CN111689905A

CN111689905A - Eutectic of olaparib and maleic acid and preparation method thereof

Info

Publication number: CN111689905A
Application number: CN202010708667.2A
Authority: CN
Inventors: 陈嘉媚; 吕文婷; 戴霞林
Original assignee: Tianjin University of Technology
Current assignee: Tianjin University of Technology
Priority date: 2020-07-22
Filing date: 2020-07-22
Publication date: 2020-09-22
Anticipated expiration: 2040-07-22
Also published as: CN111689905B

Abstract

The invention discloses an olaparib and maleic acid eutectic crystal and a preparation method thereof. The molar ratio of olaparib to maleic acid in the eutectic is 1: 1, and the X-ray powder diffraction pattern of the eutectic has characteristic peaks at 2theta values of 5.1 +/-0.2 degrees, 9.8 +/-0.2 degrees, 13.7 +/-0.2 degrees, 16.0 +/-0.2 degrees, 17.7 +/-0.2 degrees and 20.0 +/-0.2 degrees. The preparation method of the eutectic crystal provided by the invention has the advantages of simple process, easy control of the crystallization process, good reproducibility and suitability for industrial production. Compared with the free base of Olaparib, the eutectic has larger apparent solubility, and is beneficial to improving the oral absorption efficiency of Olaparib.

Description

Eutectic of olaparib and maleic acid and preparation method thereof

Technical Field

The invention relates to the technical field of medicinal chemistry, in particular to an olaparib and maleic acid eutectic crystal and a preparation method thereof.

Background

The pharmaceutically active ingredient is usually present in crystalline forms, such as polymorphs, hydrates, solvates, salts, co-crystals and the like. Different crystalline forms have different physicochemical properties for the same pharmaceutically active ingredient. Therefore, obtaining a suitable crystalline form of a drug is of great importance in the pharmaceutical industry. The medicament exists in a eutectic form, can improve the stability, solubility, processability and the like of active ingredients of the medicament, and has remarkable advantages. Therefore, the pharmaceutical co-crystal is an effective means for improving the physicochemical properties of the active ingredients of the drugs.

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 CN105439961A discloses crystal form I of olaparib, and patent CN 105777651a discloses crystal form B of olaparib. Currently, olaparib is marketed as crystal form a, which has low solubility and limits the oral absorption efficiency of the drug. Patent CN 105753789B discloses a eutectic crystal form a of olaparib and urea, however, the inventors of the present invention have repeated the preparation method of the embodiment of patent 105753789B, and have failed to obtain the eutectic crystal form a of olaparib and urea described in the patent. In order to improve the solubility of olaparib, a large number of eutectic screens are carried out to obtain an olaparib and maleic acid eutectic, so that the solubility of olaparib can be effectively improved.

Disclosure of Invention

One of the purposes of the invention is to provide an olaparib and maleic acid eutectic crystal; the second purpose of the invention is to provide a preparation method of the eutectic crystal of olaparib and maleic acid; the invention also aims to provide application of the eutectic crystal of the olaparib and the maleic acid.

Through a large number of experimental researches, the inventor tries to perform a eutectic screening experiment on olaparib, maleic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid and the like, and finally successfully finds the eutectic of olaparib, maleic acid and malonic acid, can effectively improve the solubility of olaparib, and provides a material basis for improving the oral absorption efficiency of olaparib.

The technical scheme adopted by the invention is as follows:

the invention provides an olaparib and maleic acid eutectic crystal.

An olaparib and maleic acid eutectic crystal has a structural formula shown in formula (I):

in the eutectic, the molar ratio of the olaparib to the maleic acid is 1: 1; the eutectic has characteristic peaks at 2theta values of 5.1 +/-0.2 degrees, 9.8 +/-0.2 degrees, 13.7 +/-0.2 degrees, 16.0 +/-0.2 degrees, 17.7 +/-0.2 degrees and 20.0 +/-0.2 degrees in an X-ray powder diffraction pattern measured by Cu Kalpha rays.

Preferably, the X-ray powder diffraction pattern of the eutectic crystal of olaparib and maleic acid measured by Cu Ka ray also has characteristic peaks at one or more of 2theta values of 7.0 +/-0.2 degrees, 13.0 +/-0.2 degrees, 25.7 +/-0.2 degrees and 26.3 +/-0.2 degrees.

The invention provides a preparation method of the eutectic crystal of olaparib and maleic acid.

