WO2015132679A1

WO2015132679A1 - Teneligliptin compositions

Info

Publication number: WO2015132679A1
Application number: PCT/IB2015/050164
Authority: WO
Inventors: Ulhas Rameshchandra Dhuppad; Nitin Shivajirao DESHMUKH; Girish Omkar; Suresh Mahadev Kadam; Bipin Parsottam Kansagra; Shailendra Nilkanth BHADANE; Vinayak Kacheshwar BHUJADE
Original assignee: Glenmark Pharmaceuticals Ltd
Priority date: 2014-03-05
Filing date: 2015-01-09
Publication date: 2015-09-11

Abstract

The present invention relates to teneligliptin, process for preparation thereof and pharmaceutical compositions of teneligliptin.

Description

TENELIGLIPTIN COMPOSITIONS

PRIORITY DOCUMENT This patent application claims priority to Indian Provisional Patent

Application number 759/MUM/2014 (filed on Mar 05, 2014), the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Dipeptidyl peptidase-4 (DPP-IV) inhibitors is a class of anti-diabetic drugs act by inhibiting the degradation of the incretins, glucagon-like peptide- 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Generically these compounds are termed as "gliptins".

DPP-IV inhibitors are commonly used in a combination therapy along with other antidiabetic drugs.

International Patent Application No. WO0152825 discloses combinations of a DPP-IV inhibitor and antidiabetic compounds, preferably selected from the group consisting of insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT), compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (G6Pase), inhibitors of fructose- 1,6-bisphosphatase (F- 1,6-BPase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers, insulin secretion enhancers, alpha -glucosidase inhibitors, inhibitors of gastric emptying, insulin, and alpha 2-adrenergic antagonists, for simultaneous, separate or sequential use in the prevention, delay of progression or treatment of conditions mediated by dipeptidylpeptidase - IV (DPP-IV), in particular diabetes, more especially type 2 diabetes mellitus, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity and osteoporosis; and the use of such combination for the cosmetic treatment of a mammal in order to effect a cosmetically beneficial loss of body weight.

International Patent Application No. WO0197808 discloses combinations of dipeptidyl peptidase IV inhibitors- L-threo-isoleucyl pyrrolidide, L-allo- isoleucyl thiazolidide, L-allo-isoleucyl pyrrolidide; and salts thereof or 1 [2- [ (5- cyanopyridin-2-yl) aminoethylamino] acetyl-2- cyano-(S)-pyrrolidine and (2S)-1- [(2S)-2-amino-3, 3-dimethylbutanoyl]-2pyrrolidinecarbonitrile and antidiabetic agents such as alpha glucosidase inhibitor, a biguanide, an insulin secretagogue or an insulin sensitiser.

Bo Ahren et al. in "Twelve and 52-week efficacy of the Dipeptidyl

Peptidase IV inhibitor LAF237 in Metformin treated patients with type 2 diabetes."

Diabetes care, Volume 27, Number 12, published December 2004 reports a study on combination of DPP IV inhibitor (LAF237) and metformin for the treatment of diabetes. Teneligliptin is a novel DPP-IV inhibitor indicated for the treatment of type

2 diabetes mellitus and is represented by a structural formula (I)

Formula (I) It is available in the form of 20 mg tablets in Japan by the trade name Tenelia^®. It is used in cases showing insufficient improvement in glycemic control even after diet control and exercise or a combination of diet control, exercise, and sulfonylurea or thiazolidine class drugs. In adults, teneligliptin is orally administered at a dosage of 20 mg once daily, which can be increased up to 40 mg per day. Teneligliptin is disclosed in United States Patents US7074794 and US8003790.

United States Patent Application US20120276166 discloses that long-term preservation of a teneligliptin-containing solid preparation having a particular content for about several months causes delayed dissolution of teneligliptin or a salt thereof, or a solvate thereof. As a solution to this problem, to provide an elution-stabilized dosage form of teneligliptin, it offers a teneligliptin-containing solid preparation independently comprising a teneligliptin-containing part containing teneligliptin or a salt thereof, or a solvate thereof at a content percentage 1.5- to 10-fold the content percentage desired for a solid preparation. Teneligliptin-containing part is prepared by granulating teneligliptin with excipients and further adding excipients to form a finished dosage form. When the content percentage of teneligliptin or a salt thereof, or a solvate thereof in said part is less than 1.5-fold that desired for the solid preparation of the present invention, the object of prevention of delay in the dissolution of the active ingredient cannot be achieved, whereas when it is higher than 10-fold, the lack of strength necessary for maintaining the solid form of particles and the like is feared, and the possibility of problem in the production cannot be denied.

Contrary to these teachings, the present invention discloses stable pharmaceutical compositions of teneligliptin wherein the ratio of teneligliptin content in the 'teneligliptin-containing part' to that of the solid preparation being less than 1.5-fold or more than 10-fold. Also the inventors provide new alternative methods to prepare teneligliptin compositions.

SUMMARY OF THE INVENTION The invention relates to teneligliptin, process for preparation thereof and pharmaceutical compositions of teneligliptin comprising teneligliptin and one or more pharmaceutically acceptable excipients.

In one embodiment, the present invention provides 3-{(2S, 4S)-4-[4-(3- methyl- 1 -phenyl-5-pyrazolyl)- 1 -piperazinyl]-2-pyrrolidinylcarbonyl } - 1 ,3 - thiazolidine trifluoroacetate salt.

In one embodiment, the present invention provides isolated 3-{(2S,4S)-4- [4-(3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]-2-pyrrolidinylcarbonyl}-l-,3- thiazolidine trifluoroacetate salt characterized by a proton NMR spectrum having peaks at δ 9.17(brs, 1H), 7.73-7.70(d, 2H), 7.46-7.41(t, 2H), 7.28-7.24(t, 1H), 5.78 (s, 1H), 4.69-4.39 (m, 3H), 3.85-3.35 (m, 6H), 3.09- 3.02(m, 4H), 2.75-2.64 (m, 5H), 2.12 (s, 3H), 1.63-1.60 (m, 1H).

In one embodiment the present invention provides a process for the preparation of isolated 3-{(2S, 4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-l- piperazinyl]-2-pyrrolidinylcarbonyl}-l-,3-thiazolidine trifluoroacetate salt comprising;

(a) reacting 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-l- phenyl-lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with trifluoroacetic acid; and

(b) isolating the 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-l- piperazinyl]-2-pyrrolidinylcarbonyl} -l-,3 -thiazolidine trifluoroacetate salt from step a.

In one embodiment step (a) may be carried out in a solvent selected from the group consisting of dichloromethane or ethylene dichloride or chloroform.

In one embodiment, the present invention provides crystalline 3-{(2S, 4S)- 1 -tert-Butoxycarbonyl-4-[4-(3-methyl- 1 -phenyl-lH-pyrazol-5-yl) piperazin- 1 -yl] pyrrolidin-2-yl-carbonyl}thiazolidine characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 21.15, 20.35, 17.14, 16.80, 11.96 ±0.2 degrees 2 theta. In one embodiment, the present invention provides crystalline 3-{(2S, 4S)- 1 -tert-Butoxycarbonyl-4-[4-(3-methyl- 1 -phenyl-lH-pyrazol-5-yl) piperazin- 1 -yl] pyrrolidin-2-yl-carbonyl}thiazolidine characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 21.15, 20.35, 17.14, 16.80, 11.96 ±0.2 degrees 2 theta and having DSC of 248 ±2°C.

In one embodiment the present invention provides a process for the preparation of teneligliptin 2.5 hydrobromide or a hydrate thereof comprising; a. deprotecting 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-l- phenyl-lH-pyrazol-5-yl) piperazin- l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with an acid to form an acid addition salt of teneligliptin; and

b. reacting the acid addition salt of teneligliptin with a base followed by treatment with hydrobromic acid.

In one embodiment, the acid used for deprotection may be selected form the group consisting of hydrochloric acid, sulfuric acid and trifluoro acetic acid.

In one embodiment, the base in step (b) may be selected from an organic base or inorganic base.

In one embodiment, in step (b) the product obtained after treatment with a base may be isolated and treated with hydrobromic acid, optionally in presence of a solvent.

In one embodiment, in step (b) the product obtained after treatment with a base may be isolated as a residue and then treated with hydrobromic acid, optionally in presence of a solvent. In one embodiment, in step (b) the product obtained after treatment with a base may not be isolated before treatment with hydrobromic acid. In one embodiment, in step (b) after treatment with base hydrobromic acid or hydrobromic acid in acetic acid is used. In one embodiment the present invention provides a process for the preparation of 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]-2- pyrrolidinylcarbonyl}-l-,3-thiazolidine 2.5 hydrobromide or a hydrate thereof comprising;

a. deprotecting 3-{(2S,4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-l- phenyl- lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with hydrochloric acid to form teneligliptin hydrochloride; and

b. reacting the teneligliptin hydrochloride with a base followed by treatment with hydrobromic acid. In one embodiment, the hydrochloride obtained is 2, 2.5 or 3 hydrochloride of teneligliptin.

In one embodiment the present invention provides a process for the preparation of teneligliptin 2.5 hydrobromide or a hydrate thereof comprising; a. deprotecting 3-{(2S,4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-l- phenyl-lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with hydrochloric acid to form 2.5 teneligliptin hydrochloride; and

b. reacting the 2.5 hydrochloride of teneligliptin with a base followed by treatment with hydrobromic acid.

In one embodiment the 2.5 HC1 was obtained by deprotecting 3-{(2S, 4S)- 1 -tert-Butoxycarbonyl -4- [4-(3 -methyl- 1 -phenyl -lH-pyrazol-5-yl) piperazin- 1 - yl]pyrrolidin-2-yl-carbonyl}thiazolidine with hydrochloric acid in a solvent selected from the group consisting of isopropyl alcohol, tert-butanol, n- butanol, methanol or mixture thereof. In one embodiment the present invention provides a process for the preparation of teneligliptin comprising

a. deprotecting 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-l- phenyl-lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with an acid to form an acid addition salt of teneligliptin; and

b. reacting the acid addition salt of teneligliptin with a base.

In one embodiment, the present invention provides a process for preparation of teneligliptin 2.5 hydrobromide or a hydrate thereof which comprises treating teneligliptin with hydrobromic acid or hydrobromic acid in acetic acid in a solvent selected from methanol, tertiary butanol and mixtures thereof.

