NOVEL SALTS OF SITAGLIPTIN
Field of the Invention
The present invention provides novel salts of sitagliptin, its polymorphic form,
processes for their preparation and pharmaceutical compositions thereof.
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 (hereinafter "the ' 87 1patent"), in particular Example 7,
provides a process for the preparation of sitagliptin base and its hydrochloride salt. A list
of pharmaceutically acceptable salts is generally included in the '87 1patent.
U.S. Patent No. 7,326,708 provides a process for the preparation of sitagliptin
dihydrogen phosphate monohydrate.
PCT Publication WO 2005/072530 provides a process for the preparation of
crystalline salts of sitagliptin with hydrochloric acid, benzene sulfonic acid, /^-toluene
sulfonic acid, D- and L-tartaric acid and (l S)-(+)- and (lR)-(-)- 10-camphorsulfonic acid.
PCT Publication WO 2005/030 127 (hereinafter "PCT Ί 27") provides a process
for the preparation of sitagliptin dihydrogen phosphate anhydrate Form IV which involves
heating sitagliptin dihydrogen phosphate monohydrate at 120°C for about 2 hours or by
heating the sitagliptin dihydrogen phosphate monohydrate above 58°C for about 8 hours.
PCT 27 also provides a process for the preparation of sitagliptin dihydrogen
phosphate anhydrate Form I by heating sitagliptin dihydrogen phosphate anhydrate Form
IV at a temperature above 140°C for about 1 hour. According to this publication, Form IV
is metastable and converts to the crystalline monohydrate slowly under ambient conditions
and rapidly under high relative humidity (98%) at room temperature.
PCT Publication WO 2005/020920 provides a process for the preparation of
crystalline anhydrate Form I, crystalline desolvated anhydrate Form II, crystalline
anhydrate Form III, crystalline ethanol solvate of sitagliptin dihydrogen phosphate. It also
provides a process for the preparation of mixture of sitagliptin dihydrogen phosphate
anhydrate Form I and anhydrate Form III.
PCT Publication WO 2006/033848 provides a process for the preparation of
crystalline sitagliptin dihydrogen phosphate monohydrate and amorphous sitagliptin
dihydrogen phosphate.
PCT Publication WO 2007/035198 provides a process for the preparation of
dodecylsulfate salt of sitagliptin.
PCT Publication WO 2008/000418 provides a process for the preparation of
anhydrous sitagliptin hydrochloride in amorphous form.
PCT Publication WO 2009/120746 provides processes for the preparation of
crystalline form of sitagliptin phosphate, characterized by a powder XRD pattern with
peaks at about 4.7, 13.5, 17.7, 18.3, and 23.7 ±0.2° 2Qand sitagliptin phosphate Form II.
U.S. Publication 2009/247532 provides processes for the preparation of polymorph
Form V of crystalline sitagliptin phosphate and polymorph Form I of sitagliptin phosphate.
PCT Publication WO 2009/084024 provides a process for the preparation of Rsitagliptin
dibenzyl-L-tartrate.
PCT Publication WO 2009/085990 provides a process for the preparation of
crystalline anhydrate Form A of the dihydrogen phosphate salt of sitagliptin, crystalline
sitagliptin sulfate, crystalline sitagliptin hydrobromide, crystalline sitagliptin methane
sulfonate, crystalline sitagliptin acetate, crystalline sitagliptin benzoate, crystalline
sitagliptin oxalate, crystalline sitagliptin succinate, crystalline sitagliptin mandelate,
crystalline sitagliptin fumarate and crystalline sitagliptin lactate.
PCT Publication WO 2010/032264 provides a process for the preparation of
crystalline Form 3 of sitagliptin, crystalline form of dibenzoyl-L-tartaric acid salt of
sitagliptin, amorphous form of sitagliptin and anhydrous and hydrated crystalline form of
phosphate salt of sitagliptin.
PCT Publication 2010/000469 provides a process for the preparation of sitagliptin
hydrochloride Form I, sitagliptin hydrochloride Form II, sitagliptin fumarate Form I,
sitagliptin fumarate Form II, sitagliptin malate, sitagliptin sulfate Form I, sitagliptin sulfate
Form II, sitagliptin phosphate, sitagliptin succinate Form I and Form II, sitagliptin
succinate Form III, sitagliptin lactate, sitagliptin glycolate, sitagliptin maleate Form I,
sitagliptin maleate Form II, sitagliptin citrate, amorphous sitagliptin citrate, sitagliptin
mesylate Form I and sitagliptin mesylate Form II.
