CN109293576A - A kind of preparation method of small grain size olaparib - Google Patents
A kind of preparation method of small grain size olaparib Download PDFInfo
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- CN109293576A CN109293576A CN201811323787.XA CN201811323787A CN109293576A CN 109293576 A CN109293576 A CN 109293576A CN 201811323787 A CN201811323787 A CN 201811323787A CN 109293576 A CN109293576 A CN 109293576A
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- CN
- China
- Prior art keywords
- preparation
- olaparib
- grain size
- solution
- small grain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
Abstract
The present invention relates to a kind of preparation methods of small grain size olaparib.The preparation method of small grain size olaparib of the present invention, comprising the following steps: the olaparib solution that preparation concentration is 0.10-0.18mg/ml；10-20 DEG C of solution temperature of control, 80% ethanol solution of addition 1.2-2.0 times of volume of first step ethyl acetate volume, growing the grain 1.5-2.5 hours；Second step acquired solution is cooled to 0-5 DEG C and is maintained, 0.10-0.16 DEG C/minute of rate of temperature fall, is continued growing the grain 2-4 hours；Filtering, filter cake are successively washed with acetic acid second and 80% ethanol solution, and 50-60 DEG C of vacuum drying obtains product of the present invention.The present invention provides a kind of preparation methods of small grain size olaparib.
Description
Technical field
The present invention relates to a kind of preparation methods of small grain size olaparib, belong to bulk pharmaceutical chemicals preparation technical field.
Background technique
Olaparib, English name: olaparib is researched and developed by Astrazeneca AB.For treating and BRCA gene defect
Relevant women's advanced ovarian cancer and the metastatic breast cancer of system genitale BRCA gene mutation (gBRCAm), HER2 feminine gender.
Olaparib daily 2 times, each 200mg, marketed tablet specification is 100g, capsule 50mg, due to glue
Wafer needs to take 4 every time, and therefore, patient is easier to receive tablet.
Olaparib belongs to insoluble drug, dissolves out to improve, Chinese patent CN102238945A,
CN106074409A, CN104434809A are prepared as olaparib dispersion, are then prepared as tablet composition.Due to
Olaparib tablet format is 100mg, belongs to larger specification, and test proves the stability of olaparib drug dispersity not
It is good, during storage and easily occur dispersion hardness become larger, overgrowth of crystal phenomena such as, dropped so as to cause the dissolution rate of tablet
It is low, related substance increase phenomena such as.In short, solid dispersion preparation preparation process is complicated, matter more demanding to support
Amount control is difficult to the quality control of ordinary tablet.
Since olaparib is on the one hand not soluble in water, in the preparation of preparation, the grain for being crushed to needs is generally required
In this case degree first is that there is a degree of dust pollutions for meeting during crushing, second is that extending preparation process, drops
The low production efficiency of preparation.The prior art does not disclose the preparation method of small grain size olaparib.
Summary of the invention
The present invention is directed to the demand of olaparib pharmaceutical preparation preparation, provides a kind of preparation side of small grain size olaparib
Method.
The technical scheme is that a kind of preparation method of small grain size olaparib, comprising the following steps:
First step olaparib is dissolved in ethyl acetate, the solution that preparation concentration is 0.10-0.18mg/ml；
Second step control first step acquired solution temperature at 10-20 DEG C and maintains, and first step ethyl acetate volume 1.2- is added
80% ethanol solution of 2.0 times of volumes, stirring, growing the grain 1.5-2.5 hours, stirring rate was 120-160 revs/min；
Under third step stirring, second step acquired solution is cooled to 0-5 DEG C and is maintained, 0.10-0.16 DEG C/minute of rate of temperature fall, is stirred
The same second step of rate is mixed, is continued growing the grain 2-4 hours；
The filtering of 4th step, filter cake are successively washed with acetic acid second and 80% ethanol solution, and 50-60 DEG C of vacuum drying obtains production of the present invention
Product.
If crude product purity is not good enough, in first step solution, filtered after active carbon stirring can be added.
Preferably, solution concentration described in the first step is 0.14-0.17mg/ml.
Preferably, it is 14-16 DEG C that second step, which maintains solution temperature,.
Preferably, 1.4-1.8 times that the volume of 80% ethanol solution is first step ethyl acetate volume is added in second step.
Preferably, second step mixing speed is 135-146 revs/min, and rearing crystal time is 1.8-2.2 hours.
Preferably, it is 2-4 DEG C that third step, which maintains solution temperature,.
