(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2010/0041885 A1
`(43) Pub. Date:
`Feb. 18, 2010
`Perlman et al.
`
`US 2010.0041885A1
`
`(54) CRYSTALLINE FORMS OF SITAGLIPTIN
`PHOSPHATE
`
`(76) Inventors:
`
`Nurit Perlman, Kfar Saba (IL);
`Revital Ramaty, Ramat-Hasharon
`(IL); Mili Abramov, Givataim (IL);
`Nina Finkelstein, Herzliya (IL); Eli
`Lancry, Modiin (IL); Shay Asis,
`Rishon LeZion (IL); Ariel
`Mittelman, Elad (IL)
`Correspondence Address:
`KENYON & KENYON LLP
`ONE BROADWAY
`NEW YORK, NY 10004 (US)
`
`(21) Appl. No.:
`
`12/410,738
`
`(22) Filed:
`
`Mar. 25, 2009
`
`Related U.S. Application Data
`(60) Provisional application No. 61/154.491, filed on Feb.
`23, 2009, provisional application No. 61/201,304,
`filed on Dec. 8, 2008, provisional application No.
`61/190,868, filed on Sep. 2, 2008, provisional applica
`tion No. 61/092,555, filed on Aug. 28, 2008, provi
`sional application No. 61/090.736, filed on Aug. 21,
`2008, provisional application No. 61/189,128, filed on
`Aug. 14, 2008, provisional application No. 61/070,
`866, filed on Mar. 25, 2008, provisional application
`
`No. 61/201,860, filed on Dec. 15, 2008, provisional
`application No. 61/191,933, filed on Sep. 11, 2008,
`provisional application No. 61/091,759, filed on Aug.
`26, 2008, provisional application No. 61/137,489,
`filed on Jul. 30, 2008, provisional application No.
`61/134,598, filed on Jul. 10, 2008.
`
`Publication Classification
`
`(51) Int. Cl.
`(2006.01)
`C07D 47/08
`(52) U.S. Cl. ........................................................ 544/350
`
`ABSTRACT
`(57)
`A 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 pow
`der 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, processes for preparing said Sitagliptin
`crystalline form, and pharmaceutical compositions thereof,
`are provided.
`
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`Patent Application Publication
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`Patent Application Publication
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`Patent Application Publication
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`Patent Application Publication
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`Patent Application Publication
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`Patent Application Publication
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`Feb. 18, 2010 Sheet 20 of 20
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`US 2010/0041885 A1
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`US 2010/0041885 A1
`
`Feb. 18, 2010
`
`CRYSTALLINE FORMS OF STAGLIPTN
`PHOSPHATE
`
`RELATED APPLICATIONS
`0001. 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.
`
`FIELD OF THE INVENTION
`0002 The invention encompasses crystalline forms of
`Sitagliptin phosphate, processes for preparing the crystalline
`form, and pharmaceutical compositions thereof.
`
`BACKGROUND OF THE INVENTION
`0003. Sitagliptin, (3R)-3-amino-1-9-(trifluoromethyl)-1,
`4,7,8-tetrazabicyclo4.3.0nona-6,8-dien-4-yl)-4-(2,4,5-trif
`luorophenyl)butan-1-one, has the following chemical struc
`ture:
`
`F
`
`F
`
`F
`
`NH2
`
`O
`
`Sitagliptin
`
`1-y N
`N--
`
`CF
`
`0004 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
`JANUVIATM in its monohydrate form. JANUVIATM is indi
`cated to improve glycemic control in patients with type 2
`diabetes mellitus.
`0005. The following PCT Publications describe the syn
`thesis of Sitagliptin via stereoselective reduction: WO 2004/
`087650, WO 2004/085661, and WO 2004/085378.
`0006. 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.
`0007 Polymorphism, the occurrence of different crystal
`forms, is a property of Some molecules and molecular com
`plexes. 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. Ther
`mal 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.
`0008. The difference in the physical properties of different
`crystalline forms results from the orientation and intermo
`lecular interactions of adjacent molecules or complexes in the
`bulk Solid. Accordingly, polymorphs are distinct Solids shar
`ing the same molecular formula yet having distinct advanta
`geous physical properties compared to other crystalline forms
`of the same compound or complex.
`0009. 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 gas
`trointestinal 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.
`0010. The discovery of new polymorphic forms and sol
`Vates 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. There
`fore, there is a need for additional crystalline forms of Sita
`gliptin.
`
`SUMMARY OF THE INVENTION
`0011. The present invention provides a crystalline Sita
`gliptin 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.
