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Crystal form of afatinib di-meleate and method for preparing crystal form

A crystallization and form technology, applied in the fields of organic chemistry, drug combination, antitumor drugs, etc., can solve the problems of easy sticking, easy splitting or lamination, low bulk density, etc., and achieves low production cost, excellent chemical purity, and operation. simple steps

Inactive Publication Date: 2015-09-23
HEBEI SHINEWAY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

WO2009147238A discloses that the crystal form is needle-like crystals, and the process of preparing solid oral dosage forms has the following challenges: moisture sensitivity, low bulk density, poor fluidity, easy splitting or lamination by direct compression, poor compressibility, easy sticking, etc.
WO2012121764A discloses a crystalline afatinib dimaleate (referred to as crystal form B). Its DSC spectrum shows an exothermic peak at 125.9°C, a secondary endothermic peak at 156.8°C, and a main peak at 173.9°C. Endothermic peak, it can be seen that its thermal stability is poor

Method used

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  • Crystal form of afatinib di-meleate and method for preparing crystal form
  • Crystal form of afatinib di-meleate and method for preparing crystal form
  • Crystal form of afatinib di-meleate and method for preparing crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1 Preparation of Afatinib Dimaleate Crystal Form H

[0023] Dissolve 4g (8.23mmol) of afatinib base in 40ml of ethyl acetate, heat to 65°C to dissolve, then slowly add 2g (17.3mmol) of maleic acid in ethyl acetate (5ml) solution dropwise to the above solution, After the dropwise addition, it was naturally cooled to room temperature, then rapidly cooled to 0°C, stirred for 2 hours, a large amount of solids were precipitated, and the off-white powder was obtained by suction filtration, dried in vacuum at 40°C for 4 hours, and the purity (HPLC: 99.55%) was obtained.

Embodiment 2

[0024] Example 2 Preparation of Afatinib Dimaleate Crystal Form H

[0025] Dissolve 10g (20.58mmol) of afatinib base in 100ml of ethyl acetate, heat to 65°C to dissolve, then slowly add 5g (43.08mmol) of maleic acid in ethyl acetate (10ml) solution dropwise to the above solution, After the dropwise addition, it was naturally cooled to room temperature, then rapidly cooled to 0°C, stirred for 2 hours, a large amount of solids were precipitated, filtered by suction to obtain off-white powder, dried in vacuum at 40°C for 4 hours, and the purity was high (HPLC: 99.74%).

Embodiment 3

[0026] Example 3 Preparation of Afatinib Dimaleate Form H

[0027] Dissolve 50g (102.9mmol) of afatinib base in 500ml of ethyl acetate, heat to 65°C to dissolve, then slowly add 24.5g (211.0mmol) of maleic acid in ethyl acetate (50ml) dropwise to the above solution After the dropwise addition, it was naturally lowered to room temperature and then rapidly cooled to 0° C., stirred for 2 hours, a large amount of solids were precipitated, filtered by suction to obtain off-white powder, dried in vacuum at 40° C. for 6 hours, and the purity was high (HPLC: 99.77%).

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Abstract

The invention relates to a crystal form of afatinib di-meleate, a method for preparing the crystal form, pharmaceutical composition with the same and application of the pharmaceutical composition. X-ray powder diffraction spectra of the crystal form have characteristic peaks at diffraction angles 2theta of 4.9+ / -0.2 degrees, 10.5+ / -0.2 degrees, 12.8+ / -0.2 degrees, 17.2+ / -0.2 degrees and 19.8+ / -0.2 degrees, and a melting point of the crystal form is 168.68. The crystal form, the method, the pharmaceutical composition and the application have the advantage that the pharmaceutical composition can be applied to anti-cancer medicine.

Description

technical field [0001] The invention relates to a crystal form of quinazoline anticancer drugs and a preparation method thereof, belonging to the technical field of medicinal chemistry. Background technique [0002] Afatinib dimaleate, the chemical name is 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo Substituent-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline, (2Z)-2-butenedioic acid (1:2) , whose structure is as follows, [0003] [0004] Afatinib dimaleate, an irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor tyrosine kinase (HER2), is the first treatment for lung cancer after failure of EGFR inhibitor therapy The therapeutic drug can be used for the treatment of advanced non-small cell lung cancer, advanced breast cancer and intestinal cancer. [0005] International Application Publication No. WO2005037824A discloses afatinib dimaleate and a crystalline non-solvent compound thereof (...

Claims

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Application Information

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IPC IPC(8): C07D405/12A61K31/517A61P35/00
CPCC07D405/12A61K31/517
Inventor 余大海康旺李胜李志刚
Owner HEBEI SHINEWAY PHARMA
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