Crystal forms of saxagliptin and processes for preparing same

• US 7,943,656 B2
• Filed: 04/18/2008
• Issued: 05/17/2011
• Est. Priority Date: 04/20/2007
• Status: Expired due to Fees

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: DiMarco, John D., Jones, Gregory Scott, Gougoutas, Jack Z., Malley, Mary F., Yu, Jurong, Yin, Xiaotian S., Wei, Chenkou, Vu, Truc Chi, Savage, Scott A.
• Primary Examiner(s): Chung; Susannah
• Assistant Examiner(s): Shterengarts; Samantha L
• Application Number:
  US12/105,316
• Publication Number:
  US 20090054303A1
• Time in Patent Office: 1,124 Days
• Field of Search: 514/412, 548/452
• US Class Current: 514/412
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 209/52 : condensed with a ring other than six-membered

Abstract

Physical crystal structures of a compound of the formula I:

are provided including the free base monohydrate thereof (form H-1) and the hydrochloric acid salt thereof, including hydrochloric acid salt containing 0.75 equivalent of H₂O (form H0.75-3) and hydrochloric acid salt containing 2 equivalents of H₂O (form H2-1), and hydrochloric acid salt Pattern P-5, preferably in substantially pure form, and other forms as described herein, pharmaceutical compositions containing structures of compound I or IA, processes for preparing same, intermediates used in preparing same, and methods of treating diseases such as diabetes using such structures.

Claims

1. A crystalline compound of form H2-1 (1HCl), H2-1 (2HCl), H0.75-3, H1.67-1, P-5, or mixtures thereof,

wherein the crystalline compound of form H2-1 (1HCl) has structure

2. The crystalline compound of form H2-1 (1HCl) according to claim 1.

3. The crystalline compound of form H2-1 (1HCl) according to claim 2 having an observed powder x-ray diffraction pattern as shown in FIG. 6.

4. The crystalline compound of form H2-1 (2HCl) according to claim 1.

5. The crystalline compound of form H0.75-3 according to claim 1.

6. The crystalline compound of form H0.75-3 according to claim 5 having an observed powder x-ray diffraction pattern as shown in FIG. 11.

7. The crystalline compound of form H1.67-1 according to claim 1.

8. The crystalline compound of form H1.67-1 according to claim 7 having an observed powder x-ray diffraction pattern as shown in FIG. 16.

9. The crystalline compound of form P-5 according to claim 1.

10. The crystalline compound of form P-5 according to claim 9 having an observed powder x-ray diffraction pattern as shown in FIG. 28.

11. A pharmaceutical composition comprising a therapeutically effective amount of crystalline compound of form H2-1 (1HCl), H2-1 (2HCl), H0.75-3, H1.67-1, P-5, or mixtures thereof, and a pharmaceutically acceptable carrier, wherein:

the crystalline compound of form H2-1 (1HCl) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418Å

) of 6.8±

0.1, 11.1±

0.1, 13.7±

0.1, 14.6±

0.1, 15.2±

0.1, 16.4±

0.1, 17.0±

0.1, 20.2±

0.1, and 21.1±

0.1;

the crystalline compound of form H2-1 (2HCl) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 7.2±

0.1, 8.6±

0.1, 11.6±

0.1, 14.3±

0.1, 15.7±

0.1, 19.5±

0.1, and 22.5±

0.1;

the crystalline compound of form H0.75-3 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.0±

0.1, 7.0±

0.1, 8.1±

0.1, 11.4±

0.1, 13.4±

0.1, 14.0±

0.1, 14.5±

0.1, 18.6±

0.1, 19.4±

0.1, and 20.0±

0.1;

the crystalline compound of form H1.67-1 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.4±

0.1, 7.0±

0.1, 13.8±

0.1, 14.2±

0.1, 14.6±

0.1, 16.1±

0.1, 16.6±

0.1, 18.6±

0.1, 19.0±

0.1, and 20.3±

0.1; and

the crystalline compound of form P-5 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 6.2±

0.1, 10.7±

0.1, 14.5±

0.1, 15.0±

0.1, 15.6±

0.1, 16.2±

0.1, 18.1±

0.1, 18.7±

0.1, and 21.1±

0.1.