`0012. 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 'C NMR spectrum
`with signals at about 103.0, 121.5 and 173.2+0.2 ppm; and a
`solid-state 'C NMR spectrum having chemical shifts differ
`ences 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 exhib
`iting the lowest chemical shift in the chemical shift area of
`100 to 180 ppm is typically at about 103.0+ 1 ppm, and pro
`cesses for preparing thereof.
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`0013 The present invention further provides processes for
`the preparation of crystalline Sitagliptin phosphate Form II,
`Sitagliptin phosphate monohydrate, and amorphous Sitaglip
`tin.
`0014. The invention further provides a pharmaceutical
`formulation comprising the above described Sitagliptin phos
`phate crystalline forms. This pharmaceutical composition
`may additionally comprise at least one pharmaceutically
`acceptable excipient.
`0015 The invention further provides a pharmaceutical
`formulation comprising the above described Sitagliptin phos
`phate crystalline forms made by the processes of the present
`invention, and one or more pharmaceutically acceptable
`excipients.
`
`BRIEF DESCRIPTION OF THE FIGURES
`0016 FIG. 1 shows a powder XRD pattern of a crystalline
`form of Sitagliptin phosphate, obtained in Example 1.
`0017 FIG.2 shows a powder XRD pattern of a crystalline
`form of Sitagliptin phosphate, obtained in Example 2.
`0018 FIG. 3 shows a powder XRD pattern of a dry crys
`talline form of Sitagliptin phosphate, obtained in Example 3.
`0019 FIG. 4 shows a powder XRD pattern of a crystalline
`form of Sitagliptin phosphate, obtained in Example 4.
`0020 FIG. 5a shows a powder XRD pattern of wet crys
`talline Form II of Sitagliptin phosphate, obtained in Example
`5
`0021 FIG.5b shows a powder XRD pattern of a dry crys
`talline form of Sitagliptin phosphate, obtained in Example 5.
`0022 FIG. 6 shows a powder XRD pattern of a crystalline
`Form II of Sitagliptin phosphate, obtained in Example 33.
`0023 FIG. 7 shows a powder XRD pattern of amorphous
`Sitagliptin phosphate, obtained in Example 63.
`0024 FIG. 8 shows a powder XRD pattern of amorphous
`Sitagliptin phosphate, obtained in Example 73.
`0025 FIG.9 shows a powder XRD pattern of amorphous
`Sitagliptin phosphate, obtained in Example 74.
`0026 FIG. 10 shows a powder XRD pattern of a crystal
`line Form II of Sitagliptin phosphate, obtained in Example 78.
`0027 FIG. 11 shows a powder XRD pattern of Sitagliptin
`phosphate monohydrate, obtained in Example 84.
`0028 FIG. 12 shows a powder XRD pattern of Sitagliptin
`phosphate monohydrate, obtained in Example 86.
`0029 FIG. 13 shows a powder XRD pattern of Sitagliptin
`phosphate monohydrate, obtained in Example 87.
`0030 FIG. 14a shows a powder XRD pattern of a crystal
`line form of Sitagliptin phosphate, obtained in Example 88.
`0031
`FIG. 14b shows a powder XRD pattern of a crystal
`line form of Sitagliptin phosphate, obtained in Example 88.
`0032 FIG. 15 shows a powder XRD pattern of a crystal
`line form of Sitagliptin phosphate, obtained in Example 92.
`0033 FIG.16 shows a powder XRD pattern of crystalline
`Form II of Sitagliptin phosphate, obtained in Example 96.
`0034 FIG. 17 shows a solid-state 'PNMR spectrum of a
`crystalline form of Sitagliptin phosphate in the (-150)-(150)
`ppm range.
`0035 FIG. 18 shows a solid-state 'PNMR spectrum of a
`crystalline form of Sitagliptin phosphate in the (-20)-(20)
`ppm range.
`
`DETAILED DESCRIPTION OF THE INVENTION
`0036. 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 pat
`tern 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.
`0037. 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.
`0038. As used herein, Sitagliptin phosphate monohydrate
`refers to crystalline Sitagliptin base characterized by a pow
`der XRD pattern with peaks at about 11.8, 13.9, 16.0, 18.5,
`19.6, 22.5+0.2 degrees two theta.
`0039. As used herein, the terms “Sitagliptin phosphate'
`and “Sitagliptin dihydrophosphate' may be both used to
`describe Sitagliptin phosphate having a 1:1 ratio of Sitaglip
`tin and phosphate.
