CN113636979A - A kind of olaparib and fumaric acid co-crystal form α and its preparation method and application - Google Patents
A kind of olaparib and fumaric acid co-crystal form α and its preparation method and application Download PDFInfo
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一种奥拉帕尼与富马酸共晶晶型α及其制备方法与应用，本发明的奥拉帕尼与富马酸共晶晶型α具备高的口服生物利用度且其引湿性低、稳定性高、可压片性好，可以开发疗效更好、副作用更小的奥拉帕尼改良型制剂。本发明的奥拉帕尼与富马酸共晶晶型α的制备方法工艺简单，结晶过程易于控制，重现性好，适用于工业化生产，在制备预防和/或治疗癌症的药物中具有广阔的应用前景。The present invention provides a co-crystal form α of olaparib and fumaric acid and a preparation method and application thereof. The co-crystal form α of olaparib and fumaric acid of the present invention has high oral bioavailability and With low hygroscopicity, high stability and good tabletability, an improved formulation of olaparib with better curative effect and fewer side effects can be developed. The preparation method of the olaparib and fumaric acid co-crystal form α of the present invention is simple in process, easy to control the crystallization process, and has good reproducibility, is suitable for industrial production, and has broad application in the preparation of drugs for preventing and/or treating cancer. application prospects.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to an olaparib and fumaric acid eutectic crystal form alpha, and a preparation method and application 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 (Olaparib) has the chemical name 1- (cyclopropylformyl) -4- [5- [ (3, 4-dihydro-4-oxo-1-phthalazinyl) methyl ] -2-fluorobenzoyl ] piperazine with CAS number 763113-22-0 and the chemical formula shown below:
olaparib was first developed by the british biotechnology couscous (KuDOS) drugs ltd, and is an pioneer oral Poly ADP Ribose Polymerase (PARP) inhibitor that can take advantage of the defects in the DNA repair pathway to preferentially kill cancer cells. In 2005, the availability of Coudos by Asricon continued to develop Olaparib for the treatment of ovarian cancer. 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. The crystal form of the olaparib on the market is the crystal form A, the solubility is low, the oral bioavailability and the curative effect of the olaparib are limited, the clinical daily dose is up to 600-800 mg, and the adverse reaction is serious. Patent CN105753789A discloses a co-crystal form a of olaparib and urea, which has a 3-fold improvement in solubility in simulated gastric fluid at 1 hour, but a 20% reduction in solubility in simulated intestinal fluid at 1 hour in the fasting state. Patent CN111689905A discloses a co-crystal of olaparib and maleic acid, the apparent solubility of which is improved by 4.6 times. Patent CN111825621A discloses a co-crystal of olaparib and malonic acid, the apparent solubility of which is improved by 5.1 times. However, no report on the improvement of the oral bioavailability of the olaparib eutectic exists at present. In addition, olaparib is clinically administered in the form of tablets, and its hygroscopicity, stability and tabletability all have important influences on the formulation process. Therefore, the development of improved olaparib preparations with better curative effect and less side effect has important significance for improving the curative effect and safety of the medicine.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides an olaparib and fumaric acid eutectic crystal form alpha, which has high oral bioavailability, low hygroscopicity, high stability and good tabletting performance compared with the olaparib crystal form A.
The second aspect of the invention provides a preparation method of the above eutectic crystal form alpha of olaparib and fumaric acid.
In a third aspect, the invention provides a composition containing the above-mentioned olaparib and fumaric acid eutectic crystal form α.
The fourth aspect of the invention provides an application of the above-mentioned eutectic crystal form alpha of olaparib and fumaric acid or a composition containing the above-mentioned eutectic crystal form alpha of olaparib and fumaric acid.
