Afatinib acid additional salt as well as crystal form, preparation method and medicinal composition thereof

A technology of afatinib and crystal form, which is applied in the direction of drug combination, sulfonate preparation, sulfuric acid amide preparation, etc., which can solve the problems affecting the uniformity of preparations, reducing the content of pharmaceutical active substances, and limited hygroscopicity, so as to reduce the curative effect The effect of reducing risk and safety risk, improving the uniformity of preparation, and good crystal morphology

Active Publication Date: 2017-01-04
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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  • Afatinib acid additional salt as well as crystal form, preparation method and medicinal composition thereof
  • Afatinib acid additional salt as well as crystal form, preparation method and medicinal composition thereof
  • Afatinib acid additional salt as well as crystal form, preparation method and medicinal composition thereof

Examples

Experimental program
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Effect test

preparation example 1

[0121] Preparation Example 1 Preparation of the prior art crystal form of afatinib dimaleate

[0122] 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.

[0123] XRPD analysis such as figure 2 As shown, it is consistent with the prior art crystal form of afatinib dimaleate disclosed in CN1867564B.

[0124] TGA spectrum such as image 3 As shown, it shows that the decomposition temperature of the salt is 164.1°C.

[0125] DSC spectrum such as Figure 4 , showing that the salt has a melting point of 166.2°C.

[0126] DVS isotherm adsorption curve...

Embodiment 1

[0127] Example 1 Preparation of afatinib edisylate

[0128] 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

[0129] Example 2 Preparation of E1 crystal form afatinib edisylate

[0130] 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 invention relates to a novel afatinib acid additional salt as well as a crystal form, a preparation method and a medicinal composition thereof. The afatinib acid additional salt and the crystal form of the afatinib acid additional salt have one or more improved characteristics. The invention further relates to the preparation method, the medicinal composition and an application of the afatinib acid additional salt and the crystal form of the afatinib acid additional salt in preparing medicines for treating and / or preventing advanced non-small cell lung cancer and HER2 positive advanced breast cancer.

Description

[0001] This application is a patent application "afatinib acid addition salt and its crystal form, Its preparation method and pharmaceutical composition" divisional application. technical field [0002] The invention belongs to the technical field of medicinal chemical crystallization, and specifically relates to a novel acid addition salt of afatinib and its crystal form, its preparation method, its pharmaceutical composition and its application. Background technique [0003] 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: [0004] [0005] 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 ta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12A61K31/517A61P35/00A61P11/00A61P1/00A61P1/16
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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