CN111825621A - Eutectic of olaparib and malonic acid and preparation method thereof - Google Patents
Eutectic of olaparib and malonic acid and preparation method thereof Download PDFInfo
- Publication number
- CN111825621A CN111825621A CN202010707895.8A CN202010707895A CN111825621A CN 111825621 A CN111825621 A CN 111825621A CN 202010707895 A CN202010707895 A CN 202010707895A CN 111825621 A CN111825621 A CN 111825621A
- Authority
- CN
- China
- Prior art keywords
- olaparib
- degrees
- eutectic
- malonic acid
- solvent
- 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.)
- Pending
Links
Images
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/08—Malonic acid
-
- 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
Abstract
The invention discloses an olaparib and malonic acid eutectic crystal and a preparation method thereof. The molar ratio of olaparib to malonic acid in the eutectic is 1: 1, and the X-ray powder diffraction pattern of the eutectic has characteristic peaks at 2theta values of 6.8 +/-0.2 degrees, 9.8 +/-0.2 degrees, 12.4 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.4 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.7 +/-0.2 degrees and 21.0 +/-0.2 degrees. The preparation method of the eutectic crystal provided by the invention has the advantages of simple process, easy control of the crystallization process, good reproducibility and suitability for industrial production. Compared with the free base of Olaparib, the eutectic has larger apparent solubility, and is beneficial to improving the oral absorption efficiency of Olaparib.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to an olaparib and malonic acid eutectic crystal and a preparation method thereof.
Background
The pharmaceutically active ingredient is usually present in crystalline forms, such as polymorphs, hydrates, solvates, salts, co-crystals and the like. Different crystalline forms have different physicochemical properties for the same pharmaceutically active ingredient. Therefore, obtaining a suitable crystalline form of a drug is of great importance in the pharmaceutical industry. The medicament exists in a eutectic form, can improve the stability, solubility, processability and the like of active ingredients of the medicament, and has remarkable advantages. Therefore, the pharmaceutical co-crystal is an effective means for improving the physicochemical properties of the active ingredients of the drugs.
Olaparib (0laparib) having the chemical name 1- (cyclopropylformyl) -4- [5- [ (3, 4-dihydro-4-oxo-1-phthalazinyl) methyl ] -2-fluorobenzoyl ] piperazine and the formula:
olaparib was first developed by KuDOS drugs ltd, a biotechnology company of great britain, and is an pioneer oral Poly ADP Ribose Polymerase (PARP) inhibitor that can take advantage of the deficiencies of the DNA repair pathway to preferentially kill cancer cells. In 2005, alapab was continuously developed for the treatment of ovarian cancer after astrazen purchased KuDOS. Olaparib obtained FDA approval in the united states in 2014, was the first targeted drug specifically for BRCA-mutated ovarian cancer patients, applicable to patients who previously underwent chemotherapy treatment. KuDOS (KuDOS) pharmaceuticals, inc discloses crystalline form a of olaparib in patent CN 101528714B and crystalline form L of olaparib in CN 101821242B. In addition, patent CN105439961A discloses crystal form I of olaparib, and patent CN 105777651a discloses crystal form B of olaparib. Currently, olaparib is marketed as crystal form a, which has low solubility and limits the oral absorption efficiency of the drug. Patent CN 105753789B discloses a eutectic crystal form a of olaparib and urea, however, the present inventors have repeated the preparation method of the embodiment of patent 105753789B, and have failed to obtain the eutectic crystal form a of olaparib and urea described in the patent. In order to improve the solubility of olaparib, a large number of eutectic screens are carried out to obtain an olaparib and malonic acid eutectic, so that the solubility of olaparib can be effectively improved.
Disclosure of Invention
One of the purposes of the invention is to provide an olaparib and malonic acid eutectic; the second purpose of the invention is to provide a preparation method of the eutectic crystal of the olaparib and the malonic acid; the invention also aims to provide application of the eutectic of the olaparib and the malonic acid.
Through a large number of experimental researches, the inventor tries to perform a eutectic screening experiment on olaparib, maleic acid, fumaric acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid and the like, and finally successfully finds the eutectic of olaparib, maleic acid, fumaric acid, oxalic acid and malonic acid, can effectively improve the solubility of olaparib, and provides a material basis for improving the oral absorption efficiency of olaparib.