According to the first aspect of the invention, a eutectic crystal form alpha of olaparib and fumaric acid is provided, and the structural formula of the eutectic crystal form alpha of olaparib and fumaric acid is shown as the formula (I):
the eutectic crystal form alpha of the olaparib and the fumaric acid comprises the following components in a molar ratio of 1:1 with fumaric acid; an X-ray powder diffraction pattern of the eutectic crystal form alpha of olaparib and fumaric acid measured by Cu Kalpha rays has characteristic peaks at diffraction angles 2 theta of 12.4 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.3 +/-0.2 degrees, 17.3 +/-0.2 degrees, 21.0 +/-0.2 degrees and 26.0 +/-0.2 degrees.
In some embodiments of the invention, the X-ray powder diffraction pattern of the eutectic crystal form α of olaparib and fumaric acid measured by Cu ka radiation also has characteristic peaks at one or more of diffraction angles 2 θ of 6.6 ± 0.2 °, 9.5 ± 0.2 °, 14.4 ± 0.2 °, 15.7 ± 0.2 °, 18.8 ± 0.2 °, 19.2 ± 0.2 °, 20.0 ± 0.2 °, 22.7 ± 0.2 °, 23.6 ± 0.2 °, 26.9 ± 0.2 °, 27.5 ± 0.2 °.
In some preferred embodiments of the present invention, the differential scanning calorimetry curve of the eutectic crystalline form α of olaparib and fumaric acid shows an endothermic peak at 197.4 ℃.
In some more preferred embodiments of the present invention, the infrared absorption spectrum of the eutectic crystalline modification α of olaparib and fumaric acid is 3435, 3161, 3009, 2927, 2867, 2624, 2552, 2362, 1721, 1697, 1642, 1604, 1485, 1466, 1443, 1369, 1282, 1259, 1243, 1231, 1165, 1099, 1015, 967, 937, 894, 835, 795, 773, 738, 682, 636, 586, 542cm-1Has characteristic peaks.
According to a second aspect of the invention, a preparation method of an olaparib and fumaric acid eutectic crystal form alpha is provided, which comprises the following steps: adding olaparib and fumaric acid into a solvent, and pulping to obtain the olaparib and fumaric acid eutectic crystal form alpha.
In the present invention, "slurrying" is a common term in the field of pharmaceutical preparation, and generally means subjecting a solid pharmaceutical material to a mechanical or fluidization treatment so that the solid pharmaceutical material is dispersed or suspended in a solvent.
In some preferred embodiments of the present invention, the beating time is 5 to 30 hours in some embodiments of the present invention.
The solvent is a mixed solvent of a good solvent and a poor solvent. In the present invention, because olaparib and fumaric acid have a large solubility difference in a good solvent, a raw material having a small solubility is easily obtained or included in a part of the raw material during beating. Compared with the method adopting a single good solvent and a mixed solvent of a good solvent and a poor solvent, the method can prepare the eutectic crystal form alpha of the olaparib and the fumaric acid.
In some more preferred embodiments of the present invention, the good solvent includes any one of an alcohol solvent, an ester solvent, and a ketone solvent; further preferably, the poor solvent includes any one of an ether solvent and an alkane solvent.
In some more preferred embodiments of the present invention, the alcoholic solvent is selected from at least one of methanol, ethanol, isopropanol; further preferably, the ester solvent is at least one selected from ethyl acetate and isopropyl acetate; still more preferably, the ketone solvent is at least one selected from acetone and methyl tert-butyl ketone.
In some more preferred embodiments of the present invention, the ethereal solvent is selected from at least one of methyl tert-butyl ether, tetrahydrofuran; further preferably, the alkane solvent is at least one selected from the group consisting of n-heptane and n-hexane.
In some more preferred embodiments of the present invention, the solvent is a good solvent and a poor solvent in a volume ratio of 1: (5-100) a mixed solvent; preferably, the volume ratio is 1: (20-100); further preferably, the volume ratio is 1: (20 to 50). The poor solvent with a significantly large proportion can reduce the solubility difference of the olaparib and the fumaric acid in the good solvent, so that the preparation of the high-purity olaparib and fumaric acid eutectic crystal form alpha becomes possible.
