Compositions of dipeptidyl peptidase-IV inhibitors and antioxidants

Abstract

Disclosed are compositions, including pharmaceutical compositions, wherein the compositions comprise sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof in combination with an antioxidant.

Description

[Background technology]

[0001] Type 2 diabetes is a chronic and progressive disease resulting from complex pathophysiology involving dual endocrine abnormalities: insulin resistance and impaired insulin secretion. Treatment of type 2 diabetes typically begins with dietary restriction and exercise, followed by oral or injectable antidiabetic drug monotherapy. Many patients with type 2 diabetes are considered at high risk for coronary artery disease and its associated comorbidities. To reduce the risk of coronary artery disease, it is important to manage the entire risk spectrum. Treatment with cholesterol synthesis inhibitors reduces the risk of cardiovascular morbidity and mortality in patients with and without coronary heart disease, including coronary artery disease.

[0002] Dipeptidyl peptidase-IV (DPP-4) inhibitors are a class of drugs being developed to treat or improve glycemic control in patients with type 2 diabetes. Specific DPP-4 inhibitors already approved for marketing or in clinical development for the treatment of type 2 diabetes include sitagliptin, vildagliptin, saxagliptin, melogliptin, alogliptin, denagliptin, carmegliptin, linagliptin, dutogliptin, P93 / 01 (Prosidion), Roche 0730699, TS021 (Taisho), and E3024 (Eisai). For example, oral administration of sitagliptin, vildagliptin, alogliptin, and saxagliptin to human type 2 diabetes patients significantly reduced HbA 1c DPP-4 inhibitors have been shown to reduce fasting and postprandial blood glucose elevations, associated with significant reductions in the levels of α-glucan. For a review of the application of DPP-4 inhibitors in the treatment of type 2 diabetes, see the following publications: (1) AH Stonehouse, et al., “Management of Type 2 diabetes: the role of incretin mimetics,” Exp. Opin. Pharmacother., 7: 2095-2105 (2006); (2) BD Green, et al., “Inhibition of dipeptidyl peptidase-IV activity as a therapy of Type 2 diabetes,” Exp. Opin. Emerging Drugs , 11: 525-539 (2006); (3) MMJ Combettes, “GLP-1 and Type 2 diabetes: physiology and new clinical advances,” Curr. Opin. Pharmacol. , 6: 598-605 (2006); and RK Campbell, “Rationale for Dipeptidyl Peptidase 4 Inhibitors: A New Class of Oral Agents for the Treatment of Type 2 Diabetes Mellitus,” Ann. Pharmacother. , 41: 51-60 (2007).

[0003] Sitagliptin phosphate, having the following structural formula I, is the dihydrogen phosphate salt of (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. [ka]

[0004] In one embodiment, sitagliptin phosphate is in the form of a crystalline monohydrate. Sitagliptin free base and its pharmaceutically acceptable salts are disclosed in U.S. Patent No. 6,699,871, the contents of which are incorporated herein by reference in their entirety. Crystalline sitagliptin phosphate monohydrate is disclosed in U.S. Patent No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. Sitagliptin phosphate has been approved for sale in several countries, including the United States, Europe, Canada, and Mexico, for the treatment of type 2 diabetes, and is marketed as a monotherapy product under the trademark "JANUVIA®" and as a combination therapy product with metformin hydrochloride under the trademark "JANUMET®." For a review, see D. Drucker, et al., "Sitagliptin," Nature Reviews Drug Discovery , 6: 109-110 (2007); CF Deacon, “Dipeptidyl peptidase 4 inhibition with sitagliptin: a new therapy for Type 2 diabetes,” Exp. Opin. Invest. Drugs , 16: 533-545 (2007); KA Lyseng-Williamson, “Sitagliptin,” Drugs , 67: 587-597 (2007); and B. Gallwitz, “Sitagliptin: Profile of a Novel DPP-4 Inhibitor for the Treatment of Type 2 Diabetes (Update),” Drugs of Today , 43: 801-814 (2007).

[0005] N-nitrosamines are present at low levels in water and foods such as dairy products, meat, and vegetables. In foods, nitrosamine formation and inhibition chemistry are typically due to the high temperatures used in cooking and smoking (N.P. Sen et al., "Inhibition of Nitrosamine Formation in Fried Bacon by Propyl Gallate and L-Ascorbyl Palmitate", J. Agric. Food Chem., 24 (1976), 397; T. Rudlof et al., "Potential Nitrite Scavengers as Inhibitors of the Formation of N-Nitrosamines in Solution and Tobacco Matrix Systems", J. Agric. Food Chem., 48 (2000), 4381). A preliminary control goal of 37 ng / day exposure has been set by many health regulatory agencies.

[0006] Antioxidants are used to reduce the oxidation and resulting oxidative degradation of active pharmaceutical ingredients in pharmaceutical compositions and formulations.

[0007] The use of antioxidants to inhibit the formation of nitrosamines is discussed in the following: M. Homsak et al, “Assessment of a Diverse Array of Nitrite Scavengers in Solution and Solid State: A Study of Inhibitory Effect on the Formation of Alkyl-Aryl and Dialkyl N-Nitrosamine Derivatives”, Processes, 10 (2022), 2428; S. Pandit, VH Grassian, “Gas-Phase Nitrous Acid (HONO) Is Controlled by Surface Interactions of Adsorbed Nitrite (NO2-) on Common Indoor Material Surfaces”, Environ. Sci. Technol., 56 (2022), 12045; IW Ashworth et al, “Potential for the Formation of N-Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water”, Org. Process Res. Dev., 24 (2020), 1629.

[0008] Pharmaceutical compositions containing a combination of sitagliptin dihydrogen phosphate and metformin hydrochloride are disclosed in WO2007 / 078726, WO2009 / 099734 and WO2009 / 111200. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Patent No. 6,699,871

Patent document 2

Patent document 3

Patent document 4

Patent document 5

Non-licensed literature

[0010] [Non-licensed document 1] AH Stonehouse, et al., “Management of Type 2 diabetes: the role of incretin mimetics,” Exp. Opin. Pharmacother., 7: 2095-2105 (2006) [Non-licensed document 2] BD Green, et al., “Inhibition of dipeptidyl peptidase-IV activity as a therapy of Type 2 diabetes,” Exp. Opin. Emerging Drugs, 11: 525-539 (2006) [Non-licensed document 3] MMJ Combettes, “GLP-1 and Type 2 diabetes: physiology and new clinical advances,” Curr. Opin. Pharmacol., 6: 598-605 (2006)

Non-licensed Document 4

Non-licensed Document 5

[0011] summary A sitagliptin-antioxidant composition for use in a pharmaceutical composition of sitagliptin is provided.

[0012] Additionally, a process for preparing a sitagliptin-antioxidant composition is provided.

[0013] Processes for preparing sitagliptin-antioxidant compositions for use in pharmaceutical compositions and formulations of sitagliptin or its salts and / or hydrates are also provided.

[0014] The present disclosure provides sitagliptin-antioxidant compositions that reduce the amount of NTTP formed in formulations and pharmaceutical compositions containing sitagliptin or its salts and / or hydrates.

[0015] Also provided are pharmaceutical compositions and formulations comprising the sitagliptin-antioxidant composition, alone or in combination with ertugliflozin, or a salt or cocrystal thereof. These pharmaceutical compositions and formulations can include additional excipients. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 is a graph showing the reduction in NTTP in JANUVIA® tablet cores containing either sitagliptin dihydrogen phosphate monohydrate-propyl gallate complex powder (PG) or sitagliptin dihydrogen phosphate monohydrate-butylated hydroxyanisole complex powder (BHA) compared to JANUVIA® tablet cores containing sitagliptin dihydrogen phosphate monohydrate powder without antioxidant (control). DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description N-nitrosamines can also be formed in drug formulations during manufacturing, formulation, and storage by chemical reactions of nitrites with amines in the formulation.

[0018] It has been unexpectedly discovered that nitrosamines, particularly N-7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo-[4,3-a]pyrazine (NTTP), can be formed in sitagliptin formulations. NTTP can be formed by nitrosation of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyrazine, formed by hydrolysis of sitagliptin, with trace nitrite species in the formulation, such as nitrous acid, nitrosonium ion, nitric oxide, and mixed nitrites.

[0019] There is a need for sitagliptin formulations that reduce the amount of the N-nitrosamine 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (also known as NTTP) that is formed during manufacturing, formulation, and storage.

[0020] It has been unexpectedly discovered that some antioxidants also act to reduce the formation and buildup of N-nitrosamines, including NTTP, in the presence of nitrite in solutions and in formulations or pharmaceutical compositions containing sitagliptin or its salts and / or hydrates. Without being limited to a particular theory, it has been proposed that the antioxidants may act in these formulations and pharmaceutical compositions by reacting with nitrite and with NO+, a nitrosating agent formed from nitrite. Furthermore, it has been unexpectedly discovered that antioxidants, including but not limited to butylated hydroxyanisole (BHA) and propyl gallate (PG), may react with nitrite to prevent the formation of NTTP in solutions, formulations, and pharmaceutical compositions of sitagliptin dihydrogen phosphate monohydrate.

[0021] The present disclosure relates to antioxidant-containing compositions, pharmaceutical compositions, and formulations of sitagliptin and its salts and / or hydrates that minimize or reduce the formation of NTTP. In particular, the present disclosure relates to antioxidant-containing compositions, pharmaceutical compositions, and formulations of sitagliptin dihydrogen phosphate monohydrate that minimize or reduce NTTP formation. In one embodiment, the pharmaceutical compositions and formulations can be used in compressed tablets for oral administration. Furthermore, the antioxidant-containing compositions, pharmaceutical compositions, and formulations of the present disclosure inhibit or reduce NTTP formation without increasing the chemical degradation of sitagliptin.

[0022] The present disclosure also relates to antioxidant-containing compositions, pharmaceutical compositions, and formulations of sitagliptin and its salts and / or hydrates in fixed dose combination with ertugliflozin or its salts or cocrystals, which reduce NTTP formation. In particular, the present disclosure relates to antioxidant-containing compositions, pharmaceutical compositions, and formulations of sitagliptin dihydrogen phosphate monohydrate in fixed dose combination with ertugliflozin L-pyroglutamic acid cocrystal, which reduce NTTP formation. In one embodiment, the pharmaceutical compositions and formulations can be used in compressed tablets for oral administration. Furthermore, the antioxidant-containing compositions, pharmaceutical compositions, and formulations of the present disclosure inhibit or reduce NTTP formation without increasing the chemical degradation of sitagliptin.

[0023] It has been surprisingly found that compositions, pharmaceutical compositions, formulations, and tablets containing sitagliptin dihydrogen phosphate monohydrate and an antioxidant inhibit the formation of NTTP over time for comparable periods of time compared to compositions, pharmaceutical compositions, formulations, and tablets that do not contain an antioxidant. Furthermore, it has been found that the use of antioxidants in sitagliptin compositions, pharmaceutical compositions, formulations, and tablets reduces NTTP formation without increasing the chemical degradation of sitagliptin.

[0024] Furthermore, it has also been surprisingly found that compositions, pharmaceutical compositions, formulations, and tablets comprising sitagliptin dihydrogen phosphate monohydrate in combination with ertugliflozin L-pyroglutamic acid cocrystal and comprising an antioxidant inhibit the formation of NTTP over time, compared to compositions, pharmaceutical compositions, formulations, and tablets that do not contain an antioxidant. Furthermore, it has also been found that the use of antioxidants in sitagliptin and ertugliflozin compositions, pharmaceutical compositions, formulations, and tablets reduces NTTP formation without increasing the chemical degradation of sitagliptin.

[0025] It has also been unexpectedly discovered that antioxidants are effective when added to sitagliptin dihydrogen phosphate monohydrate compositions, pharmaceutical compositions, and formulations prior to tableting by multiple routes, including: (1) forming a sitagliptin antioxidant composition (including, but not limited to, a sitagliptin dihydrogen phosphate monohydrate antioxidant composition) and adding the sitagliptin antioxidant composition to dry pharmaceutical composition ingredients prior to tableting; (2) adding the antioxidant as a dry powder to a sitagliptin dihydrogen phosphate monohydrate pharmaceutical composition prior to tableting; and (3) attaching the antioxidant to an excipient and adding the antioxidant excipient composition to a sitagliptin dihydrogen phosphate monohydrate pharmaceutical composition prior to tableting.

[0026] Furthermore, it has been unexpectedly found that compositions, pharmaceutical compositions, formulations and tablets comprising sitagliptin dihydrogen phosphate monohydrate, metformin and an antioxidant do not consistently inhibit the formation of NTTP over time compared to compositions, pharmaceutical compositions, formulations and tablets that do not contain an antioxidant, over a comparable period of time.

[0027] One aspect of the present disclosure is directed to a composition comprising sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof and an antioxidant.

[0028] The present disclosure provides pharmaceutical compositions comprising sitagliptin phosphate-antioxidant compositions. In one embodiment, the sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate and an antioxidant. In another embodiment, the sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate monohydrate and an antioxidant. In another embodiment, the sitagliptin dihydrogen phosphate monohydrate and antioxidant composition is a solid. In another embodiment, the sitagliptin dihydrogen phosphate monohydrate and antioxidant composition is a crystalline solid.

[0029] In another embodiment, the sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate and propyl gallate. In another embodiment, the sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate monohydrate and propyl gallate. In another embodiment, the sitagliptin dihydrogen phosphate monohydrate and propyl gallate composition is a solid. In another embodiment, the sitagliptin dihydrogen phosphate monohydrate and propyl gallate composition is a crystalline solid.

[0030] In another embodiment, the sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate and butylated hydroxyanisole. In another embodiment, the sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate monohydrate and butylated hydroxyanisole. In another embodiment, the sitagliptin dihydrogen phosphate monohydrate and butylated hydroxyanisole composition is a solid. In another embodiment, the sitagliptin dihydrogen phosphate monohydrate and butylated hydroxyanisole composition is a crystalline solid.

[0031] In another embodiment, the sitagliptin dihydrogen phosphate monohydrate-antioxidant composition is used in a pharmaceutical composition.

[0032] The present disclosure further provides pharmaceutical compositions comprising the sitagliptin dihydrogen phosphate monohydrate-antioxidant composition for use in pharmaceutical compositions, formulations and tablets.

[0033] The present disclosure includes a pharmaceutical composition of sitagliptin or a pharmaceutically acceptable salt thereof and an antioxidant. Also included is a pharmaceutical composition of sitagliptin dihydrogen phosphate monohydrate and an antioxidant. The pharmaceutical composition may contain additional excipients, including, but not limited to, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and / or sodium stearyl fumarate. The pharmaceutical composition may be compressed into a tablet and, optionally, film-coated.

[0034] In one embodiment, the pharmaceutical composition contains 32.13 mg, 64.25 mg, or 128.5 mg of sitagliptin dihydrogen phosphate monohydrate, which corresponds to 25 mg, 50 mg, or 100 mg of sitagliptin free base, respectively. In another embodiment, the pharmaceutical composition contains one or more of the following ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. In another embodiment, the pharmaceutical composition contains microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. In another embodiment, the pharmaceutical composition may be formed into a tablet. In another embodiment, the tablet may be coated with a film coating. In another embodiment, the film coating contains polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.

[0035] In one embodiment, the pharmaceutical composition comprises: (a) 10 to 50% by weight of sitagliptin dihydrogen phosphate monohydrate; (b) 0.001 to 1 wt. % antioxidant; (c) 10-50 wt% microcrystalline cellulose; (d) 10 to 50 wt. % anhydrous dibasic calcium phosphate; (e) 0.5 to 5% by weight of croscarmellose sodium; (f) 0.5 to 5% by weight of sodium stearyl fumarate; and (g) 0.5 to 2% by weight of magnesium stearate; Contains:

[0036] In one class of this embodiment, the antioxidant is butylated hydroxyanisole. In a subclass of this class, the particle size of the butylated hydroxyanisole is ≦400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 22-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦22 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 22 microns.

[0037] In another class of this embodiment, the antioxidant is propyl gallate. In a subclass of this class, the particle size of the propyl gallate is ≦400 microns. In another subclass of this class, the particle size of the propyl gallate is 1-400 microns. In another subclass of this class, the particle size of the propyl gallate is <375 microns. In another subclass of this class, the particle size of the propyl gallate is 1-375 microns. In another subclass of this class, the particle size of the propyl gallate is 22-375 microns. In another subclass of this class, the particle size of the propyl gallate is ≦150 microns. In another subclass of this class, the particle size of the propyl gallate is 1-150 microns. In another subclass of this class, the particle size of the propyl gallate is ≦83 microns. In another subclass of this class, the particle size of the propyl gallate is 1-83 microns. In another subclass of this class, the propyl gallate has a particle size of ≦44 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 44 microns. In another subclass of this class, the propyl gallate has a particle size of ≦22 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 22 microns.

[0038] In another class of this embodiment, the pharmaceutical composition is formed into a tablet. In a subclass of this class, the tablet is film coated. In another subclass, the tablet is film coated with Opadry 85F. In another subclass, the tablet is film coated with 2-8% by weight of Opadry 85F.

[0039] In one embodiment, the pharmaceutical composition comprises: (a) 21 to 50% by weight of sitagliptin dihydrogen phosphate monohydrate; (b) 0.001 to 1 wt. % antioxidant; (c) 10-50 wt% microcrystalline cellulose; (d) 10 to 50 wt. % anhydrous dibasic calcium phosphate; (e) 0.5 to 5% by weight of croscarmellose sodium; (f) 0.5 to 5% by weight of sodium stearyl fumarate; and (g) 0.5 to 2% by weight of magnesium stearate; Contains:

[0040] In one class of this embodiment, the antioxidant is butylated hydroxyanisole. In a subclass of this class, the particle size of the butylated hydroxyanisole is ≦400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 22-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦22 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 22 microns.

[0041] In another class of this embodiment, the antioxidant is propyl gallate. In a subclass of this class, the particle size of the propyl gallate is ≦400 microns. In another subclass of this class, the particle size of the propyl gallate is 1-400 microns. In another subclass of this class, the particle size of the propyl gallate is ≦375 microns. In another subclass of this class, the particle size of the propyl gallate is 1-375 microns. In another subclass of this class, the particle size of the propyl gallate is 22-375 microns. In another subclass of this class, the particle size of the propyl gallate is ≦150 microns. In another subclass of this class, the particle size of the propyl gallate is 1-150 microns. In another subclass of this class, the particle size of the propyl gallate is ≦83 microns. In another subclass of this class, the particle size of the propyl gallate is 1-83 microns. In another subclass of this class, the propyl gallate has a particle size of ≦44 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 44 microns. In another subclass of this class, the propyl gallate has a particle size of ≦22 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 22 microns.

[0042] In another class of this embodiment, the pharmaceutical composition is formed into a tablet. In a subclass of this class, the tablet is film coated. In another subclass, the tablet is film coated with Opadry 85F. In another subclass, the tablet is film coated with 2-8% by weight of Opadry 85F.

[0043] In another embodiment, the pharmaceutical composition comprises: (a) 10 to 50% by weight of sitagliptin dihydrogen phosphate monohydrate; (b) 0.001 to 1 wt. % antioxidant; (c) 10-50 wt% microcrystalline cellulose; (d) 10 to 50 wt. % anhydrous dibasic calcium phosphate; (e) 0.5 to 5% by weight of croscarmellose sodium; (f) 0.5 to 5% by weight of sodium stearyl fumarate; and (g) 0-2% by weight magnesium stearate; Contains:

[0044] In one class of this embodiment, the antioxidant is butylated hydroxyanisole. In a subclass of this class, the particle size of the butylated hydroxyanisole is ≦400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 22-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦22 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 22 microns.

[0045] In another class of this embodiment, the antioxidant is propyl gallate. In a subclass of this class, the particle size of the propyl gallate is ≦400 microns. In another subclass of this class, the particle size of the propyl gallate is 1-400 microns. In another subclass of this class, the particle size of the propyl gallate is ≦375 microns. In another subclass of this class, the particle size of the propyl gallate is 1-375 microns. In another subclass of this class, the particle size of the propyl gallate is 22-375 microns. In another subclass of this class, the particle size of the propyl gallate is ≦150 microns. In another subclass of this class, the particle size of the propyl gallate is 1-150 microns. In another subclass of this class, the particle size of the propyl gallate is ≦83 microns. In another subclass of this class, the particle size of the propyl gallate is 1-83 microns. In another subclass of this class, the propyl gallate has a particle size of ≦44 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 44 microns. In another subclass of this class, the propyl gallate has a particle size of ≦22 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 22 microns.

[0046] In another class of this embodiment, the pharmaceutical composition is formed into a tablet. In a subclass of this class, the tablet is film coated. In another subclass, the tablet is film coated with Opadry 85F. In another subclass, the tablet is film coated with 2-8% by weight of Opadry 85F.

[0047] In another embodiment, the pharmaceutical composition comprises: (a) 21 to 50% by weight of sitagliptin dihydrogen phosphate monohydrate; (b) 0.001 to 1 wt. % antioxidant; (c) 10-50 wt% microcrystalline cellulose; (d) 10 to 50 wt. % anhydrous dibasic calcium phosphate; (e) 0.5 to 5% by weight of croscarmellose sodium; (f) 0.5 to 5% by weight of sodium stearyl fumarate; and (g) 0-2% by weight of magnesium stearate; Contains:

[0048] In one class of this embodiment, the antioxidant is butylated hydroxyanisole. In a subclass of this class, the particle size of the butylated hydroxyanisole is ≦400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 22-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦22 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 22 microns.

[0049] In another class of this embodiment, the antioxidant is propyl gallate. In a subclass of this class, the particle size of the propyl gallate is ≦400 microns. In another subclass of this class, the particle size of the propyl gallate is 1-400 microns. In another subclass of this class, the particle size of the propyl gallate is ≦375 microns. In another subclass of this class, the particle size of the propyl gallate is 1-375 microns. In another subclass of this class, the particle size of the propyl gallate is 22-375 microns. In another subclass of this class, the particle size of the propyl gallate is ≦150 microns. In another subclass of this class, the particle size of the propyl gallate is 1-150 microns. In another subclass of this class, the particle size of the propyl gallate is ≦83 microns. In another subclass of this class, the particle size of the propyl gallate is 1-83 microns. In another subclass of this class, the propyl gallate has a particle size of ≦44 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 44 microns. In another subclass of this class, the propyl gallate has a particle size of ≦22 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 22 microns.

[0050] In another class of this embodiment, the pharmaceutical composition is formed into a tablet. In a subclass of this class, the tablet is film coated. In another subclass, the tablet is film coated with Opadry 85F. In another subclass, the tablet is film coated with 2-8% by weight of Opadry 85F.

[0051] In another embodiment, pharmaceutical compositions of sitagliptin dihydrogen phosphate monohydrate and an antioxidant are prepared by forming a sitagliptin dihydrogen phosphate monohydrate-antioxidant composition and adding the composition or complex to dry pharmaceutical composition ingredients prior to tableting. In one class of this embodiment, the antioxidant is butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate.

[0052] In another embodiment, the pharmaceutical composition of sitagliptin dihydrogen phosphate monohydrate and an antioxidant is prepared by adding the antioxidant as a dry powder to a pharmaceutical composition of sitagliptin dihydrogen phosphate monohydrate prior to tableting.

[0053] In one class of this embodiment, the antioxidant is butylated hydroxyanisole. In a subclass of this class, the particle size of the butylated hydroxyanisole is ≦400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 22-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦22 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 22 microns.

[0054] In another class of this embodiment, the antioxidant is propyl gallate. In a subclass of this class, the particle size of the propyl gallate is ≦400 microns. In another subclass of this class, the particle size of the propyl gallate is 1-400 microns. In another subclass of this class, the particle size of the propyl gallate is ≦375 microns. In another subclass of this class, the particle size of the propyl gallate is 1-375 microns. In another subclass of this class, the particle size of the propyl gallate is 22-375 microns. In another subclass of this class, the particle size of the propyl gallate is ≦150 microns. In another subclass of this class, the particle size of the propyl gallate is 1-150 microns. In another subclass of this class, the particle size of the propyl gallate is ≦83 microns. In another subclass of this class, the particle size of the propyl gallate is 1-83 microns. In another subclass of this class, the propyl gallate has a particle size of ≦44 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 44 microns. In another subclass of this class, the propyl gallate has a particle size of ≦22 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 22 microns.

[0055] In another embodiment, the pharmaceutical composition of sitagliptin dihydrogen phosphate monohydrate and an antioxidant is prepared by depositing the antioxidant on an excipient and adding the antioxidant / excipient composition to the pharmaceutical composition of sitagliptin dihydrogen phosphate monohydrate prior to tableting. In one class of this embodiment, the antioxidant is butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate.

[0056] In another embodiment, the sitagliptin phosphate-antioxidant composition is used in the JANUVIA® pharmaceutical composition. In another embodiment, the sitagliptin dihydrogen phosphate monohydrate-antioxidant composition is used in the pharmaceutical composition for JANUVIA®. In another embodiment, the sitagliptin phosphate-antioxidant composition is used in the JANUVIA® tablet. In another embodiment, the sitagliptin dihydrogen phosphate monohydrate-antioxidant composition is used in the JANUVIA® tablet. In another embodiment, the sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate and an antioxidant. In another embodiment, the sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate and propyl gallate. In another embodiment, the sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate monohydrate and propyl gallate. In another embodiment, a sitagliptin dihydrogen phosphate monohydrate-propyl gallate composition is used in JANUVIA® tablets. In another embodiment, a sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate and butylated hydroxyanisole. In another embodiment, a sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate monohydrate and butylated hydroxyanisole. In another embodiment, a sitagliptin dihydrogen phosphate monohydrate-butylated hydroxyanisole composition is used in JANUVIA® tablets.

[0057] In another embodiment, a sitagliptin-containing tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 4 ppm or less. In a class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 4 ppm or less after 2.5 days of storage at 70°C. In another class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 4 ppm or less after 1.5 weeks of storage at 60°C and 60% relative humidity; after 2.5 days of storage at 70°C and 60% relative humidity; after 1.5 months of storage at 40°C and 75% relative humidity; or after 1.5 weeks of storage at 40°C and 65% relative humidity. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Januvia® 25 mg tablet core, a Januvia® 50 mg tablet core, or a Januvia® 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating.

[0058] In another embodiment, a sitagliptin-containing tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 2 ppm or less. In a class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 2 ppm or less after 2.5 days of storage at 70°C. In another class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 2 ppm or less after 1.5 weeks of storage at 60°C and 60% relative humidity; after 2.5 days of storage at 70°C and 60% relative humidity; after 1.5 months of storage at 40°C and 75% relative humidity; or after 1.5 weeks of storage at 40°C and 65% relative humidity. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Januvia® 25 mg tablet core, a Januvia® 50 mg tablet core, or a Januvia® 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating.

[0059] In another embodiment, a sitagliptin-containing tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 1 ppm or less. In a class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 1 ppm or less after 2.5 days of storage at 70°C. In another class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 1 ppm or less after 1.5 weeks of storage at 60°C and 60% relative humidity; after 2.5 days of storage at 70°C and 60% relative humidity; after 1.5 months of storage at 40°C and 75% relative humidity; or after 1.5 weeks of storage at 40°C and 65% relative humidity. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Januvia® 25 mg tablet core, a Januvia® 50 mg tablet core, or a Januvia® 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating.

[0060] In another embodiment, sitagliptin-containing tablet cores are prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 0.37 ppm or less. In a class of this embodiment, said tablet cores are prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 0.37 ppm or less after 2.5 days of storage at 70° C. In another class of this embodiment, said tablet cores are prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 0.37 ppm or less after 1.5 weeks of storage at 60° C. and 60% relative humidity; after 2.5 days of storage at 70° C. and 60% relative humidity; after 1.5 months of storage at 40° C. and 75% relative humidity; or after 1.5 weeks of storage at 40° C. and 65% relative humidity. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Januvia® 25 mg tablet core, a Januvia® 50 mg tablet core, or a Januvia® 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating.

[0061] In another embodiment, a sitagliptin-containing tablet core is prepared by adding an antioxidant as a dry powder, wherein the NTTP level is 4 ppm or less. In one class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, the NTTP level is 4 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 1.5 weeks of storage at 60°C and 60% relative humidity; after 2.5 days of storage at 70°C and 60% relative humidity; after 1.5 months of storage at 40°C and 75% relative humidity; or after 1.5 weeks of storage at 40°C and 65% relative humidity, the NTTP level is 4 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Januvia® 25 mg tablet core, a Januvia® 50 mg tablet core, or a Januvia® 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate.

[0062] In another embodiment, a sitagliptin-containing tablet core is prepared by adding an antioxidant as a dry powder, wherein the NTTP level is 2 ppm or less. In one class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, the NTTP level is 2 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 1.5 weeks of storage at 60°C and 60% relative humidity; after 2.5 days of storage at 70°C and 60% relative humidity; after 1.5 months of storage at 40°C and 75% relative humidity; or after 1.5 weeks of storage at 40°C and 65% relative humidity, the NTTP level is 2 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Januvia® 25 mg tablet core, a Januvia® 50 mg tablet core, or a Januvia® 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate.

[0063] In another embodiment, a sitagliptin-containing tablet core is prepared by adding an antioxidant as a dry powder, wherein the NTTP level is 1 ppm or less. In one class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, the NTTP level is 1 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 1.5 weeks of storage at 60°C and 60% relative humidity; after 2.5 days of storage at 70°C and 60% relative humidity; after 1.5 months of storage at 40°C and 75% relative humidity; or after 1.5 weeks of storage at 40°C and 65% relative humidity, the NTTP level is 1 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Januvia® 25 mg tablet core, a Januvia® 50 mg tablet core, or a Januvia® 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate.

[0064] In another embodiment, a sitagliptin-containing tablet core is prepared by adding an antioxidant as a dry powder, wherein the NTTP level is 0.37 ppm or less. In one class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, the NTTP level is 0.37 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 1.5 weeks of storage at 60°C and 60% relative humidity; after 2.5 days of storage at 70°C and 60% relative humidity; after 1.5 months of storage at 40°C and 75% relative humidity; or after 1.5 weeks of storage at 40°C and 65% relative humidity, the NTTP level is 0.37 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Januvia® 25 mg tablet core, a Januvia® 50 mg tablet core, or a Januvia® 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate.

[0065] In another embodiment, a sitagliptin-containing tablet core is prepared by adding an antioxidant deposited on an excipient, wherein the NTTP level is 4 ppm or less. In a class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 2.5 days of storage at 70°C, the NTTP level is 4 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 1.5 weeks of storage at 60°C and 60% relative humidity; after 2.5 days of storage at 70°C and 60% relative humidity; after 1.5 months of storage at 40°C and 75% relative humidity; or after 1.5 weeks of storage at 40°C and 65% relative humidity, the NTTP level is 4 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the tablet core is a Januvia® 25 mg tablet core, a Januvia® 50 mg tablet core, or a Januvia® 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate.

[0066] In another embodiment, a sitagliptin-containing tablet core is prepared by adding an antioxidant deposited on an excipient, wherein the NTTP level is 2 ppm or less. In a class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 2.5 days of storage at 70°C, the NTTP level is 2 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 1.5 weeks of storage at 60°C and 60% relative humidity; after 2.5 days of storage at 70°C and 60% relative humidity; after 1.5 months of storage at 40°C and 75% relative humidity; or after 1.5 weeks of storage at 40°C and 65% relative humidity, the NTTP level is 2 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the tablet core is a Januvia® 25 mg tablet core, a Januvia® 50 mg tablet core, or a Januvia® 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate.

[0067] In another embodiment, a sitagliptin-containing tablet core is prepared by adding an antioxidant deposited on an excipient, wherein the NTTP level is 1 ppm or less. In a class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 2.5 days of storage at 70°C, the NTTP level is 1 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 1.5 weeks of storage at 60°C and 60% relative humidity; after 2.5 days of storage at 70°C and 60% relative humidity; after 1.5 months of storage at 40°C and 75% relative humidity; or after 1.5 weeks of storage at 40°C and 65% relative humidity, the NTTP level is 1 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the tablet core is a Januvia® 25 mg tablet core, a Januvia® 50 mg tablet core, or a Januvia® 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate.

[0068] In another embodiment, a sitagliptin-containing tablet core is prepared by adding an antioxidant deposited on an excipient, wherein the NTTP level is 0.37 ppm or less. In a class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 2.5 days of storage at 70°C, the NTTP level is 0.37 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 1.5 weeks of storage at 60°C and 60% relative humidity; after 2.5 days of storage at 70°C and 60% relative humidity; after 1.5 months of storage at 40°C and 75% relative humidity; or after 1.5 weeks of storage at 40°C and 65% relative humidity, the NTTP level is 0.37 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the tablet core is a Januvia® 25 mg tablet core, a Januvia® 50 mg tablet core, or a Januvia® 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate.

[0069] The present disclosure encompasses pharmaceutical compositions comprising sitagliptin or a pharmaceutically acceptable salt thereof, ertugliflozin or a salt or cocrystal thereof, and an antioxidant. The present disclosure also encompasses pharmaceutical compositions comprising sitagliptin dihydrogen phosphate monohydrate, ertugliflozin L-pyroglutamic acid cocrystal, and an antioxidant. The pharmaceutical compositions may contain additional excipients, including, but not limited to, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and / or sodium stearyl fumarate. The pharmaceutical compositions may also contain Opadry 20 and / or carnauba wax. The pharmaceutical compositions may be compressed into tablets and, optionally, film-coated.

[0070] In one embodiment, the pharmaceutical composition contains 6.48 mg of ertugliflozin L-pyroglutamic acid and 128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 5 mg of ertugliflozin and 100 mg of sitagliptin free base. In another embodiment, the pharmaceutical composition contains 19.43 mg of ertugliflozin L-pyroglutamic acid and 128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 15 mg of ertugliflozin and 100 mg of sitagliptin free base.

[0071] In another embodiment, the sitagliptin phosphate-antioxidant composition is used in a STEGLUJAN® pharmaceutical composition. In another embodiment, the sitagliptin dihydrogen phosphate monohydrate-antioxidant composition is used in a pharmaceutical composition for STEGLUJAN®. In another embodiment, the sitagliptin phosphate-antioxidant composition is used in a STEGLUJAN® tablet. In another embodiment, the sitagliptin dihydrogen phosphate monohydrate-antioxidant composition is used in a STEGLUJAN® tablet. In another embodiment, the sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate and an antioxidant. In another embodiment, the sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate and propyl gallate. In another embodiment, the sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate monohydrate and propyl gallate. In another embodiment, a sitagliptin dihydrogen phosphate monohydrate-propyl gallate composition is used in STEGLUJAN® tablets. In another embodiment, a sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate and butylated hydroxyanisole. In another embodiment, a sitagliptin phosphate-antioxidant composition comprises sitagliptin dihydrogen phosphate monohydrate and butylated hydroxyanisole. In another embodiment, a sitagliptin dihydrogen phosphate monohydrate-butylated hydroxyanisole composition is used in STEGLUJAN® tablets.

[0072] In one embodiment, the pharmaceutical composition comprises: (a) 10 to 50% by weight of sitagliptin dihydrogen phosphate monohydrate; (b) 0.5 to 15 wt.% ertugliflozin L-pyroglutamate; (c) 0.01 to 0.5 wt. % antioxidant; (d) 10-50 wt. % microcrystalline cellulose; (e) 10 to 50 wt. % anhydrous dibasic calcium phosphate; (f) 0.5 to 5% by weight of croscarmellose sodium; (g) 0.5 to 5% by weight of sodium stearyl fumarate; and (h) 0.5 to 2% by weight of magnesium stearate; Contains:

[0073] In one class of this embodiment, the antioxidant is butylated hydroxyanisole. In a subclass of this class, the particle size of the butylated hydroxyanisole is ≦400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 22-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦22 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 22 microns.

[0074] In another class of this embodiment, the antioxidant is propyl gallate. In a subclass of this class, the particle size of the propyl gallate is ≦400 microns. In another subclass of this class, the particle size of the propyl gallate is 1-400 microns. In another subclass of this class, the particle size of the propyl gallate is ≦375 microns. In another subclass of this class, the particle size of the propyl gallate is 1-375 microns. In another subclass of this class, the particle size of the propyl gallate is 22-375 microns. In another subclass of this class, the particle size of the propyl gallate is ≦150 microns. In another subclass of this class, the particle size of the propyl gallate is 1-150 microns. In another subclass of this class, the particle size of the propyl gallate is ≦83 microns. In another subclass of this class, the particle size of the propyl gallate is 1-83 microns. In another subclass of this class, the propyl gallate has a particle size of ≦44 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 44 microns. In another subclass of this class, the propyl gallate has a particle size of ≦22 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 22 microns.

[0075] In another class of this embodiment, the pharmaceutical composition is formed into a tablet. In a subclass of this class, the tablet is film coated.

[0076] In another embodiment, the pharmaceutical composition comprises: (a) 10 to 50% by weight of sitagliptin dihydrogen phosphate monohydrate; (b) 0.5 to 15 wt.% ertugliflozin L-pyroglutamate; (c) 0.01 to 0.5 wt. % antioxidant; (d) 10-50 wt. % microcrystalline cellulose; (e) 10 to 50 wt. % anhydrous dibasic calcium phosphate; (f) 0.5 to 5% by weight of croscarmellose sodium; (g) 0.5 to 5% by weight of sodium stearyl fumarate; (h) 0.5 to 2% by weight of magnesium stearate; and (i) 1~6% by weight Opadry 20A; Contains:

[0077] In one class of this embodiment, the antioxidant is butylated hydroxyanisole. In a subclass of this class, the particle size of the butylated hydroxyanisole is ≦400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 22-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦22 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 22 microns.

[0078] In another class of this embodiment, the antioxidant is propyl gallate. In a subclass of this class, the particle size of the propyl gallate is ≦400 microns. In another subclass of this class, the particle size of the propyl gallate is 1-400 microns. In another subclass of this class, the particle size of the propyl gallate is ≦375 microns. In another subclass of this class, the particle size of the propyl gallate is 1-375 microns. In another subclass of this class, the particle size of the propyl gallate is 22-375 microns. In another subclass of this class, the particle size of the propyl gallate is ≦150 microns. In another subclass of this class, the particle size of the propyl gallate is 1-150 microns. In another subclass of this class, the particle size of the propyl gallate is ≦83 microns. In another subclass of this class, the particle size of the propyl gallate is 1-83 microns. In another subclass of this class, the propyl gallate has a particle size of ≦44 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 44 microns. In another subclass of this class, the propyl gallate has a particle size of ≦22 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 22 microns.

[0079] In another class of this embodiment, the pharmaceutical composition is formed into a tablet. In a subclass of this class, the tablet is film coated.

[0080] In another embodiment, the pharmaceutical composition comprises: (a) 10 to 50% by weight of sitagliptin dihydrogen phosphate monohydrate; (b) 0.5 to 15 wt.% ertugliflozin L-pyroglutamate; (c) 0.01 to 0.5 wt. % antioxidant; (d) 10-50 wt. % microcrystalline cellulose; (e) 10 to 50 wt. % anhydrous dibasic calcium phosphate; (f) 0.5 to 5% by weight of croscarmellose sodium; (g) 0.5 to 5% by weight of sodium stearyl fumarate; (h) 0.5 to 2% by weight of magnesium stearate; (i) 1 to 6 wt. % Opadry 20A; and (j) 0.001 to 0.005% by weight of carnauba wax; Contains:

[0081] In one class of this embodiment, the antioxidant is butylated hydroxyanisole. In a subclass of this class, the particle size of the butylated hydroxyanisole is ≦400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 22-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦22 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 22 microns.

[0082] In another class of this embodiment, the antioxidant is propyl gallate. In a subclass of this class, the particle size of the propyl gallate is ≦400 microns. In another subclass of this class, the particle size of the propyl gallate is 1-400 microns. In another subclass of this class, the particle size of the propyl gallate is ≦375 microns. In another subclass of this class, the particle size of the propyl gallate is 1-375 microns. In another subclass of this class, the particle size of the propyl gallate is 22-375 microns. In another subclass of this class, the particle size of the propyl gallate is ≦150 microns. In another subclass of this class, the particle size of the propyl gallate is 1-150 microns. In another subclass of this class, the particle size of the propyl gallate is ≦83 microns. In another subclass of this class, the particle size of the propyl gallate is 1-83 microns. In another subclass of this class, the propyl gallate has a particle size of ≦44 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 44 microns. In another subclass of this class, the propyl gallate has a particle size of ≦22 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 22 microns.

[0083] In another class of this embodiment, the pharmaceutical composition is formed into a tablet. In a subclass of this class, the tablet is film coated.

[0084] In another embodiment, the pharmaceutical composition of sitagliptin dihydrogen phosphate monohydrate, ertugliflozin L-pyroglutamate, and an antioxidant is prepared by forming a sitagliptin dihydrogen phosphate monohydrate-antioxidant composition or complex and adding the composition or complex to the dry pharmaceutical composition ingredients prior to tableting. In one class of this embodiment, the antioxidant is butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate.

[0085] In another embodiment, the pharmaceutical composition of sitagliptin dihydrogen phosphate monohydrate, ertugliflozin L-pyroglutamate and an antioxidant is prepared by adding the antioxidant as a dry powder to a pharmaceutical composition of sitagliptin dihydrogen phosphate monohydrate prior to tableting.

[0086] In one class of this embodiment, the antioxidant is butylated hydroxyanisole. In a subclass of this class, the particle size of the butylated hydroxyanisole is ≦400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-400 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 22-375 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-150 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1-83 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 44 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is ≦22 microns. In another subclass of this class, the particle size of the butylated hydroxyanisole is 1 to 22 microns.

[0087] In another class of this embodiment, the antioxidant is propyl gallate. In a subclass of this class, the particle size of the propyl gallate is ≦400 microns. In another subclass of this class, the particle size of the propyl gallate is 1-400 microns. In another subclass of this class, the particle size of the propyl gallate is ≦375 microns. In another subclass of this class, the particle size of the propyl gallate is 1-375 microns. In another subclass of this class, the particle size of the propyl gallate is 22-375 microns. In another subclass of this class, the particle size of the propyl gallate is ≦150 microns. In another subclass of this class, the particle size of the propyl gallate is 1-150 microns. In another subclass of this class, the particle size of the propyl gallate is ≦83 microns. In another subclass of this class, the particle size of the propyl gallate is 1-83 microns. In another subclass of this class, the propyl gallate has a particle size of ≦44 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 44 microns. In another subclass of this class, the propyl gallate has a particle size of ≦22 microns. In another subclass of this class, the propyl gallate has a particle size of 1 to 22 microns.

[0088] In another embodiment, the pharmaceutical composition of sitagliptin dihydrogen phosphate monohydrate, ertugliflozin L-pyroglutamate, and an antioxidant is prepared by depositing the antioxidant on an excipient and adding the antioxidant / excipient composition to the sitagliptin dihydrogen phosphate monohydrate pharmaceutical composition prior to tableting. In one class of this embodiment, the antioxidant is butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate.

[0089] In another embodiment, a tablet core comprising sitagliptin and ertugliflozin is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 4 ppm or less. In a class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 4 ppm or less after 2.5 days of storage at 70°C. In another class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 4 ppm or less after 2.5 days of storage at 70°C or after 1.5 weeks of storage at 60°C and 30% relative humidity. In a class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Steglujan® 5 mg / 100 mg tablet core or a Steglujan® 15 mg / 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the ertugliflozin is ertugliflozin L-pyroglutamate.

[0090] In another embodiment, a tablet core comprising sitagliptin and ertugliflozin is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 2 ppm or less. In a class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein after 2.5 days of storage at 70°C, the NTTP level is 2 ppm or less. In another class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein after 2.5 days of storage at 70°C, the NTTP level is 2 ppm or less. In a class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Steglujan® 5 mg / 100 mg tablet core or a Steglujan® 15 mg / 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the ertugliflozin is ertugliflozin L-pyroglutamate.

[0091] In another embodiment, a tablet core comprising sitagliptin and ertugliflozin is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 1 ppm or less. In a class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein after 2.5 days of storage at 70°C, the NTTP level is 1 ppm or less. In another class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein after 2.5 days of storage at 70°C, the NTTP level is 1 ppm or less. In another class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein after 2.5 days of storage at 70°C, or after 1.5 weeks of storage at 60°C and 30% relative humidity, the NTTP level is 1 ppm or less. In a class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Steglujan® 5 mg / 100 mg tablet core or a Steglujan® 15 mg / 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the ertugliflozin is ertugliflozin L-pyroglutamate.

[0092] In another embodiment, a tablet core comprising sitagliptin and ertugliflozin is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein the NTTP level is 0.37 ppm or less. In a class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein after 2.5 days of storage at 70°C, the NTTP level is 0.37 ppm or less. In another class of this embodiment, the tablet core is prepared by adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition, wherein after 2.5 days of storage at 70°C, the NTTP level is 0.37 ppm or less after 1.5 weeks of storage at 60°C and 30% relative humidity. In a class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Steglujan® 5 mg / 100 mg tablet core or a Steglujan® 15 mg / 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the ertugliflozin is ertugliflozin L-pyroglutamate.

[0093] In another embodiment, a tablet core comprising sitagliptin and ertugliflozin is prepared by adding an antioxidant deposited on an excipient, wherein the NTTP level is 4 ppm or less. In a class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 2.5 days of storage at 70°C, the NTTP level is 4 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 2.5 days of storage at 70°C, or after 1.5 weeks of storage at 60°C and 30% relative humidity, the NTTP level is 4 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the tablet core is a Steglujan® 5 mg / 100 mg tablet core or a Steglujan® 15 mg / 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the ertugliflozin is ertugliflozin L-pyroglutamate.

[0094] In another embodiment, a tablet core comprising sitagliptin and ertugliflozin is prepared by adding an antioxidant deposited on an excipient, wherein the NTTP level is 2 ppm or less. In a class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 2.5 days of storage at 70°C, the NTTP level is 2 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 2.5 days of storage at 70°C, or after 1.5 weeks of storage at 60°C and 30% relative humidity, the NTTP level is 2 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the tablet core is a Steglujan® 5 mg / 100 mg tablet core or a Steglujan® 15 mg / 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the ertugliflozin is ertugliflozin L-pyroglutamate.

[0095] In another embodiment, a tablet core comprising sitagliptin and ertugliflozin is prepared by adding an antioxidant deposited on an excipient, wherein the NTTP level is 1 ppm or less. In a class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 2.5 days of storage at 70°C, the NTTP level is 1 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 2.5 days of storage at 70°C, or after 1.5 weeks of storage at 60°C and 30% relative humidity, the NTTP level is 1 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the tablet core is a Steglujan® 5 mg / 100 mg tablet core or a Steglujan® 15 mg / 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the ertugliflozin is ertugliflozin L-pyroglutamate.

[0096] In another embodiment, a tablet core comprising sitagliptin and ertugliflozin is prepared by adding an antioxidant deposited on an excipient, wherein the NTTP level is 0.37 ppm or less. In a class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 2.5 days of storage at 70°C, the NTTP level is 0.37 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant deposited on an excipient, wherein after 2.5 days of storage at 70°C, or after 1.5 weeks of storage at 60°C and 30% relative humidity, the NTTP level is 0.37 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the tablet core is a Steglujan® 5 mg / 100 mg tablet core or a Steglujan® 15 mg / 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the ertugliflozin is ertugliflozin L-pyroglutamate.

[0097] In another embodiment, a tablet core comprising sitagliptin and ertugliflozin is prepared by adding an antioxidant as a dry powder, wherein the NTTP level is 4 ppm or less. In one class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, the NTTP level is 4 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, the NTTP level is 4 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, or after 1.5 weeks of storage at 60°C and 30% relative humidity, the NTTP level is 4 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Steglujan® 5 mg / 100 mg tablet core or a Steglujan® 15 mg / 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the ertugliflozin is ertugliflozin L-pyroglutamate.

[0098] In another embodiment, a tablet core comprising sitagliptin and ertugliflozin is prepared by adding an antioxidant as a dry powder, wherein the NTTP level is 2 ppm or less. In one class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, the NTTP level is 2 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, the NTTP level is 2 ppm or less after 1.5 weeks of storage at 60°C and 30% relative humidity. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Steglujan® 5 mg / 100 mg tablet core or a Steglujan® 15 mg / 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the ertugliflozin is ertugliflozin L-pyroglutamate.

[0099] In another embodiment, a tablet core comprising sitagliptin and ertugliflozin is prepared by adding an antioxidant as a dry powder, wherein the NTTP level is 1 ppm or less. In one class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, the NTTP level is 1 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, the NTTP level is 1 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, or after 1.5 weeks of storage at 60°C and 30% relative humidity, the NTTP level is 1 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Steglujan® 5 mg / 100 mg tablet core or a Steglujan® 15 mg / 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the ertugliflozin is ertugliflozin L-pyroglutamate.

[0100] In another embodiment, a tablet core comprising sitagliptin and ertugliflozin is prepared by adding an antioxidant as a dry powder, wherein the NTTP level is 0.37 ppm or less. In a class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, the NTTP level is 0.37 ppm or less. In another class of this embodiment, the tablet core is prepared by adding an antioxidant as a dry powder, wherein after 2.5 days of storage at 70°C, or after 1.5 weeks of storage at 60°C and 30% relative humidity, the NTTP level is 0.37 ppm or less. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the tablet core is a Steglujan® 5 mg / 100 mg tablet core or a Steglujan® 15 mg / 100 mg tablet core. In another class of this embodiment, the tablet core further comprises a film coating. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the ertugliflozin is ertugliflozin L-pyroglutamate.

[0101] In another embodiment is a pharmaceutical composition comprising sitagliptin, microcrystalline cellulose, and an antioxidant, wherein the NTTP level is 4 ppm or less. In a class of this embodiment, the pharmaceutical composition comprising sitagliptin, microcrystalline cellulose, and an antioxidant, wherein after storage at 70°C for 2.5 days, the NTTP level is 4 ppm or less. In another class of this embodiment, the pharmaceutical composition comprising sitagliptin, microcrystalline cellulose, and an antioxidant, wherein after storage at 70°C for 2.5 days; after storage at 60°C and 60% relative humidity for 1.5 weeks; after storage at 70°C and 60% relative humidity for 2.5 days; after storage at 40°C and 75% relative humidity for 1.5 months; or after storage at 40°C and 65% relative humidity for 1.5 weeks. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the pharmaceutical composition is prepared by (1) adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition; (2) adding the antioxidant as a dry powder; or (3) adding the antioxidant deposited on an excipient. In a subclass of this class, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the pharmaceutical composition further comprises ertugliflozin. In another class of this embodiment, the pharmaceutical composition further comprises ertugliflozin L-pyroglutamate.

[0102] In another embodiment is a pharmaceutical composition comprising sitagliptin, microcrystalline cellulose, and an antioxidant, wherein the NTTP level is 1 ppm or less. In a class of this embodiment, the pharmaceutical composition comprising sitagliptin, microcrystalline cellulose, and an antioxidant, wherein after storage at 70°C for 2.5 days, the NTTP level is 1 ppm or less. In another class of this embodiment, the pharmaceutical composition comprising sitagliptin, microcrystalline cellulose, and an antioxidant, wherein after storage at 70°C for 2.5 days; after storage at 60°C and 60% relative humidity for 1.5 weeks; after storage at 70°C and 60% relative humidity for 2.5 days; after storage at 40°C and 75% relative humidity for 1.5 months; or after storage at 40°C and 65% relative humidity for 1.5 weeks. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the pharmaceutical composition is prepared by (1) adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition; (2) adding the antioxidant as a dry powder; or (3) adding the antioxidant deposited on an excipient. In a subclass of this class, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the pharmaceutical composition further comprises ertugliflozin. In another class of this embodiment, the pharmaceutical composition further comprises ertugliflozin L-pyroglutamate.

[0103] In another embodiment is a pharmaceutical composition comprising sitagliptin, microcrystalline cellulose, and an antioxidant, wherein the NTTP level is 0.37 ppm or less. In a class of this embodiment, the pharmaceutical composition comprising sitagliptin, microcrystalline cellulose, and an antioxidant, wherein after storage at 70° C. for 2.5 days, the NTTP level is 0.37 ppm or less. In another class of this embodiment, the pharmaceutical composition comprising sitagliptin, microcrystalline cellulose, and an antioxidant, wherein the NTTP level is 0.37 ppm or less after storage at 70° C. for 2.5 days; after storage at 60° C. and 60% relative humidity; after storage at 70° C. and 60% relative humidity for 2.5 days; after storage at 40° C. and 75% relative humidity for 1.5 months; or after storage at 40° C. and 65% relative humidity for 1.5 weeks. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the pharmaceutical composition is prepared by (1) adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition; (2) adding the antioxidant as a dry powder; or (3) adding the antioxidant deposited on an excipient. In a subclass of this class, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the pharmaceutical composition further comprises ertugliflozin. In another class of this embodiment, the pharmaceutical composition further comprises ertugliflozin L-pyroglutamate.

[0104] In another embodiment is a pharmaceutical composition comprising sitagliptin, dicalcium phosphate, and an antioxidant, wherein the NTTP level is 4 ppm or less. In a class of this embodiment, the pharmaceutical composition comprising sitagliptin, dicalcium phosphate, and an antioxidant, wherein after storage at 70°C for 2.5 days, the NTTP level is 4 ppm or less. In another class of this embodiment, the pharmaceutical composition comprising sitagliptin, dicalcium phosphate, and an antioxidant, wherein after storage at 70°C for 2.5 days; after storage at 60°C and 60% relative humidity for 1.5 weeks; after storage at 70°C and 60% relative humidity for 2.5 days; after storage at 40°C and 75% relative humidity for 1.5 months; or after storage at 40°C and 65% relative humidity for 1.5 weeks. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the pharmaceutical composition is prepared by (1) adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition; (2) adding the antioxidant as a dry powder; or (3) adding the antioxidant deposited on an excipient. In a subclass of this class, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the pharmaceutical composition further comprises ertugliflozin. In another class of this embodiment, the pharmaceutical composition further comprises ertugliflozin L-pyroglutamate.

[0105] In another embodiment is a pharmaceutical composition comprising sitagliptin, dicalcium phosphate, and an antioxidant, wherein the NTTP level is 1 ppm or less. In a class of this embodiment, the pharmaceutical composition comprising sitagliptin, dicalcium phosphate, and an antioxidant, wherein after storage at 70°C for 2.5 days, the NTTP level is 1 ppm or less. In another class of this embodiment, the pharmaceutical composition comprising sitagliptin, dicalcium phosphate, and an antioxidant, wherein after storage at 70°C for 2.5 days; after storage at 60°C and 60% relative humidity for 1.5 weeks; after storage at 70°C and 60% relative humidity for 2.5 days; after storage at 40°C and 75% relative humidity for 1.5 months; or after storage at 40°C and 65% relative humidity for 1.5 weeks. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the pharmaceutical composition is prepared by (1) adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition; (2) adding the antioxidant as a dry powder; or (3) adding the antioxidant deposited on an excipient. In a subclass of this class, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the pharmaceutical composition further comprises ertugliflozin. In another class of this embodiment, the pharmaceutical composition further comprises ertugliflozin L-pyroglutamate.

[0106] In another embodiment is a pharmaceutical composition comprising sitagliptin, dicalcium phosphate, and an antioxidant, wherein the NTTP level is 0.37 ppm or less. In a class of this embodiment, the pharmaceutical composition comprising sitagliptin, dicalcium phosphate, and an antioxidant, wherein after storage at 70° C. for 2.5 days, the NTTP level is 0.37 ppm or less. In another class of this embodiment, the pharmaceutical composition comprising sitagliptin, dicalcium phosphate, and an antioxidant, wherein after storage at 70° C. for 2.5 days; after storage at 60° C. and 60% relative humidity for 1.5 weeks; after storage at 70° C. and 60% relative humidity for 2.5 days; after storage at 40° C. and 75% relative humidity for 1.5 months; or after storage at 40° C. and 65% relative humidity for 1.5 weeks. In another class of this embodiment, the antioxidant is propyl gallate or butylated hydroxyanisole. In another class of this embodiment, the antioxidant is propyl gallate. In another class of this embodiment, the pharmaceutical composition is prepared by (1) adding a sitagliptin dihydrogen phosphate monohydrate antioxidant composition; (2) adding the antioxidant as a dry powder; or (3) adding the antioxidant deposited on an excipient. In a subclass of this class, the antioxidant is propyl gallate and the excipient is dicalcium phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate. In another class of this embodiment, the sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another class of this embodiment, the pharmaceutical composition further comprises ertugliflozin. In another class of this embodiment, the pharmaceutical composition further comprises ertugliflozin L-pyroglutamate.

[0107] Specific embodiments of sitagliptin-antioxidant compositions include, but are not limited to, the following:

[0108] A composition comprising: (a) sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) Antioxidants.

[0109] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0110] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0111] A composition consisting essentially of: (a) sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) Antioxidants.

[0112] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0113] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0114] A composition comprising: (a) about 90% to 99.99% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.01% to 10% by weight of an antioxidant.

[0115] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0116] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0117] A composition consisting essentially of: (a) about 90% to 99.99% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.01% to 10% by weight of an antioxidant.

[0118] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0119] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0120] A composition comprising: (a) about 90% to 99.95% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.05% to 10% by weight of an antioxidant.

[0121] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0122] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0123] A composition consisting essentially of: (a) about 90% to 99.95% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.05% to 10% by weight of an antioxidant.

[0124] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0125] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0126] A composition comprising: (a) about 90% to 99.9% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.1% to 10% by weight of an antioxidant.

[0127] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0128] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0129] A composition consisting essentially of: (a) about 90% to 99.9% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.1% to 10% by weight of an antioxidant.

[0130] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0131] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0132] A composition comprising: (a) about 95% to 99.99% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.01% to 5% by weight of an antioxidant.

[0133] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0134] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0135] A composition consisting essentially of: (a) about 95% to 99.99% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.01% to 5% by weight of an antioxidant.

[0136] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0137] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0138] A composition comprising: (a) about 95% to 99.95% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.05% to 5% by weight of an antioxidant.

[0139] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0140] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0141] A composition consisting essentially of: (a) about 95% to 99.95% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.05% to 5% by weight of an antioxidant.

[0142] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0143] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0144] A composition comprising: (a) about 95% to 99.9% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.1% to 5% by weight of an antioxidant.

[0145] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0146] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0147] A composition consisting essentially of: (a) about 95% to 99.9% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.1% to 5% by weight of an antioxidant.

[0148] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0149] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0150] A composition comprising: (a) about 98% to 99.99% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.01% to 2% by weight of an antioxidant.

[0151] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0152] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0153] A composition consisting essentially of: (a) about 98% to 99.99% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.01% to 2% by weight of an antioxidant.

[0154] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0155] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0156] A composition comprising: (a) about 98% to 99.9% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.1% to 2% by weight of an antioxidant.

[0157] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0158] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0159] A composition consisting essentially of: (a) about 98% to 99.9% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.1% to 2% by weight of an antioxidant.

[0160] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0161] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0162] A composition comprising: (a) about 99% to 99.99% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.01% to 1% by weight of an antioxidant.

[0163] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0164] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0165] A composition consisting essentially of: (a) about 99% to 99.99% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.01% to 1% by weight of an antioxidant.

[0166] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0167] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0168] A composition comprising: (a) about 99.3% to 99.8% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.2% to 0.7% by weight of an antioxidant.

[0169] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0170] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0171] A composition consisting essentially of: (a) about 99.3% to 99.8% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.2% to 0.7% by weight of an antioxidant.

[0172] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0173] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0174] A composition comprising: (a) about 99.60% to 99.75% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.25% to 0.40% by weight of an antioxidant.

[0175] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0176] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0177] A composition consisting essentially of: (a) about 99.60% to 99.75% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.25% to 0.40% by weight of an antioxidant.

[0178] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0179] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0180] A composition comprising: (a) about 99% to 99.9% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.1% to 1% by weight of an antioxidant.

[0181] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0182] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0183] A composition consisting essentially of: (a) about 99% to 99.9% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.1% to 1% by weight of an antioxidant.

[0184] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0185] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0186] A composition comprising: (a) about 99.2% to 99.9% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.1% to 0.8% by weight of an antioxidant.

[0187] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0188] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0189] A composition consisting essentially of: (a) about 99.2% to 99.9% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.1% to 0.8% by weight of an antioxidant.

[0190] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0191] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0192] A composition comprising: (a) about 90% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 10% by weight of an antioxidant.

[0193] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0194] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0195] A composition consisting essentially of: (a) about 90% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 10% by weight of an antioxidant.

[0196] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0197] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0198] A composition comprising: (a) about 99% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 1 wt. % antioxidant.

[0199] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0200] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0201] A composition consisting essentially of: (a) about 99% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 1 wt. % antioxidant.

[0202] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0203] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0204] A composition comprising: (a) about 99.2% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.8 wt. % antioxidant.

[0205] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0206] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0207] A composition consisting essentially of: (a) about 99.2% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.8 wt. % antioxidant.

[0208] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0209] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0210] A composition comprising: (a) about 99.5% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.5 wt. % antioxidant.

[0211] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0212] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0213] A composition consisting essentially of: (a) about 99.5% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.5 wt. % antioxidant.

[0214] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0215] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0216] A composition comprising: (a) about 99.65% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.35 wt. % antioxidant.

[0217] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0218] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0219] A composition consisting essentially of: (a) about 99.65% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.35 wt. % antioxidant.

[0220] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0221] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0222] A composition comprising: (a) about 99.70% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.30 wt. % antioxidant.

[0223] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0224] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0225] A composition consisting essentially of: (a) about 99.70% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.30 wt. % antioxidant.

[0226] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0227] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0228] A composition comprising: (a) about 99.85% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.15 wt. % antioxidant.

[0229] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0230] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0231] A composition consisting essentially of: (a) about 99.85% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.15 wt. % antioxidant.

[0232] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0233] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0234] A composition comprising: (a) about 99.88% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.12 wt. % antioxidant.

[0235] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0236] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0237] A composition consisting essentially of: (a) about 99.88% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.12 wt. % antioxidant.

[0238] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0239] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0240] A composition comprising: (a) about 99.9% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.1 wt. % antioxidant.

[0241] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0242] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0243] A composition consisting essentially of: (a) about 99.9% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.1 wt. % antioxidant.

[0244] In one embodiment, the pharmaceutically acceptable salt of sitagliptin is the dihydrogen phosphate salt (sitagliptin phosphate) represented by the above structural formula I. In another embodiment, the pharmaceutically acceptable hydrate of sitagliptin is a monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is the dihydrogen phosphate monohydrate. In another embodiment, the dihydrogen phosphate form is the crystalline monohydrate disclosed in U.S. Pat. No. 7,326,708, the contents of which are incorporated herein by reference in their entirety. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the pharmaceutically acceptable salt and hydrate of sitagliptin is crystalline sitagliptin dihydrogen phosphate monohydrate.

[0245] In one embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl (lauryl) gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from the group consisting of ascorbic acid, butylated hydroxytoluene, propyl gallate, butyl gallate, butylated hydroxyanisole, thymol, tocopherol, and vitamin E. In another embodiment, the antioxidant is selected from propyl gallate and butylated hydroxyanisole. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0246] The preparation of sitagliptin and its pharmaceutically acceptable salts is disclosed in U.S. Patent No. 6,699,871, the contents of which are incorporated herein by reference in their entirety. The preparation of sitagliptin phosphate monohydrate is disclosed in U.S. Patent No. 7,326,708, the contents of which are incorporated herein by reference in their entirety.

[0247] Additionally, a process for preparing a formulation of sitagliptin dihydrogen phosphate monohydrate and an antioxidant is provided.

[0248] The following stages: (1) dissolving sitagliptin dihydrogen phosphate monohydrate in a suitable solvent at a suitable temperature to obtain a solution; (2) adding seed crystals of sitagliptin dihydrogen phosphate monohydrate to the solution of step 1; (3) adding an antisolvent to the solution of step 2 to form a mixture; (4) adding an antioxidant to the mixture of step 3 to form a mixture; (5) cooling the mixture of step 4; and (6) filtering the mixture of step 5 to isolate a solid sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition; The present invention provides a process for preparing a sitagliptin and antioxidant complex or composition, comprising:

[0249] In one embodiment, a suitable solvent in step 1 is a mixture of water and isopropanol, and a suitable temperature in step 1 is about 65°C to 80°C.

[0250] In another embodiment, a suitable solvent in step 1 is a 79:21 mixture of isopropanol:water, and a suitable temperature in step 1 is about 70°C to 80°C.

[0251] In another embodiment, the process further comprises cooling the Step 1 solution to about 65° C. to 67° C. In one class of this embodiment, the Step 1 solution is cooled before adding sitagliptin dihydrogen phosphate monohydrate seed crystals.

[0252] In another embodiment, the sitagliptin dihydrogen phosphate monohydrate seed crystals from Step 2 are milled.

[0253] In another embodiment, the process further comprises cooling the solution of step 2 to about 15°C to 25°C.

[0254] In another embodiment, the antisolvent in Step 3 is isopropanol.

[0255] In another embodiment, the mixture of Step 5 is cooled to about -10 to 0°C.

[0256] In another embodiment, the process further comprises drying the solid sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition of step 6.

[0257] In another embodiment, the process further comprises de-lumping and blending the dried sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition of step 6.

[0258] In another embodiment, the process further comprises, after filtering in step 6, washing the wet sitagliptin dihydrogen phosphate monohydrate antioxidant complex or composition with a cold wash solution comprising propyl gallate in aqueous isopropanol.

[0259] In another embodiment, the antioxidant in step 4 is propyl gallate; and the sitagliptin dihydrogen phosphate monohydrate antioxidant complex or composition in step 6 is a sitagliptin dihydrogen phosphate monohydrate propyl gallate complex or composition.

[0260] In another embodiment, the antioxidant in step 4 is butylated hydroxyanisole; and the sitagliptin dihydrogen phosphate monohydrate antioxidant complex or composition in step 6 is a sitagliptin dihydrogen phosphate monohydrate butylated hydroxyanisole complex or composition.

[0261] In another embodiment, the dried solid sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition of Step 6 is crystalline.

[0262] Additionally, the following steps: (1) dissolving sitagliptin dihydrogen phosphate monohydrate in a suitable solvent at a suitable temperature to obtain a solution; (2) adding sitagliptin dihydrogen phosphate monohydrate seed crystals to the solution of step 2; (3) cooling the solution of step 2; (4) adding an antisolvent to the solution of step 4 to form a mixture; (5) adding an antioxidant to the mixture of step 5 to form a mixture; (6) cooling the mixture of step 5; and (7) filtering the mixture of step 6 to isolate a solid sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition; Also provided is a process for preparing a sitagliptin and antioxidant complex or composition, comprising:

[0263] In one embodiment, a suitable solvent in step 1 is a mixture of water and isopropanol, and a suitable temperature in step 1 is about 65°C to 80°C.

[0264] In another embodiment, a suitable solvent in step 1 is a 79:21 mixture of isopropanol:water, and a suitable temperature in step 1 is about 70°C to 80°C.

[0265] In another embodiment, the process further comprises cooling the solution of step 1 to about 65°C to 67°C.

[0266] In another embodiment, the process further comprises cooling the solution of step 2 to about 15°C to 25°C.

[0267] In another embodiment, the sitagliptin dihydrogen phosphate monohydrate seed crystals from Step 2 are milled.

[0268] In another embodiment, the antisolvent in step 4 is isopropanol.

[0269] In another embodiment, the mixture of Step 5 is cooled to about -10 to 0°C.

[0270] In another embodiment, the process further comprises drying the solid sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition of step 7.

[0271] In another embodiment, the process further comprises de-lumping and blending the dried sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition of step 7.

[0272] In another embodiment, the process further comprises, after filtering in step 7, washing the wet sitagliptin dihydrogen phosphate monohydrate antioxidant complex or composition with a cold wash solution comprising propyl gallate in aqueous isopropanol.

[0273] In another embodiment, the antioxidant in step 5 is propyl gallate; and the sitagliptin dihydrogen phosphate monohydrate antioxidant complex or composition in step 7 is a sitagliptin dihydrogen phosphate monohydrate propyl gallate complex or composition.

[0274] In another embodiment, the antioxidant in step 5 is butylated hydroxyanisole; and the sitagliptin dihydrogen phosphate monohydrate antioxidant complex or composition in step 7 is a sitagliptin dihydrogen phosphate monohydrate butylated hydroxyanisole complex or composition.

[0275] In another embodiment, the dried solid sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition of Step 7 is crystalline.

[0276] Additionally, the following steps: (1) dissolving sitagliptin dihydrogen phosphate monohydrate in a suitable solvent at a suitable temperature to obtain a solution; (2) cooling the solution of step 1; (3) adding sitagliptin dihydrogen phosphate monohydrate seed crystals to the solution of step 2; (4) cooling the solution of step 3; (5) adding an antisolvent to the solution of step 4 to form a mixture; (6) adding an antioxidant to the mixture of step 5 to form a mixture; (7) cooling the mixture of step 6; and (8) filtering the mixture of step 7 to isolate a solid sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition; Also provided is a process for preparing a sitagliptin and antioxidant complex or composition, comprising:

[0277] In one embodiment, a suitable solvent in step 1 is a mixture of water and isopropanol, and a suitable temperature in step 1 is about 65°C to 80°C.

[0278] In another embodiment, a suitable solvent in step 1 is a 79:21 mixture of isopropanol:water, and a suitable temperature in step 1 is about 70°C to 80°C.

[0279] In another embodiment, the process further comprises cooling the solution of step 1 to about 65°C to 67°C.

[0280] In another embodiment, the sitagliptin dihydrogen phosphate monohydrate seed crystals from Step 3 are milled.

[0281] In another embodiment, the process further comprises cooling the solution of step 3 to about 15°C to 25°C.

[0282] In another embodiment, the antisolvent in step 5 is isopropanol.

[0283] In another embodiment, the mixture of Step 6 is cooled to about -10 to 0°C.

[0284] In another embodiment, the process further comprises drying the solid sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition of Step 8.

[0285] In another embodiment, the process further comprises de-lumping and blending the dried sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition of step 8.

[0286] In another embodiment, the process further comprises, after filtering in step 8, washing the wet sitagliptin dihydrogen phosphate monohydrate antioxidant complex or composition with a cold wash solution comprising propyl gallate in aqueous isopropanol.

[0287] In another embodiment, the antioxidant in step 6 is propyl gallate; and the sitagliptin dihydrogen phosphate monohydrate antioxidant complex or composition in step 8 is a sitagliptin dihydrogen phosphate monohydrate propyl gallate complex or composition.

[0288] In another embodiment, the antioxidant in step 6 is butylated hydroxyanisole; and the sitagliptin dihydrogen phosphate monohydrate antioxidant complex or composition in step 8 is a sitagliptin dihydrogen phosphate monohydrate butylated hydroxyanisole complex or composition.

[0289] In another embodiment, the dried solid sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition of Step 8 is crystalline.

[0290] Additionally, the following steps: (1) dissolving sitagliptin dihydrogen phosphate monohydrate in a suitable solvent at a suitable temperature to obtain a solution; (2) cooling the solution of step 1 to a seed point temperature; (3) adding ground seed crystals of sitagliptin dihydrogen phosphate monohydrate to the solution of step 2; (4) cooling the solution of step 3 to about 15°C to 25°C; (5) adding an antisolvent to the solution of step 4 to form a mixture; (6) adding an antioxidant to the mixture of step 5 to form a mixture; (7) cooling the mixture of step 6 to about -10 to 0°C; (8) filtering the mixture of step 7 to isolate a solid sitagliptin dihydrogen phosphate monohydrate-antioxidant composition; and (9) drying the solid sitagliptin dihydrogen phosphate monohydrate-antioxidant composition; Also provided is a process for preparing a sitagliptin and antioxidant complex or composition, comprising:

[0291] In one embodiment, the process further comprises de-lumping and blending the sitagliptin dihydrogen phosphate monohydrate-antioxidant composition of Step 9.

[0292] In another embodiment, the process further comprises, after filtering in step 8, washing the wet sitagliptin dihydrogen phosphate monohydrate antioxidant composition with a cold wash solution comprising propyl gallate in aqueous isopropanol.

[0293] In another embodiment, the suitable solvent in step 1 is a mixture of water and isopropanol, and the suitable temperature in step 1 is about 65°C to 80°C.

[0294] In another embodiment, a suitable solvent in step 1 is a 79:21 mixture of isopropanol:water, and a suitable temperature in step 1 is about 70°C to 80°C.

[0295] In another embodiment, the temperature in stage 2 is about 65°C to 67°C.

[0296] In another embodiment, the antisolvent in step 4 is isopropanol.

[0297] In another embodiment, the antioxidant of Step 6 is propyl gallate; and the sitagliptin dihydrogen phosphate monohydrate antioxidant composition of Step 9 is a sitagliptin dihydrogen phosphate monohydrate propyl gallate composition.

[0298] In another embodiment, the antioxidant of Step 6 is butylated hydroxyanisole; and the sitagliptin dihydrogen phosphate monohydrate antioxidant composition of Step 9 is a sitagliptin dihydrogen phosphate monohydrate butylated hydroxyanisole composition.

[0299] In another embodiment, the solid sitagliptin dihydrogen phosphate monohydrate-antioxidant composition of Steps 8 and 9 is crystalline.

[0300] Also provided are methods for treating type 2 diabetes by administering to a host in need of such treatment a pharmaceutical composition comprising a sitagliptin dihydrogen phosphate monohydrate antioxidant complex or composition. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of sitagliptin dihydrogen phosphate monohydrate in a sitagliptin dihydrogen phosphate monohydrate antioxidant complex or composition. In another embodiment, the antioxidant is propyl gallate. In another embodiment, the antioxidant is butylated hydroxyanisole.

[0301] These and other aspects of the present disclosure will become readily apparent from the following detailed description.

[0302] The following schemes, procedures, processes, and examples further describe and demonstrate embodiments within the scope of the present disclosure, which are given for illustrative purposes only and are not intended to be construed as limiting, as many variations thereof are possible without departing from the spirit and scope of the disclosure.

[0303] Abbreviations: "≦" means less than or equal to; "BHA" means butylated hydroxyanisole; "DI" means deionized water; "dibasic calcium phosphate" means dicalcium phosphate and dibasic calcium phosphate anhydrous; "hr" means hours; "IPA" means isopropanol or 2-propanol; "MPa" means megapascals; "ng" means nanograms; "NTTP" means 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine; "PG" means propyl gallate; "ppm" means parts per million; "RH" means relative humidity; and "w / w" means weight by weight or weight for weight.

[0304] 37 ng of NTTP in a tablet containing 100 mg of sitagliptin free base corresponds to 0.37 ppm of NTTP. 18.5 ng of NTTP in a tablet containing 50 mg of sitagliptin free base corresponds to 0.37 ppm of NTTP. 9.25 ng of NTTP in a tablet containing 25 mg of sitagliptin free base corresponds to 0.37 ppm of NTTP. 4.625 ng of NTTP in a tablet containing 12.5 mg of sitagliptin free base corresponds to 0.37 ppm of NTTP.

[0305] The terms "wt%," "% by weight," and "weight percent" refer to the weight of one component divided by the total weight of all components in a mixture or solution. For example, for a two-component system containing components A and B, the weight percent of component A is (A / (A+B))×100.

[0306] Sitagliptin antioxidant complex is synonymous with sitagliptin antioxidant composition. Sitagliptin phosphate antioxidant complex is synonymous with sitagliptin phosphate antioxidant composition. Sitagliptin phosphate monohydrate antioxidant complex is synonymous with sitagliptin phosphate monohydrate antioxidant composition. Sitagliptin dihydrogen phosphate monohydrate antioxidant complex is synonymous with sitagliptin dihydrogen phosphate monohydrate antioxidant composition.

[0307] Sitagliptin propyl gallate complex is synonymous with sitagliptin propyl gallate composition. Sitagliptin phosphate propyl gallate complex is synonymous with sitagliptin phosphate propyl gallate composition. Sitagliptin phosphate monohydrate propyl gallate complex is synonymous with sitagliptin phosphate monohydrate propyl gallate composition. Sitagliptin dihydrogen phosphate monohydrate propyl gallate complex is synonymous with sitagliptin dihydrogen phosphate monohydrate propyl gallate composition.

[0308] Sitagliptin butylated hydroxyanisole complex is synonymous with sitagliptin butylated hydroxyanisole composition. Sitagliptin phosphate butylated hydroxyanisole complex is synonymous with sitagliptin phosphate butylated hydroxyanisole composition. Sitagliptin phosphate monohydrate butylated hydroxyanisole complex is synonymous with sitagliptin phosphate monohydrate butylated hydroxyanisole composition. Sitagliptin dihydrogen phosphate monohydrate butylated hydroxyanisole complex is synonymous with sitagliptin dihydrogen phosphate monohydrate butylated hydroxyanisole composition.

[0309] In the sitagliptin antioxidant complex or composition, sitagliptin phosphate antioxidant complex or composition, sitagliptin phosphate monohydrate antioxidant complex or composition, and sitagliptin dihydrogen phosphate monohydrate antioxidant complex or composition, the antioxidant (which includes propyl gallate and butylated hydroxyanisole) is deposited on or associated with sitagliptin before and / or after drying. In one embodiment, the antioxidant (which includes propyl gallate and butylated hydroxyanisole) is deposited on the sitagliptin dihydrogen phosphate monohydrate solid before and / or after drying. In another embodiment, the antioxidant (which includes propyl gallate and butylated hydroxyanisole) is deposited on the sitagliptin dihydrogen phosphate monohydrate solid before and / or after drying. In another embodiment, the antioxidants (including propyl gallate and butylated hydroxyanisole) are applied to the sitagliptin dihydrogen phosphate monohydrate crystals before and / or after drying. In another embodiment, the antioxidants (including propyl gallate and butylated hydroxyanisole) are applied to the dried sitagliptin dihydrogen phosphate monohydrate crystals before and / or after drying. In another embodiment, the antioxidants (including propyl gallate and butylated hydroxyanisole) are solids applied to the sitagliptin dihydrogen phosphate monohydrate. In another embodiment, the antioxidants (including propyl gallate and butylated hydroxyanisole) are glasses applied to the sitagliptin dihydrogen phosphate monohydrate.

[0310] "Core tablet" refers to a pharmaceutical composition that is molded or compressed into a tablet without a film coating.

[0311] "Core formulation" refers to a pharmaceutical composition that is not formed or compressed into a tablet and is not film coated.

[0312] "JANUVIA® core formulation" refers to a pharmaceutical composition containing sitagliptin dihydrogen phosphate monohydrate, microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. "JANUVIA® tablet core" is a compressed or molded tablet without film coating that contains sitagliptin dihydrogen phosphate monohydrate, microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate.

[0313] "JANUVIA® 100 mg tablet core" contains 128.5 mg of sitagliptin dihydrogen phosphate monohydrate (which is equivalent to 100 mg of sitagliptin free base).

[0314] "JANUVIA® 50 mg Tablet Core" contains 64.25 mg of sitagliptin dihydrogen phosphate monohydrate (which is equivalent to 50 mg of sitagliptin free base).

[0315] "JANUVIA® 25 mg tablet core" contains 32.13 mg of sitagliptin dihydrogen phosphate monohydrate (which is equivalent to 25 mg of sitagliptin free base).

[0316] The "STEGLUJAN® core formulation" is a pharmaceutical composition containing sitagliptin dihydrogen phosphate monohydrate, ertugliflozin L-pyroglutamate, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate, and optionally, Opadry 20 and / or carnauba wax.

[0317] "STEGLUJAN® Tablet Cores" are non-film-coated, compressed or molded tablets containing sitagliptin dihydrogen phosphate monohydrate, ertugliflozin L-pyroglutamate, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate, and optionally, Opadry20 and / or carnauba wax.

[0318] "STEGLUJAN® 5 mg / 100 mg tablet cores" contain 6.48 mg of ertugliflozin L-pyroglutamate and 128.5 mg of sitagliptin phosphate monohydrate (which is equivalent to 5 mg of ertugliflozin and 100 mg of sitagliptin free base).

[0319] "STEGLUJAN® 15 mg / 100 mg tablet cores" contain 19.43 mg of ertugliflozin L-pyroglutamate and 128.5 mg of sitagliptin phosphate monohydrate (which is equivalent to 15 mg of ertugliflozin and 100 mg of sitagliptin free base).

[0320] General scheme Crystallization Procedure for Sitagliptin Dihydrogen Phosphate Monohydrate-Antioxidant Complex or Composition [ka]

[0321] Sitagliptin dihydrogen phosphate monohydrate can be crystallized or recrystallized to form a complex or composition with an antioxidant agent, as provided in the following procedures.

[0322] Procedure for dissolving sitagliptin dihydrogen phosphate monohydrate (where X is the mass (or weight) of sitagliptin dihydrogen phosphate monohydrate): 1. Charge 0.920X (by weight) deionized water to Reactor 1; 2. Charge 2.247X (by weight) isopropanol or 2-propanol to reactor 1; 3. Stir and bring the contents of Reactor 1 to about 15°C to 25°C; 4. Charge 1× sitagliptin dihydrogen phosphate monohydrate into reactor 1; 5. Heat the contents of Reactor 1 to approximately 65°C-80°C and age for a minimum of 1 hour until the solids are dissolved; 6. While maintaining the batch temperature at about 75°C-80°C, transfer the contents of Reactor 1 through a 1.0 micron or smaller filter to Reactor 2; 7. Charge 0.109X (by weight) deionized water to Reactor 1 as rinse; 8. Charge 0.271X (by weight) isopropanol or 2-propanol as rinse water to Reactor 1; 9. Stir and bring the contents of Reactor 1 to 75-80°C; 10. While maintaining the batch temperature at approximately 75-80°C, transfer the contents of Reactor 1 through a 1.0 micron or smaller filter to Reactor 2.

[0323] Procedure for forming, crystallizing and isolating sitagliptin-propyl gallate complex or composition (where X is the mass (weight) of sitagliptin dihydrogen phosphate monohydrate): 11. Cool the contents of Reactor 2 to a seed point temperature of about 65°C to 67°C; 12. Charge reactor 2 with 0.005X (by weight) milled sitagliptin dihydrogen phosphate monohydrate seed crystals; 13. Stirring and aging the seed crystal bed obtained in step 12 at a temperature of about 65°C to 67°C for about 2.75 hours to 5 hours; 14. Ramp cool the contents of Reactor 2 to approximately 15°C to 25°C at a rate of -7.2°C per hour; 15. Add propyl gallate as follows: Charge 1.05X (by weight) IPA containing 0.172X (by weight) propyl gallate to Reactor 2 over approximately 1.5 to 3 hours; 16. Alternatively, add propyl gallate as a concentrated solution in IPA: add 1.451X (by weight) of a 15 wt% propyl gallate in IPA solution to a separate container and transfer to reactor 2; 17. Ramp cooling the contents of Reactor 2 to about -10°C to 0°C at a rate of -9.6°C per hour; 18. The contents of Reactor 2 are stirred and aged for a minimum of 1 hour; 19. Separating the resulting sitagliptin-antioxidant complex by filtration to form a wet cake; 20. Optionally washing the wet cake with a cold wash solution comprising propyl gallate in aqueous isopropanol; 21. Dry the sitagliptin-antioxidant conjugate under reduced pressure at a temperature not exceeding 45°C.

[0324] The dried sitagliptin-antioxidant complex / cake may then be de-lumped and blended.

[0325] In one embodiment, in Stage 3 of the dissolution procedure, the temperature is about 20°C. In another embodiment, dried propyl gallate can be added in Stage 4 of the dissolution procedure. In another embodiment, in Stage 5 of the dissolution procedure, the temperature is about 70°C to 80°C. In another embodiment, in Stage 6 of the dissolution procedure, the temperature is about 78°C. In another embodiment, in Stage 9 of the dissolution procedure, the temperature is about 78°C. In another embodiment, in Stage 10 of the dissolution procedure, the temperature is about 78°C. In another embodiment, in Stage 13 of the crystallization / isolation procedure, the seed bed is aged for about 3 hours. In another embodiment, in Stage 14 of the crystallization / isolation procedure, the contents of Reactor 2 are cooled to about 20°C. In another embodiment, in Stage 14 of the crystallization / isolation procedure, the contents of Reactor 2 are cooled for about 6.5 hours. In another embodiment, in Stage 15 of the crystallization / isolation procedure, propyl gallate is added over about 2 hours. In another embodiment, in Stage 15 of the crystallization / isolation procedure, the contents of Reactor 2 are cooled for about 2.5 hours. In another embodiment of Step 16 of the crystallization / isolation procedure, a 15 wt % propyl gallate in IPA solution contains 0.218× (by weight) PG in 1.234× (by weight) IPA. In another embodiment, in Step 17 of the crystallization / isolation procedure, the contents of Reactor 2 are cooled to about −5° C. In another embodiment, in Step 17 of the crystallization / isolation procedure, the contents of Reactor 2 are cooled for about 2.5 hours. In another embodiment, in optional Step 20 of the crystallization / isolation procedure, the temperature of the cold wash solution of propyl gallate in aqueous isopropanol is about −10° C. to 0° C. In another embodiment, in optional Step 20 of the crystallization / isolation procedure, the cold wash solution contains 3.6 wt % propyl gallate in a 10:90 water:isopropanol solution. In another embodiment, in optional step 20 of the crystallization / isolation procedure, the cold wash solution comprises about 0.193X (by weight) deionized water, 1.735X (by weight) isopropanol, and 0.072X (by weight) propyl gallate. In another embodiment, in step 21 of the crystallization / isolation procedure, the batch is dried at a temperature of about 40° C. In another embodiment, propyl gallate is replaced with butylated hydroxyanisole as the antioxidant. [Example]

[0326] Example 1 Sitagliptin dihydrogen phosphate monohydrate-propyl gallate complex or composition [Table 1]

[0327] Using the above starting materials and the following procedure, a sitagliptin dihydrogen phosphate monohydrate-propyl gallate complex or composition was formed. [ka]

[0328] A vessel was charged with sitagliptin dihydrogen phosphate monohydrate (15 g) and a 71:29 (w / w) isopropanol:water solution (53.2 g). The mixture was heated to 78°C to dissolve the sitagliptin dihydrogen phosphate monohydrate. The mixture was then cooled to 66°C, and pin-milled sitagliptin dihydrogen phosphate monohydrate seed crystals (77 mg) were added. The resulting seed bed mixture was aged for 3 hours and then cooled to 20°C at a cooling rate of 7.2°C per hour. 2-Propanol (15.75 g) was added to the mixture over 2 hours. A solution of 20 wt% propyl gallate (20 g) in 2-propanol (80 g) was prepared. The 20 wt% propyl gallate / 2-propanol solution (22.98 g) was then added to the seed crystal bed mixture to obtain a 5 wt% propyl gallate / 2-propanol solution in the mother liquor. The seed crystal bed mixture was then cooled to -5°C at a cooling rate of 9.6°C per hour. The resulting slurry was aged for 1 hour and then filtered through a filter funnel. The solid in the filter funnel was isolated and dried in a vacuum oven at 40°C for 3 days to obtain sitagliptin dihydrogen phosphate monohydrate propyl gallate complex. PG assay: 0.9736 wt%.

[0329] Example 2 Sitagliptin dihydrogen phosphate monohydrate-butylated hydroxyanisole complex or composition [Table 2]

[0330] Using the above starting materials and the following procedure, a sitagliptin dihydrogen phosphate monohydrate-butylated hydroxyanisole complex or composition was formed. [ka]

[0331] A vessel was charged with sitagliptin dihydrogen phosphate monohydrate (15.002 g) and a 71:29 (w / w) IPA:water solution (53.2 g). The mixture was heated to 80°C to dissolve the resulting slurry. The resulting solution was then cooled to a seed temperature of 66°C. Pin-milled sitagliptin dihydrogen phosphate monohydrate seed crystals (76 mg) were added to the solution, and the seed crystal bed mixture was aged for 3 hours. The seed crystal bed mixture was then cooled to 20°C at a cooling rate of 7.2°C per hour. 2-Propanol (15.75 g) was added to the mixture over 2 hours. A solution of 10 wt% butylated hydroxyanisole in 2-propanol (17.2 g) was then added to the seed crystal bed mixture to obtain a 2 wt% BHA solution in the mother liquor. The resulting mixture was cooled to -5°C at a cooling rate of 9.6°C per hour. The resulting mixture was aged for 1 hour. The resulting solid was isolated by filtration through a filter funnel and the damp filter cake was dried in a vacuum oven at 40° C. for approximately 1 day. BHA Assay: 0.411108 wt %, F.

[0332] Example 3 NTTP Formation in JANUVIA® Tablet Cores Manufactured with Sitagliptin Dihydrogen Phosphate Monohydrate-Antioxidant Complex or Composition Powder Increase in NTTP after stable aging under the conditions shown in Table 3 for JANUVIA® tablet cores made with sitagliptin dihydrogen phosphate monohydrate powder without antioxidant (control) or JANUVIA® tablet cores made with sitagliptin dihydrogen phosphate monohydrate antioxidant complex powder (wherein the antioxidant is propyl gallate (PG) or butylated hydroxyanisole (BHA) at the wt % antioxidant concentrations listed in Table 3). [Table 3]

[0333] Experimental Summary: Sitagliptin dihydrogen phosphate monohydrate powder was slurry washed twice with a 90:10 (w / w) isopropanol:water solution containing either 0% (Table 3 control) or approximately 1% antioxidant (either propyl gallate or butylated hydroxyanisole). The sitagliptin dihydrogen phosphate monohydrate powder and sitagliptin dihydrogen phosphate monohydrate antioxidant complex powder were drained and then dried. The sitagliptin-antioxidant complex powder was confirmed by assay. JANUVIA® (sitagliptin 100 mg dose) tablet cores (13 / 32" diameter concave image) were compressed at 200 MPa after blending excipients with (1) sitagliptin dihydrogen phosphate monohydrate powder (control); (2) sitagliptin dihydrogen phosphate monohydrate propyl gallate complex powder (PG; prepared by a procedure similar to that in Example 1); or (3) sitagliptin dihydrogen phosphate monohydrate butylated hydroxyanisole complex powder (BHA; prepared by a procedure similar to that in Example 2). The compressed tablets were aged under simulated open-dish conditions with controlled humidity, temperature, and time, as described in Table 3. Samples were then stored at -20°C until analytical testing to determine the amount of NTTP formed in each tablet.

[0334] Table 3 shows the reduction in NTTP formation in JANUVIA® tablet cores using either sitagliptin dihydrogen phosphate monohydrate propyl gallate complex powder or sitagliptin dihydrogen phosphate monohydrate butylated hydroxyanisole complex powder compared to JANUVIA® tablet cores using sitagliptin dihydrogen phosphate monohydrate powder without antioxidant (control).

[0335] Example 4 Reduction of NTTP in JANUVIA® tablet cores containing sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition powder Figure 1 shows the reduction in NTTP gain in JANUVIA® tablet cores manufactured using sitagliptin dihydrogen phosphate monohydrate-antioxidant complex powder as a function of antioxidant concentration in the sitagliptin dihydrogen phosphate monohydrate-antioxidant complex powder after 2.5 days of accelerated aging at 70°C. NTTP gain is reported as a percentage of the 0.6 ppm NTTP gain observed in tablets made with unmodified sitagliptin dihydrogen phosphate monohydrate, the same ingredient / excipient lot, and the same processing / stability aging. The line is a logarithmic fit to guide the line of sight.

[0336] Figure 1. Experimental Overview: Sitagliptin dihydrogen phosphate monohydrate powder was slurry washed with a 90:10 (w / w) isopropanol:water solution containing either propyl gallate or butylated hydroxyanisole as the drug substance at antioxidant concentrations of 10 wt%, 1 wt%, or 0.1 wt% (or wt% DS). The resulting powder was then drained and dried to yield sitagliptin dihydrogen phosphate monohydrate propyl gallate complex powder (PG) and sitagliptin dihydrogen phosphate monohydrate butylated hydroxyanisole complex powder (BHA), which were confirmed by assay. JANUVIA® (sitagliptin free amine 100 mg dose) tablet cores (13 / 32" diameter concave image) were compressed at 200 MPa after blending excipients with (1) sitagliptin dihydrogen phosphate monohydrate powder (control); and (2) sitagliptin dihydrogen phosphate monohydrate antioxidant complex powder (wherein the antioxidant was propyl gallate (PG DS) or butylated hydroxyanisole (BHA DS)). The compressed tablets were packaged in heat-sealed aluminum foil sachets and aged at 70°C for approximately 60 hours. Tablet samples were stored at -20°C until analytical testing to determine NTTP gain, which was 0.6 ppm for tablets of unmodified sitagliptin dihydrogen phosphate monohydrate powder (control DS without propyl gallate and butylated hydroxyanisole).

[0337] Figure 1 shows the reduction in NTTP formation in JANUVIA® tablet cores using sitagliptin dihydrogen phosphate monohydrate propyl gallate complex powder (PG) or sitagliptin dihydrogen phosphate monohydrate butylated hydroxyanisole complex powder (BHA) compared to JANUVIA® tablet cores using sitagliptin dihydrogen phosphate monohydrate powder without antioxidant (control).

[0338] Example 5 NTTP formation in JANUVIA® tablet cores containing sitagliptin antioxidant complexes or compositions [Table 4]

[0339] Experimental Summary: JANUVIA® 100 mg cores containing sitagliptin antioxidant complex or composition were compressed into tablets and stored at 70° C. for 2.5 days.

[0340] The control (antioxidant-free) formulation, described in Table 6, was prepared by dry blending sitagliptin dihydrogen phosphate monohydrate with microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate and directly compressing the tablets. The antioxidant-free tablets were stored at 70°C for 2.5 days to simulate 2 years of storage at 30°C.

[0341] The remaining formulation examples shown in Table 5 were prepared by dry blending either (1) sitagliptin dihydrogen phosphate monohydrate-propyl gallate complex or composition or (2) sitagliptin dihydrogen phosphate monohydrate-butylated hydroxyanisole complex or composition with microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. The JANUVIA® tablet core formulations were directly compressed to yield tablets. The tablets were stored at 70°C for 2.5 days to simulate storage at 30°C for 2 years.

[0342] The data in Table 5 show that as the levels of propyl gallate and butylated hydroxyanisole increase, the formation of NTTP in JANUVIA® tablet cores decreases. The data in Table 5 also show that the concentration of NTTP decreases as (1) the concentration of propyl gallate increases and (2) the concentration of butylated hydroxyanisole increases.

[0343] Example 6 NTTP formation in STEGLUJAN® tablet cores containing sitagliptin antioxidant complexes or compositions [Table 5]

[0344] Experimental Summary: STEGLUJAN® 5 mg / 100 mg tablet cores containing sitagliptin antioxidant complex or composition were compressed and stored at 70° C. for 2.5 days.

[0345] The control (antioxidant-free) formulation, described in Table 6, was prepared by dry blending sitagliptin dihydrogen phosphate monohydrate with ertugliflozin L-pyroglutamate, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate, followed by direct compression to obtain tablets. The antioxidant-free tablets were stored at 70°C for 2.5 days to simulate 2 years of storage at 30°C.

[0346] The remaining formulation examples in Table 6 were prepared by dry blending either (1) sitagliptin dihydrogen phosphate monohydrate propyl gallate complex or composition or (2) sitagliptin dihydrogen phosphate monohydrate butylated hydroxyanisole complex or composition with ertugliflozin L-pyroglutamate, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. The resulting formulations were directly compressed into tablets, which were stored at 70°C for 2.5 days to simulate storage at 30°C for 2 years.

[0347] Example 7 NTTP Formation in JANUVIA® Film-Coated Tablets Prepared with Sitagliptin Propyl Gallate Complexes or Compositions [Table 6]

[0348] Experimental Summary: JANUVIA® 25 mg and 100 mg film-coated tablets containing sitagliptin-propyl gallate complex or composition were stored at 40° C. and 75% relative humidity for 1.5 months.

[0349] The control (antioxidant-free) formulation, described in Table 7, was prepared by dry blending sitagliptin dihydrogen phosphate monohydrate with microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate, followed by direct compression to obtain tablets. The antioxidant-free formulation was film-coated and stored at 40°C and 75% RH for 1.5 months.

[0350] The remaining examples in Table 7 were prepared by dry blending sitagliptin dihydrogen phosphate monohydrate propyl gallate complex or composition with microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. The resulting formulations were directly compressed into tablets, which were film-coated and stored at 40°C and 75% relative humidity for 1.5 months.

[0351] The data in Table 7 demonstrate that propyl gallate effectively reduces NTTP formation in JANUVIA® 25 mg and 100 mg film-coated tablets after aging for 1.5 months at 40°C and 75% relative humidity (RH).

[0352] Example 8 NTTP formation in JANUVIA® tablet cores prepared by dry addition of antioxidants [Table 7]

[0353] Experimental Summary: JANUVIA® 100 mg core tablets dry-added with antioxidants were stored at 70°C and 60% relative humidity for 2.5 days.

[0354] The control (antioxidant-free) formulation described in Table 8 was prepared by dry blending sitagliptin dihydrogen phosphate monohydrate with microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate, followed by direct compression to obtain tablets. The control (antioxidant-free) tablets were stored at 70°C and 60% relative humidity for 2.5 days.

[0355] The remaining examples listed in Table 8 were prepared by dry-adding propyl gallate or butylated hydroxyanisole (each particle size 150 μm or less) to sitagliptin dihydrogen phosphate monohydrate, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. The resulting formulations were directly compressed to form JANUVIA® 100 mg tablet cores, which were stored at 70°C and 60% relative humidity for 2.5 days.

[0356] The data in Table 8 demonstrate that dry addition of propyl gallate or butylated hydroxyanisole to JANUVIA® 100 mg tablet cores reduces NTTP formation compared to control tablets after 2.5 days of accelerated aging at 70°C and 60% relative humidity.

[0357] Example 9 NTTP Formation in JANUVIA® Tablet Cores Prepared by Dry Addition of Milled and Unmilled Propyl Gallate [Table 8]

[0358] Experimental Summary: Various concentrations of unmilled or milled propyl gallate were dry blended into JANUVIA® 100 mg tablet cores, which were stored at 60° C. and 60% relative humidity for 1.5 weeks.

[0359] The control (non-propyl gallate) formulation described in Table 9 was prepared by dry blending sitagliptin dihydrogen phosphate monohydrate, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate and directly compressing them to obtain tablets. The control (non-propyl gallate) tablets were stored at 60°C and 60% relative humidity for 1.5 weeks.

[0360] The remaining example formulations in Table 9 were prepared by dry blending unmilled propyl gallate (Mv = 375 μm) or pin-milled propyl gallate to a smaller particle size (Mv = 83 μm, 44 μm, or 22 μm, as measured by static light scattering). Unmilled propyl gallate or milled propyl gallate was dry-blended with sitagliptin dihydrogen phosphate monohydrate, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. The resulting formulations were directly compressed to produce JANUVIA® 100 mg tablet cores. The tablet cores were stored at 60°C and 60% relative humidity for 1.5 weeks.

[0361] The data in Table 9 demonstrate that propyl gallate dry blended into the JANUVIA® 100 mg tablet core formulation, either unmilled or milled propyl gallate, effectively inhibits NTTP formation in the tablet core compared to the control tablets.

[0362] Table 9 further shows that when the particle size of propyl gallate is reduced, a lower propyl gallate concentration is required to achieve the same reduction in NTTP formation in JANUVIA® 100 mg tablet cores.

[0363] Example 10 Formation of NTTP in STEGLUJAN® tablet cores prepared by dry addition of antioxidants [Table 9]

[0364] Experimental Summary: Propyl gallate was dry added to a STEGLUJAN® 5 mg / 100 mg tablet core formulation, which was stored at 60° C. and 30% relative humidity for 1.5 weeks.

[0365] The control (non-propyl gallate) formulation described in Table 10 was prepared by dry blending sitagliptin dihydrogen phosphate monohydrate, ertugliflozin L-pyroglutamate, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate and directly compressing them to obtain tablets. The control (non-propyl gallate) tablets were stored at 60°C and 30% relative humidity for 1.5 weeks.

[0366] The remaining example formulations listed in Table 10 were prepared as follows: Propyl gallate particles were dispersed in a mortar and pestle, and antioxidant particles were sieved through a 150 μm sieve. The dispersed propyl gallate particles were dry-blended with sitagliptin dihydrogen phosphate monohydrate, ertugliflozin L-pyroglutamate, microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. Tablet cores were prepared using this formulation and stored at 60°C and 30% RH for 1.5 weeks, which is intended to simulate storage at 30°C for 2 years.

[0367] The data in Table 10 demonstrate that the dry addition of propyl gallate to a STEGLUJAN® 5 mg / 100 mg tablet core formulation stored at 60° C. and 30% RH for 1.5 weeks effectively reduces the formation of NTTP in the tablet core formulation compared to the control tablets.

[0368] Example 11 NTTP formation in JANUVIA® tablet cores prepared by liquid addition of antioxidants [Table 10]

[0369] Experimental Summary: Propyl gallate was added to dibasic calcium phosphate via liquid addition, which was then added to tablet cores of a 100 mg sitagliptin formulation and stored at 60°C and 60% relative humidity for 1.5 weeks.

[0370] The control (non-propyl gallate) formulation described in Table 9 was prepared by dry blending sitagliptin dihydrogen phosphate monohydrate with microcrystalline cellulose, dicalcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate, followed by direct compression to obtain tablets. The control (non-propyl gallate) tablets were stored at 60°C and 60% relative humidity for 1.5 weeks.

[0371] The remaining formulation examples in Table 11 were prepared by adding propyl gallate as a liquid to the tablet core formulation. Propyl gallate was dissolved in undenatured ethanol along with PEG 400 (PG:PEG 400 1:1 (w / w)). The ethanol solution was added to dicalcium phosphate, and the dicalcium phosphate was thoroughly wetted with minimal excess ethanol. The ethanol was then evaporated, leaving the propyl gallate / PEG 400 on the dicalcium phosphate, which was dry-blended with sitagliptin dihydrogen phosphate monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. JANUVIA® tablet cores were prepared and stored at 60°C for 1.5 weeks, and NTTP formation was measured.

[0372] The data in Table 11 demonstrate that the addition of liquid propyl gallate on dicalcium phosphate to a JANUVIA® 100 mg tablet core formulation effectively inhibits the formation of NTTP in the tablet core.

[0373] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein can be employed in carrying out the methods and uses disclosed herein.

Claims

1. A composition comprising: (a) about 90% to 99.99% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.01% to 10% by weight of an antioxidant.

2. below, (a) about 95% to 99.95% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.05% to 5% by weight of an antioxidant; The composition of claim 1 comprising:

3. below, (a) about 99% to 99.9% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.1% to 1% by weight of an antioxidant; The composition of claim 1 comprising:

4. below, (a) about 99.3% to 99.8% by weight of sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof; and (b) about 0.2% to 0.7% by weight of an antioxidant; The composition of claim 1 comprising:

5. 2. The composition of claim 1, wherein the salt of sitagliptin is sitagliptin dihydrogen phosphate.

6. 2. The composition of claim 1, wherein the salt and hydrate of sitagliptin is sitagliptin dihydrogen phosphate monohydrate.

7. 2. The composition of claim 1, wherein the antioxidant is selected from ascorbic acid, methyl gallate, ethyl gallate, propyl gallate, butyl gallate, pentyl gallate, octyl gallate, dodecyl gallate, lauryl gallate, butylated hydroxyanisole, butylated hydroxytoluene, thymol, tocopherol, and vitamin E.

8. 2. The composition of claim 1, wherein the antioxidant is selected from ascorbic acid, propyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, thymol, tocopherol, and vitamin E.

9. The composition of claim 1 , wherein the antioxidant is propyl gallate.

10. 10. The composition of claim 1, wherein the antioxidant is butylated hydroxyanisole.

11. 10. A process for preparing a sitagliptin and antioxidant composition according to claim 1, which comprises the steps of: (1) dissolving sitagliptin dihydrogen phosphate monohydrate in a suitable solvent at a suitable temperature to obtain a solution; (2) adding seed crystals of sitagliptin dihydrogen phosphate monohydrate to the solution of step 1; (3) adding an antisolvent to the solution of step 2 to form a mixture; (4) adding an antioxidant to the mixture of step 3 to form a mixture; (5) cooling the mixture of step 4; and (6) filtering the mixture of step 5 to isolate a solid sitagliptin dihydrogen phosphate monohydrate-antioxidant complex or composition; The process comprising:

12. The following steps: (1) dissolving sitagliptin dihydrogen phosphate monohydrate in a suitable solvent at a suitable temperature to obtain a solution; (2) cooling the solution of step 1 to a seed point temperature; (3) adding milled seed crystals of sitagliptin dihydrogen phosphate monohydrate to the solution of step 2; (4) cooling the solution of step 3 to about 15°C to 25°C; (5) adding an antisolvent to the solution of step 4 to form a mixture; (6) adding an antioxidant to the mixture of step 5 to form a mixture; (7) cooling the mixture of step 6 to about −10 to 0° C.; (8) filtering the mixture of step 7 to isolate the sitagliptin dihydrogen phosphate monohydrate-antioxidant complex; and (9) drying the sitagliptin dihydrogen phosphate monohydrate-antioxidant complex; The process of claim 11, comprising:

13. 13. The process of claim 12, further comprising de-lumping and blending the sitagliptin dihydrogen phosphate monohydrate-antioxidant complex of step 9.

14. 13. The process of claim 12, further comprising, after filtering in step 8, washing the wet sitagliptin dihydrogen phosphate monohydrate antioxidant complex with a cold wash solution comprising propyl gallate in aqueous isopropanol.

15. 13. The process of claim 12, wherein the suitable solvent in step 1 is a mixture of water and isopropanol, and the suitable temperature in step 1 is about 65°C to 80°C.

16. 13. The process of claim 12, wherein the suitable solvent in step 1 is a 79:21 mixture of isopropanol:water and the suitable temperature in step 1 is about 70°C to 80°C.

17. 13. The process of claim 12, wherein the seed point temperature in Stage 2 is about 65°C to 67°C.

18. 13. The process of claim 12, wherein the antisolvent in step 4 is isopropanol.

19. 13. The process of claim 12, wherein the antioxidant in step 6 is propyl gallate; and the sitagliptin dihydrogen phosphate monohydrate antioxidant complex in step 9 is sitagliptin dihydrogen phosphate monohydrate propyl gallate complex.

20. 13. The process of claim 12, wherein the antioxidant in step 6 is butylated hydroxyanisole; and the sitagliptin dihydrogen phosphate monohydrate antioxidant complex in step 9 is sitagliptin dihydrogen phosphate monohydrate butylated hydroxyanisole complex.

21. 13. The process of claim 12, wherein the sitagliptin dihydrogen phosphate monohydrate-antioxidant complex of steps 8 and 9 is a solid.

22. 13. The process of claim 12, wherein the sitagliptin dihydrogen phosphate monohydrate-antioxidant complex of steps 8 and 9 is a crystalline solid.

23. 1. A pharmaceutical composition comprising: (a) the composition of claim 1; and (b) at least one excipient selected from microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate; The pharmaceutical composition comprising:

24. below, (a) the composition of claim 1; (b) microcrystalline cellulose; (c) anhydrous dibasic calcium phosphate; (d) croscarmellose sodium; (e) magnesium stearate; and (f) sodium stearyl fumarate; 24. The pharmaceutical composition of claim 23, comprising:

25. The pharmaceutical composition of claim 24, wherein the composition of claim 1 is a sitagliptin dihydrogen phosphate monohydrate-butylated hydroxyanisole composition.

26. 25. The pharmaceutical composition of claim 24, wherein the composition of claim 1 is a sitagliptin dihydrogen phosphate monohydrate-propyl gallate composition.

27. 1. A pharmaceutical composition comprising: (a) 10 to 50% by weight of sitagliptin dihydrogen phosphate monohydrate; (b) 0.001 to 1 wt. % of an antioxidant; (c) 10 to 50% by weight of microcrystalline cellulose; (d) 10 to 50 wt. % anhydrous dibasic calcium phosphate; (e) 0.5 to 5% by weight of croscarmellose sodium; (f) 0.5 to 5% by weight of sodium stearyl fumarate; and (g) 0-2% by weight of magnesium stearate; The pharmaceutical composition comprising:

28. 28. The pharmaceutical composition of claim 27, comprising 32.13, 64.25, or 128.5 mg of sitagliptin phosphate monohydrate.

29. 28. The pharmaceutical composition of claim 27, further comprising a film coating.

30. 28. The pharmaceutical composition of claim 27, comprising the sitagliptin and antioxidant composition of claim 1.

31. 28. The pharmaceutical composition of claim 27, comprising an antioxidant deposited on the excipient.

32. 32. The pharmaceutical composition of claim 31, wherein the antioxidant is propyl gallate and the excipient is dicalcium phosphate.

33. 28. The pharmaceutical composition of claim 27, comprising the antioxidant as a dry powder.

34. 34. The pharmaceutical composition of claim 33, wherein the antioxidant has a particle size of 1 to 400 microns.

35. 1. A pharmaceutical composition comprising: (a) the composition of claim 1; (b) ertugliflozin or a pharmaceutically acceptable salt or co-crystal thereof; and (c) at least one excipient selected from microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, sodium stearyl fumarate, and magnesium stearate; The pharmaceutical composition comprising:

36. below, (a) the composition of claim 1; (b) ertugliflozin or a pharmaceutically acceptable salt or co-crystal thereof; (c) microcrystalline cellulose; (d) anhydrous dibasic calcium phosphate; (e) croscarmellose sodium; (f) sodium stearyl fumarate; and (g) magnesium stearate; 36. The pharmaceutical composition of claim 35, comprising:

37. The pharmaceutical composition of claim 35, wherein the composition of claim 1 is a sitagliptin dihydrogen phosphate monohydrate-butylated hydroxyanisole composition.

38. The pharmaceutical composition of claim 35, wherein the composition of claim 1 is a sitagliptin dihydrogen phosphate monohydrate-propyl gallate composition.

39. below, (a) 10 to 50% by weight of sitagliptin dihydrogen phosphate monohydrate; (b) 0.5 to 15 wt% of an ertugliflozin L-pyroglutamic acid cocrystal; (c) 0.001 to 1 wt. % of an antioxidant; (d) 10 to 50% by weight of microcrystalline cellulose; (e) 10 to 50 wt. % anhydrous dibasic calcium phosphate; (f) 0.5 to 5% by weight of croscarmellose sodium; (g) 0.5 to 5% by weight of sodium stearyl fumarate; and (h) 0.5 to 2 wt. % magnesium stearate; 36. The pharmaceutical composition of claim 35, comprising:

40. 40. The pharmaceutical composition of claim 39, comprising 128.5 mg of sitagliptin phosphate monohydrate.

41. 40. The pharmaceutical composition of claim 39, comprising 6.48 mg or 19.43 mg of ertugliflozin L-pyroglutamic acid cocrystal.

42. 40. The pharmaceutical composition of claim 39, further comprising a film coating.

43. 40. The pharmaceutical composition of claim 39, comprising a composition of sitagliptin and an antioxidant as described in claim 1.

44. 40. The pharmaceutical composition of claim 39, comprising an antioxidant deposited on the excipient.

45. 45. The pharmaceutical composition of claim 44, wherein the antioxidant is propyl gallate and the excipient is dicalcium phosphate.

46. 40. The pharmaceutical composition of claim 39, comprising the antioxidant as a dry powder.

47. 47. The pharmaceutical composition of claim 46, wherein the antioxidant has a particle size of 1 to 400 microns.

48. A core tablet containing sitagliptin prepared using the sitagliptin and antioxidant composition of claim 1, wherein the core tablet has an NTP level of 4 ppm or less after storage at 70°C for 2.5 days.

49. The tablet core of claim 48, wherein the NTP level is 1 ppm or less after storage at 70°C for 2.5 days.

50. The tablet core of claim 48, wherein the NTP level is 0.37 ppm or less after storage at 70°C for 2.5 days.

51. The tablet core according to claim 48, wherein the antioxidant is propyl gallate or butylated hydroxyanisole.

52. A core tablet containing sitagliptin prepared using the composition of sitagliptin and an antioxidant described in claim 1, wherein the core tablet has an NTP level of 4 ppm or less after storage at 70°C for 2.5 days, and the sitagliptin is equivalent to 25 mg sitagliptin free base, 50 mg sitagliptin free base, or 100 mg sitagliptin free base.

53. The tablet core of claim 52, further comprising a film coating.

54. A tablet core containing sitagliptin prepared with an antioxidant attached to an excipient, wherein the tablet core has an NTP level of 4 ppm or less after storage at 70°C for 2.5 days.

55. The tablet core of claim 54, wherein the NTP level is 1 ppm or less after storage at 70°C for 2.5 days.

56. The tablet core of claim 54, wherein the NTP level is 0.37 ppm or less after storage at 70°C for 2.5 days.

57. 55. The pharmaceutical composition of claim 54, wherein the antioxidant is propyl gallate and the excipient is dicalcium phosphate.

58. A core tablet containing sitagliptin prepared with an antioxidant attached to an excipient, wherein the core tablet has an NTP level of 4 ppm or less after storage at 70°C for 2.5 days, and the sitagliptin is equivalent to 25 mg sitagliptin free base, 50 mg sitagliptin free base, or 100 mg sitagliptin free base.

59. The tablet core of claim 58, further comprising a film coating.

60. A tablet core containing sitagliptin prepared using an antioxidant as a dry powder, wherein the tablet core has an NTP level of 4 ppm or less after storage at 70°C for 2.5 days.

61. The tablet core of claim 60, wherein the NTP level is 1 ppm or less after storage at 70°C for 2.5 days.

62. 61. The tablet core of claim 60, wherein the NTP level is 0.37 ppm or less after storage at 70°C for 2.5 days.

63. The tablet core according to claim 60, wherein the antioxidant is propyl gallate or butylated hydroxyanisole.

64. A tablet core containing sitagliptin prepared using an antioxidant as a dry powder, wherein the tablet core has an NTP level of 4 ppm or less after storage at 70°C for 2.5 days, and the sitagliptin is equivalent to 25 mg sitagliptin free base, 50 mg sitagliptin free base, or 100 mg sitagliptin free base.

65. The tablet core of claim 64, further comprising a film coating.

66. A tablet core containing sitagliptin and ertugliflozin prepared using the sitagliptin and antioxidant composition of claim 1, wherein the tablet core has an NTP level of 4 ppm or less after storage at 70°C for 2.5 days.

67. The tablet core of claim 66, wherein the NTP level is 1 ppm or less after storage at 70°C for 2.5 days.

68. The tablet core of claim 66, wherein the NTP level is 0.37 ppm or less after storage at 70°C for 2.5 days.

69. The tablet core according to claim 66, wherein the antioxidant is propyl gallate or butylated hydroxyanisole.

70. 10. A core tablet containing sitagliptin and ertugliflozin prepared using the composition of sitagliptin and an antioxidant according to claim 1, wherein the core tablet has an NTTP level of 4 ppm or less after storage at 70°C for 2.5 days, and the ertugliflozin is equivalent to 5 mg of ertugliflozin and the sitagliptin is equivalent to 100 mg of sitagliptin free base, or the ertugliflozin is equivalent to 15 mg of ertugliflozin and the sitagliptin is equivalent to 100 mg of sitagliptin free base.

71. 71. The pharmaceutical composition of claim 70, further comprising a film coating.

72. A tablet core containing sitagliptin and ertugliflozin prepared using an antioxidant attached to an excipient, wherein the tablet core has an NTP level of 4 ppm or less after storage at 70°C for 2.5 days.

73. The tablet core of claim 72, wherein the NTP level is 1 ppm or less after storage at 70°C for 2.5 days.

74. The tablet core according to claim 72, wherein the NTP level is 0.37 ppm or less after storage at 70°C for 2.5 days.

75. 73. The pharmaceutical composition of claim 72, wherein the antioxidant is propyl gallate and the excipient is dicalcium phosphate.

76. A tablet core containing sitagliptin and ertugliflozin prepared with an antioxidant deposited on an excipient, wherein after storage at 70°C for 2.5 days, the tablet core has an NTTP level of 4 ppm or less, and the ertugliflozin is equivalent to 5 mg of ertugliflozin and the sitagliptin is equivalent to 100 mg of sitagliptin free base, or the ertugliflozin is equivalent to 15 mg of ertugliflozin and the sitagliptin is equivalent to 100 mg of sitagliptin free base.

77. The tablet core of claim 76, further comprising a film coating.

78. A tablet core containing ertugliflozin and sitagliptin prepared using an antioxidant as a dry powder, wherein the tablet core has an NTP level of 4 ppm or less after storage at 70°C for 2.5 days.

79. The tablet core of claim 78, wherein the NTP level is 1 ppm or less after storage at 70°C for 2.5 days.

80. The tablet core of claim 78, wherein the NTP level is 0.37 ppm or less after storage at 70°C for 2.5 days.

81. The tablet core according to claim 78, wherein the antioxidant is propyl gallate or butylated hydroxyanisole.

82. A tablet core containing sitagliptin and ertugliflozin prepared using an antioxidant as a dry powder, wherein after storage at 70°C for 2.5 days, the tablet core has an NTTP level of 4 ppm or less, and the ertugliflozin is equivalent to 5 mg of ertugliflozin and the sitagliptin is equivalent to 100 mg of sitagliptin free base, or the ertugliflozin is equivalent to 15 mg of ertugliflozin and the sitagliptin is equivalent to 100 mg of sitagliptin free base.

83. The tablet core of claim 82, further comprising a film coating.

84. A pharmaceutical composition comprising sitagliptin, microcrystalline cellulose and an antioxidant, wherein the level of NTP is 4 ppm or less after storage at 70°C for 2.5 days.

85. 85. The pharmaceutical composition of claim 84, having an NTP level of 1 ppm or less after storage at 70°C for 2.5 days.

86. 85. The pharmaceutical composition of claim 84, wherein the level of NTP is less than or equal to 0.37 ppm after storage at 70°C for 2.5 days.

87. 85. The pharmaceutical composition of claim 84, wherein the antioxidant is propyl gallate or butylated hydroxyanisole.

88. below, (1) Prepared using the composition of sitagliptin and an antioxidant according to claim 1; (2) Prepared using the antioxidant as a dry powder; or (3) Prepared with antioxidants deposited on the excipients; 85. The pharmaceutical composition of claim 84.

89. 85. The pharmaceutical composition of claim 84, wherein the excipient is dicalcium phosphate.

90. A pharmaceutical composition comprising sitagliptin, dicalcium phosphate and an antioxidant, wherein the level of NTP is 4 ppm or less after storage at 70°C for 2.5 days.

91. 91. The pharmaceutical composition of claim 90, having an NTP level of 1 ppm or less after storage at 70°C for 2.5 days.

92. 91. The pharmaceutical composition of claim 90, wherein the level of NTP is less than or equal to 0.37 ppm after storage at 70°C for 2.5 days.

93. 91. The pharmaceutical composition of claim 90, wherein the antioxidant is propyl gallate or butylated hydroxyanisole.

94. below, (1) Prepared using the composition of sitagliptin and an antioxidant according to claim 1; (2) Prepared using the antioxidant as a dry powder; or (3) Prepared with antioxidants deposited on the excipients; 91. The pharmaceutical composition of claim 90.

95. 91. The pharmaceutical composition of claim 90, wherein the excipient is dicalcium phosphate.

96. A pharmaceutical composition which is a tablet core containing sitagliptin or a pharmaceutically acceptable salt thereof and an antioxidant, wherein the antioxidant is added before tableting, and the level of NTP is 4 ppm or less after storing the composition at 70°C for 2.5 days.

97. 97. The pharmaceutical composition of claim 96, having an NTP level of 1 ppm or less after storage at 70°C for 2.5 days.

98. 97. The pharmaceutical composition of claim 96, wherein the level of NTP is less than or equal to 0.37 ppm after storage at 70°C for 2.5 days.

99. 97. The pharmaceutical composition of claim 96, wherein the antioxidant is propyl gallate or butylated hydroxyanisole.

100. 97. The pharmaceutical composition of claim 96, wherein the pharmaceutically acceptable salt of sitagliptin is sitagliptin dihydrogen phosphate.

101. 97. The pharmaceutical composition of claim 96, wherein the pharmaceutically acceptable salt of sitagliptin is sitagliptin dihydrogen phosphate monohydrate.

102. 97. The pharmaceutical composition of claim 96, wherein the sitagliptin corresponds to 25 mg of sitagliptin free base, 50 mg of sitagliptin free base, or 100 mg of sitagliptin free base.

103. 97. The pharmaceutical composition of claim 96, further comprising a film coating.

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