NOVEL POLYMORPHIC FORMS OF AN ANTIDIABETIC AGENT: PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

NOUVELLES FORMES POLYMORPHES D'UN AGENT ANTIDIABETIQUE, LEUR PROCEDE DE PREPARATION ET COMPOSITIONS PHARMACEUTIQUES LES RENFERMANT

English Abstract

This invention relates to novel polymorphic/pseudopolymorphic forms of
arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, having formula (I). The invention also relates to a pharmaceutical
composition comprising the novel polymorphic form or their mixture and a
pharmaceutically acceptable carrier. The polymorphic forms of the present
invention are more active, as antidiabetic and hypolipidemic agent, than the
novel 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

French Abstract

L'invention concerne de nouvelles formes polymorphes/pseudompolymorphes d'un sel arginine d'acide 3-[4-[2-(phénoxazine-10-yl)éthoxy]phényl]-2-éthoxypropanoïque de formule (I). L'invention concerne aussi une composition pharmaceutique comprenant les nouvelles formes polymorphes ou leur mélange et un support pharmaceutiquement acceptable. Les formes polymorphes sont plus actives comme agent antidiabétique et hypolipidémique que le nouvel acide 3-[4-[2-(phénoxazin-10-yl)éthoxy]phényl]-2-éthoxypropanoïque.

Claims

34

We claim

1. A polymorphic Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,

Image

which is characterized by the data described hereunder:
DSC: Endotherms at 181.21 °C (onset at 177.70 °C)
X-ray powder diffraction (2~): 8.18, 12.40, 16.66, 18.80, 19.44, 22.32, 22.84,
23.10, 23.50, 24.72, 29.84,
Infrared absorption bands (cm-1): 3249, 3062, 1709, 1587, 1489, 1374, 1272,
1243, 1112, 1043, 919, 737, 673, 543.

2. A polymorphic Form-II of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,

Image

which is characterized by the data described hereunder:
DSC: Endotherms at 131 °C, 166.24 °C and 178.96 °C
Exotherm at 169.73 °C
X-ray powder diffraction (2~): 6.78, 11.5, 12.08, 16.44, 19.34, 22.30, 22.72,
24.40, 26.66
Infrared absorption bands (cm-1): 3055, 1711, 1589, 1510, 1491, 1376, 1274,
1111, 1039, 810, 730, 543.

3. A polymorphic Form-III of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,



35

Image

which is characterized by the data described hereunder:
DSC: Exotherm at 168.00 °C
Endotherm at 182.20 °C (onset at 171 °C),
Small endotherms at 99.66 °C, 164.38 °C
X-ray powder diffraction (2~): 6.80, 12.10, 15.84, 17.02, 19.40, 22.32, 22.68,
24.38, 26.36,
Infrared absorption bands (cm-1): 3061, 1710, 1588, 1510, 1491, 1379, 1273,
1110, 1040, 805, 739, and 543.

4. A polymorphic Form-IV of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid,having the formula I,

Image

which is characterized by the data described hereunder:
DSC: Small Exotherm at 171.80 °C
Endotherms at 149.85 °C, 185.60 °C (onset at 147.78 °C)
Small Endotherm at 164.51 °C
X-ray powder diffraction (2~): 6.78, 12.66, 15.96, 16.54, 19.34, 22.78, 24.42,
26.70, 31.70,
Infrared absorption bands (cm-1): 3056, 1711, 1589, 1493, 1381, 1274, 1242,
1101, 1060, 805, 743, and 543.7.

5. A polymorphic Form-V of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,



36

Image

which is characterized by the data described hereunder:
DSC: Small exotherm at 173.82 °C
Endotherm at 185.95 °C, (onset at 178.09 °C)
Small endotherms at 119.81 °C, 164.69 °C, 172.44 °C
X-ray powder diffraction (2~): 6.76, 12.10, 15.96, 17.00, 18.50, 19.40, 22.38,
22.44, 24.44, 26.30,
Infrared absorption bands (cm-1): 3266, 3055, 1711, 1589, 1510, 1492, 1379,
1274, 1175, 1111, 1040, 918, 819, 730, 676, 544.

6. A polymorphic Form-VI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,

Image

which is characterized by the data described hereunder:
DSC: Exotherm at 157.98 °C,
Endotherms at 179.11 °C and 183.69 °C (onset at 157.98
°C),
Small endotherm at 77.80 °C
X-ray powder diffraction (2~): No diffraction peaks due to its amorphous
nature,
Infrared absorption bands (cm-1): 3065, 1629, 1490, 1377, 1273, 1244, 1109,
1042, 805, 740, 539.

7. A polymorphic Form-VII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,



37

Image

which is characterized by the data described hereunder:
DSC: Exotherm at 132.93 °C,
Endotherms at 176.63 °C (onset at 169.06 °C) and 184.09
°C
X-ray powder diffraction (2~): No diffraction peaks due to its amorphous
nature,
Infrared absorption bands (cm-1): 3065, 1629, 1490, 1377, 1273, 1109, 1042,
740,541.

8. A polymorphic Form-VIII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,

Image

which is characterized by the data described hereunder:
DSC: Exotherm at 158.27 °C
Endotherm at 178.12 °C (onset at 167.15 °C),
Small Endotherm at 152.72 °C
X-ray powder diffraction (2~): 4.16, 11.02, 15.94, 19.50, 20.22, 22.22, 27.38,
Infrared absorption bands (cm-1): 3151, 1629, 1490, 1378, 1272, 1244, 1104,
1041, 742, 549.

9. A polymorphic Form-IX of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,

Image



38

which is characterized by the data described hereunder:

DSC: Endotherm at 176.67 °C (onset at 173.36 °C), (Fig -21)
X-ray powder diffraction (2~): 8.20, 12.42, 16.66, 18.80, 19.44, 22.30, 23.08,
27.38, 28.48, 29.84, (Fig -9)
Infrared absorption bands (cm-1): 3066, 1588, 1489, 1376, 1273, 1243, 1110,
1043, 919, 805, 737, 543, (Fig -33)

10. A polymorphic Form-X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,

Image

which is characterized by the data described hereunder:
DSC: Endotherm at 184.53 °C,)
Exotherm at, 162.67 °C
X-ray powder diffraction (2~): No diffraction peaks due to its amorphous
nature,
Infrared absorption bands (cm-1): 3413, 1630, 1511, 1491, 1377, 1273, 1244,
1176, 1108, 741.

11. A polymorphic Form-XI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,

Image

which is characterized by the data described hereunder:
DSC: Endotherm at 184.40 °C (onset at 177.67 °C),
X-ray powder diffraction (2~): 7.38, 7.56, 11.90, 12.32, 14.80, 16.40, 19.58,
20.48, 22.34, 22.90, 23.54,



39

Infrared absorption bands (cm-1): 3383, 2925, 1629, 1510, 1490, 1377, 1273,
1243, 1090, 1041, 739, 539.

12. A mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I,

Image

which is characterized by the following data:

DSC: Endotherms at 181.28 °C, 185.31 °C, (onset at 173.54
°C)
X-ray powder diffraction (2~): 8.16, 12.40, 16.64, 18.78, 19.42, 22.34, 22.80,
23.08, 29.84,
Infrared absorption bands (cm-1): 3247, 3066, 1708, 1587, 1510, 1489, 1375,
1273, 1244, 1178, 1111, 1043, 805, 737, 673, 543.

13. A pharmaceutical composition comprising any one of polymorphic Form
selected from Form I to XI or a mixture of polymorphic Form I and X of L-
arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid, having the formula I

Image

and a pharmaceutically acceptable carrier, diluent, excipient or solvate.

14. A process for the preparation of the polymorphic Form-I of L-arginine salt
of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having
the characteristics defined in claim 1, which comprises:


40

(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the
solution
obtained in step (i),
(iii) stirring the reaction mixture at a temperature of 40-80 °C for a
period in the
range of 18-30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4-
16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

15. A process for the preparation of the polymorphic Form-I of L-arginine salt
of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having
the characteristics defined in claim 1, which comprises:

(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the
solution
obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the
range of 90-
100 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4-
16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

16. A process for the preparation of the polymorphic Form-II of L-arginine
salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having
the characteristics defined in claim 2, which comprises:



41

(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in acetone,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the
solution
obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the
range of 18-
30 h to obtain a white crystalline precipitate
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4-
16 h to yield Form-II of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

17. A process for the preparation of the polymorphic Form-III of L-arginine
salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having
the characteristics defined in claim 3, which comprises:

(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in 1,4-dioxane,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the
solution
obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the
range of 18-
30 h to obtain a white crystalline precipitate
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45 C for a period in the range
of 4-
16 h to yield Form-III of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

18. A process for the preparation of the polymorphic Form-IV of L-arginine
salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having
the characteristics defined in claim 4, which comprises:





42

(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in dimethyl sulfoxide,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the
solution
obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the
range of 18-
30 h to obtain a white crystalline precipitate
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45°C for a period in the
range of 4-
16 h to yield Form-IV of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

19. A process for the preparation of the polymorphic Form-V of L-arginine salt
of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having
the characteristics defined in claim 5, which comprises:

(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in dimethyl formamide,
(ii) adding L-arginine dissolved in water slowly with constant stirring in the
solution
obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the
range of 18-
30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(vi) drying under vacuum at a temperature of 40-45°C for a period in
the range of 4-
16 h to yield Form-V of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

20. A process for the preparation of the polymorphic Form-VI of L-arginine
salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having
the characteristics defined in claim 6, which comprises:




43

(i) dissolving any of the polymorphic Forms I-V of L-arginine salt of (2S) 3-
[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, in water and
(ii) freeze drying the resulting solution to yield an amorphous white powder
of
Form-VI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid.

