WO2013046229A1

WO2013046229A1 - Novel salts of alogliptin

Info

Publication number: WO2013046229A1
Application number: PCT/IN2012/000611
Authority: WO
Inventors: Bandi Parthasaradhi Reddy; Kura Rathnakar Reddy; Dasari Muralidhara Reddy; Maradolla MOHANBABU; Bandi Vamsi Krishna
Original assignee: Hetero Research Foundation
Priority date: 2011-09-26
Filing date: 2012-09-12
Publication date: 2013-04-04
Also published as: EP2760853A4; EP2760853A1

Abstract

The present invention provides a novel process for the preparation of amorphous alogliptin benzoate. The present invention also provides amorphous alogliptin benzoate co-precipitated on copovidone, process for its preparation and pharmaceutical compositions comprising it. The present invention further provides novel salts of alogliptin, processes for their preparation and pharmaceutical compositions comprising them. The present invention further provides crystalline hydrochloride salt of alogliptin, process for its preparation and pharmaceutical compositions comprising it. The present invention further provides crystalline tartrate salt of alogliptin, process for its preparation and pharmaceutical compositions comprising it.

Description

NOVEL SALTS OF ALOGLIPTIN

This application claims the benefit of Indian Provisional Patent Application No. 3317/CHE/201 1, filed September 26, 201 1 , which is incorporated herein by reference.

Filed of the Invention

Background of the Invention

Alogliptin, chemically 2-({6-[(3i?)-3-aminopiperidin- l -yl]-3-methyl-2,4-dioxo- 3,4-dihydropyrimidin- l (2H)-yl}methyl)benzonitrile and has the structural formula:

Alogliptin benzoate is an investigational anti-diabetic drug in the DPP-4 inhibitor class, being developed by Takeda Pharmaceutical Company.

Alogliptin and its benzoate salt were disclosed in U.S. patent no. 7,807,689.

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

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

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

PCT publication no. WO 2007/035372 described a polymorphic Form A and amorphous Form I of alogliptin benzoate.

PCT publication no. WO 2010/ 109468 described acetate, trifluoroacetate, citrate, hydrochloric acid, L-lactate, succinate, benzoate and L-tartrate salts of alogliptin.

We have found a novel process for the preparation of alogliptin benzoate.

We have also found a novel amorphous alogliptin benzoate co-precipitated on copovidone. The amorphous alogliptin benzoate co-precipitated on copovidone has been found to be stable over the time and reproducible and so, suitable for pharmaceutical preparations.

We have also found novel salts of alogliptin such as fumarate, malate, sulfate, tosylate, oxalate and nitrate.

We have also found a novel crystalline alogliptin hydrochloride.

We have also found a novel crystalline alogliptin tartrate. Thus, one object of the present invention is to provide a novel process for the preparation of amorphous alogliptin benzoate.

Another object of the present invention is to provide amorphous alogliptin benzoate co-precipitated on copovidone, process for its preparation and pharmaceutical compositions comprising it.

Another object of the present invention is to provide a fumarate salt of alogliptin, process for its preparation and pharmaceutical composition comprising it.

Another object of the present invention is to provide a malate salt of alogliptin, process for its preparation and pharmaceutical composition comprising it.

Another object of the present invention is to provide a sulfate salt of alogliptin, process for its preparation and pharmaceutical composition comprising it.

Another object of the present invention is to provide a tosylate salt of alogliptin, process for its preparation and pharmaceutical composition comprising it.

Another object of the present invention is to provide an oxalate salt of alogliptin, process for its preparation and pharmaceutical composition comprising it.

Another object of the present invention is to provide a nitrate salt of alogliptin, process for its preparation and pharmaceutical composition comprising it.

Another object of the present invention is to provide crystalline alogliptin hydrochloride, process for its preparation and pharmaceutical composition comprising it.

Another object of the present invention is to provide crystalline alogliptin tartrate, process for its preparation and pharmaceutical composition comprising it.

The salts of the present invention may also serve as intermediate for preparation of alogliptin free base or another salt of alogliptin.

Summary of the Invention

In one aspect, the present invention provides a process for the preparation of amorphous alogliptin benzoate, which comprises:

a) dissolving alogliptin benzoate in a solvent;

b) heating the contents at reflux;

c) optionally adding an anti solvent to the solution obtained in step (b);

d) cooling the reaction mass at below 35°C; and e) isolating amorphous alogliptin benzoate.

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

a) dissolving alogliptin benzoate in a mixture of an alcoholic solvent, nitrile solvent and water;

b) cooling the solution obtained in step (a) at below 10°C;

c) removing the solvent from the solution to obtain a residual mass;

d) slurrying the residual mass obtained in step (c) with aromatic solvent; and e) isolating amorphous alogliptin benzoate.

In another aspect, the present invention provides an amorphous alogliptin benzoate co-precipitated on copovidone.

In another aspect, the present invention provides a process for the preparation of amorphous alogliptin benzoate co-precipitated on copovidone, which comprises:

a) dissolving a mixture of alogl iptin benzoate and copovidone in a suitable solvent; b) heating the contents at reflux;

c) cooling the reaction mass at below 35°C; and

d) removing the solvent by drying at about 50 to 80°C to obtain amorphous alogliptin benzoate co-precipitated on copovidone.

In another aspect, the present invention provides a pharmaceutical composition comprising amorphous alogliptin benzoate co-precipitated on copovidone and pharmaceutically acceptable excipients.

In another aspect, the present invention provides a fumarate salt of alogliptin, that is, alogliptin fumarate.

