CN111995582A - Eutectic of olaparib and urea and preparation method thereof - Google Patents

Abstract

The invention discloses a co-crystal of olaparib and urea and a preparation method thereof. The molar ratio of olaparib and urea in the co-crystal is 1:2, and the 2 theta values of the co-crystal X-ray powder diffraction pattern are 6.4±0.2°, 14.3±0.2°, 15.0±0.2°, 18.6±0.2°, There are characteristic peaks at 19.2±0.2°, 24.3±0.2°, and 24.8±0.2°. The eutectic preparation method provided by the invention has the advantages of simple process, easy control of the crystallization process and good reproducibility, and is suitable for industrial production. This co-crystal has greater apparent solubility than olaparib free base, which is beneficial to improve the oral absorption efficiency of olaparib.

Description

A kind of co-crystal of olaparib and urea and preparation method thereof

technical field

The invention relates to the technical field of medicinal chemistry, in particular to a co-crystal of olaparib and urea and a preparation method thereof.

Background technique

Pharmaceutically active ingredients usually exist in crystalline forms such as polymorphs, hydrates, solvates, salts, co-crystals, and the like. For the same active pharmaceutical ingredient, different crystalline forms have different physicochemical properties. Therefore, in the pharmaceutical industry, it is of great significance to obtain suitable crystalline forms of drugs. Drugs exist in the form of co-crystals, which can improve the stability, solubility and processability of active pharmaceutical ingredients, and have significant advantages. Therefore, drug co-crystals are an effective means to improve the physicochemical properties of active pharmaceutical ingredients.

The chemical name of Olaparib 1-(cyclopropanecarbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2- Fluorobenzoyl]piperazine, its chemical structural formula is:

Olaparib, first developed by UK biotech company KuDOS (Kudos) Pharmaceuticals Ltd cell. After AstraZeneca acquired KuDOS in 2005, it continued to develop olaparib for the treatment of ovarian cancer. Olaparib was approved by the FDA in the United States in 2014. It is the first targeted drug specifically for BRCA-mutated ovarian cancer patients and is suitable for patients who have previously experienced chemotherapy. KuDOS (Kodos) Pharmaceutical Co., Ltd. disclosed the crystalline form A of olaparib in patent CN 101528714B, and disclosed the crystalline form L of olaparib in CN 101821242B. In addition, the patent CN105439961A discloses the crystal form I of olaparib, and the patent CN 105777651A discloses the crystal form B of olaparib. Olaparib is currently marketed as Form A, which has low solubility and limits the oral absorption efficiency of the drug. Patent CN105753789B discloses a co-crystal form A of olaparib and urea with a molar ratio of 1:1, but the inventor of the present invention fails to obtain the olaparib described in the patent according to the preparation method of the embodiment of patent 105753789B Cocrystal Form A of Pani and urea. We have carried out a lot of experimental research and obtained a new crystal form of olaparib and urea co-crystal with a molar ratio of 1:2, and significantly improved the solubility of olaparib.

SUMMARY OF THE INVENTION

One of the objects of the present invention is to provide a co-crystal of olaparib and urea; the second object of the present invention is to provide a preparation method of this co-crystal of olaparib and urea; the third object of the present invention is to provide this Application of olaparib and urea co-crystals.

After a large number of experimental studies, the inventors tried to conduct co-crystal screening experiments of olaparib with oxalic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, fumaric acid, urea, etc., Finally, the co-crystal of olaparib with oxalic acid, fumaric acid and urea was successfully discovered, which can effectively improve the solubility of olaparib and provide a material basis for improving the oral absorption efficiency of olaparib.

The technical scheme adopted by the present invention is:

The invention provides a co-crystal of olaparib and urea.

A kind of olaparib and urea co-crystal, the structural formula of this co-crystal is as shown in formula (I):

In this co-crystal, the molar ratio of olaparib and urea is 1:2; the X-ray powder diffraction pattern of this co-crystal measured by Cu Kα rays is 6.4±0.2°, 14.3±0.2°, 15.0 There are characteristic peaks at ±0.2°, 18.6±0.2°, 19.2±0.2°, 24.3±0.2°, and 24.8±0.2°.

