U.S. patent application number 12/511503 was filed with the patent office on 2010-03-18 for crystalline salt forms of a 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine derivative.
This patent application is currently assigned to Medichem S.A.. Invention is credited to Monica BENITO VELEZ, Ernesto DURAN LOPEZ, Stephen Benedict David WINTER.
Application Number | 20100069637 12/511503 |
Document ID | / |
Family ID | 41347846 |
Filed Date | 2010-03-18 |
United States Patent
Application |
20100069637 |
Kind Code |
A1 |
WINTER; Stephen Benedict David ;
et al. |
March 18, 2010 |
CRYSTALLINE SALT FORMS OF A
5,6,7,8-TETRAHYDRO-1,2,4-TRIAZOLO[4,3-a]PYRAZINE DERIVATIVE
Abstract
This invention provides novel crystalline acid salt forms of
7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro--
3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine, i.e.
sitagliptin, to processes for their preparation and isolation, and
to pharmaceutical compositions comprising the same.
Inventors: |
WINTER; Stephen Benedict David;
(Barcelona, ES) ; BENITO VELEZ; Monica;
(Barcelona, ES) ; DURAN LOPEZ; Ernesto;
(Barcelona, ES) |
Correspondence
Address: |
COHEN, PONTANI, LIEBERMAN & PAVANE LLP
551 FIFTH AVENUE, SUITE 1210
NEW YORK
NY
10176
US
|
Assignee: |
Medichem S.A.
Sant Joan Despi
ES
|
Family ID: |
41347846 |
Appl. No.: |
12/511503 |
Filed: |
July 29, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61137429 |
Jul 29, 2008 |
|
|
|
61137428 |
Jul 29, 2008 |
|
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Current U.S.
Class: |
544/350 |
Current CPC
Class: |
C07D 487/04
20130101 |
Class at
Publication: |
544/350 |
International
Class: |
C07D 471/04 20060101
C07D471/04 |
Claims
1. A crystalline acid salt form of sitagliptin, wherein said acid
is selected from the group consisting of ethanedisulfonic acid,
galactaric acid, thiocyanic acid, and glutaric acid.
2. The crystalline acid salt form of sitagliptin of claim 1,
wherein said crystalline acid salt form is sitagliptin
ethanedisulfonate Form I, which shows an XRD pattern (2.theta.)
(.+-.0.2.degree.) having characteristics peaks at 8.0, 13.8, 16.0,
18.0, 18.7, 19.6, 21.2, 21.4, 21.6, 22.7, 23.5, 24.4, 25.4, 25.6,
and 27.1.degree..
3. The sitagliptin ethanedisulfonate Form I of claim 2, which shows
an XRD pattern (2.theta.) (.+-.0.2.degree.) having further peaks at
6.3, 6.6, 7.1, 11.2, 14.4, 20.4, 23.0, 24.8, 26.5, 27.9, and
34.7.degree..
4. A process for preparing the sitagliptin ethanedisulfonate Form I
of claim 2, said process comprising contacting sitagliptin base
with ethanedisulfonic acid in the presence of a suitable solvent,
and removing the solvent.
5. A process for preparing the sitagliptin ethanedisulfonate Form I
of claim 3, said process comprising contacting sitagliptin base
with ethanedisulfonic acid in the presence of a suitable solvent,
and removing the solvent.
6. The process of claim 4, wherein the suitable solvent is a
C.sub.1-C.sub.5 alcohol solvent.
7. The crystalline acid salt form of sitagliptin of claim 1,
wherein said crystalline acid salt form is sitagliptin galactarate
Form I, which shows an XRD pattern (2.theta.) (.+-.) 0.2.degree.)
having characteristics peaks at 4.4, 13.2, 19.6, 22.4, and
30.7.degree..
8. The sitagliptin galactarate Form I of claim 7, which shows an
XRD pattern (2.theta.) (.+-.0.2.degree.) having further peaks at
14.3, 15.5, 16.5, 17.5, 18.6, 19.0, 23.0, 24.1, 25.4, 26.0, 26.9,
27.1, 34.5, and 37.7.degree..
9. A process for preparing the sitagliptin galactarate Form I of
claim 7, said process comprising contacting sitagliptin base with
galactaric acid in the presence of a suitable solvent, and removing
the solvent.
10. A process for preparing the sitagliptin galactarate Form I of
claim 8, said process comprising contacting sitagliptin base with
galactaric acid in the presence of a suitable solvent, and removing
the solvent.
11. The process of claim 9, wherein the suitable solvent is a
C.sub.1-C.sub.5 alcohol solvent.
12. The crystalline acid salt form of sitagliptin of claim 1,
wherein said crystalline acid salt form is sitagliptin thiocyanate
Form I, which shows an XRD pattern (2.theta.) (.+-.) 0.2.degree.)
having characteristics peaks at 7.9, 13.7, 15.8, 17.7, 17.9, 19.4,
22.4, 22.5, 23.3, 25.2, 25.3, 26.9, 31.7, and 45.4.degree..