21. A process for the preparation of the polymorphic Form-VII of L-arginine
salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having
the characteristics defined in claim 7, which comprises
(i) dissolving any of the polymorphic Forms I-V of L-arginine salt of (2S) 3-
[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, in methanol and
(ii) evaporating the resulting solution under vacuum to obtain an amorphous
white
powder of Form-VII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

22. A process for the preparation of the polymorphic Form-VIII of L-arginine
salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having
the characteristics defined in claim 8, which comprises
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring in the
solution
obtained in step (i),
(iii) stirring the reaction mixture at a temperature of 40-80°C for a
period in the
range of 18-30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45°C for a period in the
range of 4-
16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid,




44

(vi) refluxing the Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained above in step (v) in 1,4-
dioxane for a period in the range of 8-16 h and
(vii) filtering and drying under vacuum at a temperature of 40-45°C for
a period in
the range of 4-16 h to yield Form-VIII of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

23. A process for the preparation of the polymorphic Form-IX of L-arginine
salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having
the characteristics defined in claim 9, which comprises
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring in the
solution
obtained in step (i),
(iii) stirring the reaction mixture at a temperature of 40-80°C for a
period in the
range of 18-30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45°C for a period in the
range of 4-
16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
(vi) refluxing the Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained above in step (v) in 1,4-
dioxane for a period in the range of 8-16 h,
(vii) filtering and drying under vacuum at a temperature of 40-45°C for
a period in
the range of 4-16 h to yield Form-VIII of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
(viii) refluxing the Form-VIII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-
10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained in step (vii) above in
isopropyl alcohol for a period in the range of 8-16 h and




45

(viii) filtering and drying under vacuum at a temperature of 40-45°C
for a period in
the range of 4-16 h to yield Form-IX of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

24. A process for the preparation of the polymorphic Form-X of L-arginine salt
of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having
the characteristics defined in claim 10, which comprises
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the
solution
obtained in step (i),
(iii) stirring the reaction mixture at a temperature of 40-80°C for a
period in the
range of 18-30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45°C for a period in the
range of 4-
16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid and
(vi) heating the polymorphic Form-I obtained in step (v) at 185°C and
cooling it to
room temperature to yeild Form-X of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

25. A process for the preparation of the polymorphic Form-XI of L-arginine
salt of
(2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having
the characteristics defined in claim 11, which comprises
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the
solution
obtained in step (i),




46

(iii) stirring the reaction mixture at a temperature of 40-80°C for a
period in the
range of 18-30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45°C for a period in the
range of 4-
16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
(vi) heating the polymorphic Form-I obtained in step (v) to 185°C and
cooling it to
room temperature to yeild Form-X of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid and
(vii) heating the polymorphic Form-X obtained in step (vi) to 175°C and
cooling it to
room temperature to yield Form-XI of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

26. A process for the preparation of the mixture of polymorphic Form I and X
of L-
arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid, having the characteristics defined in claim 11, which
comprises
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent
(ii) adding L-arginine dissolved in water slowly with constant stirring in the
solution
obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the
range of 18-
30 h to separate white crystalline powder,
(iv) filtering the white crystalline powder obtained in step (iii) and
(v) drying under vacuum at a temperature of 40-45°C for a period in the
range of 4-
16 h to yield mixture of polymorphic Form I and X of L-arginine salt of (2S) 3-

[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.




47

27. A process for the preparation of polymorphic Form I of L-arginine salt of
(2S) 3-
[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the
characteristics defined in claim 1, which comprises:
(i) suspending any of the polymorphic Form II to XI or the mixture of
polymorphic
Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid in isopropyl alcohol and stirring in
dark conditions at room temperature for a period of 35-50 h,
(ii) filtering and washing with isopropyl alcohol and
(iii) drying under vacuum at a temperature of 40-45°C for a period in
the range of 4-
16 h to yield polymorphic Form of I of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.

28. A pharmaceutical composition comprising a mixture of any of polymorphic
Forms I to XI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula (I) and a
pharmaceutically acceptable carrier, diluent, excipient or solvate.

29. A process as claimed in claims 14 and 22 to 26, wherein the organic
solvents are
selected from acetonitrile, ethanol, methanol, 1,4-dioxane, and isopropanol.

30. A pharmaceutical composition as claimed in claim 13, in the form of a
tablet,
capsule, powder, syrup, solution or suspension.

31. A method of preventing or treating hyperlipemia, hypercholesteremia,
hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance,
insulin resistance, or diseases in which insulin resistance is the underlying
pathophysiological mechanism comprising administering a polymorphic Form
selected from Form I to XI or a mixture of polymorphic Form I and X of L-
arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid, having the formula I as defined in claims 1-12 or a
pharmaceutical composition as claimed in claims 13, 28 and 30 to a patient in
need thereof.




48

32. A method according to claim 31, wherein the disease is type II diabetes,
impaired
glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as
hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery
disease
and other cardiovascular disorders, certain renal diseases including
glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive
nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial
cell
activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose
reductase inhibitors, for improving cognitive functions in dementia and
treating
diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic
dystrophy, pancreatitis, arteriosclerosis, xanthoma and cancer.

33. A method according to claim 31 for the treatment and/or prophylaxis of
disorders related to Syndrome X, which comprises administering an agonist of
PPARa, and/or PPARy of formula (I).

34. A method of reducing plasma glucose, triglycerides, total cholesterol,
LDL,
VLDL and free fatty acids in the plasma comprising administering a
polymorphic Form selected from Form I to XI or a mixture of polymorphic Form
I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid, having the formula I as defined in claims 1-12 or a
pharmaceutical composition as claimed in claims 13 and 30.

35. A method of preventing or treating hyperlipemia, hypercholesteremia,
hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance,
insulin resistance, or diseases in which insulin resistance is the underlying
pathophysiological mechanism comprising administering a polymorphic Form
selected from Form I to XI or a mixture of polymorphic Form I and X of L-
arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid, having the formula I as defined in claims 1-12 or a
pharmaceutical composition as claimed in claims 13, 28 and 30 in combination/
concomittant with HMG CoA reductase inhibitors or fibrates or nicotinic acid
or
cholestyramine or colestipol or probucol which may be administered together or
within such a period as to act synergistically together to a patient in need
thereof.

36. A method according to claim 35, wherein the disease is type II diabetes,
impaired
glucose tolerance, dyslipidaemia, disorders related to Syndrome X such as




49

hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery
disease
and other cardiovascular disorders, certain renal diseases including
glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive
nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial
cell
activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose
reductase inhibitors, for improving cognitive functions in dementia and
treating
diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic
dystrophy, pancreatitis, arteriosclerosis, xanthoma and cancer.

37. A method according to claim 35 for the treatment and/or prophylaxis of
disorders related to Syndrome X, which comprises administering a polymorphic
Form selected from Form I to XI or a mixture of polymorphic Form I and X of
L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid, having the formula I as defined in claims 1-12 in
combination with HMG CoA reductase inhibitors or fibrates or nicotinic acid or
cholestyramine or colestipol or probucol which may be administered together or
within such a period as to act synergistically together.

38. A method of reducing plasma glucose, triglycerides, total cholesterol,
LDL,
VLDL and free fatty acids in the plasma, which comprises administering a
polymorphic Form selected from Form I to XI or a mixture of polymorphic Form
I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid, having the formula I as defined in claims 1-12 or a
pharmaceutical composition as claimed in claims 13, 28 and 30 in combination/
concomittant with HMG CoA reductase inhibitors or fibrates or nicotinic acid
or
cholestyramine or colestipol or probucol which may be administered together or
within such a period as to act synergistically together to a patient in need
thereof.

39. A method according to claim 35 for the treatment and/or prophylaxis of
disorders related to Syndrome X, which comprises administering to a patient in
need thereof an agonist of PPARa and/or PPARy of formula (I) as claimed in
claims 1-12 or a pharmaceutical composition according to claim 13 or 30 and
HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine,
colestipol or probucol or their combination within such a period as to act
synergistically.





50

40. Use of a polymorphic Form selected from Form I to XI or a mixture of
polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in
claims 1-12 or a pharmaceutical composition as claimed in claims 13, 28 and 30
for preventing or treating hyperlipidemia, hypercholesteremia, hyperglycemia,
osteoporosis, obesity, glucose intolerance, leptin resistance, insulin
resistance, or
diseases in which insulin resistance is the underlying pathophysiological
mechanism.

41. Use of a polymorphic Form according to claim 40, wherein the disease is
type II
diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to
Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia,
coronary artery disease and other cardiovascular disorders, certain renal
diseases
including glomerulonephritis, glomerulosclerosis, nephrotic syndrome,
hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to
endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS),
useful as aldose reductase inhibitors, for improving cognitive functions in
dementia and treating diabetic complications, osteoporosis, inflammatory bowel
diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or
cancer.