In some more preferred embodiments of the invention, the ratio of the total mass of olaparib and fumaric acid to the amount of the solvent is 1 g: (10-25) mL; more preferably 1 g: (15-20) mL.
According to a third aspect of the present invention, a pharmaceutical composition is provided, which comprises the olaparib and fumaric acid cocrystal form α 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.
In some embodiments of the invention, the pharmaceutically acceptable excipient comprises 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.
In some preferred embodiments of the present invention, the pharmaceutical composition is a solid formulation; preferably, the solid formulation is a tablet; further preferably, the tablet contains 25-150 mg of the eutectic crystal form alpha of the olaparib and fumaric acid. The tabletting performance of the tablet is related to the tabletting pressure and the tensile strength of the tablet, the eutectic crystal form alpha of olaparib and fumaric acid in the invention has better tabletting performance, the material can be molded by smaller pressure, and the extruded tablet has higher tensile strength and is not easy to crack.
According to a fourth aspect of the invention, the application of the olaparib and fumaric acid eutectic crystal form alpha or the pharmaceutical composition in the preparation of a medicament for preventing and/or treating cancer is provided.
In some embodiments of the invention, the cancer is selected from at least one of ovarian cancer, prostate cancer, breast cancer, pancreatic cancer.
The invention has the beneficial effects that:
(1) the invention converts the olaparib into a brand-new eutectic crystal form alpha of the olaparib and the fumaric acid for the first time, and the olaparib and the fumaric acid eutectic crystal form alpha have higher oral bioavailability, lower hygroscopicity, better stability and tabletting property, and can develop an improved olaparib preparation with better curative effect and smaller side effect.
(2) The preparation method of the eutectic crystal form alpha of olaparib and fumaric acid has the advantages of simple process, easy control of the crystallization process, good reproducibility and suitability for industrial production.
(3) The eutectic crystal form alpha of olaparib and fumaric acid has wide application prospect in preparing medicaments for preventing and/or treating cancers.
Drawings
The invention is further described with reference to the following figures and examples, in which:
fig. 1 is an X-ray powder diffraction pattern of an olaparib and fumaric acid eutectic crystal form α prepared in example 1 of the present invention.
Fig. 2 is a differential scanning calorimetry analysis diagram of an olaparib and fumaric acid eutectic crystal form α prepared in example 1 of the present invention.
Fig. 3 is a thermogravimetric analysis chart of the eutectic crystal form α of olaparib and fumaric acid obtained in example 1.
Fig. 4 is a tabletting property curve of the olaparib prepared in example 1 and the fumaric acid eutectic crystal form α, and the olaparib prepared in comparative example and the crystal form a.
Fig. 5 is a blood concentration-time curve of the olaparib form a prepared in example 1 and the fumaric acid cocrystal form a prepared in comparative example.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention.
Detection instrument and method
X-ray powder diffraction analysis Using Rigaku SmartLab 9KW type diffractometer, manufactured by Japan science Ltd, Cu Ka ray
The voltage is 40 kilovolts, the current is 150 milliamperes, the step size 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 Differential Scanning Calorimetry (DSC) is detected by a DSC 214 differential calorimeter of German Steady scientific instruments, the atmosphere is nitrogen, and the heating rate is 10 ℃/min.
Thermal Gravimetric Analysis (TGA) A thermo gravimetric analyzer model TG 209F 3, Germany Steady scientific instruments and Co., Ltd, was used, the atmosphere was nitrogen, and the temperature rise rate was 10 ℃/min.
The infrared spectrum analysis adopts ALPHA II Fourier transform infrared spectrometer of Bruker company to detect, and the detection range is 4000-500 cm-1。
The hydrogen nuclear magnetic resonance spectroscopy was carried out by using an Avance III 400M nuclear magnetic resonance spectrometer (Bruker, Germany).