13. The sitagliptin thiocyanate Form I of claim 12, which shows an
XRD pattern (2.theta.) (.+-.0.2.degree.) having further peaks at
6.2, 26.5, and 27.3.degree..
14. A process for preparing the sitagliptin thiocyanate Form I of
claim 12, said process comprising contacting sitagliptin base with
thiocyanic acid in the presence of a suitable solvent, and removing
the solvent.
15. A process for preparing the sitagliptin thiocyanate Form I of
claim 13, said process comprising contacting sitagliptin base with
thiocyanic acid in the presence of a suitable solvent, and removing
the solvent.
16. The process of claim 14, wherein the suitable solvent is a
C.sub.1-C.sub.5 alcohol solvent.
17. The crystalline acid salt form of sitagliptin of claim 1,
wherein said crystalline acid salt form is sitagliptin glutarate
Form I, which shows an XRD pattern (2.theta.) (.+-.0.2.degree.)
having characteristics peaks at 15.3, 16.3, 17.5, 18.0, 18.3, 20.7,
22.4, 22.8, 23.4, 24.6, and 25.4.degree..
18. The sitagliptin glutarate Form I of claim 17, which shows an
XRD pattern (2.theta.) (.+-.0.2.degree.) having further peaks at
6.3, 7.9, 9.4, 12.7, 12.8, 16.7, 19.9, 26.4, 27.8, 28.5, 28.6,
29.0, 30.5, and 33.8.degree..
19. A process for preparing the sitagliptin glutarate Form I of
claim 17, said process comprising contacting sitagliptin base with
glutaric acid in the presence of a suitable solvent, and removing
the solvent.
20. A process for preparing the sitagliptin glutarate Form I of
claim 18, said process comprising contacting sitagliptin base with
glutaric acid in the presence of a suitable solvent, and removing
the solvent.
21. The process of claim 19, wherein the suitable solvent is a
C.sub.1-C.sub.5 alcohol solvent.
Description
PRIORITY
[0001] This application claims priority from U.S. Provisional
Applications No. 61/137,428 and 61/137,429, both filed on Jul. 29,
2008, the contents of each of which are herein incorporated by
reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates generally to novel crystalline
salt forms of
7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-te-
trahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine, i.e.
sitagliptin, to processes for their preparation and isolation, and
to pharmaceutical compositions comprising the same.
BACKGROUND OF THE INVENTION
[0003] Sitagliptin (Compound I) is the international commonly
accepted name for
7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-te-
trahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine (which
is also known as
(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-
-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine), and
has an empirical formula of C.sub.16H.sub.15F.sub.6N.sub.5O and a
molecular weight of 407.31.
##STR00001##
[0004] The phosphate salt of sitagliptin has been selected for
medical purposes since has been proved to be useful for the
treatment of diabetes. Sitagliptin phosphate is a selective
inhibitor of dipeptidyl peptidase IV which lowers blood sugar
levels in patients with Type 2 diabetes, also known as non-insulin
dependent diabetes mellitus. In the United States, sitagliptin
phosphate is marketed under the name Januvia.TM. for the treatment
of Type 2 diabetes.
[0005] Sitagliptin phosphate salt and different forms thereof have
been disclosed in a number of references (i.e. U.S. Pat. No.
7,326,708, and U.S. Patent Application Nos. 20060287528,
20070021430 and 20070281941).
[0006] Sitagliptin base and its pharmaceutically acceptable acid
addition salts have been described in U.S. Pat. No. 6,699,871. In
particular, Example 7 of U.S. Pat. No. 6,699,871 discloses the
preparation of sitagliptin base and its hydrochloride salt.
[0007] Different salt forms of the same pharmaceutically active
moiety differ in their physical properties such as melting point,
solubility, etc. These properties may appreciably influence
pharmaceutical properties such as dissolution rate and
bioavailability. In addition, polymorphism, which is defined as the
ability of a substance to crystallize in more than one crystal
lattice arrangement, can also influence many aspects of solid state
properties of a drug. Different crystal modifications of a
substance may differ considerably from one another in many respects
such as their solubility, dissolution rate and finally
bioavailability.
[0008] In this regard, International Patent Publication No. WO
05/072530 described several novel crystalline salts of sitagliptin,
i.e. the hydrochloric acid, tartaric acid, benzenesulfonic acid,
p-toluenesulfonic acid, and 10-camphorsulfonic acid crystalline
salts. In addition, the hemifumarate salt of sitagliptin has been
described by D. Kim et al. in J. Med. Chem. 2005, 48, 141-151.