PCT Publication WO 2010/012781 provides a process for the preparation of
sitagliptin galactarate, sitagliptin hemi-L-malate, sitagliptin D-gluconate, sitagliptin
succinate, sitagliptin hydrobromide, sitagliptin thiocyanate, sitagliptin oxalate, sitagliptin
aspartate, sitagliptin ethanedisulfonate, sitagliptin pyroglutamate, sitagliptin glutarate,
sitagliptin acetate, sitagliptin hydrochloride amorphous form, sitagliptin citrate amorphous
form, sitagliptin hemicitrate amorphous form, sitagliptin glycolate amorphous form and
sitagliptin malate amorphous form.
PCT Publication WO 2010/1 17738 provides a process for the preparation of
crystalline Form S1 of sitagliptin sulfate, crystalline Form S2 of sitagliptin sulfate,
crystalline Form S3 of sitagliptin sulfate, crystalline Form S4 of sitagliptin sulfate,
crystalline Form S5 of sitagliptin sulfate, crystalline Form S6 of sitagliptin sulfate,
crystalline Form S7 of sitagliptin sulfate, crystalline Form S8 of sitagliptin sulfate,
crystalline Form D1 of sitagliptin (+)-dibenzoyl- tartrate, crystalline Form D2 of sitagliptin
(+)-dibenzoyl-tartrate, crystalline Form F1 of sitagliptin fumarate, crystalline Form F2 of
sitagliptin fumarate, crystalline Form Ml of sitagliptin (D)-(+)-malate, crystalline Form
M2 of sitagliptin (D)-(+)-malate, crystalline Form I I of sitagliptin L-malate, crystalline
Form 0 1 of sitagliptin oxalate, crystalline Form 0 2 of sitagliptin oxalate, crystalline Form
Ql of sitagliptin quinate, crystalline Form Ul of sitagliptin succinate, crystalline Form El
of sitagliptin acetate, crystalline Form Al of sitagliptin maleate, crystalline Form Nl of
sitagliptin (S)-mandelate, crystalline Form N2 of sitagliptin (S)-mandelate, crystalline
Form N3 of sitagliptin (S)-mandelate, crystalline Form N4 of sitagliptin (S)-mandelate,
amorphous sitagliptin mandelate, crystalline Form N5 of sitagliptin (R)-mandelate,
crystalline FormN6 of sitagliptin (R)-mandelate, crystalline Form LI of sitagliptin lactate,
crystalline Form L2 of sitagliptin lactate, crystalline Form L3 of sitagliptin lactate,
crystalline Form L4 of sitagliptin lactate and amorphous sitagliptin orotate.
PCT Publication WO 2010/092090 provides a process for the preparation of
crystalline sitagliptin D-glucuronate, crystalline sitagliptin glutarate, crystalline sitagliptin
hydrogen sulfate, crystalline sitagliptin L-lactate, crystalline sitagliptin oxalate, sitagliptin
caprate, sitagliptin L-mandelate, crystals of sitagliptin ethanesulfonate.
PCT Publication WO 2010/122578 provides a process for the preparation of
sitagliptin hydrogen phosphate monohydrate and sitagliptin mandalate.
PCT Publication WO 201 1/025932 provides a process for the preparation of
sitagliptin phosphate and sitagliptin hydrochloride.
PCT Publication WO 201 1/060213 provides a process for the preparation of
sitagliptin phosphate, sitagliptin formate and sitagliptin acetate.
PCT Publication WO 201 1/018494 provides a process for the preparation of
sitagliptin fumarate.
Journal of Medicinal Chemistry, 48(1), p. 141-151 (2005) provides a process for
the preparation of sitagliptin hydrochloride and sitagliptin fumarate.
Several processes are known in the literature for making sitagliptin or a salt
thereof, for example, PCT Publications WO 201 1/049344, WO 2010/131025, WO
2010/078440, WO 2004/083212, WO 2006/065826, WO 2010/097420, WO 2004/080958,
WO 2004/087650 and WO 2004/085661.
In the pharmaceutical industry, there is a constant need to identify the critical
physicochemical parameters such as novel salts, novel polymorphic forms that affect the
drug's performance, stability, etc., which may play a key role in determining a drug's
market acceptance and success.