Preferably, the X-ray powder diffraction pattern of the olaparib and urea co-crystal measured by Cu Kα rays also has 2 theta values of 8.9±0.2°, 12.5±0.2°, 17.4±0.2°, 18.3±0.2°, One or more of 20.0±0.2°, 22.4±0.2°, 26.3±0.2°, and 30.5±0.2° have characteristic peaks.

The present invention provides a preparation method of the olaparib and urea co-crystal.

A method for preparing a co-crystal of olaparib and urea comprises the following steps: feeding olaparib and urea in a molar ratio of 1:2, adding an appropriate amount of solvent, and then stirring or grinding to obtain a co-crystal.

Preferably, in the preparation method of this co-crystal, the solvent is at least one of alcohol solvents, ester solvents, ketone solvents, ether solvents, nitrile solvents, and alkane solvents. Wherein, alcohol solvents include but are not limited to methanol, ethanol, propanol, butanol; ester solvents include but are not limited to ethyl acetate and isopropyl acetate; ketone solvents include but are not limited to acetone; ether solvents include but are not limited to Limited to isopropyl ether, methyl tert-butyl ether; nitrile solvents include but not limited to acetonitrile; alkane solvents include but are not limited to n-heptane; further preferably, the solvent is selected from methanol, ethanol, ethyl acetate, acetone, isopropyl alcohol One or more of propyl ether and n-heptane.

Preferably, in the preparation method of this co-crystal, the ratio of the total mass of olaparib and urea to the amount of solvent during stirring is 1 g: (4-20) mL; the total mass of olaparib and urea during grinding is the same as The dosage ratio of the solvent is 1 g:(100-200) μL.

In some preferred embodiments of the present invention, the preparation method of this co-crystal is specifically: feeding olaparib and urea according to a molar ratio of 1:2, adding a solvent, stirring, filtering, and drying the obtained solid product to obtain Eutectic.

In other preferred embodiments of the present invention, the preparation method of the co-crystal is as follows: feeding olaparib and urea in a molar ratio of 1:2, adding a solvent and grinding to obtain a co-crystal.

Preferably, in the preparation method of this co-crystal, the ratio of the total mass of olaparib and urea to the amount of solvent used during stirring is 1 g: (4-20) mL.

Preferably, in the preparation method of this co-crystal, the ratio of the total mass of olaparib and urea to the amount of solvent used during grinding is 1 g: (100-200) μL.

The present invention provides a pharmaceutical composition comprising the co-crystal of olaparib and urea and a pharmaceutically acceptable excipient.

In the present invention, pharmaceutically acceptable excipients refer to pharmaceutically acceptable materials, mixtures or vehicles that are related to the consistency of dosage forms or pharmaceutical compositions. Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form chosen. Furthermore, pharmaceutically acceptable excipients can be selected based on their particular 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 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.

The present invention also provides the application of the olaparib-urea co-crystal in the preparation of a medicament for preventing and/or treating cancer.

The beneficial effects of the present invention are:

The present invention converts olaparib into a brand-new olaparib-urea co-crystal for the first time, and the olaparib-urea co-crystal has higher apparent solubility than olaparib crystal form A. The oral absorption efficiency of olaparib provides a material basis.

The preparation method of the olaparib-urea cocrystal disclosed by the invention has simple process, easy control of the crystallization process, good reproducibility, and is suitable for industrial production.

The co-crystal of olaparib and urea of the present invention has broad application prospects in preparing medicines for preventing and/or treating cancer.

