DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]

A NOVEL POLYMORPH OF SITAGLIPTIN HYDROCHLORIDE AND PROCESS FOR ITS PREPARATION THEREOF

HIKAL LIMITED, an Indian company of 3A & 3B, International Biotech Park, Hinjewadi, Pune – 411057, Maharashtra, India

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION:
The present invention relates to a novel polymorphic form of Sitagliptin hydrochloride and processes for its preparation thereof.

BACKGROUND OF THE INVENTION:
Sitagliptin is an orally-active dipeptidyl peptidase-4 (DPP-IV) enzyme inhibitor that improves glycaemic control in patients with Type 2 diabetes mellitus. Sitagliptin is chemically known as (R)-3-amino-1-[3-(trifluoromethyl)-5,6,dihydro [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-1-one and is represented by the following structural Formula I:

Sitagliptin is currently marketed under the brand name JANUVIA which contains Sitagliptin phosphate monohydrate.

The U.S. Patent 6,699,871 discloses a class of beta-amino- tetrahydrotriazolo[4,3-a]pyrazines such as Sitagliptin, processes for their preparation, pharmaceutical compositions and method of use thereof. This patent also discloses a process for the preparation of hydrochloride salt of Sitagliptin.

The PCT publication WO 2005/072530 discloses crystalline Sitagliptin hydrochloride monohydrate characterized by its PXRD, IR spectra and DSC thermogram. This publication also discloses process for its preparation and pharmaceutical composition comprising the same.
The PCT publication WO 2010/000469 discloses crystalline forms of Sitagliptin monobasic, dibasic and tribasic acid addition salts such as hydrochloric acid (Form I and Form II).

The US patent 8,183,373 discloses crystalline forms of Sitagliptin hydrochloride designated as Form III, Form IV and Form V.

The PCT publication WO 2008/000418 discloses a process for the preparation of Sitagliptin hydrochloride in amorphous form.

The PCT publication WO 2012/147092 discloses crystalline form of Sitagliptin hydrochloride and process for its preparation.

The US patent publication 2013/158265 discloses crystalline forms of Sitagliptin hydrochloride designated as Form III, Form IV and Form V.

The PCT publication WO 2015/170340 discloses Sitagliptin hydrochloride Form-Ll (acetonitrile solvate), Form-L2 (ethyl acetate solvate), Form-L3, Form-L4 (ethanol solvate), Form-L5 (methyl acetate solvate), Form-L6 (formic acid solvate), Form-L7 (1-butanol solvate), Form-L8, Form-L9, Form-L10, Form-L11, Form-L12, Form-L13 (isobutyl methyl ketone solvate), Form-L14 and Form-L15.

The Indian patent publication IN202021034338 discloses preparation of Sitagliptin hydrochloride monohydrate.

Polymorphic forms of a compound can be distinguished by analytical methods such as X-ray diffraction spectroscopy, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself, or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.

The discovery of new polymorphic forms of a pharmaceutically useful compound, like Sitagliptin, may provide a new opportunity to scientists to improve the physicochemical properties, and performance characteristics of a pharmaceutical product.

The inventors of the present application have discovered the new polymorphic form of Sitagliptin hydrochloride designated as Sitagliptin hydrochloride Form-H1. The inventors of the present application have also discovered the process for preparation of said Sitagliptin hydrochloride Form-H1.

SUMMARY OF THE INVENTION:
The present invention provides a novel polymorphic form “Form-H1” of Sitagliptin hydrochloride.

The present invention also provides a process for preparation of Sitagliptin hydrochloride Form-H1, comprising:
a) adding Sitagliptin phosphate in isopropyl alcohol,
b) adding hydrochloric acid,
c) heating the reaction mixture to 50 to 80 °C to obtain clear solution,
d) optionally adding the seed crystals Sitagliptin hydrochloride monohydrate,
e) cooling the solution to precipitate the solid, and
f) isolating.

The present invention also provides a process for preparation of Sitagliptin hydrochloride Form-H1, comprising:
a) adding Sitagliptin free base in isopropyl alcohol,
b) adding hydrochloric acid,
c) heating the reaction mixture to 50 to 80 °C to obtain clear solution,
d) optionally adding the seed crystals Sitagliptin hydrochloride monohydrate,
e) cooling the solution to precipitate the solid, and
f) isolating.

The present invention further relates to converting Sitagliptin hydrochloride Form-H1 into Sitagliptin hydrochloride monohydrate.