Since sitagliptin is an important therapeutic agent, developing other, hitherto
unknown salts is of value to pharmaceutical science, especially in terms of having
improved solubility, stability, excellent storage and handling stabilities, bioavailability,
etc.
Polymorphism is commonly defined as the ability of any substance to have two or
more different crystal structures. Drug substances may also encapsulate solvent molecules
when crystallized. These solvates or hydrates are referred to as pseudo polymorphs.
Different polymorphs, pseudo polymorphs or the amorphous form differ in their
physical properties such as melting point, solubility, etc. These can appreciably influence
pharmaceutical properties such as dissolution rate and bioavailability. It is also
economically desirable that the product is stable for extended periods of time without the
need for specialized storage conditions.
It is therefore important to evaluate polymorphism of drug substances. Therefore,
there is also strong need for developing various polymorphic forms of salts of sitagliptin.
Summary of the Invention
In one general aspect, the present invention provides sitagliptin 4-methyl
salicylate.
In another general aspect, the present invention provides amorphous form of
sitagliptin 4-methyl salicylate.
In another general aspect, the present invention provides sitagliptin myristate.
In yet another general aspect, the present invention provides crystalline form of
sitagliptin myristate.
In another general aspect, the present invention provides sitagliptin isophthalate.
In yet another general aspect, the present invention provides crystalline form of
sitagliptin isophthalate.
In another general aspect, the present invention provides sitagliptin isonicotinate.
In yet another general aspect, the present invention provides crystalline form of
sitagliptin isonicotinate.
In another general aspect, the present invention provides sitagliptin adipate.
In yet another general aspect, the present invention provides crystalline form of
sitagliptin adipate.
In another general aspect, the present invention provides a process for the
preparation of a compound of Formula 1.
Formula 1
The process comprises: treating sitagliptin or its salt and HA, wherein HA is selected from
the group consisting of 4-methylsalicylic acid, myristic acid, isophthalic acid, isonicotinic
acid and adipic acid.
In another general aspect, the present invention provides the use of sitagliptin 4-
methyl salicylate, sitagliptin myristate, sitagliptin isophthalate, sitagliptin isonicotinate or
sitagliptin adipate for the preparation of sitagliptin, salts, solvates, or polymorphs thereof.
In yet another general aspect, the present invention provides a pharmaceutical
composition comprising salt of sitagliptin 4-methyl salicylate, sitagliptin myristate,
sitagliptin isophthalate, sitagliptin isonicotinate or sitagliptin adipate and a pharmaceutical
acceptable carrier.
In another general aspect, 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 sitagliptin 4-methyl salicylate, sitagliptin
myristate, sitagliptin isophthalate, sitagliptin isonicotinate or sitagliptin adipate and a
pharmaceutical acceptable carrier.
Detailed Description of the Invention
The present invention provides various salts of sitagliptin. For example, the present
invention provides sitagliptin 4-methyl salicylate. Sitagliptin 4-methyl salicylate of the
present invention may be in amorphous form. Amorphous form of sitagliptin 4-methyl
salicylate of the present invention may be characterized by an XRPD pattern substantially
the same as depicted in Figure 1. Amorphous form of sitagliptin 4-methyl salicylate of the
present invention may be characterized by FTIR as depicted in Figure 2.
The present invention also provides sitagliptin myristate. Sitagliptin myristate of
the present invention may be in crystalline form. Crystalline form of sitagliptin myristate
of the present invention may be characterized by an XRPD pattern substantially the same
as depicted in Figure 3. Crystalline form of sitagliptin myristate of the present invention
may be characterized by FTIR as depicted in Figure 4. The crystalline form of sitagliptin
myristate has an XRPD pattern which may include interplanar spacing (d) values
substantially at about 18.31, 9.21, 4.20, 4.19, and 3.71 A. The crystalline form of
sitagliptin myristate has an XRPD pattern which may further include interplanar spacing
(d) values substantially at about 4.76, 4.68, 4.56, 4.43, 4.44, 4.30, 3.82, 3.49, 3.42, 3.36,
and 3.18 A. The crystalline form of sitagliptin myristate has an XRPD pattern with the
following characteristic peak values (2Q) at about 4.82, 9.60, 21.1 1, 21.20, and 23.91 ±
0.2°. The crystalline form of sitagliptin myristate has an XRPD pattern with the following
additional characteristic peak values (2Q) at about: 18.63, 18.97, 19.46, 19.96, 20.06,
20.62, 23.26, 25.46, 25.99, 26.48, and 27.98 ± 0.2°.
