.42,18.58,18.91,19.41,20.24,20.65,21.84, 22.63,23.67,24.66,25.35,29.63.
It is comprising 2 θ ± 0.20 ° in the XRPD collection of illustrative plates of γ crystal forms：4.52,11.80,13.10,14.18,15.21,15.95, 17.14,18.19,18.76,20.37,21.25,23.54,27.96,29.62.
US20150266841（201380060097.9）The δ crystal forms of Vortioxetine hydrobromate are disclosed, by Vortioxetine Hydrobromide monohydrate in 130 DEG C be dried under vacuum 4 it is small when obtain.
It is comprising 2 θ ± 0.2 ° in the XRPD collection of illustrative plates of δ crystal forms：5.5,12.2,13.7,14.5,14.8,16.2,16.7, 20.0,20.7,22.4,22.8,23.7,24.6,25.6,27.6,28.1,28.4,28.6,29.1,30.5,34.4.
WO2016015706 discloses the λ crystal forms, ω crystal forms, σ crystal forms of Vortioxetine hydrobromate.
It is comprising 2 θ ± 0.2 ° in the XRPD collection of illustrative plates of λ crystal forms：4.0,12.0,12.7,15.7,16.0,16.4,19.0, 20.1 20.3.
It is comprising 2 θ ± 0.20 ° in the XRPD collection of illustrative plates of ω crystal forms：3.75,11.27,13.05,15.25,16.54,17.11, 17.483,18.66,18.83,19.72,20.45,20.66,22.59,23.92,27.02,28.41.
It is comprising 2 θ ± 0.20 ° in the XRPD collection of illustrative plates of σ crystal forms：3.8,11.6,13.0,14.0,15.5,18.2,18.4, 19.2,20.2,21.0,21.4,22.3,23.4,23.8,27.0,28.2.
CN201410143889.9（CN104974110）The A crystal forms of Vortioxetine hydrobromate are disclosed, by being replaced fertile Western spit of fland alkali dissolves by heating in material of organic ethers solvent, and hydrogen bromide solution crystallization is added dropwise after cooling, crystal form A is obtained by filtration.
It is comprising 2 θ ± 0.20 ° in the XRPD collection of illustrative plates of A crystal forms：4.18,11.98,12.56,14.02,14.60,14.72, 16.55,16.84,17.54,18.66,19.14,20.27,20.70,21.70,22.20,22.57,24.31,25.10, 25.62,27.56,28.34,28.74,29.40,31.06.
CN201410197164.8（CN105254590）Disclose the B crystal form of Vortioxetine hydrobromide monohydrate.It is logical Cross and dissolve by heating Vortioxetine alkali in organic solvent, excessive hydrogen bromide solution crystallization is added dropwise after cooling, crystalline substance is obtained by filtration Type B.
It is comprising 2 θ ± 0.20 ° in the XRPD collection of illustrative plates of hydrate crystal forms B：3.76,4.49,11.28,13.01,13.53, 15.21,16.50,17.10,17.47,18.65,19.68,20.44,22.56,23.28,23.89,27.03,28.40, 30.38 31.58.
CN201310591418.X（CN104650003）Disclose Vortioxetine hydrobromide hydrate（Containing 1.5 water） Crystal form.By the way that Vortioxetine is dissolved in Ethanol-Acetic Acid-heated in water solution, then add hydrobromic acid and cool down to obtain stage by stage. It is comprising 2 θ ± 0.20 ° in the XRPD collection of illustrative plates of its hydrate crystal forms：3.30,5.63,8.98,10.76,12.04,15.47, 19.48,20.85,21.84,23.62,25.04,26.12,27.35,29.04,30.82,31.14,33.62,34.94, 36.60 40.04.
CN201410253970.2（CN105198837）Disclose the δ crystal forms of Vortioxetine hydrobromate.By being replaced fertile Western spit of fland hydrobromate is dissolved in methanol aqueous solution, is concentrated under reduced pressure and is evaporated to obtain solid, and solid vacuum drying is obtained.δ crystal forms It is comprising 2 θ ± 0.2 ° in XRPD collection of illustrative plates：4.5,9.1,11.8,15.9,17.1,18.7,23.4,25.4.
CN201410855479.7（CN105801517）Disclose the δ crystal forms of Vortioxetine hydrobromide monohydrate.Will Vortioxetine hydrobromate is mixed with aprotic solvent, is heated to be completely dissolved, overanxious.It is molten that filtrate adds polarity after cooling Agent, continues to stir, filtration drying obtains Vortioxetine hydrobromate novel crystal forms δ after separating out solid.Wrapped in the XRPD collection of illustrative plates of δ crystal forms It is containing 2 θ ± 0.2 °：4.0,11.5,15.5,17.7,19.1,20.8,22.9,27.2,28.6.
