CN105753789A - Olaparib and urea eutectic and preparation method thereof - Google Patents
Olaparib and urea eutectic and preparation method thereof Download PDFInfo
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- CN105753789A CN105753789A CN201610235001.3A CN201610235001A CN105753789A CN 105753789 A CN105753789 A CN 105753789A CN 201610235001 A CN201610235001 A CN 201610235001A CN 105753789 A CN105753789 A CN 105753789A
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- 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
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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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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention relates to olaparib and urea eutectic and a preparation method thereof and particularly provides a eutectic form A, an X-ray powder diffraction of the crystal form shows characteristic peaks at 17.4 DEG +/- 0.2 DEG, 20.7 DEG +/- 0.2 DEG and 10.5 DEG +/- 0.2 DEG of value 2theta.The eutectic has better stability, lower hygroscopicity and higher solubility than existing olaparib free base crystal forms and is of significant value to the optimization and development of its drugs in future.
Description
Technical field
The present invention relates to a kind of Aura handkerchief Buddhist nun eutectic with carbamide and its production and use.
Background technology
Aura handkerchief Buddhist nun (Olaparib) is first researched and developed by biotech company of Britain KuDOS (Ku Duosi) Pharm Pur GmbH, AstraZeneca in 2005 by after KuDOS corporate buyout, continual exploitation Aura handkerchief Buddhist nun, be used for treating ovarian cancer.December in 2014 Aura handkerchief Buddhist nun on the 19th obtains FDA approval listing in the U.S., is first of the FDA approval targeted drug that is specifically designed to the ovarian cancer patients of BRCA sudden change, it is adaptable to previously lived through the patient of chemotherapeutic treatment.Having been demonstrated in preclinical models, Aura handkerchief Buddhist nun is a kind of pioneering oral many Poly ADP-ribose polymerases (PARP) inhibitor, it is possible to utilizes DNA to repair the defect of approach, preferentially kills cancerous cell.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, shown in its structure such as formula (I):
KuDOS (Ku Duosi) Pharm Pur GmbH free alkali crystal form A of Aura handkerchief Buddhist nun disclosed in patent CN101528714B, the free alkali crystal formation L of Aura handkerchief Buddhist nun disclosed in CN101821242B.In addition, there is no the crystal formation patent of other open Aura handkerchief Buddhist nuns.But the free alkali crystal formation dissolubility of Aura handkerchief Buddhist nun listing is low, it is necessary to find the crystal formation that dissolubility is high, to improve drug absorption efficiency.
Based on this, the present inventor have developed the eutectic of a kind of Aura handkerchief Buddhist nun, solves the difficult problem that free alkali crystal formation dissolubility is low.Eutectic is the crystal in same crystal structure containing two kinds of molecules.It act as non-covalent bond (such as hydrogen bond, π-pi-conjugated, halogen key etc.) between two kinds of molecules.The formation of pharmaceutical co-crystals will not destroy the covalent bond of active constituents of medicine, and have an opportunity to improve crystal property and the physico-chemical property of medicine itself, such as bioavailability (Pharmaceut.Res.23 (8), 2006, pp.1888-1897.), and stability and technique exploitability (Int.J.Pham.320,2006, pp.114-123.), one that becomes pharmaceutical solid preparation the newly selected.
Eutectic good stability provided by the invention, low in hygroscopicity, the crystal formation in compared to existing technology, dissolubility improves, and is conducive to improving the bioavailability of medicine, and the raising for curative effect of medication and safety is significant.
Summary of the invention
The technical problem to be solved is to overcome the deficiencies in the prior art, it is provided that a kind of dissolubility is high, the eutectic of the Aura handkerchief Buddhist nun of good stability and carbamide.
Preferably, the eutectic of Aura handkerchief Buddhist nun provided by the present invention and carbamide, shown in its structural formula such as formula (II),
Concrete, eutectic called after eutectic crystal form A provided by the invention, its X-ray powder diffraction figure is that 17.4 ° ± 0.2 °, 20.7 ° ± 0.2 °, 10.5 ° ± 0.2 ° place has characteristic peak in 2theta value.
Further, eutectic crystal form A provided by the invention, its X-ray powder diffraction figure is also the place in 21.1 ° ± 0.2 °, 24.6 ° ± 0.2 °, 12.2 ° ± 0.2 ° or many places have characteristic peak in 2theta value.