Description of drawings

Fig. 1 is the X-ray powder diffractogram of the olaparib and urea eutectic obtained in Example 1;

Fig. 2 is the differential scanning calorimetry analysis figure of the olaparib and urea co-crystal obtained in Example 1;

Fig. 3 is the thermogravimetric analysis figure of the olaparib and urea co-crystal obtained in Example 1;

Fig. 4 is the Fourier transform infrared spectrogram of the olaparib and urea eutectic obtained in Example 1;

Fig. 5 is the hydrogen nuclear magnetic resonance spectrogram of the olaparib and urea co-crystal obtained in Example 1;

Fig. 6 is the powder dissolution curve diagram of olaparib and urea co-crystal and olaparib crystal form A prepared in Example 1;

Detailed ways

The content of the present invention will be further described in detail below through specific embodiments. The raw materials used in the examples can be obtained from conventional commercial channels unless otherwise specified.

Example 1

Weigh 1000 mg of olaparib and 276 mg of urea, add 15 mL of ethyl acetate to obtain a suspension, stir the suspension at room temperature for 1 h, filter, and dry the obtained white solid at 40 ° C to obtain olaparib and urea Solid sample of co-crystal in 84% yield.

Example 2

Weigh 60 mg of olaparib and 16.5 mg of urea, add 1 mL of isopropyl acetate to obtain a suspension, stir the suspension at room temperature for 12 h, filter, and dry the obtained white solid at 40 ° C to obtain olaparib Solid samples of co-crystals with urea.

Example 3

Weigh 60 mg of olaparib and 16.5 mg of urea into a ball milling jar, then add 20 μL of ethanol, and grind at 20 Hz for 30 min. The obtained white solid is dried at 40 °C to obtain a solid sample of olaparib and urea co-crystal.

Example 4

Weigh 60 mg of olaparib and 16.5 mg of urea and add them to 1 mL of acetone to obtain a suspension. The suspension is stirred at room temperature for 12 h, filtered, and the obtained white solid is dried at 40 ° C to obtain a mixture of olaparib and urea. crystalline solid samples.

Example 5

Weigh 60 mg of olaparib and 16.5 mg of urea into a ball milling jar, then add 20 μL of methanol, and grind at 20 Hz for 30 min. The obtained white solid is dried at 40 °C to obtain a solid sample of olaparib and urea co-crystal.

Example 6

Weigh 60 mg of olaparib and 16.5 mg of urea, add them to a ball mill, then add 20 μL of n-butanol, grind at 20 Hz for 30 min, and dry the obtained white solid at 40 ° C to obtain a solid of olaparib and urea co-crystal sample.

Example 7

Weigh 120 mg of olaparib and 33 mg of urea, add 1 mL of ethyl acetate to obtain a suspension, stir the suspension at room temperature for 1 h, filter, and dry the obtained white solid at 40 ° C to obtain olaparib and urea Eutectic solid samples.

Example 8

Weigh 60 mg of olaparib and 16.5 mg of urea, add them to 1 mL of isopropyl ether to obtain a suspension, stir the suspension at room temperature for 12 h, filter, and dry the obtained white solid at 40 ° C to obtain olaparib and Solid sample of urea co-crystal.

Characterization Analysis

The co-crystal of olaparib and urea provided by the invention is characterized by methods such as X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared spectroscopy, hydrogen nuclear magnetic resonance spectroscopy and the like.

电压为40千伏，电流为15毫安，步长0.01°，扫描速度20°/min，扫描范围5.0～40.0°，测试温度为室温。其分析结果见附图1的X射线粉末衍射图，X射线粉末衍射数据如表1所示。The solid sample of the olaparib and urea co-crystal prepared in Example 1 was subjected to X-ray powder diffraction analysis, using a Rigaku MiniFlex 600 diffractometer of Japan Rigaku Co., Ltd., Cu Kα rays

The voltage is 40 kV, the current is 15 mA, the step size is 0.01°, the scanning speed is 20°/min, the scanning range is 5.0-40.0°, and the test temperature is room temperature. 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 1 The X-ray powder diffraction data of olaparib and urea co-crystal of Example 1

Based on the same X-ray powder diffraction test method as in Example 1, the X-ray powder diffraction data of the solid sample of olaparib and urea co-crystal prepared in Example 2 are shown in Table 2.

