CN106699672A - Olaparib amorphous compound, and preparation method thereof - Google Patents
Olaparib amorphous compound, and preparation method thereof Download PDFInfo
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- CN106699672A CN106699672A CN201510785406.XA CN201510785406A CN106699672A CN 106699672 A CN106699672 A CN 106699672A CN 201510785406 A CN201510785406 A CN 201510785406A CN 106699672 A CN106699672 A CN 106699672A
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- olaparib
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- amorphous article
- room temperature
- amorphous compound
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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 invention discloses an olaparib amorphous compound, and a preparation method thereof. The x-ray powder diffraction pattern of the olaparib amorphous compound is represented by formula 1. The preparation method comprises following steps: olaparib raw material is heated directly under insert gas protection until complete fusion is realized; an obtained molten product is delivered into a clean metal container, or added into stirred ice-water mixture, or is cooled to room temperature in 2 to 3h directly so as to obtain the olaparib amorphous compound, wherein the temperature in the clean metal container is controlled to be room temperature, or the clean metal container is subjected to precooling until the temperature is lower than room temperature. The olaparib amorphous compound is high in solubility and stability; solvent residue amount is extremely low; the olaparib amorphous compound possesses significant importance in preparation, storage, and applications of subsequent preparations; the preparation method is simple; yield is high; quality is stable; production period is short; and large-scale production is convenient to realize.
Description
Technical field
The present invention is to be related to a kind of olaparib amorphous article and preparation method thereof, belongs to field of pharmaceutical chemistry technology.
Background technology
Olaparib (Olaparib), chemistry is entitled：1- (cyclopropane carbonyl) -4- [5- [(3,4- dihydro -4- oxo -1- phthalazinyls) first
Base] -2- fluorobenzoyls] piperazine, shown in its chemical constitution such as formula (I)：
The medicine is formulated by biotechnological pharmaceuticses company of Britain (KuDOS Pharmaceuticals), by U.S.'s AstraZeneca
(AstraZeneca) continue to develop after corporate buyout, successively obtain European Union's medicine office (EMA) and U.S.'s food and medicine pipe
Reason office (FDA) preferential examination qualification, respectively on December 18th, 2014 and on December 19th, 2014 in Europe and the U.S.
Go through listing.Trade name LynparzaTM, the advanced ovarian cancer related to oophoroma BRCA gene defects for treating women.
Olaparib is brand-new oral PAR polymerase [poly (ADP-ribose) polymerase, PAR P]
Inhibitor, acts on BRCA1 or BRCA2 mutation, and it utilizes DNA to repair the defect of approach, preferentially kills cancer cell.
Olaparib takes in a clinical trial phase and random experiment as a kind of PARP inhibitor compared with liposomal doxorubicin
Obtained preferable tumor inhibition effect.
KuDOS Pharmaceuticals companies first reported the PARP inhibitory activity of this phthalazine derivative
(WO2004080976, US20050059663), and disclose the crystal formation A (WO2008047082A) of olaparib with
Crystal formation L (WO2009050469A) and their preparation method.Now there are some researches show：Olaparib is that low-solubility is low
There is the defect that solubility is poor, be unfavorable for absorption of human body in bioavailability medicine, existing crystal formation, and in preparation mistake
There is compound crystal form conversion in Cheng Zhonghui, it is impossible to ensure the stability of drug-eluting.Therefore, searching one kind is badly in need of at present both to have
Have good solubility has the olaparib kenel of good stability again simultaneously, is suitable for the preparation of industrialization of preparation and meets system
The various performance requirements of agent.
The content of the invention
In view of the above-mentioned problems existing in the prior art and demand, both had good solubility same it is an object of the invention to provide a kind of
When olaparib amorphous article and preparation method thereof with good stability again.
Olaparib amorphous article of the present invention, with the x-ray diffractogram of powder spectrum shown in Fig. 1.
Furtherly, olaparib amorphous article of the present invention, is 12.0~40.0 in 2 θ under powder x-ray diffraction
There is a broad peak between degree, have an acromion between 2 θ are for 5.0~15.0 degree.
A kind of method for preparing olaparib amorphous article of the present invention, comprises the following steps：
Under inert gas shielding, directly heat olaparib raw material and melted completely to it；Then by transfer of melt to temperature
It is cooled to below in the clean canister of room temperature for room temperature or in advance, so that material is quickly cooled to solid；Gained solid is entered again
Row is crushed, and gained powder is described olaparib amorphous article.