The present invention also provides sitagliptin isophthalate. Sitagliptin isophthalate
of the present invention may be in crystalline form. Crystalline form of sitagliptin
isophthalate of the present invention may be characterized by an XRPD pattern
substantially the same as depicted in Figure 5. Crystalline form of sitagliptin isophthalate
of the present invention may be characterized by FTIR as depicted in Figure 6. The
crystalline form of sitagliptin isophthalate has an XRPD pattern which may include
interplanar spacing (d) values substantially at about 3.49, 4.59, 3.91, 3.77, and 4.71 A. The
crystalline form of sitagliptin isophthalate has an XRPD pattern which may further include
interplanar spacing (d) values substantially at about 23.73, 14.89, 7.03, 6.12, 5.80, 5.66,
5.51, 5.23, 5.16, 4.99, 4.78, 4.42, 4.32, 4.06, 3.99, 3.58, 3.34, 3.24, 3.13, 3.00, and 2.81 A.
The crystalline form of sitagliptin isophthalate has an XRPD pattern with the following
characteristic peak values (2Q) at about 18.82, 19.35, 22.72, 23.59, and 25.54 ± 0.2°. The
crystalline form of sitagliptin isophthalate has an XRPD pattern with the following
additional characteristic peak values (2Q) at about: 3.72, 5.94, 12.59, 14.48, 15.27, 15.67,
16.09, 16.95, 17.19, 17.76, 18.55, 20.10, 20.56, 21.90, 22.24, 24.86, 26.72, 27.56, 28.54,
29.73, and 31.84 ± 0.2°.
The present invention also provides sitagliptin isonicotinate. Sitagliptin
isonicotinate of the present invention may be in crystalline form. Crystalline form of
sitagliptin isonicotinate of the present invention may be characterized by an XRPD pattern
substantially the same as depicted in Figure 7. Crystalline form of sitagliptin isonicotinate
of the present invention may be characterized by FTIR as depicted in Figure 8. The
crystalline form of sitagliptin isonicotinate has an XRPD pattern which may include
interplanar spacing (d) values substantially at about 7.95, 5.17, 3.99, 3.65, and 3.58 A. The
crystalline form of sitagliptin isonicotinate has an XRPD pattern which may further
include interplanar spacing (d) values substantially at about: 15.84, 5.39, 5.32, 4.52, 4.16,
3.83, 3.81, 3.35, and 3.24 A. The crystalline form of sitagliptin isonicotinate has an XRPD
pattern with the following characteristic peak values (2Q) at about: 11.12, 17.14, 22.26,
24.41, and 24.85 ± 0.2°. The crystalline form of sitagliptin isonicotinate has an XRPD
pattern with the following additional characteristic peak values (2Q) at about: 5.58, 16.45,
16.66, 19.64, 21.34, 23.23, 23.36, 26.59 and 27.53 ± 0.2°.
The present invention also provides sitagliptin adipate. Sitagliptin adipate of the
present invention may be in crystalline form. Crystalline form of sitagliptin adipate of the
present invention may be characterized by an XRPD pattern substantially the same as
depicted in Figure 9. Crystalline form of sitagliptin adipate of the present invention may
be characterized by FTIR as depicted in Figure 10. Crystalline form of sitagliptin adipate
has an XRPD pattern which may include interplanar spacing (d) values substantially at
about 4.70, 4.38, 4.00, 3.82, 3.77 and 3.71 A. Crystalline form of sitagliptin adipate has an
XRPD pattern which may further include interplanar spacing (d) values substantially at
about 17.57, 10.99, 6.31, 5.50, 4.79, 4.74, 4.22, 3.95, 3.70, 3.62 and 3.33 A. Crystalline
form of sitagliptin adipate has an XRPD pattern with the following characteristic peak
values (2Q) at about 18.90, 20.27, 22.20, 23.29, 23.63 and 23.97 ± 0.2°. Crystalline form
of sitagliptin adipate has an XRPD pattern with the following additional characteristic
peak values (2Q) at about: 5.03, 8.05, 14.04, 16.13, 18.53, 18.72, 21.03, 22.50, 24.04,
24.60 and 26.74 ± 0.2°.
The present invention provides a process for the preparation of a compound of
Formula 1.
Formula 1
The process comprises: treating sitagliptin or its salt and HA, wherein HA is
selected from the group consisting of 4-methylsalicylic acid, myristic acid, isophthalic
acid, isonicotinic acid or adipic acid.
