U.S. patent application number 16/243404 was filed with the patent office on 2019-12-12 for hydrochloride salts of 8-[{1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaz- a-spiro[4.5]decan-2-one and pr.
This patent application is currently assigned to OPKO Health, Inc.. The applicant listed for this patent is OPKO Health, Inc.. Invention is credited to Frank Bruno Guenter, Mengwei Hu, Ingrid Mergelsberg, Sunil Paliwal, Neng-Yang Shih.
Application Number | 20190375751 16/243404 |
Document ID | / |
Family ID | 38542035 |
Filed Date | 2019-12-12 |
![](/patent/app/20190375751/US20190375751A1-20191212-C00001.png)
![](/patent/app/20190375751/US20190375751A1-20191212-C00002.png)
![](/patent/app/20190375751/US20190375751A1-20191212-C00003.png)
![](/patent/app/20190375751/US20190375751A1-20191212-C00004.png)
![](/patent/app/20190375751/US20190375751A1-20191212-C00005.png)
![](/patent/app/20190375751/US20190375751A1-20191212-C00006.png)
![](/patent/app/20190375751/US20190375751A1-20191212-C00007.png)
![](/patent/app/20190375751/US20190375751A1-20191212-C00008.png)
![](/patent/app/20190375751/US20190375751A1-20191212-D00001.png)
![](/patent/app/20190375751/US20190375751A1-20191212-D00002.png)
![](/patent/app/20190375751/US20190375751A1-20191212-D00003.png)
View All Diagrams
United States Patent
Application |
20190375751 |
Kind Code |
A1 |
Hu; Mengwei ; et
al. |
December 12, 2019 |
HYDROCHLORIDE SALTS OF
8-[{1-(3,5-BIS-(TRIFLUOROMETHYL)PHENYL)-ETHOXY}-METHYL]-8-PHENYL-1,7-DIAZ-
A-SPIRO[4.5]DECAN-2-ONE AND PREPARATION PROCESS THEREFOR
Abstract
Disclosed are hydrochloride and tosylate crystalline salt forms
of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one, represented by Formula I and
methods of preparing the same.
Inventors: |
Hu; Mengwei; (Washington
Township, NJ) ; Paliwal; Sunil; (Monroe Township,
NJ) ; Shih; Neng-Yang; (Warren, NJ) ; Guenter;
Frank Bruno; (Schachen, CH) ; Mergelsberg;
Ingrid; (Mahwah, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OPKO Health, Inc. |
Miami |
FL |
US |
|
|
Assignee: |
OPKO Health, Inc.
Miami
FL
|
Family ID: |
38542035 |
Appl. No.: |
16/243404 |
Filed: |
January 9, 2019 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14683871 |
Apr 10, 2015 |
10196394 |
|
|
16243404 |
|
|
|
|
13923859 |
Jun 21, 2013 |
|
|
|
14683871 |
|
|
|
|
12614108 |
Nov 6, 2009 |
8470842 |
|
|
13923859 |
|
|
|
|
11732548 |
Apr 4, 2007 |
8178550 |
|
|
12614108 |
|
|
|
|
60789280 |
Apr 5, 2006 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/04 20180101;
C07D 471/10 20130101; A61K 45/06 20130101; A61K 31/435 20130101;
A61P 1/00 20180101; C07B 2200/13 20130101; A61P 43/00 20180101;
A61P 25/06 20180101; A61P 29/00 20180101; A61P 1/08 20180101; A61K
31/495 20130101 |
International
Class: |
C07D 471/10 20060101
C07D471/10; A61K 45/06 20060101 A61K045/06; A61K 31/495 20060101
A61K031/495; A61K 31/435 20060101 A61K031/435 |
Claims
1-39. (canceled)
40. A crystalline hydrochloride anhydrous Form I salt form of
8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-
-diazaspiro[4.5]decan-2-one (Formula I), ##STR00006## characterized
by an X-ray powder diffraction pattern having peaks present at
diffraction angles (in 2.theta..+-.0.2) of: 12.9; 15.4; 17.3; and
20.2.
41. A crystalline hydrochloride anhydrous Form II salt form of
8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-
-diazaspiro[4.5]decan-2-one (Formula I), ##STR00007## characterized
by an x-ray powder diffraction pattern having peaks present at
diffraction angles (in 2.theta..+-.0.2) of: 7.0; 9.0; 12.6; and
20.2.
