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Cocrystal of olaparib and urea and preparation method thereof

A technology of eutectic crystal form and constant temperature, which is applied in the preparation of organic compounds, preparation of urea derivatives, chemical instruments and methods, etc., can solve the problem of low solubility of free base crystal form, simplify the preparation and post-treatment process, facilitate Long-term storage, the effect of improving drug absorption efficiency

Active Publication Date: 2018-09-25
CRYSTAL PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, there are no other patents disclosing the crystal form of olaparib
However, the free base crystalline form of olaparib on the market has low solubility, so it is necessary to find a crystalline form with high solubility to improve drug absorption efficiency
[0005] Based on this, the inventors of the present invention have developed a co-crystal of olaparib, which solves the problem of low solubility of the free base crystal form

Method used

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  • Cocrystal of olaparib and urea and preparation method thereof
  • Cocrystal of olaparib and urea and preparation method thereof
  • Cocrystal of olaparib and urea and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Preparation of Olaparib and Urea Cocrystal Form A:

[0056] Dissolve 10.0 mg of olaparib free base (amorphous) in 0.6 mL of ethanol, add 11.8 mg of urea, heat to 60 °C at a heating rate of 1.0 °C / min, stir at 60 °C for 600 min, and then heat at 0.37 °C / min The temperature was lowered to 5° C. at a cooling rate of min, and the above heating and cooling process was repeated three times. After the reaction was completed, it was filtered, and the obtained solid was washed with ethanol, dried, and collected. After testing, the solid obtained in this example is eutectic crystal form A, and its X-ray powder diffraction data are shown in Table 1. Its DSC diagram is as follows figure 2 , and its TGA figure is shown in image 3 ,That 1 H NMR picture as Image 6 .

[0057] The eutectic product of olaparib and urea prepared by the above method, its 1H NMR identification data are as follows:

[0058] 1 H NMR (400MHz, DMSO) δ12.57(s, 1H), 8.26(d, J=7.8Hz, 1H), 7.97(d, J=7.9Hz...

Embodiment 2

[0063] Preparation method of co-crystal of olaparib and urea: 101.9 mg of olaparib free base was dissolved in 3.0 mL of ethanol, 98.7 mg of urea was added, heated to 60 °C at a heating rate of 1.0 °C / min, and then Stir at 60°C for 600min, then cool down to 5°C at a cooling rate of 0.37°C / min, repeat the above heating and cooling process three times, filter after the reaction, and wash the obtained solid with ethanol and dry.

[0064] After testing, the solid obtained in this embodiment is crystal form A, and its X-ray powder diffraction data are shown in Table 2, and its XRPD pattern is as follows figure 1 .

[0065] Table 2

[0066] 2theta

Embodiment 3

[0068] Preparation of co-crystals of olaparib and urea:

[0069] Dissolve 10.0 mg of olaparib free base (amorphous) in 0.6 mL of acetone, add 10.8 mg of urea, heat to 60 °C at a heating rate of 1.0 °C / min, stir at 60 °C for 600 min, and cool down (cooling rate 0.37 °C / min) to 5 °C, repeat the above heating and cooling process three times, filter after the reaction, and wash the obtained solid with ethanol, dry, cool to room temperature, and collect the solid.

[0070] After testing, the solid obtained in this example is consistent with the crystal form obtained in Example 1, which is the eutectic crystal form A, and its X-ray powder diffraction data are shown in Table 3.

[0071] table 3

[0072]

[0073]

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PUM

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Abstract

Disclosed are a co-crystal of olaparib and urea and a preparation method therefor. Specifically disclosed is a co-crystal form A, and an X-ray powder diffraction pattern of this crystal form has characteristic peaks at points where 2theta value is 17.4°±0.2°, 20.7°±0.2°, 10.5°±0.2°. The disclosed co-crystal has better stability, lower hygroscopicity and higher solubility as compared to existing olaparib free alkali crystal forms.

Description

technical field [0001] The invention relates to a co-crystal of olaparib and urea, a preparation method and application thereof. Background technique [0002] Olaparib was first developed by the British biotechnology company KuDOS (Kudos) Pharmaceutical Co., Ltd. After AstraZeneca acquired KuDOS in 2005, it continued to develop Olaparib for the treatment of ovarian cancer. On December 19, 2014, Olaparib was approved by the FDA for marketing in the United States. It is the first targeted drug approved by the FDA for ovarian cancer patients with BRCA mutations, and is suitable for patients who have previously undergone chemotherapy. It has been demonstrated in preclinical models that olaparib is a first-in-class oral poly ADP ribose polymerase (PARP) inhibitor that exploits 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 its str...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D237/32C07C273/02C07C273/16A61K31/502A61P35/00
CPCA61K31/502C07C273/02C07D237/32
Inventor 陈敏华张炎锋刘凯张晓宇
Owner CRYSTAL PHARMATECH CO LTD
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