FIELD OF THE INVENTION

The present invention relates to novel pharmaceutically acceptable salts of 7-[(3R)-3- amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-[l,2,4]-triazolo[4,3-a]pyrazine of Formula I,

or solvates or hydrates thereof.

wherein salt represents formate, picolinate, nicotinate, stearate, palmitate and laurate.

BACKGROUND OF THE INVENTION

Sitagliptin, chemically known as 7-[(3R)~3-amino-l-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-[ 1,2,4]-triazolo[4,3-a]pyrazine of Formula II,

is marketed in the form of a phosphate monohydrate in United States under the trade name JANUVIA® and is indicated to improve glycemic control in patients with type 2 diabetes mellitus.

Sitagliptin phosphate is a glucagon-like peptide 1 (GLP-1) metabolism modulator, hypoglycemic agent, and dipeptidyl peptidase IV inhibitor.

US 6,699,871 discloses class of p-amino tetrahydrotriazolo[4,3-a]pyrazines that are potent inhibitors of DPP-IV and therefore useful for the treatment of Type 2 diabetes and specifically discloses Sitagliptin and its pharmaceutically acceptable salts.

US 7,326,708 discloses crystalline Sitagliptin dihydrogenphosphate monohydrate; US 7,612,072 discloses amorphous Sitagliptin dihydrogenphosphate; US 2006/0287528 and US 2007/021430 discloses the crystalline anhydrous forms of Sitagliptin dihydrogenphosphate.

US 2009/0221592 discloses crystalline anhydrous Sitagliptin dodecyl sulfate.

US 2008/0227786 discloses crystalline Sitagliptin hydrochloric acid, benzenesufonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, tartaric acid salts and hydrates thereof.

WO 2009/085990 discloses Sitagliptin salts such as anhydrous crystalline dihydrogen phosphate Form A, sulfuric acid, hydrobromic acid, methane sulfonic acid, acetic acid, benzoic acid, oxalic acid, succinic acid, mandelic acid, fumaric acid and lactic acid.

WO 2010/000469 discloses Sitagliptin malate, glycolate, citrate, maleate salts.

WO 2010/012781 discloses crystalline Sitagliptin galactarate Form I, hemi-L-malate Form I, D-gluconate Form I, thiocyanate Form I, L-aspartate Form I, ethanedisulfonate Form I, pyrroglutamate Form I, glutarate Form I, acetate Form I, citrate amorphous form, hemicitrate amorphous form, glycolate amorphous form, malate amorphous form.

WO 2010/092090 discloses Sitagliptin salts, such as D- & L-glucuronic acid, D- & L-lactic acid, D- & L-mandelic acid, ethanesulfonic acid, capric acid, benzoic acid, hippuric acid, trans-cinnamic acid, malonic acid, l-hydroxy-2-naphtholic acid, crotonic acid, ascorbic acid.

US 2010/0249140 discloses Sitagliptin salts, such as sulfate & its isopropanol solvate, quinate, (+)-dibenzoyltartrate and orotate.

IP.COM Journal, IPCOM000200626 D, discloses novel salts of Sitagliptin with acids such as cinnamic, (phenylthio)acetic, caffeic, crotonic, nitric, hydroiodic, malonic, hippuric, 4-hydroxybenzoic acid.

Salts often improve physical and biological characteristics of mother compounds without modifying primary pharmacological activity, based on mechanism of action. Different salt forms of the same pharmaceutically active moiety differ in their physical properties such as melting point, solubility etc. These properties may appreciably influence pharmaceutical properties such as dissolution rate, bioavailability. Discovery of new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutical ly useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. New salts of Sitagliptin that may have advantageous physico-chemical and biokinetic properties such as suitable solubility in neutral, acidic or alkaline water medium, solubility in technologically important organic solvents, water/lipid partition coefficient, electrochargeability, thermal stability, water and oxygen inertness, hygroscopicity, crystal shape, particle size and surface, dissolution profile, compatibility with excipients and combined active ingredients or special properties for final dosage form design.

In view of the foregoing, we have now found novel salts of Sitagliptin and new polymorphic forms of Sitagliptin salts, which are stable and can be used in medical therapy.

OBJECTIVE

The objective of the present invention is to provide novel pharmaceutical ly acceptable salts of Sitagliptin or solvates or hydrates thereof, having improved physical and chemical properties.