42. A pharmaceutical composition comprising the crystalline salt
form of claim 40 and a pharmaceutically acceptable carrier
optionally in combination with one or more additional therapeutic
agents.
43. A pharmaceutical composition comprising the crystalline salt
form of claim 41 and a pharmaceutically acceptable carrier
optionally in combination with one or more additional therapeutic
agents.
44. A method of treating or delaying the onset of nausea and/or
emesis in a mammal which comprises administering to said mammal the
crystalline salt form of claim 40.
45. A method of treating or delaying the onset of nausea and/or
emesis in a mammal which comprises administering to said mammal the
crystalline salt form of claim 41.
46. A method of treating or delaying the onset of
chemotherapy-induced nausea and/or chemotherapy induced emesis in a
mammal receiving chemotherapy, which comprises administering to
said mammal the crystalline salt form of claim 40.
47. The method of claim 46 further comprising contemporaneous
administration of a chemotherapeutic agent.
48. A method of treating or delaying the onset of
chemotherapy-induced nausea and/or chemotherapy induced emesis in a
mammal receiving chemotherapy, which comprises administering to
said mammal the crystalline salt form of claim 41.
49. The method of claim 48 further comprising contemporaneous
administration of a chemotherapeutic agent.
50. A process for preparing a crystalline salt form of
8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-
-diazaspiro[4.5]decan-2-one ##STR00008## comprising a step of
treating Formula 1 with at least one equivalent of an acid selected
from hydrochloric acid and 4-toluenesulfonic acid to provide the
crystalline salt form of Formula 1.
51. The process of claim 50, wherein the acid is hydrochloric
acid.
52. The process of claim 50, wherein the acid is 4-toluenesulfonic
acid.
53. The process of claim 51, further comprising a step of
precipitating from a solvent a crystalline hydrochloride
monohydrate form of Formula 1.
54. The process of claim 53, wherein the solvent comprises ethanol
and water.
55. The process of claim 54, wherein the crystalline hydrochloride
monohydrate form of Formula 1 is a Form I crystalline salt form of
8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-
-diazaspiro[4.5]decan-2-one monohydrate hydrochloride.
56. The process of claim 55, wherein the Form I crystalline salt
form of
8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-
-diazaspiro[4.5]decan-2-one monohydrate hydrochloride is
characterized by an X-ray powder diffraction pattern having a
diffraction angle (in 2.theta.) of 21.6.+-.0.2.
57. The process of claim 52, further comprising a step of
precipitating from a first solvent a crystalline tosylate form of
Formula 1.
58. The process of claim 57, wherein the first solvent comprises
ethanol and diethyl ether.
59. The process of claim 58, wherein the crystalline tosylate form
of Formula 1 is a Form I crystalline salt form of
8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-
-diazaspiro[4.5]decan-2-one tosylate.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority from U.S.
Provisional Application 60/789,280 filed Apr. 5, 2006.
FIELD OF THE INVENTION
[0002] This patent application generally relates to
pharmaceutically useful salts and a novel process to prepare
pharmaceutically useful salts. It specifically relates to a novel
process to synthesize pharmaceutically useful salts of
8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaz-
a-spiro[4.5]decan-2-one.
BACKGROUND OF THE INVENTION
[0003] The preparation of diazaspirodecan-2-ones, in particular,
8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaz-
a-spiro[4.5]decan-2-ones, for example,
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) is
disclosed in U.S. Pat. No. 7,049,320, issued May 23, 2006 (the '320
patent) which is incorporated herein by reference in its
entirety.
##STR00001##
[0004] The novel compounds disclosed in the '320 patent are
classified as Tachykinin compounds, and are antagonists of
neuropeptide neurokinin-1 receptors (referred to herein for
convenience as "NK-1 receptor antagonists").
[0005] The compounds described in the '320 patent are classified as
tachykinin compounds, and are antagonists of neuropeptide
neurokinin-1 receptors (herein, "NK-1" receptor antagonists). Other
NK.sub.1 receptor antagonists and their synthesis have been
described, for example, those described in Wu et al, Tetrahedron
56, 3043-3051 (2000); Rombouts et al, Tetrahedron Letters 42,
7397-7399 (2001); Rogiers et al, Tetrahedron 57, 8971-8981 (2001)
and in each of the following publications: published international
application no. WO05/100358; U.S. Pat. No. 5,760,018 (1998); U.S.
