CN105439961A - Crystalline form I of Olaparib and preparation method therefor - Google Patents
Crystalline form I of Olaparib and preparation method therefor Download PDFInfo
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- CN105439961A CN105439961A CN201510320070.XA CN201510320070A CN105439961A CN 105439961 A CN105439961 A CN 105439961A CN 201510320070 A CN201510320070 A CN 201510320070A CN 105439961 A CN105439961 A CN 105439961A
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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
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Abstract
The present invention relates to a crystalline form I of Olaparib and a preparation method therefor. The present invention particularly provides a crystalline form I. The crystalline form I is characterized in that the X-ray powder diffraction pattern of the crystalline form I has characteristic peaks when the 2 theta value is 6.4 degrees +/- 0.2 degree, 12.7 degrees +/- 0.2 degree and 15.1 degrees +/- 0.2 degree. The crystalline form I provided by the present invention is better in stability, and has important values for optimization and development of the drug in the future.
Description
Technical field
The present invention relates to chemical medicine, crystal formation I particularly relating to Aura handkerchief Buddhist nun and preparation method thereof.
Background technology
First Aura handkerchief Buddhist nun is researched and developed by biotech company of Britain KuDOS (Ku Duosi) Pharm Pur GmbH, after being purchased, continues the medicine of a treatment ovarian cancer of research and development by AstraZeneca.On December 19th, 2014, Aura handkerchief Buddhist nun obtained FDA approval listing in the U.S., was the targeted drug of ovarian cancer patients that first of FDA approval is specifically designed to BRCA sudden change, was applicable to the patient previously living through chemotherapeutic treatment.Be proved to be in preclinical models, Aura handkerchief Buddhist nun is a kind of pioneering oral many Poly ADP-ribose polymerases (PARP) inhibitor, DNA can be utilized to repair the defect of approach, preferentially kill cancer cells.
The chemical name of Aura handkerchief Buddhist nun is 4-[3-(4-cyclopropane carbonyl-piperazine-1-carbonyl) the fluoro-benzyl of-4-]-2H-phthalazines-1-ketone, and its structure is such as formula shown in (I):
KuDOS (Ku Duosi) Pharm Pur GmbH discloses free alkali crystal form A and a solvate crystal formation of Aura handkerchief Buddhist nun at patent CN101528714B, discloses the free alkali crystal formation L of Aura handkerchief Buddhist nun at CN101821242B.There is no the crystal formation patent of the open Aura handkerchief Buddhist nun of other companies.
Solid chemical crystal formation is different, its solubleness can be caused different with stability, thus affect absorption and the bioavailability of medicine, and can cause the difference of clinical drug effect.Therefore, be necessary to carry out comprehensive and systematic screening polymorph to formula (I) compound, select the crystal formation of the most applicable exploitation.
The present inventor have developed the new crystal of a kind of Aura handkerchief Buddhist nun, this new crystal stability is better, solubleness, draw and moistly meet medicinal requirements, and preparation method's solvent for use asepsis environment-protecting, there is important value, for pharmaceutical solid preparation provides one better to select to the optimization of this medicine following and exploitation.
Summary of the invention
An object of the present invention is to provide a kind of new crystal of Aura handkerchief Buddhist nun, called after crystal formation I.
Concrete, crystal formation I provided by the invention, is characterized in that, its X-ray powder diffraction figure is that 6.4 ° ± 0.2 °, 12.7 ° ± 0.2 °, 15.1 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal formation I provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that 6.9 ° ± 0.2 °, 19.7 ° ± 0.2 °, 22.2 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, crystal formation I provided by the invention, is further characterized in that, its X-ray powder diffraction figure is that 17.7 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.0 ° ± 0.2 ° place has characteristic peak in 2theta value.
Crystal formation I provided by the invention, is characterized in that, its X-ray powder diffraction figure substantially as shown in Figure 1.
Crystal formation I provided by the invention, is characterized in that, its differential scanning calorimetric thermogram substantially as shown in Figure 2.
Crystal formation I provided by the invention, is characterized in that, its thermogravimetric analysis figure substantially as shown in Figure 3.
Another object of the present invention is to provide the preparation method of the crystal formation I of a kind of Aura handkerchief Buddhist nun, it is characterized in that, the solid of Aura handkerchief Buddhist nun is placed in pure water or water-containing solvent and stirs and obtain.
