CN105753789B - The eutectic and preparation method thereof of olaparib and urea - Google Patents
The eutectic and preparation method thereof of olaparib and urea Download PDFInfo
- Publication number
- CN105753789B CN105753789B CN201610235001.3A CN201610235001A CN105753789B CN 105753789 B CN105753789 B CN 105753789B CN 201610235001 A CN201610235001 A CN 201610235001A CN 105753789 B CN105753789 B CN 105753789B
- Authority
- CN
- China
- Prior art keywords
- crystal form
- preparation
- eutectic
- olaparib
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/02—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of urea, its salts, complexes or addition compounds
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the eutectics and preparation method thereof of olaparib and urea.Specifically, the present invention provides eutectic crystal form A, its X-ray powder diffraction figure of the crystal form is to have characteristic peak at 17.4 ° ± 0.2 °, 20.7 ° ± 0.2 °, 10.5 ° ± 0.2 ° in 2theta values.Eutectic provided by the invention and existing olaparib free alkali crystal form are more preferable than stability, draw moist lower, solubility higher.There is important value to the optimization and exploitation of the following drug.
Description
Technical field
The present invention relates to the eutectics and its preparation method and application of a kind of olaparib and urea.
Background technology
Olaparib (Olaparib) is ground by biotech company of Britain KuDOS (Ku Duosi) Pharm Pur GmbH first
Hair, AstraZeneca in 2005 is by after KuDOS corporate buyouts, continual exploitation olaparib, for treating oophoroma.2014 12
The moon, olaparib on the 19th was listed in U.S.'s acquisition FDA approvals, was first oophoroma being mutated dedicated for BRCA of FDA approvals
The targeted drug of patient, suitable for previously living through the patient of chemotherapeutic treatment.It is had been demonstrated in preclinical models, olaparib
It is a kind of pioneering oral more Poly ADP-ribose polymerase (PARP) inhibitor, DNA can be utilized to repair the defect of approach, preferentially killed
Dead cancer cell.The chemical name of olaparib is 4- [3- (4- cyclopropane carbonyls-piperazine -1- carbonyls) the fluoro- benzyls of -4-] -2H-
Phthalazines -1- ketone, shown in structure such as formula (I)：
The free alkali that KuDOS (Ku Duosi) Pharm Pur GmbH discloses olaparib in patent CN101528714B is brilliant
Type A discloses the free alkali crystal form L of olaparib in CN101821242B.In addition to this, other open olaparibs be there is no
Crystal form patent.But the free alkali crystal form solubility of olaparib listing is low, it is necessary to the high crystal form of solubility is found, to carry
High drug absorption efficiency.
Based on this, the present inventor has developed a kind of eutectic of olaparib, solves the dissolving of free alkali crystal form
Spend low problem.Eutectic is in same crystal structure containing there are two types of the crystal of molecule.Acting as between two kinds of molecules is non-covalent
Key (such as hydrogen bond, π-is pi-conjugated, halogen key etc.).The formation of pharmaceutical co-crystals will not destroy the covalent bond of active constituents of medicine, and organic
It can improve the crystal property and physico-chemical property of drug itself, such as bioavilability (Pharmaceut.Res.23 (8), 2006,
Pp.1888-1897.), stability and technique exploitability (Int.J.Pham.320,2006, pp.114-123.), become drug
The new selection of one of solid pharmaceutical preparation.
Eutectic stability provided by the invention is good, low in hygroscopicity, compared with prior art in crystal form, solubility improve, have
Conducive to the bioavilability of drug is improved, it is of great significance for the raising of curative effect of medication and safety.
Invention content
The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide, a kind of solubility is high, stability
The eutectic of good olaparib and urea.
Preferably, the eutectic of olaparib provided by the present invention and urea, shown in structural formula such as formula (II),
Specifically, eutectic provided by the invention is named as eutectic crystal form A, X-ray powder diffraction figure is in 2theta values
There is characteristic peak at 17.4 ° ± 0.2 °, 20.7 ° ± 0.2 °, 10.5 ° ± 0.2 °.
