DESC:FIELD OF THE INVENTION
The present application relates to substantially pure Sitagliptin and its pharmaceutically acceptable salts, and more particularly a process for preparing substantially pure Sitagliptin and its pharmaceutically acceptable salts and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION
The drug compound having the adopted name “sitagliptin phosphate” has chemical names: 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1); or (2R)-4-oxo-4-[3-(trifluoromethyl) -5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine phosphate; and is represented by structural Formula I.

Sitagliptin is a glucagon like peptide 1 metabolism modulator, hypoglycemic agent and dipeptidyl peptidase IV inhibitor, and is believed to exert its action in patients with type 2 diabetes by slowing the inactivation of incretin hormones. An oral tablet product containing sitagliptin phosphate monohydrate as the active ingredient is marketed in the United States by Merck & Co., Inc. using the brand JANUVIA™. JANUVIA is indicated to improve glycemic control in patients with type 2 diabetes mellitus.
Sitagliptin phosphate monohydrate, in combination with metformin hydrochloride, is sold by Merck & Co., Inc. using the brand JANUMET™ in the form of tablets for oral administration, for combination therapy in the treatment of type 2 diabetes.
U.S. Patent No. 6,699,871, describes various DPP-IV inhibitors including sitagliptin and their pharmaceutically acceptable salts, a pharmaceutical composition and method of treatment and a process for the preparation of sitagliptin hydrochloride.
International Application Publication No. WO 2004/085661 A2 discloses a process for the preparation of sitagliptin, in which (S)-phenylglycine amide is used as a chiral auxilary to form an intermediate, which subsequently provides the desired enantiomer (sitagliptin).
International Application Publication No. WO 2009/085990 A2 discloses a process for the preparation of sitagliptin in which a (R)-1-phenylalkylamine is used as a chiral auxiliary to form an intermediate, which subsequently provides the desired enantiomer (sitagliptin).
The prior art processes involve use of the Triazole compound of Formula VII or it’s salt as an intermediate or a starting material. The secondary amine of the Triazole compound of Formula VII upon contacting with a nitrosating agent leads to formation of N-nitrosamine impurity of the compound of formula VIII, and if the Triazole compound of Formula VII is carry forwarded to final Sitagliptin, the final pharmaceutical compound upon contacting with a nitrosating agent may form the N-nitrosamine impurity.

If the final active pharmaceutical ingredient (API) (viz. Sitagliptin or a pharmaceutically acceptable salt thereof) is contaminated with Triazole compound of Formula VII or salt thereof, while preparation of a formulation using the API contaminated with the compound of Formula VII, the drug product (DP) may also be contaminated with the N-nitrosamine impurity of the compound of Formula VIII.
Nitrosamines are classified by the ICH M7(R1) Guidelines as class 1 impurities, ‘known mutagenic carcinogens’ based on both rodent carcinogenicity and mutagenicity data. They are categorized by the International Agency for Cancer Research (IARC) as 2A-Probable Carcinogens based on data on a number of species studied.
None of the prior art references disclose the content of compound of Formula VII or Formula VIII in Sitagliptin or its salts or methods for controlling these impurities.
Therefore, there is a need in the art for an improved method in the process chemistry of Sitagliptin and its pharmaceutically acceptable salts to be prepared in the purest form which is suitable for large scale cGMP production for its pharmaceutical formulation manufacturing.

SUMMARY OF THE INVENTION
It is therefore an object of the present invention is to provide a simple, safe, cost-effective, time saving and reliable process for the preparation of Sitagliptin and its pharmaceutically acceptable salts in bulk scale and in substantially pure form which is preferably devoid of compound of Formula VII and/or compound of Formula VIII. “Substantially pure” is defined herein as Sitagliptin or its pharmaceutically acceptable salts wherein the content of a compound of Formula VII is less than 100 ppm and/or less than 1 ppm of Nitrosamine impurity of Formula VIII.
