Olaparib and urea eutectic and preparation method thereof

A technology of urea and eutectic crystal form, which is applied in the field of cocrystal and preparation of olaparib and urea, can solve the problem of low solubility of free base crystal form, simplify the preparation and post-treatment process, and improve bioavailability , Improve the effect of drug absorption efficiency

Active Publication Date: 2016-07-13
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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  • Olaparib and urea eutectic and preparation method thereof
  • Olaparib and urea eutectic and preparation method thereof
  • Olaparib and urea eutectic 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 embodiment is eutectic crystal form A, and its XRPD pattern is as follows figure 1 , 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 HNMR picture as shown Figure 6 .

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

[0058] 1 HNMR(400MHz,DMSO)δ...

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 example is crystal form A, and its X-ray powder diffraction data are shown in Table 2.

[0065] Table 2

[0066]

[0067]

Embodiment 3

[0069] Preparation of co-crystals of olaparib and urea:

[0070] 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.

[0071] 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.

[0072] table 3

[0073]

[0074]

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PUM

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Abstract

The invention relates to olaparib and urea eutectic and a preparation method thereof and particularly provides a eutectic form A, an X-ray powder diffraction of the crystal form shows characteristic peaks at 17.4 DEG +/- 0.2 DEG, 20.7 DEG +/- 0.2 DEG and 10.5 DEG +/- 0.2 DEG of value 2theta.The eutectic has better stability, lower hygroscopicity and higher solubility than existing olaparib free base crystal forms and is of significant value to the optimization and development of its drugs in future.

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 Applications(China)
IPC IPC(8): C07D237/32C07C273/02C07C273/16A61K31/502A61P35/00
CPCA61K31/502C07C273/02C07D237/32C07B2200/13
Inventor 陈敏华张炎锋刘凯张晓宇
Owner CRYSTAL PHARMATECH CO LTD
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