Pat. No. 5,620,989 (1997), and international publication nos. WO
95/19344 (1995), WO 94/13639 (1994), and WO 94/10165 (1994), each
of which are incorporated herein in their entirety by
reference.
[0006] "NK-1" receptor antagonists have been shown to be useful
therapeutic agents, for example, in the treatment of pain,
inflammation, migraine, emesis (vomiting), and nociception. The
novel NK-1 compounds disclosed in the above-mentioned '320 patent
include the compound of Formula I, which is useful in the treatment
of nausea and emesis associated with chemotherapy treatments
(Chemotherapy-induced nausea and emesis, CINE). Emesis and nausea
have been a problem in the provision of chemotherapy.
Chemotherapeutic agents, for example, cisplatin carboplatin and
temozolomide have been associated with both acute and delayed onset
nausea and vomiting. It is known to administer chemotherapeutic
agents with an anti-emetic, for example, as described in U.S. Pat.
No. 5,939,098, which describes coadministration of temozolomide and
with ondansetron, however such therapy is not effective in
preventing delayed onset nausea and vomiting.
[0007] As reported in the '320 patent, the compound of Formula I
was characterized by TLC and by GC/MS techniques. The procedures
described in the '320 patent yielded the compound of Formula I in
the form of an amorphous white foam. Repeated attempts to
crystallize the free base have not provided a crystalline
material.
[0008] In general, compounds which have been identified as having
therapeutic activity must be provided in a highly pure form for
pharmaceutical use. Moreover, it is desirable to provide compounds
intended for pharmaceutical use in a form such that it is handled
easily for incorporation into a medicament, and when incorporated
into a medicament the compound possesses a sufficiently robust
character that it is resistant to chemical degradation, and thereby
imparts a long shelf life to the medicament.
OBJECTIVES AND SUMMARY OF THE INVENTION
[0009] In view of the foregoing, what is desired is a form of the
therapeutic agent which lends itself to providing the therapeutic
agent in a highly purified form. What is desired also is a form of
the therapeutic agent which is robust toward degradation under the
environmental conditions in which it is handled and stored.
[0010] These and other objectives are advantageously provided by
the present invention, which in one aspect provides the compound of
Formula I in a salt form which is crystalline and optionally
incorporates one or more solvent molecules thereinto, for example,
a crystalline monohydrate. In some embodiments it is preferred to
select the salt form of compound I from a hydrochloride salt and a
Tosylate salt, more preferably, a hydrochloride monohydrate salt
form of the compound of Formula I.
[0011] Another aspect of the present invention is the provision of
a crystalline hydrochloride monohydrate salt form of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one (the hydrochloride monohydrate
compound of Formula II)
##STR00002##
which is characterized by the x-ray powder diffraction pattern
shown in Table I expressed in terms of diffraction angle (in
2.theta., all values reflect an accuracy of .+-.0.2) lattice "d"
spacing (in angstroms) and relative peak intensities ("RI"):
TABLE-US-00001 TABLE I Diffraction angle (2.theta., .+-.0.2 RI
Lattice Spacing (.ANG. .+-. 0.04) 16.1 Medium 5.49 18.4 Medium 4.83
21.6 Strong 4.11 23.5 Weak 3.78
[0012] Another aspect of the present invention is the provision of
a crystalline hydrochloride anhydrous salt form (HCl Anhydrous Form
1) of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one which is characterized by the
x-ray powder diffraction pattern shown in Table II expressed in
terms of diffraction angle (in 2.theta.), lattice "d" spacing (in
angstroms) and relative peak intensities ("RI"):
TABLE-US-00002 TABLE II Diffraction angle (2.theta., .+-.0.2 RI
Lattice Spacing (.ANG. .+-. 0.04) 12.9 Strong 6.86 15.4 Strong 5.75
17.3 Strong 5.13 20.2 Strong 4.39
[0013] Another aspect of the present invention is the provision of
a crystalline hydrochloride anhydrous salt form (HCl Anhydrous Form
II) of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one which is characterized by the
x-ray powder diffraction pattern shown in Table III expressed in
terms of diffraction angle (in 2.theta.), lattice "d" spacing (in
angstroms) and relative peak intensities ("RI"):