Also, International Patent Publication No. WO 07/035,198 relates to
a crystalline anhydride form of the dodecylsulfate salt of
sitagliptin. Furthermore, International Patent Publication No. WO
08/000,418 discloses the preparation of sitagliptin hydrochloride
in amorphous form. In addition, International Patent Publication
No. WO 09/085,990 describes other acid addition salts of
sitagliptin, i.e. sitagliptin salts of di-p-tolyl-L-tartaric acid,
phosphoric acid, sulfuric acid, hydrobromic acid, methanesulfonic
acid, acetic acid, benzoic acid, oxalic acid, succinic acid,
mandelic acid, fumaric acid, and lactic acid.
[0009] In view of the foregoing, it would be desirable to provide
new salt forms of sitagliptin. Further, it would be desirable to
have reliable processes for producing these salt forms of
sitagliptin. Additionally, the various salt forms of sitagliptin
could be used to prepare improved pharmaceutical compositions.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin galactarate.
[0011] FIG. 2 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin hemi-L-malate.
[0012] FIG. 3 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin D-gluconate.
[0013] FIG. 4 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin succinate.
[0014] FIG. 5 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin hydrobromide.
[0015] FIG. 6 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin thiocyanate.
[0016] FIG. 7 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin oxalate.
[0017] FIG. 8 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin aspartate.
[0018] FIG. 9 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin ethanedisulfonate.
[0019] FIG. 10 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin pyroglutamate.
[0020] FIG. 11 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin glutarate.
[0021] FIG. 12 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin acetate.
[0022] FIG. 13 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin hydrochloride amorphous form.
[0023] FIG. 14 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin citrate amorphous form.
[0024] FIG. 15 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin hemicitrate amorphous form.
[0025] FIG. 16 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin glycolate amorphous form.
[0026] FIG. 17 illustrates the X-ray powder diffraction pattern
(XRD) of sitagliptin malate amorphous form.
SUMMARY OF THE INVENTION
[0027] The present invention relates generally to novel crystalline
salt forms of
7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-te-
trahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine, i.e.
sitagliptin, to processes for their preparation and isolation, and
to pharmaceutical compositions comprising the same.
[0028] It has been found that sitagliptin can exist in a number of
crystalline salt forms.
[0029] The novel salt forms of sitagliptin have been prepared and
structurally characterized as described herein and are referred to
herein as sitagliptin galactarate crystalline form (Form I),
sitagliptin hemi-L-malate crystalline form (Form I), sitagliptin
D-gluconate crystalline form (Form I), sitagliptin succinate
crystalline form (Form I), sitagliptin hydrobromide crystalline
form (Form I), sitagliptin thiocyanate crystalline form (Form I),
sitagliptin oxalate crystalline form (Form I), sitagliptin
L-aspartate crystalline form (Form I), sitagliptin
ethanedisulfonate crystalline form (Form I), sitagliptin
pyroglutamate crystalline form (Form I), sitagliptin glutarate
crystalline form (Form I), and sitagliptin acetate crystalline form
(Form I).
[0030] The solid crystalline salt forms of sitagliptin of the
present invention have been characterized by means of Powder X-ray
diffraction pattern (XRD).
[0031] In addition, a selected group of the novel crystalline salt
forms of sitagliptin of the present invention have been found to be
highly stable in terms of polymorphic form after 10 months of
storage, which makes them suitable for pharmaceutical formulation
use.
[0032] Further, some of the selected crystalline salt forms of
sitagliptin of the present invention exhibit a good solubility
profile in water, i.e. equal to or higher than 20 g/L, and hence
also show enhanced pharmaceutical properties regarding the
dissolution rate and bioavailability.
[0033] Additionally, the formation of the selected crystalline salt
forms of sitagliptin of the invention might be an efficient way of
purifying sitagliptin base.
[0034] It has also been found that sitagliptin can exist in a
number of amorphous salt forms.
[0035] The novel amorphous salt forms of sitagliptin have been
prepared and structurally characterized as described herein and are
referred to herein as sitagliptin citrate amorphous form,
sitagliptin hemicitrate amorphous form, sitagliptin glycolate
amorphous form, and sitagliptin L-malate amorphous form.
[0036] The solid amorphous salt forms of sitagliptin of the present
invention have been characterized by means of Powder X-ray
diffraction pattern (XRD).
[0037] A first aspect of the present invention includes a new
sitagliptin galactarate salt in crystalline form (designated herein
as Form I).
[0038] The sitagliptin galactarate Form I of the present invention
shows an XRD pattern (2.theta.) having characteristic peaks at
approximately 4.4, 13.2, 19.6, 22.4 and 30.7.degree. and with
further peaks at: 14.3, 15.5, 16.5, 17.5, 18.6, 19.0, 23.0, 24.1,
25.4, 26.0, 26.9, 27.1, 34.5 and 37.7.degree.. FIG. 1 illustrates
the XRD of sitagliptin galactarate crystalline Form I.