The sitagliptin or its salt prepared by any of the methods known in the art including
those described in, for example, U.S. Patent Nos. 6,699,871, 7,326,708, US Publication
No. 2009/247532, 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, WO
2010/122578 may be used as the starting material.
The sitagliptin or its salt prepared by any of the methods known in the art may be
isolated or directly treated with HA.
The sitagliptin or its salt prepared by any of the methods known in the art before
treatment with HA may be optionally clarified to remove foreign particulate matter or
treated with activated charcoal to remove coloring and other related impurities in a
suitable solvent. The solution of sitagliptin or its salt may be optionally concentrated to
reduce the amount of solvent. The sitagliptin salt may optionally be converted to
sitagliptin base before the treatment with HA.
Treating sitagliptin or its salt with HA may include adding, dissolving, slurrying,
stirring or a combination thereof. Sitagliptin or its salt may be treated with HA directly or
in the presence of a suitable solvent at a suitable 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 alkanol 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 or its salt may be treated with HA at a temperature of about 30°C to
reflux temperature for a time period sufficient to complete the reaction, preferably for
about 10 minutes to 6 hours.
After the completion of the reaction, the compound of Formula 1 can be isolated
by the common isolation technique such as cooling, extraction, one or more of washing,
crystallization, precipitation, filtration, filtration under vacuum, decantation and
centrifugation, or a combination thereof.
The present invention also provides for the use of sitagliptin 4-methyl salicylate,
sitagliptin myristate, sitagliptin isophthalate, sitagliptin isonicotinate or sitagliptin adipate
for the preparation of sitagliptin, salts, solvates, or polymorphs thereof.
The compound of Formula 1may be used for preparation of sitagliptin by
contacting with a base. The base may be selected from group comprising of hydroxides,
carbonates and bicarbonates of alkali and alkaline earth metals, ammonia, alkyl amines,
hydrazine, and the like. Examples of hydroxides, carbonates and bicarbonates of alkali
and alkaline earth metals may include lithium hydroxide, sodium hydroxide, potassium
hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium
bicarbonate. Examples of alkyl amines may include diethyl amine, triethyl amine or
methyl diethyl amine. Sitagliptin thus obtained may be converted to salts, solvates, or
polymorphs thereof.
The present invention also provides for a pharmaceutical composition comprising
salt of sitagliptin 4-methyl salicylate, sitagliptin myristate, sitagliptin isophthalate,
sitagliptin isonicotinate or sitagliptin adipate and a pharmaceutical acceptable carrier.
The present invention provides for a method of treating or preventing type 2
diabetes mellitus which comprises administering to a patient in need thereof a
therapeutically effective amount of sitagliptin 4-methyl salicylate, sitagliptin myristate,
sitagliptin isophthalate, sitagliptin isonicotinate or sitagliptin adipate and a pharmaceutical
acceptable carrier.
Brief Description of the Figures
Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of sitagliptin 4-methyl
salicylate prepared as per Example 1.
Figure 2 depicts the Fourier-Transform Infra-red (FTIR) spectrum of sitagliptin 4-
methyl salicylate prepared as per Example 1.
Figure 3 and Figure 3a depict the X-Ray Powder Diffractogram (XRPD) of
sitagliptin myristate and the associated values, respectively, prepared as per Example 2.
Figure 4 depicts the Fourier-Transform Infra-red (FTIR) spectrum of sitagliptin
myristate prepared as per Example 2.
Figure 5 and Figure 5a depict the X-Ray Powder Diffractogram (XRPD) of
sitagliptin isophthalate and the associated values, respectively, prepared as per Example 3.
Figure 6 depicts the Fourier-Transform Infra-red (FTIR) spectrum of sitagliptin
isophthalate prepared as per Example 3.
Figure 7 and Figure 7a depict the X-Ray Powder Diffractogram (XRPD) of
sitagliptin isonicotinate and the associated values, respectively, prepared as per Example
4.
Figure 8 depicts the Fourier-Transform Infra-red (FTIR) spectrum of sitagliptin
isonicotinate prepared as per Example 4.
Figure 9 and Figure 9a depict the X-Ray Powder Diffractogram (XRPD) of
sitagliptin adipate and the associated values, respectively, prepared as per Example 5.
Figure 10 depicts the Fourier-Transform Infra-red (FTIR) spectrum of sitagliptin
adipate prepared as per Example 5.