12. A pharmaceutical combination comprising a therapeutically effective amount of crystalline compound of form H2-1 (1HCl), H2-1 (2HCl), H0.75-3, H1.67-1, or P-5, and at least one or more antidiabetic agent(s) other than a DPP4 inhibitor for treating diabetes, wherein:

the crystalline compound of form H2-1 (1HCl) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 6.8±

0.1, 11.1±

0.1, 13.7±

0.1, 14.6±

0.1, 15.2±

0.1, 16.4±

0.1, 17.0±

0.1, 20.2±

0.1, and 21.1±

0.1;

the crystalline compound of form H2-1 (2HCl) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 7.2±

0.1, 8.6±

0.1, 11.6±

0.1, 14.3±

0.1, 15.7±

0.1, 19.5±

0.1, and 22.5±

0.1;

the crystalline compound of form H0.75-3 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.0±

0.1, 7.0±

0.1, 8.1±

0.1, 11.4±

0.1, 13.4±

0.1, 14.0±

0.1, 14.5±

0.1, 18.6±

0.1, 19.4±

0.1, and 20.0±

0.1;

the crystalline compound of form H1.67-1 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.4±

0.1, 7.0±

0.1, 13.8±

0.1, 14.2±

0.1, 14.6±

0.1, 16.1±

0.1, 16.6±

0.1, 18.6±

0.1, 19.0±

0.1, and 20.3±

0.1; and

the crystalline compound of form P-5 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 6.2±

0.1, 10.7±

0.1, 14.5±

0.1, 15.0±

0.1, 15.6±

0.1, 16.2±

0.1, 18.1±

0.1, 18.7±

0.1, and 21.1±

0.1.

13. The pharmaceutical combination according to claim 12 wherein the antidiabetic agent is a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ

agonist, a CTEP inhibitor, a PPAR α

/γ

dual agonist, an SGLT2 inhibitor, an aP2inhibitor, a glycogen phosphorylase inhibitor, an AGE inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1) or mimetic thereof, insulin and/or a meglitinide.

14. The pharmaceutical combination according to claim 12 wherein the antidiabetic agent is metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, dapagliflozin, rosiglitazone, insulin, Gl-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, APR-H039242, GW-409544, KRP297, AC2993, Exendin-4, LY307161, NN2211, and/or LY315902.

15. The pharmaceutical combination according to claim 12 wherein the antidiabetic agent is metformin, glyburide, glipizide, or dapagliflozin.

16. The pharmaceutical combination as defined in claim 12 wherein the antidiabetic agent is metformin or dapagliflozin.

17. The pharmaceutical combination as defined in claim 12 wherein the antidiabetic agent is dapagliflozin.

18. A pharmaceutical combination comprising a therapeutically effective amount of crystalline compound of form H2-1 (1HCl), H2-1 (2HCl), H0.75-3, H1.67-1, or P-5, and an anti-obesity agent, wherein:

the crystalline compound of form H2-1 (1HCl) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 6.8±

0.1, 11.1±

0.1, 13.7±

0.1, 14.6±

0.1, 15.2±

0.1, 16.4±

0.1, 17.0±

0.1, 20.2±

0.1, and 21.1±

0.1;

the crystalline compound of form H2-1 (2HCl) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 7.2±

0.1, 8.6±

0.1, 11.6±

0.1, 14.3±

0.1, 15.7±

0.1, 19.5±

0.1, and 22.5±

0.1;

the crystalline compound of form H0.75-3 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.0±

0.1, 7.0±

0.1, 8.1±

0.1, 11.4±

0.1, 13.4±

0.1, 14.0±

0.1, 14.5±

0.1, 18.6±

0.1, 19.4±

0.1, and 20.0±

0.1;

the crystalline compound of form H1.67-1 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.4±

0.1, 7.0±

0.1, 13.8±

0.1, 14.2±

0.1, 14.6±

0.1, 16.1±

0.1, 16.6±

0.1, 18.6±

0.1, 19.0±

0.1, and 20.3±

0.1; and

the crystalline compound of form P-5 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 6.2±

0.1, 10.7±

0.1, 14.5±

0.1, 15.0±

0.1, 15.6±

0.1, 16.2±

0.1, 18.1±

0.1, 18.7±

0.1, and 21.1±

0.1.

19. The pharmaceutical combination according to claim 18 comprising the crystalline compound of form H2-1 (1HCl), H2-1 (2HCl), H0.75-3, H1.67-1, or P-5, wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol.

