CN113636979B - Olaparib and fumaric acid eutectic crystal form alpha and preparation method and application thereof - Google Patents
Olaparib and fumaric acid eutectic crystal form alpha and preparation method and application thereof Download PDFInfo
- Publication number
- CN113636979B CN113636979B CN202110925622.5A CN202110925622A CN113636979B CN 113636979 B CN113636979 B CN 113636979B CN 202110925622 A CN202110925622 A CN 202110925622A CN 113636979 B CN113636979 B CN 113636979B
- Authority
- CN
- China
- Prior art keywords
- fumaric acid
- olaparib
- crystal form
- solvent
- eutectic crystal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
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
- 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
Landscapes
- 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)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an Olaparib and fumaric acid eutectic crystal form alpha, a preparation method and application thereof, and the Olaparib and fumaric acid eutectic crystal form alpha has high oral bioavailability, low hygroscopicity, high stability and good tabletting property, and can be used for developing an Olaparib improved preparation with better curative effect and smaller side effect. The preparation method of the eutectic crystal form alpha of the Olaparib and the fumaric acid has the advantages of simple process, easy control of crystallization process, good reproducibility, suitability for industrial production and wide application prospect in preparing medicines for preventing and/or treating cancers.
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 form, such as polymorphs, hydrates, solvates, salts and co-crystals, etc. Different crystalline forms have different physicochemical properties for the same pharmaceutical active ingredient. Therefore, in the pharmaceutical industry, it is of great importance to obtain a suitable crystalline form of a drug. The medicine exists in a eutectic form, can improve the stability, the solubility, the processability and the like of the active ingredients of the medicine, and has remarkable advantages. Therefore, pharmaceutical co-crystals are an effective means of improving the physicochemical properties of the pharmaceutically active ingredient.
Olaparib (Olaparib) chemical name 1- (cyclopropoyl) -4- [5- [ (3, 4-dihydro-4-oxo-1-phthalazinyl) methyl ] -2-fluorobenzoyl ] piperazine, CAS number 763113-22-0, has the chemical structural formula shown below:
olaparib was first developed by the UK Biotechnology Kokudo (KuDOS) pharmaceutical Co., ltd, and is an initial oral Poly ADP Ribose Polymerase (PARP) inhibitor capable of utilizing the defect of DNA repair pathway to preferentially kill cancer cells. After the acquisition of kudo corporation by aslicon in 2005, the development of olaparib was continued for the treatment of ovarian cancer. Olaparib was approved by the FDA in the United states for marketing in 2014, the first targeted drug specifically for patients with ovarian cancer with BRCA mutations, and was suitable for patients who had previously undergone chemotherapy. The crystal form of the Olaparib on the market is the crystal form A, and the solubility is very low, so that the oral bioavailability and the curative effect of the Olaparib are limited, the daily dosage of the Olaparib is 600-800 mg clinically, and the adverse reaction is serious. Patent CN105753789a discloses a eutectic crystal form a of olaparib and urea, whose solubility in simulated artificial gastric fluid for 1 hour is improved by 3 times, but whose solubility in simulated empty stomach state in artificial intestinal fluid for 1 hour is reduced by 20%. Patent CN111689905a discloses an olaparib and maleic acid co-crystal whose apparent solubility is improved by 4.6 times. Patent CN111825621a discloses an olaparib and malonic acid co-crystal, the apparent solubility of which is improved by 5.1 times. However, no report of improving the oral bioavailability of the Olaparib co-crystal exists at present. In addition, the Olaparib is clinically administrated in the form of tablets, and the hygroscopicity, stability and tabletting property of the Olaparib have important influences on the preparation process. Therefore, the improved preparation of the Olaparib with better curative effect and smaller side effect is developed, which has important significance for improving the curative effect and the safety of the medicament.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the first aspect of the invention provides the oxidapamide and fumaric acid eutectic crystal form alpha, which has high oral bioavailability, low hygroscopicity, high stability and good tabletting property compared with the oxidapamide crystal form A.
The second aspect of the invention provides a preparation method of the Olaparib and fumaric acid eutectic crystal form alpha.
In a third aspect the invention provides a composition comprising the above-mentioned crystalline form α of the eutectic of olaparib and fumaric acid.
The fourth aspect of the invention provides an application of the oxipa and fumaric acid eutectic crystal form alpha or a composition containing the oxipa and fumaric acid eutectic crystal form alpha.