Preferably, 0.12-0.14 DEG C/minute of third step rate of temperature fall.
Preferably, third step rearing crystal time is 2.5-3.5 hours.
The utility model has the advantages that technical solution of the present invention can obtain D90It is crystallized in the olaparib of 18-64 micron range, is preparation
The bulk pharmaceutical chemicals that can directly use are provided, avoid pollution of the dust to environment in crushing process, while also avoiding crushing
In the process to the destruction of drug crystal forms.
The embodiment embodiment of the present invention uses prior art preparation, purity 96.68%, efficient liquid with olaparib crude product
Phase chromatography measurement.
Embodiment 1.
First step 10g olaparib is dissolved in 100ml ethyl acetate, and the olaparib that preparation concentration is 0.10mg/ml is molten
Liquid；
Second step control first step acquired solution temperature at 10 DEG C and maintains, and 80% ethanol solution of 120ml, stirring, growing the grain is added
1.5 hours, stirring rate was 120 revs/min；
Under third step stirring, second step acquired solution is cooled to 0 DEG C and is maintained, 0.10 DEG C/minute of rate of temperature fall, stirring rate
Same second step continues growing the grain 2 hours；
The filtering of 4th step, filter cake are successively washed with acetic acid second and 80% ethanol solution, and 50 DEG C of vacuum drying obtain product of the present invention.
It is 99.98%, D that high performance liquid chromatography, which measures purity,90It is 64 microns, yield 93.62%.
Embodiment 2.
First step 18g olaparib is dissolved in 100ml ethyl acetate, and the olaparib that preparation concentration is 0.18mg/ml is molten
Liquid；
Second step control first step acquired solution temperature at 20 DEG C and maintains, and 80% ethanol solution of 200ml, stirring, growing the grain is added
2.5 hours, stirring rate was 160 revs/min；
Under third step stirring, second step acquired solution is cooled to 5 DEG C and is maintained, 0.16 DEG C/minute of rate of temperature fall, stirring rate
Same second step continues growing the grain 4 hours；
The filtering of 4th step, filter cake are successively washed with acetic acid second and 80% ethanol solution, and 60 DEG C of vacuum drying obtain product of the present invention.
It is 99.99%, D that high performance liquid chromatography, which measures purity,90It is 18 microns, yield 93.02%.
Embodiment 3.
First step 15g olaparib is dissolved in 100ml ethyl acetate, and the olaparib that preparation concentration is 0.15mg/ml is molten
Liquid；
Second step control first step acquired solution temperature at 15 DEG C and maintains, and 80% ethanol solution of 150ml, stirring, growing the grain is added
2 hours, stirring rate was 140 revs/min；
Under third step stirring, second step acquired solution is cooled to 3 DEG C and is maintained, 0.13 DEG C/minute of rate of temperature fall, stirring rate
Same second step continues growing the grain 3 hours；
The filtering of 4th step, filter cake are successively washed with acetic acid second and 80% ethanol solution, and 55 DEG C of vacuum drying obtain product of the present invention.
It is 99.99%, D that high performance liquid chromatography, which measures purity,90It is 27 microns, yield 93.42%.
Claims (8)
1. a kind of preparation method of small grain size olaparib, which comprises the following steps:
First step olaparib is dissolved in ethyl acetate, the solution that preparation concentration is 0.10-0.18mg/ml；
Second step control first step acquired solution temperature at 10-20 DEG C and maintains, and first step ethyl acetate volume 1.2- is added
80% ethanol solution of 2.0 times of volumes, stirring, growing the grain 1.5-2.5 hours, stirring rate was 120-160 revs/min；
Under third step stirring, second step acquired solution is cooled to 0-5 DEG C and is maintained, 0.10-0.16 DEG C/minute of rate of temperature fall, is stirred
The same second step of rate is mixed, is continued growing the grain 2-4 hours；
The filtering of 4th step, filter cake are successively washed with acetic acid second and 80% ethanol solution, and 50-60 DEG C of vacuum drying obtains production of the present invention
Product.
2. the preparation method of small grain size olaparib according to claim 1, which is characterized in that solution concentration described in the first step
For 0.14-0.17mg/ml.
3. the preparation method of small grain size olaparib according to claim 1, which is characterized in that second step maintains solution temperature
It is 14-16 DEG C.
4. the preparation method of small grain size olaparib according to claim 1, which is characterized in that 80% ethyl alcohol is added in second step
The volume of solution is 1.4-1.8 times of first step ethyl acetate volume.