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1: Characteristic powder X-ray diffraction (XRD) pattern of Sitagliptin hydrochloride Form-H1.
Figure 2: Thermogravimetric analysis (TGA) curve of Sitagliptin hydrochloride Form-H1.
Figure 3: Differential scanning calorimetry (DSC) curve of Sitagliptin hydrochloride Form-H1.
Figure 4: Characteristic powder X-ray diffraction (XRD) pattern of Sitagliptin hydrochloride monohydrate.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention now will be described more detail hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements.

In one aspect the present invention provides novel polymorphic form of Sitagliptin hydrochloride and processes for its preparation.

The polymorphic form of Sitagliptin hydrochloride of the present invention have advantageous properties selected from at least one of: chemical purity, flowability, solubility, morphology or crystal habit, stability, low hygroscopicity, and low content of residual solvents.

The term “solvent” as used herein, refers to the single solvent or mixture of solvents.

The term "solvate" as used herein, refers to a crystal form that incorporates a solvent in the crystal structure. The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

The polymorphic form of Sitagliptin hydrochloride of the present invention is characterized by one or more analytical methods such as X-ray Powder Diffraction (XRPD) Patterns, Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC).

In one embodiment, the present invention provides novel polymorphic form of Sitagliptin hydrochloride, which is designated as Sitagliptin hydrochloride Form-H1.

In another embodiment, the Sitagliptin hydrochloride Form-H1 of the present invention is an isopropyl alcohol solvate.

In another embodiment, the present invention provides Sitagliptin hydrochloride Form-H1 characterized by a powder X-Ray diffraction pattern in accordance with Figure 1.

In another embodiment, the present invention provides Sitagliptin hydrochloride Form-H1 characterized by a powder X-Ray diffraction pattern having one or more peaks at about 5.9, 6.9, 10.0, 16.2, 17.4, 20.1, 22.0, 24.7, 26.0, 27.8 and 33.6 ± 0.2° 2?.

In another embodiment, the present invention provides Sitagliptin hydrochloride Form-H1 characterized by a thermogravimetric analysis (TGA) curve in accordance with Figure 2.

In another embodiment, the present invention provides Sitagliptin hydrochloride Form-H1 characterized by a thermogravimetric analysis (TGA) wherein Sitagliptin hydrochloride Form-H1 indicated a weight loss of about 7 - 11 % from ambient temperature to about 120 °C.

In another embodiment, the present invention provides Sitagliptin hydrochloride Form-H1 characterized by a differential scanning calorimetry (DSC) curve in accordance with Figure 3.

In another embodiment, the present invention provides Sitagliptin hydrochloride Form-H1 characterized by a differential scanning calorimetry (DSC) wherein Sitagliptin hydrochloride Form-H1 exhibited a broad endotherm at about 70 - 120 °C, may be attributed due to evolution of isopropyl alcohol solvent.

In another aspect, the present invention provides a process for preparation of Sitagliptin hydrochloride Form-H1, comprising:
a) adding Sitagliptin phosphate in isopropyl alcohol,
b) adding hydrochloric acid,
c) heating the reaction mixture to 50 to 80 °C to obtain clear solution,
d) optionally adding the seed crystals Sitagliptin hydrochloride monohydrate,
e) cooling the solution to precipitate the solid, and
f) isolating.

In yet another aspect, the present invention provides a process for preparation of Sitagliptin hydrochloride Form-H1, comprising:
a) adding Sitagliptin free base in isopropyl alcohol,
b) adding hydrochloric acid,
c) heating the reaction mixture to 50 to 80 °C to obtain clear solution,
d) optionally adding the seed crystals Sitagliptin hydrochloride monohydrate,
e) cooling the solution to precipitate the solid, and
f) isolating.

In one embodiment of the present invention, the Sitagliptin phosphate salt is anhydrate or monohydrate having at least 95 % HPLC purity.

In another embodiment of the present invention, the Sitagliptin free base having at least 95 % HPLC purity.
In another embodiment of the present invention, the isopropyl alcohol added to Sitagliptin phosphate or sitagliptin free base at temperature 25 to 35 °C.

In another embodiment of the present invention, the hydrochloric acid added at temperature 25 to 35 °C.

In another embodiment of the present invention, wherein the reaction mixture heated to 50 - 80 °C to obtain clear solution and optionally filtered through micron filter.

In another embodiment of the present invention, wherein the filtrate obtained by filtering the clear solution through micron filter is heated to 50 - 80 °C.

In another embodiment of the present invention, wherein the Sitagliptin hydrochloride monohydrate seed crystals having HPLC purity at least 99.5 % used.

