CN106632291A - Brexpiprazole crystal, its preparation method and application, and pharmaceutical composition comprising brexpiprazole crystal - Google Patents
Brexpiprazole crystal, its preparation method and application, and pharmaceutical composition comprising brexpiprazole crystal Download PDFInfo
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- CN106632291A CN106632291A CN201610878661.3A CN201610878661A CN106632291A CN 106632291 A CN106632291 A CN 106632291A CN 201610878661 A CN201610878661 A CN 201610878661A CN 106632291 A CN106632291 A CN 106632291A
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- crystal formation
- epirizole
- piperazine
- crystal
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry and particularly relates to brexpiprazole crystal, its preparation method and application, and a pharmaceutical composition comprising the brexpiprazole crystal. X-ray powder diffraction spectrum of the brexpiprazole crystal has characteristic peaks at 2Theta=6.7+/-0.2 degree, 12.2+/-0.2 degree, 14.4+/-0.2 degree, 17.3+/-0.2 degree, 19.1+/-0.2 degree, 20.1+/-0.2 degree, 21.3+/-0.2 degree and 23.1+/-0.2 degree. The brexpiprazole crystal has good stability and low hygroscopicity; the brexpiprazole crystal is simple to prepare, low in cost, suitable for industrial production, and is of important value to the development of pharmaceutical preparations in future.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of crystal formation of epirizole piperazine and preparation method thereof and use
Way and Pharmaceutical composition.
Background technology
Epirizole piperazine (brexpiprazole) is first dopamine, the part 5- of Japanese Otsuka Pharmaceutical Co., Ltd.'s research and development
HT1A receptor stimulating agents and 5-HT2A receptor agonist compounds, have extensive activity, to DOPA in multiple monoamine systems
The partial agonist activity of amine D2 acceptors declines, and to the affinity of specific 5-HT acceptors (such as 5-HT1A, 5-HT2A, 5-HT7)
Improve, with more preferable curative effect and tolerance, can reduce patient cathisophobia, the bad reaction such as uneasy and/or insomnia.2015
The U.S. FDA of July 10 ratifies its listing.Epirizole piperazine is the next-generation of the Aripiprazole of big tomb pharmacy exploitation, is a kind of
There is very much the Mutiple Targets resisting mental disease medicine of clinical meaning, with good market prospects.
Epirizole piperazine it is chemical entitled：7- (4- (4- (benzo [b] thienyl) -1- piperazinyls) butoxy) -2 (1H)-quinolines
Quinoline ketone.
The numerous patents such as the compound synthesis method of epirizole piperazine existing CN103717587, CN104447723 are disclosed respectively
Plant different methods.But it is few with regard to the report document of epirizole piperazine crystal formation.Epirizole piperazine is in the formulation typically with solid shape
Formula is used, therefore, the research tool of its crystal formation is of great significance.
CN104844586 discloses the amorphous article of epirizole piperazine.
CN104254530 discloses a kind of according to a crystal formation for piperazine azoles dihydrate, and its X-ray powder diffraction collection exists
There is characteristic peak at 8.1 °, 8.9 °, 15.1 °, 15.6 ° and 24.4 ° of the angle of diffraction (2 θ) place.
CN104829603 discloses a kind of according to a crystal formation for piperazine triazole hydrochloride, its X-ray powder diffraction collection 9.2 °,
There is characteristic peak at 16.0 °, 17.6 °, 20.2 °, 23.8 ° and 25.1 ° of the angle of diffraction (2 θ) place.
The content of the invention
It is an object of the invention to provide a kind of crystal formation of epirizole piperazine, the stability of crystal form is good, hygroscopicity is low, facilitate medicine
Long term storage；Invention also provides the preparation method and purposes of the crystal formation of epirizole piperazine, scientific and reasonable, simple；
Present invention also offers a kind of Pharmaceutical composition, for treating mental disease.
The crystal formation of epirizole piperazine of the present invention, its X-ray powder diffraction collection 2 θ=6.7 ± 0.2 °, 12.2 ±
0.2 °, 14.4 ± 0.2 °, 17.3 ± 0.2 °, 19.1 ± 0.2 °, 20.1 ± 0.2 °, 21.3 ± 0.2 °, have at 23.1 ± 0.2 °
Characteristic peak.
The X-ray powder diffraction collection of described crystal formation 2 θ=10.7 ± 0.2 °, 13.8 ± 0.2 °, 14.8 ± 0.2 °,
26.8 ± 0.2 °, there is at 29.1 ± 0.2 ° characteristic peak.
