CRYSTALLINEFORM OF AFATINIB DIMALEATE
Field of the Invention
The present invention provides crystalline Form I of afatinib dimaleate, its process
for preparation and pharmaceutical composition thereof, and its use in 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
The discovery of new polymorphic forms of a compound is important in the
development of pharmaceuticals, as these new forms may result in improved as ease of
handling, ease of processing, storage stability, ease of purification, improved dissolution
profile, and/or improved shelf-life.
U.S. Patent No. 8,426,586 and PCT Publication Nos. WO 2012/121764 andWO
2013/052157 provide processes forthe preparation of crystalline forms of afatinib and its
salts.
Summary of the Invention
The present invention relates to crystalline Form I of afatinib dimaleate, its
preparation and pharmaceutical composition thereof, and its use in the treatment of
metastatic non-small cell lung cancer.
The crystalline Form I of afatinib dimaleate of t e present invention is highly pure,
free-flowing, has good solubility, and prolonged shelf life. It is also stable towards
polymorphic conversion and exhibits good bioavailability.
Brief Description of the Drawings
Figure 1: X-ray powder diffraction (XRPD) pattern of t e crystalline Form I of
afatinib dimaleate.
Figure 2 : Thermogravimetric Analysis thermogram of the crystalline Form I of
afatinib dimaleate.
Figure 3: XRPD pattern of crystalline Form A of afatinib dimaleate prepared as per
Example 1 and as disclosed in PCT Publication No. WO 2013/052157.
Detailed Description of the Invention
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 "triple layer package," as used herein, refers to the afatinib dimaleate
being packed in a low density polyethylene (LDPE) pouch, then inserted and heat sealed
under vacuum in a bag with a mixture of polyester/LDPE with silica sachet as a desiccant,
and then further inserted and heat sealed under vacuum into an outer bag with a mixture of
polyester film/aluminum foil/polyester LDPE.
A first aspect of the present invention provides crystalline Form I of afatinib
dimaleate characterized by an X-ray powder diffraction (XRPD) pattern having peaks at dspacings
of about 4.9 and 3.4 A.
The crystalline Form I of afatinib dimaleate is further characterized by an XRPD
pattern having additional peaks at d-spacings of about 17.2, 8.0, 5.8, 4.3, and 3.6 A.
The crystalline Form I of afatinib dimaleate is also characterized by an XRPD
pattern having additional peaks at d-spacings of about 4.4, 4.2, 4.1, 3.5, 3.3, and 3.2 A.
Table 1 summarizes the d-spacing values in A, and the corresponding 2Qvalues,
and the relative intensity of the crystalline Form I of afatinib dimaleate.
Table 1
Crystalline Form I of afatinib dimaleate is further characterized by an XRPD
pattern and a TGA thermogram substantially as depicted in Figures 1 and 2, respectively.
A second aspect of t e present invention provides a process for the preparation of
crystalline Form I of afatinib dimaleate, characterized by an XRPD pattern having peaks at
d-spacings of about 4.9 and 3.4 Acomprising:
i) dissolving afatinib dimaleate in an alcohol to obtain a solution;
ii) adding t e solution of step i) to a polar aprotic solvent; and
iii) isolating the crystalline Form I of afatinib dimaleate
Afatinib dimaleate used as t e starting material can be obtained by following the
process as provided in Example 1 of t e present invention or as described in U.S. Patent
No. 8,426,586.
A third aspect of the present invention provides a process for the preparation of a
crystalline Form I of afatinib dimaleate characterized by an XRPD pattern having peaks at
d-spacings of about 4.9 and 3.4 Acomprising:
i) dissolving afatinib base and maleic acid in an alcohol to obtain a solution;
ii) adding the solution of step i) to a polar aprotic solvent; and
iii) isolating the crystalline Form I of afatinib dimaleate.
Afatinib base used as a starting material can be obtained by following the process
as described in U.S. Patent No. RE43,431.
The solution of afatinib dimaleate of step i) is obtained by suspending a crystalline
form of afatinib dimaleate in an alcohol, or suspending afatinib and maleic acid in an
alcohol, and stirring at a temperature of about 40°C to about 80°C.