Example 1
In this embodiment, an olaparib and fumaric acid eutectic crystal form α is prepared, and the specific process is as follows:
600mg of olaparib and 160mg of fumaric acid are weighed and added into 10mL of n-heptane and 200 mu L of methanol to obtain a suspension, the suspension is placed at room temperature and stirred for 12 hours, the suspension is filtered, and the obtained white solid is dried in vacuum at 40 ℃ to obtain the eutectic crystal form alpha of the olaparib and the fumaric acid.
X-ray powder diffraction analysis was performed on the eutectic crystal form α of olaparib and fumaric acid obtained in example 1, and the analysis results are shown in the X-ray powder diffraction pattern of fig. 1, and the X-ray powder diffraction data are shown in table 1.
Table 1X-ray powder diffraction data for the olaparib and fumaric acid cocrystal form α of example 1
The differential scanning calorimetry pattern is shown in FIG. 2, and the product has a melting endothermic peak at 197.4 ℃.
The thermogravimetric analysis is shown in FIG. 3, and the product is heated to about 197.7 ℃ and starts to decompose.
The Fourier transform infrared characteristic peak position is as follows: 3435. 3161, 3009, 2927, 2867, 2624, 2552, 2362, 1721, 1697, 1642, 1604, 1485, 1466, 1443、1369、1282、1259、1243、1231、1165、1099、1015、967、937、894、835、795、773、738、682、636、586、542cm-1。
Nuclear magnetic resonance hydrogen spectrum of the product1H NMR (400MHz, DMSO-d6) data: characteristic peaks of olaparib: δ 12.62(s,1H),8.30-8.20(m,1H),7.97(d, J ═ 7.6Hz,1H),7.90(t, J ═ 7.3Hz,1H),7.84(dd, J ═ 10.9,4.1Hz,1H),
7.45(dd, J ═ 7.1,4.3Hz,1H),7.38(s,1H),7.25(t, J ═ 9.0Hz,1H),4.34(s,2H),3.64(dd, J ═ 59.7,6.5Hz,5H),3.39(s,1H),3.19(d, J ═ 28.4Hz,2H),1.96(d, J ═ 40.3Hz,1H),0.73(t, J ═ 6.3Hz, 4H). Characteristic peaks of fumaric acid: δ 13.16(s,2H),6.63(s, 2H). From the integration results of the characteristic peaks, the stoichiometric ratio of olaparib and fumaric acid in the cocrystal was 1: 1.
Example 2
In this embodiment, an olaparib and fumaric acid eutectic crystal form α is prepared, and the specific process is as follows:
weighing 60mg of olaparib and 16mg of fumaric acid, adding the weighed materials into 1mL of n-hexane and 200 mu L of methanol to obtain a suspension, placing the suspension at room temperature, stirring for 24 hours, filtering, and drying the obtained white solid at 40 ℃ in vacuum to obtain the eutectic crystal form alpha of the olaparib and the fumaric acid.
X-ray powder diffraction analysis was performed on the eutectic crystal form α of olaparib and fumaric acid obtained in example 2, and the analysis results are shown in table 2.
Table 2X-ray powder diffraction data of the olaparib and fumaric acid eutectic crystal form α of example 2
Example 3
In this embodiment, an olaparib and fumaric acid eutectic crystal form α is prepared, and the specific process is as follows:
weighing 60mg of olaparib and 16mg of fumaric acid, adding the weighed materials into 1mL of n-heptane and 10 muL of ethanol to obtain a suspension, placing the suspension at room temperature, stirring for 24h, filtering, and drying the obtained white solid at 40 ℃ in vacuum to obtain the eutectic crystal form alpha of the olaparib and the fumaric acid.
X-ray powder diffraction analysis was performed on the eutectic crystal form α of olaparib and fumaric acid obtained in example 3, and the analysis results are shown in table 3.
