CN101747272B - Crystal form B of blonanserin and preparing method thereof - Google Patents
Crystal form B of blonanserin and preparing method thereof Download PDFInfo
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- CN101747272B CN101747272B CN2008102038915A CN200810203891A CN101747272B CN 101747272 B CN101747272 B CN 101747272B CN 2008102038915 A CN2008102038915 A CN 2008102038915A CN 200810203891 A CN200810203891 A CN 200810203891A CN 101747272 B CN101747272 B CN 101747272B
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Abstract
The invention provides a crystal form B of medicament 2-ethylpiperazine-4-(4-fluorobenzene)-5,6,7,8,9,10-hexahydro cyclooctane pyridine, which is characterized in that powder diffraction occurs in the positions of approximately 7.74+/-0.2, 15.6+/-0.2, 19.1+/-0.2 and 31.64+/-0.2 of a reflecting angle 2 theta through X-ray. The invention also provides a preparing method of the crystal form B, which is characterized by comprising the following steps of: ensuring that the medicament 2-ethylpiperazine-4-(4-fluorobenzene)-5,6,7,8,9,10-hexahydro cyclooctane pyridine is dissolved in ethanol by heating, and then obtaining the crystal form B through recrystallization.
Description
Technical field
The present invention relates to 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-six hydrogen ring sufferings are [b] pyridine (blonanserin, crystal form B Blonanserin) and preparation method thereof also.
Background technology
2-(4-ethyl-1-the piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9 of following structural formula, 10-six hydrogen ring sufferings are the blonanserin general by name (Blonanserin) of [b] pyridine also, is mainly used in the treatment of atypical psychosis.
Blonanserin (Blonanserin)
EP385237 and JP4099768A have all reported the compound method of blonanserin, but do not tell about the problem of crystal formation.At document Analytical Sciences, 2002, mentioned the single crystal diffraction of blonanserin in chloroform among the 18:1289-1290, this also is unique crystal formation report to blonanserin.We have made crystallization according to above-mentioned literature method, are crystal form A through its crystal formation of X-ray powder diffraction proof, and its X-ray powder diffraction is seen accompanying drawing 1.
According to existing document, the blonanserin oral prepns selects for use 0.1mol/L hydrochloric acid as dissolution fluid, yet crystal form A is sl. sol. in 0.1mol/L hydrochloric acid, and solubleness is merely 1mg/160ml, and its stability is also not ideal enough.Therefore, need to seek the new crystal of blonanserin.
Summary of the invention
We are through the screening of various recrystallization conditions; Like acetone, ethanol, normal hexane, Virahol, isopropyl ether, ETHYLE ACETATE and normal hexane, THF and water, DMF and water; Find through adopting acetone and ethanol as recrystallization solvent; The purity of products obtained therefrom can reach more than 99.8%, and single foreign matter content meets the regulation of SFDA to the bulk drug related substance less than 0.1%.
Through the X-ray powder diffraction, we find that blonanserin belongs to the polymorphic material simultaneously; Adopting chloroform, acetone, Virahol, isopropyl ether, ETHYLE ACETATE equal solvent recrystallization gained crystal formation is crystal form A, and adopts ethyl alcohol recrystallization will obtain a kind of 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6 of novelty; 7; 8,9,10-six hydrogen ring sufferings are the crystal form B of [b] pyridine also.
Therefore, to prior art 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7; 8,9,10-six hydrogen ring sufferings are the above-mentioned deficiency of the crystal form A of [b] pyridine also, and the technical problem that the present invention will solve provides a kind of 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5 of novelty; 6,7,8,9; 10-six hydrogen ring sufferings are the crystal form B of [b] pyridine also, and this crystal formation has satisfactory stability property, and its solid preparation also has good dissulution.Said crystal form B is characterised in that its X-ray powder diffraction occurs in reflection angle 2 θ and is about: 7.74 ± 0.2,15.6 ± 0.2,19.1 ± 0.2,31.64 ± 0.2 parts.
Wherein " ± 0.2 " is measuring error scope of permission.
Said 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9, the 10-six hydrogen ring sufferings also fusing point of the crystal form B of [b] pyridine are 125～127 ℃.
The present invention also provides this 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8; 9,10-six hydrogen ring sufferings are the preparation method of the crystal form B of [b] pyridine also, and this method may further comprise the steps: make 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5; 6,7,8; 9,10-six hydrogen ring sufferings also [b] pyridine after the heating for dissolving, obtain crystal form B through recrystallization in ethanol.
In the inventive method, said consumption of ethanol is 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9, and 10-six hydrogen ring sufferings are 5～10 times of [b] pyridines (ml/g) also.
