PROCESS FOR PREPARING NOVEL CRYSTALLINE FORMS OF PELIGLITAZAR, NOVEL STABLE FORMS PRODUCED THEREIN AND FORMULATIONS

• US 20070238770A1
• Filed: 04/02/2007
• Published: 10/11/2007
• Est. Priority Date: 04/05/2006
• Status: Abandoned Application

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Gougoutas, Jack Z., Kim, Soojin, Wu, Yongmei, Petsch, Dejah T.
• Application Number:
  US11/695,124
• Publication Number:
  US 20070238770A1
• Time in Patent Office: Days
• US Class Current: 514/374
• CPC Class Codes: C07D 263/32 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

A process is provided for selectively preparing novel stable crystalline forms, namely selectively and consistently preparing Form N-1 of the free acid peliglitazar, Form N-2 of the free acid peliglitazar and Form P-1 of the L-lysine salt of the free acid peliglitazar. The process preferably employs solvent systems which produce crystals having suitable flow properties and desired particle size.

Novel Form N-1 crystals of the free acid, Form N-2 crystals of the free acid, Form P-1 crystals of the L-lysine salt of the free acid, pharmaceutical compositions containing such novel forms and a method of treating diabetes, dyslipidemia and atherosclerosis employing such novel forms are also provided.

Claims

1. A crystalline form of the free acid I which has the structure

(also referred to as peliglitazar)

or a salt thereof.

2. The crystalline form as defined in claim 1 which is Form N-1 of the free acid I, Form N-2 of the free acid I or Form P-1 of the L-lysine salt of the free acid I.

29. The process as defined in claim 1 wherein the free acid I is dissolved in methanol, ethanol, toluene, isopropyl alcohol, methanol/water, acetonitrile/water, N,N-dimethylacetamide (DMA), acetone, 2-butanone (MEK) or butyl acetate.

30. The process as defined in claim 1 wherein the free acid I is dissolved in ethanol or isopropyl alcohol.

31. The process as defined in claim 1 wherein the solution from step b) seeded with seeds of Form N-1 of free acid I is cooled to a temperature within the range from about 5 to about 25°

C.

39. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically-acceptable carrier or diluent.

40. A pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically-acceptable carrier or diluent.

43. A method of treating diabetes, dyslipidemia or atherosclerosis which comprises administering to a human patient in need of such treatment a therapeutic amount of a pharmaceutical composition according to claim 40.

3. Form N-1 of crystalline free acid I.

4. The crystalline form as defined in claim 3 which is Form N-1 of the free acid I and is characterized by unit cell parameters substantially equal to the following:

Cell Dimensions;

a=10.387(3) Å

b=17.638(2) Å

c=15.073(4) Å

α

=90°

β

=96.70(2)

γ

7=90°

Space group P2₁

Molecules/asymmetric unit 2

wherein said crystalline form is at about +22°

C.

5. The crystalline form as defined in claim 3 which is Form N-1 of the free acid I and is characterized by fractional atomic coordinates substantially as listed in Table 3.

6. The crystalline form as defined in claim 3 which is Form N-1 of the free acid I and is characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in FIG. 1.

7. The crystalline form as defined in claim 3 which is Form N-1 of the free acid I having a powder X-ray diffraction pattern comprising the following 2θ

values at a temperature of 22°

C. (CuKα

λ

=1.5418 Å

) 5.9±

0.1, 7.7±

0.1, 10.1±

0.1, 11.7±

0.1, 12.8±

0.1, 15.5±

0.1, 16.2±

0.1, 17.5±

0.1, 19.2±

0.1, and 20.2±

0.1.

8. The crystalline form as defined in claim 3 which is Form N-1 of the free acid I and is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 4, having an endotherm with peak onset in the range from about 123 to about 128°

C.

9. The crystalline form as defined in claim 3 which is Form N-1 of the free acid I and is characterized by a thermal gravimetric analysis curve substantially in accordance with that shown in FIG. 7 having a negligible weight loss up to about 110°

C.

10. The crystalline form as defined in claim 3 which is Form N-1 of the free acid I and is characterized by a moisture-sorption isotherm substantially in accordance with that shown in FIG. 10 having negligible moisture uptake in the range from 25 to 75% RH at 25°

C.

11. The crystalline form as defined in claim 3 which is Form N-1 of the free acid I having a Diamond ATR FT-IR spectrum substantially as shown in FIG. 11.

12. The crystalline form as defined in claim 3 which is Form N-1 of the free acid I having IR vibrational bands (cm⁻

1) at 1707, 1554, 1247, 1051, and 856.

13. The crystalline form as defined in claim 3 which is Form N-1 of the free acid I having a melting point between about 122 and 128°

C.

41. A pharmaceutical composition comprising a compound according to claim 3 and a pharmaceutically acceptable carrier or diluent.

