This application claims the benefit of Indian Provisional Patent Application No. 2973/CHE/2012, filed on July 20, 2012, which is incorporated herein by reference.

Filed of the Invention

The present invention provides a novel amorphous Form of vildagliptin, process for its preparation and pharmaceutical compositions comprising it. The present invention also provides a solid dispersion of vildagliptin in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.

Background of the Invention

Vildagliptin, chemically (5)-l-[N-(3-hydroxy-l-adamantyl)glycyl]pyrrolidine-2- carbonitrile and has the structure formula:

Vildagliptin (LAF237) is an oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the inactivation of GLP-1 and GIP by DPP-4, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas. Vildagliptin has been shown to reduce hyperglycemia in type 2 diabetes mellitus. The generic name vildagliptin is marketed by NOVARTIS under the brand name Zomelis ^® .

Vildagliptin and its process were disclosed in U.S. Patent No. 6, 166,063.

Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (1R).

Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.

Vildagliptin can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.

International application publication no. WO 2006/078593 disclosed crystalline Form A of vildagliptin.

We have found a novel amorphous Form of vildagliptin. The amorphous vildagliptin is stable, reproducible and so, the amorphous vildagliptin is suitable for pharmaceutical preparations.

We have also found a solid dispersion of vildagliptin in combination with a pharmaceutically acceptable carrier. The solid dispersion of vildagliptin is stable, reproducible and amicable for large scale preparation.

Normally amorphous Forms are hygroscopic. Amorphous Form of vildagliptin is found to be non-hygroscopic.

Thus, one abject of the present invention is to provide amorphous Form of vildagliptin, process for its preparation and pharmaceutical compositions comprising it. Another object of the present invention is to provide a solid dispersion of vildagliptin in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it. Summary of the Invention

In one aspect, the present invention provides an amorphous vildagliptin.

In another aspect, the present invention provides a process for the preparation of amorphous vildagliptin, which comprises:

a) dissolving vildagliptin in water; and

b) removing the water to obtain amorphous vildagliptin.

In another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of amorphous vildagliptin and at least one pharmaceutically acceptable excipient.

In another aspect, the present invention provides a solid dispersion of vildagliptin in combination with a pharmaceutically acceptable carrier.

In another aspect, the present invention there is provided a process for the preparation of solid dispersion of vildagliptin in combination with a pharmaceutically acceptable carrier, which comprises:

a) preparing a solution comprising a mixture of vildagliptin and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, span-20 or soluplus in a solvent; and

b) removing the solvent to obtain a solid dispersion of vildagliptin in combination with a pharmaceutically acceptable carrier.

Yet in another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of solid dispersion of vildagliptin along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient. Brief Description of the Drawing

Figure 1 is a powder X-ray diffractogram patterns of amorphous vildagliptin. Figure 2 is a powder X-ray diffractogram patterns of solid dispersion of vildagliptin in combination with a pharmaceutically acceptable carrier.

Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffractometer having a copper- α radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 kV and current 35 mA. Detailed Description of the Invention

The term "room temperature" refers to temperature at about 25 to 35°C.

According to one aspect of the present invention, there is provided an amorphous vildagliptin. The powdered x-ray diffractogram (PXRD) of amorphous vildagliptin is shown in figure 1.

According to another aspect of the present invention, there is provided a process for the preparation of amorphous vildagliptin, which comprises:

a) dissolving vildagliptin in water; and ' b) removing the water to obtain amorphous vildagliptin.

The dissolution in step (a) may be performed, for example, by heating the vildagliptin in water.

The water may be removed from the solution in step (b) by known methods, for example, distillation, freeze drying or spray drying.

The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.

As used herein, "reduced pressure" refers to a pressure of less than 100 mmHg.

The term "Freeze drying" refers to a sublimation process that removes free water in the form of solid.

