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Ibrutinib salts, crystals, preparation method, pharmaceutical compositions and applications thereof

An ibrutinib salt and ibrutinib technology are applied in ibrutinib salt, its crystal, preparation, pharmaceutical composition and application fields, can solve problems such as lack, achieve improved hygroscopicity, simple preparation method, The effect of good industrial application prospects

Inactive Publication Date: 2019-05-21
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the present invention is to solve the problem of the lack of a pharmaceutically acceptable salt of ibrutinib with higher solubility and bioavailability in the art, and further provide ibrutinib salt, its crystal, preparation method, pharmaceutical composition and application

Method used

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  • Ibrutinib salts, crystals, preparation method, pharmaceutical compositions and applications thereof
  • Ibrutinib salts, crystals, preparation method, pharmaceutical compositions and applications thereof
  • Ibrutinib salts, crystals, preparation method, pharmaceutical compositions and applications thereof

Examples

Experimental program
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preparation Embodiment 1

[0044] Preparation Example 1 Preparation of Ibrutinib Hydrochloride Crystals

[0045] Add ibrutinib (2.0g, 4.5mmol) and methanol 4ml into a 100ml reaction bottle, add HCl methanol solution (2.25ml, 2.0M) dropwise under stirring, heat to about 50°C after dropping, and make the reaction solution Dissolved, cooled to 20°C and stirred for 4h. Filter, wash with a small amount of methanol, and dry under vacuum at 60°C for 6 hours to obtain ibrutinib hydrochloride crystals as a white crystalline powder, 1.4 g in total, yield 65%, M.P.: 214-216°C, HPLC content 99.5%. C 25 h 24 N 6 o 2 .HCl elemental analysis experimental value: C: 62.37, H: 5.38, N: 17.39; theoretical value C: 62.95, H: 5.28, N: 17.62, through X-ray powder diffraction (XRD) and differential thermal scanning calorimetry ( DSC) characterization and identification, the results are as follows Figure 1-2 shown.

preparation Embodiment 2

[0046] Preparation Example 2 Preparation of Ibrutinib Hydrochloride Crystals

[0047] Add ibrutinib (2.0g, 4.5mmol) and 10ml of ethanol to a 100ml reaction bottle, add HCl ethanol solution (2.75ml, 2.0M) dropwise under stirring, heat to about 80°C after dropping, and make the reaction solution Dissolved, cooled to 0°C and stirred for 4h. Filter, wash with a small amount of ethanol, and dry under vacuum at 60°C for 6 hours to obtain ibrutinib hydrochloride crystals as a white crystalline powder, totaling 1.6g, yield 74%, M.P.: 214-216°C, HPLC content 99.6%. The XRD and DSC characterization results are the same as in Example 1.

preparation Embodiment 3

[0048] Preparation Example 3 Preparation of Ibrutinib Hydrochloride Crystals

[0049] Add ibrutinib (2.0g, 4.5mmol) and 8ml of isopropanol to a 100ml reaction bottle, add HCl in isopropanol (3.4ml, 2.0M) dropwise with stirring, and heat to about 60°C after dropping , The reaction solution was dissolved, cooled to 0°C and stirred for 4h. Filter, wash with a small amount of isopropanol, and dry under vacuum at 60°C for 6 hours to obtain ibrutinib hydrochloride crystals as a white crystalline powder, totaling 1.5g, yield 69%, M.P.: 214-216°C, HPLC content 99.5%. The XRD and DSC characterization results are the same as in Example 1.

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Abstract

The invention discloses ibrutinib salts, crystals, a preparation method, pharmaceutical compositions and the application thereof. The crystals of the ibrutinib salts have a structure as shown in formula (I), wherein X is HCl, HBr or benzoic acid. The preparation method comprises the following steps: mixing ibrutinib with X in an organic solvent, heating to 40-130 DEG C, completely dissolving, cooling, and crystallizing. The crystals of the three ibrutinib salts are all of new crystal forms, have excellent solubility and thermal stability, greatly improve the hygroscopic property, and greatly improve the solubility and bioavailability of ibrutinib. The preparation method of the crystals is simple, is suitable for large-scale industrial production, and has a good industrial application prospect.

Description

technical field [0001] The present invention relates to ibrutinib salt, its crystal, preparation method, pharmaceutical composition and application. Background technique [0002] Ibrutinib (Ibrutinib) is a BTK inhibitor anti-tumor drug developed by Pharmacyclics and Johnson & Johnson. Its chemical name is 1-[(3R)-3-[4-amino-3-(4-phenoxy Phenyl)-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 indications are mantle cell lymphoma, chronic lymphocytic leukemia, paroxysmal macroglobulinemia and marginal zone lymphoma. Its structural formula is as follows: [0003] [0004] The patent WO2013184572 discloses the crystal form, solvate and pharmaceutical composition of ibrutinib, including the commercially available pharmaceutical crystal form A, but the solubility of ibrutinib in crystal form A is still poor, and the solubility in pH=8.0 aqueous solution With only 0.013mg / ml, BCS is classified as Class II (i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00
Inventor 孙辉周伟澄
Owner SHANGHAI INST OF PHARMA IND CO LTD
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