In one aspect the present application provides a process for preparation of Sitagliptin or a pharmaceutically acceptable salt thereof containing less than about 100 ppm of compound of formula VII or salt thereof and/or less than about 1 ppm of Nitrosamine impurity of the compound of formula VIII by mass, the process comprising:
(a) providing a solution of Sitagliptin or a pharmaceutically acceptable salt thereof in a suitable solvent,
(b) optionally, adding an anti-solvent to the solution obtained in step (a), and
(c) isolating Sitagliptin or a pharmaceutically acceptable salt thereof containing less than about 100 ppm of compound of formula VII or salt thereof and/or less than about 1 ppm of Nitrosamine impurity of the compound of formula VIII.
In another aspect the present application provides a process for preparation of Sitagliptin or a pharmaceutically acceptable salt thereof free from compound of formula VII or salt thereof and/or Nitrosamine impurity of the compound of formula VIII, the process comprising:
(a) providing a solution of Sitagliptin or a pharmaceutically acceptable salt thereof in a suitable solvent,
(b) optionally, adding an anti-solvent to the solution obtained in step (a), and
(c) isolating Sitagliptin or a pharmaceutically acceptable salt thereof free from compound of formula VII or salt thereof and/or Nitrosamine impurity of the compound of formula VIII.
In another aspect the present application provides Sitagliptin or a pharmaceutically acceptable salt thereof containing less than about 100 ppm of compound of formula VII or salt thereof and/or less than about 1 ppm of Nitrosamine impurity of the compound of formula VIII.
In another aspect the present application provides Sitagliptin or a pharmaceutically acceptable salt thereof containing less than about 10 ppm of compound of formula VII or salt thereof and/or less than about 0.1 ppm of Nitrosamine impurity of the compound of formula VIII.
In another aspect the present application provides Sitagliptin or a pharmaceutically acceptable salt thereof free from a compound of formula VII salt thereof and/or Nitrosamine impurity of the compound of formula VIII.
In another aspect the present application provides a pharmaceutical composition comprising Sitagliptin or a pharmaceutically acceptable salt thereof containing less than about 100 ppm of compound of formula VII or salt thereof and/or less than about 1 ppm of Nitrosamine impurity of the compound of formula VIII.
In another aspect the present application provides a pharmaceutical composition comprising Sitagliptin or a pharmaceutically acceptable salt thereof containing less than about 10 ppm of compound of formula VII or salt thereof and/or less than about 0.1 ppm of Nitrosamine impurity of the compound of formula VIII.
In another aspect the present application provides a pharmaceutical composition comprising Sitagliptin or a pharmaceutically acceptable salt thereof free from a compound of formula VII or salt thereof and/or Nitrosamine impurity of the compound of formula VIII.
In another aspect the present application provides a pharmaceutical composition comprising Sitagliptin or a pharmaceutically acceptable salt thereof containing less than about 1 ppm of Nitrosamine impurity of the compound of formula VIII.
In another aspect the present application provides a pharmaceutical composition comprising Sitagliptin or a pharmaceutically acceptable salt thereof free from Nitrosamine impurity of the compound of formula VIII.

DETAILED DESCRIPTION
The present application provides a process for preparation of Sitagliptin or a pharmaceutically acceptable salt thereof containing less than about 100 ppm of compound of formula VII or salt thereof and/or less than about 1 ppm of Nitrosamine impurity of the compound of formula VIII by mass, the process comprising:
(a) providing a solution of Sitagliptin or a pharmaceutically acceptable salt thereof in a suitable solvent,
(b) optionally, adding an anti-solvent to the solution obtained in step (a), and
(c) isolating Sitagliptin or a pharmaceutically acceptable salt thereof containing less than about 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75 ppm, 70 ppm, 65 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII.