Table 3X-ray powder diffraction data for the olaparib and fumaric acid cocrystal form α of example 3
Example 4
In this embodiment, an olaparib and fumaric acid eutectic crystal form α is prepared, and the specific process is as follows:
60mg of olaparib and 16mg of fumaric acid are weighed and added into 1mL of n-heptane and 20 muL of isopropanol to obtain a suspension, the suspension is placed at room temperature and stirred for 24 hours, the suspension is filtered, and the obtained white solid is dried in vacuum at 40 ℃ to obtain the eutectic crystal form alpha of the olaparib and the fumaric acid.
X-ray powder diffraction analysis was performed on the eutectic crystal form α of olaparib and fumaric acid obtained in example 4, and the analysis results are shown in table 4.
Table 4X-ray powder diffraction data for the olaparib and fumaric acid cocrystal form α of example 4
Example 5
In this embodiment, an olaparib and fumaric acid eutectic crystal form α is prepared, and the specific process is as follows:
weighing 60mg of olaparib and 16mg of fumaric acid, adding the weighed materials into 1mL of methyl tert-butyl ether and 20 muL of methanol to obtain a suspension, placing the suspension at room temperature, stirring for 24h, filtering, and drying the obtained white solid at 40 ℃ in vacuum to obtain the eutectic crystal form alpha of the olaparib and the fumaric acid.
X-ray powder diffraction analysis was performed on the eutectic crystal form α of olaparib and fumaric acid obtained in example 5, and the analysis results are shown in table 5.
Table 5X-ray powder diffraction data for the olaparib and fumaric acid cocrystal form α of example 5
Example 6
In this embodiment, an olaparib and fumaric acid eutectic crystal form α is prepared, and the specific process is as follows:
60mg of olaparib and 16mg of fumaric acid are weighed and added into 1mL of n-heptane and 20 muL of ethyl acetate to obtain a suspension, the suspension is placed at room temperature and stirred for 12 hours, the suspension is filtered, and the obtained white solid is dried in vacuum at 40 ℃ to obtain the eutectic crystal form alpha of the olaparib and the fumaric acid.
Example 7
In this embodiment, an olaparib and fumaric acid eutectic crystal form α is prepared, and the specific process is as follows:
weighing 60mg of olaparib and 16mg of fumaric acid, adding the weighed materials into 1mL of n-heptane and 20 muL of acetone to obtain a suspension, placing the suspension at room temperature, stirring for 12h, filtering, and drying the obtained white solid at 40 ℃ in vacuum to obtain the eutectic crystal form alpha of the olaparib and the fumaric acid.
Comparative example
The comparative example prepares an olaparib crystal form a, and the specific process is as follows:
weighing 300mg of olaparib, adding into 10mL of ethanol to obtain a suspension, placing the suspension at room temperature, stirring for 12h, filtering, and vacuum-drying the obtained white solid at 40 ℃ to obtain the olaparib crystal form A.
Test example 1 dynamic moisture adsorption analysis
The powder samples of the olaparib and fumaric acid eutectic crystal form alpha prepared in the example 1 and the olaparib crystal form A prepared in the comparative example are respectively sieved by a 100-mesh sieve and a 200-mesh sieve after being ground, and the particle size is controlled to be 75-150 mu m. The system was kept in equilibrium under a nitrogen flow with a relative humidity of 0% until the mass remained unchanged by using a DVS Intrinsic dynamic moisture adsorption apparatus of the british SMS company with a constant temperature of 25 ℃, then the relative humidity was controlled to run from 0% to 95%, and the mass change after the moisture absorption weight gain of each relative humidity sample reached equilibrium was recorded, and the experimental results are shown in table 6.
TABLE 6 hygroscopicity data at different relative humidities
As can be seen from table 6, as the relative humidity increases, the mass of the sample gradually increases, and the maximum weight gains of the eutectic crystal form α of olaparib and fumaric acid and the crystal form a of olaparib are both lower than 0.3%, indicating that both have lower hygroscopicity.