Yet another objective of the present invention is to provide novel salts of Sitagliptin or solvates or hydrates thereof, which are crystalline or amorphous in nature.

Yet another objective of the present invention is to provide a safe, productive and easy to handle process for the preparation of salts of Sitagliptin or solvates or hydrates thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 - Powder X-ray Diffraction (PXRD) of crystalline Sitagliptin cinnamate hemi- hydrate.

Figure 2 - Powder X-ray Diffraction (PXRD) of amorphous Sitagliptin cinnamate.

Figure 3 - Powder X-ray Diffraction (PXRD) of amorphous Sitagliptin nitrate.

Figure 4 - Powder X-ray Diffraction (PXRD) of crystalline Sitagliptin nitrate Form-II.

Figure 5 - Powder X-ray Diffraction (PXRD) of crystalline Sitagliptin formate.

Figure 6 - Powder X-ray Diffraction (PXRD) of amorphous Sitagliptin formate.

Figure 7- Powder X-ray Diffraction (PXRD) of crystalline Sitagliptin picolinate.

Figure 8- Powder X-ray Diffraction (PXRD) of crystalline Sitagliptin palmitate.

Figure 9- Powder X-ray Diffraction (PXRD) of crystalline Sitagliptin stearate.

Figure 10- Powder X-ray Diffraction (PXRD) of crystalline Sitagliptin Iaurate.

Figure 11- Powder X-ray Diffraction (PXRD) of amorphous Sitagliptin nicotinate.

Figure 12- Powder X-ray Diffraction (PXRD) of crystalline Sitagliptin nicotinate.

SUMMARY OF THE INVENTION

The present invention relates to novel salts of Sitagliptin of Formula I or solvates or hydrates thereof, wherein salt represents formate, picolinate, nicotinate, stearate, palmitate and Iaurate.

In another embodiment, present invention also relates to novel salts of Sitagliptin or solvates or hydrates thereof, which are crystalline.

In another embodiment, present invention also relates to novel salts of Sitagliptin or solvates or hydrates thereof, which are amorphous.

In another embodiment, present invention also relates to the amorphous Sitagliptin nitrate salt having the PXRD as per figure 3 and crystalline Sitagliptin nitrate salt having the PXRD as per figure 4.

In another embodiment, present invention also relates to the Sitagliptin cinnamate hemihydrate having the PXRD as per figure 1.

In another embodiment, present invention also relates to a process for the preparation of novel crystalline salts of Sitagliptin selected from formate, picolinate, nicotinate, stearate, palmitate, nitrate and laurate.

In another embodiment, present invention also relates to a process for the preparation of novel amorphous salts of Sitagliptin selected from formate, picolinate, nicotinate, stearate, nitrate, palmitate and laurate.

In another embodiment, present invention also relates to a process for the preparation of Sitagliptin cinnamate hemihydrate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel salts of Sitagliptin of formula I or solvates or hydrates thereof,

wherein salt represents formate, picolinate, nicotinate, stearate, palmitate and laurate.

In another aspect of the present invention also relates to the crystalline Sitagliptin formate or solvates or hydrates thereof.

In another aspect present invention relates to the crystalline Sitagliptin formate having powder X-ray diffraction °29 values (±0.2) at 14.95, 15.88, 19.32, 19.71, 26.24. The crystalline Sitagliptin formate is further characterised by PXRD having °28 values (±0.2) at 6.27, 7.80, 9.84, 12.53, 14.57, 16.62, 18.33, 20.32, 22.47, 23.47, 24.13, 24.87, 26.99, 29.18, 30.37, 31.00, 34.31, 34.99, 36.98.

Another aspect of the present invention relates to the amorphous form of Sitagliptin formate.

In another aspect present invention relates to the crystalline Sitagliptin cinnamate or solvates or hydrates thereof.

In another aspect present invention, provides a crystalline Sitagliptin cinnamate hemihydrate having powder X-ray diffraction °26 values (±0.2) at 5.96, 18.51, 19.63, 22.62, 23.71. The crystalline Sitagliptin cinnamate is further characterized by PXRD having °20 values (±0.2) at 6.49, 10.01, 11.82, 13.04, 14.93, 15.73, 16.41, 17.63, 20.70, 21.44, 23.71, 25.14, 25.76, 26.30, 27.30, 28.83, 31.71, 33.19, 34.73, 36.07, 38.12.

Another aspect of the present invention relates to the amorphous form of Sitagliptin cinnamate.