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

a) dissolving alogl iptin in a suitable solvent;

b) adding fumaric acid to the solution obtained in step (a);

c) heating the contents at reflux;

d) cooling the reaction mass at below 35°C; and

e) isolating alogliptin fumarate. In another aspect, the present invention provides a pharmaceutical composition comprising alogliptin fumarate and a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a malate salt of alogliptin, that is, alogliptin malate.

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

a) dissolving alogl iptin in a suitable solvent;

b) adding malic acid to the solution obtained in step (a);

c) heating the contents at reflux;

d) cooling the reaction mass at below 35°C; and

e) isolating alogl iptin malate.

In another aspect, the present invention provides a pharmaceutical composition comprising alogliptin malate and a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a sulfate salt of alogliptin, that is, alogliptin sulfate.

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

a) dissolving alogl iptin in a suitable solvent;

b) adding sulfuric acid to the solution obtained in step (a);

c) heating the contents at reflux;

d) cooling the reaction mass at below 35°C; and

e) isolating alogl iptin sulfate.

In another aspect, the present invention provides a pharmaceutical composition comprising alogl iptin sulfate and a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a tosylate salt of alogliptin, that is, alogliptin tosylate.

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

a) dissolving alogl iptin in a suitable solvent;

b) adding /?-tol uenesulfonic acid to the solution obtained in step (a);

c) heating the contents at reflux; d) cooling the reaction mass at below 35 C; and

e) isolating alogliptin tosylate.

In another aspect, the present invention provides a pharmaceutical composition comprising alogliptin tosylate and a pharmaceutically acceptable excipient.

In another aspect, the present invention provides an oxalate salt of alogliptin, that is, alogliptin oxalate.

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

a) dissolving alogliptin in a suitable solvent;

b) adding oxalic acid to the solution obtained in step (a);

c) heating the contents at reflux;

d) cooling the reaction mass at below 35°C; and

e) isolating alogliptin oxalate.

In another aspect, the present invention provides a pharmaceutical composition comprising alogliptin oxalate and a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a nitrate salt of alogliptin, that is, alogliptin nitrate.

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

a) dissolving alogliptin in a suitable solvent;

b) adding nitric acid to the solution obtained in step (a);

c) heating the contents at reflux;

d) cooling the reaction mass at below 35°C; and

e) isolating alogl iptin nitrate.

In another aspect, the present invention provides a pharmaceutical composition comprising alogl iptin nitrate and a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a crystalline alogliptin hydrochloride.

In another aspect, the present invention provides a process for the preparation of crystalline alogl iptin hydrochloride, which comprises:

a) dissolving alogl iptin in a suitable solvent; b) adding hydrochloric acid to the solution obtained in step (a);

c) heating the contents at reflux;

d) cooling the reaction mass at below 35°C; and

e) isolating crystalline alogliptin hydrochloride.

In another aspect, the present invention provides a pharmaceutical composition comprising crystal l ine alogliptin hydrochloride and a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a crystalline alogliptin tartrate. In another aspect, the present invention provides a process for the preparation of crystalline alogl iptin tartrate, which comprises:

a) dissolving alogliptin in a suitable solvent;

b) adding tartaric acid to the solution obtained in step (a);

c) heating the contents at reflux;

d) cooling the reaction mass at below 35°C; and

e) isolating crystalline alogliptin tartrate.

Yet in another aspect, the present invention provides a pharmaceutical composition comprising crystalline alogliptin tartrate and a pharmaceutically acceptable excipient. Brief Description of the Drawing

Figure 1 is X-ray powder diffraction spectrum of amorphous alogliptin benzoate.

Figure 2 is X-ray powder diffraction spectrum of amorphous alogliptin benzoate co-precipitated on copovidone.

Figure 3 is X-ray powder diffraction spectrum of crystalline alogliptin fumarate. Figure 4 is X-ray powder diffraction spectrum of crystalline alogliptin malate.

Figure 5 is X-ray powder diffraction spectrum of crystalline alogliptin sulfate.

Figure 6 is X-ray powder diffraction spectrum of crystalline alogliptin tosylate.

Figure 7 is X-ray powder diffraction spectrum of crystalline alogliptin oxalate.

Figure 8 is X-ray powder diffraction spectrum of crystalline alogliptin nitrate. Figure 9 is X-ray powder diffraction spectrum of crystalline alogliptin hydrochloride. Figure 10 is X-ray powder diffraction spectrum of crystalline alogliptin tartrate.

X-Ray Powder Diffractogram was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper- α radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.019 to 0.020 degrees two theta per step and a step time of 10.6 to 1 19 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 V and current 35 mA.

Detailed Description of the Invention

As used herein the term "room temperature" refers to a temperature of about 25°C to about 35°C.

According to one aspect of the present invention, there is provided a process for the preparation of amorphous alogliptin benzoate, which comprises:

a) dissolving alogliptin benzoate in a solvent;

b) heating the contents at refl ux;

c) optionally adding an anti solvent to the solution obtained in step (b);

d) cooling the reaction mass at below 35°C; and

e) isolating amorphous alogliptin benzoate.

The solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, isobutyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, benzene, xylene, toluene, cyclohexane, hexane and n-heptane. More preferably the solvents are water, acetone, methanol and toluene.

The anti solvent used in step (c) may preferably be a solvent or mixture of solvents selected from 1,4-dioxane, teterahydrofuran, tert-butyl methyl ether and diethyl ether, and more pre ferably the solvent is 1 ,4-dioxane.

The reaction mass may preferably be cooled in step (d) at about 0 to 30°C and more preferably at about 0 to 1 0°C.

