SOLID DISPERSIONS OF SITAGLIPTIN AND PROCESSES FOR THEIR
PREPARATION
Field of the Invention
The present invention provides processes for the preparation of amorphous form of
sitagliptin dihydrogen phosphate. It also provides a solid dispersion of sitagliptin
dihydrogen phosphate, including in the amorphous form, and a process for its preparation.
Background of the Invention
Sitagliptin dihydrogen phosphate monohydrate of Formula A, an orally-active
inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, chemically designated as 7-[(3R)-
3-amino- l-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-
l ,2,4-triazolo[4,3-a]pyrazine phosphate ( 1:1) monohydrate is indicated as an adjunct to
diet and exercise to improve glycemic control in adults with Type 2 diabetes mellitus.
Formula A
U.S. Patent No. 6,699,87 1, in particular Example 7, provides a process for the
preparation of sitagliptin base and its hydrochloride salt.
U.S. Patent No. 7,326,708 provides a process for the preparation of sitagliptin
dihydrogen phosphate monohydrate.
PCT Publication WO 2006/033848 provides a process for the preparation of
amorphous sitagliptin dihydrogen phosphate which involves dissolving sitagliptin
dihydrogen phosphate monohydrate in water and filtering to get a clear solution. The
solution thus obtained was then frozen under a dry ice/methanol bath and then pulled
under vacuum to remove the solvent to provide a fluffy, white amorphous solid of
sitagliptin dihydrogen phosphate.
PCT Publication WO 2009/120746 provides a process for the preparation of
sitagliptin dihydrogen phosphate in amorphous form. t involves slurrying sitagliptin base
Form I in diethyl carbonate at 25°C followed by the addition of phosphoric acid under
stirring at 25°C for 10 minutes. The reaction mixture is then filtered under vacuum to
provide the amorphous form of sitagliptin phosphate. Another method involves slurrying
sitagliptin base Form I in dimethyl carbonate at 50°C followed by addition of phosphoric
acid under stirring at 50°C for 8 minutes. The reaction mixture is then filtered under
vacuum to provide the amorphous form of sitagliptin phosphate.
Several processes are known in the literature for the preparation of sitagliptin or a
salt thereof, for example, U.S. Publication No. 2009/0247532; PCT Publication Nos. WO
2010/097420; WO 201 1/025932; WO 2010/122578; WO 2010/032264; WO
2010/131025; WO 2009/085990; WO 2005/020920; WO 2005/030127; WO
2004/085661; WO 2004/087650; WO 2006/065826; WO 2004/083212; and WO
2004/080958.
In the pharmaceutical industry there is a constant need to work on identifying
different pharmaceutical compositions that positively affect the drug's dissolution profile,
bioavailability, bioequivalence, stability, etc., which all play important roles in
determining a drug's market acceptance and success.
In the case of sitagliptin too, there is a need for the development of pharmaceutical
compositions with improved solubility, stability, excellent storage and handling stabilities,
bioavailability, etc.
The present inventors have developed processes for the preparation of the
amorphous form of sitagliptin dihydrogen phosphate. However, the present inventors
found that sitagliptin dihydrogen phosphate in its amorphous form has a tendency to
undergo crystallization at about 50% relative humidity (herein after "RH") and 25°C in a
time period of about 4 days. Under certain circumstances, especially from a regulatory
point of view, such interconversion is generally undesired.
The present inventors have surprisingly found that a solid dispersion of sitagliptin
dihydrogen phosphate exhibits enhanced stability under humid conditions compared to
amorphous sitagliptin dihydrogen phosphate, thus providing a viable solid dispersion
product that eliminates the problem described above.
Summary of the Invention
A first aspect of the present invention provides a process for the preparation of
amorphous sitagliptin dihydrogen phosphate which comprises:
a) obtaining a solution of sitagliptin dihydrogen phosphate;
b) removing the solvent from the solution obtained in step a) by spray drying; and
c) collecting sitagliptin dihydrogen phosphate in amorphous form.
A second aspect of the present invention provides a process for the preparation of
amorphous sitagliptin dihydrogen phosphate which comprises:
a) obtaining a solution of sitagliptin dihydrogen phosphate;
b) removing the solvent from the solution obtained in step a) by agitated thin film
drying; and
c) collecting sitagliptin dihydrogen phosphate in amorphous form.
A third aspect of the present invention provides an amorphous solid dispersion of
sitagliptin dihydrogen phosphate.
A fourth aspect of the present invention provides a process for the preparation of a
solid dispersion of sitagliptin dihydrogen phosphate which comprises:
a) combining sitagliptin dihydrogen phosphate with one or more pharmaceutically
acceptable carriers; and
b) isolating a solid dispersion of amorphous sitagliptin dihydrogen phosphate.
A fifth aspect of the present invention provides a method of treating or preventing
Type 2 diabetes mellitus which comprises administering to a patient in need thereof a
therapeutically effective amount of solid dispersion of sitagliptin dihydrogen phosphate.
