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1. (WO2016001844) AMORPHOUS FORM OF AFATINIB DIMALEATE
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AMORPHOUS FORM OF AFATINIB DIMALEATE

Field of the Invention

The present invention provides an amorphous form of afatinib dimaleate, processes for its preparation, a pharmaceutical composition comprising it, and its use for the treatment of metastatic non-small cell lung cancer.

Background of the Invention

Afatinib dimaleate is a tyrosine kinase inhibitor, chemically designated as 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(35)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2£)-, (2Z)-2-butenedioate (1:2) having the structure depicted by Formula I.


Formula I

U.S. Patent Nos. RE43,431 and 6,251,912 provide processes for the preparation of afatinib dimaleate.

U.S. Patent No. 8,426,586 and PCT Publication Nos. WO 2012/121764 and WO

2013/052157 provide processes for the preparation of crystalline forms of afatinib and their salts.

Summary of the Invention

The present invention provides an amorphous form of afatinib dimaleate, processes for its preparation, a pharmaceutical composition comprising it, and its use for the treatment of metastatic non-small cell lung cancer. The amorphous form of afatinib dimaleate is a highly pure, easy to filter, free-flowing solid, and is stable towards polymorphic conversion.

A first aspect of the present invention provides an amorphous form of afatinib dimaleate.

A second aspect of the present invention provides a process for the preparation of an amorphous form of afatinib dimaleate comprising:

i) adding afatinib to maleic acid in the presence of one or more solvents and heating at a temperature of about 40°C to about 80°C to form a reaction mixture;

ii) stirring the reaction mixture;

iii) cooling the reaction mixture; and

iv) isolating the amorphous form of afatinib dimaleate.

A third aspect of the present invention provides a process for the preparation of an amorphous form of afatinib dimaleate comprising:

i) adding afatinib to maleic acid in the presence of one or more solvents and heating at a temperature of about 40°C to about 80°C to form a reaction mixture;

ii) stirring the reaction mixture;

iii) cooling the reaction mixture;

iv) scratching the reaction mixture; and

v) isolating the amorphous form of afatinib dimaleate.

A fourth aspect of the present invention provides a process for the preparation of an amorphous form of afatinib dimaleate comprising subjecting a solution of afatinib dimaleate to spray drying, agitated thin film drying, lyophilization, or concentrating a reaction mixture containing afatinib dimaleate in a solvent under reduced pressure.

A fifth aspect of the present invention provides a pharmaceutical composition comprising an amorphous afatinib dimaleate and one or more pharmaceutically acceptable carriers, diluents, or excipients.

A sixth aspect of the present invention provides the use of an amorphous form of afatinib dimaleate for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have an epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.

Other objects, features, advantages, and aspects of the present invention will become apparent to those skilled in the art from the description provided herein.

Brief Description of the Drawing

Figure 1 : X-ray powder diffraction (XRPD) pattern of an amorphous form of afatinib dimaleate.

Detailed Description of the Invention

Various embodiments and variants of the present invention are described hereinafter.

The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.

The term "ambient temperature," as used herein, refers to a temperature in the range of about 20°C to about 35°C.

The term "scratching," as used herein, refers to the act of getting solid material (for example, seed crystals) out of a reaction mixture by rubbing or crushing the reaction vessel by any means, for example, through glass rod, spatula, etc.

Afatinib can be obtained by following the processes disclosed in U.S. Patent No. RE43,431.

In an embodiment of the present invention, the preparation of the amorphous form of afatinib dimaleate is carried out by reacting afatinib with maleic acid in the presence of one or more solvents and heating the reaction mixture at about 40°C to about 80°C for about 2 hours followed by cooling the reaction mixture to ambient temperature, then scratching the material obtained with a spatula.

The solvent may be selected from the group comprising alcohols, ketones, alkyl acetates, and mixtures thereof. Examples of alcohols include methanol, ethanol, n-propanol, isopropanol, «-butanol, and 2-methyl-l-pentanol. Examples of ketones include acetone, methyl ethyl ketone, and i-butyl ketone. Examples of alkyl acetates include ethyl acetate, propyl acetate, and /-butyl acetate.

Isolation of the amorphous form of afatinib dimaleate from its reaction mixture is carried out by concentration, precipitation, cooling, filtration, centrifugation, or a combination thereof, followed by drying. Drying can be carried out using any suitable method, such as drying under reduced pressure, air drying, vacuum tray drying or heating.

In an embodiment of the present invention, the isolation of the amorphous form of afatinib dimaleate is carried out by filtration, followed by drying at a temperature of about 40°C to about 55°C.

In another embodiment of the present invention, the amorphous form of afatinib dimaleate can be prepared by subjecting a solution of afatinib dimaleate to spray drying, agitated thin film drying, lyophilization, or concentrating a reaction mixture containing afatinib dimaleate in a solvent under reduced pressure

The amorphous form of afatinib dimaleate of the present invention exhibits an X-ray powder diffraction (XRPD) pattern substantially as depicted in Figure 1.

The amorphous form of afatinib dimaleate is a highly pure, easy to filter, free-flowing solid, and is stable towards polymorphic conversion.

In the foregoing section, embodiments are described by way of an example to illustrate the process of the present invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.

Method

X-ray diffraction patterns were recorded using a PANalytical® X'pert PRO with X'celerator® as the detector, 0.02 as step size, and 3-40° 2Θ as range, using CuKa radiation.

Example: Preparation of an amorphous form of afatinib dimaleate

In a round bottom flask, a mixture of afatinib (3 g) and ethyl acetate (30 mL) was heated to about 65°C to obtain a turbid solution. In another round bottom flask, a mixture of maleic acid (1.6 g) and ethyl acetate (30 mL) was heated to about 50°C to obtain a clear solution. The maleic acid solution was added to the afatinib solution, and then the reaction mixture was heated at about 75°C to about 80°C. The reaction mixture was stirred at about 75°C to about 80°C for about 1 hour. The reaction mixture was cooled to about

20°C to obtain a sticky material. The sticky material was scratched with a spatula, and then the reaction mixture was further stirred at about 20°C to about 25°C for about 1 hour. The material obtained was filtered, and then washed with ethyl acetate (20 mL). The solid obtained was dried under vacuum at about 45°C to about 50°C for about 15 hours to obtain the amorphous form of afatinib dimaleate.

Yield: 2.5 g (56%)