Amorphous alogliptin benzoate may be isolated in step (e) by methods known such as filtration or centrifugation. According to another aspect of the present invention, there is provided a process for the preparation of amorphous alogliptin benzoate, which comprises:

b) cooling the solution obtained in step (a) at below 10°C;

c) removing the solvent from the solution to obtain a residual mass;

d) slurrying the residual mass obtained in step (c) with aromatic solvent; and e) isolating amorphous alogl iptin benzoate.

The alcohol ic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from methanol, ethanol, isopropanol, tert-butyl alcohol and n-butanol, and more preferably the alcohol ic solvent is methanol.

Preferably the nitrile solvent used in step (a) may be a solvent or mixture of solvents selected from acetonitrile, propionitrile, butyronitrile and benzonitrile. More preferably the nitri le solvent is acetonitrile.

The reaction mass may preferably be cooled in step (d) at about 0 to 5°C.

Removal of the solvent in step (c) may be carried out at atmospheric pressure or at reduced pressure. Removal of the solvent may preferably be carried out until the solvent is almost completely distil led off.

Preferably the aromatic solvent used in step (d) may be a solvent or mixture of solvents selected from benzene, xylene, toluene, cyclohexane, hexane and n-heptane, and more preferably the aromatic solvent is hexane.

Isolation of amorphous alogl iptin benzoate in step (e) may preferably be performed by conventional techniques such as centrifugation or filtration.

According to another aspect of the present invention, there is provided an amorphous alogliptin benzoate co-precipitated on copovidone. The powdered x-ray diffractogram (PX R.D) of amorphous alogliptin benzoate co-precipitated on copovidone is shown in figure 2.

According to another aspect of the present invention, there is provided a process for the preparation of amorphous alogliptin benzoate co-precipitated on copovidone, which comprises:

a) dissolving a mixture of alogliptin benzoate and copovidone in a suitable solvent; b) heating the contents at reflux;

c) cooling the reaction mass at below 35°C; and

The suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitri !e, propionitrile. butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, methylene chloride, chloroform, carbontetrachloride, ethylene dichloride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydrofuran 1 ,4-dioxane, tert-butyl methyl ether and diethyl ether. More preferably the solvents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate.- and still more preferably the solvents are water, methanol, ethanol and acetonitri le.

The reaction mass may preferably be cooled in step (c) at about 0 to 30°C and more preferably at about 0 to 1 0^(IC.

Drying in step (b) may preferably be carried out at about 60 to 70°C under high vacuum.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising amorphous alogliptin benzoate co-precipitated on copovidone and pharmaceutical ly acceptable excipients, and optionally other therapeutic ingredients. The amorphous alogliptin benzoate co-precipitated on copovidone may preferably be formu lated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

According to another aspect of the present invention, there is provided an alogliptin fumarate.

The alogl iptin fumarate may preferably be a solid.

The powdered x-ray d i ffractogram (PXR.D) of alogliptin fumarate is shown in figure 3. According to another aspect of the present invention, there is provided a process for the preparation of alogiiptin fumarate, which comprises:

a) dissolving alogi iptin in a suitable solvent;

b) adding fumaric acid to the solution obtained in step (a);

c) heating the contents at reflux;

d) cooling the reaction mass at below 35°C; and

e) isolating alogi i ptin fumarate.

The suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitri le, propionitri le, butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide. benzene, tol uene, xylene, methylene chloride, chloroform, carbontetrachloride. ethylene d ich loride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydrofuran, 1 ,4-dioxane, tert-butyl methyl ether and diethyl ether. More preferably the sol vents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrahydrofuran and acetonitrile.

Alogiiptin fumarate may be isolated in step (e) by methods known such as filtration or centrifugation.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprisi ng alogiiptin fumarate and pharmaceutically acceptable excip ients, and optional ly other therapeutic ingredients. The alogiiptin fumarate may preferably be formu lated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

According to another aspect of the present invention, there is provided an alogiiptin malate.

The alogi i pt i n malate may pre ferably be a solid. The powdered x-ray diffractogram (PXRD) of alogliptin malate is shown in figure

4.

According to another aspect of the present invention, there is provided a process for the preparation o f alogliptin malate, which comprises:

a) dissolving a logl iptin in a suitable solvent;

b) adding mal ic acid to the solution obtained in step (a);

c) heating the contents at reflux;

d) cooling the reaction mass at below 35°C; and

e) isolating alogl iptin malate.

The suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitri le, propionitri le. butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, methylene chloride, chloroform, carbontetrachloride. ethylene dichloride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydi ofuran, 1 ,4-dioxane, tert-butyl methyl ether and diethyl ether. More preferably the solvents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrahydrofuran and acetonitrile.

The reaction mass may preferably be cooled in step (d) at about 0 to 30°C and more preferably at about 0 to 1 0^l)C.

Isolation of alogliptin malate in step (e) may preferably be performed by conventional techniques such as centrifugation or filtration.

Accord ing to another aspect of the present invention, there is provided a pharmaceutica l composition comprising alogliptin malate and pharmaceutically acceptable e.xcipients. and optional ly other therapeutic ingredients. The alogliptin malate may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutica l forms.

Accord ing to another aspect of the present invention, there is provided an alogliptin sul fate. The alogliptin su l fate may preferably be a solid.

The powdered x-ray diffractogram (PXRD) of alogliptin sulfate is shown in figure

5.

According to another aspect of the present invention, there is provided a process for the preparation of alogl iptin su lfate, which comprises:

a) dissolving alogl iptin in a su itable solvent;

b) adding sulfuric acid to the solution obtained in step (a);

c) heating the contents at reflux;

d) cool ing the reaction mass at below 35°C; and

e) isolating alogliptin su lfate.

The suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitrile, propionitri le, butyronitrile, benzonitrile, dirnethylformamide, dimethylsu lfoxide, benzene, tol uene, xylene, methylene chloride, chloroform, carbontetrachloride, ethylene d ichloride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tctrahydrofuran. 1 ,4-dioxane, tert-butyl methyl ether and diethyl ether. More preferably the sol vents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dirnethylformamide, dimethylsu l oxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrnhydrofuran and acetonitrile.

The reaction mass may preferabl y be cooled in step (d) at about 0 to 30°C and more preferably at about 0 to 1 0°C.

Alogliptin sulfate may be isolated in step (e) by methods known such as filtration or centrifugation.

According to . another aspect of the present invention, there is provided a pharmaceutical composition comprising alogliptin sulfate and pharmaceutically acceptable excipients, and optional ly other therapeutic ingredients. The alogliptin sulfate may preferably be formu lated i nto tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms. According to another aspect of the present invention, there is provided an alogliptin tosylate.

The alogliptin tosylate may preferably be a solid.

The powdered x-ray di^'ffractogram (PXRD) of alogliptin tosylate is shown in figure 6.

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

a) dissolving alogliptin in a su itable solvent;

b) adding p-toluenesulfonic acid to the solution obtained in step (a);

c) heating the contents at reflux;

d) cooling the reaction mass at be low 35°C; and

e) isolating alogliptin tosylate.

The suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitrile, propion itri le, butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, methylene chloride, chloroform, carbontetrachloride, ethylene dichloride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydrofuran, 1 ,4-dioxane, tert-butyl methyl ether and diethyl ether. More preferably the solvents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrahydrofur n and acetonitrile.

The reaction mass may preferably be cooled in step (d) at about 0 to 30°C and more preferably at about 0 to 10°C.

Isolation of alogl iptin tosylate in step (e) may preferably be performed by conventional techniques such as centri ugation or filtration.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising alogliptin tosylate and pharmaceutically acceptable excipients, and optional ly other therapeutic ingredients. The alogliptin tosylate may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

According to another aspect of the present invention, there is provided an alogliptin oxalate.

The alogliptin oxalate may preferably be a solid.

The powdered x-ray di ffractogram (PXRD) of alogliptin oxalate is shown in figure 7.

According to another aspect o f the present invention, there is provided a process for the preparation of alogliptin oxal ate, which comprises:

a) dissolving alogliptin in a su itab le solvent;

b) adding oxalic acid to the sol ution obtained in step (a);

c) heating the contents at refl ux;

d) cooling the reaction mass at below 35°C; and

e) isolating alogliptin oxalate.

The suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitrile, propion itri le, butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide, benzene, tol uene, xylene, methylene chloride, chloroform, carbontetrachloride, ethylene d ich loride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydrofu ran. 1 ,4-dioxane, tert-butyl methyl ether and diethyl ether. More preferably the solvents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrahydro fu ran and acetonitrile.

Alogliptin oxalate may be iso lated in step (e) by methods known such as filtration or centrifugation.

According to another aspect of the present invention, there is provided a pharmaceutical composition compri si ng alogliptin oxalate and pharmaceutically acceptable excipients, and optional ly other therapeutic ingredients. The alogliptin oxalate may preferably be formu lated into tab lets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

According to another aspect of the present invention, there is provided an alogliptin nitrate.

The alogliptin nitrate may preferably be a solid.

The powdered x-ray diffractogram (PXRD) of alogliptin nitrate is shown in figure

8.

According to another aspect o f the present invention, there is provided a process for the preparation of alogl iptin n itrate, which comprises:

a) dissolving alogliptin in a su itab le solvent;

b) adding nitric acid to the solution obtained in step (a);

c) heating the contents at re flux;

d) cooling the reaction mass at below 35°C; and

e) isolating alogliptin nitrate.

The suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitrile, propion i tri le. butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide, benzene, tol uene, xylene, methylene chloride, chloroform, carbontetrachloride, ethylene d ichloride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahyd i ofu i an, 1 ,4-dioxane, tert-butyl methyl ether and diethyl ether. More preferably the sol vents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, tetei ahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrahydro furan and acetonitrile.

Isolation of alogl iptin n itrate i n step (e) may preferably be performed by conventional techniques such as centri fugation and filtration. According to another aspect of the present invention, there is provided a pharmaceutical composition comprising alogliptin nitrate and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. The alogliptin nitrate may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

According to another aspect of the present invention, there is provided a crystalline alogliptin hydrochloride.

The powdered x-ray diffractogram (PXRD) of crystalline alogliptin hydrochloride is shown in figure 9.

According to another aspect of the present invention, there is provided a process for the preparation of crystalline alogliptin hydrochloride, which comprises:

a) dissolving alogliptin in a suitable solvent;

b) adding hydrochloric acid to the solution obtained in step (a);

c) heating the contents at reflux;

d) cooling the reaction mass at below 35°C; and

e) isolating crystalline alogliptin hydrochloride.

The suitable solvent used in step (a) may preferably be a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n- butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitrile, propionitrile, butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, methylene chloride, chloroform, carbontetrachloride, ethylene dichloride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydrofuran, 1 ,4-dioxane, tert-butyl methyl ether and diethyl ether. More preferably the solvents are water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, acetone, teterahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide and ethyl acetate, and still more preferably the solvents are water, ethanol, ethyl acetate, tetrahydrofuran and acetonitrile.