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 degree 2 theta, CuKa radiation at 45kV.
FTIR of the samples was determined by using Instrument: Perkin Elmer, SCAN:
16 scans, Resolution: 4.0 cm 1, potassium bromide pellet method.
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 Sitagliptin 4-Methyl salicylate Salt
Sitagliptin base ( 1 g, 0.00245 mole) was charged in isopropyl alcohol (10 ml) at
25°C to 32°C. 4-Methyl salicylic acid (0.37 g, 0.00245 mole) was charged at 25°C to
32°C. The reaction mixture was heated to 50°C and stirred for 2 hours at 50°C. The
reaction mixture was then cooled to 25°C to 32°C and distilled under vacuum completely
at 50°C to obtain a solid. The solid was dried under vacuum at 40°C for 16 hours to
obtain the titled compound.
Yield: 1 g
Example 2 : Preparation of Sitagliptin Myristate Salt
Sitagliptin base (2 g, 0.0049 mole) was charged in isopropyl alcohol (20 ml) at
25°C to 32°C. Myristic acid ( 1.12 g, 0.0049 mole) was charged at 25°C to 32°C to obtain
a reaction mixture. The reaction mixture was heated to 50°C and stirred for 2.5 hours at
50°C. The reaction mixture was cooled to 25°C to 32°C and stirred for 16 hours at 25°C
to 32°C. The reaction mixture was concentrated completely under vacuum at 50°C.
Hexanes (10 ml) was charged to reaction mixture and stirred for 1 hour at 20°C. The solid
was filtered and washed with isopropyl alcohol (2x10 ml). Material was dried under
vacuum at 40°C for 16 hours to obtain the titled compound.
Yield: 2.9 g
Example 3 : Preparation of Sitagliptin Isophthalate Salt
Sitagliptin base (2 g, 0.0049 mole) was charged in isopropyl alcohol (20 ml) at
25°C to 32°C. Isophthalic acid (0.81 g, 0.0049 mole) was charged at 25°C to 32°C to
obtain a reaction mixture. The reaction mixture was heated to 50°C and stirred for 2 hours
at 50°C. The reaction mixture was cooled to 25°C to 32°C and stirred for 16 hours at
25°C to 32°C to obtain a solid. The solid was filtered and washed with isopropyl alcohol
(2x10 ml). The solid was dried under vacuum at 40°C for 16 hours to obtain the titled
compound.
Yield: 2.6 g
Example 4 : Preparation of Sitagliptin Isonicotinate Salt
Sitagliptin base ( 1 g, 0.00245 mole) was charged in ethanol (10 ml) at 25°C to
32°C. Isonicotinic acid (0.3 g, 0.00245 mole) was charged at 25°C to 32°C. The reaction
mixture was heated to 60°C and stirred for 30 minutes at 60°C. The reaction mixture was
cooled to 25°C to 32°C and stirred for 30 minutes at 25°C to 32°C to obtain a solid. The
solid was filtered and washed with ethanol (10 ml). The solid was dried under air oven at
40°C for 16 hours to obtain the titled compound.
Yield: 0.5 g
Example 5 : Preparation of Sitagliptin Adipate
Sitagliptin base (2 g, 0.0049 moles) was charged in isopropyl alcohol (20 ml) at
25°C to 32°C. Adipic acid (0.71 g, 0.0049 moles) was charged at 25°C to 32°C. The
reaction mixture was heated to 50°C and stirred for 2 hours at 50°C. The reaction mixture
was then cooled to 25°C to 32°C and distilled under vacuum completely at 50°C to obtain
a solid. The solid was dried under vacuum at 40°C for 16 hours to obtain the titled
compound.
Melting point: 99°C to 104°C
Yield: 2.6 g (1.3 w/w, 95.9%)

CLAIMS
1. A salt of sitagliptin with an organic acid selected from the group consisting of 4-
methylsalicyclic acid, myristic acid, isophthalic acid, isonicotnic acid, and adipic acid.
2. Sitagliptin 4-methyl salicylate.
3. Sitagliptin 4-methyl salicylate of claim 2, in amorphous form.
4. Sitagliptin 4-methyl salicylate of claim 3, wherein the amorphous form is
characterized by an XRPD pattern substantially the same as depicted in Figure 1.
5. Sitagliptin 4-methyl salicylate of claim 3, wherein the amorphous form is
characterized by FTIR as depicted in Figure 2.