A preparation method of an olaparib and maleic acid eutectic crystal comprises the following steps: feeding the olaparib and the maleic acid according to the molar ratio of 1: 1, adding a proper amount of solvent, and stirring or grinding to obtain the eutectic crystal.

Preferably, in the method for preparing the co-crystal, the solvent is at least one of an alcohol solvent, an ester solvent, a ketone solvent, an ether solvent, a nitrile solvent, and an alkane solvent. Wherein, the alcohol solvent includes but is not limited to ethanol, isopropanol; 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, anisole; nitrile solvents include, but are not limited to, acetonitrile; alkane solvents include, but are not limited to, n-heptane, n-hexane; further preferably, the solvent is selected from one or more of ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetone, isopropyl ether, anisole, n-hexane and n-heptane.

Preferably, in the preparation method of the eutectic, the ratio of the total mass of the olaparib and the maleic acid to the amount of the solvent is 1g to (4-20) mL during stirring; the total mass of the olaparib and the maleic acid and the dosage of the solvent are 1g to (100-200) mu L during grinding.

In some preferred embodiments of the present invention, the preparation method of the eutectic is specifically as follows: feeding the olaparib and the maleic acid according to a molar ratio of 1: 1, adding the solvent, stirring, filtering, and drying the obtained solid product to obtain the eutectic crystal.

In other preferred embodiments of the present invention, the preparation method of the eutectic is specifically: feeding the olaparib and the maleic acid according to the molar ratio of 1: 1, 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 maleic acid 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 maleic acid to the using amount of the solvent during grinding is 1g to (100-200) mu L.

The invention provides a pharmaceutical composition, which comprises the eutectic crystal of the olaparib and maleic acid and a pharmaceutically acceptable excipient.

In the present invention, the pharmaceutically acceptable excipient refers to a pharmaceutically acceptable material, mixture or solvent related to the consistency of the administration form or pharmaceutical composition. Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition.

Preferably, the pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers.

The invention also provides application of the co-crystal of olaparib and maleic acid in preparing a medicament for preventing and/or treating cancer.

The invention has the beneficial effects that:

according to the invention, the olaparib is firstly converted into a brand-new eutectic of the olaparib and the maleic acid, the olaparib and the maleic acid 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 maleic acid disclosed by the invention is simple in process, easy to control the crystallization process, good in reproducibility and suitable for industrial production.

The co-crystal of olaparib and maleic acid has wide application prospect in preparing medicaments for preventing and/or treating cancers.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of a cocrystal of Olaparib and maleic acid obtained in example 1;

FIG. 2 is a differential scanning calorimetry trace of a cocrystal of Olaparib and maleic acid obtained in example 1;

fig. 3 is a graph showing thermogravimetric analysis of the eutectic of olaparib and maleic acid obtained in example 1;

FIG. 4 is a Fourier transform infrared spectrum of a cocrystal of Olaparib and maleic acid obtained in example 1;

FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of a cocrystal of Olaparib and maleic acid obtained in example 1;

fig. 6 is a powder dissolution profile of the olaparib and maleic acid co-crystal, olaparib form a, prepared in example 1;

Detailed Description

The present invention will be described in further detail with reference to specific examples. The starting materials used in the examples are, unless otherwise specified, commercially available from conventional sources.

Example 1

900mg of olaparib and 240mg of maleic acid are weighed, added into 15mL of n-heptane and 250 μ L of ethanol to obtain a suspension, the suspension is placed at room temperature and stirred for 3h, filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of olaparib and maleic acid, wherein the yield is 93.0%.

Example 2

60mg of olaparib and 16mg of maleic acid are weighed, 1mL of anisole and 10 muL of ethanol are added 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 olaparib and maleic acid eutectic.

Example 3

60mg of olaparib and 16mg of maleic acid are weighed, added into a ball milling tank, then 10 mu L of ethanol is added, grinding is carried out for 30min at the frequency of 20Hz, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of the olaparib and the maleic acid.

Example 4

60mg of olaparib and 16mg of maleic acid are weighed, 1mL of isopropyl ether and 10 μ L of ethanol are added 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 olaparib and maleic acid eutectic.

Example 5

60mg of olaparib and 16mg of maleic acid are weighed, added into 1mL of n-hexane and 10 muL of ethanol to obtain a suspension, the suspension is placed at room temperature and stirred for 12 hours, filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of olaparib and maleic acid.

Example 6

60mg of olaparib and 16mg of maleic acid are weighed, added into 1mL of n-heptane and 10 muL of ethanol to obtain a suspension, the suspension is placed at room temperature and stirred for 3h, filtered, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of olaparib and maleic acid.

