FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
NOVEL SALTS OF SITAGLIPTIN AND THEIR PREPARATION
2. APPLICANT:
a. NAME: INDOCO REMEDIES LIMITED
b. NATIONALITY: INDIAN
c. ADDRESS: Indoco House, 166 C.S.T. Road, Santacruz East,
Mumbai - 400 098, Maharashtra, India

TITLE: Novel salts of sitagliptin and their preparation.
FIELD OF INVENTION:
The present invention relates to novel pharmaceutically acceptable salts of sitagliptin, their polymorphs and process for preparation thereof.
BACKGROUND OF THE INVENTION:
Sitagliptin, chemically known as 7-[(3R)-3-amino-l-oxo-4-(2,4,5-
trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-[l,2,4]-triazolo[4,3-a]-pyrazine of Formula I. Sitagliptin is an orally active dipeptidyl peptidase-IV (DPP-IV) enzyme inhibitor and marketed in the form of a phosphate monohydrate in United States under the trade name JANUVIA®. Sitagliptin phosphate is glucagon-like peptide 1 metabolism modulator, hypoglycemic agent. It is indicated to improve glycemic control in patients with type-2 diabetes mellitus.
Sitagliptin and it pharmaceutically acceptable salt as well as their process for preparation first disclosed in the US Patent 6,699,871, assigned to Merck & Co.
US Patent 7,326,708 discloses the preparation of sitagliptin dihydrogenphosphate salt and crystalline hydrates thereof, in particular crystalline monohydrate and their pharmaceutical compositions.
US Patent 7,612,072 discloses amorphous sitagliptin dihydrogenphosphate; US Patent Applications 2006/0287528 and 2007/021430 discloses the crystalline anhydrous forms of sitagliptin dihydrogenphosphate.

Another US Patent Application 2008/0227786 discloses crystalline salts of sitagliptin with acids such as hydrochloric acid, benzenesulfonic acid, /7-toluenesulfonic acid, 10-camphorsulfonic acid, tartaric acid and hydrates thereof.
PCT Application WO 2009/085990 discloses sitagliptin salts such as anhydrous crystalline dihydrogen phosphate Form A, sulfate, hydrobromide, methane sulfonate, acetate, benzoate, oxalate, succinate, mandelate, fumarate and lactate.
Another PCT Application WO 2010/012781 discloses crystalline sitagliptin galactarate, hemi-L-malate, D-gluconate, thiocyanate, L-aspartate, ethanedisulfonate, pyroglutamate, glutarate, acetate, citrate amorphous form, hemicitrate amorphous form, glycolate amorphous form and malate amorphous form.
IP.COM Journal, IPCOM000200626 D, discloses novel salts of sitagliptin with acids such as cinnamic acid, caffeic acid, crotonic acid, hydroiodic acid, hippuric acid, (phenylthio)acetic acid, nitric acid, malonic acid, and 4-hydroxy benzoic acid.
The formation of salts is invaluable for the preparation of safe and effective dosage forms of many drugs. Choosing the suitable salt, however, can be a very difficult task due to their unique properties impart by each salt to its API. Basic salt formation consideration includes stability, solubility, hygroscopicity, flowability, particle size, dissolution and bioavailability. The salt formation process is a simple way to modify the properties of a drug with ionizable functional groups to overcome undesirable features of the parent drug. The properties of counter ion species significantly affect the pharmaceutical properties of a drug and can greatly benefit pharmaceutical chemists and formulators in various facets of drug discovery and process development. Thus there is a continuing need to obtain new salts of sitagliptin having improved physical and/or chemical properties.
In this aspect, we found novel stable salts of sitagliptin and their new polymorphic forms for medical therapy. Additionally, the various salt forms of sitagliptin could be used to prepare improved pharmaceutical compositions.