The technical scheme adopted by the invention is as follows:
the invention provides an olaparib and malonic acid eutectic.
An olaparib and malonic acid eutectic crystal has a structural formula shown in formula (I):
in the eutectic, the molar ratio of the olaparib to the malonic acid is 1: 1; the eutectic has characteristic peaks at 2theta values of 6.8 +/-0.2 degrees, 9.8 +/-0.2 degrees, 12.4 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.4 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.7 +/-0.2 degrees and 21.0 +/-0.2 degrees by an X-ray powder diffraction pattern measured by Cu Kalpha rays.
Preferably, the olaparib and malonic acid eutectic crystal also has characteristic peaks at one or more of the 2theta values of 15.9 +/-0.2 degrees, 20.0 +/-0.2 degrees, 22.2 +/-0.2 degrees, 23.8 +/-0.2 degrees, 24.5 +/-0.2 degrees and 26.9 +/-0.2 degrees, measured by Cu Kalpha ray.
The invention provides a preparation method of the eutectic of olaparib and malonic acid.
A preparation method of an olaparib and malonic acid eutectic comprises the following steps: feeding the olaparib and the malonic acid according to the molar ratio of 1: 1, adding a proper amount of solvent, and stirring or grinding to obtain the eutectic crystal.
Preferably, in the method for preparing the co-crystal, the solvent is at least one of an alcohol solvent, an ester solvent, a ketone solvent, an ether solvent, a nitrile solvent, and an alkane solvent. Wherein, the alcohol solvent includes but is not limited to ethanol; ester solvents include, but are not limited to, ethyl acetate, isopropyl acetate; ketone solvents include, but are not limited to, acetone; ether solvents include, but are not limited to, anisole, isopropyl ether; nitrile solvents include, but are not limited to, acetonitrile; alkane solvents include, but are not limited to, n-heptane, n-hexane, n-pentane; further preferably, the solvent is selected from one or more of ethanol, ethyl acetate, acetone, isopropyl ether and n-heptane.
Preferably, in the preparation method of the eutectic, the ratio of the total mass of the olaparib and the malonic acid to the amount of the solvent is 1g to (4-20) mL during stirring; the total mass of the olaparib and the malonic acid and the dosage of the solvent are 1g to (100-200) mu L during grinding.
In some preferred embodiments of the present invention, the preparation method of the eutectic is specifically as follows: feeding the olaparib and the malonic acid according to the molar ratio of 1: 1, adding the solvent, stirring, filtering, and drying the obtained solid product to obtain the eutectic crystal.
In other preferred embodiments of the present invention, the preparation method of the eutectic is specifically: feeding the olaparib and the malonic acid according to the molar ratio of 1: 1, adding a solvent, and grinding to obtain the eutectic.
Preferably, in the preparation method of the eutectic crystal, the ratio of the total mass of the olaparib and the malonic acid to the amount of the solvent is 1g to (4-20) mL during stirring.
Preferably, in the preparation method of the eutectic crystal, the ratio of the total mass of the olaparib and the malonic acid to the using amount of the solvent during grinding is 1g to (100-200) mu L.
The invention provides a pharmaceutical composition, which comprises the olaparib and malonic acid eutectic crystal and a pharmaceutically acceptable excipient.
In the present invention, the pharmaceutically acceptable excipient refers to a pharmaceutically acceptable material, mixture or solvent related to the consistency of the administration form or pharmaceutical composition. Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition.
Preferably, the pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers.
The invention also provides application of the co-crystal of olaparib and malonic acid in preparation of a medicament for preventing and/or treating cancer.
The invention has the beneficial effects that:
according to the invention, the olaparib is converted into a brand-new eutectic of the olaparib and the malonic acid for the first time, the olaparib and the malonic acid eutectic have higher apparent solubility than the olaparib crystal form A, and a material basis is provided for improving the oral absorption efficiency of the olaparib.
The preparation method of the eutectic of olaparib and malonic acid, disclosed by the invention, is simple in process, easy to control the crystallization process, good in reproducibility and suitable for industrial production.
