CN109928941A - A kind of crystalline compounds and preparation method thereof of hydrobromic acid Vortioxetine - Google Patents
A kind of crystalline compounds and preparation method thereof of hydrobromic acid Vortioxetine Download PDFInfo
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Abstract
The present invention relates to hydrobromic acid Vortioxetine crystalline compounds and preparation method thereof.The hydrobromic acid Vortioxetine crystalline compounds that the present invention obtains are with high purity, dissolubility is good, hygroscopicity is small, it is with good stability under high temperature, super-humid conditions, and the hydrobromic acid Vortioxetine crystalline compounds preparation method of this hair is simple, is suitble to long term storage and industrialized production.
Description
Technical field
The present invention relates to chemical medicines, and in particular to a kind of hydrobromic acid Vortioxetine crystalline compounds and its preparation side
Method.
Background technique
Vortioxetine is one researched and developed jointly by Takeda Pharmaceutical Company Limited (Takeda) and Lundbeck drugmaker (Lundbeck)
The antidepressants of item treatment major depressive disorder were ratified to exist on September 30th, 2013 by U.S. Food and Drug Administration (FDA)
U.S.'s listing, trade name Brintellix, using Wo Saiting hydrobromate as active constituent, tablet format is respectively tablet
5,10,15 and 20mg.
The chemical name of hydrobromic acid Vortioxetine is 1- [2- (2,4- methylphenyl-sulfanyl) phenyl] piperazine hydrobromide, structure
Formula is shown in formula I:
The compound shows the antagonist properties to 5-HT 3A and 5-HT7 receptor, to the partial agonist of 5-HT 1B receptor
Property, the exciting property to 5-HT 1A receptor and the effective serotonin via inhibition serotonin transporter (SERT)
Reabsorption inhibits.Therefore treatment of the clinical development for cognitive disorders such as major depressive disorder, generalized anxiety disorder.
WO2007144005A makes public for the first time the solvate of the hydrobromate of Vortioxetine, hydrobromate (as half is hydrated
Object, ethyl acetate solvate) and other acid-addition salts.Particularly, this application also discloses a variety of of hydrobromic acid Wo Saiting
Crystal form, including α, β, γ etc..Due to the stringent limitation to residual solvent in active constituent, the solvate of hydrobromic acid Vortioxetine
Be not suitable for being prepared into medicament forms.Although alpha-crystal form has better solubility compared with beta crystal, alpha-crystal form itself is in static electrification
Flocculent structure, poor fluidity are not easy the problems such as being sieved, and tablet is made and easily causes the non-uniform problem of dispersion；Secondly alpha-crystal form is steady
Qualitative difference is easy to happen in crushing process and turns crystalline substance.The solubility of beta crystal is relatively poor, and therefore, it is desirable to its bioavilability energy
Access further raising.γ crystal form is very unstable, it is difficult to and it obtains, and significantly absorbs moisture in high humidity environment, moisture absorption
Property reaches 4.5%, it is difficult to be used as medicine.Furthermore WO2007144005A and more documents (such as CN105017176B,
CN105198837A) show that the yield of alpha-crystal form and beta crystal is lower, yield is no more than 80%, even as low as 47%.
Therefore, it for hydrobromic acid Vortioxetine, develops a kind of yield and purity is high, stability is good, bioavilability
High and simple process is suitble to the crystalline compounds of industrialized production to be of great significance.
Summary of the invention
The purpose of the present invention is to provide a kind of crystalline compounds of hydrobromic acid Vortioxetine, crystallizations provided by the invention
It closes object and solves the defects of organic solvent residual existing for existing crystal form, moisture content are high, solubility is small, stability is poor, and this
The preparation method of invention is simple, at low cost, has important value to the exploitation of the following drug.
Specifically, it is an object of the present invention to provide a kind of crystalline compounds of hydrobromic acid Vortioxetine, features
It is that its X-ray powder diffraction figure has characteristic peak at 2 θ values is 14.17 ° ± 0.2 °.
Further, crystalline compounds provided by the invention, it is characterised in that its X-ray powder diffraction figure is in 2 θ values
There is characteristic peak at 4.17 ° ± 0.2 °, 14.6 ° ± 0.2 °, 17.5 ° ± 0.2 °, 19.1 ° ± 0.2 °, 20.7 ° ± 0.2 °.
