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Acid addition salt of afatinib and its crystal form, its preparation method and pharmaceutical composition

A technology of afatinib and tinib ethanedisulfonate, applied in the directions of drug combination, carboxylate preparation, sulfonate preparation, etc., can solve the problem of affecting the uniformity of preparations, reducing the content of pharmaceutical active substances, and limiting hygroscopicity and other problems, to achieve the effect of reducing the risk of curative effect decline and safety risk, improving the uniformity of the preparation, and having a good crystal morphology.

Active Publication Date: 2016-12-21
倪云
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Preferably, the pharmaceutically active substance should only have limited hygroscopicity, higher hygroscopicity often brings adverse effects
For example, during the manufacturing period, the absorption of moisture reduces the content of pharmaceutical active substances, affects the preparation process, and affects the uniformity of the preparation; moisture-proof measures must be taken during storage, such as adding a desiccant or storing in a moisture-proof environment, which increases the cost. There is also a risk of poor long-term storage stability

Method used

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  • Acid addition salt of afatinib and its crystal form, its preparation method and pharmaceutical composition
  • Acid addition salt of afatinib and its crystal form, its preparation method and pharmaceutical composition
  • Acid addition salt of afatinib and its crystal form, its preparation method and pharmaceutical composition

Examples

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Effect test

preparation example 1

[0321] Preparation Example 1 Preparation of the prior art crystal form of afatinib dimaleate

[0322] Take 100mg of afatinib free base and add 1.5mL of ethanol to stir and dissolve, heat to 70°C, take 50mg of maleic acid and add 0.4mL of ethanol to stir and dissolve, slowly add the ethanol solution of maleic acid to the solution of afatinib free base In the ethanol solution, stirring, after the solid precipitated, the reaction solution was cooled to room temperature, stirred at room temperature for 2-3h, filtered, and vacuum-dried at 40°C overnight to obtain afatinib dimaleate.

[0323] XRPD analysis such as figure 2 As shown, it is consistent with the prior art crystal form of afatinib dimaleate disclosed in CN1867564B.

[0324] TGA spectrum such as image 3 As shown, it shows that the decomposition temperature of the salt is 164.1°C.

[0325] DSC spectrum such as Figure 4 , showing that the salt has a melting point of 166.2°C.

[0326] DVS isotherm adsorption curve...

Embodiment 1

[0327] Example 1 Preparation of afatinib edisylate

[0328] Take 50mg of afatinib free base and add 1mL of ethyl acetate and stir to dissolve, take 19.6mg of ethanedisulfonic acid and add 2mL of ethyl acetate and stir to dissolve, slowly add the ethyl acetate solution of ethanedisulfonic acid to the free base of afatinib A slurry was formed in the ethyl acetate solution of the base, stirred, reacted overnight at room temperature, and a solid precipitated out, and was spin-dried under vacuum at 40°C to obtain 68 mg of afatinib edisylate, with a yield of 97.7%.

Embodiment 2

[0329] Example 2 Preparation of E1 crystal form afatinib edisylate

[0330] Add 50 mg of afatinib free base to 1 mL of acetonitrile and stir to dissolve, take 19.6 mg of ethanedisulfonic acid to add 2 mL of acetonitrile and stir to dissolve, slowly add the acetonitrile solution of ethanedisulfonic acid to the acetonitrile solution of afatinib free base to form The slurry was stirred, reacted overnight at room temperature, and solids precipitated out, filtered, and dried under vacuum at 40°C overnight to obtain 62 mg of afatinib edisylate in E1 crystal form, with a yield of 89%.

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Abstract

The present invention relates to novel afatinib acid addition salts and crystal forms thereof. Compared with the prior art, the afatinib acid addition salts and crystal forms thereof of the present invention have one or more improved properties. The present invention also relates to a preparation method of the novel afatinib acid addition salts and crystal forms thereof, a pharmaceutical composition thereof, and the use thereof in preparing drugs for treating and / or preventing advanced non-small cell lung cancer 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 afatinib acid addition salt and its crystal form, its preparation method, its pharmaceutical composition and its application. 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 , whose structure is as follows: [0003] [0004] Afatinib was developed by Boehringer Ingelheim, Germany, and is suitable for patients with advanced non-small cell lung cancer (NSCLC) and HER2-positive advanced breast cancer. It is taken as an oral tablet, and the standard dose is 40 mg once a day. Now Boehringer Ingelheim is submitting a marketing authorization application to the European Medicines Agency, and it is expected to be listed...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07C309/05C07C303/32C07C309/35C07C55/08C07C51/41C07C59/105C07C307/02C07C303/34C07C309/46C07C59/06C07C57/145A61K31/517A61P35/00
CPCC07B2200/13C07C55/08C07C57/145C07C59/06C07C59/105C07C303/32C07C303/34C07C307/02C07C309/05C07C309/35C07C309/46C07D405/12A61P1/00A61P1/16A61P11/00A61P35/00
Inventor 沈涛盛晓霞盛晓红
Owner 倪云
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