According to a first aspect of the invention, an oxidapamide and fumaric acid eutectic crystal form alpha is provided, wherein the structural formula of the oxidapamide and fumaric acid eutectic crystal form alpha is shown as a formula (I):
the oxilapatinib and fumaric acid eutectic crystal form alpha comprises the following components in a molar ratio of 1:1 Olaparib and fumaric acid; the X-ray powder diffraction pattern of the oxidapamide and fumaric acid eutectic crystal form alpha measured by Cu K alpha 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 crystalline form α of the olapamide and fumaric acid measured by Cu ka radiation also has characteristic peaks at one or more of diffraction angles 2θ 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°, and 27.5±0.2 °.
In some preferred embodiments of the invention, the differential scanning calorimetric curve of the olaparib and the fumaric acid eutectic crystal form α exhibits an endothermic peak at 197.4 ℃.
In some more preferred embodiments of the invention, the co-crystalline form α of olaparib and fumaric acid has an infrared absorption spectrum at 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 With characteristic peaks.
According to a second aspect of the present invention, a method for preparing an oxipa and fumaric acid eutectic crystal form α is provided, comprising the following steps: adding the Olaparib and the fumaric acid into a solvent, and pulping to obtain the Olaparib and the fumaric acid eutectic crystal form alpha.
In the present invention, "beating" is a common term in the art of pharmaceutical preparation and generally refers to the mechanical or fluid treatment of solid pharmaceutical materials such that the solid pharmaceutical material is dispersed or suspended in a solvent.
In some preferred embodiments of the invention, the beating time is between 5h and 30h.
The solvent is a mixed solvent of a good solvent and a poor solvent. In the invention, because of the large solubility difference of the Olaparib and the fumaric acid in the good solvent, raw materials with small partial solubility are easily obtained or mixed during beating. Compared with the single good solvent, the mixed solvent of the good solvent and the poor solvent is adopted, so that the eutectic crystal form alpha of the Olaparib and the fumaric acid can be prepared.
In some more preferred embodiments of the present invention, the good solvent comprises 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 selected from at least one of acetone and methyl tert-butyl ketone.
In some more preferred embodiments of the present invention, the ether solvent is selected from at least one of methyl tertiary butyl ether, tetrahydrofuran; further preferably, the alkane solvent is at least one selected from n-heptane and n-hexane.
In some more preferred embodiments of the present invention, the solvent is a good solvent to 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: (20-50). The poor solvent with a larger 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 the olaparib to fumaric acid to the amount of the solvent is 1g: (10-25) mL; further preferably 1g: (15-20) mL.
According to a third aspect of the present invention, a pharmaceutical composition is presented, comprising the co-crystalline form α of olaparib and fumaric acid and a pharmaceutically acceptable excipient.
In the present invention, a pharmaceutically acceptable excipient refers to a pharmaceutically acceptable material, mixture or vehicle associated with the consistency of the dosage form or pharmaceutical composition being administered. Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form selected. Furthermore, pharmaceutically acceptable excipients may be selected according to their particular function in the composition.
In some embodiments of the invention, 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, tackifiers, antioxidants, preservatives, stabilizers, surfactants, and buffers.
In some preferred embodiments of the invention, the pharmaceutical composition is a solid formulation; preferably, the solid formulation is a tablet; more preferably, the tablet contains the eutectic crystal form alpha of the olaparib and the fumaric acid in an amount of 25mg to 150mg. The tabletting property of the tablet is related to the tabletting pressure and the tensile strength of the tablet, the Olaparib and fumaric acid eutectic crystal form alpha in the invention has better tabletting property, 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 present invention, there is provided the use of the co-crystal form α of olaparib and fumaric acid or the pharmaceutical composition in the manufacture of a medicament for the prevention and/or treatment of cancer.
In some embodiments of the invention, the cancer is selected from at least one of ovarian cancer, prostate cancer, breast cancer, pancreatic cancer.
The beneficial effects of the invention are as follows:
(1) The invention converts the Olaparib into a brand new Olaparib and fumaric acid eutectic crystal form alpha for the first time, and the Olaparib and fumaric acid eutectic crystal form alpha has higher oral bioavailability, lower hygroscopicity, better stability and tabletting property, and can develop an Olaparib improved preparation with better curative effect and smaller side effect.
(2) The preparation method of the oxidapamide and fumaric acid eutectic crystal form alpha has the advantages of simple process, easy control of crystallization process and good reproducibility, and is suitable for industrial production.
