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Polymorphic forms and salt forms of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide

IP.com Disclosure Number: IPCOM000241387D
Publication Date: 2015-Apr-22
Document File: 24 page(s) / 1M

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Page 01 of 24

Polymorphic forms and salt forms of 4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3- (trifluoromethyl)phenyl] benzamide

Herein are described the preparation of different polymorphic forms of nilotinib, 4- methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1 H-imidazol-1-yl)-3- (trifluoromethyl)phenyl] benzamide, different salt forms of nilotinib and different polymorphic forms thereof.

Preparation of Nilotinib form C

Nilotinib base (20 mg) was dissolved in 1-pentanol (2 mL) with stirring and heating to 100ºC, before cooling the solution to - 17ºC. Precipitation was observed and the product was filtered on a Buchner funnel under vacuum. The solid was analyzed by XRD as shown in figure 1.

Figure 1:

Counts

1400

1200

1000

800

600

400

200

0

Position [º2The

ta](Copper(Cu))

XRD diffractogram of Nilotinib form C

Preparation of Nilotinib form D

Nilotinib

base (202 mg) was dissolved in 3-pentanone (50 mL) with stirring and heating

to 100ºC. Heptane

(120 mL) was

added to the

solution resulting

in immediate.

precipitation. The

product was filtered

on a Buchner

funnel under

vacuum. The solid

was analyzed by XRD

as shown in figure 2.


Page 02 of 24

Counts

1400

1200

1000

800

600

400

200

0

Position [º2The

ta](Copper(Cu))

Figure 2:

XRD diffractogram of Nilotinib form D

Preparation of Nilotinib form E

Nilotinib base (20

mg) was dissolved

in 2,2,2

-trifluoroethanol (0.5

mL) with stirring at

room temperature.

Crystallization

was observed

after 7

days by slow solvent

evaporation. The

product was filtered

on a Buchner

funnel under

vacuum. The solid

was analyzed by XRD

as shown in figure 3

.

Counts

400

300

200

100

0

Position [º2The

ta](Copper(Cu))

Figure 3:

XRD diffractogram of Nilotinib form E

Preparation of Nilotinib form F

Nilotinib base (50

mg) was dissolved

in ethanol


(6.3 mL) with

stirring at 80ºC. The

solvent was removed

under vacuum.

The solid

was analyzed

by XRD as shown in

figure 4.


Page 03 of 24

Counts

500

400

300

200

100

0

Position [º2The

ta](Copper(Cu))

Figure 4:

XRD diffractogram of Nilotinib form F

Preparation of Nilotinib form G

Nilotinib base (20 mg) was dissolved in N,N-dimethylformamide (0.5 mL) with stirring at

room temperature.

Crystallization

was observed

after 12 days

by slow solvent

evaporation. The

product was filtered

on a Buchner

funnel under

vacuum. The solid

was analyzed by XRD as shown in figure 5.

Counts

1800

1600

1400

1200

1000

800

600

400

200

0

Position [º2The

ta](Copper(Cu))

Figure 5:

XRD diffractogram of Nilotinib form G

Preparation of amorphous

Nilotinib

Nilotinib base (500

mg) was dissolved

in THF (50

mL) with stirring

and heating. The

solution was concentrated

using a

rotory evaporator

to give

amorphous nilotinib. The

solid was analyzed by XRD as shown in figure 6.


Page 04 of 24

XRD diffractogram of amorphous Nilotinib

Preparation of Nilotinib hydrobromide form V

Figure 6:

A mixture of Nilotinib

base (100 mg)

and hydrobromic

acid 9M (14

mg) was stirred in

e...