DESC:A STABLE PHARMACEUTICAL COMPOSITION OF DPP-IV INHIBITOR IN COMBINATION WITH METFORMIN

FIELD OF THE INVENTION
The present invention provides a stable pharmaceutical composition comprising (a) Metformin hydrochloride treated with alkalizing agent; b) a DPP-IV inhibitor; and (c) one or more pharmaceutically acceptable excipients and a process for the preparation thereof.

BACKGROUND OF THE INVENTION
DPP-IV is an enzyme that degrades the incretin hormones like GLP- 1 (glucagon- like peptide 1) and GIP (glucose dependent insulinotropic polypeptide). DPP-IV inhibitors block DPP-IV enzyme, and thus inhibit the degradation of GLP-1 and GIP, which in turn increases insulin secretion and decreases blood glucose levels. The several chemical compounds were developed for the treatment or improvement in glycemic control in patients with Type 2 diabetes. These chemical compounds include Vildagliptin, Saxagliptin, Sitagliptin, Alogliptin, Anagliptin, Dutogliptin, Gemigliptin & Linagliptin.
EP 1137635 discloses Vildagliptin, which is also known as (S)-l-[(3-hydroxy-l-adamantyl) amino] acetyl-2-cyano-pyrrolidine and has the structure of compound (I).

Compound (I)
Vildagliptin has been evaluated as monotherapy (marketed as Galvus®) and in combination with other hyperglycemic agents such as metformin, thiazolidinediones, sulfonylureas and insulin.
Metformin is one of the therapeutic agents, recommended as the first-line antidiabetic medication in most patients with Type 2 diabetes. Metformin is most commonly administered in the form of its hydrochloride salt.
The fixed dose combination of Vildagliptin and Metformin hydrochloride is marketed under the trademark Eucreas® (50mg/850mg and 50mg/1000mg dosage forms of Vildagliptin and metformin hydrochloride).
WO 2007/041053 A2 discloses the fixed dose combination Vildagliptin and Metformin hydrochloride prepared by aqueous granulation, solvent granulation and melt granulation. According to WO 2007/041053 A2, the melt granulation appears the promising formulation technique to accommodate high dose of poorly compactable metformin with moisture sensitive Vildagliptin as compared aqueous granulation and/or solvent granulation.
US 2011/0206766 discloses pharmaceutical formulation comprising a DPP-IV inhibitor, a partner drug, and a basic agent selected from the group consisting of L-arginine, L-lysine, and L-histidine which provides a stabilizing effect on the formulation by suppressing degradation of the DPP-IV inhibitor in the presence of the partner drug, e.g., biguanides, thiazolidinones, statins, or ARBs.
According to WO 2015/097234, Metformin granulate is obtained first which is admixed with Vildagliptin in the form of drug particles or granulated form.
WO 2014/080383 A1 discloses a pharmaceutical composition comprising (i) a DPP-IV inhibitor; (ii) an additional antidiabetic drug; (iii) at least one alkalizing agent; and (iv) one or more pharmaceutically acceptable excipients. The alkalizing agents used are other than the basic amino acids. WO 2014/080383 A1 discloses methods of preparing the formulations and provided stability data of one example.
Surprisingly, it has been found out that composition comprising (a) Metformin hydrochloride treated with alkalizing agent; b) a DPP-IV inhibitor; and (c) one or more pharmaceutically acceptable excipients provides stable composition.

OBJECT OF THE INVENTION
A main object of present invention is to provide a stable composition comprising a DPP-IV inhibitor and Metformin or its pharmaceutically acceptable salts.
Another object of present invention is to provide a stable composition of a DPP-IV inhibitor and Metformin or its pharmaceutically acceptable salts, which is capable to accommodate high dose of poorly compactable Metformin with moisture sensitive DPP-IV inhibitor.
Another object of present invention is to prepare a stable composition of a DPP-IV inhibitor and Metformin or its pharmaceutically acceptable salts by cost effective process.
Another object of present invention is to provide a stable composition comprising Vildagliptin and Metformin or its pharmaceutically acceptable salts.
Another object of present invention is to provide the use of aforementioned pharmaceutical composition for the treatment of diabetes.