Examples of alcohol solvents include methanol, ethanol, 1-propanol, 1-butanol, 2-
butanol, and mixtures thereof.
Examples of polar aprotic solvents include ethyl acetate, acetone, methyl isobutyl
ketone, methyl ethyl ketone, acetonitrile, N,N -dimethylformamide, dimethylsulfoxide,
tetrahydrofuran and mixtures thereof.
The solution of afatinib dimaleate of step i) is added to a polar aprotic solvent at a
temperature of about 20°C to about 40°C, and optionally stirred at a temperature of about
20°C to about 40°C for about 5 hours to about 24 hours, and further stirred at a
temperature of about 0°C to about 5°C for about 1 hour to about 3 hours.
The isolation of crystalline Form I of afatinib dimaleate may be carried out by
concentration, cooling, precipitation, washing, filtration, centrifugation, or combinations
thereof, followed by drying using any suitable method, such as drying under reduced
pressure, vacuum drying, or air drying.
Drying can be carried out at a temperature of about 35°C to about 55°C for about
10 hours to about 24 hours.
A fourth aspect of the present invention provides a pharmaceutical composition
comprising crystalline Form I of afatinib dimaleate characterized by an XRPD pattern
having peaks at d-spacings of about 4.9 and 3.4 Aand one or more pharmaceutically
acceptable carriers, diluents, or excipients.
A fifth aspect of t e present invention provides the use of crystalline Form I of
afatinib dimaleate characterized by an XRPD pattern having peaks at d-spacings of about
4.9 and 3.4 Afor the first-line treatment of patients with metastatic non-small cell lung
cancer whose tumors have an epidermal growth factor receptor exon 19 deletions or exon
2 1 (L858R) substitution mutations.
The crystalline Form I of afatinib dimaleate of present invention is a stable form. It
is not converted to any other form of afatinib dimaleate when kept under storage
conditions 25°C ±2°C and 60% ±5% relative humidity for two months under triple layer
package.
While the present invention has been described in terms of its specific aspects and
embodiments, certain modifications and equivalents will be apparent to those skilled in the
art, and are intended to be included within the scope of the present invention.
Method
The 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° 2Qas range, using CuKa
radiation.
The TGA was recorded using a TA Instruments® Q500.
The following examples are for illustrative purposes only and should not be
construed as limiting the scope of the invention in any way.
EXAMPLES
Example 1: Preparation of a crystalline Form A of afatinib dimaleate
In a round bottom flask, afatinib (20 g) was dissolved in methanol (200 mL) by
stirring at 20°C to 35°C to obtain a solution. Maleic acid (9.5 g) was added to the solution
at the same temperature to obtain a reaction mixture. The reaction mixture was heated and
stirred at 55°C to 60°C for 30 minutes. The reaction mixture was concentrated under
vacuum at 45°C to 46°C to obtain a solid. Cyclohexane (100 mL) was added to the solid
and the mixture was stirred at 45°C to 46°C for 5 minutes. The solution was cooled to
20°C to 30°C to obtain a solid. The solid obtained was filtered and dried under vacuum at
40°C to 45°C to obtain the crystalline Form A of afatinib dimaleate.
Yield: 26.5 g
Example 2 : Preparation of a crystalline Form I of afatinib dimaleate
In a round bottom flask, crystalline Form A of afatinib dimaleate (5 g, as prepared
in Example 1) was suspended in methanol (50 mL) and stirred at 60°C to obtain a clear
solution. The clear solution was added to ethyl acetate (100 mL) at 20°C to 30°C to obtain
a reaction mixture. The reaction mixture was stirred at 20°C to 30°C for 18 hours. The
reaction mixture was cooled to 0°C to 5°C, and then stirred for 1.5 hours to obtain a solid.
The solid was filtered, then washed with ethyl acetate (15 mL) under nitrogen atmosphere,
and then dried under vacuum at 40°C to 45°C for 14 hours to obtain t e crystalline Form I
of afatinib dimaleate.