Preferably, eutectic crystal form A provided by the invention, its X-ray powder diffraction figure is locate all to have characteristic peak in 21.1 ° ± 0.2 °, 24.6 ° ± 0.2 °, 12.2 ° ± 0.2 ° in 2theta value.
Further, eutectic crystal form A provided by the invention, its its X-ray powder diffraction figure is also the place in 9.2 ° ± 0.2 °, 15.0 ° ± 0.2 °, 23.4 ° ± 0.2 ° or many places have characteristic peak in 2theta value.
Preferably, eutectic crystal form A provided by the invention, its X-ray powder diffraction figure is that 9.2 ° ± 0.2 °, 15.0 ° ± 0.2 °, 23.4 ° ± 0.2 ° place all has characteristic peak in 2theta value.
A concrete and preferred aspect according to the present invention, the X-ray powder diffraction figure of eutectic crystal form A is substantially as shown in Figure 1.Further, showing 26 diffraction maximums in this X-ray powder diffraction figure altogether, shown in the position of these diffraction maximums and relative peak intensities such as table 1 or table 2, wherein, peak position changes within the scope of 0.2 °.
Another concrete aspect according to the present invention, shows in the X-ray powder diffraction figure of eutectic crystal form A that 34 diffraction maximums, the position of these diffraction maximums and relative peak intensities are as shown in table 3 altogether, and wherein, peak position changes within the scope of 0.2 °.
Preferably, the collection of illustrative plates that described eutectic crystal form A measures with means of differential scanning calorimetry is shown in 170 ± 2 DEG C start heat absorption thermal spike.
Preferably, the collection of illustrative plates that described eutectic crystal form A measures with thermogravimetric analysis is shown in heating to 120 ± 2 DEG C, there is the loss in weight gradient of about 1.8%.
According to the present invention, eutectic crystal form A can pass through by Aura handkerchief Buddhist nun and carbamide alcohols, ketone, alkyl nitrile, cyclic ethers apoplexy due to endogenous wind one or more dicyandiamide solutions in reaction prepare.Wherein alcohols solvent preferred alcohol, the preferred acetone of ketones solvent, the preferred acetonitrile of alkyl nitrile kind solvent, the preferred oxolane of cyclic ether solvents, Isosorbide-5-Nitrae-dioxane.
The preparation method that it is a further object to provide a kind of Aura handkerchief Buddhist nun and the eutectic of carbamide, it include by Aura handkerchief Buddhist nun and carbamide alcohols, ketone, alkyl nitrile, cyclic ethers apoplexy due to endogenous wind one or more dicyandiamide solutions in reaction, by including but not limited to that the Crystallization method such as volatilization, stirring or cooling obtain.
Further, described alcohols solvent preferred alcohol, the preferred acetone of described ketones solvent.
According to the present invention one is concrete and preferred aspect, the mixed system containing Aura handkerchief Buddhist nun, carbamide and solvent carries out the cooling operation of heating for multiple times constant temperature, has solid to precipitate out, filter, and washing dries, obtains eutectic crystal form A of the present invention.Wherein preferred, solvent is ethanol or acetone or combination.Preferably, with Aura handkerchief Buddhist nun's free alkali for raw material, it is dissolved in described solvent, adds carbamide and obtain the described mixed system containing Aura handkerchief Buddhist nun, carbamide and solvent.Described heated constant temperature cooling operation refers to the higher temperature higher than room temperature first system heating to set, and then constant temperature one sets the time, is finally cooled to a lower temperature being set below room temperature.The higher temperature of described setting can be such as 40～80 DEG C, it is preferred to 50～70 DEG C, more preferably 55～65 DEG C, and a concrete higher temperatures angle value is about 60 DEG C.The lower temperature of described setting can be such as-5～18 DEG C, it is preferred to-5～10 DEG C, more preferably-5～5 DEG C, it is most preferred that is 0～5 DEG C.The speed of described heating can be 0.5～3 DEG C/min, preferably 1～2 DEG C/min.The speed of described cooling can be 0.1～1 DEG C/min, preferably 0.3～0.6 DEG C/min.Described constant temperature time is preferably more than 5 hours, more preferably more than 8 hours, more preferably more than 9 hours, more preferably 9～12 hours, specifically such as 10 hours.The number of times of described heated constant temperature cooling operation is preferably 2 times～4 times, it is most preferred that be 3 times.