The term "Spray drying" refers to is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas. According to another aspect of the present invention, there is provided pharmaceutical compositions comprising a therapeutically effective amount of amorphous vildagliptin, and at least one pharmaceutically acceptable excipient. The amorphous vildagliptin may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

According to another aspect of the present invention, there is provided a solid dispersion of vildagliptin in combination with a pharmaceutically acceptable carrier.

The powdered x-ray diffractogram (PXRD) of solid dispersion of vildagliptin in combination with a pharmaceutically acceptable carrier is shown in figure 2.

Solid dispersion of vildagliptin in combination with a pharmaceutically acceptable carrier is found to be stable.

Preferably, the solid dispersion of vildagliptin in combination with a pharmaceutically acceptable carrier may be amorphous.

Preferably, the ratio of vildagliptin to the pharmaceutically acceptable carrier is 1 :0.5 to 1 :4.0.

Preferably the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, span- 20 or soluplus.

According to another aspect of the present invention, there is provided a process for the preparation of solid dispersion of vildagliptin in combination with a pharmaceutically acceptable carrier, which comprises:

a) preparing a solution comprising a mixture of vildagliptin and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, span-20 or soluplus in a / solvent; and

b) removing the solvent to obtain a solid dispersion of vildagliptin in combination with a pharmaceutically acceptable carrier.

Vildagliptin used in step (a) may preferably be vildagliptin obtained by the known process.

The solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from water, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol. More preferably the solvents are water, methylene chloride, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, n- butanol and ethanol.

Preferably the pharmaceutically acceptable carriers used in step (a) may be selected from copovidone, soluplus or hydroxypropyl methylcellulose.

The solvent may be removed from the solution in step (b) by known methods, for example, distillation, freeze drying or spray drying.

The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.

According to another aspect of the present invention, there is provided pharmaceutical compositions comprising a therapeutically effective amount of solid dispersion of vildagliptin along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient. The solid dispersion of vildagliptin may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

The invention will now be further described by the following examples, which are illustrative rather than limiting.

Examples

Example 1 :

Preparation of vildagliptin

To the (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile (100 gm) was added ^■ » isopropyl acetate (400 ml) and dimethylformamide (400 ml) at room temperature and then heated to 40°C for 15 minutes to provide a solution. A mixture of 3-hydroxy-l- aminoadamantane (100 gm), 2-butanone (700 ml), potassium iodide (5 gm) and potassium carbonate (400 gm) were added to the solution. The reaction mixture was maintained for 1 hour at room temperature and then heated to 75 to 80°C. The reaction mass was maintained for 1 hour at 75 to 80°C, filtered and then concentrated to provide a residual solid. To the residual solid was added a mixture of diisopropyl ether (900 ml) and isopropyl acetate (100 ml) and then heated to 70°C. The reaction mass was then cooled to room temperature and further cooled to 0 to 5°C. The contents were maintained for 1 hour at room temperature and filtered. The solid thus obtained was dried to provide 100 gm of vildagliptin.

Example 2:

Preparation of amorphous vildagliptin

Vildagliptin (20 gm) was dissolved in water (400 ml) and then heated to 60°C to provide a clear solution. The solution was stirred for 10 minutes at 60°C and filtered through celite bed. The water was distilled off under reduced pressure at below 65°C to provide 19 gm of amorphous vildagliptin.

Example 3:

Preparation of amorphous vildagliptin

Vildagliptin (20 gm) was dissolved in water (400 ml) and then heated to 60°C to provide a clear solution. The solution was stirred for 10 minutes at 60°C and filtered through celite bed. The resulting filtrate was subjected to freeze drying at room temperature for 24 hours to provide 19 gm of amorphous vildagliptin. Example 4:

Preparation of amorphous vildagliptin

Vildagliptin (20 gm) was dissolved in water (400 ml) and then heated to 60°C to provide a clear solution. The solution was stirred for 10 minutes at 60°C and filtered through celite bed. The resulting filtrate was subjected to spray drying at 60 to 65°C to provide 19 gm of amorphous vildagliptin.