Detailed Description of the Invention
The sitagliptin dihydrogenphosphate prepared by any of the methods known in the
art including those described in, for example, U.S. Patent No. 7,326,708; U.S. Publication
No. 2009/0247532; PCT Publication Nos. WO 2010/131025; WO 2004/083212; WO
2006/065826; WO 2010/097420; WO 2004/080958; WO 2004/087650; WO
2004/085661; WO 2005/072530; WO 2005/030127; WO 2005/020920; WO
2007/035198; WO 2008/000418; WO 2009/120746; WO 2006/033848; WO
2009/085990; WO 2010/032264; WO 2010/000469; WO 2010/012781; WO
2010/1 17738; WO 2010/092090; and WO 2010/122578; or amorphous sitagliptin
dihydrogen phosphate prepared by the process of the present invention may be used as the
starting material.
A first aspect of the present invention provides a process for the preparation of
amorphous sitagliptin dihydrogen phosphate which comprises:
a) obtaining a solution of sitagliptin dihydrogen phosphate;
b) removing the solvent from the solution obtained in step a) by spray drying; and
c) collecting sitagliptin dihydrogen phosphate in amorphous form.
Embodiments of this aspect may include the following features:
A solution of sitagliptin dihydrogen phosphate can be obtained by treating
sitagliptin dihydrogen phosphate with one or more solvent.
The term "solvent" includes any solvent or solvent mixture, including, for
example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic
solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl
acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and
tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include
methanol, ethanol, n-propanol, isopropanol and butanol. Examples of halogenated
hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of
ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include
diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one
or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide,
acetonitrile and N-methylpyrrolidone.
Treating sitagliptin dihydrogen phosphate with one or more solvents may include
adding, dissolving, slurrying, stirring, or a combination thereof.
Sitagliptin dihydrogen phosphate may be treated with solvent at a temperature of
about 25°C to reflux temperature.
The amount of solvent can be about 5 times to 20 times the quantity of sitagliptin
dihydrogen phosphate.
The solution of sitagliptin dihydrogen phosphate obtained in step a) may be
optionally clarified to remove foreign particulate matter or treated with activated charcoal
to remove coloring and other related impurities. The solution of sitagliptin dihydrogen
phosphate may be optionally concentrated to reduce the amount of solvent.
Step b) of removing the solvent from the solution obtained in step a) by spray
drying involves feeding the solution obtained in step a) to a spray drying apparatus. The
inlet and outlet temperatures, feed rate, and atomizer type can be adjusted to optimize
output and particle size.
The air inlet temperature is preferably controlled at from about 70°C to about
130°C. The outlet temperature is preferably controlled at from about 30°C to about 65°C.
An inert gas, for example nitrogen gas, can be used as a carrier gas.
After the drying process, the amorphous sitagliptin dihydrogen phosphate is
collected from the spray dryer using techniques such as by scraping, or by shaking the
container or other techniques specific to the equipment used.
A second aspect of the present invention provides a process for the preparation of
amorphous sitagliptin dihydrogen phosphate which comprises:
a) obtaining a solution of sitagliptin dihydrogen phosphate;
b) removing the solvent from the solution obtained in step a) by agitated thin film
drying; and
c) collecting sitagliptin dihydrogen phosphate in amorphous form.
Embodiments of this aspect may include the following features:
A solution of sitagliptin dihydrogen phosphate can be obtained by treating
sitagliptin dihydrogen phosphate with one or more solvents.
Treating sitagliptin dihydrogen phosphate with one or more solvents may include
adding, dissolving, slurrying, stirring, or a combination thereof.
The term "solvent" includes any solvent or solvent mixture, including, for
example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic
solvents, or mixtures thereof.
The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl
acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and
tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include
methanol, ethanol, n-propanol, isopropanol and butanol. Examples of halogenated
hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of
ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include
diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one
or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide,
acetonitrile and N-methylpyrrolidone.
Sitagliptin dihydrogen phosphate may be treated with solvent at a temperature of
about 25°C to reflux temperature.
The amount of solvent can be about 5 times to 20 times the quantity of sitagliptin
dihydrogen phosphate.
The solution of sitagliptin dihydrogen phosphate obtained in step a) may be
optionally clarified to remove foreign particulate matter or treated with activated charcoal
to remove coloring and other related impurities. The solution of sitagliptin dihydrogen
phosphate may be optionally concentrated to reduce the amount of solvent.
Step b) of removing the solvent from the solution obtained in step a) by agitated
thin film drying involves feeding the solution obtained in step a) to an agitated thin film
dryer. The solvent is subsequently removed from the solution by agitated thin film drying
by heating at a temperature of about 35°C or above. The feeding rate of the solution is
controlled in such a way as to facilitate the thin film formation and the evaporation rate.
The rotor and vapor duct can have a sealing system so that the drying can preferably be
carried out under vacuum. Vacuum operation also facilitates amorphous sitagliptin
dihydrogen phosphate to be obtained without degradation.