Yield: 2.5 g
Chromatographic purity: 99.9%
Example 3: Preparation of crystalline Form I of afatinib dimaleate
In a round bottom flask, afatinib (5 g) and maleic acid (2.45 g) were suspended in
methanol (70 mL) and stirred at 25°C for 10 minutes. The reaction mixture was stirred at
60°C to 65°C for 45 minutes. Activated carbon (0.5 g) was added to the reaction mixture
and the mixture was stirred at 60°C to 65°C for 30 minutes. The reaction mixture was
filtered through a Hyflo® bed, and then washed with methanol (5 mL). The filtrate
obtained was stirred at 60°C for 20 minutes to obtain a clear solution. The clear solution
obtained was added to ethyl acetate (150 mL) at 20°C to 30°C to obtain a reaction
mixture. The reaction mixture was stirred at 20°C to 30°C for 5 hours. The reaction
mixture was cooled to 0°C to 5°C, and then stirred for 1.5 hours to obtain a solid. The
solid was filtered, then washed with ethyl acetate (15 mL) under nitrogen atmosphere, and
then dried under vacuum at 40°C to 45°C for 14 hours to obtain the crystalline Form I of
afatinib dimaleate.
Yield: 4.8 g
Chromatographic purity: 99.78%

We Claim :
1. Crystalline Form I of afatinib dimaleate characterized by an X-ray Powder
Diffraction pattern having diffraction peaks at d-spacings of about 4.9 and 3.4 A.
2 . The crystalline Form I of afatinib dimaleate of claim 1, further characterized by an
X-ray Powder Diffraction pattern having additional diffraction peaks at d-spacings of
about 17.2, 8.0, 5.8, 4.4, 4.3, 4.2, 4.1, 3.6, 3.5, 3.3, and 3.2 A.
3 . The crystalline Form I of afatinib dimaleate of claim 1, characterized by an X-ray
Powder Diffraction pattern substantially as depicted in Figure 1.
4 . The crystalline Form I of afatinib dimaleate of claim 1, characterized by a
Thermogravimetric Analysis thermogram substantially as depicted in Figure 2 .
5 . A process for the preparation of t e crystalline Form I of claim 1, comprising:
i) dissolving afatinib dimaleate in an alcohol to obtain a solution;
ii) adding the solution of step i) to a polar aprotic solvent; and
iii) isolating the crystalline Form I of afatinib dimaleate.
6 . A process for the preparation of the crystalline Form I of claim 1 comprising:
i) dissolving afatinib and maleic acid in an alcohol to obtain a solution;
ii) adding the solution of step i) to a polar aprotic solvent; and
iii) isolating the crystalline Form I of afatinib dimaleate.
7 . The process according to claim 5 or 6, wherein the alcohol is selected from
methanol, ethanol, 1-propanol, 1-butanol, 2-butanol, or mixtures thereof.
8. The process according to claim 7, wherein the alcohol is methanol.
9 . The process according to claim 5 or 6, wherein the polar aprotic solvent is selected
from ethyl acetate, acetone, methyl isobutyl alcohol, methyl ethyl ketone, acetonitrile,
N,N -dimethylformammide, dimethylsulfoxide, tetrahydrofuran, or mixtures thereof.
10. The process according to claim 9, wherein the polar aprotic solvent is ethyl acetate.
11. A pharmaceutical composition comprising the crystalline Form I of afatinib
dimaleate of claim 1.
12. The pharmaceutical composition of claim 11 further comprising one or more
pharmaceutically acceptable carriers, diluents, or excipients.
13. A method for first-line treatment of patients with metastatic non-small cell lung
cancer whose tumors have an epidermal growth factor receptor exon 19 deletions or exon
2 1 (L858R) substitution mutations comprising administering to a patient in need thereof
the crystalline Form 1 of afatinib dimaleate of claim 1.
14. A process for manufacturing a pharmaceutical composition comprising mixing t e
crystalline form I of afatinib dimaleate of claim 1together with pharmaceutically
acceptable carriers, diluents, and/or excipients.