5. the preparation method of small grain size olaparib according to claim 1, which is characterized in that second step mixing speed is
135-146 revs/min, rearing crystal time is 1.8-2.2 hours.
6. the preparation method of small grain size olaparib according to claim 1, which is characterized in that third step maintains solution temperature
It is 2-4 DEG C.
7. the preparation method of small grain size olaparib according to claim 1, which is characterized in that third step rate of temperature fall
0.12-0.14 DEG C/minute.
8. the preparation method of small grain size olaparib according to claim 1, which is characterized in that third step rearing crystal time is
2.5-3.5 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811323787.XA CN109293576A (en) | 2018-11-08 | 2018-11-08 | A kind of preparation method of small grain size olaparib |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811323787.XA CN109293576A (en) | 2018-11-08 | 2018-11-08 | A kind of preparation method of small grain size olaparib |
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| Publication Number | Publication Date |
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| CN109293576A true CN109293576A (en) | 2019-02-01 |
Family
ID=65146477
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| CN201811323787.XA Withdrawn CN109293576A (en) | 2018-11-08 | 2018-11-08 | A kind of preparation method of small grain size olaparib |
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Citations (9)
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|---|---|---|---|---|
| CN102238945A (en) * | 2008-10-07 | 2011-11-09 | 阿斯利康(英国)有限公司 | Pharmaceutical formulation 514 |
| US20130018035A1 (en) * | 2011-06-22 | 2013-01-17 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
| CN104434809A (en) * | 2014-12-10 | 2015-03-25 | 北京科莱博医药开发有限责任公司 | Olaparib solid dispersion preparation and preparation method thereof |
| CN105254572A (en) * | 2015-11-09 | 2016-01-20 | 北京科莱博医药开发有限责任公司 | Crystal form, preparing method and application of Olaparib |
| CN106074409A (en) * | 2016-06-13 | 2016-11-09 | 佛山市腾瑞医药科技有限公司 | A kind of Aura handkerchief Buddhist nun's preparation and application thereof |
| CN107162985A (en) * | 2017-06-05 | 2017-09-15 | 山东裕欣药业有限公司 | A kind of olaparib compound and preparation method thereof |
| CN107304186A (en) * | 2016-04-25 | 2017-10-31 | 杭州容立医药科技有限公司 | A kind of process for purification of olaparib |
| CN107304187A (en) * | 2016-04-25 | 2017-10-31 | 杭州容立医药科技有限公司 | A kind of recrystallization method of olaparib |
| CN108201536A (en) * | 2016-12-16 | 2018-06-26 | 中国科学院上海药物研究所 | A kind of olaparib takes orally sustained and controlled release medicament composition and application thereof |
-
2018
- 2018-11-08 CN CN201811323787.XA patent/CN109293576A/en not_active Withdrawn
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102238945A (en) * | 2008-10-07 | 2011-11-09 | 阿斯利康(英国)有限公司 | Pharmaceutical formulation 514 |
| US20130018035A1 (en) * | 2011-06-22 | 2013-01-17 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
| CN104434809A (en) * | 2014-12-10 | 2015-03-25 | 北京科莱博医药开发有限责任公司 | Olaparib solid dispersion preparation and preparation method thereof |
| CN105254572A (en) * | 2015-11-09 | 2016-01-20 | 北京科莱博医药开发有限责任公司 | Crystal form, preparing method and application of Olaparib |
| CN107304186A (en) * | 2016-04-25 | 2017-10-31 | 杭州容立医药科技有限公司 | A kind of process for purification of olaparib |
| CN107304187A (en) * | 2016-04-25 | 2017-10-31 | 杭州容立医药科技有限公司 | A kind of recrystallization method of olaparib |
| CN106074409A (en) * | 2016-06-13 | 2016-11-09 | 佛山市腾瑞医药科技有限公司 | A kind of Aura handkerchief Buddhist nun's preparation and application thereof |
| CN108201536A (en) * | 2016-12-16 | 2018-06-26 | 中国科学院上海药物研究所 | A kind of olaparib takes orally sustained and controlled release medicament composition and application thereof |
| CN107162985A (en) * | 2017-06-05 | 2017-09-15 | 山东裕欣药业有限公司 | A kind of olaparib compound and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 王志富 等: "反溶剂重结晶法制备无定形依贝沙坦微粉", 《北京化工大学学报》 * |
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Application publication date: 20190201 |