42. Use of a polymorphic Form selected from Form I to XI or a mixture of
polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in
claims 1-12 or a pharmaceutical composition as claimed in claims 13, 28 and 30
for reducing plasma glucose, triglycerides, total cholesterol, LDL, VLDL and
free fatty acids in the plasma.

43. Use of a polymorphic Form selected from Form I to XI or a mixture of
polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in
claims 1-12 or a pharmaceutical composition as claimed in claims 13, 28 and 30
in combination/concomittant with HMG CoA reductase inhibitors, fibrates,
nicotinic acid, cholestyramine, colestipol or probucol which may be
administered
together or within such a period as to act synergistically together for
preventing
or treating hyperlipidemia, hypercholesteremia, hyperglycemia, osteoporosis,




51

obesity, glucose intolerance, leptin resistance, insulin resistance, or
diseases in
which insulin resistance is the underlying pathophysiological mechanism to a
patient in need thereof.

44. Use of a polymorphic Form according to claim 43, wherein the disease is
type II
diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to
Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia,
coronary artery disease and other cardiovascular disorders, certain renal
diseases
including glomerulonephritis, glomerulosclerosis, nephrotic syndrome,
hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to
endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS),
useful as aldose reductase inhibitors, for improving cognitive functions in
dementia and treating diabetic complications, osteoporosis, inflammatory bowel
diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or
cancer.

45. Use of a polymorphic Form selected from Form I to XI or a mixture of
polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in
claims 1-12 or a pharmaceutical composition as claimed in claims 13, 28 and 30
in combination/concomittant with HMG CoA reductase inhibitors, fibrates,
nicotinic acid, cholestyramine, colestipol or probucol for reducing plasma
glucose, triglycerides, total cholesterol, LDL, VLDL or free fatty acids in
the
plasma.

46. Use of a polymorphic Form selected from Form I to XI or a mixture of
polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in
claims 1-12 or a pharmaceutical composition as claimed in claims 13, 28 and 30
for preparing a medicament for preventing or treating hyperlipidemia,
hypercholesteremia, hyperglycemia, osteoporosis, obesity, glucose intolerance,
leptin resistance, insulin resistance, or diseases in which insulin resistance
is the
underlying pathophysiological mechanism.

47. Use of a polymorphic form according to claim 37, wherein the disease is
type II
diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to
Syndrome X such as hyper-tension, obesity, atherosclerosis, hyperlipidemia,




52

coronary artery disease and other cardiovascular disorders, certain renal
diseases
including glomerulonephritis, glomerulosclerosis, nephrotic syndrome,
hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to
endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS),
useful as aldose reductase inhibitors, for improving cognitive functions in
dementia and treating diabetic complications, osteoporosis, inflammatory bowel
diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or
cancer.

48. Use of a polymorphic Form selected from Form I to XI or a mixture of
polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in
claims 1-12 or a pharmaceutical composition as claimed in claims 13, 28 and 30
for preparing a medicament for reducing plasma glucose, triglycerides, total
cholesterol, LDL, VLDL and free fatty acids in the plasma.

49. Use of a polymorphic Form selected from Form I to XI or a mixture of
polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in
claims 1-12 or a pharmaceutical composition as claimed in claims 13, 28 and 30
for preparing a medicament in combination/concomittant with HMG CoA
reductase inhibitors, fibrates, nicotinic acid, cholestyramirie, colestipol or
probucol for preventing or treating hyperlipemia, hypercholesteremia,
hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance,
insulin resistance, or diseases in which insulin resistance is the underlying
pathophysiological mechanism.

50. Use of a polymorphic form according to claim 49, wherein the disease is
type II
diabetes, impaired glucose tolerance, dyslipidaemia, disorders related to
Syndrome X such as hypertension, obesity, atherosclerosis, hyperlipidemia,
coronary artery disease and other cardiovascular disorders, certain renal
diseases
including glomerulonephritis, glomerulosclerosis, nephrotic syndrome,
hypertensive nephrosclerosis, retinopathy, nephropathy, disorders related to
endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS),
useful as aldose reductase inhibitors, for improving cognitive functions in




53

dementia and treating diabetic complications, osteoporosis, inflammatory bowel
diseases, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma or
cancer.

51. Use of a polymorphic Form selected from Form I to XI or a mixture of
polymorphic Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in
claims 1-12 or a pharmaceutical composition as claimed in claims 13, 28 and 30
for preparing a medicament in combination/concomittant with HMG CoA
reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or
probucol for reducing plasma glucose, triglycerides, total cholesterol, LDL,
VLDL or free fatty acids in the plasma.

52. A medicine for preventing or treating hyperlipidemia, hypercholesteremia,
hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance,
insulin resistance, or diseases in which insulin resistance is the underlying
pathophysiological mechanism comprising administering an effective amount of
a polymorphic Form selected from Form I to XI or a mixture of polymorphic
Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I as defined in
claims 1-12 or a pharmaceutical composition as claimed in claims 13, 28 and
30.

53. A medicine according to claim 52, wherein the disease is type II diabetes,
impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X
such
as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery
disease
and other cardiovascular disorders, certain renal diseases including
glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive
nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial
cell
activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose
reductase inhibitors, for improving cognitive functions in dementia and
treating
diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic
dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.

54. A medicine for reducing plasma glucose, triglycerides, total cholesterol,
LDL,
VLDL and free fatty acids in the plasma comprising an effective amount of a
polymorphic Form selected from Form I to XI or a mixture of polymorphic Form
I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-




54

ethoxypropanoic acid, having the formula I as defined in claims 1-12 or a
pharmaceutical composition as claimed in claims 13, 28 and 30.

55. A medicine for preventing or treating hyperlipidemia, hypercholesteremia,
hyperglycemia, osteoporosis, obesity, glucose intolerance, leptin resistance,
insulin resistance, or diseases in which insulin resistance is the underlying
pathophysiological mechanism comprising a polymorphic Form selected from
Form I to XI or a mixture of polymorphic Form I and X of L-arginine salt of
(2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the
formula I as defined in claims 1-12 or a pharmaceutical composition as claimed
in claims 13, 28 and 30 and HMG CoA reductase inhibitors, fibrates, nicotinic
acid, cholestyramine, colestipol or probucol.

56. A medicine according to claim 55, wherein the disease is type II diabetes,
impaired glucose tolerance, dyslipidaemia, disorders related to Syndrome X
such
as hypertension, obesity, atherosclerosis, hyperlipidemia, coronary artery
disease
and other cardiovascular disorders, certain renal diseases including
glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive
nephrosclerosis, retinopathy, nephropathy, disorders related to endothelial
cell
activation, psoriasis, polycystic ovarian syndrome (PCOS), useful as aldose
reductase inhibitors, for improving cognitive functions in dementia and
treating
diabetic complications, osteoporosis, inflammatory bowel diseases, myotonic
dystrophy, pancreatitis, arteriosclerosis, xanthoma or cancer.

57. A medicine for reducing plasma glucose, triglycerides, total cholesterol,
LDL,
VLDL and free fatty acids in the plasma, which comprises a polymorphic Form
selected from Form I to XI or a mixture of polymorphic Form I and X of L-
arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid, having the formula I as defined in claims 1-12 or a
pharmaceutical composition as claimed in claims 13, 28 and 30 and HMG CoA
reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or
probucol.

Description

CA 02370401 2001-10-16
WO 00/63192 PCT/IB00/00470
1
NOVEL POLYMORPHIC FORMS OF AN ANTIDIABETIC
AGENT : PROCESS FOR THEIR PREPARATION AND
PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
Background of the invention
This invention relates to novel polymorphic / pseudopolymorphic forms of
arginine salt
of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
preferably, L-
arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid,
1 o having the formula I shown below. The invention also relates to a ,
pharmaceutical
composition comprising the novel polymorphic form or their mixture and a
pharmaceutically acceptable carrier. The polymorphic forms of the present
invention are
more active, as antidiabetic and hypolipidemic agent, than the novel 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
O
C~2.H~~NH NH2
(CH2)2\ ~ = TC02H_
O OCH2CH3
(I)
The present invention also relates to a process for the preparation of novel
polymorphic /
pseudopolymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula (I).
The polymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-
ethoxypropanoic acid, of formula (I) defined above of the present invention
lower total
cholesterol (TC); increase high density lipoprotein (HDL) and decrease low
density
lipoprotein (LDL), which have a beneficial effect on coronary heart disease
and
atherosclerosis.
SUBSTITUTE SHEET (RULE 26)



CA 02370401 2001-10-16
WO 00/63192 PCT/IB00/00470
2
The novel polymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of formula (I) defined above of the
present
invention are useful in reducing body weight and for the treatment and/or
prophylaxis of
diseases such as hypertension, coronary heart disease, atherosclerosis,
stroke, peripheral
vascular diseases and related disorders. These novel polymorphic Forms
compounds are
useful for the treatment of familial hypercholesterolemia,
hypertriglyceridemia, lowering
of atherogenic lipoproteins, VLDL (very low density lipoprotein) and LDL. The
novel
polymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-
2-
ethoxypropanoic acid, of formula (I) of the present invention can be used for
the
treatment of certain renal diseases including glomerulonephritis,
glomerulosclerosis,
nephrotic syndrome, hypertensive nephrosclerosis and nephropathy. The novel
polymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-
2-
ethoxypropanoic acid, of formula (I) are also useful for the treatment and/or
prophylaxis
of insulin resistance (type II diabetes), leptin resistance, impaired glucose
tolerance,
dyslipidemia, disorders related to syndrome X such as hypertension, obesity,
insulin
resistance, coronary heart disease and other cardiovascular disorders. These
novel
polymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-
2-
ethoxypropanoic acid, of formula (I) may also be useful as aldose reductase
inhibitors,
for improving cognitive functions in dementia, treating diabetic
complications, disorders
related to endothelial cell activation, psoriasis, polycystic ovarian syndrome
(PCOS),
inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis,
arteriosclerosis, retinopathy, xanthoma, inflammation and for the treatment of
cancer.
The novel polymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of formula (I) of the present
invention are
useful in the treatment and/or prophylaxis of the above said diseases in
combination/con-comittant with one or more HMG CoA reductase inhibitors,
hypolipidemic/ hypolipoproteinemic agents such as fabric acid derivatives,
nicotinic
acid, cholestyramine, colestipol, probucol.



