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Ibrutinib-nicotinic acid eutectic crystal and preparation method thereof

A technology of nicotinic acid and niacin, applied in the field of ibrutinib-nicotinic acid co-crystal, can solve the problem that crystal form B has high hygroscopicity, crystal form A is not easy to absorb moisture, and the stability and solubility of crystal form C are not reported. Data and other issues, to achieve the effect of high crystal purity and yield, and simple preparation method

Active Publication Date: 2022-07-01
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the other three crystal forms, the hygroscopicity of the crystal form B is relatively large, and the crystal form A is not easy to absorb moisture in comparison, and the stability and solubility data of the crystal form C are not reported.

Method used

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  • Ibrutinib-nicotinic acid eutectic crystal and preparation method thereof
  • Ibrutinib-nicotinic acid eutectic crystal and preparation method thereof
  • Ibrutinib-nicotinic acid eutectic crystal and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] 88.1 mg (0.2 mmol) of ibrutinib and 25.6 mg (0.2 mmol) of nicotinic acid were added to 6 mL of ethanol and 4 mL of water, heated to 65 °C with stirring to dissolve, refluxed for 2 hours, slowly cooled to 10 to 20 °C, and then controlled. It was left to stand for crystallization for 25 hours, filtered, the filter cake was washed with ethanol, and vacuum-dried at 50° C. for 6 hours to obtain ibrutinib-nicotinic acid co-crystal with a yield of 91.55% and a purity of 99.91%.

Embodiment 2

[0053] 88.1 mg (0.2 mmol) of ibrutinib and 29.5 mg (0.24 mmol) of nicotinic acid were added to 4 mL of acetonitrile and 2 mL of water, heated to 80 °C with stirring to dissolve, refluxed for 3 hours, and slowly cooled to 10 to 20 °C. Allow to stand for crystallization for 36 hours, filter, wash the filter cake with acetonitrile, and vacuum dry at 50°C for 10 hours to obtain ibrutinib-nicotinic acid co-crystal with a yield of 94.05% and a purity of 99.95%.

Embodiment 3

[0055] 88.1 mg (0.2 mmol) of ibrutinib and 27.1 mg (0.22 mmol) of niacin were added to 7 mL of acetone and 2 mL of water, heated to 50 °C with stirring to dissolve, refluxed for 2 hours, slowly cooled to 10 to 20 °C, and then controlled. It was left to stand for crystallization for 24 hours, filtered, and the filter cake was washed with acetone, and vacuum-dried at 50°C for 5 hours to obtain ibrutinib-nicotinic acid co-crystal with a yield of 95.32% and a purity of 99.95%.

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Abstract

The invention belongs to the technical field of crystal form drug molecules, and particularly provides an ibrutinib-nicotinic acid eutectic crystal. The ibrutinib-nicotinic acid eutectic prepared by the invention is radiated by Cu-K alpha, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at the positions of 5.46 + / -0.2 degrees, 15.22 + / -0.2 degrees, 20.10 + / -0.2 degrees, 20.97 + / -0.2 degrees, 24.57 + / -0.2 degrees, 25.71 + / -0.2 degrees, 26.78 + / -0.2 degrees and 27.76 + / -0.2 degrees. The method for preparing the ibrutinib-nicotinic acid eutectic crystal provided by the invention is simple to operate, and the prepared crystal is high in yield and purity. The ibrutinib-nicotinic acid eutectic crystal prepared by the invention has relatively good chemical stability and relatively good solubility, and is of great significance for improving the bioavailability and the drug effect of ibrutinib.

Description

technical field [0001] The invention relates to the technical field of crystal drug molecules, and specifically discloses an ibrutinib-nicotinic acid co-crystal. Background technique [0002] Ibrutinib (Ibrutinib) is jointly developed by the US Pharmacyclics and Johnson & Johnson, the trade name is Imbruvica, and its chemical name is: 1-[(3R)-3-[4-amino-3-(4-phenoxybenzene) base)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one, the structural formula is as follows: [0003] [0004] Ibrutinib is a first-in-class oral Bruton's tyrosine kinase (BTK) inhibitor that selectively binds to a cysteine ​​residue (Cys-481) in the active site of the target protein Btk. It binds and irreversibly inhibits BTK, thereby effectively preventing tumor migration from B cells to lymphoid tissues adapted to the tumor growth environment. In November 2013, the U.S. Food and Drug Administration (FDA) approved its listing for the treatment of a rare aggressive blood cancer, mant...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D213/80A61K31/519A61P35/00
CPCC07D487/04C07D213/80A61P35/00C07B2200/13
Inventor 张贵民翟立海张明明夏祥来王聚聚
Owner LUNAN PHARMA GROUP CORPORATION