(3) The oxidapamide and fumaric acid eutectic crystal form alpha has wide application prospect in preparing medicines for preventing and/or treating cancers.
Drawings
The invention is further described with reference to the accompanying drawings and examples, in which:
FIG. 1 is an X-ray powder diffraction pattern of the eutectic crystalline form alpha of Olaparib and fumaric acid prepared in example 1 of the present invention.
Fig. 2 is a differential scanning calorimetric 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 of the crystalline form α of the eutectic of olaparib and fumaric acid obtained in example 1.
Fig. 4 is a graph showing the tabletability of the crystalline form a of olaparib from example 1 versus the crystalline form α of fumaric acid and the crystalline form a of olaparib from the comparative example.
Fig. 5 is a graph of blood concentration versus time for crystalline form a of the co-crystal of olaparib and fumaric acid prepared in example 1, and crystalline form a of olaparib prepared in comparative example.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
Detection instrument and method
The X-ray powder diffraction analysis was carried out by using a diffractometer, cu K.alpha.ray, of Rigaku SmartLab 9KW, japan Physics Co., ltd
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 testing temperature is room temperature.
Differential scanning calorimetric analysis (DSC) was performed using a DSC 214 differential calorimeter from German resistant sciences instruments, under nitrogen at a heating rate of 10 ℃/min.
Thermal Gravimetric Analysis (TGA) was performed using a German Chi science instruments Co., ltd. TG 209F 3 thermogravimetric analyzer with an atmosphere of nitrogen and a heating rate of 10℃per minute.
The infrared spectrum analysis adopts an ALPHA II Fourier transform infrared spectrometer of Bruker company to detect with 4000-500 cm detection range -1 。
The NMR hydrogen spectrum was analyzed by using an Avance III 400M NMR spectrometer from Bruker, germany.
Example 1
The embodiment prepares the eutectic crystal form alpha of the Olaparib and the fumaric acid, and the specific process is as follows:
600mg of Olaparib and 160mg of fumaric acid are weighed, 10mL of n-heptane and 200 mu L of methanol are added to obtain a suspension, the suspension is stirred for 12 hours at room temperature, filtration is carried out, and the obtained white solid is dried in vacuum at 40 ℃ to obtain the Olaparib and fumaric acid eutectic crystal form alpha.
The crystalline form α of the olaparib and fumaric acid obtained in example 1 was subjected to X-ray powder diffraction analysis, the analysis results of which 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 Olaparib and fumaric acid Co-crystalline form alpha of example 1
The differential scanning calorimetric profile is shown in FIG. 2, and the product shows a melting endothermic peak at 197.4 ℃.
Thermogravimetric analysis pattern as shown in fig. 3, the product was heated to about 197.7 ℃ to begin decomposition.
The Fourier transform infrared characteristic peak positions are 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 product 1 H NMR (400 MHz, DMSO-d 6) data: characteristic peaks of olaparib: δ12.62 (s, 1H), 8.30-8.20 (m, 1H), 7.97 (d, j=7.6 hz, 1H), 7.90 (t, j=7.3 hz, 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=9.0 hz, 1H), 4.34 (s, 2H), 3.64 (dd, j=59.7, 6.5hz, 5H), 3.39 (s, 1H), 3.19 (d, j=28.4 hz, 2H), 1.96 (d, j=40.3 hz, 1H), 0.73 (t, j=6.3 hz, 4H). Characteristic peaks of fumaric acid: delta 13.16 (s, 2H), 6.63 (s, 2H). From the integration results of the characteristic peaks, the stoichiometric ratio of the olaparib and fumaric acid in the co-crystal was 1:1.
Example 2
The embodiment prepares the eutectic crystal form alpha of the Olaparib and the fumaric acid, and the specific process is as follows:
60mg of Olaparib and 16mg of fumaric acid are weighed, 1mL of normal hexane and 200 mu L of methanol are added to obtain a suspension, the suspension is stirred for 24 hours at room temperature, filtration is carried out, and the obtained white solid is dried in vacuum at 40 ℃ to obtain the Olaparib and fumaric acid eutectic crystal form alpha.
The results of the X-ray powder diffraction analysis of the crystalline form α of the eutectic of olaparib and fumaric acid obtained in example 2 are shown in table 2.