Crystalline alogliptin hydrochloride may be isolated in step (e) by methods known such as filtration or centrifugation. According to another aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline alogliptin hydrochloride and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. The crystalline alogliptin hydrochloride may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

According to another aspect of the present invention, there is provided a crystalline alogliptin tartrate.

The powdered x-ray diffractogram (PXRD) of crystalline alogliptin tartrate is shown in figure 10.

According to another aspect of the present invention, there is provided a process for the preparation of crystalline alogliptin tartrate, which comprises:

a) dissolving alogliptin in a suitable solvent;

b) adding tartaric acid to the solution obtained in step (a);

c) heating the contents at reflux;

d) cooling the reaction mass at below 35°C; and

e) isolating crystalline alogliptin tartrate.

Isolation of crystalline alogliptin tartrate in step (e) may preferably be performed by conventional techniques such as centrifugation or filtration. According to another aspect of the present invention, there is provided a pharmaceutical composition comprising crystalline alogliptin tartrate and pharmaceutically acceptable excipients, and optionally other therapeutic ingredients. The crystalline alogliptin tartrate may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

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

Preparative example

Preparation of alogliptin benzoate

Step - I: Preparation of 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)methyl)benzonitrile

To a 6-chloropyrimidine-2,4(l H,3H)-dione (21 gm) was added N- methylpyrrolidone (80 ml) under stirring and then added diisopropylethylamine (17 ml) slowly for 30 minutes. To the solution was added a solution of 2- (bromomethyl)benzonitrile (20 gm) in toluene (80 ml) slowly for 1 hour and the temperature of the reaction mass was raised to 70 to 80°C. The reaction mass was maintained for 4 hours at 70 to 80°C and then cooled to 15 to 20°C. The reaction mass was quenched with water and maintained for 30 minutes at 15 to 20°C. The reaction mass was then cooled to 0 to 5°C and stirred for 1 hour. The reaction mass was filtered and washed with water and hexane to obtain a wet solid. To the wet solid thus obtained was added water (200 ml) and pH was adjusted to 9.0 to 10.0 with sodium hydroxide (IN). The reaction mass was stirred for 30 minutes and then added methylene chloride (300 ml) and then the layers were separated. The pH of the aqueous layer was adjusted to 4.0 to 5.0 with hydrochloric acid (IN) and stirred for 30 minutes. The solid obtained was collected by filtration and then dried to obtain 19.3 gm of 2-((6-chloro-2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)methyl)benzonitrile.

Step - II: Preparation of 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)methyl)benzonitrile

Acetone (286 ml) was added to 2-((6-chloro-2,4-dioxo-3,4-dihydropyrimidin- l(2H)-yl)methyl)benzonitrile (18.5 gm) and then added potassium carbonate (13 gm). To the reaction mixture was added methyl iodide (5.5 ml) slowly for 30 minutes and the temperature of the reaction mass was raised to 50 to 60°C. The reaction mass was maintained for 6 hours at 50 to 60°C and the acetone solvent was distilled off under vacuum at low temperature to obtain a residual mass. To the residual mass was added ethyl acetate (300 ml) and water (200 ml) and then the layers were separated. The separated organic layer was dried with sodium sulfate and the ethyl acetate solvent was distilled off under vacuum at low temperature to obtain a residual solid. To the residual solid was added hexane (200 ml) and stirred for 30 minutes. The separated solid was filtered and then dried to obtain 18 gm of 2-((6-chloro-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)methyl)benzonitrile.

Step - III: Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)methyl)benzonitrile (Alogliptin)

Methanol (518 ml), 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin- l(2H)-yl)methyl)benzonitrile (41.5 gm), sodium bicarbonate (63 gm), (R)-piperidin-3- amine dihydrochloride salt (34 gm) and molecular sieves (25 gm) were added at room temperature under stirring. The temperature of the reaction mass was raised to 65 to 70°C and maintained for 6 hours. The reaction mass was filtered through hi-flow bed and the solvent was distilled off under vacuum at low temperature to obtain a residual solid. To the residual solid was added water (275 ml) and pH was adjusted to 7.0. The reaction mass was extracted with methylene chloride and then the layers were separated. The organic layer was dried with sodium sulfate and then concentrated to obtain a solid. The solid obtained was then dried to obtain 42 gm of alogliptin. Step - IV: Preparation of alogliptin benzoate

Ethanol (48 ml) was added to alogliptin (9.5 gm) and then added benzoic acid (6.8 gm) under stirring for 20 minutes to obtain a solution. The solution was then heated to 75 to 80°C and maintained for 2 hours. The reaction mass was then cooled to room temperature and then further cooled to -5 to 0°C. The contents were stirred for 1 hour at 0°C and filtered. The solid obtained was dried to give 12 gm of alogliptin benzoate. Examples

Example 1 :

Preparation of amorphous alogliptin benzoate

Alogliptin benzoate (1 gm) was added to isopropanol (50 ml) under stirring at room temperature. The reaction mass was then heated to reflux and then added isopropanol (13 ml), stirred for 15 minutes at reflux to obtain a clear solution. To the solution was added 1,4-dioxane (50 ml) slowly at reflux and then cooled to room temperature. The reaction mass was further cooled to 0 to 5°C and stirred for 20 minutes. The reaction mass was then concentrated and then dried under vacuum at 60°C for 13 hours to obtain 0.8 gm of amorphous alogliptin benzoate.

