Claims:1) A process for the preparation of amorphous Teneligliptin Oxalate (I)

(I)
comprising the steps of:
a. providing a solution of Teneligliptin oxalate in an organic solvent;
b. heating the solution at temperature ranging between 40°C - reflux temperature of the solvent;
c. adding a co-solvent slowly to the solution;
d. cooling the solution and stirring the reaction mass at temperature ranging between 20-40°C;
e. recovering the amorphous Teneligliptin oxalate (I).

2) A process for the preparation of amorphous Teneligliptin oxalate (I), according to claim 1, wherein organic solvent and co-solvent are selected from alcohols, ethers and mixture thereof.

3) A process for the preparation of amorphous Teneligliptin oxalate (I), according to claim 2, wherein organic solvent and co-solvent as alcohol is selected from Methanol, Ethanol, Propanol and Isopropanol or ether solvent is selected from diisopropyl ether, di-tertiary butyl ether, methyl tertiary butyl ether, tetrahydrofuran and mixture thereof.

4) Amorphous Teneligliptin Oxalate (I) characterized by powder X ray diffraction pattern which is substantially as illustrated in Fig. l.

5) Amorphous Teneligliptin Oxalate (I)

having water content ranging between 2-6 %w/w(KF) (I)

6) A process for the preparation of crystalline form of Teneligliptin Oxalate (I) characterized by X-ray powder diffraction comprising diffraction angle peaks selected from 4.7, 5.6, 6.4, 7.2, 9.7, 9.9, 13.9, 15.8, 16.9, 18.4, 19.1, 20.8, 21.0, 21.6, 23.1, 23.9 and 24.6 ± 0.05 2?° comprising steps of:
a. providing a solution of amorphous Teneligliptin oxalate (I) according to claim 4 in a suitable organic solvent;
b. stirring the reaction mass obtained in step a for time duration ranging between 3-15 hours at temperature ranging between 20 - 50°C;
c. reaction mass filtered and washed with a suitable organic solvent;
d. recovering the crystalline Teneligliptin oxalate salt.

7) A process for the preparation of crystalline form of Teneligliptin Oxalate (I) according to claim 6, organic solvent as ester solvent is selected from isopropyl acetate, ethyl acetate, isobutyl acetate, methyl acetate or alcohol is selected from methanol, ethanol, propanol and isopropanol or ether solvent is selected from diisopropyl ether, di-tertiary butyl ether, methyl tertiary butyl ether, tetrahydrofuran and mixture thereof.

8) A pharmaceutical composition comprising Amorphous Teneligliptin Oxalate (I) and at least one or more pharmaceutically acceptable excipients.
, Description:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Teneligliptin Oxalate of Formula (I).

(I)
The invention relates to Teneligliptin in the form of Oxalate salt and also relates to its process for preparation.

Further, this invention also relates to amorphous form of Teneligliptin oxalate obtained by the process of the present invention, the said amorphous form being substantially pure and stable.

The present invention further relates to pharmaceutical compositions comprising amorphous form of Teneligliptin Oxalate, useful in treatment of type 2 diabetes mellitus.

BACKGROUND OF THE INVENTION
Teneligliptin approved as Teneligliptin hydrobromide hydrate is indicated for the treatment of Type 2 Diabetes Mellitus and marketed as Tenelia in Japan.

Teneligliptin chemically known as {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl]-1-piperazinyl}(1,3-thiazolidin-3-yl)methanone and is represented by the general Formula II.

(II)

Teneligliptin or a pharmaceutically acceptable salt thereof was first disclosed in US7074794. It also discloses process for the preparation of Teneligliptin. Below scheme summarizes the process as disclosed in the patent.

Crystalline forms of Teneligliptin hydrobromide hydrate such as From A, Form B and Form C which are claimed in US8604198. Below scheme summarizes the process as disclosed in the patent.

Teneligliptin in amorphous form is described in PCT Publication No.WO2014/041560.

Teneligliptin hydrobromide process is also described patent application No.WO2015/019239 A and the process flowdiagram is described as follows:

Yan Jie et al in Chinese patent application no. CN104650065 A disclosed a crystalline form of Teneligliptin 2.5 hydrobromide trihydrate which is characterized using Cu-?a radiation, X-Ray powder diffraction (XRD) peaks at 2?° expressed in 4.680, 10.180, 11.960, 12.220, 16.100, 17.920, 19.720, 20.420, 22.620, 24.360, 25.620, 24.360, 25.620, 27.200, 29.410, 30.380, 32.320, 34.900, 35.780, 36.100, 38.980, 39.980, 40.080, 42.560 and 43.660.