Further, eutectic crystal form A provided by the invention, X-ray powder diffraction figure are also in 2theta values
One or more in 21.1 ° ± 0.2 °, 24.6 ° ± 0.2 °, 12.2 ° ± 0.2 ° are with characteristic peak.
Preferably, eutectic crystal form A provided by the invention, X-ray powder diffraction figure 2theta values be 21.1 ° ±
There is characteristic peak in 0.2 °, 24.6 ° ± 0.2 °, 12.2 ° ± 0.2 °.
Further, eutectic crystal form A provided by the invention, X-ray powder diffraction figure are also in 2theta values
One or more in 9.2 ° ± 0.2 °, 15.0 ° ± 0.2 °, 23.4 ° ± 0.2 ° are with characteristic peak.
Preferably, eutectic crystal form A provided by the invention, X-ray powder diffraction figure 2theta values be 9.2 ° ± 0.2 °,
There is characteristic peak at 15.0 ° ± 0.2 °, 23.4 ° ± 0.2 °.
One according to the present invention specific and preferred aspect, the X-ray powder diffraction figure of eutectic crystal form A is substantially such as Fig. 1
It is shown.Further, 26 diffraction maximums are shown in the X-ray powder diffraction figure altogether, the position of these diffraction maximums and opposite
Peak intensity is as shown in table 1 or table 2, wherein peak position changes within the scope of 0.2 °.
Another specific aspect according to the present invention shows 34 in the X-ray powder diffraction figure of eutectic crystal form A altogether
Diffraction maximum, the position of these diffraction maximums and relative peak intensities are as shown in table 3, wherein peak position changes within the scope of 0.2 °.
Preferably, in the collection of illustrative plates that the eutectic crystal form A is measured with differential scanning calorimetry 170 ± 2 DEG C are shown in start suction
Thermal spike.
Preferably, it is shown in the collection of illustrative plates that the eutectic crystal form A is measured with thermogravimetric analysis and is heated to 120 ± 2 DEG C, had about
1.8% weight loss gradient.
According to the present invention, eutectic crystal form A can by by olaparib and urea in alcohols, ketone, alkyl nitrile, cyclic ethers class
One or more dicyandiamide solutions in react be made.Wherein alcohols solvent preferred alcohol, the preferred acetone of ketones solvent, alkyl nitrile
The preferred acetonitrile of solvent, the preferred tetrahydrofuran of cyclic ether solvents, 1,4- dioxane.
It is a further object to provide the preparation methods of a kind of olaparib and the eutectic of urea comprising will be difficult to understand
La Pani and urea react in one or more dicyandiamide solutions in alcohols, ketone, alkyl nitrile, cyclic ethers class, by including but
The Crystallization methods such as volatilization, stirring or cooling are not limited to obtain.
Further, the alcohols solvent preferred alcohol, the preferred acetone of ketones solvent.
One according to the present invention specific and preferred aspect will be carried out containing the mixed system of olaparib, urea and solvent
The cooling operation of heating for multiple times constant temperature, has solid precipitation, filters, and washing is dry to get eutectic crystal form A of the present invention.It is wherein excellent
Choosing, solvent is ethyl alcohol or acetone or combination.Preferably, using olaparib free alkali as raw material, it is dissolved in institute
It states in solvent, adds urea and obtain the mixed system containing olaparib, urea and solvent.The heated constant temperature cooling
Operation refers to that system is first heated to the higher temperature higher than room temperature of a setting, and then one setting time of constant temperature, finally cools down
The lower temperature for being set below room temperature to one.The higher temperature of the setting can be such as 40~80 DEG C, preferably 50~
70 DEG C, more preferably 55~65 DEG C, a specific higher temperature value are 60 DEG C or so.The lower temperature of the setting can be
Such as -5~18 DEG C, preferably -5~10 DEG C, more preferably -5~5 DEG C, most preferably 0~5 DEG C.The rate of the heating can
Think 0.5~3 DEG C/min, preferably 1~2 DEG C/min.The rate of the cooling can be 0.1~1 DEG C/min, preferably 0.3~
0.6℃/min.The constant temperature time is preferably 5 hours or more, more preferably 8 hours or more, further preferably 9 hours with
On, more preferably 9~12 hours, specifically such as 10 hours.The number of the heated constant temperature cooling operation is preferably 2 times~4
It is secondary, most preferably 3 times.