OBJECTIVES OF THE INVENTION:
The objective of the present invention is to provide novel pharmaceutically acceptable salts of sitagliptin or its solvates.
Another objective of the present invention is to provide novel salts of sitagliptin or its solvates having improved physical and chemical properties.
Yet another objective of the present invention is to provide process for preparing novel salts of sitagliptin or its solvates.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 1: Powder X-ray Diffraction (PXRD) of crystalline sitagliptin saccharinate n-propanol monohydrate.
Figure 2: Powder X-ray Diffraction (PXRD) of crystalline sitagliptin sorbate.
Figure 3: Powder X-ray Diffraction (PXRD) of crystalline sitagliptin furoate form-I.
Figure 4: Powder X-ray Diffraction (PXRD) of crystalline sitagliptin furoate form-II.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides novel pharmaceutically acceptable salts of sitagliptin of Formula I or solvates thereof.
In another aspect, the present invention provides novel crystalline salts of sitagliptin or solvates thereof.

In yet another aspect, the present invention provides process for the preparation of novel salts of sitagliptin or solvates thereof, which comprises the steps of;
a) suspending sitagliptin base in a suitable solvent;
b) treating the solution with pharmaceutical^ acceptable acid to form an acid addition salt;
c) inducing crystallization of the salt or solvate, optionally by addition of an anti-solvent or by cooling the solution; and
d) isolating the crystalline salt or solvate of sitagliptin the compound of Formula I.
In yet another aspect, wherein the pharmaceutically acceptable acid as in item (b) is selected from the group consisting of sorbic acid, 2-furoic acid and saccharin.
In yet another aspect of the present invention, the novel salts of sitagliptin or its solvates are sorbate, furoate and saccharinate.
In another aspect of the present invention, novel salt of sitagliptin is sitagliptin saccharin adduct or solvate thereof, optionally being in amorphous form or in crystalline form.
In another aspect of the present invention novel salt of sitagliptin is sitagliptin saccharin n-propanol monohydrate being in crystalline form and having the powder X-ray diffraction pattern substantially as shown in figure 1.
In another aspect of the present invention, a novel salt of sitagliptin is sitagliptin sorbate or solvate thereof, optionally being in amorphous form or in crystalline form.
In another aspect of the present invention, sitagliptin sorbate being crystalline form and having the powder X-ray diffraction pattern substantially as shown in figure 2.
In another aspect of the present invention, a novel salt of sitagliptin is sitagliptin furoate or solvate thereof, optionally being in amorphous form or in crystalline form.
In another aspect of the present invention, sitagliptin furoate being crystalline Form I having the powder X-ray diffraction pattern substantially as shown in figure 3.
In another aspect of the present invention, sitagliptin furoate being crystalline Form II having the powder X-ray diffraction pattern substantially as shown in figure 4.

DETAIL DESCRIPTION OF THE INVENTION:
The term "salts" as used in the present invention herein includes amorphous forms, crystalline forms and solvates forms of such salts.
The term "crystalline form" as used herein includes reference to anhydrous crystalline forms, partially crystalline forms, mixture of crystalline forms and solvate crystalline forms.
The term "solvate" as used herein refers to a crystalline form containing water and/or solvent molecules in a three-dimensional periodic arrangement.
The present invention will be described in more detail by preferred embodiments while referring to the attached drawings, noting, however, that these embodiments and drawings are presented for illustrative purposes only and shall not limit the invention in any way.
The present invention provides novel pharmaceutical^ acceptable salts of sitagliptin of Formula I or its solvates.
In an aspect, the present invention provides a process for the preparation of novel salts of sitagliptin or its solvates thereof, which comprises the steps of;
a) suspending sitagliptin base in a suitable solvent;
b) treating the solution with pharmaceutically acceptable acid to form an acid addition salt;
c) inducing crystallization of the salt or solvate, optionally by addition of an anti-solvent or by cooling the solution; and
d) isolating the crystalline salt or solvate of sitagliptin the compound of Formula I.
In an embodiment of the present invention, the suitable solvent used in step (a) is selected from the group consisting of alcohols, ketones, esters and hydrocarbons or mixture thereof.
In an embodiment of the present invention, the solvent alcohols are preferably selected from straight or branched chain C1-C4 alcohols such as methanol, ethanol, n-propanol, butanol, sec-butanol, isopropanol and mixture thereof.