Another aspect of the present invention relates to the amorphous form of Sitagliptin nitrate.

In another aspect, present invention relates to the crystalline form of Sitagliptin nitrate (herein after referred as Form II) having powder X-ray diffraction °29 values (±0.2) at 17.20, 18.48, 22.30, 23.42, 25.60. The crystalline form of Sitagliptin nitrate is further characterized by PXRD having °20 values (±0.2) at 7.36, 9.19, 10.84, 13.74, 14.48, 15.23, 17.00, 17.76, 20.78, 21.32, 24.27, 25.9, 26.67, 27.56, 27.93, 28.82, 29.92.

In another aspect, present invention relates to the crystalline Sitagliptin picolinate or solvates or hydrates thereof.

In another aspect, present invention relates to crystalline Sitagliptin picolinate having powder X-ray diffraction °29 values (±0.2) at 14.76, 16.72, 22.93, 26.51, 26.85. The crystalline Sitagliptin picolinate is further characterized by PXRD having °29 values (±0.2) at 10.36, 13.63, 14.27, 15.83, 17.81, 18.99, 19.41, 20.57, 20.85, 22.17, 24.43, 27.24, 28.76, 29.99, 30.55, 31.06, 31.85, 33.72, 34.63, 35.40, 36.59, 37.62, 38.47.

Another aspect of the present invention relates to the amorphous form of Sitagliptin picolinate.

In another aspect, present invention relates to the crystalline Sitagliptin nicotinate or solvates or hydrates thereof.

In another aspect, present invention, crystalline Sitagliptin nicotinate having powder X-ray diffraction °29 values (±0.2) at 15.31, 16.73, 18.96, 22.57, 26.94. The crystalline Sitagliptin nicotinate is further characterised by PXRD having c20 values (±0.2) at 3.88, 5.49, 5.89, 10.40, 14.82, 16.26, 17.38, 18.04, 19.46, 19.90, 21.11, 21.87, 23.01, 23.40, 23.71, 24.26, 24.63, 25.00, 25.9327.64, 29.93, 30.66, 31.27, 33.92.

Another aspect of the present invention relates to the amorphous form of Sitagliptin nicotinate.

In another aspect, present invention relates to the crystalline Sitagliptin stearate or solvates or hydrates thereof.

In another aspect, present invention relates to the crystalline Sitagliptin stearate having powder X-ray diffraction °20 values (±0.2) at 18.99, 19.41, 20.57, 22.93, 24.43. The crystalline Sitagliptin stearate is further characterized by PXRD having °20 values (±0.2) at 10.36, 13.63, 14.27, 14.76, 15.83, 16.72, 17.81, 20.85, 22.17°, 26.51, 26.85, 27.24, 28.76, 29.99, 30.55, 31.06, 31.85, 33.72, 34.63, 35.40, 36.59, 37.62, 38.47.

Another aspect of the present invention relates to the amorphous form of Sitagliptin stearate.

In another aspect, present invention relates to the crystalline Sitagliptin palmitate or solvates or hydrates thereof.

In another aspect, present invention, crystalline Sitagliptin palmitate having powder X-ray diffraction °29 values (±0.2) at 19.46, 19.90, 21.11, 23.40, 24.26. The crystalline Sitagliptin palimitate is further characterised by PXRD having °29 values (±0.2) at 3.88, 5.49, 5.89, 10.40, 14.82, 15.31, 16.26, 16.73, 17.38, 18.04, 18.96, 21.87, 22.57, 23.01, 23.71, 24.63, 25.00, 25.93, 26.94,27.64,29.93, 30.66,31.27, 33.92.

Another aspect of the present invention relates to the amorphous form of Sitagliptin palmitate.

In another aspect, present invention relates to the crystalline Sitagliptin laurate or solvates or hydrates thereof.

Another aspect of the present invention also relates to a crystalline Sitagliptin laurate having powder X-ray diffraction °29 values (±0.2) at 15.80, 18.90, 21.62, 23.90, 24.59. The crystalline Sitagliptin laurate is further characterised by PXRD having °29 values (±0.2) at 7.08, 7.29, 12.24, 12.47, 14.15, 14.38, 14.63, 16.24 19.24, 20.13, 22.01, 25.57, 25.83, 26.22, 26.57, 28.49, 29.19, 29.93, 30.99, 31.81, 32.72, 33.01, 34.17, 35.70, 36.48, 38.40.