A concrete preferred embodiment according to the present invention, higher temperature is 40～80 DEG C, and lower temperature is-5～18 DEG C, and the time of constant temperature is more than 5 hours.In further preferred version, higher temperature is 55～65 DEG C, and lower temperature is 0～5 DEG C, and the time of constant temperature is 9～11 hours.
It is a further object to provide a kind of Pharmaceutical composition and the method utilizing its treatment cancer, Pharmaceutical composition comprises the eutectic of Aura handkerchief Buddhist nun and carbamide and at least one pharmaceutically acceptable excipient.The method for the treatment of cancer includes the described pharmaceutical composition by applying effective dose to cancer patient.
According to the present invention, described cancer includes but not limited to melanoma, cancer of pancreas, ovarian cancer, breast carcinoma, lymphoma, pulmonary carcinoma etc..
The invention have the benefit that
The eutectic good stability of Aura handkerchief Buddhist nun provided by the invention and carbamide, and have and relatively low draw moist, without special drying condition in preparation process, simplify preparation and the aftertreatment technology of medicine, it is easy to industrialized production.Further, divide content to be held essentially constant at different humidity Water Under, it is simple to the long storage periods of medicine, there is very strong economic worth.
Free alkali crystal form A dissolubility disclosed in the eutectic ratio patent CN101528714B of Aura handkerchief Buddhist nun provided by the invention and carbamide is higher, be conducive to improving drug absorption efficiency, improving the bioavailability of medicine, the raising for curative effect of medication and safety is significant.
Accompanying drawing explanation
Fig. 1 is the XRPD figure of eutectic crystal form A；
Fig. 2 is the DSC figure of eutectic crystal form A；
Fig. 3 is the TGA figure of eutectic crystal form A；
Fig. 4 is the DVS figure of eutectic crystal form A；
Fig. 5 is the DVS figure of free alkali crystal form A in patent CN101528714B；
Fig. 6 is eutectic crystal form A1HNMR schemes.
Detailed description of the invention
Hereinafter the present invention will be expanded on further by specific embodiment, but be not limited to protection scope of the present invention.Preparation method and use instrument can be made improvements by those skilled in the art in right, and 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 as the criterion with claims.
In following embodiment, the condition of described test method generally conventionally condition or manufacturer's suggestion is implemented；The powder of described Aura handkerchief Buddhist nun is obtained by commercially available method.
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
1.540598；1.544426
K α 2/K α 1 intensity: 0.50
Voltage: 45 KVs (kV)
Electric current: 40 milliamperes (mA)
Sweep limits: spend from 3.0 to 40.0
Differential scanning calorimetric analysis of the present invention (DSC) figure gathers on TAQ200.The method parameter of differential scanning calorimetric analysis of the present invention (DSC) is as follows:
Sweep speed: 10 DEG C/min；
Protective 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:
Sweep speed: 10 DEG C/min；
Protective gas: nitrogen.
Embodiment 1
The preparation of Aura handkerchief Buddhist nun and carbamide eutectic crystal form A:
10.0mg Aura handkerchief Buddhist nun's free alkali (amorphous) is dissolved in 0.6mL ethanol, add 11.8mg carbamide, heat after 60 DEG C with 1.0 DEG C/min of the rate of heat addition, at 60 DEG C, stir 600min, be then cooled to 5 DEG C with the rate of temperature fall of 0.37 DEG C/min, repeat above-mentioned heating temperature-fall period three times, after reaction terminates, filter, the solid washing with alcohol of gained, dry, collect solid.After testing, the solid that the present embodiment obtains is eutectic crystal form A, and its XRPD figure is such as Fig. 1, and its X-ray powder diffraction data are as shown in table 1.Its DSC figure such as Fig. 2, its TGA scheme such as Fig. 3, its1HNMR schemes such as Fig. 6.
The eutectic product of the Aura handkerchief Buddhist nun that said method prepares and carbamide, its 1HNMR appraising datum is as follows:
1HNMR (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 Aura handkerchief Buddhist nun and carbamide: Aura handkerchief Buddhist nun's free alkali of 101.9mg is dissolved in the ethanol of 3.0mL, add the carbamide of 98.7mg, heat after 60 DEG C with 1.0 DEG C/min of the rate of heat addition, 600min is stirred at 60 DEG C, then being cooled to 5 DEG C with 0.37 DEG C/min of rate of temperature fall, repeat above-mentioned heating temperature-fall period three times, reaction is filtered after terminating, the solid washing with alcohol of gained, dry.
After testing, it is crystal form A that the present embodiment obtains solid, and its X-ray powder diffraction data are as shown in table 2.