Example 5:

Preparation of vildagliptin solid dispersion with hydroxypropyl methylcellulose

A mixture of vildagliptin (25 gm) and hydroxypropyl methylcellulose (25 gm) was dissolved in a mixture of ethanol (500 ml) and methylene chloride (250 ml) at room temperature. The contents were heated to 50°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55 C and then dried to provide 49 gm of vildagliptin solid dispersion with hydroxypropyl methylcellulose.

Example 6:

Preparation of vildagliptin solid dispersion with hydroxypropyl methylcellulose

A mixture of vildagliptin (25 gm) and hydroxypropyl methylcellulose (25 gm) was dissolved in ethanol (750 ml) at room temperature. The contents were heated to 50°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 47 gm of vildagliptin solid dispersion with hydroxypropyl methylcellulose.

Example 7:

Preparation of vildagliptin solid dispersion with hydroxypropyl methylcellulose

A mixture of vildagliptin (25 gm) and hydroxypropyl methylcellulose (25 gm) was dissolved in methylene chloride (500 ml) at room temperature. The contents were heated to 50°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 47 gm of vildagliptin solid dispersion with hydroxypropyl methylcellulose. Example 8:

Preparation of vildagliptin solid dispersion with hydroxypropyl methylcellulose

A mixture of vildagliptin (20 gm) and hydroxypropyl methylcellulose (20 gm) was dissolved in water (400 ml) at room temperature. The contents were heated to 60°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 38 gm of vildagliptin solid dispersion with hydroxypropyl methylcellulose.

Example 9:

Preparation of vildagliptin solid dispersion with hydroxypropyl methylcellulose Example 6 was repeated using dimethylformamide solvent instead of ethanoi solvent to provide vildagliptin solid dispersion with hydroxypropyl methylcellulose.

Example 10:

Preparation of vildagliptin solid dispersion with hydroxypropyl methylcellulose

Example 6 was repeated using dimethylacetamide solvent instead of ethanoi solvent to provide vildagliptin solid dispersion with hydroxypropyl methylcellulose.

Example 1 1 :

Preparation of vildagliptin solid dispersion with hydroxypropyl methylcellulose

Example 6 was repeated using dimethyl sulfoxide solvent instead of ethanoi solvent to provide vildagliptin solid dispersion with hydroxypropyl methylcellulose.

Example 12:

Preparation of vildagliptin solid dispersion with hydroxypropyl methylcellulose

Example 6 was repeated using n-butanol solvent instead of ethanoi solvent to provide vildagliptin solid dispersion with hydroxypropyl methylcellulose.

Example 13:

Preparation of vildagliptin solid dispersion with copovidone

A mixture of vildagliptin (10 gm) and copovidone (10 gm) was dissolved in a mixture of ethanoi (200 ml) and methylene chloride (100 ml) at room temperature. The contents were heated to 50°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 18 gm of vildagliptin solid dispersion with copovidone.

Example 14:

Preparation of vildagliptin solid dispersion with copovidone

A mixture of vildagliptin (10 gm) and copovidone (10 gm) was dissolved in ethanoi (300 ml) at room temperature. The contents were heated to 50°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55 C and then dried to provide 17 gm of vildagliptin solid dispersion with copovidone.

Example 15:

Preparation of vildagliptin solid dispersion with copovidone

A mixture of vildagliptin (10 gm) and copovidone (10 gm) was dissolved in methylene chloride (200 ml) at room temperature. The contents were heated to 50°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 16 gm of vildagliptin solid dispersion with copovidone.

Example 16:

Preparation of vildagliptin solid dispersion with copovidone

A mixture of vildagliptin (10 gm) and copovidone (10 gm) was dissolved in water (150 ml) at room temperature. The contents were heated to 60°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 17 gm of vildagliptin solid dispersion with copovidone.

Example 17:

Preparation of vildagliptin solid dispersion with copovidone

Example 14 was repeated using dimethylformamide solvent instead of ethanol solvent to provide vildagliptin solid dispersion with copovidone.