Step (a) involves providing a solution of Sitagliptin or a pharmaceutically acceptable salt thereof in a suitable solvent. Sitagliptin or an acid addition salts such as Sitagliptin HCl, Sitagliptin phosphate, Sitagliptin sulphate or Sitagliptin benzoate may be obtained by any processes known in the art. The mixture comprising sitagliptin or an acid addition salt may be a suspension or a solution. A mixture of sitagliptin or an acid addition salt and a solvent may require heating to form a solution of desired concentrations, and the temperatures can be as high as the reflux temperature of the solvent, as long as stability of the compound is not affected. Solvents that may be used in step (a) include, but are not limited to, methanol, ethanol, isopropanol, dichloromethane, ethylacetate and water or a mixture thereof. A suitable solution also can be provided from a process step that synthesizes Sitagliptin or an acid addition salt, without isolating it.
In certain embodiments, the process employed to prepare the Sitagliptin or a pharmaceutically acceptable salt thereof employed in step (a) is prepared by a process that employs a compound of formula VII or salt thereof as an intermediate or starting material in the synthesis of the Sitagliptin or a pharmaceutically acceptable salt. In a further aspect of this embodiment, the process employed to prepare the Sitagliptin or a pharmaceutically acceptable salt thereof employed in step (a) and prepared by a process that employs a compound of formula VII or salt thereof in the synthesis of the Sitagliptin or a pharmaceutically acceptable salt is a one pot or continuous process none of the intermediates are isolated or purified until the final step to obtain the Sitagliptin or a pharmaceutically acceptable salt thereof employed in step (a). The process employed to prepare Sitagliptin and its salts can be followed from PCT publication WO2020109938A1, which is incorporated herein for reference.
The Sitagliptin or a pharmaceutically acceptable salt thereof employed in step (a) may contain more than 20, ppm, 25 ppm, 30 ppm, 35 ppm, 40 ppm, 45 ppm, 50 ppm, 55 ppm, 60 ppm, 65 ppm, 70 ppm, 75 ppm, 80 ppm, 85 ppm, 90 ppm, 95 ppm, 100 ppm of more of a compound of formula VII or salt thereof.
In step (b), an anti-solvent like MTBE, diisopropyl ether or diethyl ether is added to the solution of step (a). Seed crystals of Sitagliptin or an acid addition salt may be added to the solution. Then the obtained mixture is stirred for about 10 minutes to about 10 hours.
In step (c), the precipitation obtained is isolated by filtration. The solid may be washed with a suitable solvent. The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure.
The Sitagliptan or pharmaceutically acceptable salt obtained in step (c) should be stable for 1, 2, 3, 4, 5, 6, 7, 8 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months or longer when stored in a pharmaceutically acceptable container under normal or accelerated storage conditions. More specifically, Sitagliptin or pharmaceutically acceptable salt obtained in step (c) should contain less than about 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75 ppm, 70 ppm, 65 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII when Sitagliptan or pharmaceutically acceptable salt obtained in step (c) is stored in a sealed bottle, preferably a sealed glass or plastic bottle such as a high density polyethylene bottle (with or without a desiccant) at approximately 25°C and approximately 60% relative humidity for at least 3, 6, 12, 18 or 24 months one year and/or at approximately 40°C and approximately 75% relative humidity for 1, 2, 3, 4, 5 or 6 months.
In another aspect, the present application provides Sitagliptin or a pharmaceutically acceptable salt thereof prepared by the process of the present invention contains less than about 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and/or less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides Sitagliptin or a pharmaceutically acceptable salt thereof prepared by the process of the present invention contains less than about 10 ppm, 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, 4 ppm, 3 ppm, 2 ppm, 1 ppm or less of compound of formula VII or salt thereof and/or less than about 0.1 ppm of Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides Sitagliptin or a pharmaceutically acceptable salt thereof prepared by the process of the present invention is free from the compound of formula VII or salt thereof and/or Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides a pharmaceutical composition comprising Sitagliptin or a pharmaceutically acceptable salt thereof prepared by the process of the present invention containing less than about 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75 ppm, 70 ppm, 65 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides a pharmaceutical composition comprising Sitagliptin or a pharmaceutically acceptable salt thereof prepared by the process of the present invention is free from the compound of formula VII or salt thereof and/or Nitrosamine impurity of the compound of formula VIII.