20. A pharmaceutical combination comprising a therapeutically effective amount of crystalline compound of form H2-1 (1HCl), H2-1 (2HCl), H0.75-3, H1.67-1, or P-5, and a lipid-modulating agent, wherein:

the crystalline compound of form H2-1 (1HCl) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 6.8±

0.1, 11.1±

0.1, 13.7±

0.1, 14.6±

0.1, 15.2±

0.1, 16.4±

0.1, 17.0±

0.1, 20.2±

0.1, and 21.1±

0.1;

the crystalline compound of form H2-1 (2HCl) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 7.2±

0.1, 8.6±

0.1, 11.6±

0.1, 14.3±

0.1, 15.7+0.1, 19.5±

0.1, and 22.5±

0.1;

the crystalline compound of form H0.75-3 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.0±

0.1, 7.0±

0.1, 8.1±

0.1, 11.4±

0.1, 13.4±

0.1, 14.0±

0.1, 14.5±

0.1, 18.6±

0.1, 19.4±

0.1, and 20.0±

0.1;

the crystalline compound of form H1.67-1 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.4±

0.1, 7.0±

0.1, 13.8±

0.1, 14.2±

0.1, 14.6±

0.1, 16.1±

0.1, 16.6±

0.1, 18.6±

0.1, 19.0±

0.1, and 20.3±

0.1; and

the crystalline compound of form P-5 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 6.2±

0.1, 10.7±

0.1, 14.5±

0.1, 15.0±

0.1, 15.6±

0.1, 16.2±

0.1, 18.1±

0.1, 18.7±

0.1, and 21.1±

0.1.

21. The pharmaceutical combination according to claim 20 comprising the crystalline compound of form H2-1 (1HCl), H2-1 (2HCl), H0.75-3, H1.67-1, or P-5, wherein the lipid modulating agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, ZD-4522, fenofibrate, gemfibrozil, clofibrate, implitapide, CP-529,414, avasimibe, TS-962, MD-700, and/or LY295427.

22. A process for preparing crystalline compound of form H2-1 (1HCl) having powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 6.8±

0.1, 11.1±

0.1, 13.7±

0.1, 14.6±

0.1, 15.2±

0.1, 16.4±

0.1, 17.0±

0.1, 20.2±

0.1, and 21.1±

0.1, comprising;

(a) dissolving saxagliptin trifluoroacetic acid salt in water;

(b) adjusting the pH of the aqueous solution of step (a) to a pH within the range from 9 to 9.8 with a strong base;

(c) treating the mixture from step (b) with an organic solvent to extract the aqueous layer from the organic layer;

(d) adding a solution of hydrochloric acid to the organic solution of step (c);

(e) evaporating the organic solution of step (d) to dryness;

(f) dissolving the resulting solids from step (e) in an alcohol solvent;

(g) heating the solution from step (f) to a temperature within the range from 35 to 60°

C.;

(h) adding t-butylmethyl ether (MTBE) to the heated solution from step (g) to form a slurry;

(i) cooling the slurry from step (h);

(j) filtering the slurry from step (i); and

(l) drying the resulting wet cake from step (j) to obtain the crystalline compound of form H2-1 (1HCl).

23. A process for preparing crystalline compound of form H2-1 (2HCl) having powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 7.2±

0.1, 8.6±

0.1, 11.6±

0.1, 14.3±

0.1, 15.7±

0.1, 19.5±

0.1, and 22.5±

0.1, comprising;

(a) dissolving crystalline compound of form H-1 (1H₂O) in HCl, dioxane and ethanol; and

(b) upon standing at room temperature, isolating the crystalline compound of form H2-1 (2HCl).

24. A process for preparing crystalline compound of form H1.67-1 having powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.4±

0.1, 7.0±

0.1, 13.8±

0.1, 14.2±

0.1, 14.6±

0.1, 16.1±

0.1, 16.6±

0.1, 18.6±

0.1, 19.0±

0.1, and 20.3±

0.1, comprising;

(a) dissolving Boc protected compound

25. A process for preparing crystalline compound of form H0.75-3 having x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.0±

0.1, 7.0±

0.1, 8.1±

0.1, 11.4±

0.1, 13.4±

0.1, 14.0±

0.1, 14.5±

0.1, 18.6±

0.1, 19.4±

0.1, and 20.0±

0.1, comprising;

(a) heating crystalline compound of form H2-1 (1HCl) at a temperature from 25 to 55°

C. for 1 to 2 hours; and

(b) isolating the crystalline compound of form H0.75-3 from step (a).