Tomohiro Yoshida et al US patent US8604198 B2 discloses form B crystal of Teneligliptin 2.0 hydrobromide hydrate, which has peaks at diffraction angles represented by 2? of 5.2°, 10.4°, 19.1°, 19.8° and 20.7°. This patent also discloses form A of Teneligliptin 2.0 hydrobromide 3.5 hydrate, which has peaks at diffraction angles represented by 2? of 5.7°, 7.7°, 11.3°, 16.2° and 17.0° (each ±0.2°) in a powder X-ray diffraction pattern. This patent also discloses form C crystal of Teneligliptin 2.0 hydrobromide hydrate, which has peaks at diffraction angles represented by 2? of 5.5°, 13.4°, 14.3°, 21.4° and 26.7° (each ±0.2°) in a powder X-ray diffraction pattern. This patent discloses hydrochloride, hydrobromide, nitrate, mesylate, maleate, tosylate, besylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, gallate, (+)-camphorsulfonate, (-)-camphorsulfonate, fumarate, sulfate, succinate, L-tartrate, ethanedisulfonate, citrate or phosphate salts of Teneligliptin.

Tomohiro Yoshida et al US patent US8003790 B2 discloses crystal of Teneligliptin 2.5 hydrochloride, which has peaks at diffraction angles represented by 2? of 5.2°, 14.3°, 16.2°, 21.8° and 25.2°. This patent also discloses crystalline form of Teneligliptin 2.5 hydrobromide, which has peaks at IR (KBr): 3600-3300 (st), 3116-2850 (st), 2800-2400 (st), 1647 (st), 1592 (m), 1572 (m), 1496 (m), 1450 (m), 1385 (m), 1361 (w), 768 (m), 692 (w). Further, this patent also discloses Teneligliptin 2.5 hydrobromide (1.0 to 2.0) hydrate, which has peaks at diffraction angles represented by 2? of 5.4°, 13.4°, 14.4°, 22.6° and 26.5° in a powder X-ray diffraction pattern. This patent also discloses Teneligliptin hydrobromide which has peaks at diffraction angles represented by 2? of 5.7°, 7.7°, 11.3°, 16.2° and 17.0°. in a powder X-ray diffraction pattern.

Teneligliptin or its pharmaceutically acceptable salts are being important therapeutic agents useful in the treatment of type 2 diabetes mellitus. Additional and improved ways of preparing new salts of Teneligliptin may provide an opportunity to improve the drug performance characteristics of such products. Hence, there exists a need for the further development of new stable salts of Teneligliptin and commercially viable processes for its preparation, which may be up scalable, safer for handling, less time consuming and with better and consistent quality parameters.

The inventors of this application have developed a process which provides amorphous form of Teneligliptin oxalate which is stable, non-hygroscopic, and thus has easy handling properties. The process of this invention provides amorphous form of Teneligliptin oxalate in substantially pure form, which is complying to ICH requirements for detectable impurities/contamination of any other previously known amorphous form of Teneligliptin.

SUMMARY OF INVENTION
Particular aspects of the present invention relates to a process for the preparation of amorphous form of Teneligliptin oxalate. Amorphous form of Teneligliptin oxalate obtained by the process of the present invention is found to be substantially pure and stable.

(I)
In one aspect of the present invention, it relates to process for the preparation of amorphous form of Teneligliptin oxalate (I), comprising the steps of:

a. providing a solution of Teneligliptin oxalate in an organic solvent;
b. heating the solution at temperature ranging between 40°C to reflux temperature of the solvent;
c. adding a co-solvent slowly to the solution;
d. cooling the solution and stirring the reaction mass at temperature ranging between 20-40°C;
e. recovering the amorphous Teneligliptin oxalate (I).

In another aspect of the present invention relates to amorphous form of Teneligliptin oxalate having water content ranging between 2-6 %w/w (KF).

In a further aspect of the present application also relates to a pharmaceutical composition comprising amorphous form of Teneligliptin oxalate of the present application and atleast one or more pharmaceutically acceptable excipients.

Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriate.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an example of X-ray powder diffraction (“XRPD”) pattern of amorphous form of Teneligliptin oxalate.
Fig. 2 is an example of Thermogravimetric analysis (“TGA”) curve of amorphous form of Teneligliptin oxalate.
Fig. 3 is an example of Differential Scanning Calorimetry (“DSC”) peaks of amorphous form of Teneligliptin oxalate.
Fig. 4 is an example of X-ray powder diffraction (“XRPD”) pattern of crystalline form of Teneligliptin oxalate.