CA 02370401 2001-10-16
WO 00/63192 PCT/IB00/00470 -
3
Background of the invention
Atherosclerosis and other peripheral vascular diseases are the major causes
effecting the quality of life of millions of people. Therefore, considerable
attention has
been directed towards understanding the etiology of hypercholesterolemia and
hyperlipidemia and development of effective therapeutic strategies.
Hypercholesterolemia has been defined as plasma cholesterol level that exceeds
arbitrarily defined value called "normal" level. Recently, it has been
accepted that
"ideal" plasma levels of cholesterol are much below the "normal" level of
cholesterol in
io the general population and the risk of coronary artery disease (CAD)
increases as
cholesterol level rises above the "optimum" (or "ideal") value. There is
clearly a
definite cause and effect-relationship between hypercholesterolemia and CAD,
particularly for individuals with multiple risk factors. Most of the
cholesterol is present
in the esterified forms with various lipoproteins such as Low density
lipoprotein (LDL),
intermediate density lipoprotein (IDL), High density lipoprotein (HDL) and
partially as
Very low density lipoprotein (VLDL). Studies clearly indicate that there is an
inverse
correlationship between CAD and atherosclerosis with serum HDL-cholesterol
concentrations. (Stampfer et al., N. Engl. J. Med., 325 (1991), 373-381) and
the risk of
CAD increases with increasing levels of LDL and VLDL.
2o In CAD, generally "fatty streaks" in carotid, coronary and cerebral
arteries, are
found which are primarily free and esterified cholesterol. Miller et al., (Br.
Med. J., 282
(1981), 1741 - 1744) have shown that increase in HDL-particles may decrease
the
number of sites of stenosis in coronary arteries of human, and high level of
HDL-
cholesterol may protect against the progression of atherosclerosis. Picardo et
al.,
(Arteriosclerosis 6 (1986) 434 - 441) have shown by in vitro experiment that
HDL is
capable of removing cholesterol from cells. They suggest that HDL may deplete
tissues
of excess free cholesterol and transfer it to liver (Macikinnon et al., J.
Biol. them. 261
(1986), 2548 - 2552). Therefore, agents that increase HDL cholesterol would
have
therapeutic significance for the treatment of hypercholesterolemia and
coronary heart
3o diseases (CHD).
Obesity is a disease highly prevalent in affluent societies and in the
developing
world and is a major cause of morbidity and mortality. It is a state of excess
body fat



CA 02370401 2001-10-16
WO 00/63192 PCT/IB00/00470
4
accumulation. The causes of obesity are unclear. It is believed to be of
genetic origin or
promoted by an interaction between the genotype and environment. Irrespective
of the
cause, the result is fat deposition due to imbalance between the energy intake
versus
energy expenditure. Dieting, exercise and appetite suppression have been a
part of
obesity treatment. There is a need for efficient therapy to fight this disease
since it may
lead to coronary heart disease, diabetes, stroke, hyperlipidemia, gout,
osteoarthritis,
reduced fertility and many other psychological and social problems.
Diabetes and insulin resistance is yet another disease which severely effects
the
quality of a large population in the world. Insulin resistance is the
diminished ability of
insulin to exert its biological action across a broad range of concentrations.
In insulin
resistance, the body secretes abnormally high amounts of insulin to compensate
for this
defect; failing which, the plasma glucose concentration inevitably rises and
develops
into diabetes. Among the developed countries, diabetes mellitus is a common
problem
and is associated with a variety of abnormalities including obesity,
hypertension, hyper-
lipidemia (J. Clin. Invest., (1985) 75 : 809 - 817; N. Engl. J. Med. (1987)
317: 350-357;
J. Clin. Endocrinol. Metab., (1988) 66 : 580 - 583; J. Clin. Invest., (1975)
68 : 957 -
969) and other renal complications (See Patent Application No. WO 95/21608).
It is
now increasingly being recognized that insulin resistance and relative
hyperinsulinemia
have a contributory role in obesity, hypertension, atherosclerosis and type 2
diabetes
2o mellitus. The association of insulin resistance with obesity, hypertension
and angina has
been described as a syndrome having insulin resistance as the central
pathogenic link-
Syndrome-X.
Hyperlipidemia is the primary cause for cardiovascular (CVD) and other
peripheral vascular diseases. High risk of CVD is related to the higher LDL
(Low
Density Lipoprotein) and VLDL (Very Low Density Lipoprotein) seen in
hyperlipidemia. Patients having glucose intolerancelinsulin resistance in
addition to
hyperlipidemia have higher risk of CVD. Numerous studies in the past have
shown that
lowering of plasma triglycerides and total cholesterol, in particular LDL and
VLDL and
increasing HDL cholesterol help in preventing cardiovascular diseases.
3o Peroxisome proliferator activated receptors (PPAR) are members of the
nuclear
receptor super family. The gamma (y) isoform of PPAR (PPARy) has been
implicated in
regulating differentiation of adipocytes (Endocrinology, (1994) 135: 798-800)
and



CA 02370401 2001-10-16
WO 00/63192 PCT/IB00/00470
energy homeostasis (Cell, (1995) 83: 803-812), whereas the alpha (a) isoform
of PPAR
(PPARa) mediates fatty acid oxidation (Trend. Endocrin. Metab., (1993) 4: 291-
296)
thereby resulting in reduction of circulating free fatty acid in plasma
(Current Biol.
(1995) 5: 618 -621). PPARa agonists have been found useful for the treatment
of
5 obesity (WO 97/36579). It has been recently disclosed that there exists
synergism for the
molecules, which are agonists for both PPARa and PPARy and suggested to be
useful
for the treatment of syndrome X (WO 97/25042). Similar synergism between the
insulin
sensitizer (PPARy agonist) and HMG CoA reductase inhibitor has been observed
which
may be useful for the treatment of atherosclerosis and xanthoma (EP 0 753
298).
to It is known that PPARy plays an important role in adipocyte differentiation
(Cell,
(1996) 87, 377-389). Ligand activation of PPAR is sufficient to cause complete
terminal
differentiation (Cell, (1994) 79, 1147-1156) including cell cycle withdrawal.
PPARy is
consistently expressed in certain cells and activation of this nuclear
receptor with PPARy
agonists would stimulate the terminal differentiation of adipocyte precursors
and cause
morphological and molecular changes characteristics of a more differentiated,
less
malignant state (Molecular Cell, (1998), 465-470; Carcinogenesis, (1998), 1949-
53;
Proc. Natl. Acad. Sci., (1997) 94, 237-241) and inhibition of expression of
prostate
cancer tissue (Cancer Research (1998) 58:3344-3352). This would be useful in
the
treatment of certain types of cancer, which express PPARy and could lead to a
quite
2o nontoxic chemotherapy.
Leptin resistance is a condition wherein the target cells are unable to
respond to
leptin signal. This may give rise to obesity due to excess food intake and
reduced energy
expenditure and cause impaired glucose tolerance, type 2 diabetes,
cardiovascular
diseases and such other interrelated complications. Kallen et al (Proc. Natl.
Acad. Sci.
(1996) 93, 5793-5796) have reported that insulin sensitizers which perhaps due
to the
PPAR agonist expression and therefore lower plasma leptin concentrations.
However, it
has been recently disclosed that compounds having insulin sensitizing property
also
possess leptin sensitization activity. They lower the circulating plasma
leptin
concentrations by improving the target cell response to leptin (WO/98/02159).