CN201410376688.3（CN105330614）Disclose the crystal form of hydrobromic acid Vortioxetine.By Vortioxetine hydrogen Bromate is dissolved in isopropanol water solution, is heated to reflux clarification, is filtered after cooling, by solid vacuum drying, obtain hydrobromic acid and irrigate For western spit of fland crystal.It is comprising 2 θ ± 0.2 ° in the XRPD collection of illustrative plates of crystal：5.8,6.9,13.2,14.1,14.6,16.2,17.0, 18.2,18.6,19.0,19.0,19.5,20.7,21.1,21.6,21.9,22.3,22.7,23.0,23.7,24.4,24.8, 25.4,28.1,28.5,30.0.
CN201410397339.X（CN104119298）Disclose the B crystal form of Vortioxetine hydrobromate.By Vortioxetine Free alkali is dissolved in toluene, adds hydrobromic acid, stirring and crystallizing, filtering, obtains Vortioxetine hydrobromate.By Vortioxetine hydrobromic acid Salt is added in toluene/water solvent, is dissolved by heating, cooling crystallization, the crystallizing and drying of leaching.Products therefrom adds propyl alcohol, and heating is stirred Mix, be stirred at room temperature, filter, vacuum drying, obtains the crystallization of B crystal form.It is comprising 2 θ ± 0.20 ° in the XRPD collection of illustrative plates of crystal form：6.89 9.73,13.78,14.62.
CN201510389271.5（CN105017176）, a kind of hydrobromic acid Vortioxetine crystal form is disclosed, ethyl acetate is made Obtained for crystallization solvent.It is comprising 2 θ ± 0.20 ° in the XRPD collection of illustrative plates of gained crystal form：8.55,13.05,13.44,14.46, 15.20,16.63,16.94,17.22,17.85,19.83,20.43,21.33,23.14,23.60,24.77,26.25, 26.72,26.96,29.69,30.52,33.33,33.89,34.89,35.54,37.03.
To sum up, the crystal form of the Vortioxetine of document report is more at present, but all multi-party in stability of crystal form, preparation method etc. Face is not fully up to expectations.The different polymorphs form of medicine is in stability, degree of dissociation, bioavilability is first-class very big difference Not, therefore to ensure to obtain each side such as stability, hygroscopicity, solubility and bioavilability more preferably crystal form, applied to medicine Product produce.
The present inventor selects the Vortioxetine of different shape a series of as initial feed, use by substantial amounts of screening Conventional solvents and their mixed solvent as recrystallisation solvent, control different crystallization times, recrystallization temperature and difference Drying condition, by largely testing, a kind of new crystal form C is prepared.Novel crystal forms solubility is good, and physicochemical properties are steady It is fixed, suitable for various forms preparation.Crystal form preparation process is simple, is easy to convert industry size, is adapted to industrialized production.
The content of the invention
It is to provide a kind of crystal form C of Vortioxetine hydrobromate semihydrate in the purpose of the invention, which has Good temperature, humidity stability, solubility is good, and there is suitable water suction stability to be suitable for formulation manufacturing processes and be adapted to Long-term storage.
The crystal form C of the Vortioxetine hydrobromate has the powder diffraction spectrum described in attached drawing 1.
Powder diffraction is made using the X ' PertPROMPD Multifunctional powders diffractometer measure of PANalytical companies of Holland Radiated with Cu-Ka, obtain the powder diffraction spectrum described in attached drawing 1.
It is including at least 2 θ ± 0.20 ° in the XRPD collection of illustrative plates of Vortioxetine hydrobromate crystal form C of the present invention：4.50 6.10,7.74,11.10,12.20,19.08,21.86,25.20,27.62 diffraction maximum.
Preferably, it is including at least 2 θ ± 0.20 ° in the XRPD collection of illustrative plates of the Vortioxetine hydrobromate crystal form C： 4.50,6.10,7.41,7.74,11.10,12.20,19.08,21.86,23.15,25.20,27.62 it is furthermore preferred that described fertile It is comprising 2 θ ± 0.20 ° in XRPD collection of illustrative plates for western spit of fland hydrobromate crystal form C：4.50,6.10,7.41,7.74,8.98, 10.64,11.10,12.20,12.81,13.20,14.19,14.58,18.02,18.68,19.07,20.57,20.91, 21.32,21.86,22.73,23.15,24.72,25.20,25.80,26.59,27.62,28.20,29.38 diffraction maximum.