Further, crystalline compounds provided by the invention, it is characterised in that its X-ray powder diffraction figure is in 2 θ values
4.17°±0.2°、6.9°±0.2°、8.4°±0.2°、9.7°±0.2°、14.6°±0.2°、17.5°±0.2°、19.1°±
There is characteristic peak at 0.2 °, 20.7 ° ± 0.2 °.
Further, crystalline compounds provided by the invention, it is characterised in that its X-ray powder diffraction figure is in 2 θ values
4.17°±0.2°、6.9°±0.2°、8.4°±0.2°、9.7°±0.2°、11.9°±0.2°、13.2°±0.2°、14.6°±
There is characteristic peak at 0.2 °, 13.8 ° ± 0.2 °, 17.5 ° ± 0.2 °, 19.1 ° ± 0.2 °, 20.7 ° ± 0.2 °.
Further, crystalline compounds provided by the invention, it is further characterized in that, X-ray powder diffraction figure is basic
As shown in Figure 1, X-ray powder diffraction data are as follows.
Crystalline compounds provided by the invention, which is characterized in that nearby start endothermic peak occur being heated to 213 DEG C,
Differential scanning calorimetric thermogram is substantially as shown in Figure 2.
It is another object of the present invention to provide the preparation method of hydrobromic acid Vortioxetine crystalline compounds, feature exists
In:
1) Vortioxetine free alkali is heated into dissolved clarification in butanone；
2) hydrobromic acid is dissolved in a small amount of butanone, anhydrous sodium sulfate is added and dries, filters, filtrate is slowly added to step 1)
At salt in solution, white solid is precipitated, stirs, filters, it is dry.
Solvent in above-mentioned preparation method is butanone, and inventor has also investigated to be made with methanol, ethyl alcohol, acetonitrile, ethyl acetate
For solvent, however when using methanol as solvent, failing precipitation solid；Yellow impurities can be precipitated using ethyl alcohol as solvent；With acetonitrile
It obtains being mixed crystal as solvent, and what is obtained using ethyl acetate as solvent is solvated compounds, it is molten residual not up to standard.
The additional amount of step 1) butanone is 20-50 times of Vortioxetine free base weight volume in above-mentioned preparation method.
In above-mentioned preparation method, in step 2) is 60 DEG C at salt temperature, and inventor has investigated different temperatures to crystal form
It influences, as a result, it has been found that obtained crystal form is mixed crystal in the range of 0 DEG C -50 DEG C.
In above-mentioned preparation method, the hydrobromic acid amount in step 2) is 0.8-1eq, and inventor investigates discovery, when hydrobromic acid amount
More than 1.2eq, obtained crystalline compounds are mixed crystal, and when hydrobromic acid amount is less than 0.8eq, product yield is low, when hydrobromic acid
Amount be 1eq, obtain be single high yield high-purity crystalline compounds.
Compared with prior art, the invention has the following advantages that the present invention has prepared a kind of yield and purity is high
Hydrobromic acid Vortioxetine crystalline compounds；Crystalline compounds no solvent residue of the invention, moisture content is low, and dissolubility is good,
It increases weight under high temperature, super-humid conditions unobvious, it is with good stability, it is suitble to long term storage；Hydrobromic acid of the invention is fertile to be replaced
The preparation process of western spit of fland crystalline compounds is simple, at low cost, is not related to the use of toxic reagent.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction collection according to the hydrobromic acid Vortioxetine crystalline compounds of the embodiment of the present invention 1；
Fig. 2 is the differential scanning calorimetry figure according to the hydrobromic acid Vortioxetine crystalline compounds of the embodiment of the present invention 1；
Specific embodiment
The present invention is described in further detail the contents of the present invention by following embodiment, can not be used to limit this
The protection scope of invention.
Detecting instrument and method:
X-ray powder diffraction (PXRD) test method: instrument model: DX 2700, diffracted ray: CuK (40KV, 30mA) is swept
Retouch rate: 0.05 °/s, scanning range: 3 ° -53 ° (2 θ).
Differential scanning calorimetry (DSC) test method: instrument model: Mettler TGA/DSC 2；Heating rate: 10 DEG C/
min。
Embodiment 1
1g Vortioxetine free alkali stirs in 20ml butanone and is warming up to 60 DEG C, dissolved clarification.The hydrobromic acid of 1eq is dissolved in 1~
In 2ml butanone, after the dry 1h of anhydrous sodium sulfate is added, filtering, filtrate is slowly added dropwise in 60 DEG C of solution into salt, and white is precipitated
Solid continues to stir 30min, is cooled to 0-5 DEG C of filtering, is placed at 50 DEG C and dries to constant weight, obtains hydrobromic acid Vortioxetine knot
Brilliant compound, yield 83.79%, purity 100%.Its XRD, DSC map difference is as shown in Figure 1, 2.