Further, described water-containing solvent, comprises the mixed solvent that moisture volume is not less than 80%.
Further, described water-containing solvent, is characterized in that, comprises alcohols, ketone, ethers, alkanes, aromatic solvents.
Another object of the present invention is to provide a kind of medicinal compositions, includes the crystal formation I eutectic of the Aura handkerchief Buddhist nun of effective amount, and the pharmaceutically acceptable vehicle of at least one.
Further, in medicinal compositions of the present invention, the crystal formation I of Aura handkerchief Buddhist nun can be used for preparing the purposes in Therapeutic cancer pharmaceutical preparation.
Further, described cancer includes but not limited to melanoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, lymphoma, lung cancer.
Beneficial effect of the present invention is:
The crystal formation I stability of Aura handkerchief Buddhist nun provided by the invention is better than the crystal form A in patent CN101528714B, in preparation, stores and can both keep stable in formulation development process, can not occur to turn brilliant, huge to the development significance of this medicine.
The preparation method of the crystal formation I of Aura handkerchief Buddhist nun provided by the invention, technique is simple, solvent for use asepsis environment-protecting, has important value, for pharmaceutical solid preparation provides one better to select to the optimization of this medicine following and exploitation.
Accompanying drawing explanation
Fig. 1 is the XRPD figure of crystal formation I
Fig. 2 is the DSC figure of crystal formation I
Fig. 3 is the TGA figure of crystal formation I
Embodiment
Below will set forth the present invention further by specific embodiment, but be not limited to protection scope of the present invention.Those skilled in the art can make improvements preparation method and use instrument in right, and these improvement also should be considered as protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
In following embodiment, the described test method condition that conveniently conditioned disjunction manufacturer advises usually is implemented.
Being explained as follows of abbreviation used in the present invention:
XRPD:X ray powder diffraction
DSC: differential scanning calorimetric analysis
TGA: thermogravimetric analysis
X-ray powder diffraction figure of the present invention gathers on PanalyticalEmpyreanX ray powder diffractometer.The method parameter of X-ray powder diffraction of the present invention is as follows:
X ray reflection parameter: Cu, K α
Kα1
：1.540598；Kα2
：1.544426
K α 2/K α 1 intensity: 0.50
Voltage: 45 KVs (kV)
Electric current: 40 milliampere(mA)s (mA)
Sweep limit: from 3.0 to 40.0 degree
Differential scanning calorimetric analysis of the present invention (DSC) figure gathers on TAQ2000.The method parameter of differential scanning calorimetric analysis of the present invention (DSC) is as follows:
Scanning speed: 10 DEG C/min
Shielding gas: nitrogen
Thermogravimetric analysis of the present invention (TGA) figure gathers on TAQ5000.The method parameter of thermogravimetric analysis of the present invention (TGA) is as follows:
Scanning speed: 10 DEG C/min
Shielding gas: nitrogen
Embodiment 1
The preparation method of Aura handkerchief Buddhist nun crystal formation I:
Be dissolved in the pure water of 1.0mL by the Aura handkerchief Buddhist nun free alkali of 10.0mg, stirred at ambient temperature 7 days, suction filtration, dry, collect solid, after testing, the crystal formation that the present embodiment prepares is crystal formation I.
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 1.Its XRPD schemes as Fig. 1, and its DSC schemes as Fig. 2, and its TGA schemes as Fig. 3.
Table 1
| 2theta | D interval | Intensity % |
| 6.42 | 13.77 | 37.75 |
| 6.85 | 12.91 | 12.20 |
| 8.31 | 10.64 | 5.94 |
| 10.41 | 8.50 | 4.95 |
| 12.68 | 6.98 | 100.00 |
| 12.91 | 6.86 | 17.03 |
| 13.29 | 6.66 | 6.06 |
| 13.74 | 6.45 | 5.39 |
| 15.06 | 5.88 | 58.69 |
| 15.86 | 5.59 | 7.48 |
| 16.73 | 5.30 | 5.69 |
| 17.67 | 5.02 | 7.54 |
| 18.65 | 4.76 | 4.83 |
| 19.17 | 4.63 | 8.24 |
| 19.76 | 4.49 | 13.29 |
| 20.19 | 4.40 | 11.20 |
| 21.01 | 4.23 | 10.88 |
| 21.56 | 4.12 | 4.04 |
| 22.15 | 4.01 | 33.47 |
| 22.65 | 3.93 | 2.82 |
| 23.03 | 3.86 | 2.93 |
| 24.26 | 3.67 | 3.90 |
| 26.25 | 3.39 | 4.17 |
| 29.05 | 3.07 | 5.77 |
| 30.41 | 2.94 | 1.81 |
| 31.30 | 2.86 | 1.56 |
| 32.44 | 2.76 | 2.36 |
| 33.80 | 2.65 | 0.66 |
| 35.54 | 2.53 | 1.17 |
| 36.84 | 2.44 | 0.90 |
Embodiment 2
The preparation method of Aura handkerchief Buddhist nun crystal formation I:
Aura handkerchief Buddhist nun crystal form A in 10.0mg patent CN101528714B is joined in the pure water of 0.5mL, then adds the crystal seed of 1.0mg crystal formation I, stirred at ambient temperature 72 hours, suction filtration, with pure water, dry, collect solid, after testing, the crystal formation that the present embodiment prepares is crystal formation I.
