CN105566222A - Stable blonanserin compound - Google Patents
Stable blonanserin compound Download PDFInfo
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- CN105566222A CN105566222A CN201410524648.9A CN201410524648A CN105566222A CN 105566222 A CN105566222 A CN 105566222A CN 201410524648 A CN201410524648 A CN 201410524648A CN 105566222 A CN105566222 A CN 105566222A
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Abstract
The present invention belongs to the technical field of medicine, and particularly relates to blonanserin and a preparation method thereof. According to the present invention, the obtained blonanserin having the new crystal form has advantages of high purity and good stability, wherein the maximum impurity is less than 0.05%; and the method has good reproducibility, wherein the purity and the crystal form can be well reproduced when the method is scaled up to the pilotscale experiment scale. The present invention further relates to applications of the blonanserin using the new crystal form in preparation of schizophrenia treatment drugs.
Description
Technical field
The invention belongs to medical art, be specifically related to crystal of blonanserin compound and preparation method thereof, the invention still further relates to and use this crystal manufacture to treat application in schizoid medicine.
Background technology
Blonanserin is the latest model atypical antipsychotic agents of Japan's listing in 2008, it belongs to the single-minded medicine acting on 5-HT2 acceptor and D2 acceptor, it is the medicine closest to selectively acting in current atypical antipsychotic market, the schizoid positive shape of obvious improvement is (as illusion, illusion etc.) and negative symptoms (as feel down in spirits, hypokinesia etc.), reduce extrapyramidal system rate of side effects (parkinson's syndrome, acute dystonia, cathisophobia) and other untoward reactions, security tolerance is obviously better than Traditional antipsychotics.Can say that the appearance of blonanserin is the much progress in schizophrenia drug treatment history.
Blonanserin (Blonanserin), chemistry 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-six hydrogen cycloocta-[b] pyridine by name
Molecular formula: C
23h
30fN
3
Molecular weight: 367.5g/mol
Its structural formula is as follows:
In research process, repeat the method for prior art, the blonanserin compound impurities number obtained is more, and total impurities is higher, and after amplifying, crystal formation is difficult to repetition.
Astoundingly, the blonanserin compound crystal that the present invention obtains has: purity is high, and maximum contaminant is less than 1 ‰; Good stability; Reproducible in industrial scale; Good water dissolution performance.
Summary of the invention
One object of the present invention, discloses a kind of compound crystal of blonanserin.
Another object of the present invention, discloses the preparation method of blonanserin compound crystal.
Another object of the present invention, discloses the pharmaceutical composition comprising blonanserin compound crystal.
The invention also discloses blonanserin compound crystal and manufacture the application in the schizoid medicine for the treatment of.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
This blonanserin compound crystal, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: CuKa target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ) and D value as follows.
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
Another object of the present invention, discloses the preparation method of blonanserin compound, by by blonanserin heating for dissolving in acetone-acetonitrile-ethanol solution, lowers the temperature stage by stage and obtains.
It is characterized in that comprising the following steps: that blonanserin adds in the mixed solution of 3-5 times of (weight or measurement (WM) ratio) acetone-acetonitrile-ethanol=1:1-2:0.5-1, be heated to 40 DEG C-50 DEG C, be incubated 30 minutes, filtered while hot.Filtrate 30 DEG C-35 DEG C, insulation 1-2 hour; Naturally cool to room temperature again, insulation 2-3 hour, filters the crystallization of separating out, through natural drying at room temperature, obtains the above-mentioned blonanserin crystal of high purity.
Under study for action, the experimental results shows, and the ratio of acetone-acetonitrile-ethanol, the multiple added, lowering the temperature stage by stage is all the guarantee obtaining blonanserin crystal of the present invention.
Meanwhile, generate the method for the blonanserin compound of crystalline forms, need applicable suitability for industrialized production, namely can obtain uniform crystal formation at industrial scale, and well reappear.
The method is reproducible, is amplified to pilot scale, and content and crystal formation all can reappear very well.
Another object of the present invention, provides the composition comprising the blonanserin that blonanserin compound and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; crystal of the present invention acceptable liquid vehicle on technology of pharmaceutics is combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations.
The amount of the active ingredient (crystal of the present invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, and the weight range of active compound is 1% ~ 20%(weight of composition).
Present invention also offers blonanserin compound and manufacture the application in the schizoid medicine for the treatment of.
stability test
The chemical stability of contriver to crystal formation of the present invention is studied, and investigation condition is high temperature (60 DEG C ± 2 DEG C), strong illumination (4500Lx ± 500lx), and high humidity (92.5%, RH) inspection target is outward appearance, content and related substance.