Table 2
Embodiment 3
The preparation of Aura handkerchief Buddhist nun and carbamide eutectic:
10.0mg Aura handkerchief Buddhist nun's free alkali (amorphous) is dissolved in 0.6mL acetone, add 10.8mg carbamide, heating after 60 DEG C with 1.0 DEG C/min of the rate of heat addition, stir 600min at 60 DEG C, cooling (0.37 DEG C/min of rate of temperature fall) is to 5 DEG C, repeat above-mentioned heating temperature-fall period three times, reaction is filtered after terminating, the solid washing with alcohol of gained, dry, it is cooled to room temperature, collects solid.
After testing, it is consistent with embodiment 1 gained crystal formation that the present embodiment obtains solid, and for eutectic crystal form A, its X-ray powder diffraction data are as shown in table 3.
Table 3
Embodiment 4
In eutectic crystal form A and patent CN101528714B, free alkali crystal form A draws moist comparative study:
The eutectic crystal form A taking the 10mg present invention respectively carries out dynamic water absorption (DVS) test with free alkali crystal form A in patent CN101528714B, and then XRPD is surveyed in sampling.Result is table 4 such as, and the DVS of eutectic crystal form A schemes as shown in Figure 4, and in patent CN101528714B, the DVS of free alkali crystal form A is as shown in Figure 5.
It is shown that at 25 DEG C, under 80% and 95% relative humidities, the weightening finish of the eutectic crystal form A of the present invention is all low than the free alkali crystal form A in patent CN101528714B, it was shown that the eutectic crystal form A of the present invention draws moist lower.
Table 4
About draw moist feature description with draw moist weightening finish define (Chinese Pharmacopoeia version annex XIXJ medicine in 2010 draws moist test direction principle):
Deliquescence: absorb the fractal one-tenth liquid of enough water
Great draw moist: draw wet weightening finish and be not less than 15%
Have draw moist: drawing wet weightening finish and less than 15% but being not less than 2%
Slightly draw moist: draw wet weightening finish and less than 2% but be not less than 0.2%
Nothing or moist almost without drawing: drawing wet weightening finish less than 0.2%
Embodiment 5
Free alkali crystal form A dissolubility comparative study in eutectic crystal form A and patent CN101528714B:
In the eutectic crystal form A present invention prepared and CN101528714B, free alkali crystal form A is respectively with the SGF (simulation simulated gastric fluid) of pH1.8, pH6.5FaSSIF (under fasted conditions simulated intestinal fluid) is configured to saturated solution, measures the content of sample in saturated solution by high performance liquid chromatography (HPLC) method after 1 hour and 4 hours.Experimental result is as shown in table 4.
Table 4
By above-mentioned comparing result it can be seen that after placing 1 hour in SGF, after 4 hours, the carbamide eutectic crystal form A of the present invention is compared with patent free alkali crystal form A, and dissolubility is higher；After placing 4 hours in FaSSIF, the carbamide eutectic crystal form A dissolubility of the present invention is higher.
Above-described embodiment only for technology design and the feature of the present invention are described, its object is to allow person skilled in the art will appreciate that present disclosure and to implement according to this, can not limit the scope of the invention with this.All equivalences made according to spirit of the invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (17)
1. the eutectic of formula (I) compound and carbamide.
2. eutectic according to claim 1, it is characterised in that: shown in the structural formula of described eutectic such as formula (II).
3. eutectic according to claim 1 and 2, including eutectic crystal form A, it is characterised in that: the X-ray powder diffraction figure of described eutectic crystal form A is that 17.4 ° ± 0.2 °, 20.7 ° ± 0.2 °, 10.5 ° ± 0.2 ° place has characteristic peak in 2theta value.
4. eutectic according to claim 3, it is characterised in that: the X-ray powder diffraction figure of described eutectic crystal form A is also the place in 21.1 ° ± 0.2 °, 24.6 ° ± 0.2 °, 12.2 ° ± 0.2 ° or many places have characteristic peak in 2theta value.
5. eutectic according to claim 4, it is characterised in that: the X-ray powder diffraction figure of described eutectic crystal form A is that 21.1 ° ± 0.2 °, 24.6 ° ± 0.2 °, 12.2 ° ± 0.2 ° place is respectively provided with characteristic peak in 2theta value.