[0039] The sitagliptin galactarate Form I of the present invention
has been found to be highly stable in terms of polymorphic form
after ten months of storage. Also, after ten months of storage, the
sitagliptin galactarate Form I of the invention has been found to
show an off-white colour and a purity higher than about 99.1%, as
determined by HPLC. Further, the sitagliptin galactarate Form I of
the invention is sparingly soluble in water (i.e. solubility about
20 g/L).
[0040] Another aspect of the invention relates to a process for
preparing sitagliptin galactarate Form I, said process comprising
contacting sitagliptin with galactaric acid, optionally in the
presence of a suitable solvent, and removing the solvent when
necessary.
[0041] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0042] The 1:1 salt correlation of sitagliptin galactarate was
confirmed by .sup.1H NMR spectrum.
[0043] Another aspect of the present invention includes a new
sitagliptin hemi-L-malate salt in crystalline form (designated
herein as Form I).
[0044] The sitagliptin hemi-L-malate Form I of the present
invention shows an XRD pattern (2.theta.) having characteristic
peaks at approximately 4.7, 9.5, 14.3, 15.6, 17.4, 18.2, 19.3 and
25.6.degree. and with further peaks at: 12.1, 12.6, 13.3, 13.6,
25.0, 26.6 and 34.3.degree.. FIG. 2 illustrates the XRD of
sitagliptin hemi-L-malate crystalline Form I.
[0045] Another aspect of the invention relates to a process for
preparing sitagliptin hemi-L-malate Form I, said process comprising
contacting sitagliptin with not more than 0.5 molar equivalents of
L-malic acid, optionally in the presence of a suitable solvent, and
removing the solvent when necessary.
[0046] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0047] The 2:1 salt correlation of sitagliptin L-hemimalate was
confirmed by .sup.1H NMR spectrum.
[0048] Another aspect of the present invention includes a new
sitagliptin D-gluconate salt in crystalline form (designated herein
as Form I).
[0049] The sitagliptin D-gluconate Form I of the present invention
shows an XRD pattern (2.theta.) having characteristic peaks at
approximately 15.7, 16.4, 17.6, 18.6, 18.9, 19.6, 20.6, 20.9, 21.5,
22.9, 24.2 and 24.9.degree. and with further peaks at: 5.0, 7.9,
10.0, 14.4, 15.2, 21.8, 24.5, 25.4, 26.0, 27.9, 28.3, 28.6, 30.6,
31.5, 31.9, 33.2, 34.3, 35.5 and 39.5.degree.. FIG. 3 illustrates
the XRD of sitagliptin D-gluconate crystalline Form I.
[0050] Another aspect of the invention relates to a process for
preparing sitagliptin D-gluconate Form I, said process comprising
contacting sitagliptin with D-gluconic acid, optionally in the
presence of a suitable solvent, and removing the solvent when
necessary.
[0051] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0052] The 1:1 salt correlation of sitagliptin D-gluconate was
confirmed by .sup.1H NMR spectrum.
[0053] Another aspect of the present invention includes a new
sitagliptin succinate salt in crystalline form (designated herein
as Form I).
[0054] The sitagliptin succinate Form I of the present invention
shows an XRD pattern (2.theta.) having characteristic peaks at
approximately 13.4, 15.7, 17.3, 20.0, 23.7, 24.4, 25.1, 25.6, 26.2
and 27.9.degree. and with further peaks at: 13.0, 13.0, 14.1, 19.5,
20.4, 21.8 and 23.0.degree.. FIG. 4 illustrates the XRD of
sitagliptin succinate crystalline Form I.
[0055] Another aspect of the invention relates to a process for
preparing sitagliptin succinate Form I, said process comprising
contacting sitagliptin with succinic acid, optionally in the
presence of a suitable solvent, and removing the solvent when
necessary.
[0056] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0057] The 1:1 salt correlation of sitagliptin succinate was
confirmed by .sup.1H NMR spectrum.
[0058] Another aspect of the present invention includes a new
sitagliptin hydrobromide salt in crystalline form (designated
herein as Form I).
[0059] The sitagliptin hydrobromide Form I of the present invention
shows an XRD pattern (2.theta.) having characteristic peaks at
approximately 5.6, 13.4, 17.6, 18.8, 19.7, 19.7, 21.9, 22.7, 23.0,
24.4, 25.0, 25.9 and 26.4.degree. and with further peaks at: 6.9,
15.0, 15.2, 20.0, 20.5, 21.3, 25.3, 25.5, 27.4, 28.1, 31.1, 32.1,
32.2, 33.3 and 34.4.degree.. FIG. 5 illustrates the XRD of
sitagliptin hydrobromide crystalline Form I.
[0060] Another aspect of the invention relates to a process for
preparing sitagliptin hydrobromide Form I, said process comprising
contacting sitagliptin with hydrobromic acid, optionally in the
presence of a suitable solvent, and removing the solvent when
necessary.
[0061] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0062] Another aspect of the present invention includes a new
sitagliptin thiocyanate salt in crystalline form (designated herein
as Form I).