A specific preferred embodiment according to the present invention, higher temperature are 40~80 DEG C, and lower temperature is -5~18
DEG C, the time of constant temperature is 5 hours or more.In further preferred embodiment, higher temperature is 55~65 DEG C, lower temperature 0
~5 DEG C, the time of constant temperature is 9~11 hours.
It is a further object to provide a kind of Pharmaceutical composition and the method for utilizing its treating cancer, pharmaceutical compositions
Object includes the eutectic of olaparib and urea, and at least one pharmaceutically acceptable excipient.The method packet for the treatment of cancer
A effective amount of described pharmaceutical composition will be applied to cancer patient by including.
According to the present invention, the cancer include but not limited to melanoma, cancer of pancreas, oophoroma, breast cancer, lymthoma,
Lung cancer etc..
Beneficial effects of the present invention are：
Olaparib provided by the invention and the eutectic stability of urea are good, and draw moist with lower, are preparing
It is not necessarily to special drying condition in journey, simplifies preparation and the aftertreatment technology of drug, is easy to industrialized production.Also, not
It is held essentially constant with moisture under damp condition, is convenient for the long-term storage of drug, there is very strong economic value.
Free alkali crystal form A disclosed in the eutectic ratio patent CN101528714B of olaparib provided by the invention and urea
Solubility higher is conducive to improve drug absorption efficiency, improves the bioavilability of drug, for curative effect of medication and safety
Raising is of great significance.
Description of the drawings
The XRPD that Fig. 1 is eutectic crystal form A schemes；
The DSC that Fig. 2 is eutectic crystal form A schemes；
The TGA that Fig. 3 is eutectic crystal form A schemes；
The DVS that Fig. 4 is eutectic crystal form A schemes；
The DVS figures that Fig. 5 is free alkali crystal form A in patent CN101528714B；
Fig. 6 is eutectic crystal form A's1H NMR figures.
Specific implementation mode
Below will by specific embodiment, the present invention is further explained, but the protection domain being not intended to restrict the invention.
Those skilled in the art can be made improvements to preparation method and using instrument within the scope of the claims, these improvement also should be regarded as
Protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
In following embodiments, the test method is usually according to normal condition or the condition of manufacturer's suggestion is implemented；
The powder of the olaparib is obtained by commercially available method.
Used abbreviation is explained as follows 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 is adopted on Panalytical Empyrean x-ray powder diffraction instruments
Collection.The method parameter of X-ray powder diffraction of the present invention is as follows：
X ray reflection parameter：Cu,Kα
1.540598；1.544426
1 intensities of K α 2/K α：0.50
Voltage：45 volt (kV)
Electric current：40 milliamperes (mA)
Scanning range：From 3.0 to 40.0 degree
Differential scanning calorimetric analysis (DSC) figure of the present invention acquires on TA Q200.Differential of the present invention is swept
The method parameter for retouching thermometric analysis (DSC) is as follows：
Sweep speed：10℃/min；
Protective gas：Nitrogen.
Thermogravimetric analysis (TGA) figure of the present invention acquires on TA Q5000.Thermogravimetric analysis of the present invention
(TGA) method parameter is as follows：
Sweep speed：10℃/min；
Protective gas：Nitrogen.
Embodiment 1
The preparation of olaparib and urea eutectic crystal form A：
10.0mg olaparibs free alkali (amorphous) is dissolved in 0.6mL ethyl alcohol, 11.8mg urea is added, to heat speed
After 1.0 DEG C/min of rate is heated to 60 DEG C, 600min is stirred at 60 DEG C, is then cooled to 5 with the rate of temperature fall of 0.37 DEG C/min
DEG C, repeat above-mentioned heating temperature-fall period three times, after reaction, filtering, the solid of gained is washed with ethyl alcohol, dry, is collected solid
Body.After testing, the solid that the present embodiment obtains is eutectic crystal form A, and X-ray powder diffraction data are as shown in table 1.Its DSC schemes
If Fig. 2, TGA scheme such as Fig. 3,1H NMR figure such as Fig. 6.
