CN106699672B - A kind of olaparib amorphous article and preparation method thereof - Google Patents
A kind of olaparib amorphous article and preparation method thereof Download PDFInfo
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- CN106699672B CN106699672B CN201510785406.XA CN201510785406A CN106699672B CN 106699672 B CN106699672 B CN 106699672B CN 201510785406 A CN201510785406 A CN 201510785406A CN 106699672 B CN106699672 B CN 106699672B
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- olaparib
- amorphous article
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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 a kind of olaparib amorphous articles and preparation method thereof; the olaparib amorphous article is composed with x-ray diffractogram of powder shown in FIG. 1; it can be by under inert gas protection; it directly heats olaparib raw material and is melted completely to it, then transfer of melt to temperature is room temperature or is cooled to below in the clean canister of room temperature or pours into the mixture of ice and water of stirring or be directly cooled to room temperature in 2~3 hours and be prepared in advance.Olaparib amorphous article of the present invention has good dissolubility and stability, and solvent residual amount is extremely low, all has significance to the preparation, storage and use of subsequent preparation；Also, preparation method of the present invention also have many advantages, such as simple process, yield are high, quality is stable, it is with short production cycle, be easily achieved scale.
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 technique
Olaparib (Olaparib), chemical name are as follows: 1- (cyclopropane carbonyl) -4- [5- [(3,4- dihydro -4- oxo -1-
Phthalazinyl) methyl] -2- fluorobenzoyl] piperazine, shown in chemical structure such as formula (I):
The medicine is formulated by biotechnological pharmaceutics company, Britain (KuDOS Pharmaceuticals), by U.S. A Sili
Continue to develop after health (AstraZeneca) corporate buyout, successively obtains European Union's medicine office (EMA) and U.S.'s food and medicine pipe
Reason office (FDA) preferential examination qualification goes through respectively on December 18th, 2014 and on December 19th, 2014 in Europe and the U.S.
Listing.Trade name LynparzaTM, for treating women's advanced ovarian cancer relevant to oophoroma BRCA gene defect.Aura pa
Buddhist nun is completely new oral Poly ADP ribose polymerase [poly (ADP-ribose) polymerase, PAR P] inhibitor,
BRCA1 or BRCA2 mutation is acted on, the defect of approach is repaired using DNA, preferentially kills cancer cell.Olaparib is as one
Kind PARP inhibitor, achieves preferable tumour in a clinical trial phase and random experiment compared with liposomal doxorubicin
Inhibiting effect.
KuDOS Pharmaceuticals company first reported the PARP inhibitory activity of this phthalazine derivative
(WO2004080976, US20050059663), and disclose the crystal form A (WO2008047082A) and crystal form L of olaparib
(WO2009050469A) and their preparation method.Now studies have shown that: olaparib is the low bioavailability of low-solubility
Drug, existing crystal form haves the defects that solubility is poor, is unfavorable for absorption of human body, and can change in production process
Object transformation of crystal is closed, it cannot be guaranteed that the stability of drug-eluting.Therefore, it is badly in need of finding at present a kind of both same with good solubility
When there is the olaparib kenel of good stability again, be suitable for the preparation of industrialization of preparation and meet the various performances of preparation wanting
It asks.
Summary of the invention
In view of the above-mentioned problems existing in the prior art and demand, both there is excellent dissolution the object of the present invention is to provide a kind of
Property simultaneously again with good stability olaparib amorphous article and preparation method thereof.
Olaparib amorphous article of the present invention has x-ray diffractogram of powder shown in FIG. 1 spectrum.
Furtherly, olaparib amorphous article of the present invention, under powder x-ray diffraction, 2 θ be 12.0~
There is a broad peak between 40.0 degree, is to have an acromion between 5.0~15.0 degree in 2 θ.
A method of olaparib amorphous article of the present invention is prepared, is included the following steps:
Under inert gas protection, it directly heats olaparib raw material and is melted completely to it；Then extremely by transfer of melt
Temperature is room temperature or is cooled to below in the clean canister of room temperature in advance, so that material is quickly cooled to solid；It is solid to gained again
Body is crushed, and gained powder is the olaparib amorphous article.
The method that another kind prepares olaparib amorphous article of the present invention, includes the following steps:
Under inert gas protection, it directly heats olaparib raw material and is melted completely to it；Then fusant is poured into and is stirred
In the mixture of ice and water mixed, so that material is quickly cooled to type；Filtering is collected solid powder, then is dried in vacuo to get institute
The olaparib amorphous article stated.
Another prepares the method for olaparib amorphous article of the present invention, includes the following steps:
Under inert gas protection, it directly heats olaparib raw material and is melted completely to it；Then stop heating, make to melt
Solid be cooled to room temperature in 2~3 hours, formed vitreous solid；Gained vitreous solid is crushed again, gained powder
End is the 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 have following conspicuousness the utility model has the advantages that
Result of study of the invention is shown: olaparib amorphous article of the present invention, have good dissolubility and
Stability is of great significance to the preparation and storage of subsequent preparation；Especially, olaparib amorphous article of the present invention
Preparation method not only have many advantages, such as simple process, yield are high, quality is stable, it is with short production cycle, be easily achieved scale, and
And by the method, volatilization can be made to remove by being heated to melting process the solvent sandwiched in olaparib raw material used
Go, so that the solvent residual amount of the olaparib amorphous article made is significantly reduced, make subsequent preparation using safe
Property is improved significantly；Therefore, the present invention compared with the existing technology, is more suitable as the raw material of pharmaceutical preparation, has significant
Industrial application value.