`0040. 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 solventisused in
`an amount that does not result in the full dissolution of the
`Substance.
`0041 As used herein, an “antisolvent” refers to a liquid
`that, when added to a solution of Sitagliptin bas, and phos
`phoric acid, or a solution of Sitagliptin phosphate in a solvent,
`induces precipitation of Sitagliptin phosphate.
`0042. As used herein, a “wet crystalline form” refers to a
`polymorph that was not dried using any conventional tech
`niques.
`0043. 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.
`0044 As used herein, the term “room temperature' pref
`erably 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.
`0045. 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.
`0046. The present invention provides a crystalline Sita
`gliptin 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
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`
`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.
`0047. In another embodiment, the crystalline form of Sita
`gliptin 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.
`0048. In another embodiment, the crystalline form of Sita
`gliptin 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.
`0049. In another embodiment, the crystalline form of Sita
`gliptin 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.
`0050. In another embodiment, the crystalline form of Sita
`gliptin 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.
`0051. The crystalline form of Sitagliptin phosphate is also
`characterized by the XRD diffractograms shown in FIGS. 1 to
`4, 6, 14, and 15.
`0052. 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 substan
`tially free of the (S)-enantiomer of Sitagliptin phosphate. By
`“substantially free” is meant 10% (w/w) or less, more pref
`erably 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.
`0053. 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 “sub
`stantially free’ is meant 20% (w/w) or less, preferably 10%
`(w/w) or less, more preferably 5% (w/w) or less, most pref
`erably 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.
`0054. 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 'C
`NMR spectrum with signals at about 103.0, 121.5 and 173.
`2+0.2 ppm; and a solid-state 'C 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.
`0055 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 embodi
`
`ment, Form VI is obtained as a mixture of about 77% of the
`enantiomer Rand about 23% of the enantiomer S.
`0056. In another example, the crystalline form, character
`ized 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 mix
`ture 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 phospho
`ric acid in the organic solvent.
`0057 Preferably the acetonitrile:toluene and the tetrahy
`drofuran: 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 tempera
`ture 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., prefer
`ably 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 prefer
`ably, 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.
`0058. 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
`23.70.2 degrees two theta, comprising combining Sitaglip
`tin 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:iso
`propylacetate, 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.
`0059 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.
`0060 Preferably, the mixture is heated to a temperature of
`about 45° to about 80°C., preferably to about 70° C., prefer
`ably 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 filtra
`tion.
`
`Mylan (IPR2020-00040) Ex. 1033 p. 024
`
`

`

`US 2010/0041885 A1
`
`Feb. 18, 2010
`
`0061 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 mix
`ture of the phosphoric acid in the organic solvent.
`0062. In another embodiment, the present invention
`encompasses another process for preparing the crystalline
`form of Sitagliptin phosphate of the present invention, com
`prising drying wet Form II.
`0063 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.
`0064. Wet Form II can be prepared by any method known
`in the art.
`0065 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-pro
`panol, toluene, isobutyl acetate, isopropyl acetate, isopro
`panol, a mixture of acetonitrile and n-butanol, acetonitrile,
`dimethyl carbonate, forming a slurry; and obtaining Sitaglip
`tin phosphate Form II.
`0066 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. Pref
`erably, 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 recov
`ered by any conventional method known in the art, for
`example by filtration.
`0067. 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.
`0068. In another example, wet Form II is prepared in a
`process comprising combining Sitagliptin base and phospho
`ric 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, form
`ing a mixture; crystallizing Sitagliptin phosphate from the
`mixture; and obtaining Sitagliptin phosphate Form II.
`0069 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.
`0070 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 prefer
`ably, 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 filtra
`tion.
`0071. 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 mix
`ture of the phosphoric acid in the organic solvent.
`0072. In one specific embodiment, the crystalline form of
`Sitagliptin phosphate, characterized by a powder XRD pat
`tern 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, dim
`ethyl carbonate, tetrahydrofuran, acetonitrile, propylene gly
`col methyl ether, methanol, n-butanol, 1-propanol, toluene,
`isobutyl acetate, isopropyl acetate, butyl acetate, isopropanol,
`dimethyl carbonate, n-hexane, acetone, cyclohexane, isobu
`tyl acetate, and mixtures thereof.
`0073. 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 Sita
`gliptin 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.
`0074. In another embodiment, the present invention
`encompasses another process for preparing crystalline Sita
`gliptin 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 character
`ized 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 pref
`erably about 35° C. to about 50° C.
`0075. In another embodiment, the present invention
`encompasses