Test example 2 evaluation of stability
The crystalline phase of the olaparib prepared in example 1 and the fumaric acid eutectic crystal form α and the olaparib prepared in comparative example, which were powder samples, were analyzed and detected by X-ray powder diffraction (PXRD) analysis after 1 month, 2 months, and 3 months, respectively, under the accelerated stability test condition of 40 ℃/75% RH, and the results are shown in table 7.
Table 740 ℃/75% RH accelerated stability test results
The results show that crystal phases of the eutectic crystal form alpha of olaparib and fumaric acid and the crystal form A of olaparib can be stable for 3 months. Therefore, the eutectic crystal form alpha of olaparib and fumaric acid and the crystal form A of olaparib have better stability.
Test example 3 evaluation of tabletting Properties
The powder samples of the olaparib and fumaric acid eutectic crystal form alpha prepared in the example 1 and the olaparib crystal form A prepared in the comparative example are respectively sieved by a 100-mesh sieve and a 200-mesh sieve after being ground, and the particle size is controlled to be 75-150 mu m. About 50mg of the sample was weighed, compressed for 30s under pressures of 50, 100, 150, 200, 250 and 300MPa using a 5mm circular mold, respectively, the compressed tablets were left to stand for 24h to release stress, and then the diameter D, thickness t of each tablet were recorded, hardness F was measured using a hardness tester, and tensile strength of each tablet was calculated by the following formula:
the results are shown in the tabletability curve of fig. 4, and it can be seen from fig. 4 that the tensile strength of the sample is gradually increased as the pressure is increased. The maximum tensile strength of 1.9MPa is reached when the pressure of the eutectic crystalline modification a of olaparib and fumaric acid is increased to 150MPa, while the maximum tensile strength of the eutectic crystalline modification a of olaparib is only 1.1MPa when the pressure is increased to 250 MPa. Therefore, compared with the eutectic crystal form alpha of the fumaric acid, the crystal form A of the olaparib has better tabletting property, and the prepared tablet has higher tensile strength and is not easy to crack.
Test example 4 pharmacokinetic testing
After the olaparib prepared in example 1 and the fumaric acid eutectic crystal form alpha and the olaparib prepared in the comparative example are ground, the crystal forms A are respectively sieved by a 100-mesh sieve and a 200-mesh sieve, and the particle size of the powder is controlled to be 75-150 mu m. 10 female Sprague-Dawley rats (body weight 195-225 g) were randomly divided into 2 groups, and administered by intragastric administration of Olaparib at a dose of 50mg/kg (cocrystal containing 50mg of Olaparib) dispersed in sodium carboxymethylcellulose solution, and blood samples were collected from the left or right retinal venous plexus at time intervals: 0, 10min, 20min, 30min, 45min, 1h, 2h, 4h, 6h, 8h, 12h and 24 h. The blood samples were added to heparin sodium blood collection tubes, centrifuged at 4200rpm for 10min, and the separated plasma was stored in a freezer at-80 ℃. And (3) quantitatively analyzing the blood concentration at each time point by adopting an ultra-high performance liquid chromatography-mass spectrometer, and finally obtaining a blood concentration-time curve (a medicine time curve) of each sample.
As shown in fig. 5, it can be seen from fig. 5 that the maximum blood concentrations of the olaparib and fumaric acid eutectic crystal form α and the olaparib crystal form a are 2431.85 ± 383.62ng/mL and 209.16 ± 68.57ng/mL, the areas under the curve during drug administration are 549097.95 ± 67716.96ng · h/mL and 90123.32 ± 26746.44ng · h/mL, respectively, and the maximum blood concentration of the olaparib and fumaric acid eutectic crystal form α and the integral under the curve during drug administration are 11.6 times and 6.1 times of the olaparib crystal form a, respectively, and it can be seen that the oral bioavailability of the olaparib and fumaric acid eutectic crystal form α is significantly better than that of the olaparib crystal form a.