CA 02370401 2001-10-16
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6
The latest trend that has, of late, crept into the pharmaceutical industry is
the studies on
polymorphism in drugs and the difference in the activity of different
polymorphic forms
of a given drug. By the term polymorphism we mean to include different
physical forms,
crystal forms, crystalline / liquid crystalline / non-crystalline (amorphous)
forms. This
has especially become very interesting after observing that many antibiotics,
antibacterials, tranquilizers etc., exhibit polymorphism and someone of the
polymorphic
forms of a given drug exhibit superior bio-availability and consequently show
much
higher activity compared to other polymorphs. Sertraline, Frentizole,
Ranitidine,
Sulfathiazole, Indomethacine etc. are some of the important examples of
to pharmaceuticals which exhibit polymorphism. Polymorphism in drugs is a
topic of
current interest and is evident from the host of patents being granted. To
cite a few, US
5700820 discloses six polymorphic forms of Troglitazone, US 5248699 discusses
about
five polymorphic forms of Sertraline hydrochloride while EP 014590 describes
four
polymorphic forms of Frentizole. EP 490648 and EP 022527 also deal with the
subject
of polymorphism in drugs.
Summary of the invention
With an objective to develop novel polymorphic forms for lowering cholesterol
and reducing body weight with beneficial effects in the treatment and/or
prophylaxis of
2o diseases related to increased levels of lipids, atherosclerosis, coronary
artery diseases,
Syndrome-X, impaired glucose tolerance, insulin resistance, insulin resistance
leading to
type 2 diabetes and diabetes complications thereof, for the treatment of
diseases wherein
insulin resistance is the pathophysiological mechanism and for the treatment
of
hypertension, with better efficacy, potency and lower toxicity, we focussed
our research
to develop new polymorphic forms effective in the treatment of the above
mentioned
diseases. Effort in this direction has led to polymorphic forms having the
formula (I).
Another objective of the present invention is to provide polymorphic forms of
arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid, their
stereoisomers, their pharmaceutically acceptable solvates and pharmaceutical
3o compositions containing them or their mixtures which may have agonist
activity against
PPARa, and/or PPARy, and optionally inhibit HMG CoA reductase, in addition to
having agonist activity against PPARa, and/or PPARy.



CA 02370401 2001-10-16
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7
Another objective of the present invention is to provide novel polymorphic
forms
of arginine , salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid,
their stereoisomers, pharmaceutically acceptable solvates and pharmaceutical
compositions containing them or their mixtures having enhanced activities,
without toxic
effect or with reduced toxic effect.
Yet another objective of the present invention to provide a process for the
preparation of novel polymorphic forms of arginine salt of 3-[4-[2-(phenoxazin-
10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, their stereoisomers,
pharmaceutically
acceptable solvates.
Still another objective of the present invention is to provide pharmaceutical
compositions containing novel polymorphic forms of arginine salt of 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, their stereoisomers,
solvates or their mixtures in combination with suitable Garners, solvents,
diluents and
other media normally employed in preparing such compositions.
In our PCT publication No. WO 99/19313 we have described novel (3-aryl a-oxy
substituted alkylcarboxylic acids of the general formula (a),
R'
R2 X
A
s / ~ a
R N R5 R6 O
R4 ~C~"~2)n~0)WA~ ~,Rg
OR'
their pharmaceutically salts, their pharmaceutically solvated and their
pharmaceutically
acceptable compositions containing them. The pharmaceutical salts of the
compounds of
the general formula (a) includes salts of the organic bases such as guanine,
arginine,
guanidine, diethylamine, choline, and the like. Particularly the compounds
disclosed
include 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid. The
current
interest in the field of polymorphism in drugs prompted us to take up the
investigation as
to the possibility of polymorphism in such compounds particularly the arginine
salt of 3-
[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid. Our
observations and
results form the subject matter of the present invention.



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8
We have, due to our sustained research directed towards finding out effective
antidiabetic drugs, observed that arginine salt of 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, exists in different polymorphic
forms
possessing enhanced anti-diabetic activity. Accordingly we have, in the course
of
research, prepared and studied at least eleven polymorphic forms of arginine
salt of 3-[4-
[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid. These polymorphs
have
been designated, by us, as Forms I, II, III, IV, V, VI, VII, VIII, IX, X and
the mixture.
to Detailed Description of the Invention
The present invention relates to an observation that arginine salt of 3-[4-[2-
(phenoxazin-
10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid exhibits polymorphism, which has
not
been reported till date. The polymorphic Forms I, II, III, IV and V are
obtained from
different solvents like isopropyl alcohol, acetone, 1,4-dioxane,
dimethylsulphoxide, and
dimethylformamide respectively. Form VI is obtained by dissolving any form
(Form I-
V) in water and freeze drying. Similarly Form VII is obtained by dissolving
any form
(Form I-V) in methanol and quick evaporation of the solvent under reduced
pressure at
40-60 °C. Form VIII is obtained by refluxing Form-I in 1,4-dioxane.
Form-IX is
obtained by refluxing Form-VIII in isopropyl alcohol. Form X is prepared by
heating
Form I to 185 °C and cooling it to room temperature. Form XI is
prepared by heating
Form X to 175 °C and cooling it to room temperature.
From powder X-ray diffraction studies Forms I, II, III, IV, V, VIII, IX and XI
are found
to be crystalline in nature. Forms VI, VII and X did not give any peaks in X-
ray
diffraction due to amorphous nature.
DSC of the polymorphic Form I shows melting endotherm at 181 °C. In the
mixture of
polymorphic Forms I and X there is an indication to one of the endotherm at
185 °C and
181 °C. Form II displays endotherms at 131 °C, 166 °C,
178 °C, 214 °C and 276 °C and
exotherms at 169 °C. Form III exhibits melting endotherm 182 °C
in addition to an



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exotherm at 168 °C. Form IV exhibits endotherms at 149 °C, 164
°C and 185 °C and an
exotherm at 171 °C. Form V exhibits endotherms at 119 °C, 164
°C, 172 °C and 185 °C
in addition to a melting exotherm at 173 °C. Form VI exhibits exotherm
at 157 °C and
endotherms at 179 °C and 183 °C. Form VII exhibits exotherm at
132 °C and
endotherms at 176 °C and 184 °C. Form VIII there was a similar
exotherm of Form VI
at 158 °C and the melting endotherm at 178 °C, whereas in Form
IX there was only one
sharp melting endotherm at 176 °C. Form X displays an exotherm at 163
°~ and melting
endotherm at 184 °C. Form XI exhibits a melting endotherm at 184
°C.
1o All these polymorphic forms were proved to be identical in solution as
evident from
Nuclear Magnetic Resonance (NMR), Ultra Violet (UV) & Mass spectral data. On
the
other hand, solid state techniques like Differential Scanning Calorimetry
(DSC), Powder
X-Ray Diffractometry (XRD) and Infra Red spectroscopy (IR) revealed the
difference
among these forms.
Brief Description of the Figures
X-ray powder diffraction pattern has been obtained on a Rigaku D/Max 2200
model
diffractometer equiped with horizontal gonimometer in O/2 O geometry. The
copper K
2o a ( ~,=1.5418A) radiation was used and the sample was scanned between 3-45
degrees
20.
Fig. 1 is a characteristic X-ray powder diffraction pattern of Form I.
Fig. 2 is a characteristic X-ray powder diffraction pattern of Form II.
Fig. 3 is a characteristic X-ray powder diffraction pattern of Form III.
Fig. 4 is a characteristic X-ray powder diffraction pattern of Form IV.
Fig. 5 is a characteristic X-ray powder diffraction pattern of Form V.
Fig. 6 is a characteristic X-ray powder diffraction pattern of Form VI.
Fig. 7 is a characteristic X-ray powder diffraction pattern of Form VII.
Fig. 8 is a characteristic X-ray powder diffraction pattern of Form VIII.
Fig. 9 is a characteristic X-ray powder diffraction pattern of Form IX.
Fig. 10 is a characteristic X-ray powder diffraction pattern of Form X.



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Fig. 11 is a characteristic X-ray powder diffraction pattern of Form XI.
Fig. 12 is a characteristic X-ray powder diffraction pattern of polymorphic
form
mixture.
5 Differential scanning calorimeter was performed on a Shimadzu DSC-50
equipped with
a controller. The data was collected on to a Pentium PC using a Shimadzu TA-50
software. The samples weighed in aluminum cells were heated from room
temperature
to 220 °C at a heating rate of 5 °C /min. The empty aluminum
cell was used as a
reference. Dry nitrogen gas was purged through DSC cell continuously
throughout the
1o analysis at a flow of 30 ml/min.
Fig. 13 is a characteristic differential scanning calorimetric thermogram of
Form I.
Fig. 14 is a characteristic differential scanning calorimetric thermogram of
Form II.
Fig. 15 is a characteristic differential scanning calorimetric thermogram of
Form III.
Fig. 16 is a characteristic differential scanning calorimetric thermogram of
Form IV.
Fig. 17 is a characteristic differential scanning calorimetric thermogram of
Form V.
Fig. 18 is a characteristic differential scanning calorimetric thermogram of
Form VI.
Fig. 19 is a characteristic differential scanning calorimetric thermogram of
Form VII.
Fig. 20 is a characteristic differential scanning calorimetric thermogram of
Form VIII.
Fig. 21 is a characteristic differential scanning calorimetric thermogram of
Form IX.
2o Fig. 22 is a characteristic differential scanning calorimetric thermogram
of Form X.
Fig. 23 is a characteristic differential scanning calorimetric thermogram of
Form XI.
Fig. 24 is a characteristic differential scanning calorimetric thermogram of
polymorphic
form mixture.
FT-IR Spectrum was recorded in solid state as KBr dispersion using Perkin-
Elmer 1650
FT-IR Spectrophotometer.
Fig. 25 is a characteristic infrared absorption spectrum of Form I in KBr.
Fig. 26 is a characteristic infrared absorption spectrum of Form II in KBr.
Fig. 27 is a characteristic infrared absorption spectrum of Form III in KBr.
3o Fig. 28 is a characteristic infrared absorption spectrum of Form IV in KBr.
Fig. 29 is a characteristic infrared absorption spectrum of Form V in KBr.
Fig. 30 is a characteristic infrared absorption spectrum of Form VI in KBr.