In the inventive method, said Heating temperature is the alcoholic acid reflux temperature.
The present invention further provides described 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9, and 10-six hydrogen ring sufferings are the application of crystal form B in the medicine of preparation treatment atypical psychosis of [b] pyridine also.
2-provided by the present invention (4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9, the 10-six hydrogen ring sufferings also crystal form B of [b] pyridine are difficult for taking place to change brilliant phenomenon owing to have satisfactory stability property in depositing process.Particularly aspect solubleness; Crystal form B is better than crystal form A as bulk drug its solubleness in dissolution fluid 0.1mol/LHCl medium of preparation; This preparation dissulution of pointing out us to process with crystal form B is better than crystal form A, thereby the development of crystal form B has excellent development and utilizes prospect.
Description of drawings
Fig. 1 is 2-of the present invention (4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9, and 10-six hydrogen ring sufferings are the X-ray powder diffraction of the crystal form A of [b] pyridine also.
Fig. 2 is 2-of the present invention (4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9, and 10-six hydrogen ring sufferings are the X-ray powder diffraction of the crystal form B of [b] pyridine also.
Embodiment
Below in conjunction with embodiment the present invention is done further elaboration, but these embodiment do not constitute any restriction to the present invention.The analytical instrument that the following example adopted is following model:
Detecting instrument: rotating anode target 12KW X ray polycrystalline diffracted ray D/max-γ β
Detect foundation: JY/T009-1996
Sense environmental conditions: 20 ℃ of room temps; Relative humidity＜60%
Test condition: light source Cu K α line, slit: DS:1 °, SS:1 °, RS:0.15mm, Rsm:0.8mm, sweep limit 2 θ (°): 20.2 °～21.9 °.Scan mode: stepping, scanning step: 0.002 °, cumulative time: 0.5s/step, pipe is pressed: 40kv, pipe stream: 50mA.Rear-mounted graphite monochromator, DPS are the HP425e workstation.
Fusing point is measured according to Chinese Pharmacopoeia version in 2000 two appendix VI C fusing point test first method, and the synthetic sample is measured with capillary tube technique.
Blonanserin 1g is added ethanol 10mi be heated to 78 ℃ of dissolvings, be chilled to room temperature under stirring then, after 2 hours, filter.60 ℃ of oven dry.Obtain product 0.9g.This product proves 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5 through the X-ray powder diffraction; 6,7,8; 9; 10-six hydrogen ring sufferings are the crystal form B of [b] pyridine also, and it demonstrates has the 2 θ ° of X-ray powder diffraction collection of illustrative plates for the characteristic peak of about 7.74,15.6,19.1 and 31.64 expressions, as shown in Figure 2.The fusing point that records this crystal form B is 125～127 ℃.
Embodiment 2
Blonanserin 7.4g is added ethanol 100ml be heated to 78 ℃ of dissolvings, be chilled to room temperature under stirring then, after 2 hours, filter.60 ℃ of oven dry.Obtain product 6.5g.This product proves 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9 through the X-ray powder diffraction, and 10-six hydrogen ring sufferings are the crystal form B of [b] pyridine also.The fusing point that records this crystal form B is 125～126 ℃.
Embodiment 3
Blonanserin 82.8g is added ethanol 500ml be heated to 78 ℃ of dissolvings, be chilled to room temperature under stirring then, after 2 hours, filter.60 ℃ of oven dry.Obtain product 72g.This product proves 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9 through the X-ray powder diffraction, and 10-six hydrogen ring sufferings are the crystal form B of [b] pyridine also.The fusing point that records this crystal form B is 125～126 ℃.
Embodiment 4
Blonanserin 35.5g is added ethanol 180ml be heated to 78 ℃ of dissolvings, be chilled to room temperature under stirring then, after 2 hours, filter.60 ℃ of oven dry.Obtain product 32.1g.This product proves 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9 through the X-ray powder diffraction, and 10-six hydrogen ring sufferings are the crystal form B of [b] pyridine also.The fusing point that records this crystal form B is 125～126 ℃.
Comparative Examples 1: the preparation of crystal form A of blonanserin
Blonanserin 1g is added acetone 20ml, be heated to the dissolving that refluxes, be chilled to room temperature under stirring then, after 2 hours, filter.60 ℃ of oven dry.Obtain crystal form A of blonanserin sample 0.78g.126～127 ℃ of fusing points.
Test Example 1:
Instrument: LHS-100CL fixed temperature and humidity temperature-controlled box; Balance Mettler AE163
Foundation: press two appendix X of Chinese Pharmacopoeia version in 2005 IX C
Test condition: under 25 ℃, the condition of RH80%, 24h, carry out the crystal form B of embodiment 2 preparations and the moisture absorption weight increment test of crystal form A, the result sees the following form 1.