6. Sitagliptin myristate.
7. Sitagliptin myristate of claim 6, in crystalline form.
8. Sitagliptin myristate of claim 7, wherein the crystalline form is characterized by an
XRPD pattern substantially the same as depicted in Figure 3.
9. Sitagliptin myristate of claim 7, wherein the crystalline form is characterized by
FTIR as depicted in Figure 4.
10. Sitagliptin myristate of claim 7, wherein the crystalline form is characterized by an
X-ray powder diffractogram which includes interplanar spacing (d) values substantially at
about 18.31, 9.21, 4.20, 4.19, and 3.71 A.
11. Sitagliptin myristate of claim 10, wherein the crystalline form is further
characterized by an X-ray powder diffractogram which includes interplanar spacing (d)
values substantially at about 4.76, 4.68, 4.56, 4.43, 4.44, 4.30, 3.82, 3.49, 3.42, 3.36, and
3.18 A.
12. Sitagliptin myristate of claim 7, wherein the crystalline form is characterized by an
X-ray powder diffractogram which includes characteristic peak values (2Q) at about 4.82,
9.60, 21.1 1, 21.20, and 23.91 ± 0.2°.
13. Sitagliptin myristate of claim 12, wherein the crystalline form is further
characterized by an X-ray powder diffractogram with the following additional
characteristic peak values (2Q) at about: 18.63, 18.97, 19.46, 19.96, 20.06, 20.62, 23.26,
25.46, 25.99, 26.48, and 27.98 ± 0.2°.
14. Sitagliptin isophthalate.
15. Sitagliptin isophthalate of claim 14, in crystalline form.
16. Sitagliptin isophthalate of claim 15, wherein the crystalline form is characterized
by an XRPD pattern substantially the same as depicted in Figure 5.
17. Sitagliptin isophthalate of claim 15, wherein the crystalline form is characterized
by FTIR as depicted in Figure 6.
18. Sitagliptin isophthalate of claim 15, wherein the crystalline form is characterized
by an X-ray powder diffractogram which includes interplanar spacing (d) values
substantially at about 3.49, 4.59, 3.91, 3.77, and 4.71 A.
19. Sitagliptin isophthalate of claim 18, wherein the crystalline form is further
characterized by an X-ray powder diffractogram which includes interplanar spacing (d)
values substantially at about 23.73, 14.89, 7.03, 6.12, 5.80, 5.66, 5.51, 5.23, 5.16, 4.99,
4.78, 4.42, 4.32, 4.06, 3.99, 3.58, 3.34, 3.24, 3.13, 3.00, and 2.81 A.
20. Sitagliptin isophthalate of claim 15, wherein the crystalline form is characterized
by an X-ray powder diffractogram pattern with the following characteristic peak values
(2Q) at about 18.82, 19.35, 22.72, 23.59, and 25.54 ± 0.2°.
2 1. Sitagliptin isophthalate of claim 20, wherein the crystalline form is further
characterized by an X-ray powder diffractogram with the following additional
characteristic peak values (2Q) at about: 3.72, 5.94, 12.59, 14.48, 15.27, 15.67, 16.09,
16.95, 17.19, 17.76, 18.55, 20.10, 20.56, 21.90, 22.24, 24.86, 26.72, 27.56, 28.54, 29.73,
and 31.84 ± 0.2°.
22. Sitagliptin isonicotinate.
23. Sitagliptin isonicotinate of claim 22, in crystalline form.
24. Sitagliptin isonicotinate of claim 23, wherein the crystalline form is characterized
by an XRPD pattern substantially the same as depicted in Figure 7.
25. Sitagliptin isonicotinate of claim 23, wherein the crystalline form is characterized
by FTIR as depicted in Figure 8.
26. Sitagliptin isonicotinate of claim 23, wherein the crystalline form is characterized
by an X-ray powder diffractogram which includes interplanar spacing (d) values
substantially at about 7.95, 5.17, 3.99, 3.65, and 3.58 A.
27. Sitagliptin isonicotinate of claim 26, wherein the crystalline form is further
characterized by an X-ray powder diffractogram which includes interplanar spacing (d)
values substantially at about 15.84, 5.39, 5.32, 4.52, 4.16, 3.83, 3.81, 3.35, and 3.24 A.
28. Sitagliptin isonicotinate of claim 23, wherein the crystalline form is characterized
by an X-ray powder diffractogram pattern with the following characteristic peak values
(2Q) at about: 11.12, 17.14, 22.26, 24.41, and 24.85 ± 0.2°.