[0063] The sitagliptin thiocyanate Form I of the present invention
shows an XRD pattern (2.theta.) having characteristic peaks at
approximately 7.9, 13.7, 15.8, 17.7, 17.9, 19.4, 22.4, 22.5, 23.3,
25.2, 25.3, 26.9, 31.7 and 45.4.degree. and with further peaks at:
6.2, 26.5 and 27.3.degree.. FIG. 6 illustrates the XRD of
sitagliptin thiocyanate crystalline Form I.
[0064] The sitagliptin thiocyanate Form I of the present invention
has been found to be highly stable in terms of polymorphic form
after ten months of storage. Also, after ten months of storage, the
sitagliptin thiocyanate Form I of the invention has been found to
show a light pink colour and a purity higher than about 99.2%, as
determined by HPLC.
[0065] Another aspect of the invention relates to a process for
preparing sitagliptin thiocyanate Form I, said process comprising
contacting sitagliptin with thiocyanic acid, optionally in the
presence of a suitable solvent, and removing the solvent when
necessary.
[0066] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0067] The thiocyanic acid can be optionally prepared in situ from
sodium thiocyanate and hydrochloric acid.
[0068] Another aspect of the present invention includes a new
sitagliptin oxalate salt in crystalline form (designated herein as
Form I).
[0069] The sitagliptin oxalate Form I of the present invention
shows an XRD pattern (2.theta.) having characteristic peaks at
approximately 8.3, 11.1, 17.0, 17.5, 20.6, 20.9, 25.3 and
27.0.degree. and with further peaks at: 14.5, 15.3, 15.4, 18.6,
19.7, 23.1, 24.0, 24.8, 27.8, 28.9 and 34.7.degree.. FIG. 7
illustrates the XRD of sitagliptin oxalate crystalline Form I.
[0070] Another aspect of the invention relates to a process for
preparing sitagliptin oxalate Form I, said process comprising
contacting sitagliptin with oxalic acid, optionally in the presence
of a suitable solvent, and removing the solvent when necessary.
[0071] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0072] Another aspect of the present invention includes a new
sitagliptin L-aspartate salt in crystalline form (designated herein
as Form I).
[0073] The sitagliptin L-aspartate Form I of the present invention
shows an XRD pattern (2.theta.) having characteristic peaks at
approximately 7.1, 8.1, 12.2, 15.4, 16.9, 18.7, 20.0, 21.1, 21.4,
23.6, 24.0, 25.6 and 29.4.degree. and with further peaks at: 14.1,
15.7, 19.5, 26.4, 28.5, 30.0, 31.0 and 35.8.degree.. FIG. 8
illustrates the XRD of sitagliptin L-aspartate crystalline Form
I.
[0074] Another aspect of the invention relates to a process for
preparing sitagliptin L-aspartate Form I, said process comprising
contacting sitagliptin with L-aspartic acid, optionally in the
presence of a suitable solvent, and removing the solvent when
necessary.
[0075] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0076] The 1:1 salt correlation of sitagliptin L-aspartate was
confirmed by .sup.1H NMR spectrum.
[0077] Another aspect of the present invention includes a new
sitagliptin ethanedisulfonate salt in crystalline form (designated
herein as Form I).
[0078] The sitagliptin ethanedisulfonate Form I of the present
invention shows an XRD pattern (2.theta.) having characteristic
peaks at approximately 8.0, 13.8, 16.0, 18.0, 18.7, 19.6, 21.2,
21.4, 21.6, 22.7, 23.5, 24.4, 25.4, 25.6 and 27.1.degree. and with
further peaks at: 6.3, 6.6, 7.1, 11.2, 14.4, 20.4, 23.0, 24.8,
26.5, 27.9 and 34.7.degree.. FIG. 9 illustrates the XRD of
sitagliptin ethanedisulfonate crystalline Form I.
[0079] The sitagliptin ethanedisulfonate Form I of the present
invention has been found to be highly stable in terms of
polymorphic form after ten months of storage. Also, after ten
months of storage, the sitagliptin ethanedisulfonate Form I of the
invention has been found to show an off-white colour and a purity
higher than about 99.8%, as determined by HPLC. Further, the
sitagliptin ethanedisulfonate Form I of the invention is freely
soluble in water (i.e. solubility >300 g/L).
[0080] Another aspect of the invention relates to a process for
preparing sitagliptin ethanedisulfonate Form I, said process
comprising contacting sitagliptin with ethanedisulfonic acid,
optionally in the presence of a suitable solvent, and removing the
solvent when necessary.
[0081] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0082] The ethanedisulfonic acid can be optionally prepared in situ
from the disodium salt of ethanedisulfonic acid and hydrochloric
acid.
[0083] The 1:1 salt correlation of sitagliptin ethanedisulfonate
was confirmed by .sup.1H NMR spectrum.