Table 1
Test Example 2:
Foundation: make an experiment by two appendix IX of Pharmacopoeia of People's Republic of China version in 2000 B.The result sees table 7-2.
Test condition: in 0.1mol/L HCl, carry out the crystal form B of embodiment 2 preparations and the solubility test of crystal form A, the result sees the following form 2.
Table 2
Test Example 3:
Instrument: Agilent 1100 liquid chromatographs
Foundation: two appendix V of Chinese Pharmacopoeia version in 2005 D
Test condition: chromatographic column Phenomenex Hyperclone 5 μ BDS C18
4.6×250mm，5μm
Moving phase acetonitrile: methyl alcohol: the 10mM potassium primary phosphate (is regulated with NaOH
PH＝7.0)＝40∶42∶18
Wavelength 236nm
40 ℃ of column temperatures
Flow velocity 1.0ml/min
Sample introduction 10 μ l
Concentration 1.0mg/ml
Crystal form B and crystal form A to embodiment 2 and Comparative Examples 1 preparation carry out stability test, and the result sees the following form 3.
Table 3. crystal form A of blonanserin, two kinds of crystal formation influence factor tests of B
Can learn that from the data of table 2 solubleness of crystal form B 0.1mol/L hydrochloric acid is greater than crystal form A; Select for use 0.1mol/L hydrochloric acid as dissolution fluid according to document blonanserin oral prepns; This has good dissolution degree with regard to pointing out our crystal form B as the bulk drug of preparation; Table 1 and 3 shows that also crystal form B does not almost have the moisture absorption weightening finish, does not have noticeable change in stable preliminary study yet simultaneously.
Therefore select for use crystal form B to have than crystal form A good dissolution degree as the bulk drug of preparation, this helps the absorption of medicine, strengthens drug effect.
Claims (4)
- (1.2-4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-six hydrogen ring sufferings are the crystal form B of [b] pyridine also, it is characterized in that the X-ray powder diffraction of said crystal form B is as shown in Figure 2.
- 2. 2-according to claim 1 (4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8; 9,10-six hydrogen ring sufferings are the preparation method of the crystal form B of [b] pyridine also, it is characterized in that this method may further comprise the steps: with 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5; 6,7,8; 9,10-six hydrogen ring sufferings also [b] pyridine after the heating for dissolving, obtain crystal form B through recrystallization in 5-10 times of ethanol (ml/g).
- 3. preparation method according to claim 2 is characterized in that said Heating temperature is the alcoholic acid reflux temperature.
- 4. 2-according to claim 1 (4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-six hydrogen ring sufferings are the application of crystal form B in the medicine of preparation treatment atypical psychosis of [b] pyridine also.
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| CN104311487B (en) * | 2014-09-22 | 2016-08-24 | 江苏正大丰海制药有限公司 | A kind of blonanserin crystal formation and preparation method thereof |
| CN106831578A (en) * | 2017-02-14 | 2017-06-13 | 北京万全德众医药生物技术有限公司 | The method of purification of antipsychotic drug blonanserin |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0385237A2 (en) * | 1989-03-03 | 1990-09-05 | Dainippon Pharmaceutical Co., Ltd. | 2-(1-piperazinyl)-4-phenylcycloalkanopyridine derivatives, processes for the production thereof, and pharmaceutical composition containing the same |
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- 2008-12-02 CN CN2008102038915A patent/CN101747272B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0385237A2 (en) * | 1989-03-03 | 1990-09-05 | Dainippon Pharmaceutical Co., Ltd. | 2-(1-piperazinyl)-4-phenylcycloalkanopyridine derivatives, processes for the production thereof, and pharmaceutical composition containing the same |
Non-Patent Citations (5)
| Title |
|---|
| JP平4-99768A 1992.03.31 |
| Kenji Suzuki et al.Crystal structure of an antipsychotic agent,2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine.《Analytical Sciences》.2002,第18卷(第11期),1289-1290. * |
| Medicinal Chemistry Letters》.2004,第15卷(第4期),1055-1059. * |
| Takeshi Ochi et al.Syntheses and properties of the major hydroxy metabolites in humans of blonanserin AD-5423, a novel antipsychotic agent.《Bioorganic & * |
| TakeshiOchietal.SynthesesandpropertiesofthemajorhydroxymetabolitesinhumansofblonanserinAD-5423 a novel antipsychotic agent.《Bioorganic & Medicinal Chemistry Letters》.2004 |
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