Example 7

60mg of olaparib and 16mg of maleic acid are weighed, added into a ball milling tank, then 10 mu L of acetonitrile is added, grinding is carried out for 30min at the frequency of 20Hz, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of the olaparib and the maleic acid.

Example 8

60mg of olaparib and 16mg of maleic acid are weighed, added into a ball milling tank, then 10 mu L of acetone is added, the mixture is ground for 30min at the frequency of 20Hz, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of the olaparib and the maleic acid.

Example 9

60mg of olaparib and 16mg of maleic acid are weighed, added into a ball milling tank, then 10 mu L of isopropanol is added, grinding is carried out for 30min at the frequency of 20Hz, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of the olaparib and the maleic acid.

Example 10

60mg of olaparib and 16mg of maleic acid are weighed, added into a ball milling tank, then 10 mu L of ethyl acetate is added, the mixture is ground for 30min at the frequency of 20Hz, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of the olaparib and the maleic acid.

Example 11

60mg of olaparib and 16mg of maleic acid are weighed and added into a ball milling tank, then 10 mu L of isopropyl acetate is added, grinding is carried out for 30min at the frequency of 20Hz, and the obtained white solid is dried at 40 ℃ to obtain a solid sample of the eutectic crystal of olaparib and maleic acid.

Characterization analysis

The invention provides an olaparib and maleic acid eutectic which is characterized by methods such as X-ray powder diffraction, differential scanning calorimetry analysis, thermogravimetric analysis, Fourier transform infrared spectroscopy, nuclear magnetic resonance hydrogen spectrum and the like.

A solid sample of the orlapanib cocrystal with maleic acid obtained in example 1 was subjected to X-ray powder diffraction analysis using a diffractometer of Rigaku MiniFlex 600, manufactured by Nippon chemical Co., Ltd., Cu K α radiation

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 3.0-40.0 degrees, and the test temperature is room temperature. The analysis results are shown in the X-ray powder diffraction diagram of figure 1, and the X-ray powder diffraction data are shown in Table 1.

Table 1X-ray powder diffraction data for the olaparib co-crystal with maleic acid of example 1

The X-ray powder diffraction data of the solid sample of the olaparib co-crystal with maleic acid prepared in example 2 based on the same X-ray powder diffraction test method as example 1 are shown in table 2.

Table 2X-ray powder diffraction data for the olaparib co-crystal with maleic acid of example 2

The X-ray powder diffraction data of the solid sample of the olaparib co-crystal with maleic acid prepared in example 3 based on the same X-ray powder diffraction test method as in example 1 are shown in table 3.

Table 3X-ray powder diffraction data for the olaparib co-crystal with maleic acid of example 3

It is well known to those skilled in the art that crystalline materials can be characterized by X-ray diffraction techniques, but the X-ray diffraction patterns typically vary with the test conditions of the instrument. It is particularly noted that the relative intensities of the X-ray diffraction patterns may vary with the experimental conditions, so that the relative intensity order of the X-ray diffraction peaks cannot be the sole or determining factor in the characterization of crystalline material. In addition, the peak angle is usually allowed to have an error of ± 0.2 °, and due to the influence of experimental factors such as sample height and test temperature, the peak angle is shifted as a whole, and a certain shift is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of the present invention for the olaparib and maleic acid co-crystal need not be identical to the X-ray diffraction pattern in this embodiment, and any pattern having the same or similar characteristic peaks falls within the scope of the present invention. One skilled in the art can compare the profile listed in the present invention with a profile of an unknown substance to confirm whether the unknown substance is or is not the olaparib co-crystal with maleic acid according to the present invention.

Differential scanning calorimetry was performed on a solid sample of the olaparib co-crystal obtained in example 1 with maleic acid, and the differential scanning calorimetry was performed by a DSC 214 type differential calorimeter of Germany Chinesemedicine instruments GmbH, wherein the atmosphere was nitrogen and the temperature rise rate was 10 ℃/min. The analysis result is shown in the differential scanning calorimetry diagram of figure 2. As shown in fig. 2, the eutectic of olaparib and maleic acid showed a melting endothermic peak at 146.8 ℃.

The thermogravimetric analysis of the solid sample of the eutectic crystal of olaparib and maleic acid obtained in example 1 was performed by using a thermogravimetric analyzer model TG209F3, manufactured by german seikh scientific instruments ltd, in an atmosphere of nitrogen and at a temperature increase 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 maleic acid heated to around 152.2 ℃ started to decompose and there was no weight loss until this temperature.