TABLE 2X-ray powder diffraction data for Olaparib and fumaric acid Co-crystal form alpha of example 2
Example 3
The embodiment prepares the eutectic crystal form alpha of the Olaparib and the fumaric acid, and the specific process is as follows:
60mg of Olaparib and 16mg of fumaric acid are weighed, 1mL of n-heptane and 10 mu L of ethanol are added to obtain a suspension, the suspension is stirred for 24 hours at room temperature, filtration is carried out, and the obtained white solid is dried in vacuum at 40 ℃ to obtain the Olaparib and fumaric acid eutectic crystal form alpha.
The results of the X-ray powder diffraction analysis of the crystalline form α of the co-crystal of olaparib and fumaric acid obtained in example 3 are shown in table 3.
TABLE 3X-ray powder diffraction data for Olaparib and fumaric acid Co-crystal form alpha of example 3
Example 4
The embodiment prepares the eutectic crystal form alpha of the Olaparib and the fumaric acid, and the specific process is as follows:
60mg of Olaparib and 16mg of fumaric acid are weighed, 1mL of n-heptane and 20 mu L of isopropanol are added to obtain a suspension, the suspension is stirred for 24 hours at room temperature, the mixture is filtered, and the obtained white solid is dried in vacuum at 40 ℃ to obtain the Olaparib and fumaric acid eutectic crystal form alpha.
The results of the X-ray powder diffraction analysis of the crystalline form α of the co-crystal of olaparib and fumaric acid obtained in example 4 are shown in table 4.
TABLE 4X-ray powder diffraction data for Olaparib and fumaric acid Co-crystal form alpha of example 4
Example 5
The embodiment prepares the eutectic crystal form alpha of the Olaparib and the fumaric acid, and the specific process is as follows:
60mg of Olaparib and 16mg of fumaric acid are weighed, 1mL of methyl tertiary butyl ether and 20 mu L of methanol are added to obtain a suspension, the suspension is stirred for 24 hours at room temperature, filtration is carried out, and the obtained white solid is dried in vacuum at 40 ℃ to obtain the Olaparib and fumaric acid eutectic crystal form alpha.
The results of the X-ray powder diffraction analysis of the crystalline form α of the eutectic of olaparib and fumaric acid obtained in example 5 are shown in table 5.
TABLE 5X-ray powder diffraction data for Olaparib and fumaric acid Co-crystal form alpha of EXAMPLE 5
Example 6
The embodiment prepares the eutectic crystal form alpha of the Olaparib and the fumaric acid, and the specific process is as follows:
60mg of Olaparib and 16mg of fumaric acid are weighed, 1mL of n-heptane and 20 mu L of ethyl acetate are added to obtain a suspension, the suspension is stirred for 12 hours at room temperature, the mixture is filtered, and the obtained white solid is dried in vacuum at 40 ℃ to obtain the Olaparib and fumaric acid eutectic crystal form alpha.
Example 7
The embodiment prepares the eutectic crystal form alpha of the Olaparib and the fumaric acid, and the specific process is as follows:
60mg of Olaparib and 16mg of fumaric acid are weighed, 1mL of n-heptane and 20 mu L of acetone are added to obtain a suspension, the suspension is stirred for 12 hours at room temperature, filtration is carried out, and the obtained white solid is dried in vacuum at 40 ℃ to obtain the Olaparib and fumaric acid eutectic crystal form alpha.
Comparative example
The preparation method of the crystal form A of the Olaparib comprises the following specific processes:
300mg of Olaparib is weighed, added into 10mL of ethanol to obtain a suspension, the suspension is stirred for 12 hours at room temperature, filtered, and the obtained white solid is dried in vacuum at 40 ℃ to obtain the Olaparib crystal form A.
Test example 1 dynamic moisture adsorption analysis
The powder samples of the oxilapatinib and fumaric acid eutectic crystal form alpha prepared in example 1 and the oxilapatinib crystal form A prepared in comparative example are ground and then respectively pass through 100-mesh and 200-mesh sieves, and the particle size is controlled to be 75-150 mu m. The system was equilibrated under a nitrogen stream at 0% relative humidity using a DVS intrnsic dynamic moisture adsorber from SMS, uk, at a constant temperature of 25 c until the mass remained unchanged, and then the relative humidity was controlled from 0% to 95% and the mass change after the equilibrium of the hygroscopic gain for each relative humidity sample was recorded, 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 gain of both the olapamide and fumaric acid eutectic crystal form a and the olapamide crystal form a is lower than 0.3%, indicating that both have lower hygroscopicity.
