DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present application relates to novel crystalline form of Empagliflozin, process for its preparation and pharmaceutical composition thereof.

BACKGROUND OF THE INVENTION
The drug compound having the adopted name Empagliflozin, has a chemical name 1-chloro-4(beta-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl)-benzene, and is represented by the structure of formula I.

Empagliflozin is a sodium-dependent glucose cotransporter 2 (SGLT 2) inhibitor and is used for the treatment of patients with type 2 diabetes mellitus.
Empagliflozin and its synthetic methods are described in US Patent No. 7,579,449 (US ‘449). Example 3 of US ‘449 describes the isolation of Empagliflozin by drying the organic phase (ethyl acetate phase) over sodium sulphate and the solvent is removed, then the residue is purified using silica gel column chromatography (dichloromethane/ methanol 1:0?5:1).
US Patent No. 7,713,938 (US ‘938) discloses a crystalline form of Empagliflozin and a pharmaceutical composition comprising the crystalline form. The US ‘938 also discloses that “the method of manufacturing Empagliflozin as described in product patent process does not yield a crystalline form”.
Indian patent application (IN1985MUM2013A), PCT applications (WO2016051368A1, WO2016131431A1, WO2016169534A1 and WO2017046730A1), and Chinese patent applications (CN104788438A, CN105384730A1, CN105481843A, CN105496966A, CN106188021A and CN106317035A) describe various solid state forms and co-crystals of empagliflozin and processes for preparation thereof.
Polymorphism, the occurrence of different crystal forms, is a phenomenon of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties. Polymorphs in general will have different melting points, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
Discovering new polymorphic forms, hydrates and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid forms of Empagliflozin.

SUMMARY OF THE INVENTION
Aspects of the present application relate to novel crystalline forms of Empagliflozin, its preparative processes and pharmaceutical compositions thereof.
In one aspect, the present application provides a complex of empagliflozin with phenylalanine.
In another aspect, the present application provides a process for the preparation of the complex of empagliflozin with phenylalanine, comprising
(a) dissolving empagliflozin and phenylalanine in a solvent,
(b) storing the solution to precipitate the empagliflozin phenylalanine complex, and
(c) isolating the empagliflozin phenylalanine complex.
In another aspect, the present application provides a crystalline Form-Alpha (Form a) of Empagliflozin, characterized by a PXRD pattern as shown in Figure 2.
In another aspect, the present application provides a process for the preparation of crystalline Form-Alpha of Empagliflozin, comprising,
(a) dissolving empagliflozin in ethanol,
(b) adding propyl acetate to the solution of step (a),
(c) optionally cooling the suspension obtained in step (b), and
(d) isolating crystalline Form-Alpha of Empagliflozin.
In another aspect, the present application provides a crystalline Form-Beta (Form ß) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 3.44, 4.04, 9.35, 10.20 and 14.11 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form-Beta of Empagliflozin, comprising,
(a) dissolving empagliflozin in ethanol,
(b) adding butyl acetate to the solution of step (a),
(c) optionally cooling the suspension obtained in step (b), and
(d) isolating crystalline Form-Beta of Empagliflozin.
In another aspect, the present application provides a crystalline Form-Gamma (Form ?) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.82, 7.19, 10.17 and 11.20 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form ? of Empagliflozin, comprising,
(a) dissolving empagliflozin in dimethylacetamide,
(b) adding an anti-solvent to the solution of step (a),
(c) optionally cooling the suspension obtained in step (b), and
(d) isolating crystalline Form-Gamma of Empagliflozin.
In another aspect, the present application provides use of the crystalline forms of empagliflozin and the empagliflozin phenylalanine complex to improve the purity of empagliflozin.
In another aspect, the present application provides a pharmaceutical composition comprising empagliflozin phenylalanine complex or crystalline Form-Alpha or Form-Beta or Form-Gamma of Empagliflozin and at least one pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form of the complex of Empagliflozin with L-phenylalanine prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline Form-Alpha (a) of Empagliflozin prepared by the method of Example No 2.
Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline Form-Beta (ß) of Empagliflozin prepared by the method of Example No 3.
Figure 4 is an illustrative X-ray powder diffraction pattern of crystalline Form-Gamma (?) of Empagliflozin prepared by the method of Example No 4.

DETAILED DESCRIPTION
Aspects of the present application relate to novel crystalline forms of Empagliflozin, their preparative processes and pharmaceutical compositions thereof. The present application also encompasses the use of novel crystalline forms of Empagliflozin provided herein, for the preparation of other solid forms of Empagliflozin, for the purification of Empagliflozin and for the preparation of pharmaceutical dosage forms.
In one aspect, the present application provides a complex of empagliflozin with phenylalanine.
Empagliflozin forms a stable complex with L-phenylalanine. The empagliflozin phenylalanine complex can be prepared by the following process. The process comprising:
(a) dissolving empagliflozin and phenylalanine in a solvent,
(b) storing the solution to precipitate the empagliflozin phenylalanine complex, and
(c) isolating the empagliflozin phenylalanine complex.
The step (a) involves dissolving empagliflozin and phenylalanine in a suitable solvent to form a solution. The solution containing empagliflozin and phenylalanine may prepared by adding phenylalanine into a solution containing empagliflozin.
The solvent may be selected form the group comprising methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile and water or a mixture thereof. Preferably a mixture of ethanol and water is used.
To get the complete dissolution the mixture containing empagliflozin, phenylalanine and the solvent may be heated to elevated temperatures.
The step (b) involves storing the solution to precipitate empagliflozin phenylalanine complex. Storing the solution means keeping the solution or stirring the solution at below the temperature at which the solution is formed. Storing may be carried till the precipitation occurs. Storing may be continued for additional time to precipitate maximum product. Storing may be carried out at about 35 °C to about -10 °C. A precipitate will be formed upon storing the solution.
The step (c) involves isolation of empagliflozin phenylalanine complex. The suspension formed in the step (b) may be isolated by known techniques such as decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an aspect, the Empagliflozin Phenylalanine complex may optionally be dried under suitable drying conditions, at which the complex is stable.
In another aspect, the Empagliflozin Phenylalanine complex may be directly converted to any other solid form of Empagliflozin, without drying.
The Empagliflozin Phenylalanine complex is confirmed with the use of X-ray powder diffraction (XRPD), differential scanning calorimetry. The XRPD pattern is shown in Figure 1. The Empagliflozin Phenylalanine complex exhibits a crystalline character. The characteristic diffraction peaks are 8.28 and 16.45 ±0.2 °2?. Other characteristic diffraction peaks are 4.24, 24.67 and 25.32 ±0.2 °2?.
In another aspect, the present application provides a crystalline Form-Alpha (a) of Empagliflozin, characterized by a PXRD pattern as shown in Figure 2.
In another aspect, the present application provides a process for the preparation of crystalline Form-Alpha (a) of Empagliflozin, comprising,
(a) dissolving empagliflozin in a solvent,
(b) adding propyl acetate to the solution of step (a),
(c) optionally cooling the suspension obtained in step (b), and
(d) isolating crystalline Form-Alpha of Empagliflozin.
The step (a) involves dissolving empagliflozin in a solvent. The solvent may be selected from the group comprising methanol, ethanol, 2-propanol, acetone, methyl isobutyl ketone, tetrahydrofuran and water or mixtures thereof.
To dissolve empagliflozin in the solvent, empagliflozin is added to the solvent and the mixture may be heated to elevated temperatures.
Step (b) involves addition of propyl acetate. Propyl acetate may be added at about 10 °C to about 50 °C. After addition of propyl acetate the mixture may be cooled to about 0° C to about -30 °C to get suspension.