The co-crystal of olaparib and malonic acid has wide application prospect in preparing medicaments for preventing and/or treating cancers.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of a co-crystal of Olaparib and malonic acid obtained in example 1;
FIG. 2 is a differential scanning calorimetry trace of a cocrystal of Olaparib and malonic acid obtained in example 1;
fig. 3 is a graph showing thermogravimetric analysis of a cocrystal of olaparib and malonic acid obtained in example 1;
FIG. 4 is a Fourier transform infrared spectrum of the eutectic of Olaparib and malonic acid obtained in example 1;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the eutectic of Olaparib and malonic acid obtained in example 1;
fig. 6 is a powder dissolution profile of the olaparib and malonic acid cocrystal, olaparib form a, prepared in example 1;
Detailed Description
The present invention will be described in further detail with reference to specific examples. The starting materials used in the examples are, unless otherwise specified, commercially available from conventional sources.
Example 1
900mg of olaparib and 216mg of malonic acid are weighed and added into 15mL of n-heptane and 250 μ L of ethanol to obtain a suspension, the suspension is placed at room temperature and stirred for 3h, the suspension is filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of olaparib and malonic acid, wherein the yield is 90.5%.
Example 2
60mg of olaparib and 14.4mg of malonic acid are weighed, added into 1mL of anisole and 10 muL of ethanol to obtain a suspension, the suspension is placed at room temperature and stirred for 12h, filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the olaparib and malonic acid eutectic.
Example 3
60mg of olaparib and 14.4mg of malonic acid are weighed, added into a ball milling tank, then 10 mu L of ethyl acetate is added, the mixture is ground for 30min at the frequency of 20Hz, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic of olaparib and malonic acid.
Example 4
60mg of olaparib and 14.4mg of malonic acid are weighed, added into 1mL of n-pentane and 10 muL of ethanol to obtain a suspension, the suspension is placed at room temperature and stirred for 12h, filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the olaparib and malonic acid eutectic.
Example 5
60mg of olaparib and 14.4mg of malonic acid are weighed, added into 1mL of n-hexane and 10 muL of ethanol to obtain a suspension, the suspension is placed at room temperature and stirred for 12 hours, filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic of olaparib and malonic acid.
Example 6
60mg of olaparib and 14.4mg of malonic acid were weighed, added to 1mL of n-heptane and 10. mu.L of ethanol to obtain a suspension, the suspension was left at room temperature and stirred for 12 hours, filtered, and the resulting white solid was dried at 40 ℃ to obtain a solid sample of the eutectic of olaparib and malonic acid.
Example 7
Weighing 60mg of olaparib and 14.4mg of malonic acid, adding into a ball milling tank, then adding 10 mu L of ethanol, grinding for 30min at the frequency of 20Hz, and drying the obtained white solid at 40 ℃ to obtain a solid sample of the eutectic of olaparib and malonic acid.
Example 8
Weighing 60mg of olaparib and 14.4mg of malonic acid, adding into a ball milling tank, then adding 10 mu L of acetonitrile, grinding for 30min at the frequency of 20Hz, and drying the obtained white solid at 40 ℃ to obtain a solid sample of the eutectic of olaparib and malonic acid.
Example 9
Weighing 60mg of olaparib and 14.4mg of malonic acid, adding into a ball milling tank, then adding 10 mu L of acetone, grinding for 30min at the frequency of 20Hz, and drying the obtained white solid at 40 ℃ to obtain a solid sample of the eutectic of olaparib and malonic acid.
Example 10
60mg of olaparib and 14.4mg of malonic acid are weighed and added into a ball milling tank, then 10 mu of isopropyl acetate is added, the mixture is ground for 30min at the frequency of 20Hz, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic of olaparib and malonic acid.
Characterization analysis
The invention provides an olaparib and malonic acid eutectic which is characterized by methods such as X-ray powder diffraction, differential scanning calorimetry analysis, thermogravimetric analysis, Fourier transform infrared spectroscopy, nuclear magnetic resonance hydrogen spectrum and the like.
A solid sample of the Olaparib co-crystal with malonic acid obtained in example 1 was subjected to X-ray powder diffraction analysis using a diffractometer of Rigaku MiniFlex 600, manufactured by Nippon chemical Co., Ltd., Cu Ka ray
The voltage is 40 kilovolts, the current is 15 milliamps, the step length is 0.01 degrees, the scanning speed is 20 degrees/min, the scanning range is 5.0-40.0 degrees, and the test temperature is room temperature.The analysis results are shown in the X-ray powder diffraction diagram of figure 1, and the X-ray powder diffraction data are shown in Table 1.