In another embodiment of the present invention, wherein the Sitagliptin hydrochloride monohydrate seed crystals added from 0.1 to 2 % with respect to Sitagliptin phosphate salt or sitagliptin free base.

In another embodiment of the present invention, the Sitagliptin hydrochloride monohydrate seed crystals added at 25 to 50 °C.

In another embodiment of the present invention, wherein the clear reaction solution is cooled to -10 to 30 °C to precipitate the Sitagliptin hydrochloride Form-H1.

In another embodiment of the present invention, the Sitagliptin hydrochloride Form-H1 can be isolated by the methods known in the art, for example filtration.

In yet another aspect, the present invention provides converting the Sitagliptin hydrochloride Form-H1 into Sitagliptin hydrochloride monohydrate by drying, for example drying in vacuum tray dryer (VTD) or in air tray dryer (ATD) or in Rotocone vapor dryer (RCVD) or in Agitated nutsche filter dryer (ANFD).

In another embodiment of the present invention, the Sitagliptin hydrochloride Form-H1 having HPLC purity at least 99.0 %.

In another embodiment of the present invention, the Sitagliptin hydrochloride Form-H1 can be converted into Sitagliptin hydrochloride monohydrate by drying at 25 - 75 °C under vacuum.

In another embodiment, the Sitagliptin hydrochloride monohydrate obtained by drying the Sitagliptin hydrochloride Form-H1 of the present invention, is characterized by a powder X-Ray diffraction pattern in accordance with Figure 4.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXPERIMENTAL:
The X-Ray powder diffraction pattern was obtained on Bruker D8 advance diffractometer (Bruker, Germany) using Cu-Ka X-radiation (? = 1.5406 Å) at 40 kV and 40 mA powers. X-ray diffraction patterns were collected over the 2? range 2° to 40° with time per step 0.5(s).
The DSC data was obtained using Differential Scanning Calorimetry (DSC 3+) from Mettler Toledo, measuring from 25°C to 400°Cat 10°C/min and samples of 2-10 mg each were purged by a stream of nitrogen flowing at 60 mL/min. The Aluminium standard crucibles of 40µL with pin were used. The evaluation of the results was performed using STARe software from Mettler-Toledo.

TGA data were obtained using Thermogravimetric analysis (TGA 2), on Mettler Toledo measuring from 30°C to 400°C at 10°C/min and samples of 4-10 mg each were purged by a stream of nitrogen flowing at 60 mL/min. The Aluminium standard crucibles of 40µL with pin were used. The evaluation of the results was performed using STARe software from Mettler-Toledo.

Example 1: Preparation of Sitagliptin hydrochloride Form-H1.
50 gm Sitagliptin phosphate (anhydrate) was added in isopropyl alcohol (6.7 V) at 25 - 30 °C and stirred for 10 - 15 min. The dilute hydrochloric acid solution (prepared from 11.8 ml of conc. hydrochloric acid in 26 ml of Water) was added drop wise to above under stirring and maintained for 10 - 15 min. The mixture was then heated up to 65 - 70 °C, maintained for 40 - 60 min, filtered through micron filter, and washed with 0.6 V of isopropyl alcohol : water solution (0.54 : 0.06 V/V). The filtrate obtained was heated to 65 - 70 °C, cooled gradually to 25 - 30 °C, added seed (2.0% W/W Sitagliptin Hydrochloride Monohydrate) crystals, maintained for 20 - 30 min, and then cooled to 0 - 5 °C gradually and maintained for about 120 min. The solid obtained was filtered to give title compound (35.8 gm) characterized by X-Ray powder diffraction pattern as depicted in Fig. 1, thermogravimetric analysis (TGA) curve as depicted in Fig. 2, and differential scanning calorimetry (DSC) curve as depicted in Fig. 3.
Yield: 79 % Purity: 99.9 % (by HPLC).

The Sitagliptin hydrochloride Form-H1 was further converted into Sitagliptin hydrochloride monohydrate by drying at 25 – 75 °C under vacuum and characterized by X-Ray powder diffraction pattern as depicted in Fig. 4.

Example 2: Preparation of Sitagliptin hydrochloride Form-H1.
50 gm Sitagliptin phosphate (anhydrate) material was added in isopropyl alcohol (8 V) at 25-30 °C and stirred for 10-15 min. The dilute hydrochloric acid solution (prepared 20 ml of conc. hydrochloric acid in 40 ml of Water) was added drop wise to above under stirring and maintained for 10 - 15 min. The mixture was heated up to 65 - 70 °C, maintained for 15 - 20 min, cooled gradually to 45 - 50 °C, added seed (0.5% W/W Sitagliptin Hydrochloride Monohydrate) crystals, maintained for 20 - 30 min. and then cooled to 0 - 5 °C gradually and maintained for about 120 min. The solid obtained was filtered to give title compound (41.5gm).
Yield: 90 % Purity: 99.77% (by HPLC).