In one embodiment, the present invention provides a process for the preparation of teneligliptin 2.5 hydrobromide hydrate comprising crystallising teneligliptin 2.5 hydrobromide hydrate from a solvent selected from the group consisting of methanol, n-butanol, tertiary butanol, propyl acetate, isopropyl acetate, butyl acetate, ethers such as diethyl ether, tetrahydrofuran,

tetrahydropyran, diisopropyl ether, methyl tertiary butyl ether; ketones such as acetone, methyl ethyl ketone, amide as such as N, N-dimethyl formamide, N, N- dimethyl acetamide; nitriles such as acetonitrile, hydrocarbons such as toluene, xylene, cyclohexane, methyl cylcohexane; halogenated hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride and mixtures thereof.

Preferably, the solvent is methanol or a mixture of a methanol and tertiary-butanol.

In another embodiment, the present invention relates to a pharmaceutical composition of teneligliptin comprising teneligliptin and one or more

pharmaceutically acceptable excipients.

In another embodiment, the present invention relates to a pharmaceutical composition of teneligliptin comprising teneligliptin hydrobromide hydrate and one or more pharmaceutically acceptable excipients. In one embodiment, the present invention relates to a pharmaceutical composition of teneligliptin comprising granules containing teneligliptin and one or more pharmaceutically acceptable excipients.

In one embodiment, the present invention relates to a pharmaceutical composition of teneligliptin comprising granules containing teneligliptin and one or more pharmaceutically acceptable excipient, wherein the ratio of content of teneligliptin in granule to that in the pharmaceutical composition is smaller than 1.5 and wherein the total weight of the composition is greater than 215 mg and less than 600 mg.

In one aspect of this embodiment, teneligliptin is present in the form of teneligliptin hydrobromide hydrate.

In one aspect of this embodiment, the pharmaceutical composition includes one or more binders selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose; one or more diluents selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sorbitol, xylitol, starch, calcium hydrogen phosphate; and; one or more lubricants selected from the group consisting of magnesium stearate, colloidal silicon dioxide, calcium stearate, talc, stearic acid, sucrose and esters of fatty acids.

In one aspect of this embodiment, the pharmaceutical composition comprises 1.5%-15% by weight of teneligliptin or its pharmaceutically acceptable salt, l%-80% by weight of diluent, 0.1%-10% by weight of binder and 0.5%-30% by weight of lubricant.

In a preferred aspect of this embodiment, the pharmaceutical composition comprises 7%-10% by weight of teneligliptin or its pharmaceutically acceptable salt, 50%-70% by weight of diluent, 0.5%-5% by weight of a binder and 0.5%- 10% by weight of lubricant. In another preferred aspect of this embodiment, the pharmaceutical composition comprises about 8% by weight of teneligliptin or its pharmaceutically acceptable salt, about 76% by weight of diluent, 9% by weight of binder and about 1% by weight of lubricant.

In another embodiment, the present invention relates to pharmaceutical composition of teneligliptin comprising granules containing teneligliptin and one or more pharmaceutically acceptable excipients, wherein the ratio of content of teneligliptin in granules to that in the pharmaceutical composition is greater than 10.

In one embodiment, the present invention relates to pharmaceutical composition of teneligliptin comprising teneligliptin-containing granules and metformin, wherein teneligliptin and metformin are present in separate portions and wherein the ratio of content of teneligliptin in granules to that in the pharmaceutical composition is greater than 10.

In one aspect of this embodiment, the pharmaceutical composition comprises 1.5%-5% by weight of teneligliptin, l%-50% by weight of diluent, 0.1%-10% by weight of binder and 0.1%-30% by weight of lubricant. In another aspect of this embodiment, the pharmaceutical composition comprises 1.5%-2.5% by weight of teneligliptin or its pharmaceutically acceptable salt, l%-25% by weight of diluent, 0.1%-3% by weight of binder and 0.1%-25% by weight of lubricant.

In yet another aspect of this embodiment, the pharmaceutical composition comprises about 2% by weight of teneligliptin or its pharmaceutically acceptable salt, about 11% by weight of diluent, about 0.1% by weight of binder and about 0.5% by weight of lubricant.

In another embodiment, the present invention relates to a process for preparation of teneligliptin pharmaceutical composition comprising granules containing teneligliptin wherein the ratio of content of teneligliptin in granule to that in the pharmaceutical composition is smaller than 1.5 and wherein the total weight of the composition is greater than 215 mg and less than 600 mg comprising the steps of- a) mixing teneligliptin or a pharmaceutically acceptable salt with pharmaceutically acceptable excipients;

b) adding a binder solution to the mixture of step a);

c) drying the wet mixture of step b) and sifting to form granules;

d) lubricating the granules of step c);

e) compressing the blend of step d) to form a tablet or filling of step d) the blend into capsules.

In an aspect of this embodiment the process comprising the steps of- a) dry mixing teneligliptin or a pharmaceutically acceptable salt with pharmaceutically acceptable excipients to form a blend;

b) roll-compacting the blend of step a) one or more times to form flakes; c) granulating and sieving the flakes of step b);

d) lubricating the granules of step c); e) compressing the blend of step d); to form a tablet or filling the blend of step d) into capsules.

In another embodiment, the present invention relates to a process for preparation of teneligliptin pharmaceutical composition comprising the steps of- a) mixing teneligliptin with pharmaceutically acceptable excipients to form a blend for direct compression;

b) compressing the blend of step a) to form a tablet;

c) optionally coating the tablet of step b).

In another embodiment, the present invention relates to a process for preparation of teneligliptin pharmaceutical composition comprising teneligliptin- containing granules and metformin wherein the ratio of content of teneligliptin in granules to that in the pharmaceutical composition is greater than 10; comprising the steps of- granulating teneligliptin with pharmaceutically acceptable excipients;

a) lubricating the teneligliptin granules of step a);

b) granulating metformin with pharmaceutically acceptable excipients.

c) lubricating the metformin granules of step c);

d) compressing the blends of steps b) and d) to form a bi-layer tablet or filling blends of steps b) and d) into capsules.

In one aspect of this embodiment the process comprising steps of- a) spray granulating teneligliptin with pharmaceutically acceptable excipients; b) lubricating the teneligliptin granules of step a);

c) granulating metformin with pharmaceutically acceptable excipients.

d) lubricating the metformin granules of step c);

e) compressing the blends of steps b) and d) to form a bi-layer tablet or filling blends of steps b) and d) into capsules. In yet another aspect of this embodiment the process comprising the steps of- a) roll compacting and granulating teneligliptin with pharmaceutically acceptable excipients;

b) lubricating the teneligliptin granules of step a);

c) granulating metformin with pharmaceutically acceptable excipients.

d) lubricating the metformin granules of step c);

e) compressing the blends of steps b) and d) to form a bi-layer tablet or filling blends of steps b) and d) into capsules.

In another embodiment the present invention relates to a process of preparation of teneligliptin pharmaceutical composition comprising teneligliptin- containing granules and metformin, comprising the steps of- a) mixing teneligliptin with pharmaceutically acceptable excipients to form a blend for direct compression;

b) granulating metformin with pharmaceutically acceptable excipients;

c) lubricating the metformin granules of step b);

d) compressing the blends of steps a) and c) to form a bi-layer tablet or filling blends of steps a) and c) into capsules.

In another embodiment the present invention relates to a process of preparation of teneligliptin pharmaceutical composition comprising teneligliptin- containing granules and metformin, comprising the steps of- a) granulating metformin with pharmaceutically acceptable excipients;

b) lubricating the metformin granules of step a);

c) compressing the metformin blend of step b) to form a core;

d) preparing a teneligliptin containing polymer solution or suspension;

e) coating the core of step c) with the solution or suspension of step d).

BRIEF DESCRIPTION OF FIGURES Fig 1. Proton MR spectrum of 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)- l-piperazinyl]-2-pyrrolidinylcarbonyl}-l-,3-thiazolidine trifluoroacetate salt.

Fig 2. X-ray Diffraction of 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-l- phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl-carbonyl}thiazolidine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to pharmaceutical compositions of

teneligliptin comprising teneligliptin and one or more pharmaceutically acceptable excipients.

The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth later in a non-provisional application claiming priority from the present provisional application are in conflict, the definition in the non-provisional application shall control the meaning of the terms.

The term "teneligliptin" as used herein, unless mentioned otherwise mentioned, means {(2S, 4S)-4-[4-(3-Methyl-l-phenyl-lH-pyrazol-5-yl)-l- piperazinyl]-2-pyrrolidinyl} (1, 3-thiazolidin-3-yl) methanone, hydrate or a salt thereof.

The term "metformin" as used herein, unless mentioned otherwise, means metformin, hydrate or a salt thereof.

The term "salt" or "pharmaceutically acceptable salt" as used herein, means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use. Representative acid additions salts include hydrochloride, dihydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, trifluoroacetate and lauryl sulphate salts. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts. In another embodiment, the present invention relates to a pharmaceutical composition of teneligliptin comprising teneligliptin and one or more

pharmaceutically acceptable excipients.

In one embodiment, the present invention relates to a pharmaceutical composition of teneligliptin comprising teneligliptin hydrobromide hydrate and one or more pharmaceutically acceptable excipients.

In one embodiment, the present invention relates to a pharmaceutical composition of teneligliptin comprising granules containing teneligliptin and one or more pharmaceutically acceptable excipients.

In one aspect of this embodiment, teneligliptin is present in the form of teneligliptin hydrobromide hydrate

In one aspect of this embodiment, the pharmaceutical composition includes one or more binders selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose; one or more diluents selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sorbitol, xylitol, starch, calcium hydrogen phosphate; and; one or more lubricants selected from the group consisting of magnesium stearate, colloidal silicon dioxide, calcium stearate, talc, stearic acid, sucrose and esters of fatty acids. In one aspect of this embodiment, the pharmaceutical composition comprises 1.5%-15% by weight of teneligliptin or its pharmaceutically acceptable salt, l%-80% by weight of diluent, 0.1%-10% by weight of binder and 0.5%-30% by weight of lubricant.

