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Afatinib-maleate crystal form, and preparation method and pharmaceutical compositions thereof

A technology of maleate and afatinib, which is applied in the field of afatinib-maleate crystal form and its preparation, can solve the problems of not providing detection data comparison data, not providing beneficial properties, etc., to achieve Good thermal stability and storage stability, high crystallinity, good solubility effect

Active Publication Date: 2016-07-27
倪云
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this document only generally mentions that the above-mentioned acid addition salts of afatinib and their crystal forms have at least one beneficial property, and for any of the above-mentioned acid addition salts of afatinib or their crystal forms, the document None of them provided any beneficial properties, nor did they provide any test data related to beneficial properties and comparative data for practical applications

Method used

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  • Afatinib-maleate crystal form, and preparation method and pharmaceutical compositions thereof
  • Afatinib-maleate crystal form, and preparation method and pharmaceutical compositions thereof
  • Afatinib-maleate crystal form, and preparation method and pharmaceutical compositions thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0074] For the preparation of the prior art crystal form of afatinib dimaleate, refer to Example 3 of patent document CN1867564B. The specific operation is as follows:

[0075] Take 1.0 g of afatinib free base, add 14 mL of ethanol and stir to dissolve, and heat to 70°C. Take 0.5g of maleic acid, add 6mL of ethanol and stir to dissolve, slowly add the ethanol solution of maleic acid dropwise to the ethanol solution of afatinib free base and stir. After the solid precipitates, the reaction solution is cooled to 20°C and stirred for 2 hours Then, it was stirred at 0°C for 3 hours, filtered, washed with ethanol, and the solid was vacuum dried at 40°C overnight to obtain afatinib dimaleate with a yield of 90%.

[0076] Its XRPD map is as follows figure 1 As shown, the display is consistent with the prior art crystal form of afatinib dimaleate disclosed in CN1867564B.

[0077] Its DVS isotherm adsorption curve is as figure 2 As shown, it is shown that the weight change of the salt is 2...

Embodiment 1

[0079] Example 1 Preparation of afatinib maleate crystal form N

[0080] At room temperature, take 5.0 g of afatinib free base, add 20 mL of tetrahydrofuran and dissolve it ultrasonically, add 1.79 g of maleic acid to the tetrahydrofuran solution of afatinib free base to form a solution and stir, slowly add 60 mL of methyl tert The butyl ether was formed into a slurry, stirred for 1 day to crystallize, filtered, and the filter cake was vacuum dried at 40° C. for 8 hours to obtain 5.3 g of afatinib monomaleate crystal form N with a yield of 85.6%.

[0081] 1 H-NMR (DMSO) data are as follows: 9.93(s,1H), 9.77(s,1H), 8.95(s,1H), 8.57(s,1H), 8.05-8.15(m,1H), 7.72-7.85( m,1H),7.44(t,J=9.0Hz,1H),7.28(s,1H),6.81(s,1H),6.10(s,1H),5.32(s,1H),3.85-4.05(m ,5H),3.71-3.85(m,1H),2.75-2.85(m,1H), 2.83(s,6H), 2.30-2.42(m,1H), 2.06-2.20(m,1H). It shows that the ratio of afatinib free base to maleic acid in the salt is about 1:1.

[0082] HPLC detection showed that the content of afatinib in the s...

Embodiment 2

[0086] Example 2 Preparation of afatinib maleate crystal form N

[0087] At room temperature, take 100 mg of afatinib free base, add 0.5 mL of ethanol to dissolve it ultrasonically, add 24 mg of maleic acid to the ethanol solution of afatinib free base to form a solution and stir, add 2.5 mL of n-heptane, and stir After 2 days of crystallization, filtration, and vacuum drying at 40°C for 16 hours, 105 mg of afatinib maleate form N was obtained, with a yield of 84.7%.

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Abstract

The invention relates to a novel Afatinib-maleate crystal form and a preparation method thereof. Compared with a known Afatinib salt crystal form, the Afatinib-maleate crystal form provided by the invention has a plurality of improved characteristics. The invention also relates to pharmaceutical compositions containing the Afatinib-maleate crystal form, and application in preparation of drugs used for treatment of advanced non-small cell lung cancer (NSCLC) and HER2 positive advanced breast cancer.

Description

Technical field [0001] The invention belongs to the technical field of medicinal chemical crystallization, and specifically relates to a novel afatinic acid monomaleate crystal form and a preparation method thereof, as well as a pharmaceutical composition and application thereof. Background technique [0002] The chemical name of afatinib is N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furyl]oxy]-6- Quinazolinyl]-4-(dimethylamino)-2-butenamide, the English name is Afatinib, also known as BIBW2992, molecular formula C 24 H 25 ClFN 5 O 3 , Its chemical structure is as follows: [0003] [0004] Afatinib was developed by Boehringer Ingelheim and was approved by the US Food and Drug Administration and the European Medicines Agency in 2013 for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) patients with EGFR mutations. The approved dosage form is an oral tablet. Afatinib is a potent and selective dual inhibitor with epidermal growth factor re...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07C57/145C07C51/41A61K31/517A61P35/00
CPCA61K9/0053A61K9/2054A61K9/4866C07B2200/13C07D405/12A61P35/00C07C57/145
Inventor 郑剑锋盛晓红盛晓霞
Owner 倪云
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