FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation Cry; Form G1 of Ertugliflozin of Formula (I).

The invention also relates to crystalline Form Gl obtained by the process of the present invention, the said Form G 1 being substantially pure, stable and characterized by X- ray powder diffraction pattern comprising of atleast five 2Θ ⁰ peaks selected from 4.4, 1 1.0, 13.1 , 15.0, 15.4, 16.6, 1 8.1 , 18.3, 18.7, 20.3, 21.1 , 21 .7 and 23.9 ± 0.2 2Θ°.

The present invention further relates to pharmaceutical compositions comprising crystalline Form Gl of Ertugliflozin, useful in treatment of type 2 diabetes mellitus.

BACKGROUND OF THE INVENTION

Ertugliflozin, chemically (l S,2S,3S,4R,5S)-5-{4-chloro-3-[(4-etoxyphenyl)methyl] phenyl}- l-(hydroxymethyl)-6,8-dioxabicyclo[3.2. l ]octane-2,3,4-triol, is represented by formula I.

Ertugliflozin (PF-04971729, MK 8835) is a selective sodium ;lucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes mellitus. Vincent Masciiti et al in U.S. patent No. 8,080,580 discloses processes for the preparation of ertugliflozin. This patent also discloses conversion of ertugliflozin to ertugliflozin L-pyroglutamic acid.

Steven J. BRENEK et al in PCT Publication No. WO 2014/15915 1 discloses a process for the preparation of ertugliflozin and its conversion to ertugliflozin L-pyroglutamic acid. According to Example 6 of this patent application, Ertugliflozin obtained as amorphous form of ertugliflozin.

Sun Lin et al in Chinese patent application CN 105646603 A disclosed a crystalline Form A of Ertugliflozin which is characterized using Cu-κα radiation, X-Ray powder diffraction (XRD) peaks at 29° expressed in 5-0 ± 0-2°, 6-6 ± 0-2°, 7· 5 ± 0-2°, 16-2 ± 0-2°, 18 -5 ± 0 -2°, 19.1 ± 0.2°, 19.7 ± 0.2°, 21.6 ± 0.2°, 22.2 ± 0.2°, 24.5 ± 0.2°, 24.8 ± 0.2 °, 25.8 ± 0.2°, 26-8 ± 0-2°, 27-8 ± 0-2°, 29-5 ± 0-2°.

Sun Lin et al in Chinese patent application CN105646604 A disclosed another crystalline Form B of Ertugliflozin and this is characterized using Cu-κ radiation, X-Ray powder diffraction (XRD) peaks at 20° expressed in 6.7 ± 0.2°, 7.5 ± 0.2°, 11.8 ± 0.2°, 12.3 ± 0.2°, 12.6 ± 0.2°, 15.2 ± 0.2°, 15.8 ± 0.2°, 16.3 ± 0.2°, 19.8 ± 0.2°, 20.2 ± 0.2°, 20.9 ± 0.2°, 21.2 ± 0.2°, 21.8 ± 0.2°, 22.6 ± 0.2°, 24.0 ± 0.2°, 24.2 ± 0.2°, 25.1 ± 0.2°, 26.7 ± 0.2°, 27.0 ± 0.2°, 27.3 ± 0.2°, 27.4 ± 0.2°, 27.5 ± 0.2°.

Ertugliflozin being an important therapeautic agent useful in the treatment of type 2 diabetes mellitus. Additional and improved ways of preparing new polymorphic forms of Ertugliflozin 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 crystalline form of Ertugliflozin 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 a stable polymorphic crystalline form of Ertugliflozin, designated as Form Gl which is stable, non- hygroscopic, and thus has easy handling properties. The process of this invention provides the crystalline Form G 1 of Ertugliflozin in substantially pure form, which is compiling to ICH requirements for detectable impurities/contamination of any other previously known crystalline forms of Ertugliflozin. SUMMARY OF INVENTION

Particular aspects of the present invention relates to a process for the preparation of crystalline Form G l of Ertugliflozin (I). Crystalline Form G l of Ertugliflozin 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 Ertugliflozin (I), characterized by X-ray powder diffraction angle peaks at 4.4, 11.0, 13.1, 15.0, 15.4, 16.6, 18.1, 18.3, 18.7, 20.3, 21.1 , 21.7 and 23.9 ± 0.2 °2Θ comprising the steps of:

a. providing a solution of Ertugliflozin in the aqueous solution;

b. stirring the reaction mass at temperature ranging between 5 - 35°C; c. recovering the crystalline Ertugliflozin.

In another aspect of the present invention relates to crystalline Form Gl of

Ertugliflozin, which is chracterised by

a) X-ray powder diffraction pattern comprising of at least five 20° peaks selected from 4.4, 11.0, 13.1 , 15.0, 15.4, 16.6, 18.1 , 18.3, 18.7, 20.3, 21.1 , 21.7 and 23.9 ± 0.2 °2Θ;

b) DSC isothermal peak ranging 50 - 60°C;

c) TGA weight loss ranging between 5 - 6.5% w/w.