Another aspect of the present invention relates to the amorphous form of Sitagliptin laurate.

Another aspect of the present invention relates to a process for the preparation of novel salts of Sitagliptin, which comprises: a) providing a mixture comprising Sitagliptin (base) and pharmaceutically acceptable acid selected from the group consisting of formic acid, picolinic acid, nicotinic acid, stearic acid, palmitic acid and lauric acid; and

b) isolating the corresponding acid addition salt of Sitagliptin. wherein said the mixture is prepared by dissolving Sitagliptin base in a solvent selected from water, alcohols, esters, ethers, hydrocarbons, or mixture thereof at temperature in the range of 25 to 100°C and more preferably at 25 to 80°C.

Another aspect of the present invention relates to a process for the preparation of novel amorphous salts of Sitagliptin, which comprises:

a) dissolution of Sitagliptin salts in solvent; and

b) lyophilization.

wherein solvent is selected from water, alcohols or mixtures thereof. The alcohols are pereferably selected from straight chain or branched Ci-Cs alcohols such as methanol, ethanol, propanol, butanol, isopropanol, isoamyl alcohols and mixtures thereof.

Another aspect of the present invention relates to a process for the preparation of Sitagliptin cinnamate hemihydrate, which comprises:

a) addition of cinnamic acid to preheated solution of Sitagliptin base in solvent;

b) heating the solution;

c) cooling to precipitate product; and

d) isolating the product.

wherein solvent is selected from isopropyl alcohol, toluene, ethyl acetate etc.

Another aspect of the present invention relates to a process for the preparation of crystalline Form II of Sitagliptin nitrate, which comprises:

a) providing a mixture comprising Sitagliptin base and nitric acid in a solvent; and

b) isolating the crystalline Form II of Sitagliptin nitrate wherein solvent is water or isopropyl alcohol or mixture thereof.

POWDER X-RAY DIFFRACTION (PXRD)

The X-ray powder diffractogram is obtained using Seifert, XRD, 3003 TT systems. The X-ray generator was operated at 40 kv and 30 mA, using the Kα1 radiation source. It is scanned in the diffraction range of 4° to 40° 29 at a scan rate of 0.02° 20 per second.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXAMPLE-1

PREPARATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUOROPHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,4]-TRIAZOLO-[4,3-a]PYRAZINE FORMATE

Formic acid (1.13g, 0.0245 moles) was added to preheated solution of Sitagliptin base (l0g, 0.0245mole) in 150 ml of isopropyl alcohol at 65-70°C. Thereafter, the contents was heated to 75-80°C and stirred at this temperature for 1 hr. Obtained solution was cooled to 25-30°C and thereafter, precipitated product was stirred further for ~20h at this temperature. Product was filtered, washed with isopropyl alcohol (2x10ml, 25-30°C) and dried at 55-65°C under reduced pressure (10-50 mm Hg). Yield: 10.70g Water content: 0.20%w/w (by KF)

EXAMPLE-2

PREPARATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUOROPHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,4]-TRIAZOLO-[4,3-a]PYRAZINE FORMATE

Formic acid (0.60g, 0.0130 moles) was added to preheated solution of Sitagliptin base (5g, 0.0123mole) in 75 ml of toluene at 75-80°C. Obtained solution was cooled to 25-30°C and thereafter, precipitated product was stirred further for ~15h at this temperature. Product was
filtered, washed with toluene (2x10 ml, 25-30°C) and dried at 55-65°C under reduced pressure (10- 50 mm Hg).
Yield: 5.38g
Water content: 0.35%w/w (by KF)

EXAMPLE-3

PREPARATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUOROPHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,4]-TRIAZOLO-[4,3-a]PYRAZINE FORMATE

Formic acid (0.60g, 0.0130 moles) was added to solution of Sitagliptin base (5g, 0.0123mole) in 150 ml of ethyl acetate at 25-30°C. Obtained solution was stirred at 25-30°C and thereafter, precipitated product was stirred further for ~15h at this temperature. Product was filtered, washed with ethyl acetate (2x10 ml, 25-30°C) and dried at 55-65°C under reduced pressure (10-50 mmHg).
Yield:5.18g
Water content: 0.32%w/w (by KF)

EXAMPLE-4

CRYSTALLIZATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,4]-TRIAZOLO-[4,3-a]PYRAZINE FORMATE IN ACETONE / ISOPROPYL ETHER