Test example 2 stability evaluation
Powder samples of the crystalline form α of the olapamide and fumaric acid eutectic prepared in example 1 and the crystalline form a of the olapamide prepared in comparative example were placed under an accelerated stability test condition of 40 ℃/75% rh, and after 1 month, 2 months and 3 months, the crystalline phases were detected by X-ray powder diffraction (PXRD) analysis, and the results are shown in table 7.
TABLE 7 accelerated stability test results at 40 ℃/75% RH
As a result, it was found that the crystalline phases of both the oxipa and the fumaric acid eutectic crystalline form α, and the oxipa crystalline form A were stable for 3 months. Therefore, the eutectic crystal form alpha of the Olaparib and the fumaric acid and the eutectic crystal form A of the Olaparib have better stability.
Test example 3 evaluation of tabletability
The powder samples of the oxilapatinib and fumaric acid eutectic crystal form alpha prepared in example 1 and the oxilapatinib crystal form A prepared in comparative example are ground and then respectively pass through 100-mesh and 200-mesh sieves, and the particle size is controlled to be 75-150 mu m. About 50mg of the sample was weighed, pressed for 30 seconds using a 5mm round die under pressures of 50, 100, 150, 200, 250 and 300MPa, respectively, the pressed tablets were left to stand for 24 hours to release the stress, and then the diameter D and thickness t of each tablet were recorded, and the hardness F was measured using a durometer to calculate the tensile strength of each tablet by the following formula:
the results are shown in the tabletting curves of fig. 4, and it can be seen from fig. 4 that the tensile strength of the sample gradually increases with increasing pressure. The maximum tensile strength of 1.9MPa is reached when the pressure of the crystalline form α of the eutectic of olaparib and fumaric acid is increased to 150MPa, whereas the maximum tensile strength of the crystalline form a of olaparib is only 1.1MPa when the pressure is increased to 250 MPa. Therefore, compared with the fumaric acid eutectic crystal form alpha, the Olaparib crystal form A has better tabletting property, and the prepared tablet has higher tensile strength and is not easy to generate splinter.
Test example 4 pharmacokinetic testing
The oxilapatinib prepared in example 1, the fumaric acid eutectic crystal form alpha and the oxilapatinib crystal form A prepared in comparative example are respectively sieved by a 100-mesh sieve and a 200-mesh sieve after being ground, 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 Olaparib was administered by gastric lavage in a sodium carboxymethyl cellulose solution at a dose of 50mg/kg (co-crystal containing 50mg Olaparib), blood samples were collected from left or right retinal venous plexus at intervals of: 0, 10min,20min,30min,45min,1h,2h,4h,6h,8h,12h,24h. Blood samples were added to heparin sodium blood collection tubes and centrifuged at 4200rpm for 10min, and the separated plasma was stored in a-80 ℃ freezer. And 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 (medicine time curve) of each sample.
As shown in fig. 5, as can be seen from fig. 5, the maximum blood concentration of the olapamide and fumaric acid eutectic crystal form a and the maximum blood concentration of the olapamide and fumaric acid eutectic crystal form a are 2431.85 +/-383.62 ng/mL and 209.16 +/-68.57 ng/mL respectively, the area under the medicine curve is 549097.95 +/-67716.96 ng.h/mL and 90123.32 +/-26746.44 ng.h/mL respectively, and the maximum blood concentration of the olapamide and fumaric acid eutectic crystal form a and the area under the medicine curve are 11.6 times and 6.1 times of the olapamide crystal form a respectively, so that the oral bioavailability of the olapamide and the fumaric acid eutectic crystal form a is obviously better than that of the olapamide crystal form a.
The oxilapatinib and fumaric acid eutectic crystal form alpha provided by the invention can be applied to preparation of medicines for preventing and/or treating cancers, and has a wide application prospect.
While the embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
Claims (8)
1. An oxidapamide and fumaric acid eutectic crystal form alpha, which is characterized in that: the structural formula of the Olaparib and fumaric acid eutectic crystal form alpha is shown as a formula (I):
the oxilapatinib and fumaric acid eutectic crystal form alpha comprises the following components in a molar ratio of 1:1 Olaparib and fumaric acid; the X-ray powder diffraction pattern of the eutectic crystal form alpha of the Olaparib and the fumaric acid measured by Cu K alpha rays is 12.32 in diffraction angle 2 theta o 、12.55 o 、13.22 o 、14.27 o 、15.63 o 、17.22 o 、18.74 o 、19.18 o 、19.96 o 、25.97 o The position has characteristic peaks; the D (a) values correspond to 7.1781, 7.0471, 6.6915, 6.2013, 5.6648, 5.1452, 4.7312, 4.6234, 4.4448, 3.4281, respectively.