Result: from 0-10 days under high light, high temperature, super-humid conditions, outward appearance, related substance, content do not change, and illustrate that chemical stability is good, are applicable to manufacture and the standing storage of pharmaceutical preparation.
embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
Blonanserin used in the present invention is according to existing document US5021421 and Bioorganic & MedicinalChemistryLetters.2005,15, the method synthesis that 1055-1059 provides, through nuclear magnetic resonance spectrum, high resolution mass spectrum, ultimate analysis, the blonanserin chemical structure of synthesis proves that chemical structure is correct.
embodiment 1
In 100L reactor, add in the mixed solution of the acetone-acetonitrile-ethanol=1:1:0.5 of 6 kilograms of blonanserins (purity 98.06%, HPLC) and 18L, be heated to 40 DEG C, be incubated 30 minutes, filtered while hot.Filtrate 30 DEG C, is incubated 1.5 hours; Naturally cool to room temperature again, be incubated 2.5 hours, filter the crystallization of separating out, through natural drying at room temperature, obtain white crystal 5.71 kilograms, purity 99.91%, dissolvent residual detects and meets the requirements.
embodiment 2
In 100L reactor, add in the mixed solution of the acetone-acetonitrile-ammoniacal liquor=1:2:1 of 6 kilograms of blonanserins (purity 98.06%, HPLC) and 30L, be heated to 50 DEG C, be incubated 30 minutes, filtered while hot.Filtrate 35 DEG C, is incubated 1 hour; Naturally cool to room temperature again, be incubated 2 hours, filter the crystallization of separating out, through natural drying at room temperature, obtain white crystal 5.56 kilograms, purity 99.92%, dissolvent residual detects and meets the requirements.
Use standard and conventional technology, make the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics be combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations.Only citing is illustrated, and never means that it limits the scope of the invention by any way.
embodiment 3
Tablet containing blonanserin compound
Prescription: blonanserin compound 20 grams, N-METHYL-ALPHA-L-GLUCOSAMINE 10 grams, polyvinylpyrrolidone 21 grams, Microcrystalline Cellulose 200 grams, sodium starch glycolate 150 grams, Magnesium Stearate 15 grams, distilled water is appropriate, makes 10000.
Technique: blonanserin and vehicle are dissolved in 80 DEG C of distilled water, adds 5 percent amounts of Microcrystalline Cellulose, and mixing final vacuum dry, pulverize, and crosses 100 mesh sieves, compressing tablet after mixing with other material.
Claims (6)
1. the blonanserin compound of formula I,
（Ⅰ）
It is characterized in that: in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following
2 θ diffraction angle and D value,
The error of 2 θ diffraction angle is 0.2.
2. the preparation method of blonanserin compound described in claim 1, by by blonanserin heating for dissolving in acetone-acetonitrile-ethanol solution, lowers the temperature stage by stage and obtains.
3. the preparation method of blonanserin compound described in claim 2, it is characterized in that comprising the following steps: that blonanserin adds in the mixed solution of 3-5 times of (weight or measurement (WM) ratio) acetone-acetonitrile-ethanol=1:1-2:0.5-1, be heated to 40 DEG C-50 DEG C, be incubated 30 minutes, filtered while hot, filtrate 30 DEG C-35 DEG C, insulation 1-2 hour; Naturally cool to room temperature again, insulation 2-3 hour, filters the crystallization of separating out, through natural drying at room temperature, obtains the above-mentioned blonanserin compound crystal of high purity.
4. the composition formed containing blonanserin compound described in claim 1 and one or more pharmaceutically acceptable carriers.
5. composition according to claim 4, is characterized in that said composition is for the preparation of tablet, capsule.
6. blonanserin compound described in claim 1 is manufacturing the application in the schizoid medicine for the treatment of.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410524648.9A CN105566222A (en) | 2014-10-09 | 2014-10-09 | Stable blonanserin compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410524648.9A CN105566222A (en) | 2014-10-09 | 2014-10-09 | Stable blonanserin compound |
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| Publication Number | Publication Date |
|---|---|
| CN105566222A true CN105566222A (en) | 2016-05-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410524648.9A Pending CN105566222A (en) | 2014-10-09 | 2014-10-09 | Stable blonanserin compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2014
- 2014-10-09 CN CN201410524648.9A patent/CN105566222A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160511 |
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| WD01 | Invention patent application deemed withdrawn after publication |