The amorphous sitagliptin dihydrogen phosphate is collected from the agitated thin
film dryer using techniques such as by scraping, or by shaking the container, or other
techniques specific to the equipment used.
The amorphous sitagliptin dihydrogen phosphate can optionally be further dried
under vacuum to obtain amorphous sitagliptin dihydrogen phosphate with desired residual
solvent content.
A third aspect of the present invention provides a solid dispersion of sitagliptin
dihydrogen phosphate.
The solid dispersion of sitagliptin dihydrogen phosphate of the present invention
may be amorphous.
The solid dispersion of sitagliptin dihydrogen phosphate of the present invention
comprises sitagliptin dihydrogen phosphate and one or more pharmaceutically acceptable
carriers.
Pharmaceutically acceptable carrier is preferably a polymeric carrier, and more
preferably is at least one from the group consisting of gelatines, ovalbumin, soybean
proteins, gum arabic, non-sucrose fatty acid esters, starches, modified starches, cellulose,
methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC),
hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polycarbophil,
polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives,
polymethacrylates, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), PVPvinylacetate-
copolymer (PVP-VA), Kollidon® VA 64 (a vinylpyrrolidone -vinyl acetate
copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such
as cc-cyclodextrins, b-cyclodextrins, g -cyclodextrins, hydroxyl-propyl-cyclodextrins,
hydroxypropyl -P-cyclodextrin (HPpCD), sodium carboxymethyl cellulose, sodium
alginate, xantham gum, locust bean gum (ceratonia), chitosan, cross-linked high amylase
starch, cross-linked polyacrylic acid (carbopol), or a mixture thereof.
The amount of sitagliptin dihydrogen phosphate in the solid dispersion of the
present invention ranges from about 0.1% to about 95% by weight relative to the total
weight of the solid dispersion. In a preferred embodiment, the amount of sitagliptin
dihydrogen phosphate ranges from about 1% to about 70%, more preferably from about
10% to about 50% by weight relative to the total weight of the solid dispersion.
The amorphous solid dispersion of sitagliptin dihydrogen phosphate of the present
invention is stable during storage.
In a preferred embodiment, the polymeric carrier suitable for the preparation of a
solid dispersion of sitagliptin dihydrogen phosphate is HP CD.
The solid dispersion of sitagliptin dihydrogen phosphate with HP CD is in the
amorphous form.
The amorphous solid dispersion of sitagliptin dihydrogen phosphate with HRbO
of the present invention has a characteristic XRD pattern substantially as depicted in
Figure 4.
The amorphous solid dispersion of sitagliptin dihydrogen phosphate with HRbO
of the present invention has a characteristic XRD pattern substantially as depicted in
Figure 5.
The amorphous solid dispersion of sitagliptin dihydrogen phosphate with HRbO
of the present invention has a characteristic XRD pattern substantially as depicted in
Figure 6.
The amorphous solid dispersion of sitagliptin dihydrogen phosphate with HP CD
of the present invention is stable for at least 4 days when exposed to a temperature of
about 25°C and a relative humidity of about 50% and has a characteristic XRD pattern
substantially as depicted in Figure 13.
The amorphous solid dispersion of sitagliptin dihydrogen phosphate with HP CD
of the present invention is stable for at least 10 days when exposed to a temperature of
about 25°C and a relative humidity of 50% and has a characteristic XRD pattern
substantially as depicted in Figure 14.
The amorphous solid dispersion of sitagliptin dihydrogen phosphate with HP CD
of the present invention is stable for at least two months when kept in a double-sealed
polybag at about 25°C to 32°C and has a characteristic XRD pattern substantially as
depicted in Figure 15.
In another preferred embodiment, the polymeric carrier suitable for the preparation
of solid dispersion of sitagliptin dihydrogen phosphate is polyvinylpyrrolidone (PVP).
The solid dispersion of sitagliptin dihydrogen phosphate with polyvinylpyrrolidone
is in amorphous form.
The amorphous solid dispersion of sitagliptin dihydrogen phosphate with
polyvinylpyrrolidone (PVP) of the present invention has a characteristic XRD pattern
substantially as depicted in Figure 7.
The amorphous solid dispersion of sitagliptin dihydrogen phosphate with
polyvinylpyrrolidone (PVP) of the present invention has a characteristic XRD pattern
substantially as depicted in Figure 8.
The amorphous solid dispersion of sitagliptin dihydrogen phosphate with
polyvinylpyrrolidone (PVP) of the present invention has a characteristic XRD pattern
substantially as depicted in Figure 9.
The amorphous solid dispersion of sitagliptin dihydrogen phosphate with
polyvinylpyrrolidone (PVP) of the present invention is stable for at least 4 days when
exposed to a temperature of about 25°C and a relative humidity of about 50% and has a
characteristic XRD pattern substantially as depicted in Figure 16.
The amorphous solid dispersion of sitagliptin dihydrogen phosphate with
polyvinylpyrrolidone (PVP) of the present invention is stable for at least 10 days when
exposed to a temperature of about 25°C and a relative humidity of 50% and has a
characteristic XRD pattern substantially as depicted in Figure 17.