The X-ray powder diffraction data of the crystal formation I that the present embodiment obtains are as shown in table 2.
Table 2
| 2theta | D interval | Intensity % |
| 3.39 | 26.07 | 5.24 |
| 4.33 | 20.40 | 5.87 |
| 6.43 | 13.76 | 49.29 |
| 6.78 | 13.05 | 13.68 |
| 10.42 | 8.49 | 17.05 |
| 12.69 | 6.98 | 97.29 |
| 13.36 | 6.63 | 10.10 |
| 15.06 | 5.88 | 82.14 |
| 16.75 | 5.29 | 7.93 |
| 17.69 | 5.01 | 22.77 |
| 19.09 | 4.65 | 15.34 |
| 19.77 | 4.49 | 8.59 |
| 20.23 | 4.39 | 5.38 |
| 21.01 | 4.23 | 42.18 |
| 22.17 | 4.01 | 100.00 |
| 23.28 | 3.82 | 17.38 |
| 26.13 | 3.41 | 8.88 |
| 29.07 | 3.07 | 14.50 |
| 30.56 | 2.93 | 5.26 |
| 33.41 | 2.68 | 5.82 |
| 34.43 | 2.60 | 6.39 |
| 38.63 | 2.33 | 2.29 |
Embodiment 3
The stability simultaneous test of crystal form A in Aura handkerchief Buddhist nun crystal formation I and patent CN101528714B:
Get the crystal formation I for preparing in crystal form A in 10.0mg patent CN101528714B and 1.0mg embodiment 1 respectively in a bottle, add 0.5mL pure water, make suspension liquid.At room temperature stir after 72 hours, the XRPD of test sample, the crystal form A in patent CN101528714B has all been converted into the crystal formation I in the present invention, and result is as shown in table 3.
Table 3
Claims (7)
1. a crystal formation I for formula (I) compound, is characterized in that, its X-ray powder diffraction figure is that 6.4 ° ± 0.2 °, 12.7 ° ± 0.2 °, 15.1 ° ± 0.2 ° place has characteristic peak in 2theta value.
2. crystal formation I according to claim 1, is further characterized in that, its X-ray powder diffraction figure is that 6.9 ° ± 0.2 °, 19.7 ° ± 0.2 °, 22.2 ° ± 0.2 ° place has characteristic peak in 2theta value.
3. crystal formation I according to claim 2, is further characterized in that, its X-ray powder diffraction figure is that 17.7 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.0 ° ± 0.2 ° place has characteristic peak in 2theta value.
4. crystal formation I according to claim 1, is characterized in that, its X-ray powder diffraction figure is substantially consistent with Fig. 1.
5. a preparation method of the crystal formation I of claim 1, is characterized in that, the solid of Aura handkerchief Buddhist nun is placed in pure water or water-containing solvent and stirs and obtain.
6. a medicinal compositions, described medicinal compositions includes the crystal formation I described in any one of the Claims 1-4 of effective amount and pharmaceutically acceptable vehicle.