The eutectic product for the olaparib and urea that the above method is prepared, 1H NMR appraising datums are as follows：
1H NMR (400MHz, DMSO) δ 12.57 (s, 1H), 8.26 (d, J=7.8Hz, 1H), 7.97 (d, J=7.9Hz,
1H), 7.89 (t, J=6.9Hz, 1H), 7.83 (t, J=7.5Hz, 1H), 7.44 (dd, J=8.2,5.3Hz, 1H), 7.37 (d, J
=5.5Hz, 1H), 7.24 (t, J=9.1Hz, 1H), 4.33 (s, 2H), 3.59 (t, J=60.4Hz, 6H), 3.26-3.08 (m,
2H), 1.97 (s, 1H), 0.73 (t, J=7.0Hz, 4H).
Table 1
Embodiment 2
The preparation method of the eutectic of olaparib and urea：The olaparib free alkali of 101.9mg is dissolved in the ethyl alcohol of 3.0mL
In, the urea of 98.7mg is added, after being heated to 60 DEG C with 1.0 DEG C/min of the rate of heat addition, 600min is stirred at 60 DEG C, then with
0.37 DEG C/min of rate of temperature fall is cooled to 5 DEG C, repeats above-mentioned heating temperature-fall period three times, filters after reaction, gained is consolidated
Body is washed with ethyl alcohol, dry.
After testing, it is crystal form A that the present embodiment, which obtains solid, and X-ray powder diffraction data are as shown in table 2, XRPD figures
Such as Fig. 1.
Table 2
| 2theta | The intervals d | Intensity % |
| 3.19 | 27.69 | 3.95 |
| 6.66 | 13.28 | 17.03 |
| 9.21 | 9.60 | 14.41 |
| 10.48 | 8.44 | 23.01 |
| 12.20 | 7.25 | 16.21 |
| 13.34 | 6.64 | 4.44 |
| 14.99 | 5.91 | 11.75 |
| 17.41 | 5.09 | 80.90 |
| 18.49 | 4.80 | 13.15 |
| 18.65 | 4.76 | 8.79 |
| 19.54 | 4.54 | 3.32 |
| 20.11 | 4.42 | 7.32 |
| 20.66 | 4.30 | 50.82 |
| 21.08 | 4.21 | 20.78 |
| 23.43 | 3.80 | 10.94 |
| 24.18 | 3.68 | 4.12 |
| 24.56 | 3.62 | 20.51 |
| 25.15 | 3.54 | 10.06 |
| 26.23 | 3.40 | 6.73 |
| 26.92 | 3.31 | 2.25 |
| 27.65 | 3.23 | 4.14 |
| 29.56 | 3.02 | 12.32 |
| 30.26 | 2.95 | 9.71 |
| 32.94 | 2.72 | 2.59 |
| 33.69 | 2.66 | 3.30 |
| 37.04 | 2.43 | 8.81 |
Embodiment 3
The preparation of olaparib and urea eutectic：
10.0mg olaparibs free alkali (amorphous) is dissolved in 0.6mL acetone, 10.8mg urea is added, to heat speed
After 1.0 DEG C/min of rate is heated to 60 DEG C, 600min is stirred at 60 DEG C, cooling (0.37 DEG C/min of rate of temperature fall) is to 5 DEG C, weight
Multiple above-mentioned heating temperature-fall period three times, filters after reaction, and the solid of gained is washed with ethyl alcohol, dry, is cooled to room temperature, and receives
Collect solid.
After testing, it is consistent with 1 gained crystal form of embodiment to obtain solid for the present embodiment, is eutectic crystal form A, x-ray powder
Diffraction data is as shown in table 3.