Sitagliptin formate (l0g) was suspended in acetone (50ml) and stirred at 25-30°C to obtain a solution. To this solution, isopropyl ether (200ml) was added slowly during 30min. Obtained slurry was stirred at 25-30°C for ~16hr. Product was filtered, washed with isopropyl ether (2x10ml, 25-30°C) and dried at 55-65°C under reduced pressure (10-50 mm Hg).
Yield: 8.95g
Water content: 0.16%w/w (by KF)

EXAMPLE-5

CRYSTALLIZATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,4]-TRIAZOLO-[4,3-aJPYRAZINE FORMATE IN ACETONE / ISOPROPYL ETHER

Sitagliptin formate (10g) was suspended in ethanol (absolute alcohol, 50ml) at 25-30°C. Obtained solution was heated to 45-50°C to obtain a solution. To this solution, cyclohexane (100ml) was added slowly during 30min. Obtained slurry was stirred at 25-30°C for ~16hr. Product was filtered, washed with cyclohexane (2x10ml, 25-30°C) and dried at 55-65°C under reduced pressure (10-50 mm Hg).
Yield: 9.05g
Water content: 0.14%w/w (by KF)

EXAMPLE-6

PREPARATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUOROPHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,4]-TRIAZOLO-[4,3-a]PYRAZINE CINNAMATE HEMIHYDRATE

Cinnamic acid (3.63g, 0.0245 moles) was added to preheated solution of Sitagliptin base (l0g, 0.0245mole) in 150 ml of isopropyl alcohol at 65-70°C. Thereafter, the contents were heated to 70-75°C and stirred at this temperature for lh. Obtained solution was cooled to 25-30°C and thereafter, stirred further for ~20h at this temperature to obtain a product. It was filtered, washed with isopropyl alcohol (2x10ml, 25-30°C) and dried at 55-60°C under reduced pressure (10-50 mm Hg). Yield: 8.33g Water content: 1.86%w/w (by KF)

EXAMPLE-7
PREPARATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUOROPHENYL)-BUTYL]-5,6,7,8TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,4]-TRIAZOLO-[4,3-a[PYRAZINE CINNAMATE HEMIHYDRATE

Cinnamic acid (22.25g, 0.1503 moles) was added to preheated solution of Sitagliptin base (60g, 0.1474mole) in 840 ml of 2%v/v aqueous isopropyl alcohol at 65-70°C. Thereafter, the contents were heated to 70-75°C and stirred at this temperature for 1 h. Obtained solution was cooled to 25-30°C and thereafter, stirred further for ~20h at this temperature. The precipitated product was filtered, washed with isopropyl alcohol (2x60ml, 25-30°C) and dried at 55-60°C under reduced pressure (10-50 mm Hg). Yield: 65.68g Water content: 1.96%w/w (by KF)

EXAMPLES

PREPARATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUOROPHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,4]-TRIAZOLO-[4,3-a]PYRAZINE CINNAMATE HEMIHYDRATE

Cinnamic acid (3.63g, 0.0245 moles) was added to preheated solution of Sitagliptin base (l0g, 0.0245mole) in 150 ml of toluene at 70-75°C. Thereafter, the contents were maintained at 70-75°C and stirred at this temperature for lh. Obtained solution was cooled to 25-30°C and thereafter, stirred further for ~15hr at this temperature to obtain a product. It was filtered, washed with toluene (2x10ml, 25-30°C) and dried at 55-60°C under reduced pressure (10-50 mm Hg). Yield: 13.58g Water content: 1.72%w/w (by KF)

EXAMPLE-9

PREPARATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUOROPHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,4]-TRIAZOLO-[4,3-a]PYRAZINE CINNAMATE HEMIHYDRATE

Cinnamic acid (3.63g, 0.0245 moles) was added to a solution of Sitagliptin base (10g, 0.0245mole) in 150 ml of ethyl acetate at 25-30°C. Thereafter, the contents were maintained at 25- 30°C for ~15hr. The solid was filtered, washed with ethyl acetate (2x10ml, 25-30°C) and dried at 55-60°C under reduced pressure (10-50 mm Hg).