Particularly preferred, the XRPD collection of illustrative plates of the Vortioxetine hydrobromate crystal form C is as shown in Figure 1.
The present invention provides Vortioxetine hydrobromate crystal form C, possesses feature as in the table below in its powder diffraction spectrum Peak and its intensity：
The characteristic peak and its intensity of the powder diagram of the Vortioxetine hydrobromate crystal form C of the present invention of table 1
Pos.[°2Th.] Rel.Int.[%]
4.4962 20.02
6.0945 37.65
7.4048 10.28
7.7377 6.98
8.9754 4.39
10.6351 4.90
11.0981 13.78
12.2002 15.87
12.8104 24.86
13.2035 18.83
13.5330 3.31
14.1925 4.10
14.5798 4.14
14.7961 3.37
16.0008 2.39
17.8126 6.06
18.0408 4.42
18.6823 24.96
19.0764 22.24
19.4270 4.43
20.0885 6.86
20.5716 7.28
20.9066 6.64
21.3154 10.74
21.8649 17.89
22.7293 7.45
23.1577 21.20
23.3863 12.07
23.9894 5.92
24.7679 21.90
25.1965 100.00
25.8013 8.08
26.5898 6.86
27.6153 22.25
28.2020 7.66
28.5344 7.29
29.0793 4.35
29.3811 8.93
29.8336 2.86
30.4615 3.63
30.9643 9.12
31.3620 6.46
32.1796 3.02
32.5749 4.25
33.2015 5.19
33.7107 2.76
34.7647 4.21
35.1915 10.46
36.6861 4.09
37.2585 3.05
37.7689 3.76
39.5339 2.06
40.3547 3.30
40.8401 2.81
The instrument that DSC, TG detection use is the pyris1 of PERKINELMER companies of the U.S., TGS-2, DSC test conditions：Temperature 25-300 DEG C, 10.0 DEG C/min of heating rate；TG test conditions：25-300 DEG C of temperature, 10.0 DEG C/min of heating rate.
DSC is measured as shown in Figure 2.
TG is measured as shown in Figure 3.
Another object of the present invention is to provide a kind of preparation method of Vortioxetine hydrobromate crystal form C, including it is as follows Step：
1) 1- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] piperazine of any form dissolved by heating in organic solvent or directly Connect reinforcing body；
2) by the cooling of the lysate of 1- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] piperazine or directly reinforcing body to below room temperature The aqueous solution containing ammonium bromide in, stirring reaction；
3) filtering crystals obtain crystal form C.
The organic solvent is energy organic solvent miscible with water, such as methanol, ethanol, DMF, DMSO, preferably DMF.
The bromination aqueous ammonium is ammonium bromide and the freshly prepd solution of water.
Used rate of charge is that 1- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] piperazine/DMF/ ammonium bromides/water (m/m) is 1/0~25/100~200/300；
Preferably, used rate of charge is 1- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] piperazine/DMF/ ammonium bromides/water (m/ M) it is 1/0~10/125/300；
Reaction and recrystallization temperature -5~40 DEG C, most preferably preferably 0 DEG C~30 DEG C, 5~25 DEG C.
Include Vortioxetine hydrobromate crystal form C and one or more it is still a further object of the present invention is to provide a kind of The pharmaceutical composition that pharmaceutically acceptable carrier is formed.The pharmaceutical composition of the present invention is used to prepare oral formulations, preparation Form is tablet, orally disintegrating tablet, dispersible tablet, slow-release tablet, capsule or sustained and controlled release capsule.
Further aim of the present invention is to provide Vortioxetine hydrobromate crystal form C or includes the medicine of effective dose crystal form C Application of the compositions in the medicine for preparing treatment major depressive disorder.
Brief description of the drawings
The XRPD collection of illustrative plates of Fig. 1 Vortioxetine hydrobromate semihydrate crystal forms C
The DSC collection of illustrative plates of Fig. 2 Vortioxetine hydrobromate semihydrate crystal forms C
The TGA collection of illustrative plates of Fig. 3 Vortioxetine hydrobromate semihydrate crystal forms C
Specific implementation method
Below in conjunction with specific embodiment, the present invention will be further described, but protection scope of the present invention is not necessarily limited by specifically Embodiment.