The method that another kind prepares olaparib amorphous article of the present invention, comprises the following steps：
Under inert gas shielding, directly heat olaparib raw material and melted completely to it；Then fused mass is poured into stirring
In mixture of ice and water, so that material is quickly cooled to type；Filtering, collects solid powder, then is vacuum dried, and obtains final product institute
The olaparib amorphous article stated.
Another prepares the method for olaparib amorphous article of the present invention, comprises the following steps：
Under inert gas shielding, directly heat olaparib raw material and melted completely to it；Then stop heating, make melting
Solid was cooled to room temperature in 2~3 hours, formed vitreous solid；Gained vitreous solid is crushed again, gained powder
End is described olaparib amorphous article.
Above-mentioned inert gas is nitrogen, helium or argon gas.
Above-mentioned olaparib raw material is any known kenel.
Compared with prior art, the present invention has following conspicuousness beneficial effect：
Result of study of the invention shows：Olaparib amorphous article of the present invention, with good dissolubility and stabilization
Property, the preparation and storage to follow-up preparation are significant；Especially, olaparib amorphous article of the present invention
Preparation method not only have the advantages that process is simple, yield high, steady quality, it is with short production cycle, be easily achieved scale,
And by methods described, can remove volatilization by being heated to melting process the solvent sandwiched in olaparib raw material used
Go, so as to the solvent residual amount for making the olaparib amorphous article for obtaining is significantly reduced, make follow-up preparation uses safety
Property is improved significantly；Therefore, the present invention is more suitable as the raw material of pharmaceutical preparation, with notable relative to prior art
Industrial application value.
Brief description of the drawings
Fig. 1 is the XRD spectra of olaparib amorphous article of the present invention；
Fig. 2 is the DSC spectrograms of olaparib amorphous article of the present invention.
Specific embodiment
With reference to specific embodiments and the drawings, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate this
Invention rather than limitation the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally according to normal
Rule condition or according to the condition proposed by manufacturer.
XRD described in embodiment is to determine to obtain using Bruker D8advance X-ray powder diffractions instrument, specific to survey
Examination parameter is as follows：
Cu-Kα
Voltage：40Kv
Electric current：40mA
Divergent slit：Automatically
Scan pattern：Continuously
Sweep limits：From 3.0-40.0 degree
Sampling step length：0.0200 degree
Sweep speed：0.1 second/step.
DSC figures described in embodiment is obtained using DSC8500 analysis-e/or determinings, and specific test parameter is as follows：
Initial temperature：45℃
Gas flow rate：Nitrogen, 20.0mL/min
The rate of heat addition：From 45 DEG C~300 DEG C, 10 DEG C/min.
Embodiment 1：The preparation of olaparib amorphous article
Embodiment 1.1
Under inert gas shielding, directly heat olaparib raw material and melted completely to it；Then by transfer of melt to temperature
It is cooled to below in the clean canister of room temperature for room temperature or in advance, so that material is quickly cooled to solid；Gained solid is entered again
Row is crushed.
Taking gained powder carries out X-ray powder diffraction analysis and dsc analysis.
Fig. 1 is the XRD spectra of gained powder, as seen from Figure 1：Gained powder is olaparib amorphous article, is in 2 θ
There is a broad peak between 12.0~40.0 degree, have an acromion between 2 θ are for 5.0~15.0 degree.
Fig. 2 is the DSC spectrograms of gained powder, as seen from Figure 2：Gained powder turns crystalline substance in 210.6 DEG C or so heat releases.
Embodiment 1.2
Under inert gas shielding, directly heat olaparib raw material and melted completely to it；Then fused mass is poured into stirring
In mixture of ice and water, so that material is quickly cooled to type；Filtering, collects solid powder, is vacuum dried at 55 DEG C.
Through X-ray powder diffraction analysis and dsc analysis, gained powder is described olaparib amorphous article.
Embodiment 1.3
Under inert gas shielding, directly heat olaparib raw material and melted completely to it；Then stop heating, make melting
Solid was cooled to room temperature in 2~3 hours, formed vitreous solid；Gained vitreous solid is crushed again.
Through X-ray powder diffraction analysis and dsc analysis, gained powder is described olaparib amorphous article.
Above-mentioned inert gas can be nitrogen, helium or argon gas.
Above-mentioned olaparib raw material can be any known kenel.