[0084] Another aspect of the present invention includes a new
sitagliptin (S)-pyroglutamate salt in crystalline form (designated
herein as Form I).
[0085] The sitagliptin pyroglutamate Form I of the present
invention shows an XRD pattern (2.theta.) having characteristic
peaks at approximately 5.4, 7.3, 13.5, 18.2, 18.8, 19.5, 20.6,
21.2, 23.2, 25.3 and 26.0.degree. and with further peaks at: 12.3,
15.1, 16.3, 24.0, 26.7, 28.3, 29.4 and 30.6.degree.. FIG. 10
illustrates the XRD of sitagliptin (S)-pyroglutamate crystalline
Form I.
[0086] Another aspect of the invention relates to a process for
preparing sitagliptin (S)-pyroglutamate Form I, said process
comprising contacting sitagliptin with pyrrilidon-5-carboxylic
acid, optionally in the presence of a suitable solvent, and
removing the solvent when necessary.
[0087] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0088] The 1:1 salt correlation of sitagliptin (S)-pyroglutamate
was confirmed by .sup.1H NMR spectrum.
[0089] Another aspect of the present invention includes a new
sitagliptin glutarate salt in crystalline form (designated herein
as Form I).
[0090] The sitagliptin glutarate Form I of the present invention
shows an XRD pattern (2.theta.) having characteristic peaks at
approximately 15.3, 16.3, 17.5, 18.0, 18.3, 20.7, 22.4, 22.8, 23.4,
24.6, 25.4.degree. and with further peaks at: 6.3, 7.9, 9.4, 12.7,
12.8, 16.7, 19.9, 26.4, 27.8, 28.5, 28.6, 29.0, 30.5, 33.8.degree..
FIG. 11 illustrates the XRD of sitagliptin glutarate crystalline
Form I.
[0091] The sitagliptin glutarate Form I of the present invention
has been found to be highly stable in terms of polymorphic form
after ten months of storage. Also, after ten months of storage, the
sitagliptin glutarate Form I of the invention has been found to
show a white colour and a purity higher than about 98.0%, as
determined by HPLC.
[0092] Another aspect of the invention relates to a process for
preparing sitagliptin glutarate Form I, said process comprising
contacting sitagliptin with glutaric acid, optionally in the
presence of a suitable solvent, and removing the solvent when
necessary.
[0093] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0094] The 1:1 salt correlation of sitagliptin glutarate was
confirmed by .sup.1H NMR spectrum.
[0095] Another aspect of the present invention includes a new
sitagliptin acetate salt in crystalline form (designated herein as
Form I).
[0096] The sitagliptin acetate Form I of the present invention
shows an XRD pattern (2.theta.) having characteristic peaks at
approximately 6.3, 7.5, 12.5, 19.4, 19.6, 20.4, 21.6, 24.7, 25.1,
25.9 and 26.0.degree. and with further peaks at: 10.1, 16.6, 22.4,
22.8, 27.1, 29.9, 31.0 and 31.9.degree.. FIG. 12 illustrates the
XRD of sitagliptin acetate crystalline Form I.
[0097] Another aspect of the invention relates to a process for
preparing sitagliptin acetate Form I, said process comprising
contacting sitagliptin with acetic acid, optionally in the presence
of a suitable solvent, and removing the solvent when necessary.
[0098] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0099] The 1:1 salt correlation of sitagliptin acetate was
confirmed by .sup.1H NMR spectrum.
[0100] Another aspect of the present invention includes a new
sitagliptin citrate salt in amorphous form.
[0101] The sitagliptin citrate amorphous form of the present
invention shows an X-ray diffraction pattern as is substantially
illustrated in FIG. 14.
[0102] Another aspect of the invention relates to a process for
preparing sitagliptin citrate amorphous form, said process
comprising contacting sitagliptin with at least 1 molar equivalent
of citric acid, optionally in the presence of a suitable solvent,
and removing the solvent when necessary.
[0103] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0104] The 1:1 salt correlation of sitagliptin citrate was
confirmed by .sup.1H NMR spectrum.
[0105] Another further aspect of the present invention includes a
new sitagliptin hemicitrate salt in amorphous form.
[0106] The sitagliptin hemicitrate amorphous form of the present
invention shows an X-ray diffraction pattern as is substantially
illustrated in FIG. 15.
[0107] Another further aspect of the invention relates to a process
for preparing sitagliptin hemicitrate amorphous form, said process
comprising contacting sitagliptin with not more than 0.5 molar
equivalents of citric acid, optionally in the presence of a
suitable solvent, and removing the solvent when necessary.
[0108] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0109] The 2:1 salt correlation of sitagliptin hemicitrate was
confirmed by .sup.1H NMR spectrum.
[0110] Another aspect of the present invention includes a new
sitagliptin glycolate salt in amorphous form.
[0111] The sitagliptin glycolate amorphous form of the present
invention shows an X-ray diffraction pattern as is substantially
illustrated in FIG. 16.