Embodiment 1：
1- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] piperazine 5.0g and DMF50ml are placed in reaction bulb, heating stirring makes Solid is completely dissolved, and removes heating bath, is cooled to room temperature stand-by；
Ammonium bromide 625g is stirred at room temperature and is dissolved in 1500ml deionized waters, filters out mechanical admixture, filtrate is added to 3L tri- In mouth bottle, interior temperature is cooled under stirring to 20~25 DEG C, above-mentioned solution is added dropwise（It is added dropwise within 5 minutes）, in 20~25 DEG C of stirrings 1.5 it is small when, filter, 0 DEG C of water 150ml agitator treating of solid, filter, then with the washing of 0 DEG C of water 20ml × 4 time, obtain white solid, When room temperature forced air drying 20 is small, 40 DEG C be dried under reduced pressure 5 it is small when, obtain 1- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrogen Bromate hemihydrate crystal form C.
The crystal form C being prepared is subjected to powder diffraction analysis and differential thermal, thermogravimetric analysis.
Powder diffraction is made using the X ' PertPROMPD Multifunctional powders diffractometer measure of PANalytical companies of Holland Radiated with Cu-Ka, obtain the powder diffraction spectrum described in attached drawing 1.
The instrument that uses of DSC, TG detection is PERKINELMER companies of the U.S., pyris1, TGS-2, DSC test conditions：Temperature 25-300 DEG C of degree, 10.0 DEG C/min of heating rate；TG test conditions：25-300 DEG C of temperature, 10.0 DEG C/min of heating rate.Its As shown in Figure 2, TGA collection of illustrative plates is as shown in Figure 3 for DSC collection of illustrative plates.
Embodiment 2：
1- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] piperazine 5.0g and DMF50ml are placed in reaction bulb, heating stirring makes Solid is completely dissolved, and removes heating bath, is cooled to room temperature stand-by；
Ammonium bromide 625g is stirred at room temperature and is dissolved in 1500ml deionized waters, filters out mechanical admixture, filtrate is added to 3L tri- In mouth bottle, interior temperature is cooled under stirring to 0~5 DEG C, above-mentioned solution is added dropwise（It is added dropwise within 5 minutes）, it is small in 0~5 DEG C of stirring 15 When, filter, 0 DEG C of water 150ml agitator treating of solid, filter, then washed with 0 DEG C of water 20ml × 4 time, obtain white solid, room temperature When forced air drying 20 is small, 40 DEG C be dried under reduced pressure 5 it is small when 1- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] piperazine hydrobromide half Hydrate crystal form C.
Verify after testing, its X-ray powder diffraction pattern is coincide with Fig. 1, and all characteristic peak positions fluctuations are in error model In enclosing, its DSC collection of illustrative plates and TGA collection of illustrative plates also coincide with Fig. 2 and Fig. 3 respectively, it was demonstrated that gained crystal form is crystal form C.
Embodiment 3：
Ammonium bromide 625g is stirred at room temperature and is dissolved in 1500ml deionized waters, filters out mechanical admixture, filtrate is added to 3L tri- In mouth bottle, interior temperature is cooled under stirring to 5~10 DEG C, adds solid powder 1- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] piperazine Piperazine 5.0g, 5~10 DEG C stirring 48 it is small when, filter, 0 DEG C of water 150ml agitator treating of solid, suction filtration, then with 0 DEG C of water 20ml × 4 times washing, obtain white solid, when room temperature forced air drying 20 is small, 40 DEG C be dried under reduced pressure 5 it is small when 1- [2- (2,4- 3,5-dimethylphenyl sulphur Base) phenyl] piperazine hydrobromide hemihydrate crystal form C.
After testing, its X-ray powder diffraction pattern such as Fig. 1 coincide, and all characteristic peak positions are fluctuated in error range, Its DSC collection of illustrative plates and TGA collection of illustrative plates also coincide with Fig. 2 and Fig. 3 respectively, it was demonstrated that gained crystal form is crystal form C.
4 high humidity of embodiment is tested：The Vortioxetine crystal form C being prepared in embodiment 1 is placed in surface plate and is spread out into thin Layer, is put into humidity（Humidity 92.5 ± 0.5%）, control temperature（25℃）Constant humidity under conditions of, in 0 day, 5 days, 10 days, 30 days, Sampling detection moisture, censorship XRD detections, as a result see the table below.
0 day 5 days 10 days 30 days
Character White crystalline powder White crystalline powder White crystalline powder White crystalline powder
Moisture 2.15% 2.85% 2.82% 2.85%
Crystal form C C C C
Conclusion：Product is preserved in humidity lower open mouth, and nonhygroscopic, crystal form does not change；Therefore under the conditions of storehouse, sealing is protected Deposit, product will not the moisture absorption, crystal form will not change.
5 high-temperature stability of embodiment is tested：The Vortioxetine crystal form C that will be prepared in embodiment 1, is put into temperature（40 ℃）Constant temperature under conditions of, in 0 day, 5 days, 10 days, 30 days, sampling detection purity, censorship XRD detection, as a result see the table below.