Infrared spectroscopy of a sample of the eutectic olaparib and maleic acid obtained in example 1 was carried out by Fourier transforming the infrared light with NICOLET iS10 from ThermoFisher ScientificThe detection range of the spectrometer 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)：3246、3163、3072、3011、2926、2541、1722、1701、1647、1605、1491、1468、1443、1370、1353、1281、1245、1227、1164、1015、841、836、794、774、739、681、646、604、584、544。

The sample of the eutectic crystal between olaparib and maleic acid obtained in example 1 was analyzed by nmr spectroscopy, and the result of the analysis was shown in the nmr spectroscopy (HNMR) of fig. 5, using an Avance III 400M nmr spectrometer from Bruker, germany. As can be seen from fig. 5, the peaks of olaparib are: 1H NMR (400MHz, DMSO-d6)12.62(s, 1H), 8.27(d, J ═ 7.6Hz, 1H), 7.97(d, J ═ 7.8Hz, 1H), 7.90(t, J ═ 7.4Hz, 1H), 7.84(t, J ═ 7.4Hz, 1H), 7.46(d, J ═ 5.7Hz, 1H), 7.38(s, 1H), 7.25(t, J ═ 9.0Hz, 1H), 4.34(s, 2H), 3.64(dd, J ═ 58.9, 25.8Hz, 5H), 3.39(s, 1H), 3.19(d, J ═ 28.1Hz, 2H), 1.96(d, J ═ 40.9, 1H), 0.73(t, 2H), 4.6 (t, 4H). The maleic acid peaks are: 1H NMR (400MHz, DMSO-d6)6.28(s, 2H). From the integration results of the characteristic peaks, the stoichiometric ratio of olaparib and maleic acid in the co-crystal was 1: 1.

Evaluation of solubility

The comparative study is carried out on the powder dissolution data of the Olaparib and maleic acid eutectic crystal and the Olaparib crystal form A.

The source of the test sample is: the olaparib and maleic acid eutectic is prepared by the method provided by embodiment 1 of the invention; olaparib form a was purchased from shanghai shengde pharmaceutical technology ltd, having a purity of 99%.

Powder dissolution test method: and grinding the eutectic crystal of the olaparib and the maleic acid and the crystal form A of the olaparib, and then respectively sieving the powder through 100-200 meshes, wherein the particle size of the powder is controlled to be 75-150 mu m. Respectively weighing 90mg of olaparib crystal form A, 114mg of olaparib and maleic acid eutectic, adding the weighed olaparib crystal form A and 114mg of olaparib and maleic acid 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 maleic acid were 69.1 ± 4.9 and 315.1 ± 32.2 μ g/mL, respectively. It can be seen that the apparent solubility of the eutectic of olaparib and maleic acid is unexpectedly and significantly better than that of the crystal form a of olaparib, and the value of the eutectic reaches 4.6 times that of the crystal form a of olaparib.

The co-crystal of olaparib and maleic acid 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

1. An olaparib maleic acid eutectic is characterized in that: the structural formula of the eutectic is shown as the formula (I):

in the eutectic, the molar ratio of olaparib to maleic acid is 1: 1; the eutectic has characteristic peaks at 2theta values of 5.1 +/-0.2 degrees, 9.8 +/-0.2 degrees, 13.7 +/-0.2 degrees, 16.0 +/-0.2 degrees, 17.7 +/-0.2 degrees and 20.0 +/-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 7.0 +/-0.2 degrees, 13.0 +/-0.2 degrees, 25.7 +/-0.2 degrees and 26.3 +/-0.2 degrees.

3. A method of preparing a co-crystal according to any one of claims 1 to 2, wherein: comprises the following steps of feeding the olaparib and the maleic acid according to the molar ratio of 1: 1, adding a proper amount of solvent, and stirring or grinding to obtain the eutectic crystal.

4. The production method according to claim 3, characterized in that: the solvent is at least one of an alcohol solvent, an ester solvent, a ketone solvent, an ether solvent, a nitrile solvent and an alkane solvent.

5. The production method according to claim 3, characterized in that: and during stirring, the ratio of the total mass of the olaparib and the maleic acid to the using amount of the solvent is 1g to (4-20) mL.

6. The production method according to claim 3, characterized in that: during grinding, the total mass of the olaparib and the maleic acid and the dosage of the solvent are 1g to (100-200) mu L.

7. A pharmaceutical composition characterized by: comprising a co-crystal according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient.

8. Use of the co-crystal of any one of claims 1 to 2 in a medicament for the treatment of cancer.