In an aspect, optionally seeds of crystalline Form-Alpha of Empagliflozin may be added to the mixture, when the mixture forms a homogenous solution. In an embodiment, seeds may be added at a suitable temperature and sufficient quantity such that the seeds are not dissolved.
The mixture may be cooled to a relatively lower temperature. In an embodiment, the mixture may be cooled to a suitable temperature before or after addition of seeds and may be further stirred at the same temperature for time sufficient, after cooling, to obtain crystalline Form-Alpha of Empagliflozin.
Step (d) involves isolation of crystalline Form-Alpha of Empagliflozin. Isolation of crystalline Form-Alpha of Empagliflozin may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Form-Alpha may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, the crystalline Form-Alpha of Empagliflozin may be optionally dried under suitable drying conditions, at which the Form-Alpha is stable. The XRPD pattern is shown in Figure 2.
In an alternate embodiment, the crystalline Form-Alpha of Empagliflozin may be directly converted to any other solid form of Empagliflozin, without drying.
In another aspect, the present application provides a crystalline Form-Beta (Form ß) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 3.44, 4.04, 9.35, 10.20 and 14.11 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form-Beta of Empagliflozin, comprising,
(a) dissolving empagliflozin in a solvent,
(b) adding butyl acetate to the solution of step (a),
(c) optionally cooling the suspension obtained in step (b), and
(d) isolating crystalline Form-Beta of Empagliflozin.
The step (a) involves dissolving empagliflozin in a solvent. The solvent may be selected from the group comprising methanol, ethanol, 2-propanol, acetone, methyl isobutyl ketone, tetrahydrofuran and water or mixtures thereof.
To dissolve empagliflozin in the solvent, empagliflozin is added to the solvent and the mixture may be heated to elevated temperatures.
Step (b) involves addition of butyl acetate. Butyl acetate may be added at about 10 °C to about 50 °C. After addition of butyl acetate the mixture may be cooled to about 0° C to about -30 °C to get suspension.
In an aspect, optionally seeds of crystalline Form-Beta of Empagliflozin may be added to the mixture, when the mixture forms a homogenous solution. In an embodiment, seeds may be added at a suitable temperature and sufficient quantity such that the seeds are not dissolved.
The mixture may be cooled to a relatively lower temperature. In an embodiment, the mixture may be cooled to a suitable temperature before or after addition of seeds and may be further stirred at the same temperature for time sufficient, after cooling, to obtain crystalline Form-Beta of Empagliflozin.
Step (d) involves isolation of crystalline Form-Beta of Empagliflozin. Isolation of crystalline Form- Form-Beta of Empagliflozin may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Form-Beta may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, the crystalline Form-Beta of Empagliflozin may be optionally dried under suitable drying conditions, at which the Form-Beta is stable. In an alternate embodiment, the crystalline Form-Beta of Empagliflozin may be directly converted to any other solid form of Empagliflozin, without drying.
The XRPD pattern of crystalline Form-Beta of Empagliflozin is shown in Figure 3. The characteristic diffraction peaks are 3.44, 4.04, 9.35, 10.20 and 14.11 ±0.2 °2?. Other characteristic diffraction peaks are 18.21, 19.13 and 24.20 ±0.2 °2?.
In another aspect, the present application provides a crystalline Form-Gamma (Form ?) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.82, 7.19, 10.17 and 11.20 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form ? of Empagliflozin, comprising,
(a) dissolving empagliflozin in dimethylacetamide,
(b) adding an anti-solvent to the solution of step (a),
(c) optionally cooling the suspension obtained in step (b), and
(d) isolating crystalline Form-Gamma of Empagliflozin.
The step (a) involves dissolving empagliflozin in N,N-dimethylacetamide.
To dissolve empagliflozin in the solvent, empagliflozin is added to N,N-dimethylacetamide and the mixture may be heated to elevated temperatures.