Table 3
Embodiment 4
Free alkali crystal form A draws moist comparative study in eutectic crystal form A and patent CN101528714B：
Free alkali crystal form A in the eutectic crystal form A and patent CN101528714B of the 10mg present invention is taken to carry out Dynamic Water respectively
Divide absorption (DVS) test, XRPD is surveyed in then sampling.As a result such as table 4, the DVS figures of eutectic crystal form A are as shown in figure 4, patent
The DVS of free alkali crystal form A is as shown in Figure 5 in CN101528714B.
The result shows that at 25 DEG C, under 80% and 95% relative humidities, the weightening of eutectic crystal form A of the invention is compared
Free alkali crystal form A in patent CN101528714B is low, and it is moist lower to show that the eutectic crystal form A of the present invention draws.
Table 4
Define that (Chinese Pharmacopoeia version annex XIX J drugs in 2010 draw with draw moist weightening about moist feature description is drawn
Moist test direction principle)：
It deliquesces：It absorbs enough moisture and forms liquid
It is great draw it is moist：Draw wet weightening and is not less than 15%
Have draw it is moist：Draw wet weightening less than 15% but is not less than 2%
Slightly draw moist：Draw wet weightening less than 2% but is not less than 0.2%
Nothing is moist almost without drawing：Draw wet weightening and is less than 0.2%
Embodiment 5
Free alkali crystal form A solubility comparative studies in eutectic crystal form A and patent CN101528714B：
Free alkali crystal form A uses pH's 1.8 respectively in eutectic crystal form A and CN101528714B that the present invention is prepared
SGF (simulation simulated gastric fluid), pH6.5FaSSIF (simulated intestinal fluid under fasting state) is configured to saturated solution, in 1 hour and 4
The content of sample in saturated solution is measured after a hour by high performance liquid chromatography (HPLC) method.The experimental results are shown inthe following table.
It can be seen that by above-mentioned comparing result after placing 1 hour in SGF, urea of the invention is total after 4 hours
Jingjing type A is compared with patent free alkali crystal form A, solubility higher；Urea eutectic of the invention after being placed 4 hours in FaSSIF
Crystal form A solubility highers.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art
Scholar cans understand the content of the present invention and implement it accordingly, and it is not intended to limit the scope of the present invention.It is all according to the present invention
Equivalent change or modification made by Spirit Essence, should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of eutectic crystal form A of formula (II) compound,
It is characterized in that：The X-ray powder diffraction figure of the eutectic crystal form A 2theta values be 17.4 ° ± 0.2 °, 20.7 ° ±
0.2°、10.5°±0.2°、21.1°±0.2°、24.6°±0.2°、12.2°±0.2°、9.2°±0.2°、15.0°±0.2°、
Characteristic peak is all had at 23.4 ° ± 0.2 °.
2. a kind of preparation method of eutectic crystal form A as described in claim 1, it is characterised in that：Olaparib and urea are existed
It reacts in one or more dicyandiamide solutions in alcohols, ketone, alkyl nitrile, cyclic ethers class, is obtained by volatilization, stirring or cooling crystallization
It arrives.
3. preparation method according to claim 2, which is characterized in that the alcohols solvent includes ethyl alcohol, and the ketone is molten
Agent includes acetone.
4. a kind of preparation method of eutectic crystal form A as described in claim 1, it is characterised in that：To contain olaparib, urea and
The mixed system of solvent carries out the cooling operation of heating for multiple times constant temperature, has solid precipitation, filters, and washing is dry to get eutectic crystal form
A, heated constant temperature cooling operation refers to the higher temperature higher than room temperature that system is first heated to a setting, then constant temperature
One setting time is finally cooled to a lower temperature for being set below room temperature.
5. preparation method according to claim 4, it is characterised in that：The solvent is the group of ethyl alcohol or acetone or the two
It closes.
6. preparation method according to claim 4, it is characterised in that：The higher temperature is 40~80 DEG C, described relatively low
Temperature is -5~18 DEG C, and the time of the constant temperature is 5 hours or more.
