FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Teneligliptin Oxalate of Formula (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 crystalline Form Gl of Teneligliptin oxalate obtained by the process of the present invention, the said Form Gl being substantially pure and stable and characterized by X-ray powder diffraction comprising of atleast five 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 26°.
The present invention further relates to pharmaceutical compositions comprising crystalline 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-l-phenyl-lH-pyrazol-5-yl]-l-piperazinyl}(l,3-thiazolidin-3-yl)methanone and is represented by the general Formula
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-KCX radiation, X-Ray powder diffraction (XRD) peaks at 26° 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 29 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 20 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 20 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 20 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 20 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 20 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 crystalline form of Teneligliptin oxalate which is stable, non-hygroscopic, and thus has easy handling properties. The process of this invention provides crystalline form of Teneligliptin oxalate in substantially pure form, which is complying to ICH requirements for detectable impurities/contamination of any other previously known crystalline forms of Teneligliptin.

SUMMARY OF INVENTION
Particular aspects of the present invention relates to a process for the preparation of crystalline Form Gl of Teneligliptin oxalate. Crystalline Form Gl of Teneligliptin oxalate obtained by the process of the present invention is found to substantially pure and stable.In one aspect of the present invention, it relates to process for the preparation of crystalline Form Gl of Teneligliptin oxalate (I), characterized by X-ray powder diffraction angle peaks at 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 20° comprising the steps of: comprising the steps of:
a; providing a solution of Teneligliptin in an organic solvent;
b. adding oxalic acid to the step a.) solution;
c. stirring the reaction mass at temperature ranging between 20-40°C;
d. recovering the crystalline Teneligliptin oxalate salt.
In another aspect of the present invention relates to crystalline Form Gl of Teneligliptin oxalate, which is chracterised by
a) X-ray powder diffraction pattern comprising of at least five 20° 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 20°;
In another aspect of the present invention relates to substantially pure crystalline form Gl of Teneligliptin oxalate characterized by X-ray powder diffraction pattern comprising of atleast five diffraction angle peaks selected form 4. 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 26° having HPLC purity of atleast 99.5In a further aspect of the present application also relates to a pharmaceutical composition comprising crystalline Form Gl 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 crystalline Form Gl of Teneligliptin oxalate.
Fig. 2 is an example of Thermogravimetric analysis ("TGA") curve of crystalline Form Gl of Teneligliptin oxalate.

DETAILED DESCRIPTION
As set forth herein, embodiments of the present invention provide a reproducible and efficient process for the preparation of crystalline Form Gl of Teneligliptin oxalate (I). Crystalline Form Gl of Teneligliptin oxalate obtained by the process of the present invention is found to be substantially pure and stable. Said crystalline 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 crystalline Teneligliptin oxalate (I) designated as Form Gl, comprising the steps of:

comprising the steps of:
a. providing a solution of Teneligliptin in an organic solvent;
b. adding oxalic acid to the step a.) solution;
c. stirring the reaction mass at temperature ranging between 20-40°C;
d. recovering the crystalline 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 (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.
In another particular embodiment according to present application, the solution of step a. was prepared using ethyl acetate.
The solution was prepared in the temperature range between 20 - 40°C.
Inventors have also found that providing the solution of Teneligliptin may be carried out with ease in isopropyl alcohol or similar alcohols.
In the Step b of present embodiment, oxalic acid was added to the solution obtained in the Step a. Such addition of the oxalic acid to the solution was carried out preferably at temperature range between 20 - 40°C.

In the Step c of present embodiment, stirring plays a very critical role in obtaining the.-, desired characteristicsrofr-the Gl of Teneligliptin oxalate.
The stirring was carrying out at RPM ranging from 80 - 150, which resulted in the. slow crystallization forming the oxalate salt. A higher RPM may lead to formation of smaller -finer crystals with difficulty in filtration as well as effect on its shelf life stability.
The temperature during stirring remains in the range of 20-40°C, which was also found to be critical since higher temperature during stirring resulted in deterioration of quality parameters.
Usually stirring was found to be significantly important with time, as time duration longer than 4-5 hours was also found to effect deterioration of purity besides complete oxalate salt formation.
In a particular embodiment, the time for stirring was kept about 4 hour to provide a good purity (exceeding 99.5%-by HPLC) product.
In the step d of the embodiment, it provides recovering the crystalline Teneligliptin oxalate salt from the reaction mass obtained in Step c. The reaction mass was filtered and given washing with organic solvent selected from ester or alcohol.
In another embodiment of the present invention, it provides the following steps:
a. optionally adding activated carbon to the solution, stirring the solution followed by
filtering the solution and concentrating the reaction mass;
b. isolating the purified crystalline material;
c. drying under reduced pressure conditions to recover the crystalline Form Gl of
Teneligliptin oxalate.
The temperature to dry the wet compound ranges from 40-45°C. Further, drying conditions may be employed as utilized by person skilled in the art.
Process of recovering the desired particle size crystalline Form Gl of Teneligliptin oxalate may further require conventional steps to obtain such desired particle sizes.
The crystalline Form Gl of Teneligliptin oxalate described herein may be characterized by X-ray powder diffraction pattern (XRPD).

In another embodiment of the present invention provides crystalline Form Gl of Teneligliptin oxalate which is characterized by-
1. 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 29°;
2. TGA weight loss ranging between 2-5% w/w.
In another embodiment of the present invention provides substantially pure crystalline form Gl of Teneligliptin oxalate characterized by X-ray powder diffraction pattern comprising of atleast five diffraction angle peaks selected form 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 29° having HPLC purity of atleast 99.5 %.
The remaining steps of the embodiment shall be construed in line with the exemplified disclosure.
Substantially pure Crystalline Form Gl 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 crystalline Form Gl of Teneligliptin oxalate described herein may be characterized by X-ray powder diffraction pattern (XRPD). The samples of crystalline Form Gl 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 crystalline form Gl of Teneligliptin oxalate obtained in the Examples are set forth in the FIGS. 1 & 2.

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

The Crystalline Form Gl 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,
yrups, 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 Crystalline Form Gl of Teneligliptin oxalate (I), while retaining the crystalline 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 Crystalline Form Gl 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 Crystalline Form Gl of Teneligliptin oxalate of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever
EXAMPLES

Example 1: Process for the preparation of Teneligliptin Oxalate
Teneligliptin base (21.0 g) was added to ethylacetate (90 ml) at temperature 25 -30°C. Oxalic acid (6.9 gm) was added to the solution. The reaction mixture was stirred at temperature 25 - 30°C for 4 hours. The reaction mass was filtered and washed with ethyl acetate. The obtained compound was dried at 60°C under vacuum for 10 hrs to yield the crystalline Teneligliptin oxalate (designated as Form Gl). Yield: 19 g; Purity by HPLC: 99.57% Weight Loss by TGA: 3.2%
Crystalline Form Gl-XRPD diffraction angle peaks at 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 29°.

Example 2: Process for the preparation of Teneligliptin Oxalate
Teneligliptin base (21.0 g) was added to isopropanol (90 ml) at temperature 25 -30°C. Oxalic acid (6.9 gm) was added to the solution. The reaction mixture was stirred at temperature 25 - 30°C for 4-5 hours. The reaction mass was filtered and washed with isopropyl alcohol. The obtained compound was dried at 60°C under vacuum for 10 hrs to yield the crystalline Teneligliptin oxalate (designated as Form Gl).. Yield: 18 g; Purity by HPLC: 99.62%.Crystalline Form Gl-XRPD diffraction angle peaks at 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 20°.

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.