The amorphous solid dispersion of sitagliptin dihydrogen phosphate with
polyvinylpyrrolidone (PVP) of the present invention is stable for at least two months when
kept in double-sealed polybags at about 25°C to 32°C and has a characteristic XRD
pattern substantially as depicted in Figure 18.
A fourth aspect of the present invention provides a process for the preparation of a
solid dispersion of sitagliptin dihydrogen phosphate which comprises:
a) combining sitagliptin dihydrogen phosphate with one or more pharmaceutically
acceptable carriers; and
b) isolating solid dispersion of amorphous sitagliptin dihydrogen phosphate.
Combining sitagliptin dihydrogen phosphate with one or more pharmaceutically
acceptable carriers may include adding, dissolving, slurrying, stirring or a combination
thereof in a solvent at a temperature of about 25°C to reflux temperature.
The term "solvent" includes any solvent or solvent mixture, including for example,
water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents,
or mixtures thereof.
The esters may include one or more of ethyl acetate, n-propyl acetate, isopropyl
acetate, and n-butyl acetate. Examples of alkanols include those primary, secondary and
tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include
methanol, ethanol, n-propanol, isopropanol and butanol. Examples of halogenated
hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of
ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include
diethyl ether, tetrahydrofuran, and the like. A suitable polar aprotic solvent includes one
or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide,
acetonitrile and N-methylpyrrolidone.
The pharmaceutically acceptable carrier is preferably a polymeric carrier, and more
preferably is at least one from the group consisting of gelatines, ovalbumin, soybean
proteins, gum arabic, non-sucrose fatty acid esters, starches, modified starches, cellulose,
methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC),
hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polycarbophil,
polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives,
polymethacrylates, polyvinyl pyrrolidone (PVP), polyvinyl acetate (PVAc), PVPvinylacetate-
copolymer (PVP-VA), Kollidon® VA 64 (a vinylpyrrolidone -vinyl acetate
copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such
as cc-cyclodextrins, b-cyclodextrins, g -cyclodextrins, hydroxyl-propyl-cyclodextrins,
hydroxypropyl -P-cyclodextrin (HRbO ), sodium carboxymethyl cellulose, sodium
alginate, xantham gum, locust bean gum (ceratonia), chitosan, cross-linked high amylase
starch, cross-linked polyacrylic acid (carbopol), or a mixture thereof.
In a preferred embodiment, the polymeric carrier suitable for the preparation of
solid dispersion of sitagliptin dihydrogen phosphate is polyvinylpyrrolidone (PVP) or
HP CD.
Step b) of isolating the solid dispersion of sitagliptin dihydrogen phosphate
involves spray drying, lyophilization, agitated thin film drying or melt extrusion.
Isolating the solid dispersion of sitagliptin dihydrogen phosphate by spray drying
involves feeding the solution obtained in step a) to a spray drying apparatus. The inlet and
outlet temperatures, feed rate, and atomizer type can be adjusted to optimize output and
particle size.
The air inlet temperature is preferably controlled at from about 70°C to about
140°C. The outlet temperature is preferably controlled at from about 30°C to about 65°C.
An inert gas, for example nitrogen gas, can be used optionally as a carrier gas.
After the drying process, the solid dispersion of sitagliptin dihydrogen phosphate is
collected from the spray dryer using techniques such as by scraping, or by shaking the
container, or other techniques specific to the equipment used and optionally further dried
under vacuum to obtain amorphous sitagliptin dihydrogen phosphate.
Isolating a solid dispersion of sitagliptin dihydrogen phosphate by agitated thin
film drying involves feeding the solution obtained in step a) to an agitated thin film dryer.
The solvent is subsequently removed from the solution by agitated thin film drying by
heating at a temperature of about 35°C or above. The feeding rate of the solution is
controlled in such a way to facilitate the thin film formation and the evaporation rate. The
rotor and vapor duct can have a sealing system so that the drying can preferably be carried
out under vacuum. Vacuum operation also facilitates solid dispersion of sitagliptin
dihydrogen phosphate to be obtained without degradation.
The solid dispersion of sitagliptin dihydrogen phosphate is collected from the
agitated thin film dryer using techniques such as by scraping, or by shaking the container
or other techniques specific to the equipment used.
The solid dispersion of sitagliptin dihydrogen phosphate may optionally be
micronized to obtain the micronized amorphous solid dispersion of sitagliptin dihydrogen
phosphate by suitable methods known in the art.
The solid dispersion of sitagliptin dihydrogen phosphate isolated by any of the
methods above may be formulated into pharmaceutical compositions by further processing
with one or more pharmaceutically inert excipients such as one or more of diluents,
binders, disintegrants, coloring agents, flavoring agents, stabilizers, lubricants/glidants and
plasticizers.
A fifth aspect of the present invention provides a method of treating or preventing
Type 2 diabetes mellitus which comprises administering to a patient in need thereof a
therapeutically effective amount of solid dispersion of sitagliptin dihydrogen phosphate.