29. Sitagliptin isonicotinate of claim 23, wherein the crystalline form is further
characterized by an X-ray powder diffractogram with the following additional
characteristic peak values (2Q) at about: 5.58, 16.45, 16.66, 19.64, 21.34, 23.23, 23.36,
26.59 and 27.53 ± 0.2°.
30. Sitagliptin adipate.
31. Sitagliptin adipate of claim 30, in crystalline form.
32. Sitagliptin adipate of claim 31, wherein the crystalline form is characterized by an
XRPD pattern substantially the same as depicted in Figure 9.
33. Sitagliptin adipate of claim 31, wherein the crystalline form is characterized by
FTIR as depicted in Figure 10.
34. Sitagliptin adipate of claim 31, wherein the crystalline form is characterized by an
X-ray powder diffractogram which includes interplanar spacing (d) values substantially at
about 4.70, 4.38, 4.00, 3.82, 3.77 and 3.71 A.
35. Sitagliptin adipate of claim 31, wherein the crystalline form is further characterized
by an X-ray powder diffractogram which includes interplanar spacing (d) values
substantially at about 17.57, 10.99, 6.31, 5.50, 4.79, 4.74, 4.22, 3.95, 3.70, 3.62 and 3.33
A.
36. Sitagliptin adipate of claim 31, wherein the crystalline form is characterized by an
X-ray powder diffractogram pattern with the following characteristic peak values (2Q) at
about: 18.90, 20.27, 22.20, 23.29, 23.63 and 23.97 ± 0.2°.
37. Sitagliptin adipate of claim 31, wherein the crystalline form is further characterized
by an X-ray powder diffractogram with the following additional characteristic peak values
(2Q) at about: 5.03, 8.05, 14.04, 16.13, 18.53, 18.72, 21.03, 22.50, 24.04, 24.60 and 26.74
± 0.2°.
38. A process for the preparation of a compound of Formula 1
Formula 1
the process comprising: treating sitagliptin or its salt and HA, wherein HA is selected from
the group consisting of 4-methylsalicylic acid, myristic acid, isophthalic acid, isonicotinic
acid or adipic acid.
39. A process according to claim 38, wherein sitagliptin or its salt is treated with HA
directly or in the presence of a suitable solvent at a suitable temperature.
40. A process according to claim 39, wherein the solvent includes water, esters,
alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures
thereof.
4 1. A process according to claim 40, wherein the esters may include one or more of
ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
42. A process according to claim 40, wherein the alkanols include methanol, ethanol,
n-propanol, isopropanol and butanol.
43. A process according to claim 40, wherein the halogenated hydrocarbons include
dichloromethane, chloroform, and 1,2-dichloroethane.
44. A process according to claim 40, wherein the ketones include acetone and methyl
ethyl ketone.
45. A process according to claim 40, wherein the ethers include diethyl ether and
tetrahydrofuran.
46. A process according to claim 40, wherein the suitable polar aprotic solvent
includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide,
dimethylsulphoxide, acetonitrile and N-methylpyrrolidone.
47. A process according to claim 39, wherein the sitagliptin or its salt is treated with
HA at a temperature of about 30°C to reflux temperature.
48. A process for the preparation of sitagliptin, salts, solvates or polymorphs thereof,
which includes the use of compound of Formula 1.
Formula 1
49. A process according to claim 48, wherein the compound of Formula 1 includes
sitagliptin 4-methyl salicylate, sitagliptin myristate, sitagliptin isophthalate, sitagliptin
isonicotinate or sitagliptin adipate.
50. A process according to claim 48, wherein the process includes contacting
compound of Formula 1with a base.
51. A process according to claim 49, wherein the base may be selected from a group
comprising of hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals,
ammonia, alkyl amines and hydrazine.
52. A pharmaceutical composition comprising at least one salt selected from the group
consisting of sitagliptin 4-methyl salicylate, sitagliptin myristate, sitagliptin isophthalate,
sitagliptin isonicotinate and sitagliptin adipate, and a pharmaceutical acceptable carrier.
53. A method of treating or preventing type 2 diabetes mellitus which comprises
administering to a patient in need thereof a therapeutically effective amount of sitagliptin
4-methyl salicylate, sitagliptin myristate, sitagliptin isophthalate, sitagliptin isonicotinate
or sitagliptin adipate and a pharmaceutical acceptable carrier.