Embodiment 2
1g Vortioxetine free alkali stirs in 50ml butanone and is warming up to 60 DEG C, dissolved clarification.The hydrobromic acid of 0.8eq is dissolved in 1
In~2ml butanone, after the dry 1h of anhydrous sodium sulfate is added, filtering, filtrate is slowly added dropwise in 60 DEG C of solution into salt, is precipitated white
Color solid continues to stir 1h, filter while hot, is placed at 50 DEG C and dries to constant weight, obtains hydrobromic acid Vortioxetine crystalline compounds,
Yield is 80.01%, purity 100%.Its XRD, DSC map is essentially identical with attached drawing 1.
The test of 3 hygroscopicity of embodiment
The hydrobromic acid Vortioxetine crystalline compounds obtained according to 1 method of embodiment are taken, with reference to 2015 editions " Chinese Pharmacopoeias "
Middle drug draws moist guideline, is 25 DEG C ± 1 DEG C in temperature, and humidity is 90% ± 5% to place 7 days, measures to draw and moist is
0.75%.
The water-soluble test of embodiment 4
The hydrobromic acid Vortioxetine crystalline compounds weighed in embodiment 1 are appropriate, and 25 DEG C of isothermal vibration dissolutions overnight will
Undissolved Partial filtration obtains hydrobromic acid Vortioxetine saturated solution, tests its concentration, and calculating solubility is 1.65mg/ml.
5 study on the stability of embodiment
The hydrobromic acid Vortioxetine crystalline compounds obtained according to embodiment 1 are taken, in high temperature (60 DEG C ± 2 DEG C), high humidity
Its stability is investigated under the conditions of (90% ± 5%RH) and illumination (4500lx ± 500lx), as a result as follows:
| Condition | 7d | 15d | 20d |
| Illumination (4500lx) | NA | NA | NA |
| Temperature (60 DEG C) | 0.01% | 0.01% | 0.01% |
| Humidity (92.5%RH) | NA | NA | NA |
Meanwhile in order to investigate whether the crystal form under high temperature, high humidity and illumination condition changes, DSC test is carried out to sample, is melted
Point result is as follows:
| Condition | 7d | 15d | 20d |
| Illumination | It does not change | It does not change | It does not change |
| Temperature (60 DEG C) | It does not change | It does not change | It does not change |
| Humidity (90%RH) | It does not change | It does not change | It does not change |
The result shows that purity is almost unchanged under high temperature, high humidity, illumination condition, and sample does not occur to turn crystalline substance.Illustrate this hair
Bright crystalline compounds are with good stability, are suitble to long term storage and large-scale production.
Claims (9)
1. a kind of crystalline compounds of hydrobromic acid Vortioxetine, which is characterized in that its X-ray powder diffraction figure is being in 2 θ values
There is characteristic peak at 4.17 ° ± 0.2 °.
2. the crystalline compounds of hydrobromic acid Vortioxetine according to claim 1, which is characterized in that its x-ray powder spreads out
It is to have at 4.17 ° ± 0.2 °, 14.6 ° ± 0.2 °, 17.5 ° ± 0.2 °, 19.1 ° ± 0.2 °, 20.7 ° ± 0.2 ° that figure, which is penetrated, in 2 θ values
Characteristic peak.
3. the crystalline compounds of hydrobromic acid Vortioxetine according to claim 1, which is characterized in that its x-ray powder spreads out
Penetrate figure 2 θ values be 4.17 ° ± 0.2 °, 6.9 ° ± 0.2 °, 8.4 ° ± 0.2 °, 9.7 ° ± 0.2 °, 14.6 ° ± 0.2 °, 17.5 ° ±
There is characteristic peak at 0.2 °, 19.1 ° ± 0.2 °, 20.7 ° ± 0.2 °.