SUMMARY OF THE INVENTION
The present invention provides a stable pharmaceutical composition comprising (a) Metformin hydrochloride treated with alkalizing agent; b) a DPP-IV inhibitor; and (c) one or more pharmaceutically acceptable excipients and a process for the preparation thereof.
In one aspect, the present invention provides a stable pharmaceutical composition comprising (a) Metformin hydrochloride treated with alkalizing agent; b) a DPP-IV inhibitor; and (c) one or more pharmaceutically acceptable excipients.
The alkalizing agent as described herein above is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal sulfates, alkali metal borates, alkali metal citrates, alkali metal hydroxides or mixtures thereof.
In another aspect, the present invention provides a stable pharmaceutical composition comprising (a) Metformin hydrochloride treated with alkali metal carbonate; b) a DPP-IV inhibitor; and (c) one or more pharmaceutically acceptable excipients.
In another aspect, the present invention provides a stable pharmaceutical composition comprising (a) Metformin hydrochloride treated with alkali metal carbonate; b) Vildagliptin; and (c) one or more pharmaceutically acceptable excipients.
In another aspect, the present invention provides a stable pharmaceutical composition comprising (a) Metformin hydrochloride treated with sodium carbonate; b) Vildagliptin; and (c) one or more pharmaceutically acceptable excipients.
In another aspect, the present invention provides processes for the preparation of the said pharmaceutical composition, and its use for treating diabetes.

DETAILED DESCRIPTION OF THE INVENTION
Various impurities of DPP-IV inhibitors are required to be controlled during preparation and/or storage of the compositions. The impurities specifically related to vildagliptin, such as amide impurity (II), acid impurity (III) and/or dimer impurity (IV), are also need to be controlled during preparation and/or storage of the compositions.
As used herein, unless otherwise indicated, the term "amide impurity" refers to compound (II),

Compound (II).
As used herein, unless otherwise indicated, the term "acid impurity" refers to compound (III),

Compound (III).
As used herein, unless otherwise indicated, the term "dimer impurity" refers to compound (IV),