6. the eutectic described in claim any one of claim 3 to 5, it is characterised in that: the X-ray powder diffraction figure of described eutectic crystal form A is also the place in 9.2 ° ± 0.2 °, 15.0 ° ± 0.2 °, 23.4 ° ± 0.2 ° or many places have characteristic peak in 2theta value.
7. eutectic according to claim 6, it is characterised in that: the X-ray powder diffraction figure of described eutectic crystal form A is that 9.2 ° ± 0.2 °, 15.0 ° ± 0.2 °, 23.4 ° ± 0.2 ° place is respectively provided with characteristic peak in 2theta value.
8. the preparation method of the eutectic as described in a claim any one of claim 1 to 7, it is characterized in that: by Aura handkerchief Buddhist nun and carbamide alcohols, ketone, alkyl nitrile, cyclic ethers apoplexy due to endogenous wind one or more dicyandiamide solutions in reaction, by volatilizing, stirring or cooling crystallize obtain.
9. preparation method according to claim 8, it is characterised in that described alcohols solvent includes ethanol, and described ketones solvent includes acetone.
10. the preparation method of the eutectic as described in a claim any one of claim 1 to 7, it is characterized in that: the mixed system containing Aura handkerchief Buddhist nun, carbamide and solvent is carried out the cooling operation of heating for multiple times constant temperature, solid is had to precipitate out, filter, washing, dry, obtain eutectic crystal form A, described heated constant temperature cooling operation refers to the higher temperature higher than room temperature first system heating to set, and then constant temperature one sets the time, is finally cooled to a lower temperature being set below room temperature.
11. preparation method according to claim 10, it is characterised in that: described solvent is ethanol or acetone or combination.
12. preparation method according to claim 10, it is characterised in that: described higher temperature is 40～80 DEG C, and described lower temperature is-5～18 DEG C, and the time of described constant temperature is more than 5 hours.
13. preparation method according to claim 12, it is characterised in that: described higher temperature is 55～65 DEG C, and described lower temperature is 0～5 DEG C, and the time of described constant temperature is 9～11 hours.
14. according to the preparation method described in any one claim in claim 10 to 13, it is characterised in that: the number of times of described heated constant temperature cooling operation is 2 times, 3 times or 4 times.
15. a Pharmaceutical composition, it is characterised in that: described Pharmaceutical composition comprises in claim 1 to 7 eutectic described in any one and pharmaceutically acceptable excipient.
16. the method treating cancer, it is characterised in that: include the pharmaceutical composition used described in the claim 15 of effective dose to cancer patient.
17. eutectic application in preparation treatment cancer drug preparation as claimed in any of claims 1 to 7 in one of claims.
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| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
| CN111689905A (en) * | 2020-07-22 | 2020-09-22 | 天津理工大学 | Eutectic of olaparib and maleic acid and preparation method thereof |
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| CN115485271A (en) | 2020-04-28 | 2022-12-16 | 理森制药股份公司 | Novel compounds as inhibitors of poly (ADP-ribose) polymerase (PARP) |
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| CN115197152B (en) * | 2022-07-11 | 2023-07-14 | 江苏海洋大学 | Olaparib pharmaceutical co-crystal and preparation method and application thereof |
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| CN113121456A (en) * | 2020-01-15 | 2021-07-16 | 鲁南制药集团股份有限公司 | Acipimox urea eutectic |
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| CN111995582A (en) * | 2020-07-09 | 2020-11-27 | 天津理工大学 | Eutectic of olaparib and urea and preparation method thereof |
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| CN111689905B (en) * | 2020-07-22 | 2021-12-03 | 天津理工大学 | Eutectic of olaparib and maleic acid and preparation method thereof |
| WO2022058785A1 (en) | 2020-09-16 | 2022-03-24 | Nuformix Technologies Limited | Olaparib oxalic acid cocrystals and their pharmaceutical use |
| CN114539161A (en) * | 2020-11-11 | 2022-05-27 | 成都硕德药业有限公司 | Olaparib-urea eutectic crystal and preparation method thereof |
| 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 |
| CN113636979A (en) * | 2021-08-12 | 2021-11-12 | 天津理工大学 | Olaparib and fumaric acid eutectic crystal form alpha, and preparation method and application thereof |
| WO2023084311A1 (en) | 2021-11-10 | 2023-05-19 | Nuformix Technologies Limited | Olaparib hydroxybenzoic acid cocrystals and their pharmaceutical use |
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| WO2016165650A1 (en) | 2016-10-20 |
| CN105753789B (en) | 2018-09-25 |
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