In a preferred aspect of this embodiment, the pharmaceutical composition comprises 7%-10% by weight of teneligliptin or its pharmaceutically acceptable salt, 50%-70% by weight of diluent, 0.5%-5% by weight of a binder and 0.5%- 10% by weight of lubricant.

In another preferred aspect of this embodiment, the pharmaceutical composition comprises about 8% by weight of teneligliptin or its pharmaceutically acceptable salt, about 76% by weight of diluent, 9% by weight of binder and about 1%) by weight of lubricant.

In one aspect of this embodiment, the pharmaceutical composition comprises 1.5%-5% by weight of teneligliptin, l%-50% by weight of diluent, 0.1%-10% by weight of binder and 0.1%-30% by weight of lubricant.

In another aspect of this embodiment, the pharmaceutical composition comprises 1.5%-2.5% by weight of teneligliptin or its pharmaceutically acceptable salt, l%-25% by weight of diluent, 0.1%-3% by weight of binder and 0.1%-25% by weight of lubricant.

b) adding a binder solution to the mixture of step a);

c) drying the wet mixture of step b) and sifting to form granules;

d) lubricating the granules of step c);

e) compressing the blend of step d) to form a tablet or filling of step d) the blend into capsules. In an aspect of this embodiment the process comprising the steps of- a) dry mixing teneligliptin or a pharmaceutically acceptable salt with pharmaceutically acceptable excipients to form a blend;

d) lubricating the granules of step c);

e) compressing the blend of step d); to form a tablet or filling the blend of step d) into capsules.

b) compressing the blend of step a) to form a tablet;

c) optionally coating the tablet of step b).

In another embodiment, the present invention relates to a process for preparation of teneligliptin pharmaceutical composition comprising teneligliptin- containing granules and metformin wherein the ratio of content of teneligliptin in granules to that in the pharmaceutical composition is greater than 10; comprising the steps of- a) granulating teneligliptin with pharmaceutically acceptable excipients; b) lubricating the teneligliptin granules of step a);

c) granulating metformin with pharmaceutically acceptable excipients.

d) lubricating the metformin granules of step c);

In one aspect of this embodiment the process comprising the steps of- a) spray granulating teneligliptin with pharmaceutically acceptable excipients; b) lubricating the teneligliptin granules of step a);

c) granulating metformin with pharmaceutically acceptable excipients. d) lubricating the metformin granules of step c);

In yet another aspect of this embodiment the process comprising the steps of- a) roll compacting and granulating teneligliptin with pharmaceutically acceptable excipients;

b) lubricating the teneligliptin granules of step a);

c) granulating metformin with pharmaceutically acceptable excipients.

d) lubricating the metformin granules of step c);

b) granulating metformin with pharmaceutically acceptable excipients;

c) lubricating the metformin granules of step b);

b) lubricating the metformin granules of step a);

c) compressing the metformin blend of step b) to form a core;

d) preparing a teneligliptin containing polymer solution or suspension; e) coating the core of step c) with the solution or suspension of step d).

Teneligliptin granules as contemplated by this invention can be made of Teneligliptin in association with one or more of a diluent, lubricant, binder, fluidizing agent, disintegrating agent, solubilizing agent and the like.

Suitable diluents include but are not limited to, mannitol, sorbitol, xylitol, starch, lactose, cellulose, calcium hydrogen phosphate, carboxymethyl cellulose sodium and the like. The diluents can be quantitatively adjusted to manipulate the percentage content of teneligliptin in granules as well as the finished dosage form.

Suitable lubricants include but are not limited to, magnesium stearate, colloidal silicon dioxide, hydroxypropylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, starch, calcium stearate, talc, stearic acid, sucrose, ester of fatty acid and the like.

Suitable binders include but are not limited to, hydroxypropylcellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose and the like.

Finished formulations containing Teneligliptin 1.5-15%, diluent 1-80%, binder 0.1-10% and lubricant 0.5-30%, more preferably Teneligliptin 7-10%, diluent 60-70%, binder 0.5-2% and lubricant 0.5-10%) can be prepared by the methods mentioned below. The percentages are so adjusted that, the total weight of the composition is between 215 mg to 600 mg.

Teneligliptin granules can be prepared by mixing teneligliptin and pharmaceutically acceptable excipients; adding a binder solution to the mixture of teneligliptin and pharmaceutically acceptable excipients and drying the wet mixture of teneligliptin and pharmaceutically acceptable excipients followed by sieving to form granules. Alternatively, after mixing teneligliptin and

pharmaceutically acceptable excipients a binder solution can be sprayed on the mixture in a fluidized bed-processor followed by drying of the wet granules and subsequent optional sieving. As another alternative, teneligliptin flakes can be prepared by dry mixing teneligliptin and pharmaceutically acceptable excipients to form a blend; roll-compacting the blend one or more times to form flakes followed by granulating and sieving the flakes. The teneligliptin granules or flakes can be lubricated with any of the lubricants mentioned above. This mixture can then be punched in a tabletting machine or can be filled into capsules by a capsule-filling machine. Optionally, a coating can be applied to the tablet. The coating solution or suspension contains excipients like hypromellose, polyethylene glycol, colorant such as red or yellow iron oxide, titanium dioxide and talc. These tablets can be alternatively, filled into capsules of suitable size. The capsule volume can be suitably selected, ranging from 0.13- 1.37 ml to accommodate the teneligliptin containing lubricated blend or tablets.

In an alternative, a direct compression process for producing teneligliptin tablets is also contemplated by the invention. The tablets are prepared by mixing teneligliptin with one or more pharmaceutically acceptable excipients to prepare a blend for direct compression; compressing the blend of to form a tablet; optionally a coating can be applied to the tablet, as described above.

In an embodiment, the invention also relates to teneligliptin pharmaceutical composition comprising teneligliptin containing granules and a pharmaceutically acceptable excipient, wherein the percentage ratio of teneligliptin in the granules to teneligliptin in the total composition is greater than ten times wherein

thecomposition can quantitatively contain teneligliptin 1.5-15%, diluent 1-80%, binder 0.1-10% and lubricant 0.5-30%, more preferably Teneligliptin 7-10%, diluent 50-70%, binder 0.5-5% and lubricant 0.5-10%> and can be prepared by the methods mentioned above.

Teneligliptin can be formulated with metformin in a single dosage form. The content of metformin or salt thereof can be suitably selected so as to deliver a dose of metformin in the range of 1 -2000 mg, preferably 250-1000 mg. Such a pharmaceutical composition contains teneligliptin and metformin in separate portions. For example, a multi-layered composition containing teneligliptin and metformin in separate layers of a bi- or tri-layered tablet; a composition containing metformin in the core and teneligliptin in the coating and other similar variants thereof. Such a composition can quantitatively contain Teneligliptin 1.5-5%, diluent 1-50%, binder 0.1-10%) and lubricant 0.1-30%), preferably Teneligliptin 1.5-25%, diluent 1-20%, binder 0.1-3% and lubricant 0.1-25%. Suitable diluents, binders and lubricants can be selected as described above.

Such teneligliptin and metformin compositions can be prepared by a process comprising the steps of- granulating teneligliptin with pharmaceutically acceptable excipients; lubricating the teneligliptin granules with a lubricant to form a lubricated teneligliptin blend; granulating metformin with pharmaceutically acceptable excipients; lubricating the metformin granules with a lubricant to form a lubricated metformin blend; compressing the teneligliptin blend and metformin blend to form a bilayer tablet or filling the blend into capsules. Alternatively, multi-layered tablets can be prepared by introducing, in addition to the teneligliptin blend and metformin blend, a blend of pharmaceutically acceptable excipients, at the compression stage of the above process. Also, the teneligliptin granules used in the above process can be alternatively prepared by methods, mentioned earlier. In the alternative, teneligliptin and metformin compositions can be prepared by a process comprising the steps of granulating metformin with pharmaceutically acceptable excipients; lubricating the metformin granules with a lubricant to form a lubricated metformin blend; compressing the metformin blend to form a core; preparing a teneligliptin containing polymer solution or suspension; coating the core of metformin with the teneligliptin containing polymer solution or suspension. Such a composition can quantitatively contain Teneligliptin 1.5-10%), diluent 1-80%, binder 0.1-10%) and lubricant 0.1-30%), preferably, Teneligliptin 1.5-2.5%, diluent 1-20%, binder 0.1-3% and lubricant 1-25%. The percentages are so adjusted that the intragranular content of teneligliptin is more than ten times that of teneligliptin in the finished composition. The suitable diluents, binders and lubricants can be selected as described above. In a separate embodiment the pharmaceutical composition of the present invention may be useful in treatment or prophylaxis of diabetes, obesity, HIV infection, cancer metastasis, dermopathy, prostatic hyperplasia, periodontitis, autoimmune disease and the like.

In a separate embodiment, the present invention provides 3-{(2S, 4S)-4-[4- (3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]-2-pyrrolidinylcarbonyl}-l,3- thiazolidine tnfluoroacetate salt.

In one embodiment step a may be carried out in a solvent selected from the group consisting of dichloromethane or ethylene dichloride or chloroform.

In one embodiment, the present invention provides crystalline 3-{(2S, 4S)- 1 -tert-Butoxycarbonyl-4-[4-(3-methyl- 1 -phenyl-lH-pyrazol-5-yl) piperazin- 1 -yl] pyrrolidin-2-yl-carbonyl}thiazolidine characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 21.15, 20.35, 17.14, 16.80, 11.96 ±0.2 degrees 2 theta.

In one embodiment, the present invention provides crystalline 3-{(2S, 4S)- 1 -tert-Butoxycarbonyl-4-[4-(3-methyl- 1 -phenyl-lH-pyrazol-5-yl) piperazin- 1 -yl] pyrrolidin-2-yl-carbonyl}thiazolidine characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 21.15, 20.35, 17.14, 16.80, 11.96 ±0.2 degrees 2 theta and having DSC of 248 ±2°C.

Advantageously, when crystalline 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4- (3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin- 1 -yl] pyrrolidin-2-yl- carbonyl}thiazolidine is used as a starting material for the synthesis of teneligliptin 2.5 hydrobromide or a hydrate thereof, the product is obtained in high yield and purity as compared to the use of non crystalline form of the starting material.

In one embodiment, the base in step b may be selected from an organic base or inorganic base.