0 day 5 days 10 days 30 days
Character White crystalline powder White crystalline powder White crystalline powder White crystalline powder
Crystal form C C C C
Purity 99.75% 99.76% 99.75% 99.75%
Conclusion：40 DEG C of high temperature experiments show that 40 DEG C of sample is placed 30 days, and indices purity compared with the 0th day does not become Change, crystal form is also highly stable, therefore can stablize preservation under room temperature in storehouse.
6 illumination experiment of embodiment：The Vortioxetine crystal form C that will be prepared in embodiment 1, is placed on（4500Lx）、（25 ℃）Constant temperature under conditions of carry out illumination experiment, in 0 day, 5 days, 10 days, 30 days, sampling detection purity, censorship XRD detection, knot Fruit see the table below.
0 day 5 days 10 days 30 days
Character White crystalline powder White crystalline powder White crystalline powder White crystalline powder
Crystal form C C C C
Purity 99.75% 99.75% 99.76% 99.75%
Conclusion：Crystal form C, illumination experiment show that sample illumination is placed 30 days, and indices purity compared with the 0th day is not aobvious Change is write, crystal form is also highly stable.
7 solubility test of embodiment：The Vortioxetine C crystal form that will be prepared in embodiment 1, with alpha-crystal form, beta crystal into Row solubility experiment, the results are shown in Table.
Alpha-crystal form Beta crystal C crystal form
Mg/ml 1.52 0.72 2.26
Conclusion：The solubility of the results show crystal form C is better than alpha-crystal form and beta crystal.

Claims (11)

1. the novel crystal forms C of Vortioxetine hydrobromate semihydrate shown in a kind of formula (I),
（Ι）
It is characterized in that it is including at least 2 θ ± 0.20o in the crystal form XRPD spectrograms：4.50,6.10,7.74,11.10, 12.20,19.08,25.20,27.62 characteristic peak.
2. the crystal form C of Vortioxetine hydrobromate semihydrate shown in formula (I) as claimed in claim 1, it is characterised in that institute State in the XRPD collection of illustrative plates of crystal form C and be including at least 2 θ ± 0.20 °：4.50,6.10,7.41,7.74,11.10,12.20,19.08, 21.86,25.20,23.15,27.62 diffraction maximum.
3. the crystal form C of Vortioxetine hydrobromate semihydrate shown in formula (I) as claimed in claim 1, it is characterised in that institute State in the XRPD collection of illustrative plates of crystal form C and be comprising 2 θ ± 0.20 °：4.50,6.10,7.41,7.74,8.98,10.64,11.10, 12.20,12.81,13.20,14.19,14.58,18.02,18.68,19.07,20.57,20.91,21.32,21.86, 22.73,23.15,24.72,25.20,25.80,26.59,27.62,28.20,29.38 diffraction maximum.
4. the crystal form C of Vortioxetine hydrobromate semihydrate, its powder diagram shown in formula (I) as claimed in claim 1 Spectrum is shown in Fig. 1.
5. prepare the crystal form C of Vortioxetine hydrobromate semihydrate shown in the formula (I) as described in claim 1-4 any one Method, include the following steps：
1) 1- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] piperazine of any form is dissolved by heating in organic solvent；
2) by the lysate of 1- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] piperazine, it is added drop-wise in the aqueous solution containing ammonium bromide Stirring and crystallizing；
3) filtering crystals obtain crystal form C.
6. preparation method as claimed in claim 5, it is characterised in that the organic solvent is miscible with water.
7. preparation method as claimed in claim 5, it is characterised in that the bromination aqueous ammonium is the ammonium bromide water now prepared Solution.
8. preparation method as claimed in claim 5, its rate of charge used is 1- [2- (2,4- 3,5-dimethylphenyl sulfenyl) phenyl] Piperazine/DMF/ ammonium bromides/water (m/m) is 1/0~25/100~200/300, preferably 1/0~10/125/300, recrystallization temperature 5 ~40 DEG C, preferably 0 DEG C~30 DEG C, most preferably 5~25 DEG C.
9. pharmaceutical composition, including the Vortioxetine hydrobromate crystal form C described in claim 1-8 any one shown in formula (I).
10. composition as claimed in claim 9, it is characterised in that tablet or capsule is made in the composition.
11. the crystal form C of Vortioxetine hydrobromate shown in the formula (I) as described in claim 1-10 any one, or include Application of the pharmaceutical composition of effect amount crystal form C in major depression disease drug is prepared.
CN201610901186.7A 2016-10-14 2016-10-14 Vortioxetine hydrobromate crystal form C and preparation method thereof Withdrawn CN107954947A (en)

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