Example 18:

Preparation of vildagliptin solid dispersion with copovidone

Example 14 was repeated using dimethylacetamide solvent instead of ethanol solvent to provide vildagliptin solid dispersion with copovidone.

Example 19:

Preparation of vildagliptin solid dispersion with copovidone

Example 14 was repeated using dimethyl sulfoxide solvent instead of ethanol solvent to provide vildagliptin solid dispersion with copovidone. Example 20:

Preparation of vildagliptin solid dispersion with copovidone

Example 14 was repeated using n-butanol solvent instead of ethanol solvent to provide vildagliptin solid dispersion with copovidone.

Example 21 :

Preparation of vildagliptin solid dispersion with soluplus

A mixture of vildagliptin (5 gm) and soluplus (5 gm) was dissolved in a mixture of ethanol (100 ml) and methylene chloride (50 ml) at room temperature. The contents were heated to 50°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 8 gm of vildagliptin solid dispersion with soluplus.

Example 22:

Preparation of vildagliptin solid dispersion with polyethylene glycol

A mixture of vildagliptin (5 gm) and polyethylene glycol (5 gm) was dissolved in a mixture of ethanol (100 ml) and methylene chloride (75 ml) at room temperature. The contents were heated to 50°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 7.5 gm of vildagliptin solid dispersion with polyethylene glycol.

Example 23:

Preparation of vildagliptin solid dispersion with ethyl cellulose

A mixture of vildagliptin (5 gm) and ethyl cellulose (5 gm) was dissolved in a mixture of ethanol (100 ml) and methylene chloride (75 ml) at room temperature. The contents were heated to 50°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 7.5 gm of vildagliptin solid dispersion with ethyl cellulose. Example 24: Preparation of vildagliptin solid dispersion with copovidone

To the (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile (100 gm) was added isopropyl acetate (400 ml) and dimethylformamide (400 ml) at room temperature and then heated to 40°C for 15 minutes to provide a solution. A mixture of 3-hydroxy-l- aminoadamantane (100 gm), 2-butanone (700 ml), potassium iodide (5 gm) and potassium carbonate (400 gm) were added to the solution. The reaction mixture was maintained for 1 hour at room temperature and then heated to 75 to 80°C. The reaction mass was maintained for 1 hour at 75 to 80°C, filtered and then concentrated to provide a residual solid. To the residual solid was added a mixture of diisopropyl ether (900 ml) and isopropyl acetate (100 ml) and then heated to 70°C. The reaction mass was then cooled to room temperature and then added a mixture of copovidone (100 gm), ethanol (2000 ml) and methylene chloride (1000 ml). The contents were heated to 50°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 185 gm of vildagliptin solid dispersion with copovidone.

Example 25:

Preparation of vildagliptin solid dispersion with hydroxypropyl methylcellulose

To the (S)-l-(2-chloroacetyl)pyrrolidine-2-carbonitrile (100 gm) was added isopropyl acetate (400 ml) and dimethylformamide (400 ml) at room temperature and then heated to 40°C for 15 minutes to provide a solution. A mixture of 3-hydroxy-l- aminoadamantane (100 gm), 2-butanone (700 ml), potassium iodide (5 gm) and potassium carbonate (400 gm) were added to the solution. The reaction mixture was maintained for 1 hour at room temperature and then heated to 75 to 80°C. The reaction mass was maintained for 1 hour at 75 to 80°C, filtered and then concentrated to provide a residual solid. To the residual solid was added a mixture of diisopropyl ether (900 ml) and isopropyl acetate (100 ml) and then heated to 70°C. The reaction mass was then cooled to room temperature and then added a mixture of hydroxypropyl methylcellulose (100 gm), ethanol (2000 ml) and methylene chloride (1000 ml). The contents were heated to 50°C and filtered through celite bed. The solvent was distilled off under reduced pressure at below 55°C and then dried to provide 195 gm of vildagliptin solid dispersion with hydroxypropyl methylcellulose.