7. preparation method according to claim 6, it is characterised in that：The higher temperature is 55~65 DEG C, described relatively low
Temperature is 0~5 DEG C, and the time of the constant temperature is 9~11 hours.
8. preparation method according to claim 4, it is characterised in that：The number of the heated constant temperature cooling operation is 2
It is secondary, 3 times or 4 times.
9. a kind of Pharmaceutical composition, it is characterised in that：The Pharmaceutical composition include eutectic crystal form A described in claim 1 and
Pharmaceutically acceptable excipient.
10. applications of the eutectic crystal form A as described in claim 1 in preparing treating cancer pharmaceutical preparation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015101852910 | 2015-04-17 | ||
| CN201510185291 | 2015-04-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105753789A CN105753789A (en) | 2016-07-13 |
| CN105753789B true CN105753789B (en) | 2018-09-25 |
Family
ID=56333916
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610235001.3A Active CN105753789B (en) | 2015-04-17 | 2016-04-15 | The eutectic and preparation method thereof of olaparib and urea |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN105753789B (en) |
| WO (1) | WO2016165650A1 (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107286210B (en) * | 2017-06-19 | 2020-07-07 | 昆药集团股份有限公司 | Acetyl gastrodin compound and preparation method, preparation and application thereof |
| CA3031777A1 (en) | 2018-01-31 | 2019-07-31 | Apotex Inc. | Crystalline form of olaparib |
| CN113121456B (en) * | 2020-01-15 | 2024-04-26 | 鲁南制药集团股份有限公司 | Acipimox urea eutectic |
| US20230234938A1 (en) | 2020-04-28 | 2023-07-27 | Rhizen Pharmaceuticals Ag | Novel compounds useful as poly(adp-ribose) polymerase (parp) inhibitors |
| CN111995582B (en) * | 2020-07-09 | 2021-12-03 | 天津理工大学 | Eutectic of olaparib and urea 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 |
| CN111825621A (en) * | 2020-07-22 | 2020-10-27 | 天津理工大学 | Eutectic of olaparib and malonic acid and preparation method thereof |
| US12012386B2 (en) | 2020-09-16 | 2024-06-18 | Nuformix Technologies Limited | Olaparib oxalic acid cocrystals and their pharmaceutical use |
| WO2022090938A1 (en) | 2020-10-31 | 2022-05-05 | Rhizen Pharmaceuticals Ag | Phthalazinone derivatives useful as parp inhibitors |
| CN114539161B (en) * | 2020-11-11 | 2024-03-29 | 成都硕德药业有限公司 | Olaparib-urea eutectic and preparation method thereof |
| KR20240021756A (en) | 2021-04-08 | 2024-02-19 | 리젠 파마슈티컬스 아게 | Inhibitors of poly(ADP-ribose) polymerase |
| CN113636979B (en) * | 2021-08-12 | 2023-06-13 | 天津理工大学 | Olaparib and fumaric acid eutectic crystal form alpha and preparation method and application thereof |
| US12049452B2 (en) * | 2021-11-10 | 2024-07-30 | Nuformix Technologies Limited | Olaparib hydroxybenzoic acid cocrystals and their pharmaceutical use |
| CN115197152B (en) * | 2022-07-11 | 2023-07-14 | 江苏海洋大学 | Olaparib pharmaceutical co-crystal and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1788000A (en) * | 2003-03-12 | 2006-06-14 | 库多斯药物有限公司 | Phthalazinone derivatives |
| 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 |
| WO2013049581A1 (en) * | 2011-09-30 | 2013-04-04 | Beth Israel Deaconess Medical Center Inc. | Compositions and methods for the treatment of proliferative diseases |
| 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 |
-
2016
- 2016-04-15 CN CN201610235001.3A patent/CN105753789B/en active Active
- 2016-04-15 WO PCT/CN2016/079430 patent/WO2016165650A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1788000A (en) * | 2003-03-12 | 2006-06-14 | 库多斯药物有限公司 | Phthalazinone derivatives |
| 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 |