The eutectic crystal form alpha of olaparib and fumaric 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 embodiments of the present invention have been described in detail, but the present invention is not limited to the embodiments, and various changes can be made without departing from the gist of the present invention within the knowledge of those skilled in the art. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.
Claims (10)
1. An olaparib and fumaric acid eutectic crystal form alpha is characterized in that: the structural formula of the eutectic crystal form alpha of olaparib and fumaric acid is shown as the formula (I):
the eutectic crystal form alpha of the olaparib and the fumaric acid comprises the following components in a molar ratio of 1:1 with fumaric acid; an X-ray powder diffraction pattern of the eutectic crystal form alpha of olaparib and fumaric acid measured by Cu Kalpha rays has characteristic peaks at diffraction angles 2 theta of 12.4 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.3 +/-0.2 degrees, 17.3 +/-0.2 degrees, 21.0 +/-0.2 degrees and 26.0 +/-0.2 degrees.
2. The olaparib and fumaric acid eutectic crystalline form α of claim 1, characterized in that: an X-ray powder diffraction pattern of the eutectic crystal form alpha of olaparib and fumaric acid measured by Cu Kalpha rays also has characteristic peaks at one or more of diffraction angles 2 theta of 6.6 +/-0.2 degrees, 9.5 +/-0.2 degrees, 14.4 +/-0.2 degrees, 15.7 +/-0.2 degrees, 18.8 +/-0.2 degrees, 19.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 22.7 +/-0.2 degrees, 23.6 +/-0.2 degrees, 26.9 +/-0.2 degrees and 27.5 +/-0.2 degrees.
3. The olaparib and fumaric acid eutectic crystalline form α of claim 1, characterized in that: the differential scanning calorimetry curve of the eutectic crystal form alpha of olaparib and fumaric acid shows an endothermic peak at 197.4 ℃.
4. The olaparib and fumaric acid eutectic crystalline form α of claim 1, characterized in that: the infrared absorption spectrum of the eutectic crystal form alpha of olaparib and fumaric acid is 3435, 3161, 3009, 2927, 2867, 2624, 2552, 2362, 1721, 1697, 1642, 1604, 1485, 1466, 1443, 1369, 1282, 1259, 1243, 1231, 1165, 1099, 1015, 967, 937, 894, 835, 795, 773, 738, 682, 636, 586, 542cm-1Has characteristic peaks.
5. The preparation method of the olaparib and fumaric acid eutectic crystal form alpha as claimed in any one of claims 1 to 4, characterized in that: the method comprises the following steps: adding olaparib and fumaric acid into a solvent, and pulping to obtain the olaparib and fumaric acid eutectic crystal form alpha.
6. The method for preparing the olaparib and fumaric acid eutectic crystal form alpha according to claim 5, characterized in that: the solvent is a mixed solvent of a good solvent and a poor solvent; preferably, the solvent is a good solvent and a poor solvent in a volume ratio of 1: (5-100) a mixed solvent.
7. The method for preparing the olaparib and fumaric acid eutectic crystal form alpha according to claim 6, characterized in that: the good solvent comprises any one of an alcohol solvent, an ester solvent and a ketone solvent; preferably, the poor solvent includes any one of an ether solvent and an alkane solvent.
8. The preparation method of the olaparib and fumaric acid eutectic crystal form alpha according to any one of claims 5 to 7, characterized in that: the ratio of the total mass of the olaparib and the fumaric acid to the amount of the solvent is 1 g: (10-25) mL.
9. A pharmaceutical composition comprising the olaparib and fumaric acid cocrystal crystal form alpha according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.
10. Use of the olaparib and fumaric acid cocrystal form α according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 11 or 12 for the preparation of a medicament for the prevention and/or treatment of cancer.
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