DETAILED DESCRIPTION

As set forth herein, embodiments of the present invention provide a reproducible and efficient process for the preparation of amorphous form of Teneligliptin oxalate (I). amorphous form of Teneligliptin oxalate obtained by the process of the present invention is found to be substantially pure and stable. Said amorphous form is useful in preparing pharmaceutical compositions comprising Teneligliptin oxalate (I), useful in the treatment of treatment of type 2 diabetes mellitus.

In another embodiment according to present application, it provides a process for the preparation of amorphous form of Teneligliptin oxalate (I) comprising the steps of:

(I)
comprising the steps of:
a. providing a solution of Teneligliptin oxalate in an organic solvent;
b. heating the solution at a temperature ranging between 40°C to reflux temperature of the solvent;
c. adding a co-solvent slowly to the solution;
d. cooling the solution and stirring the reaction mass at temperature ranging between 20-40°C;
e. recovering the amorphous Teneligliptin oxalate salt.

Individual steps of the embodiments are detailed herein below.

In the step a. of providing a solution according to the present invention, it comprises
dissolving Teneligliptin oxalate (Any source of Teneligliptin base or may be obtained according any of prior disclosure viz. U.S. patent No. 7,074,794) in an organic solvent such as ester solvents or alcoholic solvent. Ester solvent may be selected from Ethyl acetate, Isopropyl acetate, Tertiary butyl acetate and methyl acetate or alcohol solvent is selected from Methanol, Ethanol, Propanol and Isopropanol. Heating the solution at a temperature ranging between 40°C - reflux temperature of the solvent and slowly added the co-solvent to the reaction mass and followed by cooling the reaction mass. The reaction mass is stirred for 5 hours at temperature 25 - 30°C.

In a particular embodiment of the present invention, solvent is ethanol or methanol and co-solvent is diisopropyl ether.

In another embodiment, according to step e. recovering the amorphous form of Teneligliptin oxalate is carried out by filtration and washing with a suitable organic solvent followed by drying the compound under reduced pressure.

In a particular embodiment of present embodiment, stirring plays a very critical role in obtaining the desired characteristics of the end product i.e amorphous form of Teneligliptin oxalate.

In a particular embodiment, the time for stirring is kept about 4 hour to provide a good purity (exceeding 99.5%-by HPLC) product.

In another embodiment, the recovering the amorphous Teneligliptin oxalate is carried out by filtration, concentration, centrifugation, or combinations thereof, and washing with organic solvent selected from ester or alcohol followed by drying. Drying is carried out by drying under reduced pressure, vacuum tray drying, or air drying. Drying is carried out at a temperature of about 45-70°C for 5-15 hours.

In a particular embodiment, drying wet compound at temperature 60°C. Further, drying conditions may be employed as utilized by person skilled in the art.

Process of recovering the desired particle size amorphous form of Teneligliptin oxalate may further require conventional steps to obtain such desired particle sizes.

According to one embodiment of this aspect, the amorphous form of teneligliptin oxalate is characterized by X-ray powder diffraction (XRPD) pattern substantially as depicted in Fig 1.

In another embodiment of the present invention provides amorphous form of Teneligliptin oxalate which is characterized by TGA weight loss ranging between 2-4 % w/w.

In another embodiment of the present invention provides substantially pure amorphous form of Teneligliptin oxalate having HPLC purity of atleast 99.5 %.

The remaining steps of the embodiment shall be construed in line with the exemplified disclosure.

Substantially pure amorphous form of Teneligliptin oxalate obtained according to the process of the present invention results in the final API purity by HPLC of more than 99% and preferably greater than 99.5%. The purity of the amorphous form Teneligliptin oxalate (I) samples was measured using Chromatography. Chromatography was performed with Waters Alliance HPLC system (MILD, USA) that consists of quaternary pump equipped with a 2695 seperation module with inbuilt auto injector and 2996 photodiode array detector. The output signal was monitored and processed using chromelean software version 6.8.

In another embodiment of the present invention, preparation of crystalline form of Teneligliptin oxalate comprising the steps of:
a. providing a solution of amorphous Teneligliptin oxalate (I) according to claim 4 in a suitable organic solvent;
b. stirring the reaction mass obtained in step a for 3-10 hours at temperature ranging between 20 - 50°C;
c. reaction mass filtered and washed with a suitable organic solvent;
d. recovering the crystalline Teneligliptin oxalate salt.

In step a. of the present invention, providing amorphous form of Teneligliptin oxalate in organic solvent selected from ester solvent is selected from isopropyl acetate, ethyl acetate, isobutyl acetate, methyl acetate or alcohol is selected from methanol, ethanol, propanol and isopropanol or ether solvent is selected from diisopropyl ether, di-tertiary butyl ether, methyl tertiary butyl ether, tetrahydrofuran and mixture thereof.