Compound (IV).
The term “stable,” as used herein, refers to stability of active ingredients (DPP-IV inhibitor and Metformin HCl) in a composition, wherein the chemical assay of each active ingredient is within 90%-110%, and no more than 0.5% of each known impurity and no more than 0.2% of single maximum unknown impurity is present after a specified period of time and under specified conditions according to ICH guideline.
The invention provides a stable pharmaceutical composition comprising Vildagliptin and Metformin or its pharmaceutically acceptable salts with improved stability i.e. the composition having less than about 0.5 percent by weight of any known individual impurity i.e. the acid impurity, amide impurity or dimer impurity, and less than about 0.2 percent by weight of single maximum unknown impurity.
The present invention provides a stable pharmaceutical composition comprising (a) Metformin hydrochloride treated with alkalizing agent; b) a DPP-IV inhibitor; and (c) one or more pharmaceutically acceptable excipients and a process for the preparation thereof.
The term “Metformin” as used herein, refers to Metformin or its pharmaceutically acceptable salt, preferably Metformin hydrochloride.
DPP-IV inhibitor is selected from one or more of Vildagliptin, linagliptin, sitagliptin, saxagliptin, alogliptin, anagliptin, carmegliptin, teneligliptin, melogliptin, gemigliptin, dutogliptin, and denagliptin, or a salt or polymorph thereof.
According to another embodiment, the DPP-IV inhibitor is vildagliptin or a salt or polymorph thereof.
The alkalizing agent is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal sulfates, alkali metal borates, alkali metal citrates, alkali metal hydroxides or mixtures thereof.
In preferred embodiment, the alkalizing agent is selected from sodium carbonate, sodium bicarbonate, calcium carbonate, magnesium oxide, magnesium carbonate, magnesium hydrogen carbonate, sodium hydroxide, Disodium hydrogen phosphate, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, magnesium silicate, sodium citrate, magnesium aluminate, aluminum magnesium hydroxide, tribasic calcium phosphate or a mixture thereof. More preferably, the alkalizing agent is sodium carbonate, sodium bicarbonate or Disodium Hydrogen Phosphate.
In preferred embodiment, the present invention comprises alkalizing agent at least about 0.05%, preferably 0.05% to 1%, more preferably, 0.07% to 0.3%.
The present invention provides a process for the preparation of the pharmaceutical composition of the present invention comprising the steps of:
(a) treating metformin hydrochloride with solution of alkalizing agent in a solvent;
(b) drying the resulting product obtained in step (a);
(c) mixing the dried product obtained in step (b) with a DPP-IV inhibitor and optionally one or
more pharmaceutically acceptable excipients;
(d) granulating the mixture obtained in step (c) with solvent and binder to obtain granules;
(e) drying the granules obtained in step (d);
(f) compressing the granules obtained in step (e) with one or more pharmaceutically acceptable
excipients to obtain tablets; and
(g) optionally coating the tablets obtained in step (f).
In another embodiment, the present invention provides a process for the preparation of the pharmaceutical composition of the present invention comprising the steps of:
(a) treating a metformin hydrochloride with solution of alkalizing agent in a solvent;
(b) drying the resulting product obtained in step (a);
(c) mixing the dried product obtained in step (b) with a DPP-IV inhibitor and optionally one or
more pharmaceutically acceptable excipients;
(d) compressing the mixture obtained in step (c) to obtain tablets; and
(e) optionally coating the tablets obtained in step (d).
In another aspect, the present invention provides a process for the preparation of the pharmaceutical composition of the present invention comprising the steps of:
(a) treating metformin hydrochloride with solution of alkalizing agent in a solvent;
(b) drying the resulting product obtained in step (a);
(c) mixing the dried product obtained in step (b) with vildagliptin and optionally one or more
pharmaceutically acceptable excipients;
(d) granulating the mixture obtained in step (c) with solvent and binder to obtain granules;
(e) drying the granules obtained in step (d);
(f) compressing the granules obtained in step (e) with one or more pharmaceutically acceptable
excipients to obtain tablets; and
(g) optionally coating the tablets obtained in step (f).
In another aspect, the present invention provides a process for the preparation of the pharmaceutical composition of the present invention comprising the steps of:
(a) treating a metformin hydrochloride with solution of alkalizing agent in a solvent;
(b) drying the resulting product obtained in step (a);
(c) mixing the product obtained in step (b) with vildagliptin and optionally one or more
pharmaceutically acceptable excipients;
(d) compressing the mixture obtained in step (c) to obtain tablets; and
(e) optionally coating the tablets obtained in step (d).
In another aspect, the present invention provides a process for the preparation of the pharmaceutical composition of the present invention comprising the steps of:
(a) treating a metformin hydrochloride with solution of alkalizing agent in a solvent;
(b) drying the resulting product obtained in step (a);
(c) mixing the product obtained in step (b) with a DPP-IV inhibitor and optionally one or more
pharmaceutically acceptable excipients;
(d) roller compacting the mixture obtained in step (c) to obtain granules;
(e) compressing the granules obtained in step (d) to obtain tablets; and
(f) optionally coating the tablets obtained in step (e).
In another aspect, the present invention provides a process for the preparation of the pharmaceutical composition of the present invention comprising the steps of:
(a) treating a metformin hydrochloride with solution of alkalizing agent in a solvent;
(b) drying the resulting product obtained in step (a);
(c) mixing the product obtained in step (b) with vildagliptin and optionally one or more
pharmaceutically acceptable excipients;
(d) roller compacting the mixture obtained in step (c) to obtain granules;
(e) compressing the granules obtained in step (d) to obtain tablets; and
(f) optionally coating the tablets obtained in step (e).
The treatment of Metformin or its pharmaceutically acceptable salts can be carried out, using the solution and/or suspension of alkalizing agent and solvent, by various processes including granulation, mixing or spraying; preferably, spraying the solution and/or suspension of alkalizing agent and solvent on the Metformin or its pharmaceutically acceptable salts. Drying of treated Metformin hydrochloride can be carried out at 50±10°C.