A suitable base may be selected from organic or an inorganic base. The inorganic base may be selected from, but is not limited to hydroxides such as sodium hydroxide, potassium hydroxide; carbonates such as sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate, hydrides such as sodium hydride, alkoxides such as sodium methoxide, potassium methoxide, potassium tert-butoxide; while the organic base may be selected from, but is not limited to triethyl amine, trimethyl amine, pyridine, diisopropyl amine and dimethyl amino pyridine.

In one embodiment, in step b the product obtained after treatment with a base may be isolated and treated with hydrobromic acid, optionally in presence of a solvent.

In one embodiment, in step b the product obtained after treatment with a base may be isolated as a residue and then treated with hydrobromic acid, optionally in presence of a solvent.

In one embodiment, in step b the product obtained after treatment with a base may not be isolated before treatment with hydrobromic acid.

In one embodiment, in step b after treatment with base hydrobromic acid or hydrobromic acid in acetic acid is used.

In one embodiment the present invention provides a process for the preparation of 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]-2- pyrrolidinylcarbonyl}-l-,3-thiazolidine 2.5 hydrobromide or a hydrate thereof comprising;

a. deprotecting 3-{(2S,4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-l- phenyl-lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with hydrochloric acid to form teneligliptin hydrochloride; and

b. reacting the teneligliptin hydrochloride with a base followed by treatment with hydrobromic acid.

In one embodiment, the hydrochloride obtained is 2, 2.5 or 3 hydrochloride of teneligliptin.

b. reacting the 2.5 hydrochloride of teneligliptin with a base followed by treatment with hydrobromic acid. In one embodiment the 2.5 HC1 was obtained by deprotecting 3-{(2S, 4S)- 1 -tert-Butoxycarbonyl -4- [4-(3 -methyl- 1 -phenyl -lH-pyrazol-5-yl) piperazin- 1 - yl]pyrrolidin-2-yl-carbonyl}thiazolidine with hydrochloric acid in a solvent selected from the group consisting of isopropyl alcohol, tert-butanol, n- butanol, methanol or mixture thereof.

In one embodiment the present invention provides a process for the preparation of teneligliptin comprising

a. deprotecting 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-l- phenyl-lH-pyrazol-5-yl) piperazin- l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine with an acid to form an acid addition salt of teneligliptin; and

b. reacting the acid addition salt of teneligliptin with a base.

In one embodiment, teneligliptin is dissolved in a mixture of methanol and tertiary butanol. In one embodiment, the present invention provides a process for the preparation of teneligliptin 2.5 hydrobromide hydrate comprising crystallising teneligliptin 2.5 hydrobromide hydrate from a solvent selected from the group consisting of methanol, n-butanol, tertiary butanol, propyl acetate, isopropyl acetate, butyl acetate, ethers such as diethyl ether, tetrahydrofuran,

Preferably, the solvent is methanol or a mixture of a methanol and tertiary-butanol. The compounds were characterized and analyzed by following techniques Proton NMR spectra was recorded in DMSO-d6 using NMR instrument- Varian 300 MHZ.

Instrumental settings for XRPD: The measurements were performed on Philips X-Ray Diffractometer model XPERT-PRO (PANalytical) Detector:

X'celerator [1] using Cu lamp with type and wavelength of the X-ray radiation: K- <xl 1.54060[A], K-o2 1.5444[A]

Instrumental settings for DSC: The DSC thermogram was measured by a Differential Scanning Calorimeter (DSC 822, Mettler Toledo).

Instrumental settings for TGA: Instrument Name: TGA Q 500; C.

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

EXAMPLES

Example 1: Pharmaceutical composition comprising Teneligliptin

Titanium Dioxide and Yellow iron oxide

TG/TW = 1.15

TG/TW = % intragranular teneligliptin ÷ % teneligliptin in finished dosage form Manufacturing process:

Teneligliptin hydrobromide hydrate was geometrically mixed with maize starch and sifted through sieve no. 40. This blend was further mixed with microcrystalline cellulose and blend of microcrystalline cellulose and ferric oxide yellow in a rapid mixer granulator. Binder solution was prepared by dissolving hydroxypropyl cellulose under stirring, in purified water. This binder solution was added to the mixture in the rapid mixer granulator. The granular mass was air dried for 5 to 10 minutes and further dried at 45°C to 55°C for 5 to 10 minutes and passed through sieve No. 10. Dry granules were sifted through sieve no. 30 using vibratory sifter. In a clean dry blender, the dried granules were mixed with 1- hydroxy propyl cellulose, colloidal silicon dioxide and magnesium stearate. These lubricated granules were compressed to form tablets in a tabletting machine. The tablets were coated with opadry yellow dispersion in a coating pan.

Dissolution studies were performed for three batches of teneligliptin tablets 1A, IB and 1C prepared according to example 1. The results are shown in Table 1.

Dissolution method for Teneligliptin 20 mg (By HPLC)

Dissolution conditions:

Table 1 - Dissolution studies of batches 1A, IB and 1C

Batch No. % of Teneligliptin dissolved in 45 minutes

Initial 3 months at 30°C/75% 6 months at 30°C/75%

RH RH

1A 100.5 98.9 97.3 IB 100.5 100.0 97.7

1C 100.5 99.7 98.3

Example 2: Pharmaceutical composition comprising Teneligliptin

TG/TW = 1.15

Manufacturing process:

Teneligliptin hydrobromide hydrate, microcrystalline cellulose, maize starch and ferric oxide yellow were sifted through 40 sieve twice. All sifted material was loaded in to a clean & dried bowl of fluid bed processor with top spray and the blend was pre-heated. Hydroxypropylcellulose was dissolved in purified water to prepare a binder solution. The blend was sprayed with binder solution to obtain granules. The granules were dried at an inlet temperature of 60 to 65°C until loss-on-drying is achieved below 3.5%w/w and then, sifted through 20 sieve using vibratory sifter. These granules were blended with sifted L-hydroxy propyl cellulose and colloidal silicon dioxide and mixed. Sifted magnesium stearate was added and mixed for additional 2 minutes. This lubricated blend was compressed in a tabletting machine. The tablets were coated with opadry yellow dispersion in a coating pan. Example 3: Pharmaceutical composition comprising Teneligliptin

TG/TW= 1.14

Manufacturing process:

Teneligliptin hydrobromide hydrate, microcrystalline cellulose, maize starch, hydroxypropylcellulose and ferric oxide yellow were sifted through 40 sieve twice. All sifted material was loaded in a clean and dry blender and mixed for 10 minutes. Magnesium stearate was added and mix for additional 2 minutes. The blend was passed through roller compactor. The roller speed and feeder speed were adjusted to get the desired flakes. These flakes were passed through oscillating granulator using 10, 14 and finally 20 sieve. These granules were blended with sifted L-hydroxy propyl cellulose and colloidal silicon dioxide and mixed. Sifted magnesium stearate was added and mixed for additional 2 minutes. This lubricated blend was compressed in a tabletting machine. The tablets were coated with opadry yellow dispersion in a coating pan.

Example 4: Pharmaceutical composition comprising Teneligliptin S.No Ingredients mg/tablet % w/w

1) Teneligliptin hydrobromide hydrate 31.3 8.7

2) Microcrystalline cellulose 233.3 64.8

3) Maize starch 46 12.8

4) Ferric oxide yellow 0.4 0.1

5) Hydroxy propyl cellulose 3 0.8

6) L-hydroxypropyl cellulose 32.5 9.0

7) Colloidal silicon dioxide 1.75 0.5

8) Magnesium stearate 1.75 0.5

9) Opadry Yellow 06B 82444 10 2.8

Total weight 360 100

Manufacturing process:

Teneligliptin hydrobromide hydrate, microcrystalline cellulose,

hydroxypropyl cellulose, L-hydroxypropyl cellulose and colloidal silicon dioxide were sifted through 40 sieve twice. Ferric oxide yellow and starch were separately sifted through 80 sieve. All sifted material was loaded in a clean and dry blender and mixed for 13 minutes. Magnesium stearate was added and mixed for additional 2 minutes. This lubricated blend was compressed in a tabletting machine. The tablets were coated with opadry yellow dispersion in a coating pan.

Example 5: Pharmaceutical composition comprising Teneligliptin

S.No Ingredients mg/tablet % w/w

1) Teneligliptin hydrobromide hydrate 31.30 8.69

2) Lactose monohydrate 233.3 64.8

3) Maize starch 46 12.8

4) Ferric oxide yellow 0.4 0.1

5) Hydroxypropyl cellulose 3 0.8

6) Purified water 0

7) L-hydroxypropyl cellulose 32.5 9.0 S.No Ingredients mg/tablet % w/w

8) Colloidal silicon dioxide 1.75 0.5

9) Magnesium stearate 1.75 0.5

10) Opadry Yellow 06B 82444 10 2.8

Total weight 360

TG/TW= 1.15

Manufacturing process:

Teneligliptin hydrobromide hydrate was geometrically mixed with maize Starch and sifted through sieve no. 40. This blend was further mixed with lactose and blend of lactose and ferric oxide yellow in a rapid mixer granulator. Binder solution was prepared by dissolving hydroxypropylcellulose under stirring, in purified water. This binder solution was added to the mixture in the rapid mixer granulator. The granular mass was air dried for 5 to 10 minutes and further dried at 45°C to 55°C for 5 to 10 minutes and passed through sieve no. 10. Dry granules were sifted through sieve no. 30 using vibratory sifter. In a clean dry blender, the dried granules were mixed with 1-hydroxypropyl cellulose, colloidal silicon dioxide and magnesium stearate. These lubricated granules were compressed to form tablets in a tabletting machine. The tablets were coated with opadry yellow dispersion in a coating pan.