7. medicinal compositions according to claim 6, is characterized in that, the crystal formation I described in any one of described Claims 1-4 is for the preparation of the purposes in Therapeutic cancer pharmaceutical preparation.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510320070.XA CN105439961A (en) | 2015-06-12 | 2015-06-12 | Crystalline form I of Olaparib and preparation method therefor |
| CN202010211575.3A CN112010809A (en) | 2015-06-12 | 2015-06-12 | Crystal form I of olaparib and preparation method thereof |
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|---|---|---|---|
| CN201510320070.XA CN105439961A (en) | 2015-06-12 | 2015-06-12 | Crystalline form I of Olaparib and preparation method therefor |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017123156A1 (en) * | 2016-01-14 | 2017-07-20 | Scinopharm Taiwan, Ltd. | Crystalline forms of olaparib and manufacturing processes therefor |
| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
| US10703728B1 (en) | 2019-06-18 | 2020-07-07 | Scinopharm Taiwan, Ltd. | Crystalline form of olaparib and a process for preparing the same |
| CN111689905A (en) * | 2020-07-22 | 2020-09-22 | 天津理工大学 | Eutectic of olaparib and maleic acid and preparation method thereof |
| CN111995582A (en) * | 2020-07-09 | 2020-11-27 | 天津理工大学 | Eutectic of olaparib and urea and preparation method thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113264887B (en) * | 2021-05-27 | 2022-03-25 | 神隆医药（常熟）有限公司 | Novel crystal form X of olaparib and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101528714A (en) * | 2006-10-17 | 2009-09-09 | 库多斯药物有限公司 | Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2h-phthalazin-1-one |
| CN102238945A (en) * | 2008-10-07 | 2011-11-09 | 阿斯利康(英国)有限公司 | Pharmaceutical formulation 514 |
-
2015
- 2015-06-12 CN CN201510320070.XA patent/CN105439961A/en active Pending
- 2015-06-12 CN CN202010211575.3A patent/CN112010809A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101528714A (en) * | 2006-10-17 | 2009-09-09 | 库多斯药物有限公司 | Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2h-phthalazin-1-one |
| CN102238945A (en) * | 2008-10-07 | 2011-11-09 | 阿斯利康(英国)有限公司 | Pharmaceutical formulation 514 |
Non-Patent Citations (1)
| Title |
|---|
| 朱良漪 主编: "《分析仪器手册》", 31 May 1997, 化学工业出版社 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017123156A1 (en) * | 2016-01-14 | 2017-07-20 | Scinopharm Taiwan, Ltd. | Crystalline forms of olaparib and manufacturing processes therefor |
| US10138211B2 (en) | 2016-01-14 | 2018-11-27 | Scinopharm Taiwan, Ltd. | Crystalline forms of olaparib and manufacturing processes therefor |
| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
| US10703728B1 (en) | 2019-06-18 | 2020-07-07 | Scinopharm Taiwan, Ltd. | Crystalline form of olaparib and a process for preparing the same |
| CN111718300A (en) * | 2019-06-18 | 2020-09-29 | 台湾神隆股份有限公司 | Novel crystal form of olaparib and preparation method thereof |
| CN111995582A (en) * | 2020-07-09 | 2020-11-27 | 天津理工大学 | Eutectic of olaparib and urea and preparation method thereof |
| CN111995582B (en) * | 2020-07-09 | 2021-12-03 | 天津理工大学 | Eutectic of olaparib and urea and preparation method thereof |
| CN111689905A (en) * | 2020-07-22 | 2020-09-22 | 天津理工大学 | Eutectic of olaparib and maleic acid and preparation method thereof |
| CN111689905B (en) * | 2020-07-22 | 2021-12-03 | 天津理工大学 | Eutectic of olaparib and maleic acid and preparation method thereof |
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| CN112010809A (en) | 2020-12-01 |
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Address after: 215123 B4-101, biological park, No. 218, Xing Hu Street, Suzhou Industrial Park, Suzhou, Jiangsu Applicant after: Suzhou crystal cloud medicine Polytron Technologies Inc Address before: 215123 B4-101, biological park, No. 218, Xing Hu Street, Suzhou Industrial Park, Suzhou, Jiangsu Applicant before: Crystal Pharmatech Co., Ltd. |
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Effective date of registration: 20191115 Address after: Xinghu Street Industrial Park of Suzhou city in Jiangsu province 215123 No. 218 BioBAY B4-301 Applicant after: Suzhou best Pharmaceutical Co., Ltd. Address before: Suzhou City, Jiangsu Province, Suzhou City Industrial Park 215123 Xinghu Street No. 218 BioBAY B4-101 Applicant before: Suzhou crystal cloud medicine Polytron Technologies Inc |
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Application publication date: 20160330 |