The alkalizing agent used to treat Metformin hydrochloride can be in an amount of about 0.0015 to about 0.015 mole equivalent (per mole) of Metformin hydrochloride. Preferably, 0.0015 to 0.0050 mole equivalent (per mole) of Metformin hydrochloride. A preferred alkalizing agent used to prepare the alkalizing agent treated Metformin hydrochloride for the present invention is alkali metal carbonate, or alkali metal bicarbonate or alkali metal phosphates. More preferably, the alkalizing agent is sodium carbonate, or sodium bicarbonate or Disodium Hydrogen Phosphate.
The term "about", as used herein, refers to variation of ± 10%.
Other pharmaceutically acceptable excipients include, but are not limited to, binders, diluents, disintegrants, and lubricants/glidants/antiadherents. Suitable diluents or fillers are selected from the group comprising microcrystalline cellulose (MCC), powdered cellulose, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium carbonate, lactose monohydrate, lactose anhydrous, sucrose, sorbitol, xylitol, mannitol, erythritol, kaolin, calcium silicate, maltodextrin, starch, modified starch e.g., pregelatinized starch, maize starch, corn starch, or mixtures thereof. The present invention comprises a diluent in an amount of from about 2% to about 50% by total weight of the pharmaceutical composition.
Suitable binders are selected from the group comprising povidone, copovidone, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, xanthan gum, gum acacia, gum arabic, tragacanth, sorbitol, dextrose, sucrose, mannitol, gelatin, pullulan, sodium alginate, propylene glycol, polyvinyl alcohol, corn syrup, methacrylates, carboxyvinyl polymers e.g., carbomers, or mixtures thereof. The present invention comprises a binder in an amount of from about 1% to about 15% by weight of the composition.
Suitable disintegrants are selected from the group comprising hydroxypropyl cellulose (L-HPC), crospovidone, croscarmellose sodium, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, sodium starch glycolate, gums, alginic acid or alginates, starch, corn starch, modified starch, carboxymethyl starch, polyacrylates, or mixtures thereof. The present invention comprises a disintegrant in an amount of from about 1% to about 10% by weight of the composition.
Suitable lubricants/glidants/antiadherents are selected from the group comprising hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, stearic acid, sodium stearyl fumarate, sodium starch fumarate, magnesium stearate, calcium stearate, zinc stearate, aluminum silicate, talc, colloidal silicon dioxide, sucrose esters of fatty acid, waxes, silica gel, or mixtures thereof. The present invention comprises a lubricant in an amount of from about 0.25% to about 5% by weight of the composition.
The pharmaceutical composition of the present invention can be obtained by using known conventional methods i.e. granulation or direct compression. The process to obtain granulate includes, but is not limited to, wet granulation, fluid bed granulation, spray drying, or dry granulation. Drying of granules can be carried out at 50±10°C.
Suitable solvents are selected from the group comprising methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.
The pharmaceutical composition of the present invention is intended for oral use, and can be in the form of tablets, capsules, minitablets, granules, or pellets, wherein the composition can be further film coated.
The pharmaceutical composition prepared by any of the above described processes may further be coated with a film- forming polymer and one or more pharmaceutically acceptable excipients, using techniques well known in the art e.g., spray coating in a conventional coating pan, or a fluidized bed processor, or dip coating. Alternatively, coating can also be performed using a hot melt technique.
The film coating may contain one or more film-forming polymers, and optionally one or more pharmaceutically acceptable excipients. A suitable film-forming polymer is selected from the group comprising hydroxypropylmethyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropylmethyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers e.g., Eudragit®, polyvinylpyrrolidone, polyvinylalcohol, polyethylene glycol, or mixtures thereof. A preferred film- forming polymer is hydroxypropylmethyl cellulose. Other suitable film- forming polymers which are known in the art may also be used. The film coating may also contain opacifiers like titanium dioxide, flow aids like talc and pigment like iron oxide yellow. Preferably, the film coating material is Opadry® Yellow, which consists of hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide, talc, and iron oxide yellow.
The invention is further illustrated by the following examples, which are for illustrative purposes only, and should not be construed as limiting the scope of the invention in any way.
Examples:
Comparative example A: Composition prepared by using Metformin hydrochloride (untreated) and Vildagliptin.
Table-1
Sr. No. Ingredients Amount in mg/Tab
1 Metformin HCl 1000.00
2 Vildagliptin 50.00
3 Hydroxypropyl cellulose (HPC) – LF 30.00
4 Isopropyl alcohol Q.S.
5 Ceulose® KG – 1000 (MCC) 89.00
6 Magnesium stearate 11.00
Core Tablet Weight 1180.00
7. Opadry Yellow® 36.00
8. Water Q.S.
Coated Tablet Weight 1216.00
Q.S.= Quantity sufficient
Process for the preparation:
(a) Metformin hydrochloride and Vildagliptin was dry mixed,
(b) granulating solution was prepared by dissolving HPC-LF in isopropyl alcohol,
(c) mixture of step (a) was granulated by using granulating solution of step (b),
(d) granules obtained in step (c) were dried and mixed with Ceulose® KG – 1000 and magnesium stearate,
(e) mixture of step (d) was compressed to obtain tablet, and
(f) the tablet of step (e) was coated by using Opadry® yellow.
Observation: Stability data of tablets of comparative example A is presented in table-2. The tablets of comparative example-A were stored at of 40°C/75% RH for one month. It was found that impurities related to vildagliptin i.e. amide, acid and dimer were drastically increased within one month.
Table-2
Related substance Comparative
example – A (40°C/75% RH)
Initial 1 M
Amide Impurity
(NMT 0.50%) ND 0.56%
Acid Impurity
(NMT 0.50%) 0.06% 0.44%
Dimer Impurity
(NMT0.50%) ND 0.10%
Single Maximum unknown impurity
(0.20%) ND ND
Assay
(For Vildagliptin) 94.9 94.6
Assay
(For Metformin HCl) 100.9 103.3
ND = Not detected
Working Example of the present invention:

Example – 1: Composition of Metformin hydrochloride and Vildagliptin prepared by using Metformin hydrochloride treated with sodium carbonate.

Table-3
Sr. No Ingredients Amount in mg/Tab
1A 1B 1C 1D
1 Metformin HCl 1000.00 1000.00 1000.00 1000.00
2 Vildagliptin 50.00 50.00 50.00 50.00
3 Water Q.S. Q.S. Q.S. Q.S.
4 Sodium carbonate 1.50 1.00 2.00 3.00
5 Hydroxypropyl cellulose (HPC) - LF 60.00 60.00 60.00 60.00
6 Isopropyl alcohol Q.S. Q.S. Q.S. Q.S.
7. Magnesium stearate 11.00 11.00 11.00 11.00
Core Tablet Weight 1122.5 1122.00 1123.00 1124.00
8. Opadry® Yellow 33.67 33.66 33.69 33.72
9. Water Q.S. Q.S. Q.S. Q.S.
Coated Tablet Weight 1156.17 1155.66 1156.69 1157.72
Q.S.= Quantity sufficient
Process for the preparation:
(a) Metformin hydrochloride was treated with an aqueous solution of sodium carbonate,
(b) treated Metformin hydrochloride was dried and mixed with Vildagliptin,
(c) granulating solution was prepared by dissolving HPC-LF in isopropyl alcohol,
(d) mixture of step (b) was granulated by using granulating solution of step (c),
(e) granules obtained in step (d) were dried and mixed with magnesium stearate,
(f) mixture of step (e) was compressed to obtain tablet, and
(g) the tablet of step (f) was coated by using Opadry® yellow.
Observation: Stability data of tablets of working example 1A to 1D is presented in table-4. The tablets of working example-1A to 1D were stored at 40°C/75% RH for one month. It was found that all individual impurities were well within the limits of impurity even after one month. Further, there was no significant difference in the assay of vildagliptin after the storage at 40°C/75% RH for one month.
Table-4
Related substance 1A
(40°C/75% RH) 1B
(40°C/75% RH) 1C
(40°C/75% RH) 1D
(40°C/75% RH)
Initial 1 M Initial 1 M Initial 1 M Initial 1 M
Amide Impurity
(NMT 0.50%) 0.02% 0.06 BQL 0.05 BQL 0.06 BQL 0.08
Acid Impurity
(NMT 0.50%) ND ND ND ND ND ND ND ND
Dimer Impurity
(NMT 0.50%) ND BQL BQL BQL BQL BQL BQL BQL
Single Maximum unknown impurity
(NMT 0.20%) 0.03 0.05 BQL 0.07 BQL 0.07 BQL 0.25
Assay
(For Vildagliptin) 104.3 103.8 97.4 97 98 95.5 98.5 96.8
Assay
(For Metformin HCl) 99.7 98.4 98.9 97.7 98.5 98.4 99.1 99.6
ND = Not detected, BQL = Below quantification limit
The analytical results of table 2 and table 4 demonstrate that working example-1A to 1D of the present invention is more stable than comparative example-A, which shows the stabilizing effect of Metformin hydrochloride treated with alkali carbonate on the composition comprising combination of Vildagliptin and Metformin hydrochloride.