The X-ray powder diffraction collection of described crystal formation 2 θ=16.4 ± 0.2 °, 17.0 ± 0.2 °, 19.3 ± 0.2 °,
20.7 ± 0.2 °, 23.3 ± 0.2 °, 24.4 ± 0.2 °, 25.6 ± 0.2 °, there is at 26.2 ± 0.2 ° characteristic peak.
The preparation method of the crystal formation of epirizole piperazine of the present invention be epirizole piperazine stir in a solvent, crystallization, obtain final product.
Described solvent be dichloromethane, chloroform, methyl alcohol, ethanol, isopropanol, acetone, butanone, toluene, dimethylbenzene,
Tetrahydrofuran, dioxane, dimethyl sulfoxide (DMSO), N,N-dimethylformamide, methyl tertiary butyl ether(MTBE), ether, n-hexane, positive heptan
One or more in alkane, hexamethylene or water.
Described whipping temp is 40～110 DEG C.
Described recrystallization temperature is -20～20 DEG C.
The purposes of the crystal formation of epirizole piperazine of the present invention, it is characterised in that described crystal formation is used to prepare antipsychotic
Purposes in pharmaceutical preparation.
The crystal formation of epirizole piperazine of the Pharmaceutical composition of the crystal formation comprising epirizole piperazine of the present invention comprising effective dose
And pharmaceutically acceptable excipient.
The crystal formation of epirizole piperazine comprising effective therapeutic dose and the Pharmaceutical composition of pharmaceutic adjuvant of the present invention is to treat
The crystal formation of the epirizole piperazine of effective dose mixes or contact with one or more pharmaceutic adjuvant makes Pharmaceutical composition or preparation, the medicine
It is prepared in well known mode in pharmaceutical field with composition or preparation.
The present invention compared with prior art, has the advantages that：
The stability of crystal form of the present invention is good, and hygroscopicity is low；The crystal formation prepares simple, with low cost, suitable industrialized production,
There is important value to following exploitation pharmaceutical preparation.
Description of the drawings
Fig. 1 schemes for the XRPD of the epirizole piperazine crystal formation of embodiment 1.
Fig. 2 schemes for the DSC of the epirizole piperazine crystal formation of embodiment 1.
Fig. 3 schemes for the TGA of the epirizole piperazine crystal formation of embodiment 1.
Specific embodiment
The present invention is described further with reference to embodiments.
In following embodiments, the condition that described test method is generally advised according to normal condition or manufacturer is implemented；
Described epirizole piperazine is obtained by commercially available method.
Inspection apparatus used by the present invention
XRPD：X-ray powder diffraction
Radiation source：Cu targets Ka is radiated
Sample treatment：After sample is finely ground, it is placed in standard sample frame and determines.
DSC/TGA：Differential scanning calorimetric analysis
INSTRUMENT MODEL：METTLER TGA/DSC
Test condition：30℃10℃/min
Embodiment 1
The preparation method of epirizole piperazine crystal formation：
The powder of 500.0mg epirizole piperazines is placed in test tube, under the conditions of 80 DEG C isopropanol is slowly added to, it is lucky until its
It is completely dissolved (about add 12mL isopropanols), is slowly cooled to 20 DEG C, gradually crystallization, suction filtration, 85 ± 5 DEG C of forced air drying 4h obtains white
Color powder.The X-ray powder diffraction data that the present embodiment obtains the crystal formation of sample are as shown in table 1.
The X-ray powder diffraction collection (XRPD figures) of crystal formation is as shown in Figure 1；Crystal formation is being heated to starting near 184.3 DEG C
There is endothermic peak, its differential scanning calorimetric thermogram (DSC figures) is as shown in Figure 2；Crystal formation when being heated to 340 DEG C, with weight
Loss gradient, its thermogravimetric analysis figure (TGA figures) is as shown in Figure 3.
The X-ray powder diffraction data of the epirizole piperazine crystal formation of table 1
Embodiment 2
The preparation method of epirizole piperazine crystal formation：
The powder of 500.0mg epirizole piperazines is placed in test tube, 10 milliliters of tetrahydrofuran is added under the conditions of 65 DEG C, it is molten clear,
0 DEG C is slowly cooled to, gradually crystallization, suction filtration, 85 ± 5 DEG C of forced air drying 5h obtain white powder.