In an embodiment of the present invention, the solvent ketones are preferably selected from the group consisting of acetone, methyl ethyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone, methyl isobutyl ketone and mixture thereof.
In an embodiment of the present invention, the solvent esters are preferably selected from the group consisting of ethyl acetate, n-butyl acetate, n-propyl acetate isobutyl acetate, n-butyl acetate, vinyl acetate, n-amyl acetate and mixture thereof.
In an embodiment of the present invention, the solvent hydrocarbons are preferably selected from the group consisting of cyclohexane, toluene, xylene, n-hexane, n-heptane and mixture thereof.
In an embodiment of the present invention, the preferred solvent used in step (a) is selected from acetone, ethyl acetate, n-propanol, isopropanol, cyclohexane and mixture thereof.
In an embodiment of the present invention, the pharmaceutically acceptable acid used in step (b) for the acid addition salt is selected from the group consisting of sorbic acid, 2-furoic acid (hereinafter "furoic acid") and saccharin.
In an embodiment of the present invention, the reaction of step (a) and step (b) is carried out at temperature in the range of 25°C to 80°C and more preferably the reaction is carried out at 25°C to 60°C.
In an embodiment of the present invention, the crystallization of sitagliptin salt or solvate in step (c) optionally earned out by adding an anti-solvent selected form water, ethers or hydrocarbons, wherein the preferred anti-solvent used is cyclohexane.
In another embodiment of the present invention, the crystallization of sitagliptin salt or solvate in step (c) is by precipitation. The precipitation can be spontaneous depending on solvent system or the precipitation can be induced by reducing the temperature of reaction mixture, when the final temperature of reaction mixture is elevated.
In an embodiment of the present invention, the isolation of the sitagliptin salt or solvates thereof in step (d) can be carried out by any conventional method known in the art.

In an embodiment, the novel salts of the present invention relates to sitagliptin saccharinate or its solvate thereof.
In another embodiment, the present invention relates to crystalline salt of sitagliptin saccharin n-propanol monohydrate having a powder X-ray diffraction pattern comprising the following characteristic reflection angles 29 (± 0.2°): 6.21, 9.85, 11.47, 12.06, 12.30, 13.80, 14.62, 15.62, 17.35, 17.54, 17.96, 18.36, 19.17, 19.58, 20.81, 21.50, 21.74, 22.85, 23.07, 24.33, 24.75, 25.05, 25.54, 26.11, 28.00, 29.63, 30.41 and 30.92.
In another embodiment of the present invention, the crystalline salt of sitagliptin saccharin n-propanol monohydrate is charecterised by a powder X-ray diffraction pattern substantially as shown in Figure 1.
In an embodiment of the present invention, crystalline sitagliptin saccharin n-propanol monohydrate is characterized by an infrared spectrum in KBr comprising absorption bands at wave numbers of about 3390.4, 3049.4, 2972.7, 2885.2, 2147.5, 1660.5, 1610.9, 1521.9, 1497.8, 1453.0, 1427.4, 1352.2, 1336.0, 1240.2, 1203.6, 1068.9, 1051.7, 909.8, 840.0, 799.2, 755.6, 726.9, 704.8, 682.1, 638.1. The typical precision of the wave number values is in the range of ± 2 cm* .
In an embodiment of the present invention, crystalline sitagliptin saccharin n-propanol monohydrate is identified by a DSC trace showing endotherm peaks at about 103°C and melting endotherm peak at about 110°C.
In an embodiment, the novel salts of the present invention relates to sitagliptin sorbate or its solvate thereof.
In another embodiment, the present invention relates to crystalline salt of sitagliptin sorbate having a powder X-ray diffraction pattern comprising the following characteristic reflection angles 20 (± 0.2°): 6.10, 6.77, 7.19, 10.69, 11.74, 12.19, 13.54, 14.36, 16.04, 16.29, 16.49, 18.16, 18.31, 18.76, 19.22, 20.12, 20.34, 20.69, 21.44, 21.84, 22.55, 23.39, 24.46, 25.22, 26.15, 27.23, 27.47 and 28.72.