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Fig. 31 is a characteristic infrared absorption spectrum of Form VII in KBr.
Fig. 32 is a characteristic infrared absorption spectrum of Form VIII in KBr.
Fig. 33 is a characteristic infrared absorption spectrum of Form IX in KBr.
Fig. 34 is a characteristic infrared absorption spectrum of Form X in KBr.
Fig. 35 is a characteristic infrared absorption spectrum of Form XI in KBr.
Fig. 36 is a characteristic infrared absorption spectrum of polymorphic form
mixture in
KBr.
According to a feature of the present invention, there is provided a novel
polymorphic
l0 Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-
2-
ethoxypropanoic acid, having the formula I which is characterized by the
following data
DSC: Endotherms at 181.21 °C (onset at 177.70 °C) (Fig -13)
X-ray powder diffraction (20): 8.18, 12.40, 16.66, 18.80, 19.44, 22.32, 22.84,
23.10, 23.50, 24.72, 29.84, (Fig-1)
Infrared absorption bands (crri'J: 3249, 3062, 1709, 1587, 1489, 1374, 1272,
1243, 1112, 1043, 919, 737, 673, 543, (Fig -25)
According to another feature of the present invention, there is provided a
novel
2o polymorphic Form-II of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I which is
characterized
by the following
data
DSC: Endotherms at 131 °C, 166.24 °C and 178.96 °C
(Fig -14)
Exotherm at 169.73 °C
X-ray powder diffraction (20): 6.78, 11.5, 12.08, 16.44, 19.34, 22.30, 22.72,
24.40, 26.66 (Fig -2)
Infrared absorption bands (cm 1): 3055, 1711, 1589, 1510, 1491, 1376, 1274,
111 l, 1039, 810, 730, 543, (Fig -26)



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According to yet another feature of the present invention, there is provided a
novel
polymorphic Form-III of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I which is
characterized
by the following
data
DSC: Endotherm at 182.20 °C (onset at 171 °C) (Fig-15)
Small endotherms at 99.66 °C, 164.38 °C
Exotherm at 168.00 °C
X-ray powder diffraction (28): 6.80, 12.10, 15.84, 17.02, 19.40, 22.32, 22.68,
l0 24.38, 26.36, (Fig -3)
Infrared absorption bands (cm-'): 3061, 1710, 1588, 1510, 1491, 1379, 1273,
1110, 1040, 805, 739, and 543, (Fig -27)
According to yet another feature of the present invention, there is provided a
novel
polymorphic Form-IV of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I which is
characterized
by the following
data
DSC: Endotherms at 149.85 °C, 185.60 °C (onset at 147.78
°C) (Fig -16)
2o Small Endotherm at 164.51 °C
Small Exotherm at 171.80 °C
X-ray powder diffraction (20): 6.78, 12.66, 15.96, 16.54, 19.34, 22.78, 24.42,
26.70, 31.70, (Fig -4)
Infrared absorption bands (crri'): 3056, 1711, 1589, 1493, 1381, 1274, 1242,
1101, 1060, 805, 743, and 543.7, (Fig -28)
According to yet another feature of the present invention, there is provided a
novel
polymorphic Form-V of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I which is
characterized
3o by the following
data



CA 02370401 2001-10-16
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13
DSC: Endotherm at 185.95 °C, (onset at 178.09 °C) (Fig -17)
Small endotherms at 119.81 °C, 164.69 °C, 172.44 °C
Small exotherm at 173.82 °C
X-ray powder diffraction (20): 6.76, 12.10, 15.96, 17.00, 18.50, 19.40, 22.38,
22.44, 24.44, 26.30, (Fig -5)
Infrared absorption bands (cm ~): 3266, 3055, 1711, 1589, 1510, 1492, 1379,
1274, 1175, 111 l, 1040, 918, 819, 730, 676, 544, (Fig -29)
According to yet another feature of the present invention, there is provided a
novel
to polymorphic Form-VI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I which is
characterized
by the following
data
DSC: Endotherms at 179.11 °C and 183.69 °C (onset at 157.98
°C), (Fig -18)
Small endotherm at 77.80 °C
Exotherm at 157.98 °C,
X-ray powder diffraction (20): No diffraction peaks due to its amorphous
nature,
(fig-6)
Infrared absorption bands (cm 1): 3065, 1629, 1490, 1377, 1273, 1244, 1109,
1042, 805, 740, 539, (Fig -30)
According to yet another feature of the present invention, there is provided a
novel
polymorphic Form-VII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I which is
characterized
by the following
data
DSC: Endotherms at 176.63 °C (onset at 169.06 °C) and
184.09 °C (Fig -19)
Exotherm at 132.93 °C,
X-ray powder diffraction (20): No diffraction peaks due to its amorphous
nature,
(Fig-7)



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Infrared absorption bands (cm'): 3065, 1629, 1490, 1377, 1273, 1109, 1042,
740, 541, (Fig-31)
According to yet another feature of the present invention, there is provided a
novel
polymorphic Form-VIII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I which is
characterized
by the following
data
DSC: Endotherm at 178.12 °C (onset at 167.15 °C), (Fig -20)
to Small Endotherm at 152.72 °C
Exotherm at 158.27 °C
X-ray powder diffraction (28): 4.16, 11.02, 15.94, 19.50, 20.22, 22.22, 27.38,
(Fig -8)
Infrared absorption bands (cni'): 3151, 1629, 1490, 1378, 1272, 1244, 1104,
1041, 742, 549, (Fig -32)
According to yet another feature of the present invention, there is provided a
novel
polymorphic Form-IX of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I which is
characterized
2o by the following
data
DSC: Endotherm at 176.67 °C (onset at 173.36 °C), (Fig -21)
X-ray powder diffraction (20): 8.20, 12.42, 16.66, 18.80, 19.44, 22.30, 23.08,
27.38, 28.48, 29.84, (Fig -9)
Infrared absorption bands (crri'): 3066, 1588, 1489, 1376, 1273, 1243, 1110,
1043, 919, 805, 737, 543, (Fig -33)
According to still another feature of the present invention, there is provided
a novel
polymorphic Form-X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
3o yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I which is
characterized
by the following



CA 02370401 2001-10-16
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data
DSC: Endotherm at 184.53 °C, (Fig -22)
Exotherm at, 162.67 °C
X-ray powder diffraction (2B): No diffraction peaks due to its amorphous
nature,
5 (Fig -10)
Infrared absorption bands (crri'): 3413, 1630, 1511, 1491, 1377, 1273, 1244,
1176, 1108, 741, (Fig -34)
According to yet another feature of the present invention, there is provided a
novel
to polymorphic Form-XI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I which is
characterized
by the following
data
DSC: Endotherm at 184.40 °C (onset at 177.67 °C), (Fig -23)
15 X-ray powder diffraction (28): 7.38, 7.56, 11.90, 12.32, 14.80, 16.40,
19.58,
20.48, 22.34, 22.90, 23.54, (Fig -11 )
Infrared absorption bands (cm 1): 3383, 2925, 1629, 1510, 1490, 1377, 1273,
1243, 1090, 1041, 739, 539, (Fig -35)
According to yet another feature of the present invention, there is provided a
novel
mixture of polymorphic Forms I and X of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-
10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I which is
characterized by the following data
DSC: Endotherms at 181.28 °C, 185.31 °C, (onset at 173.54
°C) (Fig -24)
X-ray powder diffraction (28): 8.16, 12.40, 16.64, 18.78, 19.42, 22.34, 22.80,
23.08, 29.84, (Fig -12)
Infrared absorption bands (cm 1): 3247, 3066, 1708, 1587, 1510, 1489, 1375,
1273, 1244, 1178, 111 l, 1043, 805, 737, 673, 543, (Fig -36)
According to another feature of the present invention, there is provided a
process for the
preparation of novel polymorphic Form-I of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-



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16
10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I, having the
characteristics described earlier, which comprises
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the
solution
obtained in step (i),
(iii) stirnng the reaction mixture at a temperature of 40-80 °C for a
period in the
range of 18-30 h to obtain a white crystalline precipitate,
to (iv) filtering the white crystalline precipitate obtained in step (iii)
above and
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4-
16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
The temperature employed in the stirnng step (iii) may be preferably 40-50
°C.
According to another feature of the present invention, there is provided an
alternate
process for the preparation of novel polymorphic Form-I of L-arginine salt of
(2S) 3-[4-
[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I,
having
2o the characteristics described earlier, which comprises
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the
solution
obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the
range of 90-
100 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4-
16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.