The olaparib and urea eutectic X-ray powder diffraction data of table 2 embodiment 2

Based on the same X-ray powder diffraction test method as in Example 1, the X-ray powder diffraction data of the solid sample of the co-crystal of olaparib and urea prepared in Example 3 are shown in Table 3.

The olaparib and urea co-crystal X-ray powder diffraction data of table 3 embodiment 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 pattern will generally vary with the testing conditions of the instrument. In particular, the relative intensities of X-ray diffraction patterns may vary with experimental conditions, so the relative intensity order of X-ray diffraction peaks cannot be used as the sole or decisive factor for the characterization of crystalline substances. In addition, the peak angle is usually allowed to have an error of ±0.2°. Due to the influence of experimental factors such as sample height and test temperature, the overall peak angle will be shifted, and a certain shift is usually allowed. Therefore, those skilled in the art can understand that the X-ray diffraction pattern of the co-crystal of olaparib and urea described in the present invention does not have to be completely consistent with the X-ray diffraction pattern in this example, and any X-ray diffraction pattern with the The case where the characteristic peaks are the same or similar all fall within the scope of the present invention. Those skilled in the art can compare the spectrum listed in the present invention with that of an unknown substance to confirm that the unknown substance is or is not the co-crystal of olaparib and urea described in the present invention.

Differential scanning calorimetry analysis was carried out on the solid sample of the olaparib and urea co-crystal prepared in Example 1, which was detected by a DSC 214 differential calorimeter of NETZSCH Scientific Instrument Co., Ltd., the atmosphere was nitrogen, and the temperature was increased. The rate was 10°C/min. The analysis results are shown in the differential scanning calorimetry analysis diagram of FIG. 2 . As shown in Figure 2, no obvious endothermic or exothermic phenomena were found for the olaparib-urea co-crystal before thermal decomposition.

The solid sample of the olaparib and urea eutectic obtained in Example 1 was subjected to thermogravimetric analysis, using a TG209 F3 type thermogravimetric analyzer from Germany NETZSCH Scientific Instruments Co., Ltd., the atmosphere was nitrogen, and the heating rate was 10°C/ min. The analysis results are shown in the thermogravimetric analysis diagram of FIG. 3 . As shown in Figure 3, the olaparib and urea co-crystals were heated to around 170°C and began to decompose, and there was no weight loss before this temperature.

The olaparib and urea co-crystal sample prepared in Example 1 was analyzed by infrared spectrum, and it was detected by ALPHA II Fourier transform infrared spectrometer of Bruker Company, and the detection range was 4000～500cm ^-1 , and the analysis results are shown in the appendix. Figure 4. Fourier transform infrared spectrogram. It can be seen from Figure 4 that the characteristic peak positions of its infrared spectrum are (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 olaparib and urea eutectic samples prepared in Example 1 were subjected to hydrogen nuclear magnetic resonance spectrum analysis, and were detected by the Avance III 400M nuclear magnetic resonance spectrometer of German Bruker company. . As shown in Figure 5, the peaks of olaparib are: ¹ H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.27 (d, J=7.1 Hz, 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 Hz, 1H), 0.73 (t, J=6.5 Hz, 4H). The peaks for urea are: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.72-5.17 (m, 8H). According to the integration results of the characteristic peaks, the stoichiometric ratio of olaparib and urea in the cocrystal is 1:2.

Solubility evaluation

The powder dissolution data of olaparib and urea co-crystal and olaparib crystal form A were compared.

The source of the tested sample: the co-crystal of olaparib and urea was prepared by the method provided in Example 1 of the present invention; the crystal form A of olaparib was purchased from Shanghai Shengde Pharmaceutical Technology Co., Ltd., with a purity of 99%.

