Crystal form of neratinib dimaleate, and preparation method and pharmaceutical composition thereof

A technology of neratinib and maleic acid, applied in the field of medicinal chemistry crystallization, can solve the problems of poor efficacy, low bioavailability of solid pharmaceutical preparations, poor water solubility and the like

Inactive Publication Date: 2018-07-20
SOLIPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The solubility of maleate monohydrate crystal form II in water at room temperature is less than 1 mg / mL, which has the disadvantage of poor water solubility, which easily leads to low bioavailability and poor drug efficacy of its solid pharmaceutical preparations

Method used

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  • Crystal form of neratinib dimaleate, and preparation method and pharmaceutical composition thereof
  • Crystal form of neratinib dimaleate, and preparation method and pharmaceutical composition thereof
  • Crystal form of neratinib dimaleate, and preparation method and pharmaceutical composition thereof

Examples

Experimental program
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Effect test

preparation example 1

[0096] Preparation Example 1 Preparation of neratinib-maleate monohydrate crystal form II

[0097] Referring to the method of Example 1 in the patent document CN101918390B, neratinib monomaleate monohydrate crystal form II was prepared, and the specific operation was as follows: the crude product (E)-N-{4-[3-chloro-4- (2-pyridylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolyl}-4-(dimethylamino)-2-butenamide free base (0.100kg , 0.159 mol) was rinsed with a 10% solution of USP purified water in n-propanol (0.082 kg, 0.10 L), then a water:n-propanol solution (0.74 kg, 0.90 L) was added. Maleic acid (0.0191 kg, 0.164 mol) was added and the mixture was rinsed with 10% water: n-propanol (0.082 kg, 0.10 L). The mixture was heated rapidly to 50-60° C. for at least 15 minutes until a solution was obtained. The hot solution was clarified by passing it through a 0.2 Mm filter cartridge preheated to 50-60°C, and the filtrate was collected in a 2L multi-neck flask preheated to 45-55°C. T...

preparation example 2

[0099] Preparation example 2 Preparation of neratinib-maleate anhydrate crystal form I

[0100] Referring to the method of Example 2 in the patent document CN101918390B, neratinib-maleate anhydrate crystal form I was prepared, and the specific operation was as follows: the product (II type) obtained in Preparation Example 1 was dried (50°C, 10mmHg , 24h), to obtain 94.4g (88% yield) of crystals, namely anhydrous (E)-N-{4-[3-chloro-4-(2-pyridylmethoxy)anilino]-3- Cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide maleate (Type I).

[0101] Its XRPD pattern is as follows figure 1 As shown, it is consistent with the XRPD spectrum of neratinib-maleate anhydrate crystal form I reported in the patent document CN101918390B.

[0102] It has been tested that it is easily transformed into monohydrate crystal form II at room temperature and in water.

Embodiment 1

[0104] Take 20mg of neratinib-maleate anhydrous crystal form I, add 1.5mL of methanol, ultrasonically dissolve at 50°C, and concentrate to dryness under reduced pressure in a water bath at 30°C to obtain 18mg of neratinib-maleate of amorphous. XRPD patterns such as image 3 shown.

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Abstract

The invention relates to a crystal form of neratinib dimaleate. Compared with the prior art, the crystal form of neratinib dimaleate in the invention has better solubility in water. The invention alsorelates to a preparation method for the crystal form of neratinib dimaleate, a pharmaceutical composition of neratinib dimaleate and application of neratinib dimaleate to preparation of drugs used for treating, inhibiting and/or preventing cancers.

Description

technical field [0001] This application relates to the technical field of medicinal chemical crystallization. Specifically, the application relates to neratinib dimaleate and its crystal form, as well as its preparation method, pharmaceutical composition and use. Background technique [0002] Neratinib, the English name is Neratinib, the chemical name is (E)-N-{4-[3-chloro-4-(2-)pyridylmethoxy)anilino]-3-cyano-7- Ethoxy-6-quinolyl}-4-(dimethylamino)-2-butenamide is a highly selective HER2 and EGFR inhibitor, and its chemical structural formula is as follows: [0003] [0004] Neratinib and salts thereof are useful in the treatment of cancers including, but not limited to, pancreatic cancer, melanoma, lymphatic cancer, parotid gland tumor, Barrett's esophagus cancer, esophageal cancer, head and neck cancer, ovarian cancer, breast cancer Carcinoma, epithelioid neoplasm, cancer of major organs such as kidney, bladder, larynx, stomach and lung, colon polyps and colorectal c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/4709A61P35/00
CPCC07D401/12C07B2200/13
Inventor 盛晓红盛晓霞汪晶
Owner SOLIPHARMA
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