The pharmaceutical compositions comprising the Sitagliptan or pharmaceutically acceptable salt obtained in step (c) should be stable for 1, 2, 3, 4, 5, 6, 7, 8 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months or longer when stored in a pharmaceutically acceptable container under normal or accelerated storage conditions. More specifically, pharmaceutical composition comprising the Sitagliptan or pharmaceutically acceptable salt obtained in step (c) should contain less than about 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75 ppm, 70 ppm, 65 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII when pharmaceutical composition is stored in a sealed bottle, preferably a sealed glass or plastic bottle such as a high density polyethylene bottle (with or without a desiccant) at approximately 25°C and approximately 60% relative humidity for at least 3, 6, 12, 18 or 24 months one year and/or at approximately 40°C and approximately 75% relative humidity for 1, 2, 3, 4, 5 or 6 months.
In another aspect, the present application provides a process for preparation of Sitagliptin phosphate containing less than about 100 ppm of compound of formula VII or salt thereof and/or less than about 1 ppm of Nitrosamine impurity of the compound of formula VIII by mass, the process comprising:
(a) providing a solution of Sitagliptin phosphate in a suitable solvent,
(b) adding an anti-solvent to the solution obtained in step (a), and
(c) isolating Sitagliptin phosphate containing less than about 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75 ppm, 70 ppm, 65 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII.
Step (a) involves providing a solution of Sitagliptin phosphate in a suitable solvent. Sitagliptin phosphate may be obtained by any processes known in the art. The mixture comprising sitagliptin phosphate may be a suspension or a solution. A mixture of sitagliptin phosphate and a solvent may require heating to form a solution of desired concentrations, and the temperatures can be as high as the reflux temperature of the solvent, as long as stability of the compound is not affected. Solvents that may be used in step (a) include, but are not limited to, methanol, ethanol, isopropanol, dichloromethane, ethylacetate and water or a mixture thereof. A suitable solution also can be provided from a process step that synthesizes sitagliptin phosphate, without isolating it.
In certain embodiments, the process employed to prepare the Sitagliptin phosphate employed in step (a) is prepared by a process that employs a compound of formula VII or salt thereof as an intermediate or starting material in the synthesis of the Sitagliptin phosphate. In a further aspect of this embodiment, the process employed to prepare the Sitagliptin phosphate thereof employed in step (a) and prepared by a process that employs a compound of formula VII or salt thereof in the synthesis of the Sitagliptin phosphate is a one pot or continuous process none of the intermediates are isolated or purified until the final step to obtain the Sitagliptin free base or salt thereof used to form the Sitagliptin phosphate or until the Sitagliptin phosphate employed in step (a) is formed.
The process employed to prepare Sitagliptin and its salts can be followed from PCT publication WO2020109938A1, which is incorporated herein for reference.
The Sitagliptin phosphate thereof employed in step (a) may contain more than 20, ppm, 25 ppm, 30 ppm, 35 ppm, 40 ppm, 45 ppm, 50 ppm, 55 ppm, 60 ppm, 65 ppm, 70 ppm, 75 ppm, 80 ppm, 85 ppm, 90 ppm, 95 ppm, 100 ppm of more of a compound of formula VII or salt thereof.
In step (b), an anti-solvent like MTBE or diethyl ether is added to the solution of step (a). Seed crystals of Sitagliptin phosphate may be added to the solution. Then the obtained mixture is stirred for about 10 minutes to about 10 hours.
In step (c), the precipitation obtained is isolated by filtration. The solid may be washed with a suitable solvent. The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure.
The Sitagliptan phosphate obtained in step (c) should be stable for 1, 2, 3, 4, 5, 6, 7, 8 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months or longer when stored in a pharmaceutically acceptable container under normal or accelerated storage conditions. More specifically, Sitagliptan phosphate obtained in step (c) should contain less than about 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75 ppm, 70 ppm, 65 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII when Sitagliptan phosphate obtained in step (c) is stored in a sealed bottle, preferably a sealed glass or plastic bottle such as a high density polyethylene bottle (with or without a desiccant) at approximately 25°C and approximately 60% relative humidity for at least 3, 6, 12, 18 or 24 months one year and/or at approximately 40°C and approximately 75% relative humidity for 1, 2, 3, 4, 5 or 6 months.
In another aspect, the present application provides Sitagliptin phosphate prepared by the process of the present invention contains less than about 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and/or less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides Sitagliptin phosphate prepared by the process of the present invention contains less than about 10 ppm, 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, 4 ppm, 3 ppm, 2 ppm, 1 ppm or less of compound of formula VII or salt thereof and/or less than about 0.1 ppm of Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides Sitagliptin phosphate prepared by the process of the present invention is free from the compound of formula VII or salt thereof and/or Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides a pharmaceutical composition comprising Sitagliptin phosphate prepared by the process of the present invention containing less than about 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75 ppm, 70 ppm, 65 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides a pharmaceutical composition comprising Sitagliptin phosphate prepared by the process of the present invention is free from the compound of formula VII or salt thereof and/or Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides a pharmaceutical composition comprising Sitagliptin phosphate prepared by the process of the present invention is free from Nitrosamine impurity of the compound of formula VIII.
The pharmaceutical compositions comprising the Sitagliptin phosphate obtained in step (c) should be stable for 1, 2, 3, 4, 5, 6, 7, 8 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months or longer when stored in a pharmaceutically acceptable container under normal or accelerated storage conditions. More specifically, pharmaceutical composition comprising the Sitagliptin phosphate obtained in step (c) should contain less than about 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75 ppm, 70 ppm, 65 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII when pharmaceutical composition is stored in a sealed bottle, preferably a sealed glass or plastic bottle such as a high density polyethylene bottle (with or without a desiccant) at approximately 25°C and approximately 60% relative humidity for at least 3, 6, 12, 18 or 24 months one year and/or at approximately 40°C and approximately 75% relative humidity for 1, 2, 3, 4, 5 or 6 months.
In another aspect, the present application provides a process for preparation of Sitagliptin hydrochloride containing less than about 100 ppm of compound of formula VII or salt thereof and/or less than about 1 ppm of Nitrosamine impurity of the compound of formula VIII by mass, the process comprising:
(a) providing a mixture of Sitagliptin hydrochloride in a suitable solvent,
(b) optionally, heating the mixture obtained in step (a) to get a solution, and
(c) isolating Sitagliptin hydrochloride containing less than about 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75 ppm, 70 ppm, 65 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII.
Step (a) involves providing a mixture of Sitagliptin hydrochloride in a suitable solvent. Sitagliptin hydrochloride may be obtained by any processes known in the art. The mixture comprising sitagliptin hydrochloride may be a suspension or a solution. A mixture of sitagliptin hydrochloride and a solvent may require heating to form a solution of desired concentrations, and the temperatures can be as high as the reflux temperature of the solvent, as long as stability of the compound is not affected. Solvents that may be used in step (a) include, but are not limited to, methanol, ethanol, isopropanol, dichloromethane, ethylacetate and water or a mixture thereof. A suitable solution also can be provided from a process step that synthesizes sitagliptin hydrochloride, without isolating it.
In certain embodiments, the process employed to prepare the Sitagliptin hydrochloride employed in step (a) is prepared by a process that employs a compound of formula VII or salt thereof as an intermediate or starting material in the synthesis of the Sitagliptin hydrochloride.
In a further aspect of this embodiment, the process employed to prepare the Sitagliptin hydrochloride thereof employed in step (a) and prepared by a process that employs a compound of formula VII or salt thereof in the synthesis of the Sitagliptin hydrochloride is a one pot or continuous process none of the intermediates are isolated or purified until the final step to obtain the Sitagliptin free base or salt thereof used to form the Sitagliptin hydrochloride or until the Sitagliptin hydrochloride employed in step (a) is formed.
The Sitagliptin hydrochloride thereof employed in step (a) may contain more than 20, ppm, 25 ppm, 30 ppm, 35 ppm, 40 ppm, 45 ppm, 50 ppm, 55 ppm, 60 ppm, 65 ppm, 70 ppm, 75 ppm, 80 ppm, 85 ppm, 90 ppm, 95 ppm, 100 ppm of more of a compound of formula VII or salt thereof.
Seed crystals of Sitagliptin hydrochloride may be added to the solution. Then the obtained mixture is stirred for about 10 minutes to about 10 hours.
The precipitation obtained is isolated by filtration. The solid may be washed with a suitable solvent. The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure.
The Sitagliptin hydrochloride obtained in step (c) should be stable for 1, 2, 3, 4, 5, 6, 7, 8 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months or longer when stored in a pharmaceutically acceptable container under normal or accelerated storage conditions. More specifically, Sitagliptin hydrochloride obtained in step (c) should contain less than about 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75 ppm, 70 ppm, 65 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII when Sitagliptin hydrochloride obtained in step (c) is stored in a sealed bottle, preferably a sealed glass or plastic bottle such as a high density polyethylene bottle (with or without a desiccant) at approximately 25°C and approximately 60% relative humidity for at least 3, 6, 12, 18 or 24 months one year and/or at approximately 40°C and approximately 75% relative humidity for 1, 2, 3, 4, 5 or 6 months.
In another aspect, the present application provides Sitagliptin hydrochloride prepared by the process of the present invention contains less than about 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and/or less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides Sitagliptin hydrochloride prepared by the process of the present invention contains less than about 10 ppm, 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, 4 ppm, 3 ppm, 2 ppm, 1 ppm or less of compound of formula VII or salt thereof and/or less than about 0.1 ppm of Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides Sitagliptin hydrochloride prepared by the process of the present invention is free from the compound of formula VII or salt thereof and/or Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides use of pharmaceutically acceptable salt of Sitagliptin free from the compound of formula VII and/or Nitrosamine impurity of the compound of formula VIII in the preparation of pharmaceutical composition.
In another aspect, the present application provides a pharmaceutical composition comprising Sitagliptin or a pharmaceutically acceptable salt thereof prepared by the process of the present invention containing less than about 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75 ppm, 70 ppm, 65 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides a pharmaceutical composition comprising Sitagliptin hydrochloride prepared by the process of the present invention is free from the compound of formula VII or salt thereof and/or Nitrosamine impurity of the compound of formula VIII.
In another aspect, the present application provides a pharmaceutical composition comprising Sitagliptin hydrochloride prepared by the process of the present invention is free from Nitrosamine impurity of the compound of formula VIII.
The pharmaceutical compositions comprising the Sitagliptin hydrochloride obtained in step (c) should be stable for 1, 2, 3, 4, 5, 6, 7, 8 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months or longer when stored in a pharmaceutically acceptable container under normal or accelerated storage conditions. More specifically, Sitagliptin hydrochloride obtained in step (c) should contain less than about 100 ppm, 95 ppm, 90 ppm, 85 ppm, 80 ppm, 75 ppm, 70 ppm, 65 ppm, 60 ppm, 55 ppm, 50 ppm, 45 ppm, 40 ppm, 35 ppm, 30 ppm, 25 ppm, 20 ppm, 15 ppm, 10 ppm, 5 ppm or less of compound of formula VII or salt thereof and less than about 1 ppm, 0.9 ppm, 0.8 ppm, 0.7 ppm, 0.6 ppm, 0.5 ppm, 0.4 ppm, 0.3 ppm, 0.2 ppm, 0.1 ppm or less of Nitrosamine impurity of the compound of formula VIII when pharmaceutical composition is stored in a sealed bottle, preferably a sealed glass or plastic bottle such as a high density polyethylene bottle (with or without a desiccant) at approximately 25°C and approximately 60% relative humidity for at least 3, 6, 12, 18 or 24 months one year and/or at approximately 40°C and approximately 75% relative humidity for 1, 2, 3, 4, 5 or 6 months.
The pharmaceutical compositions comprising the Sitagliptin or pharmaceutically acceptable salt thereof, including the phosphate and hydrochloride salts, prepared in accordance with the present invention may be solid or liquid compositions, preferably for oral administration. The pharmaceutical compositions in accordance with the present invention will comprise the Sitagliptin or pharmaceutically acceptable salts prepared in accordance with the processes disclosed herein and at least once pharmaceutically acceptable excipient. In certain aspects the pharmaceutical compositions, comprise the sitagliptin phosphate salt or the sitagliptin hydrochloride salt prepared by the process of the present invention is formulated into a tablet comprising one or more excipients by a direct compression process.
Pharmaceutical compositions that include sitagliptin or a salt thereof with one or more pharmaceutically acceptable excipient may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir systems or combinations of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation, and wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that are useful for preparing formulations include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starch, or the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methyl celluloses, ethyl celluloses, methyl celluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants or the like.
As the content of the compound of formula VII or salt thereof and Nitrosamine impurity of the compound of formula VIII is controlled in sitagliptin phosphate salt or the sitagliptin hydrochloride salt well below the regulatory requirements, the formulations containing these active ingredients also contains these impurities well below the regulatory requirements.
In another aspect, the content of the compound of formula VII and/or Nitrosamine impurity of the compound of formula VIII is measured by HPLC.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25°C and atmospheric pressure unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. The present invention can comprise (open ended) the components of the present invention as well as other ingredients or elements described herein. All ranges recited herein include the endpoints, including those that recite a range "between" two values.
When a molecule or other material is identified herein as "pure," it generally means, unless specified otherwise, that the material has 99% purity or higher, as determined by methods conventional in the art such as high performance liquid chromatography (HPLC) or spectroscopic methods. In general, this refers to purity with regard to unwanted residual solvents, reaction by-products, impurities, and unreacted starting materials. In the case of stereoisomers, "pure" also means 99% of one enantiomer or diastereomer, as appropriate. “Substantially pure” is defined herein as Sitagliptin or its pharmaceutically acceptable salts wherein the content of a compound of Formula VII is less than 50ppm and/or less than 1ppm of Nitrosamine impurity of Formula VIII.

DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise.
As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
Terms such as "about," "generally," "substantially," or the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
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.

EXAMPLES
Example 1: Purification of sitagliptin phosphate anhydrous
Sitagliptin phosphate (20 g), methanol (207.5 mL) and water (42.5 mL) were charged into a round bottom flask and the mixture was heated to 65 °C and stirred for 1 hour. Then the clear solution was gradually cooled to 30 °C and stirred for 4 hours. Added 334 mL of MTBE into the reaction mass and stirred at 26 °C for 12 hours. The solid is collected by filtration, washed with MTBE (28 mL), and dried at 55°C for 12 hours under reduced pressure to obtain Sitagliptin phosphate anhydrous containing very low levels of the compound of formula VII and the compound of formula VIII. Yield: 17.9 g.
Sitagliptin Phosphate
Before Purification After Purification
Content of compound of formula VII 255.450 ppm 6.236 ppm
Content of compound of formula VIII 0.0139 ppm 0.0066 ppm

Example 2: Purification of sitagliptin hydrochloride monohydrate
Sitagliptin hydrochloride monohydrate (370 g), isopropanol (4440 mL) and water (222 mL) were charged into a round bottom flask and the mixture was heated to 75 °C and stirred for 1 hour. Then the clear solution was gradually cooled to 30 °C and stirred for 1 hour. Sitagliptin hydrochloride hydrate (3.7 g) was added. The reaction mass was further cooled to 0 °C and stirred for 2 hours. The solid is collected by filtration, washed with isopropanol (1110 mL), and dried at 75°C for 15 hours under reduced pressure to obtain Sitagliptin hydrochloride monohydrate containing very low levels of the compound of formula VII and the compound of formula VIII. Yield: 350 g.
Sitagliptin Hydrochloride
Before Purification After Purification
Content of compound of formula VII 45.12 ppm 4.683 ppm
Content of compound of formula VIII 0.0264 ppm 0.001 ppm

Example 3: Purification of sitagliptin hydrochloride monohydrate
Sitagliptin hydrochloride monohydrate (600 g), isopropanol (7800 mL) and water (360 mL) were charged into a round bottom flask and the mixture was heated to 75 °C and stirred for 1 hour. Then the clear solution was gradually cooled to 30 °C and stirred for 11 hours. Sitagliptin hydrochloride hydrate (6 g) was added. The reaction mass was further cooled to 0 °C and stirred for 2 hours. The solid is collected by filtration, washed with isopropanol (1200 mL), and dried at 65°C for 15 hours under reduced pressure to obtain Sitagliptin hydrochloride monohydrate containing very low levels of the compound of formula VII and the compound of formula VIII. Yield: 561 g.
Sitagliptin Hydrochloride
Before Purification After Purification
Content of compound of formula VII 21.4 ppm 2.462 ppm
Content of compound of formula VIII 0.029 ppm Not detected

Example 4: Sitagliptin Phosphate and Sitagliptin HCl monohydrate before & after purification according to Dr. Reddy’s process, have been used for preparation of finished product as per the conventional process. The data on SIT-Nitroso impurity at drug substance & drug product stage, have been analyzed at T0 and captured in below table,

Molecule
Operation
Drug Substance Drug Product
SIT/Formula VII (ppm) SIT-Nitroso / Formula VIII (ppm) SIT-Nitroso/ Formula VIII (ppm)
Sitagliptin Phosphate Before Purification 40-60 0.03-0.05 0.74-1.91
After Purification <1.0 <0.009 <0.009
Sitagliptin HCl monohydrate Before Purification 80-160 0.015-0.03 0.68-2.33
After Purification <2.0 <0.009 0.002-0.003 ,CLAIMS:We claim
1. Sitagliptin or a salt thereof having less than about 100 ppm of compound of Formula VII and/or having less than about 1 ppm of compound of Formula VIII.

2. Sitagliptin or a salt thereof having less than about 10 ppm of compound of Formula VII and/or having less than about 0.1 ppm of compound of Formula VIII.

3. A pharmaceutical composition comprising Sitagliptin or a salt thereof having less than about 100 ppm of compound of Formula VII and/or having less than about 1 ppm of compound of Formula VIII and a pharmaceutically acceptable excipient.

4. A pharmaceutical composition comprising Sitagliptin or a salt thereof having less than about 10 ppm of compound of Formula VII and/or having less than about 0.1 ppm of compound of Formula VIII and a pharmaceutically acceptable excipient.

5. A process for preparation of Sitagliptin or a salt thereof having less than about 100 ppm of compound of Formula VII and/or having less than about 1 ppm of compound of Formula VIII, comprising:
(d) providing a solution of Sitagliptin or a pharmaceutically acceptable salt thereof in a suitable solvent,
(e) optionally, adding an anti-solvent to the solution obtained in step (a), and
(f) isolating Sitagliptin or a pharmaceutically acceptable salt thereof containing less than about 100 ppm of compound of formula VII and/or less than about 1 ppm of Nitrosamine impurity of the compound of formula VIII.
6. A process for preparation of Sitagliptin or a salt thereof having less than about 10 ppm of compound of Formula VII and/or having less than about 0.1 ppm of compound of Formula VIII, comprising:
(a) providing a solution of Sitagliptin or a pharmaceutically acceptable salt thereof in a suitable solvent,
(b) optionally, adding an anti-solvent to the solution obtained in step (a), and
(c) isolating Sitagliptin or a pharmaceutically acceptable salt thereof containing less than about 100 ppm of compound of formula VII and/or less than about 1 ppm of Nitrosamine impurity of the compound of formula VIII.
7. The process according to claim 5 or claim 6, wherein the solvent is a mixture of an alcohol and water.
8. The process according to claim 7, wherein the alcohol solvent is isopropanol or methanol.
9. The process according to claim 5 or claim 6, wherein the anti-solvent is methyl tert. -butyl ether.
10. The sitagliptin salt according to claim 1 to claim 6 is sitagliptin phosphate or sitagliptin hydrochloride