Brief Description of the Figures
Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of amorphous
sitagliptin dihydrogen phosphate, prepared as per Example 1.
Figure 2 depicts the X-Ray Powder Diffractogram (XRPD) of amorphous
sitagliptin dihydrogen phosphate, prepared as per Example 2.
Figure 3 depicts the X-Ray Powder Diffractogram (XRPD) of amorphous
sitagliptin dihydrogen phosphate, prepared as per Example 3.
Figure 4 depicts the X-Ray Powder Diffractogram (XRPD) of an amorphous solid
dispersion of sitagliptin dihydrogen phosphate with HP CD, prepared as per Example 4.
Figure 5 depicts the X-Ray Powder Diffractogram (XRPD) of an amorphous solid
dispersion of sitagliptin dihydrogen phosphate with HP CD, prepared as per Example 5.
Figure 6 depicts the X-Ray Powder Diffractogram (XRPD) of an amorphous solid
dispersion of sitagliptin dihydrogen phosphate with HP CD, prepared as per Example 6.
Figure 7 depicts the X-Ray Powder Diffractogram (XRPD) of an amorphous solid
dispersion of sitagliptin dihydrogen phosphate with polyvinylpyrrolidone (PVP), prepared
as per Example 7.
Figure 8 depicts the X-Ray Powder Diffractogram (XRPD) of an amorphous solid
dispersion of sitagliptin dihydrogen phosphate with polyvinylpyrrolidone (PVP), prepared
as per Example 8.
Figure 9 depicts the X-Ray Powder Diffractogram (XRPD) of an amorphous solid
dispersion of sitagliptin dihydrogen phosphate with polyvinylpyrrolidone (PVP), prepared
as per Example 9.
Figure 10 depicts the X-Ray Powder Diffractogram (XRPD) of amorphous
sitagliptin dihydrogen phosphate stored at 50% RH and 25°C for 4 days.
Figure 11 depicts the X-Ray Powder Diffractogram (XRPD) of amorphous
sitagliptin dihydrogen phosphate stored at 50% RH and 25°C for 10 days.
Figure 12 depicts the X-Ray Powder Diffractogram (XRPD) of amorphous
sitagliptin dihydrogen phosphate stored in a double-sealed polybag at 25°C to 32°C after
two months.
Figure 13 depicts the X-Ray Powder Diffractogram (XRPD) of an amorphous solid
dispersion of sitagliptin dihydrogen phosphate with HRbO stored at 50% RH and 25°C
for 4 days.
Figure 14 depicts the X-Ray Powder Diffractogram (XRPD) of an amorphous solid
dispersion of sitagliptin dihydrogen phosphate with HP CD stored at 50% RH and 25°C
for 10 days.
Figure 15 depicts the X-Ray Powder Diffractogram (XRPD) of an amorphous solid
dispersion of sitagliptin dihydrogen phosphate with HP CD stored in a double-sealed
polybags at 25°C to 32°C for two months.
Figure 16 depicts the X-Ray Powder Diffractogram (XRPD) of an amorphous solid
dispersion of sitagliptin dihydrogen phosphate with polyvinyl pyrrolidone (PVP) stored at
50% RH and 25°C for 4 days.
Figure 17 depicts the X-Ray Powder Diffractogram (XRPD) of an amorphous solid
dispersion of sitagliptin dihydrogen phosphate with polyvinyl pyrrolidone (PVP) stored at
50% RH and 25°C for 10 days.
Figure 18 depicts the X-Ray Powder Diffractogram (XRPD) of an amorphous solid
dispersion of sitagliptin dihydrogen phosphate with polyvinyl pyrrolidone (PVP) stored in
a double sealed polybag at 25°C to 32°C for two months.
The X-ray powder diffractograms (XRPD) of the samples were determined by
using Instrument: PANalytical; Mode: Expert PRO; Detector: Xcelerator; ScanRange: 3-
40; Step size: 0.02; Range: 3-40° 2 theta; CuKa radiation at 45kV.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the
art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1: Preparation of Amorphous Sitagliptin Dihydrogen Phosphate
Sitagliptin dihydrogen phosphate (5.02 g) was dissolved in methanol (250 ml) by
heating at about 65°C. The solution was spray dried under the following conditions:
Air Inlet temperature: 100°C
Air Outlet temperature: 49°C
The solid so obtained was collected from the spray dryer and dried in a vacuum
tray drier at 50°C for 4 hours to obtain the titled compound having an XRPD pattern as
depicted in Figure 1.
Yield: 2.89 g
Example 2 : Preparation of Amorphous Sitagliptin Dihydrogen Phosphate
Sitagliptin dihydrogen phosphate (10.03 g) was dissolved in water (100 ml) by
heating at about 65°C. The solution was spray dried under the following conditions:
Air Inlet temperature: 130°C
Air Outlet temperature : 61°C
The solid so obtained was collected from the spray dryer and dried in a vacuum
tray drier at 60°C for 6 hours to obtain the titled compound having an XRPD pattern as
depicted in Figure 2.