Yield: 11.52g
Water content: 1.89%w/w (by KF)

EXAMPLE-10

CRYSTALLIZATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUORO-PHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,4]-TRIAZOLO-[4,3-a]PYRAZINE CINNAMATE HEMIHYDRATE IN ETHYL ACETATE

Sitagliptin cinnamate (10g) was suspended in ethyl acetate (100ml) at 25-30°C. The slurry was heated to 75-77°C to obtain a clear solution. This solution was cooled to 25-30°C and stirred further for ~15hr at this temperature. The crystallized product was filtered, washed with ethyl acetate (2x10ml, 25-30°C) and dried at 55-60°C under reduced pressure (10-50 mm Hg). Yield: 6.32g Water content: 1.75%w/w (by KF)

EXAMPLE-11

PREPARATION OF AMORPHOUS 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRI-FLUOROPHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUORO-METHYL)-[l,2,4]-TRIAZOLO-[4,3-a]PYRAZINE CINNAMATE

Crystalline Sitagliptin cinnamate hemihydrate (5g) was dissolved in 650 ml of DM water at 25-30°C. Thereafter, the contents were filtered and obtained filtrate was lyophilized to obtain amorphous Sitagliptin cinnamate, which is hygroscopic in nature. Yield: 4.61 g

EXAMPLE-12

PREPARATION OF AMORPHOUS 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRI-FLUOROPHENYL)-BUTYL]-5,6,7,8TETRAHYDRO-3-(TRIFLUORO-METHYL)-[l,2,4]-TRIAZOLO-[4,3-a]PYRAZINE FORMATE

Crystalline Sitagliptin formate (5g) was dissolved in 15 ml of DM water at 25-30°C. Thereafter, the contents were filtered and obtained filtrate was lyophilized to obtain amorphous Sitagliptin formate, which is hygroscopic in nature. Yield: 4.72 g

EXAMPLE-13

PREPARATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUOROPHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,4]-TRIAZOLO-[4,3-a]PYRAZINE NICOTINATE

Nicotinic acid (1.51g, 0.0122 moles) was added to preheated solution of Sitagliptin base (5g, 0.0245mole) in 75 ml of isopropyl alcohol at 65-70°C. Thereafter, the contents were heated to 70-75°C and stirred at this temperature for lh. Obtained solution was concentrated at 40-45°C under reduced pressure to distill ~60 of isopropyl alcohol and cyclohexane (100ml) was added. Thereafter, precipitated product was stirred further for 5h at 25-30°C. Product was filtered, washed with cyclohexane (2x10ml, 25-30°C) and dried at 50-60°C under reduced pressure (10-50 mm Hg). Yield: 7.11 g Water content: 1.72 %w/w (by KF)

EXAMPLE-14

PREPARATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUOROPHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,4]-TRIAZOLO-[4,3-a]PYRAZINE PICOLINATE

Picolinic acid (1.51g, 0. 0.0122 moles) was added to preheated solution of Sitagliptin base (5g, 0.0122mole) in 75 ml of isopropyl alcohol at 65-70°C. Thereafter, the contents were heated to 70-75°C and stirred at this temperature for lh. Obtained solution was cooled to 25-30°C and thereafter, precipitated product was stirred further for ~20h at this temperature. Product was filtered, washed with isopropyl alcohol (2x5ml, 25-30°C) and dried at 50-60°C under reduced pressure (10-50 mm Hg). Yield: 6.28 g Water content: 0.12%w/w (by KF)

EXAMPLE-15

PREPARATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUOROPHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,41-TRIAZOLO-[4,3-aJPYRAZINE NITRATE

Nitric acid (60%w/w, 2.84g„ 0.0270 moles) was added to preheated solution of Sitagliptin base (l0g, 0.0245mole) in 100 ml of isopropyl alcohol at 50-60°C and contents were stirred at this temperature for 1 hr. Obtained solution was cooled to 25-30°C and thereafter, precipitated product was stirred further for ~2h at 25-30°C. Product was filtered, washed with isopropyl alcohol (2x10ml, 25-30°C) and dried at 45-50°C under reduced pressure (-20 mm Hg).
Yield: 9.90 g
Water content: 0.28%w/w (by KF)

EXAMPLE-16

PREPARATION OF 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRIFLUOROPHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL)-[l,2,4]-TRIAZOLO-[4,3-a]PYRAZINE NITRATE HYDRATE