[0112] Another further aspect of the invention relates to a process
for preparing sitagliptin glycolate amorphous form, said process
comprising contacting sitagliptin with glycolic acid, optionally in
the presence of a suitable solvent, and removing the solvent when
necessary.
[0113] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0114] The 1:1 salt correlation of sitagliptin glycolate was
confirmed by .sup.1H NMR spectrum.
[0115] Another aspect of the present invention includes a new
sitagliptin L-malate salt in amorphous form.
[0116] The sitagliptin L-malate amorphous form of the present
invention shows an X-ray diffraction pattern as is substantially
illustrated in FIG. 17.
[0117] Another further aspect of the invention relates to a process
for preparing sitagliptin L-malate amorphous form, said process
comprising contacting sitagliptin with L-malic acid, optionally in
the presence of a suitable solvent, and removing the solvent when
necessary.
[0118] The suitable solvent comprises a C.sub.1-C.sub.5 alcohol
solvent or mixtures thereof. Preferably, the C.sub.1-C.sub.5
alcohol solvent is 2-propanol.
[0119] The 1:1 salt correlation of sitagliptin L-malate was
confirmed by .sup.1H NMR spectrum.
[0120] Another feature of the invention is to provide a
pharmaceutical composition comprising the sitagliptin crystalline
form salts of the invention.
SPECIFIC EXAMPLES
General Experimental Conditions
X-ray Powder Diffraction (XRD)
[0121] The XRD diffractograms were obtained using a RX SIEMENS
D5000 diffractometer with a vertical goniometer, a copper anodic
tube, and radiation CuK.alpha., .lamda.=1.54056.
HPLC Method
[0122] The chromatographic separation was carried out with a Waters
Sunfire C18 5 .mu.m 4.6.times.250 mm column at 30.degree. C. Mobile
phase A was a mixture of methanol and 5 mM dibasic sodium phosphate
buffer, pH=7.0 (70:30, v/v). The buffer was prepared by dissolving
0.217 g of dibasic sodium phosphate in 300 mL of water and
adjusting the pH of the solution to 7.0.+-.0.1 with phosphoric
acid, and filtered through a 0.22 .mu.m nylon membrane under
vacuum. Mobile phase B was methanol.
[0123] The flow rate was 1 mL per minute and the chromatograph was
recorded at 254 nm. Test samples (10 .mu.L) were prepared by
dissolving the appropriate amount of sample in methanol in order to
obtain 1 mg of sample per mL. The following gradient was used:
TABLE-US-00001 Time (min.) % A % B 0 100 0 26 100 0 36 90 10 70 90
10 80 100 0 90 100 0
Examples 1-4
Preparation of Sitagliptin Salt Forms
[0124] General procedure: sitagliptin base (150 mg) was suspended
in 2-propanol (2.5 mL). The acid (quantity indicated in Table 1
below) was added and the mixture was stirred for one hour at
ambient temperature and 2 hours at 40.degree. C. The mixture was
allowed to cool to ambient temperature and stirred for 24 hours at
this temperature. The solid was filtered and dried at ambient
temperature.
TABLE-US-00002 TABLE 1 Sitagliptin salt Example Acid Quantity form
XRD 1 Galactaric acid 77 mg Sitagliptin FIG. 1 galactarate 2
L-Malic acid 25 mg Sitagliptin FIG. 2 hemi-L-malate 3 D-Gluconic
acid 145 mg Sitagliptin D- FIG. 3 50% water gluconate 4 Succinic
acid 44 mg Sitagliptin FIG. 4 succinate
Examples 5-12
Preparation of Sitagliptin Salt Forms
[0125] General procedure: sitagliptin base (150 mg) was suspended
in 2-propanol (2.5 mL). The acid (quantity indicated in Table 2
below) was added and the mixture was stirred for one hour at
ambient temperature and 2 hours at 40.degree. C. The mixture was
allowed to cool to ambient temperature and stirred for 24 hours at
this temperature. The mixture was concentrated under vacuum at
ambient temperature.
TABLE-US-00003 TABLE 2 Sitagliptin salt Example Acid Quantity form
XRD 5 Hydrobromic 62 mg Sitagliptin FIG. 5 acid 48% hydrobromide 6
Thiocyanic acid 30 mg Sitagliptin FIG. 6 disodium salt* thiocyanate
7 Oxalic acid 33 mg Sitagliptin oxalate FIG. 7 (anhydrous) 8
L-Aspartic acid 49 mg Sitagliptin FIG. 8 aspartate 9
Ethanedisulfonic 86 mg Sitagliptin FIG. 9 acid disodium
ethanedisulfonate salt** 10 Pyrrolidinon-5- 47 mg Sitagliptin FIG.
10 carboxylic acid pyroglutamate 11 Glutaric acid 48 mg Sitagliptin
FIG. 11 glutarate 12 Acetic acid 22 mg Sitagliptin acetate FIG. 12
Note: *36 mg of HCl (37% aqueous) was also added. **73 mg of HCl
(37% aqueous) was also added.