Step (b) involves addition of an anti-solvent. The anti-solvent may be selected form the group comprising n-Hexane, n-Heptane, diethyl ether, tertiary butyl methyl ether, diisopropyl ether, and pet ether. The anti-solvent may be added at about 10 °C to about 50 °C. After addition of the anti-solvent, the resulted mixture may be cooled to about 0° C to about 35 °C to get suspension.
In an aspect, optionally seeds of crystalline Form-Gamma of Empagliflozin may be added to the mixture, when the mixture forms a homogenous solution. In an embodiment, seeds may be added at a suitable temperature and sufficient quantity such that the seeds are not dissolved.
The mixture may be cooled to a relatively lower temperature. In an embodiment, the mixture may be cooled to a suitable temperature before or after addition of seeds and may be further stirred at the same temperature for time sufficient, after cooling, to obtain crystalline Form-Gamma of Empagliflozin.
Step (d) involves isolation of crystalline Form-Gamma of Empagliflozin. Isolation of crystalline Form-Gamma of Empagliflozin may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Form-Gamma may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, the crystalline Form-Gamma of Empagliflozin may be optionally dried under suitable drying conditions, at which the Form-Gamma is stable. In an alternate embodiment, the crystalline Form-Gamma of Empagliflozin may be directly converted to any other solid form of Empagliflozin, without drying.
The XRPD pattern of crystalline Form-Gamma of Empagliflozin is shown in Figure 4. The characteristic diffraction peaks are 4.82, 7.19, 10.17 and 11.20 ±0.2 °2?. Other characteristic diffraction peaks are 4.18, 18.15, 23.55 and 23.90 ±0.2 °2?.
In another embodiment, the present application provides a pharmaceutical composition comprising empagliflozin phenylalanine complex or the crystalline Form-Alpha or the crystalline Form-Beta or the crystalline Form-Gamma of Empagliflozin and at least pharmaceutically acceptable carrier.
In another aspect, the present application provides crystalline forms of Empagliflozin described in this application having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC.
In another aspect, the present application provides crystalline forms of Empagliflozin described in this application or their pharmaceutical composition, wherein particle size (D90) of Empagliflozin may be less than 200 microns or less than 100 microns or less than 50 microns or less than 20 microns.
In another aspect, the present application provides a method of treating or preventing type 2 diabetes, comprising administering to a subject in need thereof an effective amount of crystalline Forms of Empagliflozin described above or a pharmaceutical composition thereof. “A therapeutically effective amount” as used herein refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject. In one embodiment, the therapeutic benefit is maintaining glucose homeostasis, or regulating blood glucose levels.
In additional embodiments, the above crystalline Forms of Empagliflozin are used for the preparation of a medicament for treating conditions mediated by SLGT2, preferably type 2 diabetes.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise.
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
The terms “crystalline" indicates that the Empagliflozin is present in substantially crystalline Form. Substantially crystalline denotes that atleast 80 %, preferably 90 % or 95 %, more preferably all of the Empagliflozin is crystalline form. In other words, "crystalline form" of Empagliflozin denotes Empagliflozin, which does not contain substantial amounts, preferably does not contain noticeable amounts, of any other crystalline portions of Empagliflozin e.g. measurable upon X-ray powder diffraction analysis. Celite is flux-calcined diatomaceous earth. Hyflo is flux-calcined diatomaceous earth treated with sodium carbonate.
X-ray powder diffraction patterns described herein were generated using a PANAlytical Advance powder X-ray diffractometer with a copper K-alpha radiation source. Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ±0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2?) ±0.2° of 6.3°" means "having a diffraction peak at a diffraction angle (2?) of 6.1° to 6.5°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peak relationships and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the PXRD peaks may vary somewhat, depending on factors such as the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrumental variation and other factors may slightly affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments may vary by plus or minus about 0.2°. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a filter is used or not).

EXAMPLES
Example 1: Preparation of Empagliflozin L-phenylalanine complex.