Example 6: Pharmaceutical composition comprising Teneligliptin

S.No Ingredients mg/tablet % w/w

1) Teneligliptin hydrobromide hydrate 31.30 8.69

2) Microcrystalline cellulose 46 12.8

3) Maize starch 233.3 64.8

4) Ferric oxide yellow 0.4 0.1

5) Hydroxypropyl cellulose 3 0.8

6) L-hydroxypropyl cellulose 32.5 9.0

7) Colloidal silicon dioxide 1.75 0.5 S.No Ingredients mg/tablet % w/w

8) Magnesium stearate 1.75 0.5

9) Opadry Yellow 06B 82444 10 2.8

Total weight 360 100

TG/TW= 1.15

Manufacturing process:

Teneligliptin hydrobromide hydrate was geometrically mixed with microcrystalline cellulose and sifted through sieve no. 40. This blend was further mixed with maize starch and blend of maize starch and ferric oxide yellow in a rapid mixer granulator. Binder solution was prepared by dissolving hydroxypropyl cellulose under stirring, in purified water. This binder solution was added to the mixture in the rapid mixer granulator. The granular mass was air dried for 5 to 10 minutes and further dried at 45°C to 55°C for 5 to 10 minutes and passed through sieve no. 10. Dry granules were sifted through sieve no. 30 using vibratory sifter. In a clean dry blender, the dried granules were mixed with 1-hydroxy propyl cellulose, colloidal silicon dioxide and magnesium stearate. These lubricated granules were compressed to form tablets in a tabletting machine. The tablets were coated with opadry yellow dispersion in a coating pan.

Example 7: Pharmaceutical composition comprising Teneligliptin

S.No Ingredients mg/tablet % w/w

1) Teneligliptin hydrobromide hydrate 31.3 8.5

2) Microcrystalline cellulose 233 63.1

3) Maize starch 46 12.4

4) Ferric oxide yellow 0.4 0.1

5) Hydroxy propyl cellulose (Klucel LF) 3 0.8

6) L-hydroxypropyl cellulose 32.5 8.8

7) Colloidal silicon dioxide 1.75 0.5

8) Magnesium stearate 1.75 0.5 S.No Ingredients mg/tablet % w/w

9) Opadry Yellow 06B 82444 20 5.4

Total weight 370 100

TG/TW= 1.2

Manufacturing process:

Example 8: Pharmaceutical composition comprising Teneligliptin and Metformin

S.No Ingredients mg/tablet % w/w

1) Teneligliptin hydrobromide hydrate 31.3 2.0

2) Microcrystalline cellulose 68 4.3

3) Maize starch 35 2.2

4) Ferric oxide yellow 0.2 0.0

5) Hydroxy propyl cellulose 0.5 0.0

6) Microcrystalline cellulose 178.8 11.4

7) Ferric oxide yellow 0.2 0.0

8) L-hydroxypropyl cellulose 32.5 2.1 S.No Ingredients mg/tablet % w/w

9) Colloidal silicon dioxide 1.75 0.1

10) Magnesium stearate 1.75 0.1

11) Metformin hydrochloride 1000 63.5

12) Carboxymethylcellulose sodium 60 3.8

13) Hydroxy propyl methyl cellulose 140 8.9

14) Hydroxy propyl methyl cellulose 5 cps 10 0.6

15) Maize Starch 10 0.6

16) Magnesium Stearate 5 0.3

Total weight 1575

TG/TW= 11.67

Manufacturing process:

Teneligliptin hydrobromide hydrate was geometrically mixed with maize starch and sifted through sieve no. 40. This blend was further mixed with a blend of microcrystalline cellulose and ferric oxide yellow in a rapid mixer granulator. Binder solution was prepared by dissolving hydroxypropyl cellulose under stirring, in purified water. This binder solution was added to the mixture in the rapid mixer granulator. The granular mass was air dried for 10 to 20 minutes and further dried at 55°C to 65°C till loss on drying is below 3.5%w/w. Dry granules were sifted through sieve no. 40, using vibratory sifter. In a clean dry blender, the sifted granules were mixed with the following excipients pre-sifted through sieve no. 40 - microcrystalline cellulose, 1-hydroxypropylcellulose and colloidal silicon dioxide. Subsequently, magnesium stearate sifted through sieve40 is mixed with this blend to form a teneligliptin blend.

Metformin hydrochloride and carboxymethylcellulose sodium were mixed in a clean dry bowl of rapid mixer granulator. Purified water was added and mixed to form a wet granular mass. The wet granular mass was unloaded in a fluid-bed drier bowl and granules were semi -dried at an inlet temperature of 50°C to 60°C for 5 to 15 minutes. The semidried granules were passed through sieve no. 8.

Subsequently, the granules were dried at an inlet temperature of 50°C to 60°C until loss on drying is achieved between 2.5 to 3.5 % w/w. The dried granules were passed through sieve no.16 using vibratory sifter. These dried granules were mixed with the following excipients pre-sifted through Sieve no. 40- hydroxypropylmethyl cellulose (Methocel K 100 Premium), hydroxypropyl methyl cellulose (Methocel E 5 Premium), Maize Starch. Subsequently, magnesium stearate sifted through sieve no. 40 is mixed with this blend to form a metformin blend.

Using a bilayer compression machine, the teneligliptin and metformin blends were compressed to form a bilayer tablet. The dimensions of the tablets were- a) length: 20.70mm to 21.10 mm, b) width: 10.70mm to 11.10mm and c) thickness: 7.50mm to 8.10mm.

Dissolution studies were performed for three batches of teneligliptin and metformin tablets 8 A, 8B and 8C prepared according to example 8. The results are shown in Table 2.

Dissolution method for Teneligliptin 20 mg and Metformin HC1 ER 1000 mg tablets a) Dissolution of Teneligliptin (By HPLC)

Dissolution conditions:

Table 2 - Dissolution studies of batches 8 A, 8B and 8C

Batch No. % of Teneligliptin dissolved in 45 minutes

Initial 3 months at 30°C/75% 6 months at 30°C/75% RH

RH

8A 99.6 98.3 97.4 8B 99.6 98.4 97.3

8C 98.5 97.9 97.3

Example 9: Pharmaceutical composition comprising Teneligliptin and Metformin

TG/TW= 11.71

Manufacturing process:

Teneligliptin hydrobromide hydrate, microcrystalline cellulose, maize starch and ferric oxide yellow were twice sifted through sieve no. 40. All the sifted material was loaded in to a clean & dried bowl of a fluid bed processor (Top spray) and preheated. Binder solution was prepared by dissolving hydroxypropyl cellulose in purified water. This solution was sprayed on the sifted material in the fluid bed processor to obtain granules. The granules were dried at an inlet temperature of 60 to 65°C until loss on drying is below 3.5 to 7% w/w. The dry granules were sifted through sieve no. 40 using vibratory sifter. Microcrystalline cellulose, ferric oxide yellow, L- hydroxypropyl cellulose and colloidal silicon dioxide were simultaneously sifted twice through sieve no. 40 and mixed with the dry granules to form a blend. Magnesium stearate was sifted through sieve no. 40 and mixed with the blend to form lubricated teneligliptin blend.

Metformin hydrochloride and carboxymethylcellulose sodium were mixed in a clean dry bowl of rapid mixer granulator. Purified water was added and mixed to form a wet granular mass. The wet granular mass was unloaded in a fluid-bed drier bowl and granules were semi -dried at an inlet temperature of 50°C to 60°C for 5 to 15 minutes. The semi-dried granules were passed through sieve no. 8. Subsequently, the granules were dried at an inlet temperature of 50°C to 60°C until loss on drying is achieved between 2.5 to 3.5 % w/w. The dried granules were passed through sieve no.16 using vibratory sifter. These dried granules were mixed with the following excipients pre-sifted through sieve no. 40 - hydroxypropyl methylcellulose (Methocel K100 Premium), hydroxypropyl methylcellulose (Methocel E5 Premium), and maize starch. Subsequently, magnesium stearate sifted through sieve no. 40 is mixed with this blend to form a metformin blend.

Using a bilayer compression machine, the teneligliptin and metformin blends were compressed to form a bilayer tablet.

Example 10: Pharmaceutical composition comprising Teneligliptin and

Metformin

S.No Ingredients mg/tablet % w/w

1) Teneligliptin hydrobromide hydrate 31.3 1.98

2) Microcrystalline cellulose 68 4.317

3) Maize starch 35 2.222

4) Ferric oxide yellow 0.2 0.012

5) Magnesium stearate 0.5 0.317

6) Microcrystalline cellulose 178.8 11.352 S.No Ingredients mg/tablet % w/w

7) Ferric oxide yellow 0.2 0.012

8) L-hydroxypropyl cellulose 32.5 2.063

9) Colloidal silicon dioxide 1.75 0.111

10) Magnesium stearate 1.25 0.079

11) Metformin hydrochloride 1000 63.492

12) Carboxymethylcellulose sodium 60 3.8095

13) Hydroxypropyl methylcellulose 140 8.888

14) Hydroxypropyl methylcellulose 5 cps 10 0.634

15) Maize starch 10 0.634

16) Magnesium stearate 5 0.317

Total weight 1575

TG/TW= 11.7

Manufacturing process:

Teneligliptin hydrobromide hydrate, microcrystalline cellulose, maize starch, hydroxypropylcellulose and ferric oxide yellow were sifted through sieve no. 40 twice. All the sifted material was loaded in a clean and dry blender and mixed for 10 minutes, and then magnesium stearate was added and mixed for additional 2 minutes. This blend was passed through a roller compactor. The roller speed and feeder speed was adjusted to get the desired flakes. The flakes were passed through oscillating granulator using sieves 10, 14, 20 and finally 40.

Microcrystalline cellulose, ferric oxide yellow, 1- hydroxypropylcellulose and colloidal silicon dioxide sifted through sieve no. 40 twice, were added to this material to form a blend. Magnesium stearate was sifted through sieve no. 40 sieve and added to prepare a teneligliptin blend.

Metformin hydrochloride and carboxymethyl cellulose sodium were mixed in a clean dry bowl of rapid mixer granulator. Purified water was added and mixed to form a wet granular mass. The wet granular mass was unloaded in a fluid-bed drier bowl and granules were semi -dried at an inlet temperature of 50°C to 60°C for 5 to 15 minutes. The semi-dried granules were passed through sieve no. 8. Subsequently, the granules were dried at an inlet temperature of 50°C to 60°C until loss on drying is achieved between 2.5 to 3.5 % w/w. The dried granules were passed through sieve no.16 using vibratory sifter. These dried granules were mixed with the following excipients pre-sifted through Sieve no. 40- hydroxypropyl methylcellulose (Methocel K100 Premium), hydroxypropyl methylcellulose (Methocel E5 Premium), and maize starch. Subsequently, magnesium stearate sifted through sieve no. 40 is mixed with this blend to form a metformin blend.