Powder dissolution test method: The co-crystal of olaparib and urea and olaparib crystal form A were ground and passed through 100 and 200 mesh sieves respectively, and the particle size of the powder was controlled to be 75-150 μm. Weigh 90 mg of olaparib crystal form A, 115 mg of olaparib and urea co-crystal, add them to 30 mL of dissolution medium, take 0.2 mL of the solution at regular intervals, filter through a 0.45 μm microporous membrane, and dilute to an appropriate level. The drug concentration at each time point was monitored by high performance liquid chromatography, and the powder dissolution curve of each sample was finally obtained.

Powder dissolution conditions:

Dissolution medium: disodium hydrogen phosphate-sodium dihydrogen phosphate buffer solution at pH 6.8;

Stirring speed: 100 rpm;

Dissolution temperature: 37±0.5℃;

Sampling time: 0.5, 1, 2, 5, 10, 15, 30, 45, 60, 75, 90, 120, 180 minutes;

Liquid phase conditions:

Instrument: SHIMADZU LC-2030C 3D;

Chromatographic column: Inertsil ODS C18 column (4.6mm×150mm, 5μm);

UV detection wavelength: 276nm;

Mobile phase: acetonitrile: water = 30:70;

Column temperature: 35℃;

Flow rate: 1mL/min;

Injection volume: 10 μL.

The experimental results are shown in the powder dissolution curve diagram of FIG. 6 . As shown in Figure 6, the maximum apparent solubility of olaparib Form A and olaparib-urea co-crystals were 69.14±4.85 and 170.69±35.38 μg/mL, respectively. It can be seen that the apparent solubility of the co-crystal of olaparib and urea is unexpectedly significantly better than that of the olaparib crystal form A, and its value is 2.5 times that of the olaparib crystal form A.

The co-crystal of olaparib and urea provided by the invention can be used for preparing medicines for preventing and/or treating cancer, and has broad application prospects.

The above-mentioned embodiment is an embodiment with better effect of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, combinations made without departing from the spirit and principle of the present invention , simplification, all should be equivalent replacement modes, and are all included in the protection scope of the present invention.

Claims (8)

1. a co-crystal of olaparib and urea, is characterized in that: the structural formula of described co-crystal is as shown in formula (I):

In the co-crystal, the molar ratio of olaparib and urea is 1:2; the X-ray powder diffraction pattern of the co-crystal measured by Cu Kα rays has 2 theta values of 6.4±0.2°, 14.3±0.2°, There are characteristic peaks at 15.0±0.2°, 18.6±0.2°, 19.2±0.2°, 24.3±0.2°, and 24.8±0.2°. 2. The co-crystal according to claim 1, wherein the X-ray powder diffraction pattern of the co-crystal also has 2 theta values of 8.9±0.2°, 12.5±0.2°, 17.4±0.2°, 18.3±0.2° , 20.0±0.2°, 22.4±0.2°, 26.3±0.2°, 30.5±0.2° have characteristic peaks at one or more places. 3. the preparation method of the described co-crystal in any one of claim 1～2, it is characterized in that: comprising the steps, olaparib and urea are fed according to mol ratio 1: 2, add an appropriate amount of solvent, then pass Stir or grind to obtain co-crystals. 4 . The preparation method according to claim 3 , wherein the solvent is at least one of alcohol-based solvents, ester-based solvents, ketone-based solvents, ether-based solvents, nitrile-based solvents, and alkane-based solvents. 5 . 5 . The preparation method according to claim 3 , wherein: during the stirring, the ratio of the total mass of olaparib and urea to the amount of solvent used is 1 g: (4～20) mL. 6 . 6 . The preparation method according to claim 3 , wherein, during the grinding, the ratio of the total mass of olaparib and urea to the amount of solvent used is 1 g: (100-200) μL. 7 . 7. A pharmaceutical composition, characterized in that it comprises the co-crystal according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient. 8. The use of the co-crystal according to any one of claims 1 to 2 in a drug for the treatment of cancer.

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