Yield: 6.29 g
0.52 g of the product obtained as per Example 2 was stored in double sealed
polybags in a humidity chamber maintained at 50% RH and 25°C for 4 days to evaluate
the stability. The XRPD pattern of the compound stored at 50% RH and 25°C for 4 days
is depicted in Figure 10.
0.54 g of the product obtained as per Example 2 was stored in double sealed
polybags in a humidity chamber maintained at 50% RH and 25°C for 10 days to evaluate
the stability. The XRPD pattern of the compound stored at 50% RH and 25°C for 10 days
is depicted in Figure 11.
The remaining product obtained as per Example 2 was stored in double-sealed
polybags at 25°C to 32°C for two months to evaluate the stability. The XRPD pattern of
the compound stored in a double sealed polybag at 25°C to 32°C after two months is
depicted in Figure 12.
Example 3 : Preparation of Amorphous Sitagliptin Dihydrogen Phosphate
Sitagliptin dihydrogen phosphate ( 1.50 g) was dissolved in 20 ml water. The
solvent was distilled off on a Buchi rotovap set at ~75°C and 250 rpm under vacuum. The
solid so obtained was collected and dried in a vacuum tray drier at 50°C for 4 hours to
obtain the titled compound having an XRPD pattern as depicted in Figure 3.
Yield: 1.12 g
Example 4 : Preparation of Amorphous Solid Dispersion of Sitagliptin Dihydrogen
Phosphate with Hrboά
Sitagliptin dihydrogen phosphate (5.02 g) and HP CD (5.01 g) were dissolved in
100 ml water by heating at about 65°C. The solution thus obtained was spray dried under
the following conditions:
Air Inlet temperature: 130°C
Air Outlet temperature: 63°C
The solid so obtained was collected from the spray dryer and dried in a vacuum
tray drier at 60°C for 6 hours to obtain the titled compound having an XRPD pattern as
depicted in Figure 4.
Yield: 6.26 g
Example 5 : Preparation of Amorphous Solid Dispersion of Sitagliptin Dihydrogen
Phosphate with HP CD
Sitagliptin dihydrogen phosphate (5.04 g) and HP CD (5.09 g) were dissolved in
water (100 ml) by heating at about 65°C. The solution thus obtained was spray dried
under the following conditions:
Air Inlet temperature: 130°C
Air Outlet temperature: 61°C
The solid so obtained was collected from the spray dryer and dried in a vacuum
tray drier at 60°C for 6 hours to obtain the titled compound having an XRPD pattern as
depicted in Figure 5.
Yield: 5.49 g
0.54 g of the product obtained as per Example 5 was stored in double-sealed
polybags in a humidity chamber maintained at 50% RH and 25°C for 4 days to evaluate
the stability. The XRPD pattern of the product stored at 50% RH and 25°C for 4 days is
depicted in Figure 13.
0.53 g of the product obtained as per Example 5 was stored in double-sealed
polybags in a humidity chamber maintained at 50% RH and 25°C for 10 days to evaluate
the stability. The XRPD pattern of the product stored at 50% RH and 25°C for 10 days is
depicted in Figure 14.
The remaining product obtained as per Example 5 was stored in a double-sealed
polybags at 25°C to 32°C for two months to evaluate the stability. The XRPD pattern of
the product stored in a double sealed polybag at 25°C to 32°C for two months is depicted
in Figure 15.
Example 6 : Preparation of Amorphous Solid Dispersion of Sitagliptin Dihydrogen
Phosphate with HP CD
Sitagliptin dihydrogen phosphate (1.02 g) and HP CD (0.99 g) were dissolved in
methanol (60 ml). The solvent was distilled off on a Buchi rotovap set at ~65°C and 250
rpm under vacuum. The solid so obtained was collected and dried in a vacuum tray drier
at 50°C for 4 hours to obtain the titled compound having an XRPD pattern as depicted in
Figure 6.
Yield: 1.61 g
Example 7 : Preparation of Amorphous Solid Dispersion of Sitagliptin Dihydrogen
Phosphate with PVP
Sitagliptin dihydrogen phosphate (5.03 g) and PVP (5.01 g) were dissolved in
water (100 ml) by heating at about 65°C. The solution thus obtained was spray dried
under the following conditions:
Air Inlet temperature: 130°C
Air Outlet temperature: 54°C
The solid so obtained was collected from the spray dryer and dried in a vacuum
tray drier at 60°C for 6 hours to obtain the titled compound having an XRPD pattern as
depicted in Figure 7.
Yield: 5.29 g
Example 8: Preparation of Amorphous Solid Dispersion of Sitagliptin Dihydrogen
Phosphate with PVP
Sitagliptin dihydrogen phosphate (5.15 g) and PVP (5.1 g) were dissolved in water
(100 ml) by heating at about 65°C. The solution thus obtained was spray dried under the
following conditions:
Air Inlet temperature: 130°C
Air Outlet temperature: 61°C
The solid so obtained was collected from the spray dryer and dried in a vacuum
tray drier at 60°C for 6 hours to obtain the titled compound having an XRPD pattern as
depicted in Figure 8.
