阅读说明：本技术 一种奥拉帕尼与马来酸的共晶及其制备方法 (Eutectic of olaparib and maleic acid and preparation method thereof ) 是由 陈嘉媚 吕文婷 戴霞林 于 2020-07-22 设计创作，主要内容包括：本发明公开了一种奥拉帕尼与马来酸共晶及其制备方法。该共晶中奥拉帕尼与马来酸的摩尔比为1∶1,该共晶X射线粉末衍射图在2theta值为5.1±0.2°、9.8±0.2°、13.7±0.2°、16.0±0.2°、17.7±0.2°、20.0±0.2°处具有特征峰。本发明提供的共晶制备方法工艺简单,结晶过程易于控制,重现性好,适用于工业化生产。这种共晶较奥拉帕尼自由碱具有较大的表观溶解度,有利于提高奥拉帕尼的口服吸收效率。(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.)

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.

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.