In another aspect of the present invention relates to substantially pure crystalline form Gl of Ertugliflozin characterized by X-ray powder diffraction pattern comprising of atleast five diffraction angle peaks selected form 4.4, 1 1.0, 13.1, 15.0, 15.4, 16.6, 18.1 , 18.3, 18.7, 20.3, 21.1, 21.7 and 23.9 ± 0.2 °2Θ having HPLC purity of atleast 99.5 % and deschloro impurity (II)

Dcsdiloi o Iiupunty (II) less than 0.15%.

In a further aspect of the present application also relates to a pharmaceutical composition comprising crystalline Form Gl of Ertugliflozin of the present application and atleast one or more pharmaceutically acceptable excipients. Such composition is sustatially free of any other previously known crystalline forms of Ertugliflozin.

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 G l of Ertugliflozin.

Fig. 2 is an example of Differential Scanning Calorimetry ("DSC") curve of Form Gl of Ertugliflozin.

Fig. 3 is an example of Thermogravimetric analysis ("TGA") curve of Form Gl of

Ertugliflozin.

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 Ertugliflozin (I). Crystalline Form Gl of Ertugliflozin obtained by the process of the present invention is found to be substantially pure and stable.

In another embodiment according to present application, it provides a process for the preparation of crystalline Form Gl of Ertugliflozin (I), comprising the steps of:

a. providing a solution of Ertugliflozin in the aqueous solution; b. stirring the reaction mass at temperature ranging between 5 to 30 °C;

c. recovering the crystalline Ertugliflozin.

Individual steps of the embodiments are detailed herein below.

In the step of providing a solution according to the present invention, it comprises the source of Ertugliflozin that may be obtained according any of prior disclosure viz. U.S. patent No. 8,080,580 B2. In the present invention, the material was obtained as per the Route of synthesis delineated in Scheme I. The material obtained was amorphous material possessing a HPLC purity of about 97 %.

Scheme I

In the step of providing a solution according to the present invention, Ertugliflozin as obtained was dissolved in aqueous solution such as sodium chloride solution or in sucrose solution or mixture of water and C 1 -C4 alcoholic solvent. The ratio of sodium chloride in water solution is in the range from 1 - 10% (w/w). The ratio of sucrose in water solution is in the range from 1 - 10% (w/w). Stirring the reaction mass performed for not less than 10 hours at temperature 5 - 30°C.

In a particular embodiment according to present application, making solution is in the temperature range of 25 - 30°C.

In a particular embodiment according to present application, solution is a mixture of water and Isopropyl alcohol.

In the Step b of present embodiment, stirring plays a very critical role in obtaining the desired characteristics of the end product i.e Form Gl of Ertugliflozin.

In a particular embodiment the stirring was carrying out at RPM ranging from 80

150.

In the step c of present invention to recover the crystalline Form G of Ertugliflozin, the reaction mass obtained in Step b is filtered and given washing with water. The amount water ranging from ranges from 1 -3 times (w/v) w.r.t the amount of Ertugliflozin used in the initial step. In another embodiment of the present invention 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 crystalline material;

c. drying under reduced pressure conditions to recover the crystalline Form Gl of Ertugliflozin.

The temperature to dry the wet compound ranges from 40-45°C. Further, drying conditions may be employed by a person skilled in the art.

Process of recovering the crystalline Form Gl of Ertugliflozin may further require conventional steps to obtain desired particle size.

The crystalline Form Gl of Ertugliflozin described herein may be characterized by X- ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetry (DSC) analysis.

In another embodiment of the present invention provides Ertugloflozin used in the present application is in the form of crystalline or in amorphous form.

In another embodiment of the present invention provides crystalline Form Gl of Ertugliflozin which is characterized by- 1 . 4.4. 1 1 .0. 1 3.1 . 15.0. 15.4. 1 6.6. 1 8.1 , 1 8.3. 1 8.7, 20.3. 2 1 .1. 21 .7 and 23.9 ± 0.2

°2Θ;

2. DSC isothermal peak ranging 50 - 60°C;

3. TGA weight loss ranging between 5 - 6.5% w/w. In another embodiment of the present invention provides substantially pure crystalline form Gl of Ertugliflozin characterized by X-ray powder diffraction pattern comprising of atleast five diffraction angle peaks selected form 4.4, 1 1.0. 13.1 , 15.0, 15.4, 16.6, 18.1 , 18.3. 18.7, 20.3, 21.1 , 21.7 and 23.9 ± 0.2 °2Θ having HPLC purity of atleast 99.5 % and deschloro impurity (II)

Deschloro Impurity

less than 0.15%.