Example 3: Preparation of Sitagliptin hydrochloride Form-H1.
15 gm Sitagliptin phosphate (anhydrate) material was added in isopropyl alcohol (10 V) at 25-30 °C and stirred for 10-15 min. Concentrated hydrochloric acid (0.3 V) and water (0.75 V) was added to above under stirring and maintained for 10 - 15 min. The mixture was heated up to 65 - 70 °C, maintained for 40 - 60 min and filtered through micron filter. The filtrate obtained was heated to 65 - 70 °C, cooled gradually to 25 - 30 °C and maintained for about 120 min. The solid obtained was filtered to give title compound (10.02 gm).
Yield: 73.4 % Purity: 99.0% (by HPLC).

Example 4: Preparation of Sitagliptin hydrochloride Form-H1.
10 gm Sitagliptin free base material was added in isopropyl alcohol (7 V) at 25-30 °C and stirred for 10-15 min. Concentrated hydrochloric acid (0.25 V) and water (0.55 V) was added to above under stirring and maintained for 10 - 15 min. The mixture was heated up to 65 - 70 °C, maintained for 40 - 60 min and filtered through micron filter. The filtrate obtained was heated to 65 - 70 °C, cooled gradually to 25 - 30 °C, added seed (2.0% W/W Sitagliptin Hydrochloride Monohydrate) crystals, maintained for 20 - 30 min, and then cooled to 0 - 5 °C gradually and maintained for about 120 min. The solid obtained was filtered to give title compound (7.5 gm).
Yield: 75.0 % Purity: 99.0% (by HPLC).

The Sitagliptin hydrochloride Form-H1 was further converted into Sitagliptin hydrochloride monohydrate by drying at 25 – 75 °C under vacuum and characterized by X-Ray powder diffraction pattern as depicted in Fig. 4.
Moisture content: 4.04% w/w.

,CLAIMS:We claim:

1) Sitagliptin hydrochloride Form-H1.

2) The sitagliptin hydrochloride Form-H1 of claim 1, characterized by one or more of the following:
a. a powder X-ray diffraction (XRD) pattern as shown in Figure 1;
b. a thermogravimetric analysis (TGA) thermogram as shown in Figure 2;
c. a Differential scanning calorimetry (DSC) thermogram as shown in Figure 3.

3) The sitagliptin hydrochloride Form-H1 of claim 1, characterized by one or more of the following:
a. a powder X-ray diffraction (XRD) pattern having one or more peaks at 5.9, 6.9, 10.0, 16.2, 17.4, 20.1, 22.0, 24.7, 26.0, 27.8 and 33.6 ± 0.2° 2?;
b. a thermogravimetric analysis (TGA) thermogram characterized by weight loss of about 7 - 11 % from ambient temperature to about 120 °C;
c. a Differential scanning calorimetry (DSC) thermogram having a broad endotherm at about 70 - 120 °C.

4) A process for preparation of Sitagliptin hydrochloride Form-H1, comprising:
a. adding Sitagliptin phosphate or sitagliptin free base in isopropyl alcohol,
b. adding hydrochloric acid,
c. heating the reaction mixture to 50 to 80 °C to obtain clear solution,
d. optionally adding the seed crystals Sitagliptin hydrochloride monohydrate,
e. cooling the solution to precipitate the solid, and
f. isolating.

5) The process according to claim 4, wherein the isopropyl alcohol is added to Sitagliptin phosphate or sitagliptin free base at temperature 25 to 35 °C.

6) The process according to claim 4, wherein the hydrochloric acid is added to Sitagliptin phosphate or sitagliptin free base at temperature 25 to 35 °C.

7) The process according to claim 4, wherein the seed crystals Sitagliptin hydrochloride monohydrate added at 25 to 50 °C.

8) The process according to claim 4, wherein the solution is cooled to -10 to 30 °C to precipitate the Sitagliptin hydrochloride Form-H1.

9) The process according to claim 4, wherein the Sitagliptin hydrochloride Form-H1 is converted to Sitagliptin hydrochloride monohydrate characterized by a powder X-ray diffraction (XRD) pattern as shown in Figure 4.