CN111995582B - Eutectic of olaparib and urea and preparation method thereof - Google Patents
Eutectic of olaparib and urea and preparation method thereof Download PDFInfo
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- CN111995582B CN111995582B CN202010654160.3A CN202010654160A CN111995582B CN 111995582 B CN111995582 B CN 111995582B CN 202010654160 A CN202010654160 A CN 202010654160A CN 111995582 B CN111995582 B CN 111995582B
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Abstract
The invention discloses an olaparib and urea eutectic crystal and a preparation method thereof. The molar ratio of olaparib to urea in the eutectic is 1: 2, and the X-ray powder diffraction pattern of the eutectic has characteristic peaks at 2theta values of 6.4 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.0 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.2 +/-0.2 degrees, 24.3 +/-0.2 degrees and 24.8 +/-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 urea 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.
The chemical name of Olaparib (Olaparib) is 1- (cyclopropylformyl) -4- [5- [ (3, 4-dihydro-4-oxo-1-phthalazinyl) methyl ] -2-fluorobenzoyl ] piperazine, which has the chemical structural 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 CN 105439961a 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 with a molar ratio of 1: 1, however, the inventor of the present invention fails to obtain the eutectic crystal form a of olaparib and urea described in the patent according to the preparation method of the patent 105753789B. A large number of experimental researches are carried out, a new crystal form of the eutectic of the olaparib and the urea with the molar ratio of 1: 2 is obtained, and the solubility of the olaparib is obviously improved.
Disclosure of Invention
One of the purposes of the invention is to provide an Olaparib and urea eutectic crystal; the second purpose of the invention is to provide a preparation method of the eutectic crystal of the olaparib and the urea; the invention also aims to provide application of the eutectic crystal of the olaparib and the urea.
Through a large number of experimental researches, the inventor tries to perform a eutectic screening experiment on olaparib, oxalic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, fumaric acid, urea and the like, and finally successfully finds the eutectic of olaparib, oxalic acid, fumaric acid and urea, 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 urea eutectic crystal.
An olaparib and urea eutectic crystal has a structural formula shown in formula (I):
in the eutectic, the molar ratio of the olaparib to the urea is 1: 2; the eutectic has characteristic peaks at 2theta values of 6.4 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.0 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.2 +/-0.2 degrees, 24.3 +/-0.2 degrees and 24.8 +/-0.2 degrees in an X-ray powder diffraction pattern measured by Cu Kalpha rays.
Preferably, the Olaparib and urea eutectic also has characteristic peaks at one or more of 2theta values of 8.9 +/-0.2 degrees, 12.5 +/-0.2 degrees, 17.4 +/-0.2 degrees, 18.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 22.4 +/-0.2 degrees, 26.3 +/-0.2 degrees and 30.5 +/-0.2 degrees, measured by an X-ray powder diffraction pattern of Cu Kalpha ray.
The invention provides a preparation method of the eutectic of olaparib and urea.
A preparation method of an olaparib and urea eutectic crystal comprises the following steps: feeding the olaparib and the urea according to the molar ratio of 1: 2, 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 methanol, ethanol, propanol, butanol; 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, isopropyl ether, methyl tert-butyl ether; nitrile solvents include, but are not limited to, acetonitrile; alkane solvents include, but are not limited to, n-heptane; further preferably, the solvent is selected from one or more of methanol, 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 urea to the amount of the solvent is 1g to (4-20) mL during stirring; the total mass of the olaparib and the urea 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 urea according to the molar ratio of 1: 2, 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 urea according to the molar ratio of 1: 2, adding a solvent, and grinding to obtain the eutectic crystal.
Preferably, in the preparation method of the eutectic crystal, the ratio of the total mass of the olaparib and the urea to the using 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 urea 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 eutectic crystal of the olaparib and urea 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 eutectic crystal of olaparib and urea 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 urea for the first time, the olaparib and the urea eutectic have higher apparent solubility than the crystal form A of the olaparib, and a material basis is provided for improving the oral absorption efficiency of the olaparib.
The preparation method of the eutectic of olaparib and urea 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 urea 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 eutectic of Olaparib and urea prepared in example 1;
FIG. 2 is a differential scanning calorimetry trace of the eutectic crystal of Olaparib and urea obtained in example 1;
FIG. 3 is a thermogravimetric analysis chart of the eutectic of Olaparib and urea prepared in example 1;
FIG. 4 is a Fourier transform infrared spectrum of the eutectic of Olaparib and urea prepared in example 1;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the Olaparib and urea eutectic obtained in example 1;
FIG. 6 is a powder dissolution profile of the Olaparib and urea 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
1000mg of olaparib and 276mg of urea are weighed and added into 15mL of ethyl acetate to obtain a suspension, the suspension is placed at room temperature and stirred for 1h, the suspension is filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of the olaparib and the urea, wherein the yield is 84%.
Example 2
60mg of olaparib and 16.5mg of urea are weighed and added into 1mL of isopropyl acetate to obtain a suspension, the suspension is placed at room temperature and stirred for 12h, the suspension is filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic of the olaparib and the urea.
Example 3
Weighing 60mg of olaparib and 16.5mg of urea, adding the weighed materials into a ball milling tank, then adding 20 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 crystal of the olaparib and the urea.
Example 4
60mg of olaparib and 16.5mg of urea are weighed and added into 1mL of acetone 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 at 40 ℃ to obtain a solid sample of the eutectic crystal of the olaparib and the urea.
Example 5
Weighing 60mg of olaparib and 16.5mg of urea, adding the weighed materials into a ball milling tank, then adding 20 mu L of methanol, grinding for 30min at the frequency of 20Hz, and drying the obtained white solid at 40 ℃ to obtain a solid sample of the eutectic crystal of the olaparib and the urea.