Example 11: Pharmaceutical composition comprising Teneligliptin and

Metformin

Manufacturing process: Teneligliptin hydrobromide hydrate, microcrystalline cellulose (Avicel PH101), hydroxypropylcellulose, microcrystalline cellulose (Avicel PH102), L- hydroxypropylcellulose (L-HPC Type 11) and colloidal silicon dioxide were sifted through sieve no. 40, twice. Ferric oxide yellow along with maize starch was sifted through sieve no. 80. All sifted material was loaded in a clean and dry blender and mixed for 13 minutes. Magnesium stearate was added and mixed for additional 2 minutes.

Subsequently, the granules were dried at an inlet temperature of 50°C to 60°C until loss on drying is achieved between 2.5 to 3.5 % w/w. The dried granules were passed through sieve no.16 using vibratory sifter. These dried granules were mixed with the following excipients pre-sifted through Sieve no. 40- hydroxypropyl methylcellulose (Methocel K 100 Premium), hydroxypropyl methyl cellulose (Methocel E 5 Premium), Maize Starch. Subsequently, magnesium stearate sifted through sieve no. 40 is mixed with this blend to form a metformin blend.

Example 12: Pharmaceutical composition comprising Teneligliptin and

Metformin

S.No Ingredients mg/tablet % w/w

1) Metformin hydrochloride 1000 77.9

2) Carboxymethylcellulose Sodium 60 4.7

3) Hydroxypropyl methylcellulose 140 10.9

4) Hydroxypropyl methylcellulose 5 cps 10 0.8

5) Maize starch 10 0.8

6) Magnesium stearate 5 0.4 S.No Ingredients mg/tablet % w/w

7) Teneligliptin hydrobromide hydrate 31.3 2.4

8) Hydroxy propyl methyl cellulose 15 cps 18 1.4

9) Polyethylene glycol 6000 1.7 0.1

10) Titanium dioxide 8 0.6

Total Weight 1284 100

Manufacturing process:

Metformin hydrochloride and carboxymethylcellulose sodium were mixed in a clean dry bowl of rapid mixer granulator. Purified water was added and mixed to form a wet granular mass. The wet granular mass was unloaded in a fluid-bed drier bowl and granules were semi -dried at an inlet temperature of 50°C to 60°C for 5 to 15 minutes. The semi-dried granules were passed through sieve no. 8. Subsequently, the granules were dried at an inlet temperature of 50°C to 60°C until loss on drying is achieved between 2.5 to 3.5 % w/w. The dried granules were passed through sieve no.16 using vibratory sifter. These dried granules were mixed with the following excipients pre-sifted through Sieve no. 40- hydroxypropyl methylcellulose (Methocel K100 Premium), hydroxypropyl methyl cellulose (Methocel E5 Premium), and maize starch. Subsequently, magnesium stearate sifted through sieve no. 40 is mixed with this blend to form a metformin blend. This blend was fed into a tabletting machine to prepare metformin tablets.

In a separate stainless steel vessel, polyethylene glycol 6000 and hydroxypropyl methylcellulose 15 cps were dissolved in purified water under stirring to prepare a polymer solution. In a separate stainless steel vessel, titanium dioxide was dispersed under stirring in purified water and homogenized for 15 minutes, and subsequently filtered through 200# nylon cloth. In another stainless steel vessel, teneligliptin hydrobromide hydrate was dissolved in purified water. To this solution; the polymer solution and titanium dioxide dispersion were added and stirred for 15 minutes to obtain a coating solution.

The metformin tablets were placed in a coating pan and coated with this coating solution. Example 13: Pharmaceutical composition comprising Teneligliptin

Microcrystalline cellulose and ferric oxide yellow were sifted through sieve no.60 using a vibratory sifter. Similarly, teneligliptin, maize starch and

microcrystalline cellulose were sifted separately. In a stainless steel bowl, teneligliptin was geometrically mixed with maize starch. Subsequently the sifted microcrystalline cellulose was added to this mixture and blended. This mixture was placed in a dry bowl of a rapid mixer granulator and mixed slowly. In a stainless steel vessel, hydroxypropyl cellulose was dissolved in purified water, to form a binder solution. This binder solution was added to the mixture in the rapid mixer granulator in small aliquots. The granular mass thus formed, was dried in the fluid bed dryer bowl for 5-10 minutes. The semi -dried mass was passed through sieve no. 10 and dried at 55-65 °C. The dried granules were sifted through sieve no. 30 using vibratory sifter. L-hydroxypropyl cellulose and colloidal silicon dioxide were sifted through sieve no.40 using a vibratory sifter and blended with the dried granules in a dry blender. These granules were then compressed into tablets. These tablets were then coated in a coating pan with opadry yellow. The final tablets had a length of 10 to 10.3 mm and thickness of 4 to 4.5 mm. Example 14: Pharmaceutical composition comprising teneligliptin and metformin

TG/TW = 11.6

Manufacturing process:

Teneligliptin hydrobromide hydrate was mixed with maize starch and microcrystalline cellulose sifted through sieve no. 40. This blend was further mixed with a blend of starch and ferric oxide yellow in a rapid mixer granulator. Binder solution was prepared by dissolving hydroxypropyl cellulose under stirring, in purified water. This binder solution was added to the mixture in the rapid mixer granulator. The granular mass was air dried for 10 to 20 minutes and further dried at 55°C to 65°C till loss on drying is below 3.5%w/w. Dry granules were sifted through sieve no. 40 using vibratory sifter. In a clean dry blender, the sifted granules were mixed with the following excipients pre-sifted through sieve no. 40- microcrystalline cellulose, ferric oxide yellow, 1-hydroxypropylcellulose and colloidal silicon dioxide. Subsequently, magnesium stearate sifted through sieve no. 40 is mixed with this blend to form a teneligliptin blend.

Metformin hydrochloride and carboxymethylcellulose sodium were sifted through screens of 0.5 mm and sieve no.40 respectively and mixed in a clean dry bowl of rapid mixer granulator. Purified water was added and mixed to form a wet granular mass. The wet granular mass was unloaded in a fluid-bed drier bowl and granules were semi-dried at an inlet temperature of 50°C to 60°C for 5 to 15 minutes until loss on drying is achieved between 2.5 to 3.5 % w/w. The dried granules were passed through sieve no. 16 using vibratory sifter. These dried granules were mixed with the following excipients pre-sifted through Sieve no. 40- hydroxypropylmethylcellulose (Methocel K 100 Premium), hydroxypropyl methyl cellulose (Methocel E5), maize starch. Subsequently, magnesium stearate sifted through sieve no. 60 is mixed with this blend to form a metformin blend. Using a bilayer compression machine, the teneligliptin and metformin blends were compressed to form a bilayer tablet. The final tablets had a length of 20.7 to 21.1 mm and thickness of 7.5 to 8.1 mm.

Example 15: 3-((2S,4S)- )-l-teri-Butoxycarbonyl-4-[4-(3-methyl-l-phenyl-lH- pyrazol-5- yl) piperazin-l-yl] pyrrolidin-2-ylcarbonyl) thiazolidine

To a stirred solution of tert-butyl (2,S)-2-(l,3-thiazolidin-3- ylcarbonyl)pyrrolidine-l-carboxylate (10.0 g) and 1 -(3 -methyl- 1 -phenyl- 1H- pyrazol-5-yl) piperazine (8.63 g) in dichloromethane (50.0 mL), acetic acid (2.20 g) and sodium triacetoxy borohydride (14.10 g) were added at 25-30 °C. The reaction mixture was stirred for 4-5 h at same temperature. The reaction was quenched with water and extracted with dichloromethane. The combined organic layer was washed with water, brine and dried. The solvent was evaporated & co- distilled with methanol under reduced pressure at 40 °C. To this was added methanol and stirred and the solution obtained was added to water at 25-30°C, and the precipitated solid was stirred. The solid was filtered and washed with water to obtain title compound (8.75 g). HPLC: (98.71%); DSC: 248.45 °C; TGA: 9.85 %.

Table 1 : XRD of 3-((2S,4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-l-phenyl-lH- pyrazol-5- yl) piperazin-l-yl] pyrrolidin-2-ylcarbonyl) thiazolidine

Example 16: Teneligliptin Hemipenta Hydrobromide To a stirred solution of Example 15 (1.50 g) in isopropyl alcohol (14.0 mL) dropwise aq. hydrobromic acid (1.10 mL) was added at 70-75 °C and the resulting mixture was stirred for 1 h at same temperature. The reaction mixture was cooled to room temperature and further stirred for 6 h at 25-30 °C. The precipitate thus obtained was filtered and washed with isopropyl alcohol. The solid was dried under reduced pressure at 50-55 °C to afford Teneligliptin hemipenta

hydrobromide (1.50 g). HPLC (100.00 %). Example 17: 3- {(2S,4S)-4- [4-(3-Methyl- l-phenyl-5-pyrazolyl)- 1-piperazinyl] - 2-pyrrolidinyl carbonyl}-l-,3-thiazolidine hydrochloride salt

To a stirred solution of 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3 -methyl- 1- phenyl-lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine compound (5.0 g) in IPA (50.0 mL) 35 % aqueous hydrochloric acid (3.5 mL) was added at room temperature and the resulting mixture was stirred for 4 h at 80 °C. The reaction was cooled to room temperature and further stirred for 3-4 h at same temperature. The precipitate was filtered, washed with IPA and dried under reduced pressure at 45-50 °C to obtain the title compound as a solid (4.1 g). 1H- MR (300MHz, DMSO-d⁶): δ 12.37(brs, 1H), 10.99 (brs, 1H), 9.122 (brs, 1H), 7.79-7.76 (d, 2H), 7.48-7.43(t, 2H), 7.32-7.29(t, 1H), 5.92 (s, 1H), 4.74-4.44 (m, 3H), 4.05 (m, 1H), 3.86-3.66 (m, 5H), 3.34 (m, 4H), 3.11-2.96 (m, 7H), 2.15 (s, 3H). HPLC: 99.8 %; DSC: 191.76°; TGA: 10.36 % w/w (calculated upto 150°C); HC1 content: 17.9 % ; Water content: 7.1 %; SOR: -28.9°

XRD

Pos[° 2 Relative Pos[°2 Relative Pos[°2 Relative theta] Intensity[%] theta] Intensity[%] theta] Intensity[%]