Example 2:

Preparation of amorphous alogliptin benzoate

Alogliptin benzoate. (3 gm) was dissolved in acetone (10 ml) and water (10 ml) at room temperature and then stirred for 30 minutes to obtain a clear solution. The solution was then heated to reflux and stirred for 1 hour. The reaction mass was then cooled to room temperature and then concentrated. The solid thus obtained was dried under vacuum at 60°C for 12 hours to obtain 2.5 gm of amorphous alogliptin benzoate. Example 3:

Preparation of amorphous alogliptin benzoate

Alogliptin benzoate (3 gm) was dissolved in a mixture of methanol (4 ml), acetonitrile (4 ml) and water (4 ml) under stirring at room temperature to obtain a clear solution. The solution was then cooled to 0 to 5°C and stirred for 30 minutes. The solvent was distilled off under vacuum to obtain a residual solid. To the residual solid was added hexane (25 ml) and then concentrated. The solid thus obtained was dried under vacuum at 60°C for 13 hours to obtain 2.6 gm of amorphous alogliptin benzoate.

Example 4:

Preparation of amorphous alogliptin benzoate Alogliptin benzoate (3 gm) was dissolved in toluene (100 ml) and water (100 ml) at room temperature and then heated to 60°C to obtain a solution. The solution was then cooled to room temperature and stirred for 6 hours. The reaction mass was then concentrated and then dried under vacuum at 60°C for 13 hours to obtain 2.5 gm of amorphous alogliptin benzoate.

Example 5:

Preparation of amorphous alogliptin benzoate co-precipitated on copovidone

A mixture of alogliptin benzoate (3 gm) and copovidone (2 gm) was suspended in methanol (25 ml) under stirring at room temperature. The reaction mass was then heated to reflux and stirred for 30 minutes to obtain a clear solution. The solution was then cooled to room temperature and stirred for 15 minutes. The reaction mass was then concentrated and then dried under vacuum at 60°C for 13 hours to obtain 4.6 gm of amorphous alogliptin benzoate co-precipitated on copovidone.

Example 6:

Preparation of amorphous alogliptin benzoate co-precipitated on copovidone

Example 5 was repeated using ethanol solvent instead of methanol solvent to obtain amorphous alogliptin benzoate co-precipitated on copovidone.

Example 7:

Preparation of amorphous alogliptin benzoate co-precipitated on copovidone

Example 5 was repeated using isopropanol solvent instead of methanol solvent to obtain amorphous alogliptin benzoate co-precipitated on copovidone.

Example 8:

Preparation of alogliptin fumarate

Alogliptin (2 gm) was dissolved in ethanol (12 ml) and then added fumaric acid (1.02 gm) under stirring. The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature and stirred for 30 minutes. The contents were further cooled to 0 to 5°C and stirred for 30 minutes. The separated solid was filtered and then dried to obtain 1.7 gm of alogliptin fumarate.

Example 9:

Preparation of alogliptin fumarate

Example 8 was repeated using acetonitrile solvent instead of ethanol solvent to obtain alogliptin fumarate.

Example 10:

Preparation of alogliptin fumarate

Example 8 was repeated using ethyl acetate solvent instead of ethanol solvent to obtain alogliptin fumarate.

Example 1 1 :

Preparation of alogliptin fumarate

Example 8 was repeated using tetrahydrofuran solvent instead of ethanol solvent to obtain alogliptin fumarate.

Example 12:

Preparation of alogliptin fumarate

Example 8 was repeated using acetone solvent instead of ethanol solvent to obtain alogliptin fumarate.

Example 13:

Preparation of alogliptin malate

Alogliptin (2 gm) was dissolved in ethanol (12 ml) and then added malic acid

(1.18 gm) under stirring. The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature and stirred for 30 minutes. The contents were further cooled to 0 to 5°C, stirred for 30 minutes and filtered. The solid obtained was dried to give 1.8 gm of alogliptin malate. Example 14:

Preparation of alogliptin malate

Example 13 was repeated using acetonitrile solvent instead of ethanol solvent to obtain alogliptin malate.

Example 15:

Preparation of alogliptin malate

Example 13 was repeated using acetone solvent instead of ethanol solvent to obtain alogliptin malate.

Example 16:

Preparation of alogliptin malate

Example 13 was repeated using tetrahydrofuran solvent instead of ethanol solvent to obtain alogliptin malate.

Example 17:

Preparation of alogliptin malate

Example 13 was repeated using ethyl acetate solvent instead of ethanol solvent to obtain alogliptin malate.

Example 18:

Preparation of alogliptin sulfate

Alogliptin (2 gm) was dissolved in ethanol (12 ml) and then added sulfuric acid (0.471 ml) slowly under stirring. The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature and stirred for 30 minutes. The contents were further cooled to 0 to 5°C and filtered. The solid obtained was dried to give 1.3 gm of alogliptin sulfate.

Example 19:

Preparation of alogliptin sulfate Example 18 was repeated using tetrahydrofuran solvent instead of ethanol solvent to obtain alogliptin sulfate.

Example 20:

Preparation of alogliptin sulfate

Example 18 was repeated using ethyl acetate solvent instead of ethanol solvent to obtain alogliptin sulfate.

Example 21 :

Preparation of alogliptin sulfate

Example 18 was repeated using acetone solvent instead of ethanol solvent to obtain alogliptin sulfate.

Example 22:

Preparation of alogliptin sulfate

Example 18 was repeated using acetonitrile solvent instead of ethanol solvent to obtain alogliptin sulfate.

Example 23:

Preparation of alogliptin tosylate

Alogliptin (2 gm) was dissolved in ethanol (12 ml) and then added p- toluenesulfonic acid (2.28 gm) slowly under stirring. The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature and stirred for 30 minutes. The contents were further cooled to 0 to 5°C and stirred for 30 minutes. The separated solid was filtered and then dried to obtain 1.6 gm of alogliptin tosylate.