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According to another feature of the present invention, there is provided a
process for the
preparation of novel polymorphic Form-II of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I,
having the
characteristics described earlier, which comprises
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in acetone,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the
solution
obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the
range of 18-
30 h to obtain a white crystalline precipitate
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4-
16 h to yield Form-II of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to yet another feature of the present invention, there is provided a
process for
2o the preparation of novel polymorphic Form-III of L-arginine salt of (2S) 3-
[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid of the formula I,
having the
characteristics described earlier, which comprises
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in 1,4-dioxane,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the
solution
obtained in step (i),
(iii) stirring the reaction mixture at room temperature for a period in the
range of 18-
h to obtain a white crystalline precipitate
30 (iv) filtering the white crystalline precipitate obtained in step (iii)
above and



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18
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4-
16 h to yield Form-III of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to yet another feature of the present invention, there is provided a
process for
the preparation of novel polymorphic Form-IV of L-arginine salt of (2S) 3-[4-
[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid of the formula I,
having the
characteristics described earlier, which comprises
to (i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in dimethyl sulfoxide,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the
solution
obtained in step (i),
(iii) stirnng the reaction mixture at room temperature for a period in the
range of 18-
30 h to obtain a white crystalline precipitate
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4-
16 h to yield Form-IV of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to another feature of the present invention, there is provided a
process for
the preparation of novel polymorphic Form-V of L-arginine salt of (2S) 3-[4-[2-

(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid of the formula I,
having the
characteristics described earlier, which comprises
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in dimethyl formamide,
(ii) adding L-arginine dissolved in water slowly with constant stirnng in the
solution
obtained in step (i),
(iii) stirnng the reaction mixture at room temperature for a period in the
range of 18-
30 h to obtain a white crystalline precipitate,



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19
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4-
16 h to yield Form-V of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to another feature of the present invention, there is provided a
process for the
preparation of novel polymorphic Form-VI of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid of the formula I,
having the
characteristics described earlier, which comprises
to
(i) dissolving any of the polymorphic Forms I-V of L-arginine salt of (2S) 3-
[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid in water and
(ii) freeze drying the resulting solution to yield an amorphous white powder
of
Form-VI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid.
According to another feature of the present invention, there is provided a
process for the
preparation of novel polymorphic Form-VII of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid of the formula I,
having the
2o characteristics described earlier, which comprises
(i) dissolving any of the polymorphic Forms I-V of L-arginine salt of (2S) 3-
[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid in methanol and
(ii) evaporating the resulting solution under vacuum to obtain an amorphous
white
powder of Form-VII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to another feature of the present invention, there is provided a
process for the
preparation of novel polymorphic Form-VIII of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I,
having the
characteristics described earlier, which comprises



CA 02370401 2001-10-16
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(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring in the
solution
obtained in step (i),
5 (iii) stirnng the reaction mixture at a temperature of 40-80 °C for a
period in the
range of 18-30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4-
16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
to yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
(vi) refluxing the Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained above in step (v) in 1,4-
dioxane for
a period in the range of 8-16 h and
(vii) filtering and drying under vacuum at a temperature of 40-45 °C
for a period in
15 the range of 4-16 h to yield Form-VIII of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to another feature of the present invention, there is provided a
process for the
preparation of novel polymorphic Form-IX of L-arginine salt of (2S) 3-[4-[2-
20 (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I,
having the
characteristics described earlier, which comprises
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring in the
solution
obtained in step (i),
(iii) stirnng the reaction mixture at a temperature of 40-80 °C for a
period in the
range of 18-30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and



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21
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4-
16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
(vi) refluxing the Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, obtained above in step (v) in 1,4-
dioxane for
a period in the range of 8-16 h,
(vii) filtering and drying under vacuum at a temperature of 40-45 °C
for a period in
the range of 4-16 h to yield Form-VIII of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
l0 (viii) refluxing the Form-VIII of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-
yl)ethoxy]phenyl)-2-ethoxypropanoic acid, obtained in step (vii) above in
isopropyl
alcohol for a period in the range of 8-16 h and
(ix) filtering and drying under vacuum at a temperature of 40-45 °C for
a period in
the range of 4-16 h to yield Form-IX of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to another feature of the present invention, there is provided a
process for the
preparation of novel polymorphic Form-X of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I,
having the
2o characteristics described earlier, which comprises
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirring to the
solution
obtained in step (i),
(iii) stirring the reaction mixture at a temperature of 40-80 °C for a
period in the
range of 18-30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4
16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10
yl)ethoxy]phenyl)-2-ethoxypropanoic acid and



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22
(vi) heating the polymorphic Form-I obtained in step (v) to 185 °C and
cooling it to
room temperature to yeild Form-X of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to another feature of the present invention, there is provided a
process for the
preparation of novel polymorphic Form-XI of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I,
having the
characteristics described earlier, which comprises
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirnng to the
solution
obtained in step (i),
(iii) stirnng the reaction mixture at a temperature of 40-80 °C for a
period in the
range of 18-30 h to obtain a white crystalline precipitate,
(iv) filtering the white crystalline precipitate obtained in step (iii) above
and
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4-
16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
(vi) heating the polymorphic Form-I obtained in step (v) to 185 °C and
cooling it to
room temperature to yeild Form-X of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid and
(vii) heating the polymorphic Form-X obtained in step (vi) to 175 °C
and cooling it to
room temperature to yield Form-XI of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10
yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to another feature of the present invention, there is provided a
process for the
preparation of novel mixture of polymorphic Form of I and X of L-arginine salt
of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the
formula I,
3o described earlier, which comprises



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23
(i) synthesizing (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid, employing known methods and dissolving in an organic solvent,
(ii) adding L-arginine dissolved in water slowly with constant stirnng in the
solution
obtained in step (i),
(iii) stirnng the reaction mixture at room temperature for a period in the
range of 18-
30 h to separate white crystalline powder,
(iv) filtering the white crystalline powder obtained in step (iii) and
(v) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4
16 h to yield mixture of polymorphic Form of I and X of L-arginine salt of
(2S) 3-[4-[2
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
According to another feature of the present invention, there is provided an
alternate
process for the preparation of novel polymorphic Form-I of L-arginine salt of
(2S) 3-[4-
[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula I,
having
the characteristics described earlier, which comprises
(i) suspending any of the polymorphic Form II to XI or the mixture of
polymorphic
Form I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2
ethoxypropanoic acid in isopropyl alcohol and stirnng in dark conditions at
room
temperature for a period of 35-50 h,
(ii) filtering and washing with isopropyl alcohol and
(iii) drying under vacuum at a temperature of 40-45 °C for a period in
the range of 4-
16 h to yield polymorphic Form of I of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
The organic solvents are selected from acetonitrile, ethanol, methanol and,
isopropanol.
The present invention also envisages a pharmaceutical composition comprising a
polymorphic Forms I to XI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
3o yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula (I) or the mixture
of
polymorphic Form of I and X and a pharmaceutically acceptable carrier .



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24
The present invention also envisages a pharmaceutical composition comprising a
mixture of any of polymorphic Forms I to XI of L-arginine salt of (2S) 3-[4-[2
(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula (I)
and a
pharmaceutically acceptable carrier .
The pharmaceutical composition may be in the forms normally employed, such as
tablets, capsules, powders, syrups, solutions, suspensions and the like, may
contain
flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents,
or in suitable
l0 sterile media to form injectable solutions or suspensions. Such
compositions typically
contain from 1 to 25 %, preferably 1 to 15 % by weight of active ingredient,
the
remainder of the composition being pharmaceutically acceptable carriers,
diluents or
solvents.
The polymorphic forms of the formula (I) as defined above are clinically
administered to
mammals, including man, via either oral, nasal, pulmonary, transdermal or
parenteral,
rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular,
intranasal,
ophthalmic solution or an ointment. Administration by the oral route is
preferred, being
more convenient and avoiding the possible pain and irritation of injection.
However, in
circumstances where the patient cannot swallow the medication, or absorption
following
oral administration is impaired, as by disease or other abnormality, it is
essential that the
drug be administered parenterally. By either route, the dosage is in the range
of about
0.01 to about 100 mg / kg body weight of the subject per day or preferably
about 0.01
to about 30 mg / kg body weight per day administered singly or as a divided
dose.
However, the optimum dosage for the individual subject being treated will be
determined by the person responsible for treatment, generally smaller doses
being
administered initially and thereafter increments made to determine the most
suitable
dosage.
Suitable pharmaceutically acceptable Garners include solid fillers or diluents
and sterile
aqueous or organic solutions. The active ingredient will be present in such
pharmaceutical compositions in the amounts sufficient to provide the desired
dosage in



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the range as described above. Thus, for oral administration, the polymorphic
form can
be combined with a suitable solid or liquid Garner or diluent to form
capsules, tablets,
powders, syrups, solutions, suspensions and the like. The pharmaceutical
compositions,
may, if desired, contain additional components such as flavourants,
sweeteners,
5 excipients and the like. For parenteral administration, the polymorphic form
can be
combined with sterile aqueous or organic media to form injectable solutions or
suspensions. For example, solutions in sesame or peanut oil, aqueous propylene
glycol
and the like can be used, as well as aqueous solutions of water-soluble
pharmaceutically-
acceptable acid addition salts or salts with base of the compounds. Aqueous
solutions
1o with the active ingredient dissolved in polyhydroxylated castor oil may
also be used for
injectable solutions. The injectable solutions prepared in this manner can
then be
administered intravenously, intraperitoneally, subcutaneously, or
intramuscularly, with
intramuscular administration being preferred in humans.
15 For nasal administration, the preparation may contain the polymorphic forms
of the
present invention dissolved or suspended in a liquid Garner, in particular an
aqueous
Garner, for aerosol application. The Garner may contain additives such as
solubilizing
agents, such as propylene glycol, surfactants, absorption enhancers such as
lecithin
(phosphatidylcholine) or cyclodextrin or preservatives such as parabenes.
Tablets, dragees or capsules having talc and / or a carbohydrate carned binder
or the
like are particularly suitable for any oral application. Preferably, carriers
for tablets,
dragees or capsules include lactose, corn starch and / or potato starch. A
syrup or elixir
can be used in cases where a sweetened vehicle can be employed.
A typical tablet production method is exemplified below
Tablet Production Example
a) 1) Active ingredient 30 g
3o 2) Lactose 95 g
3) Corn starch 30 g
4) Carboxymethyl cellulose 44 g



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26
5) Magnesium stearate 1 g
200 g for 1000 tablets
The ingredients 1 to 3 are uniformly blended with water and granulated after
drying under reduced pressure. The ingredient 4 and 5 are mixed well with the
granules
and compressed by a tabletting machine to prepare 1000 tablets each containing
30 mg
of active ingredient.
b) 1 ) Active ingredient 30 g


2) Calcium phosphate 90 g


3) Lactose 40 g


4) Corn starch 35 g


5) Polyvinyl pyrrolidone 3.5 g


6) Magnesium stearate 1.5 g



200 g for 1000
tablets


The ingredients 1-4 are uniformly moistened with an aqueous solution of 5 and
granulated after drying under reduced pressure. Ingredient 6 is added and
granules are
compressed by a tabletting machine to prepare 1000 tablets containing 30 mg of
2o ingredient 1.
Examples
Synthesis of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic
acid,
is described in our WO publication No. WO 99/19313 and copending PCT
application No. PCT/IB99/00683.
The present invention is described in detail in the examples given below which
are
provided by way of illustration only and therefore should not be construed to
limit the
scope of the invention.



