Afatinib-maleate crystal form, preparation method and pharmaceutical composition 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 test data comparison data, not providing beneficial properties, etc., to achieve Good heat stability and storage stability, high crystallinity, easy preparation effect

Active Publication Date: 2019-07-30
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, preparation method and pharmaceutical composition thereof
  • Afatinib-maleate crystal form, preparation method and pharmaceutical composition thereof
  • Afatinib-maleate crystal form, preparation method and pharmaceutical composition 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 the patent document CN1867564B, and the specific operations are as follows:

[0075] Take 1.0 g of afatinib free base, add 14 mL of ethanol, stir to dissolve, and heat to 70 °C. Take 0.5g of maleic acid, add 6mL of ethanol and stir to dissolve, slowly drop the ethanol solution of maleic acid into the ethanol solution of afatinib free base and stir, after the solid is precipitated, cool the reaction solution to 20°C and stir for 2 hours , and then stirred at 0° C. for 3 hours, filtered, rinsed with ethanol, and dried in vacuo at 40° C. overnight to obtain afatinib dimaleate with a yield of 90%.

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

[0077] Its DVS adsorption isotherm curve is as follows figure 2 As shown, the weight change of the salt in the range of 10% to 8...

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, form a solution and stir, slowly add 60 mL of tertiary methyl 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-maleate salt 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 salt-forming ratio of afatinib free base and maleic acid in the salt is about 1:1.

[0082] HPLC detection shows that the content of a...

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 ultrasonically dissolve, add 24 mg of maleic acid to the ethanol solution of afatinib free base, form a solution and stir, add 2.5 mL of n-heptane, stir After 2 days of crystallization, filtration, and vacuum drying at 40°C for 16 hours, 105 mg of afatinib-maleate salt 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 the known afatinib salt crystal form, the afatinib-maleate crystal form of the present invention has various improved properties. The present invention also relates to a pharmaceutical composition comprising the afatinib-maleate crystal form, and its use in the preparation of medicines for treating 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 afatinib-maleate 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 , and 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 patients with advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR mutations. The approved dosage form is an oral tablet. Afatinib is a potent and selective dual inhibitor of epidermal grow...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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