FIELD OF THE INVENTION
The present invention provides two processes for preparation of pure crystalline form B of
flupirtine maleate.
BACKGROUND OF THE INVENTION
Flupirtine is chemically known as 2-amino-6-[(4-flurobenzyl)amino]-3-pyridinecarbamic
acid ethyl ester and is represented by structure as shown in formula 1. Flupirtine shows
antipholgistic and analgesic activity. Flupirtine acts as an antipholgistic drug by relieving
inflammation and fever. Flupirtine also acts as an analgesic medication as it reduces or
eliminates pain.

Flupirtine and its salts of pharmaceutically acceptable acids and their preparation are
disclosedin patent US 3513171.Flupirtine maleate is specifically disclosed in patent US
4481205 and is represented by structure as shown in formula 2.

The patent US 4481205 describes preparation of mixture of crystalline forms A and B of
flupirtine maleate from isopropanol, ethanol under various conditions.
The patent US 5959115 describes preparation of pure crystalline form A of flupirtine from
ethanol or isopropanol.
The publication Karl-Friedrich Landgraf et al, European Journal of Pharmaceutics and
Biopharmaceutics 1998, 46, 329-337 describes various methods of crystallization of

flupirtine maleate from isopropanol and mixture of isopropanol-water to obtain form A, form
B and isopropanol solvate.
The PCT application WO 2008110357 describes process for preparation of crystallineform B
of flupirtine maleate by crystallization from solvent selected from aromatic hydrocarbons,
aromatic halogenated hydrocarbon, aliphatic esters, aliphatic ketones or mixtures thereof with
other solvents or water.
Another PCT application WO 2008007117 describesvarious forms V, W, X, Y and Z of
flupirtine maleate and process for their preparation.
The present invention provides two processes for preparation of pure crystalline form B of
flupirtine maleate which are robust and operable at large scale.
SUMMARY OF THE INVENTION
The present invention provides two processes for preparation of pure crystalline form B of
flupirtine maleate comprising precipitation of flupirtine maleate from mixture of isopropanol
and water.
Brief description of drawing:
Figure 1: X-ray powder diffraptogram of form B.
DETAILED DESCRIPTION OF THE INVENTION
Process I:
The present invention provides a process for preparation of pure crystalline form B of
flupirtine maleate comprising:
i) heating flupirtine maleate in mixture of isopropanol and water at65-75 °C,
ii) adding water to the solution at40-70 °C,
iii) cooling the mixture to 0-25 °C, and
iv) isolating the solid.
In step (i) of process I, the ratio of isopropanol and water is in the range of 1:1 to 1.5:1.
(Volume/Volume)

In step (i) of process I, the volume of isopropanol-watermixture is 8-10times of flupirtine
maleate. (Weight/Volume)
In step (ii) of process I, the amount of water added is 10-15 times of flupirtine maleate.
(Weight/Volume) Water addition is carried out in 5-10 minutes and during which temperature
drops to 45-50 °C.
Process II:
The present invention provides a process for preparation of pure crystalline form B of
flupirtine maleate comprising:
i) heating flupirtine maleate in mixture of isopropanol and water at60-70 °C,
ii) cooling solution to 45-55°C,
iii) adding solution of step (ii) in cold water, and
iv) isolating the solid.
In step (i) of process II, the ratio of isopropanol and water is in the range of 2:1 to 3:1.
(Volume/Volume)
In step (i) of process II, the volume of isopropanol-water mixture is 8-12times of flupirtine
maleate.(Weight/Volume)
In step (iii) of process II, the amount of cold water is 15-25 times of flupirtine maleate
(Weight/Volume) and temperature of cold water is in the range of 5-15 °C. The solution of
step (ii) is added in 5-15 minutes.
Flupirtine maleate used as starting material in the present invention may be crude, pure or
exist in any polymorphic form or mixtures thereof.
The solid may be isolated by the known techniques such as filtration or centrifugation.
The term "pure" in the present invention means crystalline form B of flupirtine maleate
obtained by the process of the present invention is free from detectable amount of any other