4. the crystalline compounds of hydrobromic acid Vortioxetine according to claim 1, which is characterized in that its x-ray powder spreads out
Penetrate figure 2 θ values be 4.17 ° ± 0.2 °, 6.9 ° ± 0.2 °, 8.4 ° ± 0.2 °, 9.7 ° ± 0.2 °, 11.9 ° ± 0.2 °, 13.2 ° ±
There is characteristic peak at 0.2 °, 13.8 ° ± 0.2 °, 14.6 ° ± 0.2 °, 17.5 ° ± 0.2 °, 19.1 ° ± 0.2 °, 20.7 ° ± 0.2 °.
5. the crystalline compounds of hydrobromic acid Vortioxetine described in any one of -4 according to claim 1, which is characterized in that its X
Ray powder diffraction pattern is substantially consistent with Fig. 1.
6. a kind of method for preparing hydrobromic acid Vortioxetine crystalline compounds of any of claims 1-5, feature
It is:
1) Vortioxetine free alkali is heated into dissolved clarification in butanone；
2) hydrobromic acid is dissolved in a small amount of butanone, anhydrous sodium sulfate is added and dries, filters, filtrate is slowly added to the solution of step 1)
It is middle that white solid is precipitated at salt, it stirs, filters, it is dry.
7. the preparation method of hydrobromic acid Vortioxetine crystalline compounds according to claim 6, it is characterised in that: step 1)
The additional amount of middle butanone is the bulking value of 20-50 times of Vortioxetine free alkali.
8. the preparation method of hydrobromic acid Vortioxetine crystalline compounds according to claim 6, it is characterised in that: step 2)
The molar ratio of middle hydrobromic acid and Vortioxetine free alkali is 0.8:1-1:1.
9. the preparation method of hydrobromic acid Vortioxetine crystalline compounds according to claim 6, it is characterised in that: step 2)
In at salt temperature be 60 DEG C.
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Citations (6)
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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 |
| CN105017176A (en) * | 2015-07-03 | 2015-11-04 | 扬子江药业集团有限公司 | Hydrobromic acid vortioxetine crystal and preparation method therefor |
| US20160200698A1 (en) * | 2013-09-12 | 2016-07-14 | Hangzhou Pushai Pharmaceutical Technology Co., Ltd | Vortioxetine salt and crystal thereof, their preparation method, pharmaceutical compositions and usage |
| CN105801517A (en) * | 2014-12-30 | 2016-07-27 | 上海奥博生物医药技术有限公司 | Novel crystal form of Vortioxetine hydrobromate and preparation method for novel crystal form of Vortioxetine hydrobromate |
| CN106316986A (en) * | 2015-07-03 | 2017-01-11 | 成都弘达药业有限公司 | Method for preparing 1-[2-(2,4-dimethyl phenyl thioalkyl)phenyl]piperazine hydrobromide alpha-type crystal |
| US20170189394A1 (en) * | 2014-04-28 | 2017-07-06 | Alembic Pharmaceuticals Limited | Novel polymorphic forms of vortioxetine and its pharmaceutically acceptable salts |
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2017
- 2017-12-19 CN CN201711370850.0A patent/CN109928941A/en active Pending
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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 |
| US20160200698A1 (en) * | 2013-09-12 | 2016-07-14 | Hangzhou Pushai Pharmaceutical Technology Co., Ltd | Vortioxetine salt and crystal thereof, their preparation method, pharmaceutical compositions and usage |
| US20170189394A1 (en) * | 2014-04-28 | 2017-07-06 | Alembic Pharmaceuticals Limited | Novel polymorphic forms of vortioxetine and its pharmaceutically acceptable salts |
| CN105801517A (en) * | 2014-12-30 | 2016-07-27 | 上海奥博生物医药技术有限公司 | Novel crystal form of Vortioxetine hydrobromate and preparation method for novel crystal form of Vortioxetine hydrobromate |
| CN105017176A (en) * | 2015-07-03 | 2015-11-04 | 扬子江药业集团有限公司 | Hydrobromic acid vortioxetine crystal and preparation method therefor |
| CN106316986A (en) * | 2015-07-03 | 2017-01-11 | 成都弘达药业有限公司 | Method for preparing 1-[2-(2,4-dimethyl phenyl thioalkyl)phenyl]piperazine hydrobromide alpha-type crystal |
Non-Patent Citations (2)
| Title |
|---|
| YONGJUN MAO，等: "A New and Practical Synthesis of Vortioxetine Hydrobromide", 《SYNTHESIS》 * |
| 张宪瑞，等: "沃替西汀盐晶体结构及理化性质", 《精细化工》 * |
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