Empagliflozin (300 mg) and L-phenylalanine (143 mg) were added to water ethanol mixture (1:1, 14 mL) at 25°C and the mixture was heated to 50 °C using a hot air gun to form clear solution. The solution was kept idle for 14 days at 5 ° C. The precipitation was filtered to obtain the title compound. PXRD pattern: Figure 1.
Example 2: Preparation of crystalline Form-Alpha of Empagliflozin.
Empagliflozin (100 mg) and ethanol (4 mL) were charged into a test tube and the mixture was heated to 70 °C to get clear solution and the clears solution was filtered for particle free. Propyl acetate (10 mL) was added to the test tube at 25°C and the mixture was kept at -20 °C for 4 days and the solid was filtered to obtain the title compound. PXRD pattern: Figure 2.
Example 3: Preparation of crystalline Form-Beta of Empagliflozin.
Empagliflozin (500 mg) and ethanol (20 mL) were charged into a round bottom flask and the mixture was heated to 70 °C to get clear solution and the clears solution was filtered for particle free. Butyl acetate (50 mL) was added to the test tube at 25°C and the mixture was kept at -20 °C for 22 days and the solid was filtered and dried in a vacuum tray drier to obtain the title compound. PXRD pattern: Figure 3.
Example 4: Preparation of crystalline Form-Gamma of Empagliflozin.
Empagliflozin (1000 mg) and dimethylacetamide (2 mL) were charged into a round bottom flask. The solid dissolved and isolated immediately. N-Hexane (20 mL) was added to the mixture at 25°C, thick mass was formed. The suspension was filtered and the solid was washed with diethyl ether (10 mL) and the solid was dried in an air tray drier obtain the title compound. PXRD pattern: Figure 4.
,CLAIMS:CLAIMS
We claim
1. A complex of empagliflozin with phenylalanine.
2. The empagliflozin phenylalanine complex of claim 1 is characterized by PXRD pattern comprising the peaks at about 8.28 and about 16.45 ±0.2 °2?.
3. The empagliflozin phenylalanine complex of claim 1 is characterized by PXRD pattern comprising the peaks at about 4.24, 24.67 and 25.32 ±0.2 °2?.
4. A process for the preparation of empagliflozin phenylalanine complex of claim 1, comprising
(a) dissolving empagliflozin and phenylalanine in a solvent,
(b) storing the solution to precipitate the empagliflozin phenylalanine complex, and
(c) isolating the empagliflozin phenylalanine complex.
5. Crystalline Form-Alpha (Form a) of Empagliflozin, characterized by a PXRD pattern as shown in Figure 2.
6. A process for preparation of crystalline Form-Alpha of Empagliflozin, comprising,
(a) dissolving empagliflozin in ethanol,
(b) adding propyl acetate to the solution of step (a),
(c) optionally cooling the suspension obtained in step (b), and
(d) isolating crystalline Form-Alpha of Empagliflozin.
7. Crystalline Form-Beta (Form ß) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 3.44, 4.04, 9.35, 10.20 and 14.11 ± 0.2° 2?.
8. A process for preparation of crystalline Form-Beta of Empagliflozin, comprising,
(a) dissolving empagliflozin in ethanol,
(b) adding butyl acetate to the solution of step (a),
(c) optionally cooling the suspension obtained in step (b), and
(d) isolating crystalline Form-Beta of Empagliflozin.
9. Crystalline Form-Gamma (Form ?) of Empagliflozin, characterized by a PXRD pattern comprising the peaks at about 4.82, 7.19, 10.17 and 11.20 ± 0.2° 2?.
10. A process for preparation of crystalline Form ? of Empagliflozin, comprising,
(a) dissolving empagliflozin in dimethylacetamide,
(b) adding an anti-solvent to the solution of step (a),
(c) optionally cooling the suspension obtained in step (b), and
(d) isolating crystalline Form-Gamma of Empagliflozin.