Yield: 5.24 g
0.5 1 g of the product obtained as per Example 8 was stored in double-sealed
polybags in a humidity chamber maintained at 50% RH and 25°C for 4 days to evaluate
the stability. The XRPD pattern of the product stored at 50% RH and 25°C for 4 days is
depicted in Figure 16.
0.50 g of the product obtained as per Example 8 was stored in double-sealed
polybags in a humidity chamber maintained at 50% RH and 25°C for 10 days to evaluate
the stability. The XRPD pattern of the product stored at 50% RH and 25°C for 10 days is
depicted in Figure 17.
The remaining product obtained as per Example 8 was stored in double-sealed
polybags at 25°C to 32°C for two months to evaluate the stability. The XRPD pattern of
the product stored in double sealed polybags at 25°C to 32°C for two months is depicted in
Figure 18.
Example 9 : Preparation of Amorphous Solid Dispersion of Sitagliptin Dihydrogen
Phosphate with PVP
Sitagliptin dihydrogen phosphate (1.5 g) and PVP (1.01 g) were dissolved in water
(40 ml). The solvent was distilled off on a Buchi rotovap set at ~65°C and 250 rpm under
vacuum. The solid so obtained was collected and dried in a vacuum tray drier at 50°C for
4 hours to obtain the titled compound having an XRPD pattern as depicted in Figure 9.
Yield: 1.89 g

CLAIMS:
1. A process for the preparation of amorphous sitagliptin dihydrogen phosphate
comprising the steps of:
a) obtaining a solution of sitagliptin dihydrogen phosphate;
b) removing the solvent from the solution obtained in step a) by spray drying; and
c) collecting sitagliptin dihydrogen phosphate in amorphous form.
2. A process according to claim 1, wherein the solution of sitagliptin dihydrogen
phosphate is obtained by treating sitagliptin dihydrogen phosphate with one or more
solvents.
3. A process according to claim 2, wherein the solvent is selected from water, esters,
alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents or mixtures
thereof.
4. A process according to claim 3, wherein the ester is selected from the group
consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
5. A process according to claim 3, wherein the alkanol is selected from the group
consisting of methanol, ethanol, n-propanol, isopropanol and butanol.
6. A process according to claim 3, wherein the halogenated hydrocarbon is selected
from the group consisting of dichloromethane, chloroform, and 1,2-dichloroethane.
7. A process according to claim 3, wherein the ketone is selected from the group
consisting of acetone and methyl ethyl ketone.
8. A process according to claim 3, wherein the ether is selected from the group
consisting of diethyl ether and tetrahydrofuran.
9. A process according to claim 3, wherein the polar aprotic solvent is selected from
the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide,
dimethylsulphoxide, acetonitrile, N-methylpyrrolidone and mixtures thereof.
10. A process according to claim 2, wherein sitagliptin dihydrogen phosphate is treated
with the solvent at a temperature of about 25°C to reflux temperature.
11. A process according to claim 2, wherein the amount of solvent is about 5 times to
20 times the quantity of sitagliptin dihydrogen phosphate.
12. A process according to claim 1, wherein step b) involves feeding the solution
obtained in step a) to a spray drying apparatus having air inlet temperature from about
70°C to about 130°C and the outlet temperature from about 30°C to about 65°C.
13. A process for the preparation of amorphous sitagliptin dihydrogen phosphate
comprising the steps of:
a) obtaining a solution of sitagliptin dihydrogen phosphate;
b) removing the solvent from the solution obtained in step a) by agitated thin film
drying; and
c) collecting sitagliptin dihydrogen phosphate in amorphous form.
14. A process according to claim 13, wherein the solution of sitagliptin dihydrogen
phosphate is obtained by treating sitagliptin dihydrogen phosphate with one or more
solvents.
15. A process according to claim 14, wherein the solvent is selected from the group
consisting of water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar
aprotic solvents, and mixtures thereof.
16. A process according to claim 15, wherein the ester is selected from the group
consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
17. A process according to claim 15, wherein the alkanol is selected from the group
consisting of methanol, ethanol, n-propanol, isopropanol and butanol.
18. A process according to claim 15, wherein the halogenated hydrocarbon is selected
from the group consisting of dichloromethane, chloroform, and 1,2-dichloroethane.
19. A process according to claim 15, wherein the ketone is selected from the group
consisting of acetone and methyl ethyl ketone.
20. A process according to claim 15, wherein the ether is selected from the group
consisting of diethyl ether and tetrahydrofuran.
21. A process according to claim 15, wherein the polar aprotic solvent is selected from
the group consisting of N ,N -dimethylformamide, N,N-dimethylacetamide,
dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
22. A process according to claim 14, wherein sitagliptin dihydrogen phosphate is
treated with solvent at a temperature of about 25°C to reflux temperature.
23. A process according to claim 14, wherein the amount of solvent is about 5 times to
20 times the quantity of sitagliptin dihydrogen phosphate.