In one of embodiment of the present invention, preparation of solution of amorphous form of Teneligliptin oxalate in ethyl acetate or diisopropyl alcohol at a temperature ranging between 20-50°C. The reaction mixture is stirred for 3-15 hours.

In a particular embodiment of the present invention, preparation of solution of amorphous form of Teneligliptin oxalate in ethyl acetate or diisopropyl ether at a temperature ranging between 20-30°C. The reaction mixture is stirred for 10 hours.

In another embodiment of the present invention, reaction mass is filtered and washed with a organic solvent selected from ester solvent is selected from isopropyl acetate, ethyl acetate, isobutyl acetate, methyl acetate or alcohol is selected from methanol, ethanol, propanol and isopropanol or ether solvent is selected from diisopropyl ether, di-tertiary butyl ether, methyl tertiary butyl ether, tetrahydrofuran and mixture thereof.

In a particular embodiment of the present invention, filtered and compound is washed with diisopropyl ether.

In another embodiment of the present invention, according to step d. is dried under reduced pressure at about 60°C for about 15 hours to obtain the crystalline form of Teneligliptin.

The amorphous form of Teneligliptin oxalate described herein may be characterized by X-ray powder diffraction pattern (XRPD). The samples of amorphous form of Teneligliptin oxalate were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source--Cu Ka radiation using the wavelength 1.5418°A. and lynx Eye detector. Illustrative examples of analytical data for the amorphous form of Teneligliptin oxalate obtained in the Examples are set forth in the FIG. 1.

In a further embodiment according to the specification, the invention also relates to a composition containing amorphous form of Teneligliptin oxalate of which at least 95%, by total weight of Teneligliptin oxalate in the composition, is the amorphous form.

The present invention provides a process for preparation of amorphous form of Teneligliptin oxalate having water content in range of 2 - 6%, preferably between 2 - 5%, as determined by the Karl Fischer method.

The amorphous form of Teneligliptin oxalate (I) obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.

In one embodiment of the present invention, it also includes premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with amorphous form of Teneligliptin oxalate (I), while retaining the amorphous form nature of the premix.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising amorphous form of Teneligliptin oxalate of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions of amorphous form of Teneligliptin oxalate of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

EXAMPLES
Example 1: Process for the preparation of amorphous Teneligliptin Oxalate:
Crystalline Teneligliptin oxalate (19.0 g) was added to methanol (75 ml) at temperature 25 - 35°C. The mass was heated to reflux. Slowly added diisopropyl ether (225 mL) to the mass. After addition the mass was cooled to room temperature. The mass was stirred at temperature 25 - 35°C for 4-5 hours. The reaction mass was filtered and washed with diisopropyl ether. The obtained compound was dried at 60°C for 10 hrs to yield the amorphous Teneligliptin oxalate.
Yield: 16 g;
Purity: 99.51% (by HPLC);
Moisture Content: 4.44% (by KF)

Example 2: Process for the preparation of amorphous Teneligliptin Oxalate:
Crystalline Teneligliptin oxalate (20.0 g) was added to mixture of ethanol (120 mL) and water (20.0 mL) at temperature 25 - 35°C. The reaction mixture was stirred at room temperature for 30-45 min. The reaction mass was filtered and washed with ethanol (20 mL). The mass was concentrated under vacuum at below 50°C and the obtained compound was dried at 60°C for 10 hrs to yield the amorphous Teneligliptin oxalate.
Yield: 19.5 g;
Purity: 99.88% (by HPLC);
Moisture Content: 5.35 % (by KF)

Example 3: Process for the preparation of Crystalline Teneligliptin Oxalate:
Amorphous Teneligliptin oxalate (5.0 g) was added to ethyl acetate (25 mL) at room temperature. The mass was stirred at room temperature for 4-5 hours. The reaction mass was filtered and washed with ethyl acetate (5.0 mL). The obtained compound was dried at 50°C for 10 hrs to yield the crystalline Teneligliptin oxalate.
Yield: 4.0 g;
Purity: 99.57% (by HPLC);

Example 4: Process for the preparation of Crystalline Teneligliptin Oxalate:
Amorphous Teneligliptin oxalate (5.0 g) was added to isopropyl alcohol (25 mL) at room temperature. The mass was stirred at room temperature for 4-5 hours. The reaction mass was filtered and washed with to isopropyl alcohol (5.0 mL). The obtained compound was dried at 50°C for 10 hrs to yield the crystalline Teneligliptin oxalate.
Yield: 4.0 g;
Purity: 99.58% (by HPLC);

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.