Table 1X-ray powder diffraction data for the olaparib co-crystal with malonic acid of example 1
The X-ray powder diffraction data of the solid sample of the olaparib co-crystal with malonic acid prepared in example 2 based on the same X-ray powder diffraction test method as in example 1 are shown in table 2.
Table 2X-ray powder diffraction data for the olaparib co-crystal with malonic acid of example 2
The X-ray powder diffraction data of the solid sample of the olaparib co-crystal with malonic acid prepared in example 3 based on the same X-ray powder diffraction test method as in example 1 are shown in table 3.
Table 3X-ray powder diffraction data for the olaparib co-crystal with malonic acid of example 3
It is well known to those skilled in the art that crystalline materials can be characterized by X-ray diffraction techniques, but the X-ray diffraction patterns typically vary with the test conditions of the instrument. It is particularly noted that the relative intensities of the X-ray diffraction patterns may vary with the experimental conditions, so that the relative intensity order of the X-ray diffraction peaks cannot be the sole or determining factor in the characterization of crystalline material. In addition, the peak angle is usually allowed to have an error of ± 0.2 °, and due to the influence of experimental factors such as sample height and test temperature, the peak angle is shifted as a whole, and a certain shift is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of the present invention for the olaparib and malonic acid co-crystal need not be identical to the X-ray diffraction pattern in this embodiment, and any situation having the same or similar characteristic peaks in this pattern is within the scope of the present invention. One skilled in the art can compare the profile listed in the present invention with a profile of an unknown substance to confirm whether the unknown substance is or is not the olaparib and malonic acid co-crystal of the present invention.
Differential scanning calorimetry was performed on a solid sample of the olaparib co-crystal prepared in example 1 with malonic acid, and the differential scanning calorimetry was performed by a DSC 214 type differential calorimeter of Germany Chinesemedicine instruments, Inc., wherein the atmosphere was nitrogen and the temperature rise rate was 10 ℃/min. The analysis result is shown in the differential scanning calorimetry diagram of figure 2. As shown in fig. 2, the eutectic of olaparib and malonic acid showed a melting endothermic peak at 132.9 ℃.
The solid sample of the olaparib and malonic acid eutectic obtained in example 1 was subjected to thermogravimetric analysis using a model TG 209F 3 from german seikaga scientific instruments ltd under nitrogen at a temperature rise rate of 10 ℃/min. The analysis result is shown in the thermogravimetric analysis chart of FIG. 3. As shown in fig. 3, the olaparib eutectic with malonic acid heated to around 137.1 ℃ started to decompose and there was no weight loss until this temperature.
Infrared spectroscopy analysis was performed on the sample of the eutectic of olaparib and malonic acid prepared in example 1, and the sample was detected by a NiCOLET iS10 Fourier transform infrared spectrometer from ThermoFisher Scientific, with a detection range of 4000-500 cm-1The analysis result is shown in the Fourier transform infrared spectrogram of figure 4. As can be seen from FIG. 4, the characteristic peak position of the infrared spectrum is (cm)-1)：3257、3169、3008、2939、2659、2604、1747、1706、1639、1607、1485、1468、1444、1371、1354、1231、1244、1229、1014、895、835、794、773、738、650、585、542、502。
The sample of the eutectic of Olaparib and malonic acid obtained in example 1 was analyzed by NMR using Avance III 400M NMR spectrometer (Bruker, Germany) and the analysis result is shown in FIG. 51HNMR) spectrum. As can be seen from fig. 5, the peaks of olaparib are:1h NMR (400MHz, DMSO-d6)12.60(s, 1H), 8.27(d, J ═ 7.7Hz, 1H), 7.97(d, J ═ 7.8Hz, 1H), 7.90(t, J ═ 7.3Hz, 1H), 7.84(t, J ═ 7.5Hz, 1H), 7.49-7.41(m, 1H), 7.38(s, 1H), 7.25(t, J ═ 9.0Hz, 1H), 4.34(s, 2H), 3.64(dd, J ═ 58.3, 24.7Hz, 5H), 3.39(s, 1H), 3.12(d, J ═ 31.9Hz, 2H), 1.95(d, J ═ 38.1, 1H), 0.84-0.55H (m, 4H). The peaks for malonic acid are:1h NMR (400MHz, DMSO-d6)12.61(s, 2H), 3.25(s, 2H). From the integration results of the characteristic peaks, the stoichiometric ratio of olaparib and malonic acid in the co-crystal was 1: 1.
