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Ibrutinib isopropyl acetate solvent compound and preparation method thereof

A technology of isopropyl acetate and solvent compounds, which is applied in the field of ibrutinib isopropyl acetate solvent compounds and its preparation, can solve problems such as easy coalescence and poor fluidity, and achieve easy preparation, mild conditions, and low toxicity Effect

Active Publication Date: 2018-11-02
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to overcome the disadvantages of the existing technology and solve the problems of poor fluidity and easy coalescence of the current commercially available products, it is necessary to use high-throughput crystal sample screening methods to investigate different crystallization methods, ultrasonic assistance, single solvents and mixed solvents, different temperatures and The effect of stirring conditions on the crystal form of the final product, combined with various analysis and testing methods such as powder diffraction, single crystal diffraction, thermogravimetric analysis and differential scanning calorimetry, to develop a simple, controllable, safe and low-toxic process technology route, preparation and Discover new crystal forms and solvates with excellent properties, which will facilitate subsequent drug development

Method used

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  • Ibrutinib isopropyl acetate solvent compound and preparation method thereof
  • Ibrutinib isopropyl acetate solvent compound and preparation method thereof
  • Ibrutinib isopropyl acetate solvent compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028]Take 0.08g of ibrutinib raw material into a 4mL sample bottle, add 4g of isopropyl acetate, turn on the ultrasonic instrument, adjust the ultrasonic frequency to 20KHz, ultrasonic power to 100W / mL solution, ultrasonic for 20min to make it dissolve and be in a supersaturated state , stirred at 25°C for 24h, filtered the suspension to obtain a white solid, dried under normal pressure at 30°C for 7h to obtain the product. The X-ray powder diffraction pattern of the product is represented by 2θ, at 7.3°, 7.7°, 8.9°, 10.2°, 14.6°, 15.6°, 17.1°, 18.2°, 18.9°, 20.5°, 21.2°, 21.8°, 22.6 There are characteristic peaks at °, 24.9°, 27.0°, and 27.6°, and the product is subjected to TGA thermogravimetric analysis, using a Swiss Mettler Toledo TGA / DSC1 thermogravimetric analyzer, the atmosphere is nitrogen, and the heating rate is 10°C / min , see the results of the analysis Figure 5 , there is an obvious desolvation peak, the desolvation weight loss ratio is 16.95%, and the product ...

Embodiment 2

[0030] Put 0.24g of ibrutinib raw material into a 20mL sample bottle, add 14.4g of isopropyl acetate, turn on the ultrasonic instrument, adjust the ultrasonic frequency to 30KHz, ultrasonic power to 200W / mL, and ultrasonic for 25min to make it dissolve and be in a supersaturated state , stirred at 40° C. for 20 h, filtered the suspension to obtain a white solid, and dried at 25° C. under normal pressure for 8 h to obtain the product. The X-ray powder diffraction pattern of the product is represented by 2θ, at 7.3°, 7.6°, 8.8°, 10.1°, 14.5°, 15.5°, 17.0°, 18.1°, 19.0°, 20.5°, 21.2°, 21.8°, 22.5 °, 24.8 °, 26.9 °, and 27.6 ° have characteristic peaks. The product is subjected to TGA thermogravimetric analysis, and the desolvation weight loss ratio is 17.12%. figure 2 Similarly, it has a bulk density of 0.6579 g / ml and an angle of repose of 26.5°.

Embodiment 3

[0032] Scale up the experiment. Weigh 0.50g of ibrutinib raw material into a 100mL crystallizer, add 28g of isopropyl acetate, turn on the ultrasonic instrument, adjust the ultrasonic frequency to 40KHz, ultrasonic power to 300W / mL, and ultrasonic for 30min to dissolve and be in a supersaturated state. Use mechanical stirring to control the stirring speed to 250 rpm, stir at 30°C for 22h, filter, and dry under normal pressure at 20°C for 10h to obtain the product. The X-ray powder diffraction pattern of the product is represented by 2θ, at 7.3°, 7.7°, 8.9°, 10.2°, 14.4°, 15.6°, 17.2°, 18.2°, 18.8°, 20.5°, 21.2°, 21.7°, 22.6 °, 24.9 °, 26.9 °, and 27.6 ° have characteristic peaks. The product is subjected to TGA thermogravimetric analysis, and the desolvation weight loss ratio is 17.36%. figure 2 Similarly, it has a bulk density of 0.6581 g / ml and an angle of repose of 26°.

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Abstract

The invention relates to an ibrutinib isopropyl acetate solvent compound and a preparation method thereof. X ray powder diffraction 2 theta shows that characteristic peaks appear at the positions of 7.3+ / -0.2 degrees, 7.7+ / -0.2 degrees, 8.9+ / -0.2 degrees, 10.2+ / -0.2 degrees, 14.6+ / -0.2 degrees, 15.6+ / -0.2 degrees, 17.1+ / -0.2 degrees, 18.2+ / -0.2 degrees, 18.9+ / -0.2 degrees, 20.5+ / -0.2 degrees, 21.2+ / -0.2 degrees, 21.8+ / -0.2 degrees, 22.6+ / -0.2 degrees, 24.9+ / -0.2 degrees, 27.0+ / -0.2 degrees and 27.6+ / -0.2 degrees. The bulk density of a product is 0.6584g / mL and a repose angle is 26 degrees. Thepreparation method is simple; the ibrutinib isopropyl acetate solvent compound can be prepared by adopting ultrasonic auxiliary constant temperature suspended crystal transformation and also can be prepared by cooling crystallization; the obtained product has the advantages of high crystallinity, complete bulk crystal habit, good fluidity, high bulk density and low possibility of coalescing.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical crystallization, and in particular relates to ibrutinib isopropyl acetate solvent compound and a preparation method thereof. Background technique [0002] Ibrutinib was jointly developed by Pharmacyclics Inc and Johnson & Johnson. On November 13, 2013, the US Food and Drug Administration (FDA) approved it for the first time as a drug for the treatment of mantle cell lymphoma. listed. The compound is a small molecule Bruton's tyrosine kinase (BTK, Bruton'styrosine kinase) inhibitor, which can be covalently combined with the cysteine ​​residue in the BTK active center, thereby inhibiting the proliferation and survival of B cells. Its chemical name is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-D]pyrimidin-1-yl]-1 -piperidinyl]-2-propen-1-one, the molecular formula is C 25 h 24 N 6 o 2 , the chemical structural formula is as follows: [0003] [0004] Polymorphism means th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07B2200/13C07D487/04
Inventor 龚俊波李中华朱培培侯宝红石鹏杨海燕
Owner TIANJIN UNIV