TABLE-US-00003 TABLE III Diffraction angle (2.theta., .+-.0.2 RI
Lattice Spacing (.ANG. .+-. 0.04) 7.0 Medium 12.70 9.0 Strong 9.87
12.6 Very 7.00 Strong 20.2 Strong 4.39
[0014] Another aspect of the present invention is the provision of
a crystalline Tosylate salt form (Tosylate Form I) of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one which is characterized by the
x-ray powder diffraction pattern shown in Table IV, expressed in
terms of diffraction angle (in 2.theta.), lattice "d" spacing (in
angstroms) and relative peak intensities ("RI"):
TABLE-US-00004 TABLE IV Diffraction angle (2.theta., .+-.0.2 RI
Lattice Spacing (.ANG. .+-. 0.04) 9.4 Medium 9.35 20.0 Very 4.43
Strong 21.0 Medium 4.22 Strong 25.3 Medium 3.51 Strong
[0015] Another aspect of the present invention is the provision of
a crystalline Tosylate salt form (Tosylate Form II) of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one which is characterized by the
x-ray powder diffraction pattern shown in Table V expressed in
terms of diffraction angle (in 2.theta.), lattice "d" spacing (in
angstroms) and relative peak intensities ("RI"):
TABLE-US-00005 TABLE V Diffraction angle (2.theta., .+-.0.2 RI
Lattice Spacing (.ANG. .+-. 0.04) 5.0 Very 17.66 Strong 10.0 Strong
8.80 13.6 Medium 6.52 19.7 Very 4.49 Strong
[0016] Another aspect of the present invention is the provision of
a crystalline Tosylate salt form (Tosylate Form ill) of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one which is characterized by the
x-ray powder diffraction pattern shown in Table VI, expressed in
terms of diffraction angle (in 2.theta.), lattice "d" spacing (in
angstroms) and relative peak intensities ("RI"):
TABLE-US-00006 TABLE VI Diffraction angle (2.theta., .+-.0.2 RI
Lattice Spacing (.ANG. .+-. 0.04) 6.3 Medium 14.02 9.7 Very 9.13
Strong 20.2 Strong 4.39 22.2 Strong 4.00
[0017] Another aspect of the present invention is the provision of
a crystalline Tosylate salt form (Tosylate Form IV) of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one which is characterized by the
x-ray powder diffraction pattern shown in Table VII, expressed in
terms of diffraction angle (in 2.theta.), lattice "d" spacing (in
angstroms) and relative peak intensities ("RI"):
TABLE-US-00007 TABLE VII Diffraction angle (2.theta., .+-.0.2 RI
Lattice Spacing (.ANG. .+-. 0.04) 6.1 Strong 14.44 9.6 Strong 9.19
20.9 Strong 4.26 22.0 Strong 4.03
[0018] Another aspect of the invention is the provision of
pharmaceutical compositions containing at least one crystalline
salt form of
((5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-p-
henyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I)
selected from hydrochloride monohydrate form I salt, anhydrous
hydrochloride forms I and II salts, and tosylate forms I, II and
III salts, and the provision of methods of treating and/or
preventing nausea and emesis by administering a medicament
containing one or more of a crystalline salt forms of the compound
of Formula I. In some embodiments it is preferred to coadminister a
salt of the compound of Formula I prepared in accordance with the
present invention with other therapeutic agents, for example, a
chemotherapeutic agent, for example, temozolomide and cisplatin,
preferably temozolomide.
[0019] In some embodiments it is preferred to administer additional
therapeutic agents in a dosing regime selected from contemporaneous
and simultaneous administration of additional therapeutic agents
contained in a separate dosage form. In some embodiments it is
preferred to administer additional therapeutic agents along with a
salt of the present invention by simultaneous administration using
a dosage form containing at least one salt of the present invention
along with one or more therapeutic agents.
[0020] In some embodiments it is preferred to provide therapy by
administering a medicament comprising the crystalline hydrochloride
monohydrate salt form I of
(5S,8S)-8-[[(1R)-1-(3,5-Bis-trifluoromethyl)phenyl]-ethoxymethyl]-8-pheny-
l-1,7-diazaspiro[4.5]decan-2-one in an amount providing a
therapeutically effective serum level of the compound of Formula I
or its salt in the treatment and/or prevention of nausea and
emesis.
BRIEF DESCRIPTION OF THE FIGURES
[0021] FIG. 1 presents a characteristic x-ray powder diffraction
pattern of the crystalline hydrochloride monohydrate salt form of
the compound of Formula I [Vertical Axis: Intensity CPS, counts
(square root)); Horizontal Axis: Two Theta (2) (degrees)].
[0022] FIG. 2 presents a characteristic infrared spectrum of the
crystalline hydrochloride monohydrate salt form of the compound of
Formula I [Vertical Axis; Transmittance (Percent); Horizontal Axis:
wavenumber (cm-1)].
[0023] FIG. 3 presents a characteristic Raman spectrum of the
crystalline hydrochloride monohydrate salt form of the compound of
Formula I, [horizontal axis; Raman shift in reciprocal centimeters,
vertical axis; relative intensity versus background]
[0024] FIG. 4 presents a characteristic differential scanning
calorimetry thermogram of the crystalline hydrochloride monohydrate
salt form of the compound of Formula I, [Vertical Axis; Heat Flow
in cal/sec/g; Horizontal Axis: Temperature in degrees
centigrade].
[0025] FIG. 5 presents a characteristic x-ray powder diffraction
pattern of the crystalline hydrochloride anhydrous salt form I of
the compound of Formula I. [Vertical Axis: Intensity (CPS, counts
(square root)); Horizontal Axis: Two Theta ((2.theta.)
degrees)].
[0026] FIG. 6 presents a characteristic x-ray powder diffraction
pattern of the cyrstalline hydrochloride anhydrous salt form II of
the compound of Formula I, [Vertical Axis: Intensity (CPS, counts
(square root)); Horizontal Axis: Two Theta ((2.theta.)
degrees)].
[0027] FIG. 7 presents a characteristic infrared spectrum of the
crystalline hydrochloride anhydrous salt form II of the compound of
Formula I [Vertical Axis; Transmittance (Percent); Horizontal Axis:
wavenumber (cm-1)].
[0028] FIG. 8 presents a characteristic Raman spectrum of the
crystalline hydrochloride anhydrous salt form II of the compound of
Formula I, [horizontal axis; Raman shift in reciprocal centimeters,
vertical axis; relative intensity versus background]
[0029] FIG. 9 presents a characteristic x-ray powder diffraction
pattern of the cyrstalline tosylate salt form I of the compound of
Formula I, [Vertical Axis: Intensity (CPS, counts (square root));
Horizontal Axis: Two Theta ((2.theta.) degrees)].
[0030] FIG. 10 presents a characteristic infrared spectrum of the
crystalline tosylate salt form I of the compound of Formula I
[Vertical Axis; Transmittance (Percent); Horizontal Axis:
wavenumber (cm-1)].
[0031] FIG. 11 presents a characteristic Raman spectrum of the
crystalline tosylate salt form I of the compound of Formula I,
[horizontal axis: Raman shift in reciprocal centimeters, vertical
axis; relative intensity versus background].
[0032] FIG. 12 presents a characteristic x-ray powder diffraction
pattern of the crystalline tosylate salt form II (crystallized from
acetonitrile) of the compound of Formula I, [Vertical Axis:
Intensity (CPS, counts (square root)); Horizontal Axis: Two Theta
((2.theta.) degrees)].
[0033] FIG. 13 presents a characteristic x-ray powder diffraction
pattern of the crystalline tosylate salt form III (hexane solvate)
of the compound of Formula I, [Vertical Axis: Intensity (CPS,
counts (square root)); Horizontal Axis: Two Theta ((2.theta.)
degrees)].
[0034] FIG. 14 presents a characteristic x-ray powder diffraction
pattern of the crystalline tosylate salt form IV (THF solvate) of
the compound of Formula I, [Vertical Axis: Intensity (CPS, counts
(square root)); Horizontal Axis: Two Theta ((2.theta.)
degrees)].
[0035] FIG. 15 presents a characteristic infrared spectrum of the
crystalline tosylate salt form II (crystallized from acetonitrile)
of the compound of Formula I [Vertical Axis; Transmittance
(Percent); Horizontal Axis: wavenumber (cm-1)].
[0036] FIG. 16 presents a characteristic Raman spectrum of the
crystalline tosylate salt form II (crystallized from acetonitrile)
of the compound of Formula I, [horizontal axis; Raman shift in
reciprocal centimeters, vertical axis; relative intensity versus
background].
[0037] FIG. 17 presents a characteristic infrared spectrum of the
crystalline tosylate salt form IV (THF solvate) of the compound of
Formula I [Vertical Axis; Transmittance (Percent); Horizontal Axis:
wavenumber (cm-1)].