5.56 27.50 22.85 82.41 34.19 17.40

8.91 2.86 23.12 75.26 34.58 7.96

11.05 21.06 23.48 37.83 35.05 6.17

11.48 9.64 23.70 12.77 35.32 6.59

12.14 2.40 23.93 12.99 35.88 8.19

13.76 25.36 24.26 10.22 36.31 6.61

14.10 15.08 24.86 16.28 36.90 13.14

14.56 51.66 25.30 76.97 37.16 13.19

14.68 49.51 26.99 100.00 37.58 8.59

16.40 68.55 27.54 49.30 38.49 11.78

17.51 29.47 27.96 12.75 38.97 8.85

17.78 31.17 28.32 70.71 39.18 8.51

17.94 19.37 28.72 21.33 40.32 8.08 18.44 48.58 28.97 34.16 41.13 8.63

19.58 14.59 29.71 19.41 41.87 12.71

20.10 13.83 30.51 11.41 42.38 7.71

20.34 43.27 30.91 14.46 43.91 7.61

20.78 8.85 31.73 12.72 44.62 8.12

21.29 6.02 32.22 20.47 45.51 6.80

21.61 43.24 32.48 31.87 47.05 7.60

21.97 57.12 32.91 8.59 47.85 2.19

22.21 45.90 33.77 11.73 49.48 10.70

Example 18: 3- {(2S,4S)-4- [4-(3-Methyl- l-phenyl-5-pyrazolyl)- 1-piperazinyl] - 2-pyrrolidinyl carbonyl}-l-,3-thiazolidine hydrobromide hydrate

To a stirred mixture of 3-{(2S, 4S)-4-[4-(3-Methyl-l-phenyl-5-pyrazolyl)-l- piperazinyl]-2-pyrrolidinyl carbonyl}-l, 3-thiazolidine hydrochloride salt (2.0 g) in water and dichloromethane was added sodium bicarbonate till pH was 8-8.5 at room temperature. The compound was extracted with dichloromethane. The organic layer was dried and concentrated followed by co-distillation with IPA. To the residue obtained was added IPA followed by addition of 48% aqueous hydrobromic acid (1.26 mL) at 75-80 °C. The resulting mixture was stirred for 1 h and cooled to room temperature and further stirred for 3-4 h at room temperature and the precipitate was filtered, washed with IPA and dried. The solvent was distilled under reduced pressure to obtain the title compound as a solid (2.2 g). HPLC- 99.9 %; DSC - 204.5°; TGA - 5.15 % w/w (calculated up to 150°C); HBr content - 31.7 %; Water content - 5.56 %; SOR - -28.9°

Example 19: 3- {(2S,4S)-4- [4-(3-Methyl- l-phenyl-5-pyrazolyl)- 1-piperazinyl] - 2-pyrrolidinyl carbonyl}-l-,3-thiazolidine sulfate salt

To the stirred solution of 3-{(2S, 4S)-l-tert-butoxycarbonyl-4-[4-(3-methyl-l- phenyl-lH-pyrazol-5-yl) piperazin-l-yl]pyrrolidin-2-yl-carbonyl}thiazolidine hydrochloride (5.0 g) in IPA dilute sulfuric acid was added at room temperature. The resulting mixture was stirred for 4 h at 80 °C, cooled to room temperature and further stirred for 3-4 h at same temperature. The precipitate was filtered, washed with IPA and dried. The solvent was distilled under reduced pressure to give the title compound as a solid (5.5 g). ¹HNMR (300MHz, DMSO-d⁶): δ 9.79(brs, 1H), 9.08 (brs, 1H), 8.17 (brs, 5H), 7.76-7.74(d, 2H), 7.49-7.44(t, 2H), 7.33-7.28(t, 1H),

5.93 (s, 1H), 4.69-4.429 (m, 3H), 4.17-4.11 (m, 1H), 3.85-3.64 (m, 3H), 3.45-3.04 (m, 11H), 2.15 (s, 3H). HPLC- 99.7 %; DSC - 240.35°, 261.30°, 266.24°; TGA - 2.84 % w/w (calculated upto 150°C); H₂S0₄ content - 40.5 % (3.0 H₂S0₄ salt of Teneligliptin); Water content - 3.0 %; SOR - -29.7°

XRD Table

5.80 1.81 24.25 14.54 34.83 5.33

9.80 3.97 24.96 11.29 35.18 1.67

11.54 1.79 25.38 11.35 35.62 3.18

12.51 11.05 25.57 9.56 36.47 2.14

13.58 10.04 25.80 4.52 36.90 1.11

13.97 6.22 26.03 7.76 37.17 2.24

15.38 1.49 26.23 3.99 37.66 2.13

15.72 5.46 26.55 9.73 38.36 0.81

16.67 14.79 27.12 3.40 39.05 4.19

17.27 17.37 27.80 11.88 39.780 2.47

18.45 3.99 28.17 6.81 40.60 2.18

18.96 8.98 29.20 3.04 41.09 1.98

19.18 18.99 29.89 3.81 41.40 2.60

19.45 100.00 30.48 5.37 42.17 2.66

19.95 20.16 30.60 5.90 43.066 3.23

20.46 11.82 30.97 12.75 43.82 2.03

20.92 76.25 31.84 6.85 44.45 2.96

21.50 18.41 32.41 4.99 46.06 1.20 21.92 54.26 33.23 2.24 47.11 1.38

23.01 20.66 33.46 2.33 48.18 1.41

23.42 19.57 34.17 1.74 48.86 0.54

Example 20: 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]- 2-pyrrolidinyl carbonyl}-l-,3-thiazolidine hydrobromide hydrate

To a stirred mixture of 3-{(2S, 4S)-l-tert-butoxycarbonyl-4-[4-(3-methyl-l- phenyl- lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl-carbonyl} thiazolidine sulfate (3.0 g) in water and dichloromethane at room temperature, sodium bicarbonate was added till pH was 8-8.5. The compound was extracted with dichloromethane. The solvent was evaporated under reduced pressure with co- distillation by IPA. To the residue was added IPA followed by drop-wise addition of -48% aqueous hydrobromic acid (1.5 mL) at 75-80 °C. The resulting mixture was stirred for 1 h at 75- 80 °C and then cooled to room temperature. The solid was further stirred for 3-4 h at room temperature and the precipitate was filtered, washed with IPA and dried. The solvent was evaporated under reduced pressure at 45-50 °C to give the title compound as a solid (2.4 g). HPLC: 99.85 %; DSC: 204.9°; TGA: 5.3 % w/w (calculated up to 150 °C); HBr content: 31.3 %; Water content: 5.52 %; SOR: -29.7°

Example 21: 3-{(2S,4S)-4-[4-(3-Methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]- 2-pyrrolidinyl carbonyl}-l-,3-thiazolidine trifluoroacetate salt To a stirred solution of 3-{(2S, 4S)-l-tert-butoxycarbonyl-4-[4-(3-methyl-l- phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl-carbonyl}thiazolidine (5.0 g) in dichloromethane was added trifluoroacetic acid (10.0 mL) at room temperature and the resulting mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure. To the oily residue water and dichloromethane were added and the pH of reaction mixture was adjusted to 4.5-

5.0 by addition of sodium bicarbonate. The compound was extracted with dichloromethane. The solvent was removed by distillation. The residue was co- distilled by diethyl ether (25.0 mL) under reduced pressure. To the residue was added diethyl ether (50.0 mL) and stirred for 8 h at room temperature. The solid was filtered and dried at 50 °C to give the title compound as a solid (4.5 g).

1HNMR (300MHz, DMSO-d⁶): δ 9.17(brs, 1H), 7.73-7.70(d, 2H), 7.46-7.41(t, 2H), 7.28-7.24(t, 1H), 5.78 (s, 1H), 4.69-4.39 (m, 3H), 3.85-3.35 (m, 6H), 3.09- 3.02(m, 4H), 2.75-2.64 (m, 5H), 2.12 (s, 3H), 1.63-1.60 (m, 1H). HPLC: 98.98 %; DSC: 169.21°; TFA content: 22.0 % (It is equivalent to 1.0 TFA salt of

Teneligliptin); Water content: 1.49 %; SOR: -30.9°

XRD Table

Example 22: 3-{(2S,4S)-4-[4-(3-Methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]- 2-pyrrolidinyl carbonyl}-l-,3-thiazolidine hydrobromide hydrate.

To a stirred mixture of 3-{(2S, 4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-l- piperazinyl]-2-pyrrolidinyl carbonyl}-!, 3-thiazolidine trifluoroacetate salt (3.0 g) in water and dichloromethane, sodium bicarbonate was added at room temperature till pH was adjusted to 8.0 and the mixture was stirred. The compound was extracted with dichloromethane. The organic layer was dried and co-distilled with IPA below 45 °C. To the oily residue IPA was added followed by drop-wise addition of -48% aqueous hydrobromic acid (1.5 mL) at 75-80 °C and the mixture was stirred for 1 h at 75-80 °C. The reaction was cooled to room temperature and the solid was stirred for 3 h. The precipitate was collected by filtration, washed with IPA and dried under reduced pressure to give the title compound as a solid (3.1 g). HPLC: 99.83 %; Water content: 5.2 %; HBr content: 32.6 %; SOR: -30.5°.

Example 23: 3- {(2S,4S) -4- [4- (3-methyl-l-phenyl-5-pyrazolyl) -1- piperazinyl] -2-pyrrolidinyl carbonyl}-l,3-thiazolidine hydrochloride.

Cone. HC1 (27 mL) was added to a stirred solution of 3-{(2S, 4S)-l-tert- Butoxycarbonyl-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl-carbonyl} thiazolidine (40.0 g) in IPA at room temperature. The resultant reaction mixture was heated at 75 - 80 °C for 4 - 5 h. After completion of reaction, reaction mass was cooled to room temperature and maintained for 3 - 4 h. The precipitate was collected by filtration, washed with IPA and dried under reduced pressure to give title compound as a solid (33.0 gm).