Example – 2: Composition of Metformin hydrochloride and Vildagliptin prepared by using Metformin hydrochloride treated with sodium bicarbonate or disodium hydrogen phosphate.
Table-5
Sr. No. Ingredients Amount in mg/Tab
2A
(with sodium bicarbonate) 2B
(with disodium hydrogen phosphate)
1 Metformin HCl 1000.00 1000.00
2 Vildagliptin 50.00 50.00
3 Water Q.S. Q.S.
Sodium bicarbonate 1.50 ---
4 Disodium hydrogen phosphate --- 1.50
5 Hydroxypropyl cellulose (HPC) - LF 60.00 60.00
6 Isopropyl alcohol Q.S. Q.S.
7. Magnesium stearate 11.00 11.00
Core Tablet Weight 1122.50 1122.50
8. Opadry® Yellow 33.68 33.68
9. Water Q.S. Q.S.
Coated Tablet Weight 1156.18 1156.18
Q.S.= Quantity sufficient
Tablets were prepared from composition of table-5 by using process as given in example-1.
Observation: Stability data of tablets of working example - 2A and 2B is presented in table-6. The tablets of working example - 2A and 2B were stored at 40°C/75% RH for one month. It was found that all individual impurities were well within the limits of impurity even after one month. Further, there was no significant difference in the assay of vildagliptin after the storage at 40°C/75% RH for one month.
Table-6
Related substance 2A
(40°C/75% RH) 2B
(40°C/75% RH)
Initial 1 M Initial 1 M
Amide Impurity
(NMT 0.50%) BQL BQL BQL 0.22
Acid Impurity
(NMT 0.50%) ND ND ND ND
Dimer Impurity
(NMT 0.50%) ND ND BQL ND
Single Maximum unknown impurity
(NMT 0.20%) 0.08 0.11 BQL 0.35
Assay
(For Vildagliptin) 97.6 97.2 98 97.2
Assay
(For Metformin HCl) 96.1 96.4 97.1 98.1
ND = Not detected, BQL = Below quantification limit
The analytical results of table-2 and table 6 demonstrate that working example-2A and 2B of the present invention is more stable than comparative example-A, which shows the stabilizing effect of Metformin hydrochloride treated with alkali bicarbonate and alkali phosphate in the composition comprising combination of Vildagliptin and Metformin hydrochloride.
In particular, stability data shown in table-2, table-4 and table-6 demonstrate that composition comprising Metformin hydrochloride treated with alkali carbonate, alkali bicarbonate or alkali phosphate was stable at accelerated storage condition as compared to the composition without alkalizing agent.

The alkalizing agent treated metformin hydrochloride provides a stable pharmaceutical composition of DPP-IV inhibitor, specifically Vildagliptin, and Metformin hydrochloride.
,CLAIMS:We Claim,
1. A stable pharmaceutical composition comprising (a) Metformin hydrochloride treated
with alkalizing agent; b) Vildagliptin; and (c) one or more pharmaceutically
acceptable excipients.

2. The stable pharmaceutical composition as claimed in claim 1, wherein the alkalizing agent is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal sulfates, alkali metal borates, alkali metal citrates, alkali metal hydroxides or mixtures thereof.

3. The stable pharmaceutical composition as claimed in any preceding claims, wherein the alkalizing agent is selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates.

4. The stable pharmaceutical composition as claimed in any preceding claims, wherein the alkalizing agent is sodium carbonate, sodium bicarbonate or disodium hydrogen phosphate.

5. The stable pharmaceutical composition as claimed in any preceding claims, wherein the alkalizing agent is at least about 0.05%.

6. The stable pharmaceutical composition as claimed in any preceding claims, wherein the alkalizing agent is at least about 0.05% to 1%.

7. A process for preparation of the stable pharmaceutical composition as claimed in claim 1, comprising:
(a) treating metformin hydrochloride with solution of alkalizing agent in a solvent;
(b) drying the resulting product obtained in step (a);
(c) mixing the dried product obtained in step (b) with vildagliptin and optionally one or
more pharmaceutically acceptable excipients;
(d) granulating the mixture obtained in step (c) with solvent and binder to obtain
granules;
(e) drying the granules obtained in step (d);
(f) compressing the granules obtained in step (e) with one or more pharmaceutically
acceptable excipients to obtain tablets; and
(g) optionally coating the tablets obtained in step (f).
8. The process for preparation of the stable pharmaceutical composition as claimed in claim 7, wherein the alkalizing agent used to treat Metformin hydrochloride is 0.0015 to about 0.015 mole per mole of Metformin hydrochloride.
9. The process for preparation of the stable pharmaceutical composition as claimed in claim 7, wherein solvent is selected from methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof.

10. The process for preparation of the stable pharmaceutical composition as claimed in claim 7, comprising:
(a) treating metformin hydrochloride with an aqueous solution of sodium carbonate,
sodium bicarbonate or disodium hydrogen phosphate;
(b) drying the resulting product obtained in step (a);
(c) mixing the dried product obtained in step (b) with vildagliptin and optionally one or
more pharmaceutically acceptable excipients;
(d) granulating the mixture obtained in step (c) with isopropyl alcohol and hydroxypropyl
cellulose to obtain granules;
(e) drying the granules obtained in step (d);
(f) compressing the granules obtained in step (e) with one or more pharmaceutically
acceptable excipients to obtain tablets; and
(g) optionally coating the tablets obtained in step (f).