crystalline form of flupirtine maleate. The detection of other crystalline form of flupirtine
maleate in form B is determined by the absence of characteristic peaks of form A at 6.9 ±
0.2° 29, form V at 6.5 ± 0.2° 29, form W at 7.9 ± 9.2° 29, form X at 6.6 ± 0.2° 29, form Y at
8.0 ± 0.2° 29 and form Z at 9.9 ± 0.2° 29 in XRPD of form B.
The crystalline form B of flupirtine maleate is characterized by a powder X-ray diffraction
pattern having peak at 5.5 ± 0.2 degree 29. The XRPD of form B is as shown in figure 1.
Experimental:
The powder X-ray diffraction spectrum is measured using PANalytical X"Pert PRO
diffractogram (copper anti cathode) and expressed in terms of inter planar distance d, bragg"s
2 theta, intensity and relative intensity (expressed as a percentage of the most intense peak).
Example 1
Preparation of pure crystalline Form B of flupirtine maleate:
The mixture of flupirtine maleate (30 g) in mixture ofisopropanol (150 mL) and water (112.5
mL) was heated at 65-70 °C for 35 min. To the resulting mixture, water (360 mL) was
addedin 5 min. Temperature drops to 50 °C. The mixture was cooled to 0 °C and maintained
for 2 hours. Solid was filtered, washed with water and dried. Yield: 27.5 g.
Example 2
Preparation of pure crystalline Form B of flupirtine maleate:
The mixture of flupirtine maleate (30 g) in mixture ofisopropanol (150 mL) and water (112.5
mL) was heated at 65-70 °C for 35 min. To the resulting mixture, water (360 mL) was added
in 5 min. Temperature drops to 46 °C. The mixture was cooled to 25 °C and maintained for 2
hours. Solid was filtered, washed with water and dried. Yield: 25.5 g.
Example 3
Preparation of pure crystalline Form B of flupirtine maleate:
The mixture of flupirtine maleate (15 g) in mixture ofisopropanol (105 mL) and water (45
mL) was heated at 65°C for 30 min. The resulting mixture was cooled to 50 °C and then

added tocoldwater (10 °C, 300 mL) in 10 min. The mixture was maintained at 15 °C for 2
hours.Solid was filtered, washed with water and dried. Yield: 11.2 g.

WE CLAIM:
Claim 1: A process for preparation of pure crystalline form B of flupirtine maleate
comprising:
i) heating flupirtine maleate in mixture of isopropanol and water at 65-75 °C,
ii) adding water to the solution at40-70 °C,
iii) cooling the mixture to 0-25 °C, and
iv) isolating the solid.
Claim 2: The process of claim 1 wherein the ratio of isopropanol and water in step (i) is in the
range of 1:1 to 1.5:1.
Claim 3: The process of claim 1 wherein volume of isopropanol-water mixture in step (i) is 8-
10times of flupirtine maleate.
Claim 4: The process of claim 1 wherein the amount of water in step (ii) is 10-15 times of
flupirtine maleate.
Claim 5: A process for preparation of pure crystalline form B of flupirtine maleate
comprising:
i) heating flupirtine maleate in mixture of isopropanol and water at 60-70 °C,
ii) cooling solution to 45-55 °C,
iii) adding solution of step (ii) in cold water, and
iv) isolating the solid.
Claim 6: The process of claim 5 wherein the ratio of isopropanol and water in step (i) is in the
range of 2:1 to 3:1.
Claim 7: The process of claim 5 wherein volume of isopropanol-water mixture in step (i) is 8-
12times of flupirtine maleate.

Claim 8: The process of claim 5 wherein the amount of water in step (iii) is 15-25 times of
flupirtine maleate.
Claim 9:The pure crystalline form B of flupirtine maleate obtained in claim 1 which is free
from detectable amount of any other crystalline form of flupirtine maleate.
Claim 10:The pure crystalline form B of flupirtine maleate obtained in claim 5 which is free
from detectable amount of any other crystalline form of flupirtine maleate.

ABSTRACT

The present invention provides two processes for preparation of pure crystalline form B of
flupirtine maleate comprising precipitation of flupirtine maleate from mixture of isopropanol
and water.