Example 24: 3-{(2S, 4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]- 2-pyrrolidinyl carbonyl}-l,3-thiazolidine hydrobromide hydrate

Sodium bicarbonate was added to a stirred mixture of example 23 (1.0 g), water and dichloromethane till pH of aq. layer becomes 8 - 8.5. The aqueous layer was extracted with dichloromethane couple of times. The combined organic layer was evaporated under reduced pressure followed by co-distillation by methanol. To the residue was added methanol and then -48% aqueous hydrobromic acid (0.6 mL) slowly at 60-65 °C. The resulting mixture was stirred for 1 h at 60-65 °C and then allowed to cool to room temperature. To the mixture was added t-butanol and stirred the mass for 3 - 4 h. The precipitate was collected by filtration, washed with t-butanol and dried under reduced pressure to give title compound as solid (1.0 g).

Example 25: 3- {(2S,4S) -4- [4- (3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl] -2-pyrrolidinyl carbonyl}-l-,3-thiazolidine hydrochloride.

Title compound was prepared by following the method of analogues example 23 by using t-butanol instead of IP A

Example 26: 3- {(2S,4S) -4- [4- (3-methyl-l-phenyl-5-pyrazolyl) -1- piperazinyl] -2-pyrrolidinyl carbonyl}-l,3-thiazolidine sulfate.

Title compound was prepared by following the method of analogues example 19 by using t-butanol instead of IP A

Example 27: 3- {(2S,4S)-4- [4-(3-methyl- l-phenyl-5-pyrazolyl)- 1-piperazinyl] -2- pyrrolidinyl carbonyl}-l,3-thiazolidine trifluoroacetate.

To a stirred solution of 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3 -methyl- 1- phenyl-lH-pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl-carbonyl} thiazolidine (5.0 g) in dichloromethane was added Trifluoroacetic acid (15.0 mL) at room temperature. The resulting mixture was stirred for overnight at same temperature. After completion of reaction, the reaction mixture was evaporated under reduced pressure below 40 °C. To the oily mass was added water and the pH of reaction mixture was adjusted to 4.5 - 5.0 by adding solid sodium bicarbonate at room temperature. The aqueous layer was extracted 3-4 times by dichloromethane. The combined organic layer was evaporated and co-distilled with ethyl acetate under reduced pressure below 40 °C. To the residue obtained was added ethyl acetate and stirred for 6-8 h at room temperature. The solid was collected by filtration and dried at 50 °C to give title compound as an off white solid (3.0 g).

Comparative example 1 Synthesis of 3-{(2S,4S)-l-terbutoxycarbonyl-4-[4-(3- methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]-2-pyrrolidinylcarbonyl}-l,3- thiazolidine To a stirred solution of l-(3-methyl-l-phenyl-lH-pyrazol-5-yl) piperazine (584 mg) ,tert-buty\ (2,S)-2-(l,3-thiazolidin-3-ylcarbonyl)pyrrolidine-l-carboxylate (604 mg ) and acetic acid ( 0.13 ml) dissolved in 1,2 dichloroethane sodium triacetoxy borohydride ( 953 mg) was added at 25-30°C. The mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried. The solvent was evaporated and the residue was purified by silica gel chromatography to give 3-{(2S, 4S)-1- terbutoxycarbonyl-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]-2- pyrrolidinylcarbonyl}-l, 3-thiazolidine (846 mg) as a pale yellow amorphous powder.

Although the invention herein has been described with reference to particular embodiments; it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

CLAIMS We Claim:

1. A pharmaceutical composition of teneligliptin comprising granules containing teneligliptin and one or more pharmaceutically acceptable excipient, wherein the ratio of content of teneligliptin in granule to that in the pharmaceutical composition is smaller than 1.5 and wherein the total weight of the composition is greater than 215 mg and less than 600 mg.

2. The pharmaceutical composition according to claim 1, wherein the composition includes one or more binders selected from the group consisting of

hydroxypropylcellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose; one or more diluents selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sorbitol, xylitol, starch, calcium hydrogen phosphate; and; one or more lubricants selected from the group consisting of magnesium stearate, colloidal silicon dioxide, calcium stearate, talc, stearic acid, sucrose and esters of fatty acids.

3. The pharmaceutical composition according to claim 1, wherein the

pharmaceutical composition comprises 1.5%-15% by weight of teneligliptin or its pharmaceutically acceptable salt, l%-80% by weight of diluent, 0.1%-10% by weight of binder and 0.5%-30% by weight of lubricant.

4. The pharmaceutical composition according to claim 1, wherein the total weight of the composition is greater than 215 mg and less than 600 mg and wherein the pharmaceutical composition comprises 7%-10% by weight of teneligliptin or its pharmaceutically acceptable salt, 50%-70% by weight of diluent, 0.5%-5% by weight of a binder and 0.5%- 10% by weight of lubricant.

5. The pharmaceutical composition according to claim 1, wherein the

pharmaceutical composition comprises about 8% by weight of teneligliptin or its pharmaceutically acceptable salt, about 76% by weight of diluent, about 9% by weight of binder and about 1% by weight of lubricant.

6. A pharmaceutical composition of teneligliptin comprising granules containing teneligliptin and one or more pharmaceutically acceptable excipients, wherein the ratio of content of teneligliptin in granules to that in the pharmaceutical composition is greater than 10.

7. A pharmaceutical composition of teneligliptin comprising teneligliptin- containing granules and metformin, wherein teneligliptin and metformin are present in separate portions and wherein the ratio of content of teneligliptin in granules to that in the pharmaceutical composition is greater than 10.

8. The pharmaceutical composition according to claim 7, wherein the ratio of content of teneligliptin in granules to that in the pharmaceutical composition is greater than 10 and wherein the composition includes one or more binders selected from the group consisting of hydroxypropylcellulose, polyvinyl alcohol, povidone, hypromellose, carmellose sodium, methylcellulose; one or more diluents selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sorbitol, xylitol, starch, calcium hydrogen phosphate; and; one or more lubricants selected from the group consisting of magnesium stearate, colloidal silicon dioxide, calcium stearate, talc, stearic acid, sucrose, esters of fatty acids.

9. The pharmaceutical composition according to claim 7, wherein the

pharmaceutical composition comprises 1.5%-5% by weight of teneligliptin, 1%-

50% by weight of diluent, 0.1%-10% by weight of binder and 0.1%-30% by weight of lubricant.

10. The pharmaceutical composition according to claim 7, wherein the

pharmaceutical composition comprises 1.5%-2.5% by weight of teneligliptin or its pharmaceutically acceptable salt, l%-25% by weight of diluent, 0.1%-3% by weight of binder and 0.1%-25% by weight of lubricant.

11. The pharmaceutical composition according to claim 7, wherein the

pharmaceutical composition comprises about 2% by weight of teneligliptin or its pharmaceutically acceptable salt, about 20% by weight of diluent, about 0.1% by weight of binder and about 0.5% by weight of lubricant.

12. A process for preparation of teneligliptin pharmaceutical composition comprising granules containing teneligliptin wherein the ratio of content of teneligliptin in granule to that in the pharmaceutical composition is smaller than 1.5 and wherein the total weight of the composition is greater than 215 mg and less than 600 mg comprising the steps of- a) mixing teneligliptin or a pharmaceutically acceptable salt with pharmaceutically acceptable excipients;

b) adding a binder solution to the mixture of step a);

c) drying the wet mixture of step b) and sifting to form granules;

d) lubricating the granules of step c);

13. A process for preparation of teneligliptin pharmaceutical composition comprising granules containing teneligliptin wherein the ratio of content of teneligliptin in granule to that in the pharmaceutical composition is smaller than 1.5 and wherein the total weight of the composition is greater than 215 mg and less than 600 mg comprising the steps of- a) dry mixing teneligliptin or a pharmaceutically acceptable salt with pharmaceutically acceptable excipients to form a blend;

14. A process for preparation of teneligliptin pharmaceutical composition comprising the steps of- a) mixing teneligliptin with pharmaceutically acceptable excipients to form a blend for direct compression;

b) compressing the blend of step a) to form a tablet;

c) optionally coating the tablet of step b).

15. A process for preparation of teneligliptin pharmaceutical composition comprising teneligliptin-containing granules and metformin wherein the ratio of content of teneligliptin in granules to that in the pharmaceutical composition is greater than 10; comprising the steps of- a) granulating teneligliptin with pharmaceutically acceptable excipients; b) lubricating the teneligliptin granules of step a);

c) granulating metformin with pharmaceutically acceptable excipients.

d) lubricating the metformin granules of step c);

16. A process for preparation of teneligliptin pharmaceutical composition comprising teneligliptin-containing granules and metformin wherein the ratio of content of teneligliptin in granules to that in the pharmaceutical composition is greater than 10; comprising the steps of- a) spray granulating teneligliptin with pharmaceutically acceptable excipients; b) lubricating the teneligliptin granules of step a);

c) granulating metformin with pharmaceutically acceptable excipients.

d) lubricating the metformin granules of step c);

17. A process for preparation of teneligliptin pharmaceutical composition comprising teneligliptin-containing granules and metformin wherein the ratio of content of teneligliptin in granules to that in the pharmaceutical composition is greater than 10; comprising the steps of- a) roll compacting and granulating teneligliptin with pharmaceutically

acceptable excipients;

b) lubricating the teneligliptin granules of step a);

c) granulating metformin with pharmaceutically acceptable excipients.

d) lubricating the metformin granules of step c);

18. A process of preparation of teneligliptin pharmaceutical composition comprising teneligliptin-containing granules and metformin, comprising the steps of- a) mixing teneligliptin with pharmaceutically acceptable excipients to form a blend for direct compression;

b) granulating metformin with pharmaceutically acceptable excipients;

c) lubricating the metformin granules of step b);

19. A process of preparation of teneligliptin pharmaceutical composition comprising teneligliptin-containing granules and metformin, comprising the steps of- a) granulating metformin with pharmaceutically acceptable excipients;

b) lubricating the metformin granules of step a);

c) compressing the metformin blend of step b) to form a core;

d) preparing a teneligliptin containing polymer solution or suspension;

e) coating the core of step c) with the solution or suspension of step d).

20. 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]-2- pyrrolidinylcarbonyl}-l-,3-thiazolidine trifluoroacetate salt.

21. Crystalline 3-{(2S, 4S)-l-tert-Butoxycarbonyl-4-[4-(3-methyl-l-phenyl-lH- pyrazol-5-yl) piperazin-l-yl] pyrrolidin-2-yl-carbonyl}thiazolidine characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 21.15, 20.35, 17.14, 16.80, 11.96 ±0.2 degrees 2 theta.