2. The crystalline co-crystal form α of olaparib and fumaric acid of claim 1, wherein: the X-ray powder diffraction pattern of the oxidapamide and fumaric acid eutectic crystal form alpha measured by Cu K alpha rays also has characteristic peaks at one or more of diffraction angles 2 theta of 6.24o, 6.56o, 7.76o, 9.42o, 20.17o, 22.15 o, 22.72o, 23.58o, 24.89o, 26.85o and 27.44 o; the D (a) values correspond to 14.1445, 13.4618, 11.3864, 9.3806, 4.3989, 4.0098, 3.9105, 3.7698, 3.5744, 3.3177, 3.2477, respectively.
3. The crystalline co-crystal form α of olaparib and fumaric acid of claim 1, wherein: the differential scanning calorimetric curve of the Olaparib and the fumaric acid eutectic crystal form alpha shows an endothermic peak at 197.4 ℃.
4. The crystalline co-crystal form α of olaparib and fumaric acid of claim 1, wherein: the infrared absorption spectrum of the oxiapamide and fumaric acid eutectic crystal form alpha has characteristic peaks at 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 >.
5. A method for preparing the crystalline form α of an eutectic of olaparib and fumaric acid according to any one of claims 1 to 4, wherein: the method comprises the following steps: adding the Olaparib and the fumaric acid into a solvent, and pulping to obtain the Olaparib and the fumaric acid eutectic crystal form alpha; the solvent is good solvent and poor solvent according to the volume ratio of 1: (5-100) a mixed solvent; the good solvent comprises any one of alcohol solvents, ester solvents and ketone solvents; the poor solvent includes any one of an ether solvent and an alkane solvent; the alcohol solvent is at least one selected from methanol, ethanol and isopropanol; the ester solvent is at least one selected from ethyl acetate and isopropyl acetate; the ketone solvent is at least one selected from acetone and methyl tertiary butyl ketone; the ether solvent is at least one selected from methyl tertiary butyl ether and tetrahydrofuran; the alkane solvent is at least one selected from n-heptane and n-hexane.
6. The method for preparing the oxipa and fumaric acid eutectic crystal form alpha according to any one of claim 5, wherein the method is characterized in that: the ratio of the total mass of the olaparib to the fumaric acid to the solvent is 1g: (10-25) mL.
7. A pharmaceutical composition comprising the crystalline co-crystal form a of olaparib and fumaric acid of any one of claims 1 to 4 and a pharmaceutically acceptable excipient.
8. Use of an olaparib and fumaric acid co-crystal form α according to any one of claims 1-4 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for the prevention and/or treatment of cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110925622.5A CN113636979B (en) | 2021-08-12 | 2021-08-12 | Olaparib and fumaric acid eutectic crystal form alpha and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110925622.5A CN113636979B (en) | 2021-08-12 | 2021-08-12 | Olaparib and fumaric acid eutectic crystal form alpha and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113636979A CN113636979A (en) | 2021-11-12 |
| CN113636979B true CN113636979B (en) | 2023-06-13 |
Family
ID=78421317
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110925622.5A Active CN113636979B (en) | 2021-08-12 | 2021-08-12 | Olaparib and fumaric acid eutectic crystal form alpha and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113636979B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056712A (en) * | 2017-06-05 | 2017-08-18 | 刘德鹏 | A kind of antineoplastic hydrate and preparation method thereof |
| WO2021125797A1 (en) * | 2019-12-20 | 2021-06-24 | 주식회사 삼양홀딩스 | Composition having improved solubility and bioavailability of olaparib |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UY30639A1 (en) * | 2006-10-17 | 2008-05-31 | Kudos Pharm Ltd | SUBSTITUTED DERIVATIVES OF 2H-FTALAZIN-1-ONA, ITS CRYSTAL FORMS, PREPARATION PROCESS AND APPLICATIONS |
| WO2016165650A1 (en) * | 2015-04-17 | 2016-10-20 | 苏州晶云药物科技有限公司 | Co-crystal of olaparib and urea and preparation method therefor |
| CN106554315A (en) * | 2015-09-28 | 2017-04-05 | 天津市汉康医药生物技术有限公司 | Stable olaparib compound |