In another embodiment of the present invention, the crystalline salt of sitagliptin sorbate is charecterised by a powder X-ray diffraction pattern substantially as shown in Figure
2.
In an embodiment of the present invention, crystalline salt of sitagliptin sorbate is characterized by an infrared spectrum in KBr comprising absorption bands at wave numbers of about 3422.5, 3053.4, 3029.2, 2918.0, 2809.3, 2632.8, 2211.9, 1564.7, 1467.2, 1442.1, 1336.7, 1281.7, 1238.2, 1214.1, 1186.2, 1103.4, 1074.1, 917.3, 888.1, 806.6, 780.9, 760.3, 745.2, 724.7, 710.6, 693.0. The typical precision of the wave number values is in the range of ± 2 cm"1.
In an embodiment of the present invention, crystalline salt of sitagliptin sorbate is identified by a DSC trace showing melting endotherm peak at about 138°C.
In an embodiment, the novel salts of the present invention relates to sitagliptin furoate or its solvate thereof.
In another embodiment, the present invention relates to crystalline salt of sitagliptin furoate Form I having a powder X-ray diffraction pattern comprising the following characteristic reflection angles 20 (± 0.2°): 6.31, 7.01, 8.06, 10.48, 12.11,12.54, 13.55, 14.10, 14.68, 15.58, 15.9, 16.34, 16.78, 17.86, 18.28, 18.71, 19.05, 20.06, 20.30, 21.41, 22.14, 23.27, 23.86, 24.33, 24.66, 25.20, 25.61, 26.38, 26.71, 28.18, 30.09 and 30.54.
In another embodiment of the present invention, the crystalline salt of sitagliptin furoate Form I is characterized by a powder X-ray diffraction pattern substantially as shown in Figure 3.
In an embodiment of the present invention, crystalline salt of sitagliptin furoate Form I is characterized by an infrared spectrum in KBr comprising absorption bands at wave numbers of about 3425.3, 2944.6, 1659.9, 1623.9, 1584.2, 1480.6, 1441.3, 1389.7, 1276.2, 1183.0, 1100.3, 1015.9, 981.6, 929.9, 880.6, 859.9, 795.9, 725.8, 705.4. The typical precision of the wave number values is in the range of ± 2 cm-1.
In an embodiment of the present invention, crystalline salt of sitagliptin furoate Form I is identified by a DSC trace showing melting endotherm peak at about 174°C.

In another embodiment, the present invention relates to crystalline salt of sitagliptin furoate Form II having a powder X-ray diffraction pattern comprising the following characteristic reflection angles 20 (± 0.2°): 7.02, 7.12, 7.47, 12.02, 12.81, 14.1, 15.06, 16.87, 18.50, 18.82, 19.17, 19.37, 19.78, 20.47, 21.09, 21.16, 22.55, 23.50, 24.18, 24.99, 25.47, 25.97, 26.58, 28.38, 28.76, 29.01, 30.33, 31.07 and 32.20.
In another embodiment of the present invention, the crystalline salt of sitagliptin furoate Form II is charecterised by a powder X-ray diffraction pattern substantially as shown in Figure 4.
In an embodiment of the present invention, crystalline salt of sitagliptin furoate Form II is characterized by an infrared spectrum in KBr comprising absorption bands at wave numbers of about 3086.1,3014.7,2947.2,2868.1,2272.1, 1666.5, 1620.2, 1537.2, 1519.9, 1502.5, 1477.4, 1448.5, 1438.9, 1425.4, 1411.9, 1382.9, 1363.6, 1350.1, 1267.2, 1247.9, 1230.5, 1139.9, 1101.3, 1091.7, 1078.2, 1037.7, 985.6, 941.2, 925.8, 900.7, 883.4, 856.4, 759.9, 705.9, 698.2, 650.0. The typical precision of the wave number values is in the range of ± 2 cm"1.
In an embodiment of the present invention, crystalline salt of sitagliptin furoate Form II is identified by a DSC trace showing melting endotherm peak at about 165°C and about 172°C.
In powder X-ray diffraction pattern the relative intensities of the peaks can vary, depending upon the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the XRPD peak assignments can vary by about ± 0.2 degrees.
The X-ray powder diffractogram (XRPD) of the above salts were obtained by using an X'Pert PRO PANalytical tool, equipped with X'Celerator detector and X-ray tube (Cu LFF PW3373/00 DK312503) with 40mA current intensity and 40kV voltage. The sample is arranged on a support and analyzed using the following parameters:
• Scanning range (°): 3.0010-39.9997
• Step size (°): 0.0167
• Scanning mode: continuous - Count time (s): 12.700