24. A process according to claim 13, wherein step b) involves feeding the solution
obtained in step a) to an agitated thin film dryer.
25. A process according to claim 13, wherein step b) involves removing the solvent
from the solution by agitated thin film drying by heating at a temperature of about 35°C or
above.
26. A solid dispersion of sitagliptin dihydrogen phosphate.
27. The solid dispersion of claim 26 in amorphous form.
28. The solid dispersion of claim 26 comprising one or more of pharmaceutically
acceptable carriers.
29. The solid dispersion of claim 28, wherein the pharmaceutically acceptable carrier
is polyvinyl pyrrolidone (PVP) or hydroxypropyl -P-cyclodextrin (HRbO ) .
30. The solid dispersion of claim 28, wherein the amount of sitagliptin dihydrogen
phosphate is from about 0.1% to about 95% by weight relative to the total weight of the
solid dispersion.
3 1. A solid dispersion of sitagliptin dihydrogen phosphate with HRbO in amorphous
form.
32. The amorphous solid dispersion of claim 3 1, having a characteristic XRPD pattern
substantially as depicted in Figure 4 .
33. The amorphous solid dispersion of claim 3 1, having a characteristic XRPD pattern
substantially as depicted in Figure 5.
34. The amorphous solid dispersion of claim 3 1, having a characteristic XRPD pattern
substantially as depicted in Figure 6.
35. The amorphous solid dispersion of claim 3 1, which is stable for at least 4 days
when exposed to a temperature of about 25°C and a relative humidity of about 50% and
has a characteristic XRPD pattern substantially as depicted in Figure 13.
36. The amorphous solid dispersion of claim 31, which is stable for at least 10 days
when exposed to temperature of about 25°C and a relative humidity of 50% and has a
characteristic XRPD pattern substantially as depicted in Figure 14.
37. The amorphous solid dispersion of claim 31, which is stable for at least two
months when kept in double sealed polybags at about 25°C to 32°C and has a
characteristic XRPD pattern substantially as depicted in Figure 15.
38. A solid dispersion of sitagliptin dihydrogen phosphate with polyvinylpyrrolidone
(PVP) in amorphous form.
39. The solid dispersion of claim 38, having a characteristic XRPD pattern
substantially as depicted in Figure 7.
40. The solid dispersion of claim 38, having a characteristic XRPD pattern
substantially as depicted in Figure 8.
41. The solid dispersion of claim 38, having a characteristic XRPD pattern
substantially as depicted in Figure 9.
42. The solid dispersion of claim 38, which is stable for at least 4 days when exposed
to temperature of about 25°C and a relative humidity of about 50% and has a characteristic
XRPD pattern substantially as depicted in Figure 16.
43. Solid dispersion of claim 38, which is stable for at least 10 days when exposed to
temperature of about 25°C and a relative humidity of 50% and has a characteristic XRPD
pattern substantially as depicted in Figure 17.
44. The solid dispersion of claim 38, which is stable for at least two months when kept
in double sealed polybags at about 25°C to 32°C and has a characteristic XRPD pattern
substantially as depicted in Figure 18.
45. A process for the preparation of a solid dispersion of sitagliptin dihydrogen
phosphate comprising the steps of:
a) combining sitagliptin dihydrogen phosphate with one or more pharmaceutically
acceptable carriers; and
b) isolating solid dispersion of amorphous sitagliptin dihydrogen phosphate.
46. The process according to claim 45, wherein combining sitagliptin dihydrogen
phosphate with one or more pharmaceutically acceptable carriers includes at least one of
the steps of adding, dissolving, slurrying, or stirring in a solvent at a temperature of about
25°C to reflux temperature.
47. The process according to claim 46, wherein the solvent is selected from the group
consisting of water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar
aprotic solvents, or mixtures thereof.
48. The process according to claim 47, wherein the ester is selected from the group
consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
49. The process according to claim 47, wherein the alkanol is selected from the group
consisting of methanol, ethanol, n-propanol, isopropanol and butanol.
50. The process according to claim 47, wherein the halogenated hydrocarbon is
selected from the group consisting of dichloromethane, chloroform, and 1,2-
dichloroethane.
51. The process according to claim 47, wherein the ketone is selected from the group
consisting of acetone and methyl ethyl ketone.
52. The process according to claim 47, wherein the ether is selected from the group
consisting of diethyl ether and tetrahydrofuran.
53. The process according to claim 47, wherein the polar aprotic solvent include is
selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide,
dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
54. The process according to claim 45, wherein the pharmaceutically acceptable carrier
is polyvinyl pyrrolidone (PVP) or hydroxypropyl -P-cyclodextrin (HRbO ) .
55. The process according to claim 45, wherein step b) involves spray drying,
lyophilization, agitated thin film drying or melt extrusion.
56. A method of treating or preventing Type 2 diabetes mellitus which comprises
administering to a patient in need thereof a therapeutically effective amount of solid
dispersion of sitagliptin dihydrogen phosphate.