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27
Examples 1-4 illustrates the process for the preparation of the polymorphic
Form-1
of L-arginine salt of (2S) 3-(4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid,
Example-1:
To a solution of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid
(1 g) in ethanol (25 ml) was added L-arginine dissolved in water (1.2 ml)
slowly with
constant stirnng. The reaction mixture was stirred at 40-50 °C for 24h.
The white
to crystalline precipitate formed was separated and dried under vacuum at 40-
45 °C for 4h
to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-
ethoxypropanoic acid (1.15 g) which has the characteristics given earlier.
Example-2
To a solution of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid
(1 g) in isopropyl alcohol (25 ml) was added L-arginine dissolved in water
(1.2 ml)
slowly with constant stirnng. The reaction mixture was stirred at 40-50
°C for 24h. The
white crystalline precipitate formed was separated and dried under vacuum at
40-45 °C
2o for 4h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1.27 g) which has the
characteristics given
earlier.
Example -3
To a solution of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid
(1 g) in acetonitrile (25 ml) was added L-arginine dissolved in water (1.2 ml)
slowly
with constant stirring. The reaction mixture was stirred at 40-50 °C
for 24h. The white
crystalline precipitate formed was separated and dried under vacuum at 40-45
°C for 4h
to yield Form-I L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-
ethoxypropanoic acid (1.24 g) which has the characteristics given earlier.



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28
Example-4
To a solution of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid
(1 g) in methanol (15 ml) was added L-arginine dissolved in water (1.2 ml)
slowly with
constant stirnng. The reaction mixture was stirred at 40-50 °C for 24h.
The white
crystalline precipitate formed was separated and dried under vacuum at 40-45
°C for 4h
to yield Form-I L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-
ethoxypropanoic acid ( 1.05 g) which has the characteristics given earlier.
to
Example-5
To a solution of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid
( 1 g) in isopropyl alcohol (25 ml) was added L-arginine dissolved in water (
1.2 ml)
slowly with constant stirnng. The reaction mixture was stirred at room
temperature for
90-100 h. The white crystalline precipitate formed was separated and dried
under
vacuum at 40-45 °C for 4h to yield Form-I L-arginine salt of (2S) 3-[4-
[2-(phenoxazin-
10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1.05 g) which has the
characteristics
given earlier.
Example 6 : Process for the preparation of the polymorphic Form-II of L-
arginine
salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
To a solution of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid
(1 g) in acetone (25 ml) was added L-arginine dissolved in water (1.2 ml)
slowly with
constant stirnng. The reaction mixture was stirred at room temperature for
24h. The
white crystalline precipitate formed was separated and dried under vacuum at
40-45 °C
for 4h to yield Form-II of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10
yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1.29 g) which has the
characteristics given
earlier.



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29
Example 7 . Process for the preparation of the polymorphic Form-III of L-
arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid,
To a solution of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid
(1 g) in 1,4-dioxane (25 ml) was added L-arginine dissolved in water (1.2 ml)
slowly
with constant stirring. The reaction mixture was stirred at room temperature
for 24h. The
white crystalline precipitate formed was separated and dried under vacuum at
40-45 °C
for 4h to yield Form-III of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
1 o yl)ethoxy]phenyl]-2-ethoxypropanoic acid ( 1.25 g) which has the
characteristics given
earlier.
Example 8 : Process for the preparation of the polymorphic Form-IV of L-
arginine
salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
To a solution of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid
(1 g) in DMSO (20 ml) was added L-arginine dissolved in water (1.2 ml) slowly
with
constant stirring. The reaction mixture was stirred at room temperature for
24h. The
white crystalline precipitate formed was separated and dried under vacuum at
40-45 °C
2o for 4h to yield Form-III of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1.3 g) which has the characteristics
given
earlier.
Example 9 : Process for the preparation of the polymorphic Form-V of L-
arginine
salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
To a solution of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid
(1 g) in DMF (25 ml) was added L-arginine dissolved in water (1.2 ml) slowly
with
constant stirnng. The reaction mixture was stirred at room temperature for
24h. The
white crystalline precipitate formed was separated and dried under vacuum at
40-45 °C



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WO 00/63192 PCT/IB00/00470
for 4h to yield Form-V of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid ( 1.17 g) which has the
characteristics given
earlier.
5 Example 10 : Process for the preparation of the polymorphic Form-VI of L-
arginine salt of (2S) 3-(4-[2-(phenoxazin-10-yl)ethoxy]phenyl)-2-
ethoxypropanoic
acid,
1o Polymorphic Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g), obtained by the process
described in
Example-2 above was dissolved in water (10 ml) and freeze dried to yield Form-
VI of L-
arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid,
as an amorphous white powder (0.95 g) which has the characteristics given
earlier.
Example 11 : Process for the preparation of the polymorphic Form-VII of L-
arginine salt of (2S) 3-(4-[2-(phenoxazin-10-yl)ethoxy]phenyl)-2-
ethoxypropanoic
acid,
2o Polymorphic Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10
yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g), obtained by the process
described in
Example-3 above was dissolved in methanol (25 ml) and evaporated under vacuum
to
yield Form-VII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2
ethoxypropanoic acid, as an amorphous white powder (0.9 g) which has the
characteristics given earlier.
Example 12 : Process for the preparation of the polymorphic form-VIII of L-
arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid,



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31
Polymorphic Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g), obtained by the process
described in
Example-2 above was refluxed in 1,4-dioxane (10 ml), filtered and dried under
vacuum
to yield Form-VIII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-
2-ethoxypropanoic acid which has the characteristics given earlier.
Example 13 . Process for the preparation of the polymorphic Form-IX of L-
arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid,
to
Polymorphic Form-VIII L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g), obtained by the process
described in
Example-12 was refluxed in isopropanol (10 ml), filtered and dried under
vacuum to
i5 yield Form-IX of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-
ethoxypropanoic acid which has the characteristics given earlier.
Example 14 . Process for the preparation of the polymorphic Form-X of L
arginine salt of (2S) 3-(4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
2o acid,
Polymorphic Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid obtained by any of the process
described in
Examples-1-5 was heated to 185 °C and cooled it to room temperature to
yield Form-X
25 of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
acid which has the characteristics given earlier.
Example 15 . Process for the preparation of the polymorphic Form-XI of L
arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic
3o acid,



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32
Polymorphic Form-X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10
yl)ethoxy]phenyl]-2-ethoxypropanoic acid obtained by the process described in
Example
14 was heated to 175 °C and cooled it to room temperature to yield Form-
XI of L
arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid
which has the characteristics given earlier.
Example 16 : Process for the preparation of mixture of polymorphic Forms I and
X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxyJphenyl]-2-
ethoxypropanoic acid,
io
To a solution of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid
( 1 g) in isopropyl alcohol (25 ml) was added L-arginine dissolved in water (
1.2 ml)
slowly with constant stirring. The reaction mixture was stirred at room
temperature for
24h. The white crystalline powder formed was separated and dried under vacuum
at 40-
45 °C for 4h to yield a mixture of polymorphic Forms I and X of L-
arginine salt of (2S)
3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1.05 g).
Example 17 : Process for the preparation of polymorphic Form I of L-arginine
salt
of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-Z-ethoxypropanoic acid,
A mixture of polymorphic Forms I and X of L-arginine salt of (2S) 3-[4-[2-
(phenoxazin-
10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1.0 g) is suspended in isopropyl
alcohol
(10 ml) the reaction flask was covered with carbon paper and stirred at room
temperature for a period of 35-50 h. The reaction mixture was filtered, washed
with little
isopropyl alcohol and dried under vacuum at 40-45 °C for 4h to yield
polymorphic Form
I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-
ethoxypropanoic acid (0.97 g).



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33
ADVANTAGES OF THE INVENTION
~ The polymorphic Forms of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-
yl)ethoxy]phenyl]-2-ethoxypropanoic acid, are more active / bio-available and
are
therefore very useful for the treatment or prophylaxis.
~ Ease in formulation containing these forms resulting in higher activity /
bioavailability, in terms of lowering plasma blood sugar and plasma
triglycerides.

Representative Drawing