Example 24:

Preparation of alogliptin tosylate

Example 23 was repeated using acetone solvent instead of ethanol solvent to obtain alogliptin tosylate. Example 25:

Preparation of alogliptin tosylate

Example 23 was repeated using acetonitrile solvent instead of ethanol solvent to obtain alogliptin tosylate.

Example 26:

Preparation of alogliptin tosylate

Example 23 was repeated using ethyl acetate solvent instead of ethanol solvent to obtain alogliptin tosylate.

Example 27:

Preparation of alogliptin tosylate

Example 23 was repeated using tetrahydrofuran solvent instead of ethanol solvent to obtain alogliptin tosylate.

Example 28:

Preparation of alogliptin oxalate

Alogliptin (2 gm) was dissolved in ethanol (12 ml) and then added oxalic acid (0.769 gm) slowly under stirring. The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature and stirred for 30 minutes. The contents were further cooled to 0 to 5°C, stirred for 30 minutes and filtered. The solid obtained was dried to give 1.8 gm of alogliptin oxalate.

Example 29:

Preparation of alogliptin oxalate

Example 28 was repeated using ethyl acetate solvent instead of ethanol solvent to obtain alogliptin oxalate.

Example 30:

Preparation of alogliptin oxalate Example 28 was repeated using tetrahydrofuran solvent instead of ethanol solvent to obtain alogliptin oxalate.

Example 31 :

Preparation of alogliptin oxalate

Example 28 was repeated using acetonitrile solvent instead of ethanol solvent to obtain alogliptin oxalate.

Example 32:

Preparation of alogliptin oxalate

Example 28 was repeated using acetone solvent instead of ethanol solvent to obtain alogliptin oxalate.

Example 33:

Preparation of alogliptin nitrate

Alogliptin (2 gm) was dissolved in ethanol (12 ml) and then added nitric acid (0.398 ml) under stirring. The contents were then heated to reflux and stirred for 3 hours. The reaction mass was then cooled to room temperature and stirred for 30 minutes. The contents were further cooled to 0 to 5°C and stirred for 30 minutes. The separated solid was filtered and then dried to obtain 1.4 gm of alogliptin nitrate.

Example 34:

Preparation of alogliptin nitrate

Example 33 was repeated using acetonitrile solvent instead of ethanol solvent to obtain alogliptin nitrate.

Example 35:

Preparation of alogliptin nitrate

Example 33 was repeated using acetone solvent instead of ethanol solvent to obtain alogliptin nitrate. g tetrahydrofuran solvent instead of ethanol solvent

led using ethyl acetate solvent instead of ethanol solvent to

•gliptin hydrochloride

dissolved in ethanol (12 ml) and then added hydrochloric tirring. The contents were then heated to reflux and stirred s was then cooled to room temperature and stirred for 30 Jrther cooled to 0 to 5°C and stirred for 30 minutes. The ¾nd then dried to obtain 1 gm of crystalline alogliptin

gliptin hydrochloride

ed using acetonitrile solvent instead of ethanol solvent to Irochloride.

gliptin tartrate

dissolved in ethanol (12 ml) and then added tartaric acid contents were then heated to reflux and stirred for 3 hours, oled to room temperature and stirred for 30 minutes. The ) 0 to 5°C, stirred for 30 minutes and filtered. The solid ' gm of crystalline alogliptin tartrate.

Claims

We claim:

1. A process for the preparation of amorphous alogliptin benzoate, which comprises: a. dissolving alogliptin benzoate in a solvent;

b. heating the contents at reflux;

c. optionally adding an anti solvent to the solution obtained in step (b);

d. cooling the reaction mass at below 35°C; and

e. isolating amorphous alogliptin benzoate.

2. The process as claimed in claim 1, wherein the solvent used in step (a) is a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, isobutyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, benzene, xylene, toluene, cyclohexane, hexane and n-heptane.

3. The process as claimed in claim 1 , wherein the anti solvent used in step (c) is a solvent or mixture of solvents selected from 1,4-dioxane, teterahydrofuran, tert-butyl methyl ether and diethyl ether.

4. A process for the preparation of amorphous alogliptin benzoate, which comprises: a. dissolving alogliptin benzoate in a mixture of an alcoholic solvent, nitrile solvent and water;

b. cooling the solution obtained in step (a) at below 10°C;

c. removing the solvent from the solution to obtain a residual mass;

d. slurrying the residual mass obtained in step (c) with aromatic solvent; and e. isolating amorphous alogliptin benzoate.

5. The process as claimed in claim 4, wherein the alcoholic solvent used in step (a) is a solvent or mixture of solvents selected from methanol, ethanol, isopropanol, tert-butyl alcohol and n-butanol.

6. The process as claimed in claim 4, wherein the nitrile solvent used in step (a) is a solvent or mixture of solvents selected from acetonitrile, propionitrile, butyronitrile and benzonitrile.

7. The process as claimed in claim 4, wherein the aromatic solvent used in step (d) is a solvent or mixture of solvents selected from benzene, xylene, toluene, cyclohexane, hexane and n-heptane.

8. An amorphous alogliptin benzoate co-precipitated on copovidone.

9. An amorphous alogliptin benzoate co-precipitated on copovidone, characterized by an x-ray powder diffractogram as shown in figure 2.

10. A process for the preparation of amorphous alogliptin benzoate co-precipitated on copovidone, which comprises:

a. dissolving a mixture of alogliptin benzoate and copovidone in a suitable solvent; b. heating the contents at reflux;

c. cooling the reaction mass at below 35°C; and

d. removing the solvent by drying at about 50 to 80°C to obtain amorphous alogliptin benzoate co-precipitated on copovidone.