Detailed description of the invention
Fig. 1 is the XRD spectra of olaparib amorphous article of the present invention；
Fig. 2 is the DSC spectrogram of olaparib amorphous article of the present invention.
Specific embodiment
Combined with specific embodiments below and attached drawing, the present invention is further explained.It should be understood that these embodiments are merely to illustrate
The present invention rather than limit the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to
Normal condition or according to the normal condition proposed by manufacturer.
XRD diagram described in embodiment is to measure to obtain using Bruker D8advance X-ray powder diffraction instrument, specifically
Test parameter is as follows:
Cu-Kα
Voltage: 40Kv
Electric current: 40mA
Divergent slit: automatic
Scan pattern: continuous
Scanning range: from 3.0-40.0 degree
Sampling step length: 0.0200 degree
Sweep speed: 0.1 second/step.
DSC figure described in embodiment is obtained using DSC8500 analysis-e/or determining, and specific test parameter is as follows:
Initial temperature: 45 DEG C
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 protection, it directly heats olaparib raw material and is melted completely to it；Then extremely by transfer of melt
Temperature is room temperature or is cooled to below in the clean canister of room temperature in advance, so that material is quickly cooled to solid；It is solid to gained again
Body is crushed.
Gained powder is taken to carry 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, is to have an acromion between 5.0~15.0 degree in 2 θ.
Fig. 2 is the DSC spectrogram 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 protection, it directly heats olaparib raw material and is melted completely to it；Then fusant is poured into and is stirred
In the mixture of ice and water mixed, so that material is quickly cooled to type；Filtering is collected solid powder, is dried in vacuo at 55 DEG C.
Through X-ray powder diffraction analysis and dsc analysis, gained powder is the olaparib amorphous article.
Embodiment 1.3
Under inert gas protection, it directly heats olaparib raw material and is melted completely to it；Then stop heating, make to melt
Solid be 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 the 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 made from above-described embodiment 1.1-1.3 is taken to be handled as follows:
1. being placed 3 months under 40 DEG C, 75% humidity；
2. being placed 3 months under 25 DEG C, 65% humidity；
By showing this to above-mentioned sample during processing 0 month, 1 month, 2 months, 3 months sampling analyses (XRD)
The invention olaparib amorphous article under accelerated test condition (40 DEG C, 75% humidity) and room temperature storage condition (25 DEG C,
65% humidity) under do not occur kenel variation, be able to maintain good stability.
Embodiment 3: solubility experiment
Olaparib amorphous article sample made from above-described embodiment 1.1-1.3 and known crystal form A sample are taken, referring in
The 1.1 solubility parts (readding 0121-0124 sections of specification in detail) of embodiment 1 in state patent CN200980150172.4 carry out
1 hour solubility experiment, specific test result are shown in Table 1.
1 solubility test data (mg/mL) of table
| Medium | 1.1 sample of embodiment | 1.2 sample of embodiment | 1.3 sample of embodiment | Crystal form A sample |
| Water | 0.258 | 0.251 | 0.257 | 0.123 |
| 0.1M HCL (pH=1.2) | 0.286 | 0.278 | 0.285 | 0.128 |
| Phosphate buffer (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 |
Seen from table 1: olaparib amorphous article of the present invention is relative to known crystal form A, with excellent molten
Xie Xing, the dissolution for being very beneficial for preparation absorb, and are more suitable for the medicine activity component of preparation, have apparent industrial application
Value has conspicuousness progress and unexpected effect compared with the existing technology.
Claims (6)
1. a kind of olaparib amorphous article, it is characterised in that: have x-ray diffractogram of powder shown in FIG. 1 spectrum.
2. a kind of method for preparing olaparib amorphous article described in claim 1, which comprises the steps of:
Under inert gas protection, it directly heats olaparib raw material and is 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；Again to obtained solid into
Row crushes, and gained powder is the olaparib amorphous article.
3. a kind of method for preparing olaparib amorphous article described in claim 1, which comprises the steps of:
Under inert gas protection, it directly heats olaparib raw material and is melted completely to it；Then fusant is poured into stirring
In mixture of ice and water, so that material is quickly cooled to type；Filtering is collected solid powder, then is dried in vacuo to get described
Olaparib amorphous article.
4. a kind of method for preparing olaparib amorphous article described in claim 1, which comprises the steps of:
Under inert gas protection, it directly heats olaparib raw material and is melted completely to it；Then stop heating, make consolidating for melting
Body is cooled to room temperature in 2~3 hours, forms vitreous solid；Gained vitreous solid is crushed again, gained powder is
For the olaparib amorphous article.
5. method according to any one of claim 2 to 4, it is characterised in that: the inert gas is nitrogen, helium
Or argon gas.
6. method according to any one of claim 2 to 4, it is characterised in that: the olaparib raw material is any
Known kenel.
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Citations (3)
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|---|---|---|---|---|
| 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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| 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1;Keith A. Menear,等;《J. Med. Chem.》;20080919;第51卷;6581-6591 * |
| Efficient Fluoride-Catalyzed Conversion of CO2 to CO at Room Efficient Fluoride-Catalyzed Conversion of CO2 to CO at Room;Camille Lescot，等;《J. Am. Chem. Soc.》;20140404;第136卷;6142-6147 * |
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