Example 13
Preparation of Sitagliptin Hydrochloride Amorphous Form
[0126] Sitagliptin base (150 mg) was suspended in 2-propanol (2.5
mL). Hydrochloric acid (36 mg of 37% aqueous solution) was added
and the mixture was stirred for one hour at ambient temperature and
2 hours at 40.degree. C. The mixture was allowed to cool to ambient
temperature and stirred for 24 hours before evaporation of the
solvent.
[0127] Analytical data: XRD: amorphous form, see FIG. 13.
Example 14
Preparation of Sitagliptin Citrate Amorphous Form
[0128] Sitagliptin base (150 mg) was suspended in 2-propanol (2.5
mL). Citric acid (71 mg) was added and the mixture was stirred for
one hour at ambient temperature and 2 hours at 40.degree. C. The
mixture was allowed to cool to ambient temperature and stirred for
24 hours at this temperature. The solid was filtered and dried at
ambient temperature.
[0129] Analytical data: XRD: amorphous form, see FIG. 14.
Example 15
Preparation of Sitagliptin Hemicitrate Amorphous Form
[0130] Sitagliptin base (150 mg) was suspended in 2-propanol (2.5
mL). Citric acid (35 mg) was added and the mixture was stirred for
one hour at ambient temperature and 2 hours at 40.degree. C. The
mixture was allowed to cool to ambient temperature and stirred for
24 hours at this temperature. The solid was filtered and dried at
ambient temperature.
[0131] Analytical data: XRD: amorphous form, see FIG. 15.
Example 16
Preparation of Sitagliptin Glycolate Amorphous Form
[0132] Sitagliptin base (150 mg) was suspended in 2-propanol (2.5
mL). Glycolic acid (28 mg) was added and the mixture was stirred
for one hour at ambient temperature and 2 hours at 40.degree. C. to
give a solution. The mixture was allowed to cool to ambient
temperature and stirred for 24 hours at this temperature. The
solution was concentrated under vacuum at ambient temperature.
[0133] Analytical data: XRD: amorphous form, see FIG. 16.
Example 17
Preparation of Sitagliptin L-Malate Amorphous Form
[0134] Sitagliptin base (150 mg) was suspended in 2-propanol (2.5
mL). L-malic acid (49 mg) was added and the mixture was stirred for
one hour at ambient temperature and 2 hours at 40.degree. C. The
mixture was allowed to cool to ambient temperature and stirred for
24 hours at this temperature. The solid was filtered and dried at
ambient temperature.
[0135] Analytical data: XRD: amorphous form, see FIG. 17.
Example 18
Stability Studies of Sitagliptin Salts
[0136] Sitagliptin salts were stored under standard conditions
(i.e. room temperature, normal pressure, and ambient atmosphere).
The samples were analyzed after 10 months by HPLC, XRD, and visual
inspection. Results are summarized in Table 3.
TABLE-US-00004 TABLE 3 Aspect/Colour XRD analysis Purity (HPLC) 10
10 10 SITAGLIPTIN months months months SALT Initial later Initial
later Initial later Galactarate n.d..sup.a off-white Form I Form I
n.d..sup.a 99.15% Hemi-L-malate n.d..sup.a light Form I n.d..sup.a
n.d..sup.a 98.91% yellow D-Gluconate n.d..sup.a beige Form I
n.d..sup.a n.d..sup.a 96.29% Succinate n.d..sup.a off-white Form I
n.d..sup.a n.d..sup.a 98.88% Hydrobromide n.d..sup.a off-white Form
I Form I n.d..sup.a 98.92% Thiocyanate n.d..sup.a light pink Form I
Form I n.d..sup.a 99.22% Oxalate n.d..sup.a white Form I Form I
n.d..sup.a 95.95% L-aspartate n.d..sup.a white Form I Different
n.d..sup.a 97.14% form Ethane- n.d..sup.a off-white Form I Form I
n.d..sup.a 99.83% disulfonate Pyroglutamate n.d..sup.a off-white
Form I Different n.d..sup.a 98.64% form Glutarate n.d..sup.a white
Form I Form I n.d..sup.a 98.50% Acetate n.d..sup.a off-white Form I
n.d..sup.a n.d..sup.a 98.90% .sup.aNot determined.
Example 19
Solubility Studies in Water of Sitagliptin Salts
[0137] Sitagliptin salts were suspended in water under standard
conditions (i.e. room temperature, normal pressure, and ambient
atmosphere), stirred until equilibration and filtered. The mother
liquors were analyzed by HPLC. Results are summarized in Table
4.
TABLE-US-00005 TABLE 4 Descriptive Sitagliptin salt Solubility
(g/L) term Galactarate About 20 Sparingly soluble Ethanedisulfonate
>300 Freely soluble
* * * * *