| CZ201682A3 (en) * | 2016-02-15 | 2017-08-23 | Zentiva, K.S. | Solvated crystalline forms of olaparib, their preparation and use |
| WO2017153958A1 (en) * | 2016-03-11 | 2017-09-14 | Lupin Limited | Novel polymorphic forms and amorphous form of olaparib |
| CA3031777A1 (en) * | 2018-01-31 | 2019-07-31 | Apotex Inc. | Crystalline form of olaparib |
| WO2021044437A1 (en) * | 2019-09-04 | 2021-03-11 | Cipla Limited | Olaparib co-crystals and process of preparation thereof |
| CN111995582B (en) * | 2020-07-09 | 2021-12-03 | 天津理工大学 | Eutectic of olaparib and urea and preparation method thereof |
| CN111689905B (en) * | 2020-07-22 | 2021-12-03 | 天津理工大学 | Eutectic of olaparib and maleic acid and preparation method thereof |
| CN111825621A (en) * | 2020-07-22 | 2020-10-27 | 天津理工大学 | Eutectic of olaparib and malonic acid and preparation method thereof |
-
2021
- 2021-08-12 CN CN202110925622.5A patent/CN113636979B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056712A (en) * | 2017-06-05 | 2017-08-18 | 刘德鹏 | A kind of antineoplastic hydrate and preparation method thereof |
| WO2021125797A1 (en) * | 2019-12-20 | 2021-06-24 | 주식회사 삼양홀딩스 | Composition having improved solubility and bioavailability of olaparib |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113636979A (en) | 2021-11-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110088088B (en) | Novel crystal form of { [5- (3-chlorphenyl) -3-hydroxypyridine-2-carbonyl ] amino } acetic acid and preparation method thereof | |
| CN111094290B (en) | Crystal form of mono succinate of Ribociclib, preparation method and application thereof | |
| CN111093668A (en) | Crystal form of GSK1278863, preparation method and pharmaceutical application thereof | |
| WO2018184185A1 (en) | Ozanimod addition salt crystal, preparation method, pharmaceutical composition, and uses | |
| EP4328226A1 (en) | Tolebrutinib crystal form, amorphous form, preparation method therefor and use thereof | |
| WO2020177645A1 (en) | Upadacitinib crystal form and preparation method therefor and use thereof | |
| CA2844765A1 (en) | Polymorph of rifaximin and process for the preparation thereof | |
| CN113242855A (en) | Crystal form of taramitose, preparation method and application thereof | |
| CN112638880B (en) | Cabotinib malate crystal form and preparation method and application thereof | |
| EP4342468A1 (en) | Tolebrutinib salt and crystal form thereof, preparation method therefor, pharmaceutical composition thereof, and use thereof | |
| CN106397298B (en) | Pharmaceutical composition and purposes containing Indobufen | |
| US20220002306A1 (en) | Crystal form of upadacitinib and preparation method and use thereof | |
| WO2016097314A1 (en) | Amorphous and crystalline forms of idelalisib and process for forming the same | |
| EA035390B1 (en) | Co-precipitate of tadalafil with pharmaceutically acceptable excipients, pharmaceutical composition thereof and process for the preparation thereof | |
| EP4180435A1 (en) | Crystal form of upadacitinib, preparation method therefor, and use thereof | |
| CN113636979B (en) | Olaparib and fumaric acid eutectic crystal form alpha and preparation method and application thereof | |
| CN114163453A (en) | Lopitinib crystal form and preparation method thereof | |
| CN109464442B (en) | Sacubitril valsartan sodium pharmaceutical composition and preparation method thereof | |
| CN107245054B (en) | Amorphous bulleyaconitine A compound and preparation method thereof | |
| CA3192243A1 (en) | Crystal form of resmetirom, preparation method therefor, and use thereof | |
| CN115745894A (en) | Olaparib and oxalic acid eutectic crystal and preparation method thereof | |
| CN114174264A (en) | Crystal form XI of varlitinib mesylate and preparation method thereof | |
| CN113045554A (en) | Fexotinib crystal form and preparation method thereof | |
| CN112794854A (en) | Crystal form CSI of hemisuccinate of Ribociclib and preparation method and application thereof | |
| CN105461610A (en) | Apremilast crystal form, and preparation method, pharmaceutical composition and application 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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |