CN112010809A - Crystal form I of olaparib and preparation method thereof - Google Patents

Abstract

The invention relates to crystal form I of olaparib and a preparation method thereof. Specifically, the crystal form I provided by the invention is characterized in that an X-ray powder diffraction pattern of the crystal form I has characteristic peaks at 2theta values of 6.4 degrees +/-0.2 degrees, 12.7 degrees +/-0.2 degrees and 15.1 degrees +/-0.2 degrees. The crystal form I provided by the invention has better stability and has important value for the optimization and development of the medicine in the future.

Description

Crystal form I of olaparib and preparation method thereof

Technical Field

The invention relates to the field of chemical medicine, in particular to a crystal form I of olaparib and a preparation method thereof.

Background

Olaparib was first developed by KuDOS (KuDOS) drugs ltd, a biotechnology company in the uk, and after being purchased by astrazen, continued to develop a drug for the treatment of ovarian cancer. Olaparib obtained FDA approval in the united states for marketing at 12/2014 at 19/h, is the first FDA-approved targeted drug specifically for BRCA mutated ovarian cancer patients, and is suitable for patients who have previously undergone chemotherapy. Olaparib has been shown in preclinical models to be an initial oral Poly ADP Ribose Polymerase (PARP) inhibitor that can take advantage of defects in the DNA repair pathway to preferentially kill cancer cells.

The chemical name of olaparib is 4- [3- (4-cyclopropanecarbonyl-piperazine-1-carbonyl) -4-fluoro-benzyl ] -2H-phthalazin-1-one, and the structure of the olaparib is shown as the formula (I):

KuDOS pharmaceuticals, inc discloses crystalline form a of the free base of olaparib and one of the solvate forms, in patent CN101528714B, and crystalline form L of the free base of olaparib, in patent CN 101821242B. No other company has disclosed crystalline forms of olaparib.

Different crystal forms of solid chemical drugs can cause different solubility and stability, thereby affecting the absorption and bioavailability of the drugs and causing the difference of clinical efficacy. Therefore, there is a need for a comprehensive and systematic polymorphic screening of the compounds of formula (I) to select the most developed form.

The inventor of the invention develops a new crystal form of olaparib, the new crystal form has better stability, the solubility and the hygroscopicity meet the medicinal requirements, and the solvent used in the preparation method is nontoxic and environment-friendly, has important value for the optimization and development of the medicine in the future, and provides a better choice for the medicine solid preparation.

Disclosure of Invention

It is an object of the present invention to provide a new crystalline form of olaparib, designated as form I.

Specifically, the crystal form I provided by the invention is characterized in that an X-ray powder diffraction pattern of the crystal form I has characteristic peaks at 2theta values of 6.4 degrees +/-0.2 degrees, 12.7 degrees +/-0.2 degrees and 15.1 degrees +/-0.2 degrees.

Furthermore, the crystal form I provided by the invention is characterized in that an X-ray powder diffraction pattern of the crystal form I has characteristic peaks at 2theta values of 6.9 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees and 22.2 degrees +/-0.2 degrees.

Furthermore, the crystal form I provided by the invention is characterized in that an X-ray powder diffraction pattern of the crystal form I has characteristic peaks at 2theta values of 17.7 degrees +/-0.2 degrees, 20.2 degrees +/-0.2 degrees and 21.0 degrees +/-0.2 degrees.

The crystal form I provided by the invention is characterized in that the X-ray powder diffraction pattern is basically as shown in figure 1.

The crystal form I provided by the invention is characterized in that a differential scanning calorimetry diagram is basically as shown in figure 2.

The crystal form I provided by the invention is characterized in that a thermogravimetric analysis graph is basically shown as a figure 3.

Another object of the present invention is to provide a method for preparing crystalline modification I of olaparib, which is characterized in that the solid of olaparib is placed in pure water or an aqueous solvent and stirred.

Further, the aqueous solvent includes a mixed solvent containing not less than 80% by volume of water.

Further, the aqueous solvent is characterized by comprising alcohols, ketones, ethers, alkanes and aromatics.

Another object of the present invention is to provide a pharmaceutical composition comprising an effective amount of crystalline form I co-crystal of olaparib, and at least one pharmaceutically acceptable excipient.

Furthermore, in the pharmaceutical composition provided by the invention, the crystal form I of the olaparib can be used for preparing a pharmaceutical preparation for treating cancer.

Still further, the cancer includes, but is not limited to, melanoma, pancreatic cancer, ovarian cancer, breast cancer, lymphoma, lung cancer.

The invention has the beneficial effects that:

the crystal form I of the olaparib provided by the invention has better stability than the crystal form A in the patent CN101528714B, can be kept stable in the processes of preparation, storage and preparation development, does not generate crystal transformation, and has great significance for the development of the drug.

The preparation method of the crystal form I of the olaparib provided by the invention is simple in process, and the used solvent is non-toxic and environment-friendly, so that the preparation method has important value for optimizing and developing the medicine in the future, and provides a better choice for a medicine solid preparation.

Drawings

FIG. 1 is an XRPD pattern for form I

FIG. 2 is a DSC of form I

FIG. 3 is a TGA profile of form I

Detailed Description

The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. The skilled person can make modifications to the preparation method and the apparatus used within the scope of the claims, and such modifications should also be considered as the protection scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

In the examples described below, the test methods described are generally carried out according to conventional conditions or conditions recommended by the manufacturer.

The abbreviations used in the present invention are explained as follows:

XRPD: powder X-ray diffraction

DSC: differential scanning calorimetry

TGA: thermogravimetric analysis

The X-ray powder diffraction pattern of the invention is collected on a Panalytical Empyrean X-ray powder diffractometer. The parameters of the X-ray powder diffraction method are as follows:

x-ray reflectance parameters: cu, K alpha

Kα1

1.540598；Kα2

1.544426

TheK alpha 2/K alpha 1 intensity ratio: 0.50

Voltage: 45 KV (kV)

Current: 40 milliampere (mA)

Scanning range: from 3.0 to 40.0 degrees

Differential Scanning Calorimetry (DSC) profile according to the invention was taken on aTAQ 2000. The parameters of the Differential Scanning Calorimetry (DSC) method are as follows:

scanning rate: 10 ℃/min

Protective gas: nitrogen gas

Thermogravimetric analysis (TGA) profiles described herein were collected on TAQ 5000. The process parameters for thermogravimetric analysis (TGA) described in the present invention are as follows:

scanning rate: 10 ℃/min

Protective gas: nitrogen gas

Example 1

The preparation method of the crystal form I of Olaparib comprises the following steps:

10.0mg of olaparib free base is dissolved in 1.0mL of pure water, stirred at room temperature for 7 days, filtered, dried, and the solid is collected, and detected, the crystal form prepared in the embodiment is the crystal form I.

The X-ray powder diffraction data of the crystalline form obtained in this example are shown in table 1. The XRPD pattern is shown in figure 1, the DSC pattern is shown in figure 2, and the TGA pattern is shown in figure 3.

TABLE 1

Example 2

The preparation method of the crystal form I of Olaparib comprises the following steps:

adding 10.0mg of olaparib crystal form a in patent CN101528714B into 0.5mL of pure water, adding 1.0mg of crystal seed of crystal form I, stirring at room temperature for 72 hours, filtering, washing with pure water, drying, collecting solid, and detecting that the crystal form prepared in this example is crystal form I.

The X-ray powder diffraction data for form I obtained in this example are shown in table 2.

TABLE 2

Example 3

Comparative stability tests of olaparib form I and form a in patent CN 101528714B:

10.0mg of the crystal form A in patent CN101528714B and 1.0mg of the crystal form I prepared in example 1 are respectively taken and put into a small bottle, and 0.5mL of pure water is added to prepare suspension. After stirring at room temperature for 72 hours, the XRPD of the test sample, form a in patent CN101528714B, had all been converted to form I of the present invention, with the results shown in table 3.

TABLE 3

Claims (9)

1. A crystal form I of a compound shown as a formula (I) is characterized in that an X-ray powder diffraction pattern of the crystal form I has characteristic peaks at 2theta values of 6.4 degrees +/-0.2 degrees, 12.7 degrees +/-0.2 degrees and 15.1 degrees +/-0.2 degrees

2. Form I according to claim 1, further characterized by an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 6.9 ° ± 0.2 °, 19.7 ° ± 0.2 °, 22.2 ° ± 0.2 °.

3. Form I according to claim 2, further characterized by an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 17.7 ° ± 0.2 °, 20.2 ° ± 0.2 °, 21.0 ° ± 0.2 °.

4. Form I according to claim 1, having a thermogravimetric analysis diagram as shown in figure 3.

5. Form I according to claim 1, characterized by a differential scanning calorimetry trace as shown in figure 2.

6. Form I according to claim 1, characterized in that its X-ray powder diffraction pattern substantially corresponds to figure 1.

7. A process for the preparation of form I according to claim 1, characterized in that the solid olaparib is obtained by stirring in pure water or an aqueous solvent.

8. A pharmaceutical composition comprising an effective amount of the crystalline form I of any one of claims 1 to 6 and a pharmaceutically acceptable excipient.

9. Use of the crystalline form I according to any one of claims 1 to 6 for the preparation of a pharmaceutical preparation for the treatment of melanoma, pancreatic cancer, ovarian cancer, breast cancer, lymphoma, lung cancer.

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