• Soller slit (rad): 0.04
• divergent slit: 1/4
• Antiscatter slit: 1/2°
For DSC it is known that the temperatures observed will depend upon the rate of temperature change as well as sample preparation technique and the particular instrument employed. Thus, the values reported herein relating to DSC thermograms can vary by about ± 4°C.
The DSC analyses were obtained by the use of a differential scanning calorimeter DSC Q 1000. The samples have been loaded on aluminum crucibles and heated to 400°C at a heating rate of 10°C/min.
The following examples, which fully illustrate the practice of the preferred embodiments of the present invention, are intended to be for illustrative purpose only, and should not be considered to be limiting to the scope of the present invention.
EXAMPLES:
Example 1: Sitagliptin sorbate:
Sitagliptin base (15 g, 0.037 moles) was dissolved in acetone (25.0 ml) at 25°C to 30°C. Sorbic acid (4.13 g, 0.037mole) was added in above clear reaction mass. The resulting solution was stirred for about 30 minutes at 25°C to 30°C. The above clear solution is slowly added over 150 ml of cyclohexane under stirring at 25°C to 30°C. After addition sitagliptin sorbate salt precipitates out in 15 to 20 minutes, and continued stirring for 2 hours. After stirring, the salt was filtered and dried at 55°C to 60°C to yield 17.60 g of sitagliptin sorbate having HPLC purity greater than 99.5% (Yield: 92.0%). IR (cm-1): 3422.5, 3053.4, 3029.2, 2918.0, 2809.3, 2632.8, 2211.9, 1564.7, 1467.2, 1442.1, 1336.7, 1281.7, 1238.2, 1214.1, 1186.2, 1103.4, 1074.1, 917.3, 888.1, 806.6, 780.9, 760.3, 745.2, 724.7, 710.6, 693.0.
1H NMR (400 MHz, DMSO-tf*): 5 1.80 (d, 3H), 2.50-2.79 (m, 3H), 3.34-3.43 (m, 1H), 3.89-3.94 (m, 2H), 3.97-4.03 (m, 1H), 4.23-4.25 (h, 1H), 4.88 (q, 1H), 4.98 (s, 1H), 4.88

(h, 3H), 5.74 (d, 1H), 6.07-6.16 (m, 1H), 6.19-6.26 (m, 1H), 7.01-7.08 (dd, 1H), 7.43-
7.53 (m, 2H).
PXRD 26 values: 6.10, 6.77, 7.19, 10.69, 11.74, 12.19, 13.54, 14.36, 16.04, 16.29,
16.49, 18.16, 18.31, 18.76, 19.22, 20.12, 20.34, 20.69, 21.44, 21.84, 22.55, 23.39,
24.46, 25.22, 26.15, 27.23, 27.47, 28.72.
DSC: 138.06°C; M/C: 0.09%.
TGA: 0.14% at 105.35°C; 100.1% at 799.68°C.
Example 2: Sitagliptin furoate Form I:
Sitagliptin base (15 g, 0.037 moles) was dissolved in isopropyl alcohol (150.0 ml) at 50°
to 55°C. Furoic acid (4.13 g, 0.037 moles) was dissolved in 50 ml of isopropyl alcohol
at 25°C to 30°C. The furoic acid solution was added to sitagliptin base solution at 50°C
to 55°C.The reaction mass was stirred for 2 hours at 50°C to 55°C resulting in
precipitation of sitagliptin furoate salt. The above salt was filtered and dried at 50°C to
55°C to yield 17.2 g of sitagliptin furoate Form I having HPLC purity greater than 99.5
% (Yield: 92.16%).
IR (cm-1): 3425.3, 2944.6, 1659.9, 1623.9, 1584.2, 1480.6, 1441.3, 1389.7, 1276.2,
1183.0, 1100.3, 1015.9, 981.6, 929.9, 880.6, 859.9, 795.9, 725.8, 705.4.
'H NMR (400 MHz, DMSO-