26. A process for preparing crystalline compound of form P-5 having x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 6.2±

0.1, 10.7±

0.1, 14.5±

0.1, 15.0±

0.1, 15.6±

0.1, 16.2±

0.1, 18.1±

0.1, 18.7±

0.1, and 21.1±

0.1, comprising;

(a) dissolving crystalline compound of form H2-1 (1HCl) in ethanol with heating at 35 to 50°

C.;

(b) allowing the mixture of step (a) to cool to 20 to 30°

C.; and

(c) isolating the crystalline compound of form P-5 from the mixture of step (b).

27. A crystalline compound of form N-3, H-1 (1H₂O), H-1 (1PhCO₂H/1H₂O), and N-1,

wherein the crystalline compound of form N-3 has structure

28. The crystalline compound of form N-3 according to claim 27.

29. The crystalline compound of form N-3 according to claim 28 having an observed powder x-ray diffraction pattern as shown in FIG. 25.

30. The crystalline compound of form H-1 (1H₂O) according to claim 27.

31. The crystalline compound of form H-1 (1H₂O) according to claim 30 having an observed powder x-ray diffraction pattern as shown in FIG. 1.

32. The crystalline compound of form H-1 (1PhCO₂H/1H₂O) according to claim 27.

33. The crystalline compound of form H-1 (1PhCO₂H/1H₂O) according to claim 32 having an observed powder x-ray diffraction pattern as shown in FIG. 22.

34. The crystalline compound of form N-1 according to claim 27.

35. The crystalline compound of form N-1 according to claim 34 having an observed powder x-ray diffraction pattern as shown in FIG. 21.

36. A pharmaceutical composition comprising a therapeutically effective amount of crystalline compound of form N-3, H-1 (1H₂O), H-1 (1PhCO₂H/1H₂O), or N-1, and a pharmaceutically acceptable carrier, wherein the crystalline compound of form N-3 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.2±

0.1, 7.9±

0.1, 10.8±

0.1, 11.5±

0.1, 13.0±

0.1, 14.6±

0.1, 15.6±

0.1, 15.9±

0.1, and 16.5±

0.1;

wherein the crystalline compound of form H-1 (1H₂O) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 12.4±

0.1, 13.3±

0.1, 13.6±

0.1, 14.7±

0.1, 16.2±

0.1, 18.2±

0.1, 19.9±

0.1, 20.9±

0.1, 21.9±

0.1, and 22.4±

0.1;

wherein the crystalline compound of form H-1 (1PhCO₂H/1H₂O) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 6.6±

0.1, 8.3±

0.1, 15.3±

0.1, 16.1±

0.1, 16.9±

0.1, 17.5±

0.1, 17.8±

0.1, 18.6±

0.1, and 21.3±

0.1; and

wherein the crystalline compound of form N-1 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.5±

0.1, 7.0±

0.1, 11.1±

0.1, 14.4±

0.1, 15.1±

0.1, 15.7±

0.1, 16.4±

0.1, 16.8±

0.1, and 19.6±

0.1.

37. A pharmaceutical combination comprising a therapeutically effective amount of crystalline compound of form N-3, H-1 (1H₂O), H-1 (1PhCO₂H/1H₂O), or N-1, and at least one or more antidiabetic agent(s) other than a DPP4 inhibitor for treating diabetes, an antidiabetic agent other than a DPP4 inhibitor for treating diabetes, wherein the crystalline compound of form N-3 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.2±

0.1, 7.9±

0.1, 10.8±

0.1, 11.5±

0.1, 13.0±

0.1, 14.6±

0.1, 15.6±

0.1, 15.9±

0.1, and 16.5±

0.1;

wherein the crystalline compound of form H-1 (1H₂O) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 12.4±

0.1, 13.3±

0.1, 13.6±

0.1, 14.7±

0.1, 16.2±

0.1, 18.2±

0.1, 19.9±

0.1, 20.9±

0.1, 21.9±

0.1, and 22.4±

0.1;

wherein the crystalline compound of form H-1 (1PhCO₂H/1H₂O) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 6.6±

0.1, 8.3±

0.1, 15.3±

0.1, 16.1±

0.1, 16.9±

0.1, 17.5±

0.1, 17.8±

0.1, 18.6±

0.1, and 21.3±

0.1; and

wherein the crystalline compound of form N-1 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.5±

0.1, 7.0±

0.1, 11.1±

0.1, 14.4±

0.1, 15.1±

0.1, 15.7±

0.1, 16.4±

0.1, 16.8±

0.1, and 19.6±

0.1.