Embodiment 2：Stability experiment
Olaparib amorphous article sample obtained in above-described embodiment 1.1-1.3 is taken to be handled as follows：
1. placed 3 months under 40 DEG C, 75% humidity；
2. placed 3 months under 25 DEG C, 65% humidity；
By to above-mentioned sample during processing 0 month, 1 month, 2 months, the sampling analysis (XRD) of 3 months, table
Bright olaparib amorphous article of the present invention is under accelerated test condition (40 DEG C, 75% humidity) and room temperature storage condition
There is no kenel change under (25 DEG C, 65% humidity), good stability can be kept.
Embodiment 3：Solubility experiment
Olaparib amorphous article sample obtained in above-described embodiment 1.1-1.3 and known crystal formation A samples are taken, with reference to China specially
The 1.1 solubility parts (readding 0121-0124 sections of specification in detail) of the embodiment 1 in sharp CN200980150172.4 are carried out
The solubility experiment of 1 hour, specific test result is shown in Table 1.
The solubility test data (mg/mL) of table 1
| Medium | The sample of embodiment 1.1 | The sample of embodiment 1.2 | The sample of embodiment 1.3 | Crystal formation A samples |
| Water | 0.258 | 0.251 | 0.257 | 0.123 |
| 0.1M HCL (pH=1.2) | 0.286 | 0.278 | 0.285 | 0.128 |
| PB (pH 6.8) | 0.249 | 0.235 | 0.251 | 0.111 |
| 0.1M NaOH (pH=12.5) | 1.05 | 0.97 | 1.07 | 0.650 |
From table 1：Olaparib amorphous article of the present invention relative to known crystal formation A, with excellent dissolving
Property, it is very beneficial for the dissolution absorption of preparation, the medicine activity component of preparation is more suitable for, with obvious commercial Application
Value, relative to prior art, with conspicuousness progress and unexpected effect.
Claims (6)
1. a kind of olaparib amorphous article, it is characterised in that：With the x-ray diffractogram of powder spectrum shown in Fig. 1.
2. a kind of method of the olaparib amorphous article prepared described in claim 1, it is characterised in that comprise the following steps：
Under inert gas shielding, directly heat olaparib raw material and melted completely to it；Then by transfer of melt to temperature
It is cooled to below in the clean canister of room temperature for room temperature or in advance, so that material is quickly cooled to solid；Gained solid is entered again
Row is crushed, and gained powder is described olaparib amorphous article.
3. a kind of method of the olaparib amorphous article prepared described in claim 1, it is characterised in that comprise the following steps：
Under inert gas shielding, directly heat olaparib raw material and melted completely to it；Then fused mass is poured into stirring
In mixture of ice and water, so that material is quickly cooled to type；Filtering, collects solid powder, then is vacuum dried, and obtains final product institute
The olaparib amorphous article stated.
4. a kind of method of the olaparib amorphous article prepared described in claim 1, it is characterised in that comprise the following steps：
Under inert gas shielding, directly heat olaparib raw material and melted completely to it；Then stop heating, make melting
Solid was cooled to room temperature in 2~3 hours, formed vitreous solid；Gained vitreous solid is crushed again, gained powder
End is described olaparib amorphous article.
5. the method according to any one of claim 2 to 4, it is characterised in that：Described inert gas be nitrogen,
Helium or argon gas.
6. the method according to any one of claim 2 to 4, it is characterised in that：Described olaparib raw material is to appoint
The known kenel of meaning.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
Citations (3)
| 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 |
| CN101821242A (en) * | 2007-10-17 | 2010-09-01 | 库多斯药物有限公司 | 4- [3- (4-cyclopropanecarbonyl-piperazine-i-carbony_, -fluoro-benzyl] -2h-phthalaz in-1-one |
| CN102107008A (en) * | 2003-12-01 | 2011-06-29 | 库多斯药物有限公司 | DNA damage repair inhibitors for treatment of cancer |
-
2015
- 2015-11-16 CN CN201510785406.XA patent/CN106699672B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102107008A (en) * | 2003-12-01 | 2011-06-29 | 库多斯药物有限公司 | DNA damage repair inhibitors for treatment of cancer |
| 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 |
| CN101821242A (en) * | 2007-10-17 | 2010-09-01 | 库多斯药物有限公司 | 4- [3- (4-cyclopropanecarbonyl-piperazine-i-carbony_, -fluoro-benzyl] -2h-phthalaz in-1-one |
Non-Patent Citations (2)
| Title |
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| CAMILLE LESCOT，等: "Efficient Fluoride-Catalyzed Conversion of CO2 to CO at Room Efficient Fluoride-Catalyzed Conversion of CO2 to CO at Room", 《J. AM. CHEM. SOC.》 * |
| KEITH A. MENEAR,等: "4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1", 《J. MED. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
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