Evaluation of solubility
Comparative study was conducted on the powder dissolution data of the olaparib and malonic acid co-crystal and the olaparib crystal form a.
The source of the test sample is: the olaparib and malonic acid eutectic is prepared by the method provided by embodiment 1 of the invention; olaparib form a was purchased from shanghai shengde pharmaceutical technology ltd, having a purity of 99%.
Powder dissolution test method: and grinding the eutectic crystal of the olaparib and the malonic acid and the crystal form A of the olaparib, and then respectively sieving the powder through 100-200 meshes, wherein the particle size of the powder is controlled to be 75-150 mu m. Respectively weighing 90mg of the olaparib crystal form A, 112mg of the olaparib and malonic acid eutectic, adding the olaparib crystal form A and the olaparib eutectic into 30mL of dissolution medium, taking 0.2mL of solution at intervals, filtering the solution through a 0.45-micrometer microporous membrane, diluting the solution to a proper multiple, monitoring the drug concentration at each time point by using high performance liquid chromatography, and finally obtaining the powder dissolution curve of each sample.
Powder dissolution conditions:
dissolution medium: disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution of pH 6.8;
stirring speed: 100 revolutions per minute;
dissolution temperature: 37 plus or minus 0.5 ℃;
sampling time: 0.5, 1, 2, 5, 10, 15, 30, 45, 60, 75, 90, 120, 180 minutes;
liquid phase conditions:
the instrument comprises the following steps: SHIMADZU LC-2030C 3D;
a chromatographic column: inertsil ODS C18 column (4.6 mm. times.150 mm, 5 μm);
ultraviolet detection wavelength: 276 nm;
mobile phase: acetonitrile and water are 30: 70;
column temperature: 35 ℃;
flow rate: 1 mL/min;
sample introduction amount: 10 μ L.
The results are shown in the powder dissolution profile of figure 6. As shown in fig. 6, the maximum apparent solubilities of olaparib form a and the eutectic of olaparib and malonic acid were 69.14 ± 4.85 and 353.60 ± 24.20 μ g/mL, respectively. It can be seen that the apparent solubility of the eutectic of olaparib and malonic acid is unexpectedly and significantly better than that of the crystal form a of olaparib, and the value of the eutectic reaches 5.1 times that of the crystal form a of olaparib.
The co-crystal of olaparib and malonic acid provided by the invention can be applied to preparation of drugs for preventing and/or treating cancers, and has a wide application prospect.
The above embodiments are only examples of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be regarded as equivalent substitutions, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (8)
1. An olaparib and malonic acid eutectic crystal is characterized in that: the structural formula of the eutectic is shown as the formula (I):
in the eutectic, the molar ratio of olaparib to malonic acid is 1: 1; the eutectic has characteristic peaks at 2theta values of 6.8 +/-0.2 degrees, 9.8 +/-0.2 degrees, 12.4 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.4 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.7 +/-0.2 degrees and 21.0 +/-0.2 degrees by an X-ray powder diffraction pattern measured by Cu Kalpha rays.
2. The co-crystal of claim 1, wherein: the X-ray powder diffraction pattern of the eutectic also has characteristic peaks at one or more of 2theta values of 15.9 +/-0.2 degrees, 20.0 +/-0.2 degrees, 22.2 +/-0.2 degrees, 23.8 +/-0.2 degrees, 24.5 +/-0.2 degrees and 26.9 +/-0.2 degrees.
3. A method of preparing a co-crystal according to any one of claims 1 to 2, wherein: the method comprises the following steps of feeding the olaparib and the malonic acid according to the molar ratio of 1: 1, adding a proper amount of solvent, and stirring or grinding to obtain the eutectic crystal.
4. The production method according to claim 3, characterized in that: the solvent is at least one of an alcohol solvent, an ester solvent, a ketone solvent, an ether solvent, a nitrile solvent and an alkane solvent.
5. The production method according to claim 3, characterized in that: and during stirring, the ratio of the total mass of the olaparib and the malonic acid to the using amount of the solvent is 1g to (4-20) mL.
6. The production method according to claim 3, characterized in that: during grinding, the total mass of the olaparib and the malonic acid and the dosage of the solvent are in a ratio of 1g to (100-200) mu L.