38. The pharmaceutical combination according to claim 37 wherein the antidiabetic agent is a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ

agonist, a CTEP inhibitor, a PPAR α

/γ

dual agonist, an SGLT2 inhibitor, an aP2inhibitor, a glycogen phosphorylase inhibitor, an AGE inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1) or mimetic thereof, insulin and/or a meglitinide.

39. The pharmaceutical combination according to claim 37 wherein the antidiabetic agent is metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, dapagliflozin, rosiglitazone, insulin, Gl-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, APR-H039242, GW-409544, KRP297, AC2993, Exendin-4, LY307161, NN2211, and/or LY315902.

40. The pharmaceutical combination according to claim 37 wherein the antidiabetic agent is metformin, glyburide, glipizide, or dapagliflozin.

41. The pharmaceutical combination as defined in claim 37 wherein the antidiabetic agent is metformin or dapagliflozin.

42. The pharmaceutical combination as defined in claim 37 wherein the antidiabetic agent is dapagliflozin.

43. A pharmaceutical combination comprising a therapeutically effective amount of crystalline compound of form N-3, H-1 (1H₂O), H-1 (1PhCO₂H/1H₂O), or N-1, and an anti-obesity agent, wherein the crystalline compound of form N-3 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.2±

0.1, 7.9±

0.1, 10.8±

0.1, 11.5±

0.1, 13.0±

0.1, 14.6±

0.1, 15.6±

0.1, 15.9±

0.1, and 16.5±

0.1;

wherein the crystalline compound of form H-1 (1H₂O) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 12.4±

0.1, 13.3±

0.1, 13.6±

0.1, 14.7±

0.1, 16.2±

0.1, 18.2±

0.1, 19.9±

0.1, 20.9±

0.1, 21.9±

0.1, and 22.4±

0.1;

wherein the crystalline compound of form H-1 (1PhCO₂H/1H₂O) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 6.6±

0.1, 8.3±

0.1, 15.3±

0.1, 16.1±

0.1, 16.9±

0.1, 17.5±

0.1, 17.8±

0.1, 18.6±

0.1, and 21.3±

0.1; and

wherein the crystalline compound of form N-1 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.5±

0.1, 7.0±

0.1, 11.1±

0.1, 14.4±

0.1, 15.1±

0.1, 15.7±

0.1, 16.4±

0.1, 16.8±

0.1, and 19.6±

0.1.

44. The pharmaceutical combination according to claim 43 comprising the crystalline compound of form N-3, H-1 (1H₂O), H-1 (1PhCO₂H/1H₂O), or N-1, wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, and/or mazindol.

45. A pharmaceutical combination comprising a therapeutically effective amount of crystalline compound of form N-3, H-1 (1H₂O), H-1 (1PhCO₂H/1H₂O), or N-1, and a lipid-modulating agent, wherein the crystalline compound of form N-3 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.2±

0.1, 7.9±

0.1, 10.8±

0.1, 11.5±

0.1, 13.0±

0.1, 14.6±

0.1, 15.6±

0.1, 15.9±

0.1, and 16.5±

0.1;

wherein the crystalline compound of form H-1 (1H₂O) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 12.4±

0.1, 13.3±

00.1, 13.6±

0.1, 14.7±

0.1, 16.2±

0.1, 18.2±

0.1, 19.9±

0.1, 20.9±

0.1, 21.9±

0.1, and 22.4±

0.1;

wherein the crystalline compound of form H-1 (1PhCO₂H/1H₂O) has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 6.6±

0.1, 8.3±

0.1, 15.3±

0.1, 16.1±

0.1, 16.9±

0.1, 17.5±

0.1, 17.8±

0.1, 18.6±

0.1, and 21.3±

0.1; and

wherein the crystalline compound of form N-1 has powder x-ray diffraction peaks at 2θ

values (CuKα

λ

−

1.5418 Å

) of 5.5±

0.1, 7.0±

0.1, 11.1±

0.1, 14.4±

0.1, 15.1±

0.1, 15.7±

0.1, 16.4±

0.1, 16.8±

0.1, and 19.6±

0.1.

46. The pharmaceutical combination according to claim 45 comprising the crystalline compound of form N-3, H-1 (1H₂O), H-1 (1PhCO₂H/1H₂O), or N-1, wherein the lipid modulating agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, ZD-4522, fenofibrate, gemfibrozil, clofibrate, implitapide, CP-529,414, avasimibe, TS-962, MD-700, and/or LY295427.