Example 6
Weighing 60mg of olaparib and 16.5mg of urea, adding the weighed materials into a ball milling tank, then adding 20 mu L of n-butyl alcohol, 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 the olaparib and the urea.
Example 7
Weighing 120mg of olaparib and 33mg of urea, adding the weighed materials into 1mL of ethyl acetate to obtain a suspension, placing the suspension at room temperature, stirring for 1h, filtering, and drying the obtained white solid at 40 ℃ to obtain a solid sample of the olaparib and urea eutectic.
Example 8
60mg of olaparib and 16.5mg of urea are weighed and added into 1mL of isopropyl ether 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 at 40 ℃ to obtain a solid sample of the eutectic of the olaparib and the urea.
Characterization analysis
The invention provides an olaparib and urea 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 urea 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 1 opaboni and urea co-crystal X-ray powder diffraction data for example 1
The X-ray powder diffraction data of the solid sample of the olaparib co-crystal with urea prepared in example 2 based on the same X-ray powder diffraction test method as example 1 are shown in table 2.
Table 2 opaboni and urea co-crystal X-ray powder diffraction data of example 2
The X-ray powder diffraction data of the solid sample of the olaparib co-crystal with urea prepared in example 3 based on the same X-ray powder diffraction test method as example 1 are shown in table 3.
Table 3 opabonib and urea co-crystal X-ray powder diffraction data for 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 olaparib and urea cocrystal according to the present invention does not necessarily correspond exactly to the X-ray diffraction pattern in the present example, and any situation having the same or similar characteristic peaks in this pattern is within the scope of the present invention. The skilled person will be able to compare the profile listed in the present invention with a profile of an unknown substance to verify whether the unknown substance is or is not the olaparib co-crystal with urea according to the present invention.
Differential scanning calorimetry was performed on a solid sample of the olaparib co-crystal with urea prepared in example 1, which was measured by a differential calorimeter of type DSC 214 of german seiki scientific instruments ltd, under nitrogen, at a temperature rise rate of 10 ℃/min. The analysis result is shown in the differential scanning calorimetry diagram of figure 2. As shown in fig. 2, no significant endothermic or exothermic phenomena were observed before thermal decomposition of the olaparib eutectic with urea.
The solid sample of the olaparib and urea eutectic obtained in example 1 was subjected to thermogravimetric analysis using a model TG 209F 3 from german seikh 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 urea heated to around 170 ℃ started to decompose and there was no weight loss until this temperature.
The sample of the eutectic olaparib and urea prepared in example 1 was subjected toPerforming infrared spectrum analysis, wherein the detection is performed by adopting an ALPHA II Fourier transform infrared spectrometer of Bruker company, and the detection range is 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)：3452、3404、3350、 3197、2898、2868、1662、1617、1464、1444、1359、1342、1290、1217、1198、1173、1034、 1013、941、848、826、808、791、771、744、684、646、606、582、562、536、509。
The sample of the eutectic of olaparib and urea prepared in example 1 was analyzed by nmr spectroscopy, and detected by an Avance III 400M nmr spectrometer, Bruker, germany, and the analysis result thereof is shown in the nmr spectroscopy of fig. 5. As shown in fig. 5, the peaks of olaparib are:1h NMR (400MHz, DMSO-d6) δ 12.62(s, 1H), 8.27(d, J ═ 7.1Hz, 1H), 7.97(d, J ═ 7.8Hz, 1H), 7.90(t, J ═ 7.3Hz, 1H), 7.84(t, J ═ 7.1Hz, 1H), 7.51-7.42(m, 1H), 7.38(s, 1H), 7.25(t, J ═ 9.0Hz, 1H), 4.34(s, 2H), 3.64(dd, J ═ 59.8, 25.7Hz, 5H), 3.39(s, 1H), 3.20(d, J ═ 26.3Hz, 2H), 1.95(d, J ═ 36.4, 1H), 0.73(t, 6.5H), 1.4H). The urea peaks are:1H NMR(400MHz，DMSO- d6) Delta 5.72-5.17(m, 8H). From the integration results of the characteristic peaks, it is found that the stoichiometric ratio of olaparib and urea in the co-crystal is 1: 2.
Evaluation of solubility
And carrying out comparative study on the dissolution data of the Olaparib and urea eutectic and the powder of the Olaparib crystal form A.
The source of the test sample is: the olaparib and urea 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 urea 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, 115mg of the olaparib and urea 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 urea are 69.14 ± 4.85 and 170.69 ± 35.38 μ g/mL, respectively. It can be seen that the apparent solubility of the eutectic of olaparib and urea is unexpectedly and significantly better than that of the crystal form a of olaparib, and the value of the eutectic reaches 2.5 times that of the crystal form a of olaparib.
The Olaparib and urea eutectic provided by the invention can be applied to preparation of a medicament for preventing and/or treating cancer, 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 urea 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 the olaparib to the urea is 1: 2; the eutectic has characteristic peaks at 2theta values of 6.4 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.0 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.2 +/-0.2 degrees, 24.3 +/-0.2 degrees and 24.8 +/-0.2 degrees in 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 8.9 +/-0.2 degrees, 12.5 +/-0.2 degrees, 17.4 +/-0.2 degrees, 18.3 +/-0.2 degrees, 20.0 +/-0.2 degrees, 22.4 +/-0.2 degrees, 26.3 +/-0.2 degrees and 30.5 +/-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 urea according to the molar ratio of 1: 2, 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 urea 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 urea 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 the manufacture of a medicament for the treatment of cancer.
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| CN113636979B (en) * | 2021-08-12 | 2023-06-13 | 天津理工大学 | Olaparib and fumaric acid eutectic crystal form alpha and preparation method and application thereof |
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