Embodiment 3
The preparation method of epirizole piperazine crystal formation：
The powder of 500.0mg epirizole piperazines is placed in test tube, 25mL ethyl acetate is slowly added under the conditions of 78 DEG C, it is molten
Clearly, -10 DEG C are slowly cooled to, gradually crystallization, suction filtration, 85 ± 5 DEG C of forced air drying 4h obtain white powder.
Stability test：
The sample of the crystal formation that Example 1 is obtained is placed under conditions of 30 DEG C, is investigated at 1 month, 3 months, 6 months
Stability, the results are shown in Table 2.
The stability test result of the epirizole piperazine crystal formation of table 2
The crystal formation for preparing of the present invention can be seen that by above-mentioned experiment there is good chemical stability and stable crystal form
Property, room temperature condition can long-time stable exist, can be preferably applied to storage.
Draws moist test：
Take dry tool plug glass measuring cup (external diameter is 50mm, a height of 15mm) and suitable 25 DEG C ± 1 are placed in the previous day
DEG C climatic chamber (design temperature is 25 DEG C ± 1 DEG C, relative humidity is 80% ± 2%) in, precise weighing (m1).Reality is taken respectively
The sample (naming sample 1, sample 2, sample 3 respectively) applied obtained by example 1, embodiment 2, embodiment 3 is appropriate, in putting above-mentioned measuring cup
And be laid in measuring cup, test sample thickness is typically about 1mm, precise weighing (m2).Measuring cup is open, and put together with bottle cap
24 hours under the conditions of above-mentioned constant temperature and humidity.Cover measuring cup lid, precise weighing (m3).Percentage weight increase=(m3-m2)/
(m2-m1) × 100%.The results are shown in Table 3.
The draws moist test result of the epirizole piperazine crystal formation of table 3
| Sample | Percentage weight increase (%) | Draw moist |
| Sample 1 | 0.11% | Nothing draws moist |
| Sample 2 | 0.09% | Nothing draws moist |
| Sample 3 | 0.13% | Nothing draws moist |
Under conditions of high humidity it is open place 24 hours after, draw wet percentage weight increase and be respectively less than 0.2%, according to drawing moist feature
Describe and draw defining for wet weightening, this epirizole piperazine crystal formation is moist without drawing.
Claims (9)
1. a kind of crystal formation of epirizole piperazine, it is characterised in that its X-ray powder diffraction collection 2 θ=6.7 ± 0.2 °, 12.2 ±
0.2 °, 14.4 ± 0.2 °, 17.3 ± 0.2 °, 19.1 ± 0.2 °, 20.1 ± 0.2 °, 21.3 ± 0.2 °, have at 23.1 ± 0.2 °
Characteristic peak.
2. the crystal formation of epirizole piperazine according to claim 1, it is characterised in that the X-ray powder diffraction of described crystal formation
Collection of illustrative plates has characteristic peak at 2 θ=10.7 ± 0.2 °, 13.8 ± 0.2 °, 14.8 ± 0.2 °, 26.8 ± 0.2 °, 29.1 ± 0.2 °.
3. the crystal formation of epirizole piperazine according to claim 1, it is characterised in that the X-ray powder diffraction of described crystal formation
Collection of illustrative plates 2 θ=16.4 ± 0.2 °, 17.0 ± 0.2 °, 19.3 ± 0.2 °, 20.7 ± 0.2 °, 23.3 ± 0.2 °, 24.4 ± 0.2 °,
25.6 ± 0.2 °, there is at 26.2 ± 0.2 ° characteristic peak.
4. the preparation method of the crystal formation of the arbitrary described epirizole piperazine of a kind of claim 1-3, it is characterised in that epirizole piperazine exists
Stirring, crystallization, obtain final product in solvent.
5. the preparation method of the crystal formation of epirizole piperazine according to claim 4, it is characterised in that described solvent is dichloro
Methane, chloroform, methyl alcohol, ethanol, isopropanol, acetone, butanone, toluene, dimethylbenzene, tetrahydrofuran, dioxane, dimethyl
One kind or several in sulfoxide, N,N-dimethylformamide, methyl tertiary butyl ether(MTBE), ether, n-hexane, normal heptane, hexamethylene or water
Kind.
6. the preparation method of the crystal formation of epirizole piperazine according to claim 4, it is characterised in that described whipping temp is
40～110 DEG C.
7. the preparation method of the crystal formation of epirizole piperazine according to claim 4, it is characterised in that described recrystallization temperature for-
20～20 DEG C.
8. the purposes of the crystal formation of the arbitrary described epirizole piperazine of a kind of claim 1-3, it is characterised in that described crystal formation is used for
Prepare the purposes in antipsychotics preparation.
9. a kind of Pharmaceutical composition of the crystal formation comprising the arbitrary described epirizole piperazine of claim 1-3, it is characterised in that medicinal
The crystal formation and pharmaceutically acceptable excipient of epirizole piperazine of the composition comprising effective dose.
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| CN201610878661.3A CN106632291A (en) | 2016-10-09 | 2016-10-09 | Brexpiprazole crystal, its preparation method and application, and pharmaceutical composition comprising brexpiprazole crystal |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107674067A (en) * | 2017-10-19 | 2018-02-09 | 上海博志研新药物技术有限公司 | A kind of purification process of her a piperazine azoles |
| CN110218209A (en) * | 2018-03-02 | 2019-09-10 | 上海现代药物制剂工程研究中心有限公司 | It is a kind of according to crystal form A, preparation method and an application for piperazine azoles laurate |
| CN111440158A (en) * | 2020-03-24 | 2020-07-24 | 石药集团中奇制药技术（石家庄）有限公司 | Novel crystal form of brexpiprazole hydrochloride and preparation method thereof |
| CN112540099A (en) * | 2019-09-20 | 2021-03-23 | 广东东阳光药业有限公司 | Differential scanning calorimetry |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103717587A (en) * | 2011-07-28 | 2014-04-09 | 大塚制药株式会社 | Method for producing benzo[B]thiophene compound |
| CN104447723A (en) * | 2014-11-28 | 2015-03-25 | 瑞阳制药有限公司 | Method for preparing 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone |
| CN105175401A (en) * | 2015-10-16 | 2015-12-23 | 北京康立生医药技术开发有限公司 | Preparation method of brexpiprazole |
| CN105399736A (en) * | 2016-01-07 | 2016-03-16 | 安徽省逸欣铭医药科技有限公司 | Novel preparation method of brexpiprazole |
| CN105461703A (en) * | 2014-12-29 | 2016-04-06 | 深圳市泛谷药业股份有限公司 | Preparation method of brexpiprazole |
| CN105541819A (en) * | 2016-02-04 | 2016-05-04 | 浙江永宁药业股份有限公司 | Preparation method and intermediate of brexpiprazole and preparation method of intermediate |
| CN105859703A (en) * | 2015-01-23 | 2016-08-17 | 苏州旺山旺水生物医药有限公司 | Preparation method of novel brexpiprazole, aripiprazole and salts thereof |
-
2016
- 2016-10-09 CN CN201610878661.3A patent/CN106632291A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103717587A (en) * | 2011-07-28 | 2014-04-09 | 大塚制药株式会社 | Method for producing benzo[B]thiophene compound |
| CN104447723A (en) * | 2014-11-28 | 2015-03-25 | 瑞阳制药有限公司 | Method for preparing 7-(4-(4-(benzo[b]thienyl)-1-piperazinyl) butoxy)-2(1H)-quinolinone |
| CN105461703A (en) * | 2014-12-29 | 2016-04-06 | 深圳市泛谷药业股份有限公司 | Preparation method of brexpiprazole |
| CN105859703A (en) * | 2015-01-23 | 2016-08-17 | 苏州旺山旺水生物医药有限公司 | Preparation method of novel brexpiprazole, aripiprazole and salts thereof |
| CN105175401A (en) * | 2015-10-16 | 2015-12-23 | 北京康立生医药技术开发有限公司 | Preparation method of brexpiprazole |
| CN105399736A (en) * | 2016-01-07 | 2016-03-16 | 安徽省逸欣铭医药科技有限公司 | Novel preparation method of brexpiprazole |
| CN105541819A (en) * | 2016-02-04 | 2016-05-04 | 浙江永宁药业股份有限公司 | Preparation method and intermediate of brexpiprazole and preparation method of intermediate |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107674067A (en) * | 2017-10-19 | 2018-02-09 | 上海博志研新药物技术有限公司 | A kind of purification process of her a piperazine azoles |
| CN110218209A (en) * | 2018-03-02 | 2019-09-10 | 上海现代药物制剂工程研究中心有限公司 | It is a kind of according to crystal form A, preparation method and an application for piperazine azoles laurate |
| CN112540099A (en) * | 2019-09-20 | 2021-03-23 | 广东东阳光药业有限公司 | Differential scanning calorimetry |
| CN111440158A (en) * | 2020-03-24 | 2020-07-24 | 石药集团中奇制药技术（石家庄）有限公司 | Novel crystal form of brexpiprazole hydrochloride and preparation method thereof |
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