7. A pharmaceutical composition characterized by: comprising a co-crystal according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient.
8. Use of the co-crystal of any one of claims 1 to 2 in a medicament for the treatment of cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010707895.8A CN111825621A (en) | 2020-07-22 | 2020-07-22 | Eutectic of olaparib and malonic acid and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010707895.8A CN111825621A (en) | 2020-07-22 | 2020-07-22 | Eutectic of olaparib and malonic acid and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111825621A true CN111825621A (en) | 2020-10-27 |
Family
ID=72923895
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010707895.8A Pending CN111825621A (en) | 2020-07-22 | 2020-07-22 | Eutectic of olaparib and malonic acid and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111825621A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2022058785A1 (en) | 2020-09-16 | 2022-03-24 | Nuformix Technologies Limited | Olaparib oxalic acid cocrystals and their pharmaceutical use |
| WO2023084311A1 (en) | 2021-11-10 | 2023-05-19 | Nuformix Technologies Limited | Olaparib hydroxybenzoic acid cocrystals and their pharmaceutical use |
-
2020
- 2020-07-22 CN CN202010707895.8A patent/CN111825621A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022058785A1 (en) | 2020-09-16 | 2022-03-24 | Nuformix Technologies Limited | Olaparib oxalic acid cocrystals and their pharmaceutical use |
| JP2023538455A (en) * | 2020-09-16 | 2023-09-07 | ナフォーミックス テクノロジーズ リミテッド | Olaparib oxalic acid cocrystal and its pharmaceutical use |
| JP7453475B2 (en) | 2020-09-16 | 2024-03-19 | ナフォーミックス テクノロジーズ リミテッド | Olaparib oxalic acid cocrystal and its pharmaceutical use |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111689905B (en) | Eutectic of olaparib and maleic acid and preparation method thereof | |
| CN111995582B (en) | Eutectic of olaparib and urea and preparation method thereof | |
| CN111825621A (en) | Eutectic of olaparib and malonic acid and preparation method thereof | |
| JP2018520205A (en) | Novel crystal form of lenvatinib mesylate and process for producing the same | |
| EP3205653B1 (en) | Crystal form of bisulfate of jak inhibitor and preparation method therefor | |
| JP2018501289A (en) | Novel crystal form of neratinib maleate and process for producing the same | |
| EP3560919A1 (en) | Salt of substituted piperidine compound | |
| WO2022000265A1 (en) | Cocrystals of axitinib and glutaric acid, and preparation method therefor | |
| CN112209887B (en) | Eutectic crystal of 5-fluorouracil and kaempferol and preparation method thereof | |
| CN111793027B (en) | Eutectic of lenvatinib and benzoic acid and preparation method thereof | |
| CN111233762B (en) | Levatinib and p-hydroxybenzoic acid eutectic crystal and preparation method thereof | |
| CN110627793B (en) | Penciclovir and 3, 5-dihydroxy benzoic acid eutectic crystal and preparation method thereof | |
| EP3604284B1 (en) | Crystalline eltrombopag monoethanolamine salt form d | |
| CN111995571B (en) | Eutectic crystal of regorafenib and maleic acid and preparation method thereof | |
| EP3992192A1 (en) | Dominant salt forms of pyrimidine derivatives, and crystal forms thereof | |
| JP2022508864A (en) | Crystal form of maleate, a tyrosine kinase inhibitor, and its preparation method | |
| AU2018343244A2 (en) | Crystalline forms of lenalidomide | |
| CN111825607A (en) | Eutectic of regorafenib and malonic acid and preparation method thereof | |
| CN111777552A (en) | Eutectic of regorafenib and pimelic acid and preparation method thereof | |
| JP2019529410A (en) | Method for producing pure and stable crystalline raltegravir potassium type 3 | |
| EP3088402A1 (en) | CRYSTALS (2) OF PYRAZINO[2,1-c][1,2,4]TRIAZINE COMPOUND | |
| CN108997248B (en) | Crystal form B of ondarot hydrochloride and preparation method thereof | |
| KR102026337B1 (en) | Novel 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine salt and method for preparing the same | |
| CN106432253A (en) | New crystal form of Velpatasvir and preparation method of new crystal form | |
| CN111689896A (en) | Eutectic of regorafenib and glutaric acid and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |