Patent Application
20100041885
The invention encompasses crystalline forms of Sitagliptin phosphate, processes for preparing the crystalline form, and pharmaceutical compositions thereof.
Sitagliptin, (3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, has the following chemical structure:
Sitagliptin phosphate is a glucagon-like peptide 1 metabolism modulator, hypoglycemic agent, and dipeptidyl peptidase IV inhibitor. Sitagliptin is currently marketed in its phosphate salt in the United States under the tradename JANUVIA™ in its monohydrate form. JANUVIA™ is indicated to improve glycemic control in patients with type 2 diabetes mellitus.
The following PCT Publications describe the synthesis of Sitagliptin via stereoselective reduction: WO 2004/087650, WO 2004/085661, and WO 2004/085378.
Several crystalline forms of Sitagliptin phosphate are described in the literature. WO 2005/020920 describes crystalline forms I, II, III and ethanol solvate; WO 2005/030127 describes crystalline form IV; WO 2005/003135 describes a monohydrate form, and WO 2006/033848 described the amorphous form.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Sitagliptin, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”), which have been used to distinguish polymorphic forms.
The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.
The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Therefore, there is a need for additional crystalline forms of Sitagliptin.
The present invention provides a crystalline Sitagliptin phosphate characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta; a powder XRD pattern with peaks at about 4.7, 13.5, and 15.5±0.2 degrees two theta and at least another two peaks selected from the following list: 14.0, 14.4, 18.3, 19.2, 19.5 and 23.7±0.2 degrees two theta; a powder XRD pattern with peaks at about 13.5, 19.2, and 19.5±0.2 degrees two theta and at least another two peaks selected from the following list: 4.7, 14.0, 15.1, 15.5, 18.3, and 18.7±0.2 degrees two theta; a powder XRD pattern with peaks at about 13.5, 15.5, 19.2, 23.7, and 24.4±0.2 degrees two theta; and a powder XRD pattern with peaks at about 4.65, 13.46, 17.63, 18.30, and 23.66±0.10 degrees two theta, and processes for preparing thereof.
The present invention also provides a crystalline Form VI of Sitagliptin phosphate characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 13.6, 14.3, 15.6, 16.9, and 19.1±0.2 degrees two theta or peaks at about 17.9, 20.3, 24.8, 26.3, and 28.9±0.2 degrees two theta; a solid-state 13C NMR spectrum with signals at about 103.0, 121.5 and 173.2±0.2 ppm; and a solid-state 13C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 0.0, 18.5 and 70.2±0.1 ppm, wherein, the signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180 ppm is typically at about 103.0±1 ppm, and processes for preparing thereof.
The present invention further provides processes for the preparation of crystalline Sitagliptin phosphate Form II, Sitagliptin phosphate monohydrate, and amorphous Sitagliptin.
The invention further provides a pharmaceutical formulation comprising the above described Sitagliptin phosphate crystalline forms. This pharmaceutical composition may additionally comprise at least one pharmaceutically acceptable excipient.
The invention further provides a pharmaceutical formulation comprising the above described Sitagliptin phosphate crystalline forms made by the processes of the present invention, and one or more pharmaceutically acceptable excipients.
a shows a powder XRD pattern of wet crystalline Form II of Sitagliptin phosphate, obtained in Example 5.
b shows a powder XRD pattern of a dry crystalline form of Sitagliptin phosphate, obtained in Example 5.
a shows a powder XRD pattern of a crystalline form of Sitagliptin phosphate, obtained in Example 88.
b shows a powder XRD pattern of a crystalline form of Sitagliptin phosphate, obtained in Example 88.
As used herein, Sitagliptin base Form I refers to crystalline Sitagliptin base characterized by data selected from the group consisting of: a PXRD pattern having any 5 peaks selected from the group consisting of 7.4, 11.5, 16.7, 17.7, 18.9, 24.1, 24.5, 27.0, 28.5 and 28.8±0.2 degrees 2-theta, wherein any combination of peaks selected includes the peak at 7.4±0.2 degrees two theta; a powder XRD pattern with peaks at about 7.4, 16.7, 17.7, 28.5 and 28.8±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 7.4, 11.5, 16.7, 17.7 and 18.9±0.2 degrees 2-theta; a powder XRD pattern with peaks at about 7.4, 11.5, 16.7, 28.5 and 28.8±0.2 degrees 2-theta and a powder XRD pattern with peaks at about 7.4, 24.1, 24.5, 27.0, and 28.8±0.2 degrees 2-theta.
As used herein, Sitagliptin phosphate Form II refers to crystalline Sitagliptin base characterized by a powder XRD pattern with peaks at about 4.7, 9.3, 12.3, 13.9, 15.1, 20.5±0.2 degrees two theta.
As used herein, Sitagliptin phosphate monohydrate refers to crystalline Sitagliptin base characterized by a powder XRD pattern with peaks at about 11. 8, 13.9, 16.0, 18.5, 19.6, 22.5±0.2 degrees two theta.
As used herein, the terms “Sitagliptin phosphate” and “Sitagliptin dihydrophosphate” may be both used to describe Sitagliptin phosphate having a 1:1 ratio of Sitagliptin and phosphate.
As used herein, the term “slurry” refers to a thin mixture of a liquid and a finely divided substance, such as any form of Sitagliptin phosphate. Typically, the solvent is used in an amount that does not result in the full dissolution of the substance.
As used herein, an “antisolvent” refers to a liquid that, when added to a solution of Sitagliptin bas, and phosphoric acid, or a solution of Sitagliptin phosphate in a solvent, induces precipitation of Sitagliptin phosphate.
As used herein, a “wet crystalline form” refers to a polymorph that was not dried using any conventional techniques.
As used herein, a “dry crystalline form” refers to a polymorph that was dried using any conventional techniques. For example, drying at elevated temperature under reduced pressure. Preferably, the crystalline form is dried at about 40° C. to about 60° C., more preferably, between about 45° C. and about 55° C., and, most preferably, about 50° C. Preferably the drying is carried out under reduced pressure (for example less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, more preferably, about 10 mbar to about 25 mbar). Preferably the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
As used herein, the term “room temperature” preferably refers to a temperature of about 20° C. to about 35° C., more preferably, about 25° C. to about 35° C., even more preferably, about 25° C. to about 30° C., and, most preferably, about 25° C.
As used herein, the term “overnight” preferably refers to about 14 hours to about 24 hours, more preferably about 14 hours to about 20 hours, and most preferably about 16 hours.
The present invention provides a crystalline Sitagliptin phosphate characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta; a powder XRD pattern with peaks at about 4.7, 13.5, and 15.5±0.2 degrees two theta and at least another two peaks selected from the following list: 14.0, 14.4, 18.3, 19.2, 19.5, and 23.7±0.2 degrees two theta; and a powder XRD pattern with peaks at about 13.5, 19.2, and 19.5±0.2 degrees two theta and at least another two peaks selected from the following list: 4.7, 14.0, 15.1, 15.5, 18.3, and 18.7±0.2 degrees two theta; a powder XRD pattern with peaks at about 13.5, 15.5, 19.2, 23.7, and 24.4±0.2 degrees two theta; and a powder XRD pattern with peaks at about 4.65, 13.46, 17.63, 18.30, and 23.66±0.10 degrees two theta.
In another embodiment, the crystalline form of Sitagliptin phosphate is characterized by a powder XRD pattern with peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
In another embodiment, the crystalline form of Sitagliptin phosphate is characterized by a powder XRD pattern with peaks at about 13.5, 15.5, 19.2, 23.7, and 24.4±0.1 degrees two theta.
In another embodiment, the crystalline form of Sitagliptin phosphate is further characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
In another embodiment, the crystalline form of Sitagliptin phosphate is characterized by a powder XRD pattern with peaks at about 4.65, 13.46, 17.63, 18.30, and 23.66±0.10 degrees two theta.
The crystalline form of Sitagliptin phosphate is also characterized by the XRD diffractograms shown in
The crystalline form of Sitagliptin phosphate, which is characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, is substantially free of the (S)-enantiomer of Sitagliptin phosphate. By “substantially free” is meant 10% (w/w) or less, more preferably 5% (w/w) or less, most preferably 2% (w/w) or less, particularly 1% (w/w) or less, more particularly 0.5% (w/w) or less, and most particularly 0.2% (w/w) or less.
The crystalline form of Sitagliptin phosphate, which is characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, is also substantially free of any other polymorph forms. By “substantially free” is meant 20% (w/w) or less, preferably 10% (w/w) or less, more preferably 5% (w/w) or less, most preferably 2% (w/w) or less, particularly 1% (w/w) or less, more particularly 0.5% (w/w) or less, and most particularly 0.2% (w/w) or less.
In another embodiment, the present invention encompasses a crystalline Form VI of Sitagliptin phosphate characterized by data selected from the group consisting of: a PXRD pattern having peaks at about 13.6, 14.3, 15.6, 16.9, and 19.1±0.2 degrees two theta or peaks at about 17.9, 20.3, 24.8, 26.3, and 28.9±0.2 degrees two theta; a solid-state 13C NMR spectrum with signals at about 103.0, 121.5 and 173.2±0.2 ppm; and a solid-state 13C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 0.0, 18.5 and 70.2±0.1 ppm, wherein, the signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180 ppm is typically at about 103.0±1 ppm.
Form VI is preferably obtained as a mixture of from about 50% to about 85% of the enantiomer R, and from about 15% to about 50% of the enantiomer S, more preferably from about 50% to about 80% of the enantiomer R, and from about 20% to about 50% of the enantiomer S, more preferably about 60% to about 80% of the enantiomer R, and from about 20% to about 40% of the enantiomer S. In one specific embodiment, Form VI is obtained as a mixture of about 77% of the enantiomer R and about 23% of the enantiomer S.
In another example, the crystalline form, characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, is obtained in a process comprising combining Sitagliptin base and phosphoric acid and a solvent selected from the group consisting of ethyl acetate, dioxane, methyl isobutyl ketone, isobutyl acetate, butyl acetate, a mixture of acetonitrile and toluene, or a mixture of tetrahydrofuran and water, forming a slurry; and obtaining the crystalline form of Sitagliptin phosphate. The obtained slurry is formed either by adding the phosphoric acid to a slurry of the Sitagliptin base in the organic solvent, or by adding the Sitagliptin base into a slurry of the phosphoric acid in the organic solvent.
Preferably the acetonitrile:toluene and the tetrahydrofuran:water ratio is about 1:1 to about 1:15, and most preferably about 3:10. Preferably, the solution is heated to a temperature of about 45° C. to about 80° C., more preferably about 50° C. to about 70° C., preferably, for about 10 minutes to about 5 hours, more preferably for about 20 minutes to about 3 hours. To promote precipitation, the solution can be cooled. Preferably, solution is gradually cooled to a temperature of about room temperature, and stirred until a precipitate is obtained. Preferably, the solution is stirred overnight. The precipitate is further recovered by any conventional method known in the art, for example by filtration. The precipitate may be further dried at about 40° C. to about 60° C., preferably between about 45° C. and about 55° C., most preferably about 50° C. Preferably the drying is carried out under reduced pressure (for example less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, more preferably, about 10 mbar to about 25 mbar). Preferably the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
In another embodiment, the present invention encompasses another process for preparing the crystalline form of Sitagliptin phosphate, which is characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, comprising combining Sitagliptin base and phosphoric acid and a mixture of a first organic solvent and a second organic solvent selected from the group consisting of acetone:n-hexane, acetone:n-heptane, acetone:cyclopentyl methyl ether, acetone:dibutyl ether, acetone:isopropylacetate, dimethylsulfoxide:methyl isobutyl ketone, and dimethylsulfoxide:methyl tert butyl ether; forming a mixture, and crystallizing Sitagliptin phosphate from the mixture. Where acetone:cyclopentyl methyl ether, acetone:isopropylacetate, and dimethylsulfoxide:methyl tert butyl ether are used, the obtained precipitate is further dried.
Preferably, the first organic solvent and the second organic solvent ratio is about 1:1 to about 1:15, and most preferably about 3:10. Alternatively, Sitagliptin phosphate can be used instead of Sitagliptin base and phosphoric acid.
Preferably, the mixture is heated to a temperature of about 45° to about 80° C., preferably to about 70° C., preferably for about an hour to about 4 hours, more preferably, for about 2 hours. To promote precipitation, the solution can be cooled. Preferably, mixture is gradually cooled to about room temperature with stirring overnight to allow the product to precipitate out. The precipitate is further recovered by any conventional method known in the art, for example by filtration.
The obtained mixture is formed either by adding the phosphoric acid to a mixture of the Sitagliptin base in the organic solvent, or by adding the Sitagliptin base into a mixture of the phosphoric acid in the organic solvent.
In another embodiment, the present invention encompasses another process for preparing the crystalline form of Sitagliptin phosphate of the present invention, comprising drying wet Form II.
Preferably, wet Form II is dried at about 40° to about 100° C., more preferably, at about 40° C. to about 60° C., even more preferably, between about 45° C. and about 55° C., and, most preferably at about 50° C. Preferably, the drying is carried out under reduced pressure (for example less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar). Preferably, the drying takes place over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
Wet Form II can be prepared by any method known in the art.
For example, wet Form II is obtained in a process comprising combining Sitagliptin base and phosphoric acid and an organic solvent selected from the group consisting of dimethyl carbonate, tetrahydrofuran, propylene glycol methyl ether, methyl ethyl ketone, ethanol, methyl acetate, dimethylformamide, diethyl carbonate, n-butanol, 1-propanol, toluene, isobutyl acetate, isopropyl acetate, isopropanol, a mixture of acetonitrile and n-butanol, acetonitrile, dimethyl carbonate, forming a slurry; and obtaining Sitagliptin phosphate Form II.
Preferably, the slurry is maintained at a temperature of about room temperature to about 70° C. Preferably, the slurry is heated to a temperature of about 50° C. to about 70° C., preferably, for about 10 minutes to about 5 hours, and, more preferably, for about 10 minutes to about 3 hours. Preferably, when the slurry is heated, it is gradually cooled to about 0° C. to about room temperature, more preferably about 10° C. to about room temperature, and, most preferably, about room temperature, and, preferably, stirred overnight to allow the product to precipitate out. The precipitate is further recovered by any conventional method known in the art, for example by filtration.
The obtained slurry is formed either by adding the phosphoric acid to a slurry of the Sitagliptin base in the organic solvent, or by adding the Sitagliptin base into a slurry of the phosphoric acid in the organic solvent.
In another example, wet Form II is prepared in a process comprising combining Sitagliptin base and phosphoric acid and a mixture of a first organic solvent and a second organic solvent selected from the group consisting of acetone:isopropylacetate, acetone:cyclohexane, acetone:isobutyl acetate, acetonitrile:n-butanol, and acetone:n-butanol, forming a mixture; crystallizing Sitagliptin phosphate from the mixture; and obtaining Sitagliptin phosphate Form II.
Preferably, the first organic solvent and the second organic solvent ratio is about 1:1 to about 1:15, and most preferably about 3:10.
Preferably, the mixture is heated to a temperature of about 45° C. to about 70° C., preferably to about 70° C., preferably for about an hour to about 4 hours, more preferably, for about 2 hours. To promote precipitation, the solution can be cooled. Preferably, the mixture is gradually cooled to about 0° C. to about room temperature, more preferably, about 10° C. to about room temperature, and, most preferably, to about room temperature with stirring overnight to allow the product to precipitate out. The precipitate is recovered by any conventional method known in the art, for example by filtration.
The obtained mixture is formed either by adding the phosphoric acid to a mixture of the Sitagliptin base in the organic solvent, or by adding the Sitagliptin base into a mixture of the phosphoric acid in the organic solvent.
In one specific embodiment, the crystalline form of Sitagliptin phosphate, characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, is prepared in a process comprising drying wet Form II, wherein the wet Form II comprises a solvent selected from the group consisting of methyl isobutyl ketone, dimethyl carbonate, tetrahydrofuran, acetonitrile, propylene glycol methyl ether, methanol, n-butanol, 1-propanol, toluene, isobutyl acetate, isopropyl acetate, butyl acetate, isopropanol, dimethyl carbonate, n-hexane, acetone, cyclohexane, isobutyl acetate, and mixtures thereof.
In another embodiment, the present invention encompasses a process for preparing crystalline Sitagliptin phosphate, characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, comprising heating a mixture of Sitagliptin phosphate Form II and the crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta to a temperature of about 40° C. to about 100° C., and, more preferably, about 40° C. to about 60° C., under reduced pressure (for example less than 1 atmosphere, more preferably, about 10 mbar to about 100 mbar, and, most preferably, about 10 mbar to about 25 mbar). Preferably, the mixture of Sitagliptin phosphate Form II and crystalline Sitagliptin phosphate, characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, is heated over a period of about 8 hours to about 36 hours, more preferably, about 10 hours to about 24 hours, and, most preferably, about 12 hours.
In another embodiment, the present invention encompasses another process for preparing crystalline Sitagliptin phosphate, characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, comprising drying a mixture of Sitagliptin phosphate Form II and the crystalline Sitagliptin phosphate characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, in a fluidized bed dryer at a temperature of about 30° C. to about 60° C., more preferably about 35° C. to about 50° C.
In another embodiment, the present invention encompasses a crystalline form of Sitagliptin phosphate, characterized by data selected from the group consisting of: a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta; a powder XRD pattern with peaks at about 4.7, 13.5, and 15.5±0.2 degrees two theta and at least another two peaks selected from the following list: 14.0, 14.4, 18.3, 19.2, 19.5 and 23.7±0.2 degrees two theta; and a powder XRD pattern with peaks at about 13.5, 19.2, and 19.5±0.2 degrees two theta and at least another two peaks selected from the following list: 4.7, 14.0, 15.1, 15.5, 18.3, and 18.7±0.2 degrees two theta; a powder XRD pattern with peaks at about 13.5, 15.5, 19.2, 23.7, and 24.4±0.2 degrees two theta; and a powder XRD pattern with peaks at about 4.65, 13.46, 17.63, 18.30, and 23.66±0.10 degrees two theta, made by the processes described above.
In another embodiment, the present invention encompasses a process for preparing Form II comprising providing a slurry of Sitagliptin phosphate characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, and a solvent selected from the group consisting of acetonitrile, methanol, ethanol, 1-propanol, isopropanol, acetone, tetrahydrofuran, n-butanol, iso-butanol, toluene, propylene glycol, propylene glycol methyl ether, chloroform, diethyl carbonate, dimethylformamide, or mixtures of dimethylformamide with methyl isobutyl ketone, or n-butanol; heating the slurry; and recovering the obtained Form II.
Preferably, the mixture is heated at a temperature of about 50° C. to about 80° C., more preferably, about 60° C. to about 75° C., even more preferably, about 65° C. to about 75° C., and, most preferably, about 70° C. The mixture is preferably stirred at this temperature for about 5 minutes to about 5 hours, and, more preferably, about 10 minutes to about 3 hours. Preferably, the mixture is gradually cooled to about 0° C. to about room temperature, more preferably about 10° C. to about room temperature, and, most preferably, to about room temperature. The mixture is stirred at this temperature overnight. The precipitate is further recovered by any conventional method known in the art, for example by filtration.
In another the present invention encompasses another process for preparing Form II comprising combining Sitagliptin base and phosphoric acid and an organic solvent selected from the group consisting of dimethyl carbonate, tetrahydrofuran, propylene glycol methyl ether, methyl ethyl ketone, ethanol, methyl acetate, dimethylformamide, diethyl carbonate, n-butanol, 1-propanol, toluene, isobutyl acetate, isopropyl acetate, isopropanol, a mixture of acetonitrile and n-butanol, acetonitrile, dimethyl carbonate, and a mixture of dimethyl carbonate and n-hexane, forming a slurry; and obtaining Form II.
Preferably, the slurry is maintained at a temperature of about room temperature to about 70° C. More preferably, the slurry is heated to a temperature of about 50° C. to about 70° C., preferably for about 10 minutes to about 5 hours, more preferably for about 10 minutes to about 3 hours. Preferably, when the slurry is heated, it is gradually cooled to a temperature of about 0° C. to about room temperature, more preferably about 10° C. to about room temperature, and most preferably to about room temperature and stirring, preferably overnight to allow the product to precipitate out. The precipitate is further recovered by any conventional method known in the art, for example by filtration.
The obtained slurry is formed either by adding the phosphoric acid to a slurry of the Sitagliptin base in the organic solvent, or by adding the Sitagliptin base into a slurry of the phosphoric acid in the organic solvent.
In another embodiment, the present invention encompasses another process for preparing Form II comprising combining Sitagliptin base and phosphoric acid and a mixture of a first organic solvent and a second organic solvent selected from the group consisting of acetone:isopropylacetate, acetone:cyclohexane, acetone:isobutyl acetate, acetonitrile:n-butanol, and acetone:n-butanol, forming a mixture; crystallizing Sitagliptin phosphate from the mixture; and recovering Sitagliptin phosphate Form II.
Preferably, the first organic solvent and the second organic solvent ratio is about 1:1 to about 1:15, and most preferably about 3:10.
Preferably, the mixture is heated to a temperature of about 45° C. to about 70° C., preferably to about 70° C., preferably for about an hour to about 4 hours, more preferably, for about 2 hours. To promote precipitation, the solution can be cooled. Preferably, mixture is gradually cooled to about 0° C. to about room temperature, more preferably, about 10° C. to about room temperature, and, most preferably, to about room temperature and stirring overnight to allow the product to precipitate out. The precipitate is recovered by any conventional method known in the art, for example by filtration.
The obtained mixture is formed either by adding the phosphoric acid to a mixture of the Sitagliptin base in the organic solvent, or by adding the Sitagliptin base into a mixture of the phosphoric acid in the organic solvent.
In another embodiment, the present invention encompasses another process for preparing Sitagliptin phosphate Form II, comprising dissolving Sitagliptin phosphate in dimethylsulfoxide; adding an antisolvent selected from the group consisting of iso-butanol, acetonitrile, diethyl ether, diethyl carbonate, and tert-butyl ether; and recovering Sitagliptin phosphate Form II.
Preferably, the solvent/antisolvent ratio is about 1:1 to about 1:20, and most preferably about 3:10.
Preferably, the starting Sitagliptin phosphate is crystalline Sitagliptin phosphate characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
In order to promote precipitation, the mixture may be cooled to about 0° C. to about 20° C., preferably, for about 2 hours to about 24 hours.
In another embodiment, the present invention encompasses another process for preparing Sitagliptin phosphate Form II, comprising granulating Sitagliptin phosphate in the presence of isopropanol. Preferably, the starting Sitagliptin phosphate is crystalline Sitagliptin phosphate characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
The term “granulation” broadly refers to a process comprising mixing the solid with a minimal amount of solvent, and stirring the mixture at about room temperature for the time needed to cause the desired transformation. A mechanical stirrer can be used in the process. Typically, about 0.1 to about 0.2 ml of solvent is used per 1 gram of compound. Preferably, the mixture is granulated using a rotary evaporator.
In another embodiment, the present invention encompasses a process for preparing Form II, comprising exposing Sitagliptin phosphate characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta to a C1-C4 alcohol, where the alcohol is preferably selected from the group consisting of ethanol, methanol, and isopropanol.
In another embodiment, the present invention encompasses a process for preparing the crystalline form VI of Sitagliptin phosphate of the present invention, comprising providing a slurry of Sitagliptin phosphate, and an organic solvent selected from the group consisting of acetonitrile (ACN), and C1-C4 alcohols, most preferably isopropanol; heating the slurry; cooling the resulting mixture; and recovering the obtained Form VI of Sitagliptin phosphate. Optionally, Sitagliptin phosphate can be formed in situ starting from Sitagliptin base and phosphoric acid. The Sitagliptin base or the Sitagliptin phosphate are introduced as a mixture of from about 50% to about 85% of the enantiomer R, and from about 15% to about 50% of the enantiomer S, more preferably from about 50% to about 80% of the enantiomer R, and from about 20% to about 50% of the enantiomer S, more preferably about 60% to about 80% of the enantiomer R, and from about 20% to about 40% of the enantiomer S.
Preferably, from about 10 ml to about 70 ml of acetonitrile, and, more preferably, about 25 ml to about 60 ml are used per gram of the Sitagliptin phosphate. Preferably, from about 2 ml to about 12 ml, and, more preferably, about 4 ml to about 10 ml of the organic solvent are used per gram of the Sitagliptin.
Preferably, the Sitagliptin or the Sitagliptin salt, which is combined with the ACN, is amorphous.
The obtained slurry is preferably heated to a temperature of about 40 to about reflux, more preferably, the slurry is heated to about 60 to about reflux, and, most preferably, the slurry is heated to about reflux. To induce precipitation, the slurry is then cooled to about 0° C. to about room temperature, more preferably to about 0° C. to about 4° C., and preferably maintained for about 1 day to about 5 days, and, more preferably, for about 3 days, to induce precipitation.
When phosphoric acid is introduced into a mixture of Sitagliptin and the organic solvent, preferably, it is added in a dropwise manner. Preferably, the acid is added to a heated solution or slurry of the Sitagliptin and the organic solvent, where the heated solution or slurry is at a temperature of about 40° C. to about 65° C., and, more preferably about 45° C. to about 60° C.
Preferably, the chemical purity of the obtained Form VI is more than 99.5%, and, more preferably, more than 99.9%.
In another embodiment, the present invention encompasses another process for preparing amorphous Sitagliptin phosphate, comprising dissolving Sitagliptin phosphate in dimethylsulfoxide; and adding an antisolvent selected form a group consisting of methyl tert-butyl ether, and tetrahydrofuran to obtain amorphous Sitagliptin phosphate.
The mixture is maintained at a temperature of about 0° C. for about 2 hours to induce precipitating.
In another embodiment, the present invention encompasses another process for preparing amorphous Sitagliptin phosphate comprising combining Sitagliptin base and phosphoric acid and an organic solvent selected from the group consisting of diethyl carbonate, dimethyl carbonate, and a mixture of cyclohexanone and methyl tert-butyl ether, forming a slurry; and recovering the precipitate from the mixture.
Preferably, the mixture is maintained at a temperature of about 15° C. to about 70° C., preferably about 20° C. to about 50° C. for about 10 minutes to about 7 days, more preferably for about 10 minutes to about an hour.
The obtained slurry is formed either by adding the phosphoric acid to a slurry of the Sitagliptin base in the organic solvent, or by adding the Sitagliptin base into a slurry of the phosphoric acid in the organic solvent.
In another embodiment, the present invention encompasses a process to obtain Sitagliptin phosphate monohydrate comprising heating a mixture of Sitagliptin phosphate with water and an organic solvent selected from a group consisting of methyl tert-butyl ether and acetonitrile; and recovering the precipitate. Alternatively, a mixture of Sitagliptin base and phosphoric acid can be introduced instead of Sitagliptin phosphate.
Preferably, the mixture is heated to about 50° C. to about 80° C., more preferably 60° C. to about 70° C., and then cooled to about 0° C. to about 25° C. Recovering the product may be carried out via any known method in the art, for example by filtration or evaporation.
The invention further provides a pharmaceutical formulation comprising the above described Sitagliptin phosphate crystalline forms. This pharmaceutical composition may additionally comprise at least one pharmaceutically acceptable excipient.
The invention further provides a pharmaceutical formulation comprising the above described Sitagliptin phosphate crystalline forms made by the processes of the present invention, and one or more pharmaceutically acceptable excipients. The compositions of the invention include powders, granulates, aggregates and other solid compositions comprising the present invention form of Sitagliptin solid crystalline.
The present invention also provides methods of treating type 2 diabetes mellitus in a patient, preferably a human, by administrating to the patient a pharmaceutical composition comprising Sitagliptin phosphate crystalline form as described herein. Preferably, the pharmaceutical composition comprises a therapeutically effective amount of Sitagliptin phosphate crystalline form.
The present invention also provides the use of the above mentioned Sitagliptin phosphate crystalline forms, for the manufacture of a pharmaceutical composition for the treatment of type 2 diabetes mellitus.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
X-Ray powder diffraction data was obtained by using methods known in the art using a SCINTAG powder X-Ray diffractometer model X'TRA equipped with a solid-state detector. Copper radiation of 1.5418 Å was used. A round aluminum sample holder with zero background was used. The scanning parameters included: range: 2-40 degrees two-theta; scan mode: continuous scan; step size: 0.05 deg.; and a rate of 3 deg/min. All peak positions are within ±0.2 degrees two theta.
The PXRD peaks positions are calibrated using silicon powder as internal standard in an admixture with the sample measured. The position of the silicon (111) peak was corrected to be 28.45 degrees two theta. The positions of Sitagliptin phosphate form peaks were corrected respectively. (No correction was performed on the presented diffractograms in the figures).
STG (Sitagliptin) base form I can be obtained according to the procedures described in PCT application No. PCT/US08/01317.
STG (Sitagliptin) base form I (100 mg) was dissolved in ethyl acetate (500 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was dissolved in tetrahydrofuran:water 2:1 (300 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours. The product was isolated by vacuum filtration to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was partially dissolved in methyl isobutyl ketone (1000 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 1.5 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta. The sample was dried at 50° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was partially dissolved in dioxane (1000 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 1.5 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was partially dissolved in dimethyl carbonate (1000 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II
The sample was dried at 50° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was dissolved in acetone (100 μL) at 25° C. Then, n-Hexane was added (500 μL) at 25° C. Two phases were formed. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was dissolved in acetone (100 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) and n-Hexane (500 μL) were then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was dissolved in acetone (100 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) and n-Heptane (500 μL) were then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was dissolved in acetone (100 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) and cyclopentyl methyl ether (1000 μL) were then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain a mixture of wet STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta and form II. The sample was dried in vacuum oven at 50° C. 24 hours to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was dissolved in acetone (300 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) and dibutyl ether (1000 μL) were then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was dissolved in methyl ethyl ketone (1000 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG base form I (100 mg) was dissolved in acetone (300 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) and cyclohexane (1000 μL) were then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG phosphate Form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (50 mg) was dissolved in dimethylsulfoxide (0.05 ml) at 25° C. Then iso-Butanol (1 ml) was added at 25° C. The solution formed was slurry (crystallization occurred) and was cooled in ice water bath for 2 hrs.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
The sample was dried at 50° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG phosphate Form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (50 mg) was dissolved in dimethylsulfoxide (0.05 ml) at 25° C. Then Acetonitrile (1 ml) was added at 25° C. Crystallization occurred and the mixture was cooled in ice water bath for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG phosphate Form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (50 mg) was dissolved in dimethylsulfoxide (0.05 ml) at 25° C. Then diethyl ether (1 ml) was added at 25° C. The solution formed was a slurry (crystallization occurred) and was cooled in ice water bath for 2 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG phosphate Form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (50 mg) was dissolved in dimethylsulfoxide (0.05 ml) at 25° C. Then diethyl carbonate (1 ml) was added at 25° C. The solution formed was a slurry (crystallization occurred) and was cooled in ice water bath for 2 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG base form I (100 mg) was partially dissolved in tetrahydrofuran (500 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
The sample was dried at 50° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was dissolved in acetonitrile (500 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain a mixture of wet STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta and form II.
The sample was dried at 50° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was dissolved in ethanol (500 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG base form I (100 mg) was dissolved in methyl acetate (1000 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2.5 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG base form I (100 mg) was dissolved in propylene glycol methyl ether (1000 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2.5 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
The sample was dried at 50° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was dissolved in dimethyl formamide (1000 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours. The product was isolated by evaporation to obtain wet STG phosphate crystalline form II.
STG base form I (100 mg) was dissolved in dimethylsulfoxide (200 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours. The product was isolated by evaporation, addition of methanol and vacuum filtration to obtain wet STG phosphate crystalline form II.
STG base form I (100 mg) was dissolved in dimethyl formamide (500 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG base form I (100 mg) was dissolved in acetone (100 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) and iso-butyl acetate (500 μL) were then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain STG phosphate crystalline form II.
STG base form I (100 mg) was dissolved in acetone (100 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) and iso-propyl acetate (1000 μL) were then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain STG phosphate crystalline form II.
The sample was dried at 50° C. for about 24 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base form I (100 mg) was dissolved in acetone (300 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) and n-butanol (1000 μL) were then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in acetonitrile (1 ml) at 25° C., then heated to 70° C., stirred at 70° C. for 5 hours, cooled gradually to 10° C. and remained at 10° C. for 16 hours.
The product was isolated by vacuum filtration to obtain STG phosphate crystalline form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in methanol (1 ml) at room temperature, then heated to 50° C., stirred at 50° C. for 5 hours, cooled gradually to 10° C. and remained at 10° C. for 16 hours.
The product was isolated by vacuum filtration to obtain STG phosphate crystalline form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in acetone (1 ml) at room temperature, then heated to 50° C., stirred at 50° C. 5 for hours, cooled gradually to 10° C. and remained at 10° C. for 16 hours.
The product was isolated by vacuum filtration to obtain STG phosphate crystalline form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in tetrahydrofuran (1 ml) at room temperature, then heated to 50° C., stirred at 50° C. for 5 hours, cooled gradually to 10° C. and remained at 10° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in n-Butanol (1 ml) at room temperature, then heated to 95° C., stirred at that temperature for 5 hours, cooled gradually to 10° C. and remained at 10° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
Sitagliptin dihydrophosphate form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (0.03g) was slurried in 0.3 ml n-butanol at 25° C., under magnetic stirring for 24 hours. The product was isolated by filtration. The wet material was analyzed by XRD and found to be Sitagliptin dihydrophosphate Form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in iso-Butanol (1 ml) at room temperature, then heated to 95° C., stirred at that temperature for 5 hours, cooled gradually to 10° C. and remained at 10° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
Sitagliptin dihydrophosphate form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (0.05g) was slurried in 1 ml iso-BuOH at 50° C., under magnetic stirring for 3 hours and at 10° C. for 16 hours. The product was isolated by filtration. The wet material was analyzed by XRD and found to be Sitagliptin dihydrophosphate Form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in toluene (1 ml) at room temperature, then heated to 95° C., stirred at that temperature for 5 hours, cooled gradually to 10° C. and remained at 10° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in N,N-Dimethyl Formamide (1 ml) at room temperature, then heated to 70° C., stirred at that temperature for 4 hours, cooled gradually to 10° C. and remained at 10° C. for 16 hours. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in N,N-Dimethyl Formamide (0.5 ml) at room temperature. Then Methyl iso-Butyl Ketone (0.5 ml) was added at room temperature. The solution formed was slurry and stirred for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in N,N-Dimethyl Formamide (0.5 ml) at room temperature. Then n-butanol (0.5 ml) was added at room temperature. The solution formed was slurry and stirred for 16 hours. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in propylene glycol (0.025 ml) at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG base Form I (100 mg) was slurried in n-butanol (1000 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
The sample was dried at 50° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base Form I (100 mg) was slurried in iso-propanol (1000 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2.5 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG base Form I (100 mg) was slurried in 1-propanol (1000 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
The sample was dried at 50° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
Sitagliptin dihydrophosphate form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (0.03g) was slurried in 0.3 ml 1-propanol at 25° C., under magnetic stirring for 24 hours. The product was isolated by filtration. The wet material was analyzed by XRD and found to be Sitagliptin dihydrophosphate Form II.
STG base Form I (100 mg) was slurried in iso-propyl acetate (1000 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in propylene glycol methyl ether (0.25 ml) at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain a wet STG phosphate crystalline form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in chloroform (0.25 ml) at 25° C., then cooled gradually to 25° C. and stirred at 25° C. for 16 hours.
The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG base Form I (100 mg) was slurried in iso-propyl acetate (1000 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours. The product was isolated by vacuum filtration to obtain a mixture of wet STG phosphate crystalline form II and form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
The sample was dried at 50° C. for 16 hours under reduced pressure to obtain a mixture of STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
Sitagliptin dihydrophosphate form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (0.03 g) was slurried in 1 ml acetonitrile at 50° C., under magnetic stirring for 3 hours and at 10° C. for 16 hours. The product was isolated by filtration. The wet material was analyzed by XRD and found to be Sitagliptin dihydrophosphate Form II.
Sitagliptin dihydrophosphate form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (0.03 g) was slurried in 0.3 ml ethanol at 25° C., under magnetic stirring for 24 hours. The product was isolated by filtration. The wet material was analyzed by XRD and found to be Sitagliptin dihydrophosphate Form II.
Sitagliptin dihydrophosphate form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (0.03 g) was slurried in 0.3 ml iso-propyl alcohol at 25° C., under magnetic stirring for 24 hours. The product was isolated by filtration. The wet material was analyzed by XRD and found to be Sitagliptin dihydrophosphate Form II.
Sitagliptin dihydrophosphate form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (0.03 g) was slurried in 0.3 ml diethylcarbonate at 25° C., under magnetic stirring for 24 hours. The product was isolated by filtration. The wet material was analyzed by XRD and found to be Sitagliptin dihydrophosphate Form II.
Sitagliptin dihydrophosphate form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (0.03 g) was granulated with 0.006 ml isopropyl alcohol at 25° C., in a rotavapor for 9-12 hours. The wet material was analyzed by XRD and found to be Sitagliptin dihydrophosphate Form II.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was dissolved in dimethylsulfoxide (0.05 ml) at 25° C. Then Methyl iso-Butyl Ketone (1 ml) was added at room temperature. The solution formed was slurry (crystallization occurred) and was cooled in ice water bath for 2 hours.
The product was isolated by vacuum filtration to obtain STG phosphate form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was dissolved in dimethylsulfoxide (0.05 ml) at 25° C. Then Tetrahydrofuran (1 ml) was added at 25° C. The solution formed was slurry (crystallization occurred) and was cooled in ice water bath for 16 hours.
The product was isolated by vacuum filtration to obtain wet amorphous STG phosphate.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was dissolved in dimethylsulfoxide (0.05 ml) at 25° C. Then methyl t-butyl ether (1 ml) was added at 25° C. The solution formed was slurry (crystallization occurred) and was cooled in ice water bath for 16 hours.
The product was isolated by vacuum filtration to obtain wet amorphous STG phosphate.
The sample was dried at 50° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG phosphate (50 mg, crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was slurried in water (300 μL) at 25° C., then heated to 60° C. and was dissolved at that temperature.
Then methyl t-butyl ether (250 μL) was added and the solution was cooled in an ice water bath, and stirred for 2 hours. Crystallization occurred.
The product was isolated by vacuum filtration to obtain wet STG phosphate monohydrate.
STG base Form I (100 mg) was dissolved in acetonitrile:water 1:1 (300 μL) at 25° C. Phosphoric acid (85%, 17 μL, 1 eq) was then added and the mixture was heated to 70° C., stirred at 70° C. for 2 hours, then cooled gradually to 25° C. and stirred at 25° C. for 16 hours. The product was isolated by evaporation to obtain wet STG phosphate crystalline monohydrate.
Sitagliptin dihydrophosphate form V, characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (0.03 g) was granulated with 0.006 ml
Iso-propanol:water 1:1 at 25° C., in a rotavapor for 9-12 hours. The wet material was analyzed by XRD and found to be Sitagliptin dihydrophosphate monohydrate.
STG base Form I (500 mg) was slurried in acetonitrile (2.5 mL) at 25° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 25° C. for 35 minutes. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG base Form I (500 mg) was slurried in toluene (2.5 mL) at 25° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 25° C. for 12 minutes. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
The sample was dried at 40° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base Form I (500 mg) was slurried in acetonitrile (1 mL) at 70° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 70° C. for 10 minutes. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
The sample was dried at 40° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base Form I (500 mg) was slurried in diethyl carbonate (2.5 mL) at 25° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 25° C. for 10 minutes.
The product was isolated by vacuum filtration to obtain wet STG phosphate amorphous.
STG base Form I (500 mg) was slurried in isobutyl acetate (2.5 mL) at 25° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 25° C. for 10 minutes.
The product was isolated by vacuum filtration to obtain wet STG phosphate form II.
STG base Form I (500 mg) was slurried in n-butanol (2.5 mL) at 25° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 25° C. for 25 minutes. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
STG base Form I (500 mg) was slurried in 1-propanol (2.5 mL) at 25° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 25° C. for 18 minutes. The product was isolated by vacuum filtration to obtain wet STG phosphate form II.
STG base Form I (500 mg) was dissolved in dimethyl carbonate (2.5 mL) at 74° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 74° C. for 13 minutes.
The product was isolated by vacuum filtration to obtain wet STG phosphate form II.
STG base Form I (500 mg) was dissolved in diethyl carbonate (2.5 mL) at 74° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 74° C. for 20 minutes.
The product was isolated by vacuum filtration to obtain wet STG phosphate form II.
STG base Form I (500 mg) was slurried in isobutyl acetate (2.5 mL) at 74° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 74° C. for 30 minutes.
The product was isolated by vacuum filtration to obtain wet STG phosphate form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base Form I (500 mg) was slurried in n-Butanol (2.5 mL) at 74° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 74° C. for 18 minutes. The product was isolated by vacuum filtration to obtain wet STG phosphate form II. The sample was dried at 40° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base Form I (500 mg) was slurried in 1-propanol (2.5 mL) at 74° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 74° C. for 23 minutes. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form II.
The sample was dried at 40° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base Form I (500 mg) was slurried in methyl isobutyl ketone (2.5 mL) at 74° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 74° C. for 25 minutes.
The product was isolated by vacuum filtration to obtain wet STG phosphate form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
The sample was dried at 40° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base Form I (500 mg) was slurried in dimethyl carbonate (5.5 mL) at 50° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 50° C. for 8 minutes.
The product was isolated by vacuum filtration to obtain wet STG phosphate amorphous.
STG base Form I (500 mg) was slurried in diethyl carbonate (10 mL) at 50° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 50° C. for 15 minutes.
The product was isolated by vacuum filtration to obtain wet STG phosphate amorphous.
STG base Form I (500 mg) was slurried in n-butanol (3.5 mL) at 50° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 50° C. for 1.25 hours. The product was isolated by vacuum filtration to obtain wet STG phosphate form II.
STG base Form I (500 mg) was slurried in 1-propanol (3.5 mL) at 50° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 50° C. for 1.25 hours. The product was isolated by vacuum filtration to obtain wet STG phosphate form II.
STG base Form I (500 mg) was slurried in acetonitrile (1.5 mL) at 50° C. Phosphoric acid (85%, 83 μL, 1 eq) was then added and the mixture was stirred at 50° C. for 10 minutes. The product was isolated by vacuum filtration to obtain wet STG phosphate form II.
STG base Form I (500 mg) slurried in acetonitrile (1.5 mL) at 70° C. was added dropwise to phosphoric acid (85%, 83 μL, 1 eq) in acetonitrile (1.5 mL) at 70° C. The mixture was stirred at 70° C. for 10 minutes.
The product was isolated by vacuum filtration to obtain wet STG phosphate form II.
STG base Form I (500 mg) slurried in acetonitrile (1 mL) at 70° C. was added dropwise to phosphoric acid (85%, 83 μL, 1 eq) in toluene (2.5 mL) at 70° C. The mixture was stirred at 70° C. for 15 minutes.
The product was isolated by vacuum filtration to obtain wet STG phosphate form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
The sample was dried at 40° C. for 16 hours under reduced pressure to obtain STG phosphate form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base Form I (500 mg) slurried in 1-propanol (1.5 mL) at 72° C. was added dropwise to phosphoric acid (85%, 83 μL, 1 eq) in 1-propanol (1.5 mL) at 70° C. The mixture was stirred at 70° C. for 15 minutes.
The product was isolated by vacuum filtration to obtain wet STG phosphate form II.
STG base Form I (500 mg) slurried in acetonitrile (2.5 mL) at 25° C. was added dropwise to phosphoric acid (85%, 83 μL, 1 eq) in n-Butanol (5 mL) at 25° C. The mixture was stirred at 25° C. for 15 minutes.
The product was isolated by vacuum filtration to obtain wet STG phosphate form II. The sample was dried in vacuum oven at 40° C. 16 hours to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base Form I (500 mg) slurried in acetonitrile (2.5 mL) at 50° C. was added dropwise to phosphoric acid (85%, 83 μL, 1 eq) in n-Butanol (5 mL) at 50° C. The mixture was stirred at 50° C. for 35 minutes.
The product was isolated by vacuum filtration to obtain a mixture of wet STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta and form II. The sample was dried in vacuum oven at 40° C. 16 hours to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base Form I (500 mg) slurried in dimethyl carbonate (2.5 mL) at 50° C. was added dropwise to phosphoric acid (85%, 83 μL, 1 eq) in n-Hexane (2.5 mL) at 50° C. The mixture was stirred at 50° C. for 10 minutes.
The product was isolated by vacuum filtration to obtain a mixture of wet STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta and form II. The sample was dried in vacuum oven at 40° C. 16 hours to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base Form I (500 mg) slurried in cyclohexanone (5 mL) at 25° C. was added dropwise to phosphoric acid (85%, 83 μL, 1 eq) in methyl tert-butyl ether (1 mL) at 25° C. The mixture crystallized after 30 minutes and was stirred for 45 minutes at 25° C.
The product was isolated by vacuum filtration to obtain wet amorphous STG phosphate. The sample was dried in vacuum oven at 40° C. 16 hours to obtain STG phosphate crystalline form monohydrate.
STG base Form I (500 mg) was added in portions to phosphoric acid (85%, 83 μL, 1 eq) in cyclopentyl methyl ether (5 mL) at 25° C. The mixture was stirred at 25° C. for 25 minutes. The product was isolated by vacuum filtration to obtain a mixture of STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta and form II. The sample was dried in vacuum oven at 40° C. 16 hours to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base Form I (500 mg) slurried in cyclohexanone (5 mL) at 25° C. was added dropwise to phosphoric acid (85%, 83 μL, 1 eq) in methyl tert-butyl ether (1 mL) at 25° C. The mixture crystallized after 30 minutes and was stirred for 3 hours and 20 minutes at 25° C. The product was isolated by vacuum filtration to obtain wet amorphous STG phosphate. The sample was dried in vacuum oven at 40° C. 16 hours to obtain STG phosphate crystalline form monohydrate.
STG base Form I (500 mg) slurried in cyclohexanone (5 mL) at 25° C. was added dropwise to phosphoric acid (85%, 83 μL, 1 eq) in methyl tert-butyl ether (1 mL) at 25° C. The mixture crystallized after 30 minutes and was stirred for 1 week at 25° C.
The product was isolated by vacuum filtration to obtain wet amorphous STG phosphate. The sample was dried in vacuum oven at 40° C. 16 hours to obtain STG phosphate crystalline form monohydrate.
STG base Form I (5.6 g, 13.8 mmol) was dissolved in ethanol-water (18 ml-13 ml) at 50° C. To that solution, 85%-H3PO4 (0.92 ml, 13.8 mmol) was added at once with stirring. The solution was at 64-68° C. for an hour, and then the stirred solution was cooled to 25° C. for 40 min. The product was precipitated after additional stirring at 25° C. for 20 minutes. Ethanol (90 ml) was added to suspension, and the suspension was stirred at 25° C. for 18 hours. The solid was filtered, washed with ethanol (12 ml), dried at 50° C. under vacuum for 7 hours to give STG phosphate (6.0 g). The solid was analyzed by XRD and found to be STG phosphate Form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta. The STG phosphate Form V, characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (30 mg) was placed in a 50 ml- beaker. The opened beaker was kept in closed 100 ml-vessel containing 20 ml of methyl tert-butyl ether at 25° C. for 40 days. The solid was analyzed by XRD and found to be STG phosphate Form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta with higher crystallinity.
STG base (500 mg) was slurried in butyl acetate (2.5 mL) at 25° C., and was added drop-wise to phosphoric acid (85%, 83 μL, 1 eq) in butyl acetate (3.5 mL) at 25° C. The mixture was stirred at 25° C. for 20 minutes. The product was isolated by vacuum filtration to obtain wet STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta. The sample was dried at 40° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base (800 mg) was dissolved in methanol (2 mL) at 25° C., and heated to 50° C. Phosphoric acid (85%, 131 μL, 1 eq) in methanol (1 mL) was then added drop-wise, and the mixture was stirred at 50° C. The solution formed a very thick slurry. Therefore, 9 ml methanol was added in portions, and then stirred at 50° C. for 1 hour and at 25° C. for 16 hours. The sample was dried at 40° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
STG base (600 mg) was slurried in isopropanol (3 mL) at 25° C., and heated to 50° C. Phosphoric acid (85%, 100 μL, 1 eq) in isopropanol (1 mL) was then added drop-wise, and the mixture was stirred at 50° C. for 16 hours. The sample was dried at 40° C. for 16 hours under reduced pressure to obtain STG phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
A 100 mg of a mixture of Form II and crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta was kept under relative humidity of 100% for one day, to obtain pure crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta, as presented in
Sitagliptin phosphate (9 gr, a dry mixture of crystalline Form II and a form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was dried in fluidized bed dryer at 40° C. at 40% humidity for four hours to obtain Sitagliptin phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta (6.8 gr).
Sitagliptin phosphate (1 gr, a dry mixture of crystalline Form II and a form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was dried in vacuum oven at 80° C. for 24 hours to obtain Sitagliptin phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
Sitagliptin phosphate (1 gr, a dry mixture of crystalline Form II and a form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta) was dried in vacuum oven at 100° C. for 24 hours to obtain Sitagliptin phosphate crystalline form characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta.
Sitagliptin phosphate from characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta was stored under ethanol vapors at 25° C. for 18 hours. It was then analyzed by PXRD, and identified as form II of Sitagliptin phosphate.
Sitagliptin phosphate from characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta was stored under methanol vapors at 25° C. for 1 week. It was then analyzed by PXRD, and identified as form II of Sitagliptin phosphate.
Sitagliptin phosphate from characterized by a powder XRD pattern with peaks at 4.7, 13.5, 17.7, 18.3, and 23.7±0.2 degrees two theta was stored under iso-propanol vapors at 25° C. for 1 week. It was then analyzed by PXRD, and identified as form II of Sitagliptin phosphate.
To 1 g of amorphous Sitagliptin-phosphate (97.8% purity and 81.9% R) was added 50 ml of acetonitrile (ACN). The slurry was heated to reflux and stirred for 1 hour, then cooled to 2° C., and stirred for 1 hour. The product was isolated by vacuum filtration at 2° C., and washed with 2 ml of ACN, and dried at 50° C. in a vacuum oven for 15 hours to yield 0.88 g of Sitagliptin-phosphate (100% purity and 75.5% R) form VI (88% yield).
To 5 g of oily STG-base (75.1 % R) was added 20 ml of isopropanol (IPA). The slurry was heated to 50° C., than H3PO4 85% (1.13 g in 10 ml IPA) was added dropwise and stirred for 1 hour. The slurry reaction was cooled to room temperature, and stirred for three days. The product was isolated by vacuum filtration, and washed with 20 ml of IPA to yield STG-Phosphate form VI, as a white-grey solid (99.5% purity and 74.7% R). Further purification accepted by adding 50 ml of ACN to the product. The slurry mixture was heated to reflux and stirred for 1 to 2 hours, than cooled to room temperature and stirred over night. Vacuum filtration followed by washings with 40 ml ACN yield a white-grey solid that was dried at 40° C. in a vacuum oven for 15 hours to yield 4.74 g of STG-Phosphate (99.7% purity and 78.0% R) form VI (95% yield).
To degaussed 2,2,2-trifluoroethanol (TFE) (30 mL) were added Rhodium(I) chloride 1,5-cycloocatadiene complex (18.3 mg, 0.05%) and (R)-(−)-1-[(S)-2-diphenylphosphino)ferrocenyl]ethyl di-tert-butylphosphine (44.2 mg, 0.11%). The solution was stirred at room temperature, degaussed three times, and then stirred for one hour at room temperature.
To 250 ml hydrogenator were added (Z)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazyn-7(8H)-yl)-4-(2,4,5-trifluorophenyl)but-2-en-1-one (30 gr, 1 equivalent) and TFE (120 ml) at room temperature and the mixture was washed three times with nitrogen gas. The catalyst solution was added and the clear solution was washed three times with nitrogen gas and then with hydrogen gas. The mixture remained under hydrogen at constant pressure of 5 bar and heated to 55° C. The mixture was stirred at 55° C. for 26 hours to obtain Sitagliptin base in TFE solution (optical purity by HPLC 76.9%, purity by HPLC 91.5%)
Two reaction mixtures which were obtained according to the above procedure were combined and the solution was divided to 10 parts.
7 parts of the solution, each contained ca ˜6 gr Sitagliptin were concentrated and Sitagliptin base was precipitated by addition of MTBE then filtrated by vacuum filtration. The combined mother liqueur from the crystallization experiments was concentrated. The residue was dissolved in isopropanol (40 mL) at room temperature, heated to 50° C. A solution of phosphoric acid (85%, 1.7 mL, ca ˜1 eq) in isopropanol (20 mL) was added and the mixture kept stirring at 50° C. for one hour, then cooled gradually to 25° C., and stirred at 25° C. over night.
The product was isolated by vacuum filtration and dried at 40° C. vacuum oven over night to obtain Sitagliptin phosphate crystalline form VI (optical purity by HPLC 51.8%, purity by HPLC 99.20%).
This application claims benefit of U.S. Provisional Patents Application No. 61/154,491, filed Feb. 23, 2009, 61/201,304, filed Dec. 8, 2008, 61/190,868, filed Sep. 2, 2008, 61/092,555, filed Aug. 28, 2008, 61/090,736, filed Aug. 21, 2008, 61/189,128, filed May 14, 2008, and 61/070,866, filed Mar. 25, 2008, the contents of which are incorporated herein in their entirety by reference. This application also claims benefit of U.S. Provisional Patents Application No. 61/201,860, filed Dec. 15, 2008, 61/191,933, filed Sep. 11, 2008, 61/091,759, filed Aug. 26, 2008, 61/137,489, filed Jul. 30, 2008, and 61/134,598, filed Jul. 10, 2008, the contents of which are incorporated herein in their entirety by reference.
| Number | Date | Country | |
|---|---|---|---|
| 61154491 | Feb 2009 | US | |
| 61201304 | Dec 2008 | US | |
| 61190868 | Sep 2008 | US | |
| 61092555 | Aug 2008 | US | |
| 61090736 | Aug 2008 | US | |
| 61189128 | Aug 2008 | US | |
| 61070866 | Mar 2008 | US | |
| 61201860 | Dec 2008 | US | |
| 61191933 | Sep 2008 | US | |
| 61091759 | Aug 2008 | US | |
| 61137489 | Jul 2008 | US | |
| 61134598 | Jul 2008 | US |