14. Form N-2 of the crystalline free acid I.

15. The crystalline form as defined in claim 14 which is Form N-2 of the free base I and is characterized by unit cell parameters substantially equal to the following:

Cell Dimensions;

a=5.346(1) Å

b=20.75(2) Å

c=49.59(4) Å

α

=90°

β

=90°

γ

=90°

Space group/orthorhombic

Molecules/asymmetric unit 2

wherein said crystalline form is at about room temperature.

16. The crystalline form as defined in claim 14 which is Form N-2 of the free base I as characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in FIG. 2.

17. The crystalline form as defined in claim 14 which is Form N-2 of the free base I as characterized by a powder X-ray diffraction pattern comprising the following 2θ

values at a temperature of 22°

C. (CuKα

λ

-1.5418 Å

) of 3.6±

0.1, 5.6±

0.1, 6.8÷

0.1, 8.7±

0.1, 12.3±

0.1, 13.9±

0.1, 14.9±

0.1, 16.7±

0.1, 17.1±

0.1, and 23.5±

0.1 at about room temperature.

18. The crystalline form as defined in claim 14 which is Form N-2 of the free acid I which is characterized by Diamond ATR FT-IR spectrum substantially as shown in FIG. 12.

19. The crystalline form as defined in claim 14 which is Form N-2 of the free acid I which is characterized by IR vibrational bands (cm⁻

1) at 1713, 1548, 1267, 1254, 1242, 825, and 767.

20. The crystalline form as defined in claim 14 which is Form N-2 of free acid I and is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 5, having an endotherm with peak onset at about 130°

.

21. The crystalline form as defined in claim 14 which is Form N-2 of free acid I and is characterized by a thermal gravimetric analysis curve in accordance with that shown in FIG. 8 having a negligible weight loss up to about 115°

C.

22. Form P-1 of the lysine salt of the free acid I of the structure

23. The crystalline form as defined in claim 22 which is Form P-1 of the L-lysine salt of the free acid I characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in FIG. 3.

24. The crystalline form as defined in claim 22 which is Form P-1 of the L-lysine salt of the free acid I characterized by a powder X-ray diffraction pattern comprising the following 2θ

values at a temperature of 22°

C. (CuKα

λ

=1.5418 Å

) of 3.4±

0.1, 8.2±

0.1, 13.6±

0.1, 14.57±

0.1, 16.7±

0.1, 20.0±

0.1, 20.5±

0.1, 22.5±

0.1, 23.9±

0.1, 25.1±

0.1, 26.7±

0.1.

25. The crystalline form as defined in claim 22 which is characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in FIG. 6, having an endotherm with peak onset at about 165°

C.

26. The crystalline form as defined in claim 22 which is characterized by a thermal gravimetric analysis curve in accordance with that shown in FIG. 9 having a weight loss of about 0.3% up to about 120°

C.

42. A pharmaceutical composition comprising a compound as defined in claim 22 and a pharmaceutically acceptable carrier or diluent.

27. A process for preparing the crystalline Form N-1 of free acid I, which comprises

a) providing the free acid I having the structure

b) dissolving the free acid I in an organic solvent;

c) seeding the solution from step b) with crystalline seeds of Form N-1 of the free acid I to initiate crystallization, and form a slurry; and

d) recovering crystalline Form N-1 of the free acid I.

28. The process as defined in claim 27 including the step of preparing the seed crystals of Form N-1 of the free acid I by recrystallizing or slurrying the crude free acid I in hexane, heptane or hexane-ethyl acetate mixture.

36. Form N-1 of the free acid I

prepared by the process defined in claim 27.

32. A process for preparing the crystalline Form N-1 of free acid I, which comprises

a) providing free acid I;

b) dissolving the free acid I in isopropyl alcohol;

c) seeding the solution from step b) with crystalline seeds of Form N-2 of free acid I to initiate crystallization; and

d) recovering crystalline Form N-2 of the free acid I.

37. Form N-2 of the free acid

prepared as defined by the process of claim 32.

33. A process is for preparing the crystalline L-lysine salt of free acid I, which comprises

a) providing free acid I;

b) dissolving the free acid I in ethanol to obtain a solution;

c) admixing L-lysine with the solution from step b) to form a slurry;

d) cooling the slurry to a temperature within the range from about 5 to about 25°

C.; and

e) recovering the crystalline L-lysine salt of free acid I.

34. The process as defined in claim 33 wherein the mixture of L-lysine and the solution from step b) is heated at a temperature within the range from about 35 to about 65°

C.

35. The process as defined in claim 33 including the step of cooling the slurry from step c) at a temperature from about 5 to about 25°

C.

38. Form P-1 of the L-lysine salt of the free acid I

prepared as defined by the process of claim 33.