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New crystal form of lumacaftor, and preparation method thereof

A technology of crystal form and powder diffraction pattern, applied in the field of chemical medicine, can solve problems such as direct obtaining of crystal form I, and achieve the effects of good stability, improved drug efficacy, and improved solubility

Inactive Publication Date: 2017-02-22
CRYSTAL PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

None of the methods for preparing crystal form I disclosed in the patent can be obtained directly from the free form of the compound of formula I.

Method used

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  • New crystal form of lumacaftor, and preparation method thereof
  • New crystal form of lumacaftor, and preparation method thereof
  • New crystal form of lumacaftor, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Preparation of Form A:

[0051] Weighed 5.3 mg of Lumacaftor free form and dissolved it in 0.5 mL of methyl isobutyl ketone, and slowly volatilized at 50°C to obtain a white solid, crystal form A.

[0052] Table 1 shows the X-ray powder diffraction data of Form A obtained in this example. Its XRPD pattern is as follows figure 1. Comprehensively considering the d value, low angle, intensity, characteristic line and peak shape integrity and other factors, the diffraction peaks at 2theta values ​​of 8.77°, 21.25°, and 22.21° are characteristic peaks, and the 2theta values ​​are 10.56°, 18.10°, The diffraction peak at 23.46° is an important peak, and the diffraction peaks at 2theta values ​​of 9.85°, 16.23°, and 20.04° are secondary important peaks.

[0053] Table 1

[0054] 2theta d interval strength% 8.77 10.08 52.78 9.58 9.24 13.30 9.85 8.98 24.45 10.56 8.38 35.38 11.14 7.94 11.76 12.60 7.02 11.70 13.35 6.63 10....

Embodiment 2

[0060] Preparation of Form A:

[0061] Weigh 5.4 mg of Lumacaftor free form and dissolve in 0.5 mL of acetone / methyl tert-butyl ether (the volume ratio of acetone / methyl tert-butyl ether is 1:2), slowly volatilize at 50°C to obtain a white solid as crystal Type A.

[0062] Table 2 shows the X-ray powder diffraction data of Form A obtained in this example. The diffraction peaks at 2theta values ​​of 8.77°, 21.26°, and 22.21° are characteristic peaks, the diffraction peaks at 2theta values ​​of 10.56°, 18.10°, and 23.46° are important peaks, and the 2theta values ​​of 9.86°, 16.24°, and 20.05° The diffraction peak at is the next most important peak.

[0063] Table 2

[0064] 2theta d interval strength% 8.77 10.08 55.12 9.86 8.97 17.80 10.56 8.38 35.17 11.13 7.95 4.50 12.61 7.02 6.16 14.14 6.27 29.04 15.54 5.70 13.39 16.24 5.46 26.21 17.38 5.10 10.27 17.66 5.02 9.46 18.10 4.90 35.72 18.91 4.69...

Embodiment 3

[0067] Preparation of Form A:

[0068] Weighed 10.1 mg of Lumacaftor free form and dissolved it in 1.0 mL of methyl isobutyl ketone, and slowly volatilized at 50°C to obtain a white solid, crystal form A.

[0069] Table 3 shows the X-ray powder diffraction data of Form A obtained in this example. The diffraction peaks at 2theta values ​​of 8.77°, 21.26°, and 22.21° are characteristic peaks, the diffraction peaks at 2theta values ​​of 10.56°, 18.10°, and 23.47° are important peaks, and the 2theta values ​​of 9.85°, 16.24°, and 20.05° The diffraction peak at is the next most important peak.

[0070] table 3

[0071] 2theta d interval strength% 8.77 10.08 70.87 9.85 8.98 11.77 10.56 8.38 50.38 11.15 7.94 5.84 12.62 7.02 6.50 13.36 6.63 15.57 14.14 6.27 24.94 15.54 5.70 14.46 16.24 5.46 47.68 16.76 5.29 3.05

[0072] 17.38 5.10 6.13 17.65 5.02 11.64 18.10 4.90 27.67 18.91 4...

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PUM

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Abstract

The present invention provides a crystal form A of lumacaftor, and a preparation method thereof, wherein the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at a 2[theta] value of 8.8+ / -0.2 DEG, 21.2+ / -0.2 DEG, and 22.2+ / -0.2 DEG. According to the present invention, the crystal form A has good stability, has high dissolubility compared to the prior art, and provides important values for the optimization and the development of future drugs. The formula I is defined in the specification.

Description

technical field [0001] The invention relates to the field of chemistry and medicine, in particular to a new crystal form of Lumacaftor and a preparation method thereof. Background technique [0002] Lumacaftor (compound represented by formula I), developed by Vertex Pharmaceuticals, is used in combination with Ivacaftor for the treatment of cystic fibrosis patients over 12 years old caused by the homozygous deletion mutation of cystic fibrosis transmembrane regulator gene F508. On July 2, 2015, the Lumacaftor / Ivacaftor combination drug was launched in the United States under the trade name Orkambi. [0003] [0004] Patent CN101910156B discloses Lumacaftor crystal form I, which is characterized by X-ray powder diffraction obtained by using Cu Ka rays at 15.2-15.6°, 16.1-16.5°, 14.6-15.0°, 17.6-18.0° and 14.3-14.7° ° peak. The crystal form is obtained by suspending the hydrochloride salt of the compound of the formula I in water, and a method for obtaining the crystal fo...

Claims

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Application Information

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IPC IPC(8): C07D405/12A61K31/443A61P43/00
CPCC07D405/12C07B2200/13A61K31/443A61P11/00A61K31/47
Inventor 陈敏华张炎锋刘凯邹坡张晓宇
Owner CRYSTAL PHARMATECH CO LTD
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