| WO2013049581A1 (en) * | 2011-09-30 | 2013-04-04 | Beth Israel Deaconess Medical Center Inc. | Compositions and methods for the treatment of proliferative diseases |
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| 药物共晶在药学中的应用;闻聪，等;《中国新药杂志》;20071231;第16卷(第15期);1167-1171 * |
| 药物共晶的最新研究进展;王义成，等;《药学进展》;20131231;第37卷(第3期);第120-130页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016165650A1 (en) | 2016-10-20 |
| CN105753789A (en) | 2016-07-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105753789B (en) | The eutectic and preparation method thereof of olaparib and urea | |
| CN105111215B (en) | A kind of crystal form and preparation method thereof of cyclin-dependent kinase inhibitor | |
| CN113527203A (en) | Novel crystal form of lenvatinib mesylate and preparation method and application thereof | |
| CN104961671B (en) | Crystal formation of the tartrate of N (4 luorobenzyl) N (base of 1 methyl piperidine 4) N ' (4 (2 methyl propoxyl group) phenyl methyl) urea half and preparation method thereof | |
| CN105669529B (en) | A kind of fulleropyrrolidine derivative and preparation method thereof | |
| CN108727263A (en) | Hydroxychloroquine sulfate crystal form A and preparation method thereof | |
| CN102875531B (en) | A kind of (R)-lansoprazole anhydrous crystal forms and preparation method thereof | |
| CN104447590B (en) | Crystal formation of 2 (the base sulfenyl of 5 bromine 4 (base of 4 cyclopropyl naphthalene 1) 1,2,4 triazoles of 4H 3) acetic acid and preparation method thereof | |
| CN107226826A (en) | Tenofovir Chinese mugwort draws phenol amine fumarate compound and its pharmaceutical composition | |
| CN109651373A (en) | A kind of preparation method of Xi Gelieting phosphate monohydrate crystal form | |
| CN103254139A (en) | Novel <18>F marked 4-aminoquinazoline derivatives, and preparation methods and tumor PET development application thereof | |
| CN104961680B (en) | The hydrochloride and its polymorphic of the diformamide of N (4 { [6,7 pairs of bases of (methyl epoxide) quinoline 4] epoxide } phenyl) N ' (4 fluorophenyl) cyclopropane 1,1 | |
| CN104961681B (en) | The rich mucate and its crystal formation for Buddhist nun of card | |
| CN104211693B (en) | Rivaroxaban crystalline form, preparation method and application | |
| CN105198947A (en) | Trifluridine compound and medicine composition thereof | |
| CN107337609A (en) | A kind of dezocine crystal formation and preparation method thereof | |
| CN105859691A (en) | Novel crystal form of thymidine phosphorylase inhibitor and preparation method thereof | |
| CN104974200B (en) | The eutectic and preparation method thereof of helicidum and L-PROLINE | |
| CN105085476B (en) | Crystal formation of 5 [2,6 2 (4 morpholinyl) 4 pyrimidine radicals] 4 (trifluoromethyl) 2 pyridine amine dihydrochlorides and preparation method thereof | |
| CN100548998C (en) | cinepazide maleate crystal form and preparation method thereof | |
| CN103382179A (en) | Ingavirin polymorph and its preparation method | |
| WO2020224208A1 (en) | Pyridone derivative crystal form and preparation method and application therefor | |
| CA2999009C (en) | Crystal form of 4-((1-methylpyrrol-2-yl)-carbonyl)-n-(4-(4-morpholin-1-yl-carbonylpiperidin-1-yl)-phenyl)-1-piperazinecarboxamide monohydrate | |
| CN105523912B (en) | Rheum emodin crystal formation Ι, its preparation method, pharmaceutical composition and application | |
| CN106794179A (en) | Novel crystal forms of Masitinib mesylate and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 215123 B4-101, biological park, No. 218, Xing Hu Street, Suzhou Industrial Park, Suzhou, Jiangsu Patentee 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 Patentee before: Crystal Pharmatech Co., Ltd. |
|
| CP01 | Change in the name or title of a patent holder |