In a specific embodiment, crystalline form Gl of Ertugliflozin can be prepared using the process in which Ertugliflozin was added to 10% sodium chloride solution at temperature 25 - 30°C. The reaction mixture was stirred at temperature 25 - 30°C. The reaction mass was filtered and washed with water. The obtained compound was dried at under vacuum to yield the crystalline Form Gl of Ertugliflozin and the characteristic °2Θ values of crystalline Form Gl of Ertugliflozin are provided in Table 1 :

Table 1

14.9 5.9 34.9%

15.3 5.7 34.3%

1 6.5 5.3 55.1 %

16.7 5.2 24.6%

17.2 5.1 20.3%

17.9 4.9 41.0%

18.2 4.8 100%

18.6 4.7 31.6%

19.5 4.5 15.6%

20.2 4.3 50.7%

21.1 4.2 42.4%

21.7 4.0 46.9%

23.8 3.7 31 .5%o

24.5 3.6 22.1 %

25.0 3.5 1 1.6%

25.5 3.4 1 1.4%

27.8 3.2 19.5%

28.6 3.1 16.4%

29.0 3.0 15.1 %

30.2 2.9 22.5%

32.6 2.7 16.0%

* The relative peak intensities may vary depending on the crystal size and habit.

In a particular embodiment according to present application, Deschloro impurity is reduced to less than 0.15% using the mixture of water and lsopropyl alcohol.

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

Substantially pure Crystalline Form Gl of Ertugliflozin 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 Ertugliflozin described herein may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetry (DSC) analysis. The samples of crystalline Form G 1 of Ertugliflozin 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. DSC was done on a Perkin Elmer instrument. Illustrative examples of analytical data for the crystalline form Gl of Ertugliflozin obtained in the Examples are set forth in the FIGS. 1 -3.

In a further embodiment according to the specification, the invention also relates to a composition containing Crystalline Form Gl of Ertugliflozin of which at least 95%, by total weight of Ertugliflozin in the composition, is the crystalline form Gl . In yet another embodiment of the invention, the composition may be substantially free of any other known forms of Ertugliflozin or any other crystalline form.

The Crystalline Form Gl of Ertugliflozin (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 Crystalline Form Gl of Ertugliflozin (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 r any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising Crystalline Form Gl of Ertugliflozin 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 Ertugliflozin 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 crystalline Form Gl of Ertugliflozin using water.

Amorphous Ertugliflozin (50.0 g) was added to water (250 ml) at temperature 25 - 30°C. The reaction mixture was stirred at temperature 25 - 30°C for 18 hours. The reaction mass was filtered and washed with water. The obtained compound was dried at 40-45 °C under vacuum to yield the crystalline Form Gl of Ertugliflozin.

Yield: 45 g; Weight Loss by TGA: 5.22%

Water content: 5.98% (by KF)

DSC: onset 49.13°C, peak average: 51.87°C,

Example 2: Process for the preparation of crystalline Form Gl of Ertugliflozin using 10 % Sodium chloride solution.

Amorphous Ertugliflozin (7.0 g) was added to 10% sodium chloride solution (35 ml) at temperature 25 - 30°C. The reaction mixture was stirred at temperature 25 - 30°C for 18 hours. The reaction mass was filtered and washed with water. The obtained compound was dried at 40-45 °C under vacuum to yield the crystalline Form G l of Ertugliflozin. Yield: 6.3 g;

PXRD Peaks: 4.4, 1 1.0, 13.1 , 15.0. 15.4, 16.6, 18.1 , 18.3, 18.7. 20.3, 21.1 , 21.7 and 23.9 °2Θ Weight Loss by TGA: 5.28%;

Water Content: 6.05% (by KF)

DSC: onset 48.1 1°C, Peak average: 51.14°C

Example 3: Process for the preparation of crystalline Form Gl of Ertugliflozin using 5% Sucrose solution.

Amorphous Ertugliflozin (1 .0 g) added to 5% sucrose solution (5 ml) at temperature 25 - 30°C. Stirring the reaction mixture was performed at temperature 25 - 30°C for 18 hours. The reaction mass was filtered and washed with water. The obtained compound was dried at 40-45°C under vacuum to yield the crystalline Form Gl of Ertugliflozin.

Yield: 0.9 g;

Weight Loss by TGA: 5.32%

Water Content: 5.97% (by KF)

DSC: onset 50.93°C, Peak average: 53.34°C

Example 4: Process for the preparation of crystalline Form Gl of Ertugliflozin using water.

Amorphous Ertugliflozin (5.0 g) was added to water (250 ml) at temperature 25 -

30°C. Stirring the reaction mixture was performed at temperature 25 - 30°C. To the reaction mass activated carbon was added and stirred at temperature 25 - 30°C. The reaction mass was concentrated and filtered. The obtained compound washed with water and dried at 40-45°C under vacuum to yield the crystalline Form Gl of Ertugliflozin.

Yield: 4.5g; Weight Loss by TGA: 5.34%

Example 5:

Ertugliflozin (5.0 g) was dissolved in mixture of water (22.5 ml) and isopropyl alcohol at temperature 25-30°C. The reaction mass was stirred at temperature 25-30°C. The reaction mass was filtered. The solid obtained was dried under vacuum to yield crystalline Form Gl of Ertugliflozin.

Yield : 4.5 g

HPLC: 99.5% (Deschloro impurity: -0.11%)

Water content: 6.27 % (by KF).

Dcschloro Impurity (Π)

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.