NOVEL CRYSTALLINE FORM OF SITAGLIPTIN SULFATE

• US 20150037406A1
• Filed: 03/01/2013
• Published: 02/05/2015
• Est. Priority Date: 03/02/2012
• Status: Active Grant

• Current Assignee: Moehs Iberica Sl (PMC Global Incorporated)
• Original Assignee: Moehs Iberica Sl (PMC Global Incorporated)
• Inventors: Bernabeu Martnez, Mara del Carmen, Dobarro Rodrguez, Alicia, Galn Rodrguez, Cristobal
• Granted Patent: US 9,181,260 B2
• Time in Patent Office: Days
• US Class Current: 424/465
• 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 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/64 Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• 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 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

A novel crystalline form of sitagliptin sulfate is provided. In addition, a method for obtaining the crystalline form, pharmaceutical compositions comprising the novel crystalline form and the crystalline form for use as a medicament are provided.

Claims

1. A crystalline form of sitagliptin sulfate (1:

1) characterized by an X-ray powder diffraction pattern having peaks at 2θ

values equal to 14.8±

0.2°

, 15.1±

0.2°

, 17.1±

0.2°

, 19.4±

0.2°

, 21.9±

0.2°

, 24.0±

0.2° and

25.4±

0.2°

.

2. The crystalline form according to claim 1, characterized in that it has an X-ray diffraction pattern further comprising peaks at the following 2θ

values equal to 18.5±

0.2°

, 19.8±

0.2°

, 23.0±

0.2° and

26.7±

0.2°

.

3. The crystalline form according to claim 1, wherein the crystalline form comprises a percentage of water less than 0.05% determined by thermal gravimetric analysis.

4. The crystalline form according to claim 1, wherein the crystalline form comprises a differential scanning calorimetry (DSC) thermogram with an endothermic peak at 216.0±

1.0°

C.

5. A method for preparing the crystalline form of sitagliptin sulfate of claim 1 comprising the following steps:

a) providing sitagliptin base,

b) preparing a sitagliptin base suspension or solution in a mixture comprising water and one or more water-miscible organic solvents,

c) adding a sulfuric acid (H₂SO₄) solution in one or more of the water-miscible organic solvents to the suspension or to the solution obtained in step b) such that the molar ratio of H₂SO₄ to sitagliptin base is comprised between 0.9;

1 and 1.1;

1, and

d) optionally, adding crystals from the crystalline form of sitagliptin sulfate of claim 1 to the suspension,

such that the ratio of volume (in ml) of organic solvent added in steps b) and c) to weight (in g) of sitagliptin base is between 10;

1 and 30;

1 and the ratio of volume (in ml) of water added in steps b) and c) to weight (in g) of sitagliptin base is between 1;

1 and 5;

1.

7. A method for preparing the crystalline form of sitagliptin sulfate of claim 1 comprising the following steps:

a) providing sitagliptin sulfate,

b) preparing a sitagliptin sulfate solution in a mixture comprising water and a water-miscible solvent such that the ratio of volume (in ml) of organic solvent to weight (in g) of sitagliptin sulfate is between 10;

1 and 30;

1 and the ratio of volume (in ml) of water to weight (in g) of sitagliptin sulfate is between 1;

1 and 5;

1, and

c) optionally, adding crystals from the crystalline form of sitagliptin sulfate of claim 1 to the suspension.

9. A pharmaceutical composition comprising the crystalline form of sitagliptin sulfate of claim 1 and at least one pharmaceutically acceptable excipient.

10. The pharmaceutical composition according to claim 9 which comprises:

from 1% to 80% by weight, with respect to the total weight of the composition, of the crystalline form of sitagliptin sulfate;

from 0% to 99% by weight, with respect to the total weight of the composition, of one or more diluents/fillers;

from 0% to 20% by weight, with respect to the total weight of the composition, of one or more disintegrants;

from 0% to 20% by weight, with respect to the total weight of the composition, of one or more glidants and/or lubricants; and

optionally a film coat;

with the proviso that at least one pharmaceutically acceptable excipient selected from the group consisting of diluents/fillers, disintegrants, glidants and lubricants, is present in the composition.

11. The pharmaceutical composition according to claim 10, which comprises:

from 10% to 50% by weight, with respect to the total weight of the composition, of the crystalline form of sitagliptin sulfate;

from 40% to 80% by weight, with respect to the total weight of the composition, of one or more diluents/fillers;

from 0% to 10% by weight, with respect to the total weight of the composition, of one or more disintegrants;

from 0% to 10% by weight, with respect to the total weight of the composition, of one or more glidants and/or lubricants; and

optionally a film coat.

12. The pharmaceutical composition according to claim 11, which comprises:

from 20% to 40% by weight, with respect to the total weight of the composition, of the crystalline form of sitagliptin sulfate;

from 50% to 70% by weight, with respect to the total weight of the composition, of one or more diluents/fillers;

from 1% to 6% by weight, with respect to the total weight of the composition, of one or more disintegrants;

from 1% to 6% by weight, with respect to the total weight of the composition, of one or more glidants and/or lubricants; and

optionally a film coat.

13. The pharmaceutical composition according to claim 9, characterized by being a solid at a temperature of 25°

C.

14. The pharmaceutical composition according to claim 9 further comprising metformin.

15. The pharmaceutical composition according to claim 9, further comprising a sulfonylurea selected from the group consisting of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride and gliclazide.

16. The pharmaceutical composition according to claim 9, further comprising a peroxisome proliferator-activated receptor gamma (PPARγ

) agonist selected from the group consisting of rosiglitazone, pioglitazone and troglitazone.

17. The pharmaceutical composition according to claim 9, further comprising a 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitor selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin and rosuvastatin.

30. A method for improving blood glucose control in type 2 diabetes mellitus patients comprising administering the crystalline form of sitagliptin sulfate of claim 1.

31. A method for improving blood glucose control in type 2 diabetes mellitus patients comprising administering the crystalline form of sitagliptin sulfate of claim 1 in combination with metformin.

32. A method for improving the of blood glucose control in type 2 diabetes mellitus patients comprising administering the crystalline form of sitagliptin sulfate of claim 1 in combination with a sulfonylurea selected from the group consisting of tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride and gliclazide.

33. A method for improving the of blood glucose control in type 2 diabetes mellitus patients comprising administering the crystalline form of sitagliptin sulfate of claim 1 in combination with a peroxisome proliferator-activated receptor gamma (PPARγ

) agonist selected from the group consisting of rosiglitazone, pioglitazone and troglitazone.

34. A method for improving the of blood glucose control in type 2 diabetes mellitus patients comprising administering the crystalline form of sitagliptin sulfate of claim 1 in combination with a 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) inhibitor selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin and rosuvastatin.

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