1 1. The process as claimed in claim 10, wherein the drying in step (d) is carried out at about 60 to 70°C under high vacuum.

12. A fumarate salt of alogliptin.

13. The compound as claimed in claim 12, wherein the fumarate salt of alogliptin is solid.

14. A process for the preparation of alogliptin fumarate, which comprises:

a. dissolving alogliptin in a suitable solvent;

b. adding fumaric acid to the solution obtained in step (a);

c. heating the contents at reflux;

d. cooling the reaction mass at below 35°C; and

e. isolating alogliptin fumarate.

15. A malate salt of alogliptin.

16. The compound as claimed in claim 15, wherein the malate salt of alogliptin is solid.

17. A process for the preparation of alogliptin malate, which comprises:

a. dissolving alogliptin in a suitable solvent;

b. adding malic acid to the solution obtained in step (a);

c. heating the contents at reflux;

d. cooling the reaction mass at below 35°C; and

e. isolating alogliptin malate.

18. A sulfate salt of alogliptin.

19. The compound as claimed in claim 18, wherein the sulfate salt of alogliptin is solid.

20. A process for the preparation of alogliptin sulfate, which comprises:

a. dissolving alogliptin in a suitable solvent; b. adding sulfuric acid to the solution obtained in step (a);

c. heating the contents at reflux;

d. cooling the reaction mass at below 35°C; and

e. isolating alogliptin sulfate.

21. A tosylate salt of alogliptin.

22. The compound as claimed in claim 21, wherein the tosylate salt of alogliptin is solid.

23. A process for the preparation of alogliptin tosylate, which comprises:

a. dissolving alogliptin in a suitable solvent;

b. adding /?-toluenesulfonic acid to the solution obtained in step (a);

c. heating the contents at reflux;

d. cooling the reaction mass at below 35°C; and

e. isolating alogliptin tosylate.

24. An oxalate salt of alogliptin.

25. The compound as claimed in claim 24, wherein the oxalate salt of alogliptin is solid.

26. A process for the preparation of alogliptin oxalate, which comprises:

a. dissolving alogliptin in a suitable solvent;

b. adding oxalic acid to the solution obtained in step (a);

c. heating the contents at reflux;

d. cooling the reaction mass at below 35°C; and

e. isolating alogliptin oxalate.

27. A nitrate salt of alogliptin.

28. The compound as claimed in claim 27, wherein the nitrate salt of alogliptin is solid.

29. A process for the preparation of alogliptin nitrate, which comprises:

a. dissolving alogliptin in a suitable solvent;

b. adding nitric acid to the solution obtained in step (a);

c. heating the contents at reflux;

d. cooling the reaction mass at below 35°C; and

e. isolating alogliptin nitrate.

30. A crystalline alogliptin hydrochloride.

31. A process for the preparation of crystalline alogliptin hydrochloride, which comprises: a. dissolving alogliptin in a suitable solvent;

b. adding hydrochloric acid to the solution obtained in step (a);

c. heating the contents at reflux;

d. cooling the reaction mass at below 35°C; and

e. isolating crystalline alogliptin hydrochloride.

32. A crystalline alogliptin tartrate.

33. A process for the preparation of crystalline alogliptin tartrate, which comprises:

a. dissolving alogliptin in a suitable solvent;

b. adding tartaric acid to the solution obtained in step (a);

c. heating the contents at reflux;

d. cooling the reaction mass at below 35°C; and

e. isolating crystalline alogliptin tartrate.

34. The process as claimed in claim 10, 14, 17, 20, 23, 26, 29, 31 and 33, wherein the suitable solvent used in step (a) is a solvent or mixture of solvents selected from water, methanol, ethanol, isopropanol, tert-butyl alcohol, n-butanol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetonitrile, propionitrile, butyronitrile, benzonitrile, dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, methylene chloride, chloroform, carbontetrachloride, ethylene dichloride, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, tetrahydrofuran, 1 ,4-dioxane, tert-butyl methyl ether and diethyl ether.

35. A pharmaceutical composition that comprises amorphous alogliptin benzoate co- precipitated on copovidone and pharmaceutically acceptable carriers, and optionally other therapeutic ingredients.

36. A pharmaceutical composition that comprises alogliptin fumarate and pharmaceutically acceptable carriers, and optionally other therapeutic ingredients.

37. A pharmaceutical composition that comprises alogliptin malate and pharmaceutically acceptable carriers, and optionally other therapeutic ingredients.

38. A pharmaceutical composition that comprises alogliptin sulfate and pharmaceutically acceptable carriers, and optionally other therapeutic ingredients.

39. A pharmaceutical composition that comprises alogliptin tosylate and pharmaceutically acceptable carriers, and optionally other therapeutic ingredients.

40. A pharmaceutical composition that comprises alogliptin oxalate and pharmaceutically acceptable carriers, and optionally other therapeutic ingredients.

41. A pharmaceutical composition that comprises alogliptin nitrate and pharmaceutically acceptable carriers, and optionally other therapeutic ingredients.

42. A pharmaceutical composition that comprises crystalline alogliptin hydrochloride and pharmaceutically acceptable carriers, and optionally other therapeutic ingredients.

43. A pharmaceutical composition that comprises crystalline alogliptin tartrate and pharmaceutically acceptable carriers, and optionally other therapeutic ingredients.

44. The pharmaceutical composition as claimed in claim 35, 36, 37, 38, 39, 40, 41, 42 and 43, wherein the polymorphic form or salt is formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.