Nitric acid (60%w/w, 2.58g, 0.024 moles) was added to a suspension of Sitagliptin base (l0g, 0.0245mole) in 50 ml of DM water at 25-35°C. Isopropyl alcohol (10ml) was added and contents were stirred at this temperature for 1 hr. The resulting slurry mass was further cooled to 5-10°C and stirred further for ~lh at the same temperature. Product was filtered, washed with precooled DM water (2x10ml, 5-10°C) and dried at 45-50°C under reduced pressure (-20 mm Hg). Yield: 9.50 g Water content: 5.49%w/w (by KF)

EXAMPLE-17

PREPARATION OF AMORPHOUS 7-[(3R)-3-AMINO-l-OXO-4-(2,4,5-TRI-FLUOROPHENYL)-BUTYL]-5,6,7,8-TETRAHYDRO-3-(TRIFLUOROMETHYL) -[1,2,4]-TRIAZOLO-[4,3-a]PYRAZINE NITRATE

Crystalline Sitagliptin nitrate (5g) was dissolved in 50 ml of DM water at 25-30°C. Thereafter, the contents were filtered and the filtrate was lyophilized to obtain amorphous Sitagliptin nitrate, which is hygroscopic in nature. Yield: 4.8g

WE CLAIM:

1. Pharmaceutically acceptable salts of 7-[(3R)-3- amino-l-oxo-4-(2,4,5-trifluorophenyl) butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-[ 1,2,4]-triazolo[4,3-a]pyrazine of Formula I,

or solvates or hydrates thereof; wherein salt represents formate, picolinate, nicotinate, stearate, palmitate and laurate.

2. A process for the preparation of salts of Sitagliptin selected from formate, picolinate, nicotinate, stearate, palmitate and laurate, which comprises:

a) providing a mixture comprising Sitagliptin (base) and pharmaceutically acceptable acid selected from the group consisting of formic acid, picolinic acid, nicotinic acid, stearic acid, palmitic acid and lauric acid; and

b) isolating the corresponding acid addition salt of Sitagliptin.

3. Amorphous Sitagliptin salt, wherein salt is selected from formate, cinnamate, picolinate, nicotinate, stearate, palmitate, laurate and nitrate.

4. A process for the preparation of amorphous salts of Sitagliptin selected from formate, picolinate, nicotinate, stearate, palmitate, laurate and nitrate comprising:

a) dissolution of Sitagliptin salts in a solvent selected from water, alcohols and mixtures thereof; and

b) lyophilization.

5. Crystalline Sitagliptin salt, wherein salt is selected from formate, picolinate, nicotinate, stearate, palmitate and laurate.

6. Crystalline Form II of Sitagliptin nitrate having powder X-ray diffraction pattern comprising °2θ values (±0.2) at 17.20, 18.48, 22.30, 23.42, 25.60.

7. A process for the preparation of crystalline Form II of Sitagliptin nitrate, which comprises:

a) providing a mixture comprising Sitagliptin base and nitric acid in a solvent; and

b) isolating the crystalline Form II of Sitagliptin nitrate wherein solvent is water or isopropyl alcohol or mixture thereof.

8. Crystalline Sitagliptin formate having powder X-ray diffraction pattern comprising °20 values (±0.2) at 14.95, 15.88, 19.32, 19.71, 26.24.

9. Crystalline Sitagliptin picolinate having powder X-ray diffraction pattern comprising °26 values (±0.2) at 14.76, 16.72, 22.93,26.51, 26.85.

10. Crystalline Sitagliptin cinnamate hemihydrate having powder X-ray diffraction pattern comprising °26 values (±0.2) at 5.96, 18.51, 19.63, 22.62, 23.71.

11. A process for the preparation of Sitagliptin cinnamate hemihydrate comprising:

a) addition of cinnamic acid to preheated solution of Sitagliptin base in solvent;

b) heating the solution;

c) cooling to precipitate product; and

d) isolating the product.

wherein solvent is selected from isopropyl alcohol, toluene and ethyl acetate.

12. Crystalline Sitagliptin stearate having powder X-ray diffraction °29 values (±0.2) at 18.99, 19.41,20.57,22.93,24.43.

13. Crystalline Sitagliptin palmitate having powder X-ray diffraction °20 values (±0.2) at 19.46, 19.90,21.11,23.40,24.26.

14. Crystalline Sitagliptin laurate having powder X-ray diffraction °29 values (±0.2) at 15.80, 18.90,21.62,23.90,24.59.

15. Crystalline Sitagliptin nicotinate having powder X-ray diffraction °29 values (±0.2) at 15.31,16.73,18.96,22.57,26.94.