[0038] FIG. 18 presents a characteristic Raman spectrum of the
crystalline tosylate salt form IV (THF solvate) of the compound of
Formula I, [horizontal axis; Raman shift in reciprocal centimeters,
vertical axis; relative intensity versus background]
[0039] FIG. 19 presents a characteristic differential scanning
calorimetry thermogram of the crystalline tosylate salt form I of
the compound of Formula I, [Vertical Axis; Heat Flow in cal/sec/g;
Horizontal Axis: Temperature in degrees centigrade].
[0040] FIG. 20 presents a characteristic differential scanning
calorimetry thermogram of the crystalline tosylate salt form II
(crystallized from acetonitrile) of the compound of Formula I,
[Vertical Axis; Heat Flow in cal/sec/g; Horizontal Axis:
Temperature in degrees centigrade].
[0041] FIG. 21 presents a characteristic differential scanning
calorimetry thermogram of the crystalline tosylate salt form III
(hexane solvate) of the compound of Formula I, [Vertical Axis; Heat
Flow in cal/sec/g; Horizontal Axis: Temperature in 25 degrees
centigrade].
[0042] FIG. 22 presents a characteristic solution proton NMR
spectrum of a hydrochloride salt of the compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0043] Salt forms of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I)
provide a therapeutic agent beneficial in the treatment of nausea
and emesis.
##STR00003##
[0044] The preparation of salts of
(5S,8S)-8-[[(1R)-1-(3,5-Bis-trifluoromethyl)phenyl]-ethoxymethyl]-8-pheny-
l-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I),
including the monohydrate hydrochloride salt of Formula II (shown
above) and various tosylate salts, having physical and chemical
properties useful in the provision of medicaments are disclosed in
U.S. application No. 60/789,280 and 60/789,513, each of which is
incorporated herein in its entirety by reference.
[0045] Two of the most debilitating side effects of cytotoxic
chemotherapy are nausea and vomiting (emesis). There is both
acute-phase chemotherapy induced nausea and emesis (CINE) and
delayed-phase CINE. Acute-phase CINE occurs in the first 24 hours
after chemotherapy administration while delayed-phase CINE
manifests from between 2 days and 5 days post chemotherapy
administration. Acute-phase CINE has been managed by administering
5HT3 receptor antagonists, often in combination with a
corticosteroid, for example, dexamethasone, this treatment has not
been effective in managing delayed-phase CINE. It is believed that
acute-phase CINE and delayed-phase CINE arise from different
physiological phenomena. It is believed that administration of an
NK-1 receptor antagonist, for example, salts of
(5S,8S)-8-[[(1R)-1-(3,5-Bis-trifluoromethyl)phenyl]-ethoxymethyl]-8-pheny-
l-1,7-diazaspiro[4.5]decan-2-one, either alone or in combination
with one or more of a corticosteroid, for example, dexamethasone
and/or a 5HT3 receptor antagonist, for example, ondensetron,
granisetron, palonosetron, dolasetron, or tropisetron will provide
a therapy effective in treatment of CINE in humans.
[0046] The salts of
(5S,8S)-8-[[(1R)-1-(3,5-Bis-trifluoromethyl)phenyl]-ethoxymethyl]-8-pheny-
l-1,7-diazaspiro[4.5]decan-2-one are useful in the provision of
therapy to address CINE and other conditions amenable to treatment
by the administration of an NK-1 inhibitor, for example, nausea
and/or emesis due to other causative factors, for example, motion
sickness and morning sickness. Optionally, a formulation containing
one of the salts of the present invention, when administered in an
effective dosage amount, and optionally, administered along with a
separate medicament containing either a 5HT3 receptor antagonists,
for example, ondensetron, granisetron, palonosetron, dolasetron, or
tropisetron and/or one or more corticosteroid, for example,
dexamethasone, will be useful in the management of CINE.
Optionally, a formulation containing a salt of the invention can
additionally include one or more 5HT3 receptor antagonist, for
example ondensetron, granisetron, palonosetron, dolasetron, or
tropisetron, and/or one or more corticosteroid, for example,
dexamethasone, in the provision of therapy in the treatment of both
acute-phase and delayed-phase CINE.
[0047] The invention further provides a method of treating nausea
and/or emesis. It is to believed that medicaments comprising salts
of the compound of Formula I are useful in the provision of
anti-nausea and anti-emesis treatment for nausea and emesis arising
from any cause, for example, arising from chemotherapy, from
radiation therapy, arising during a post-operative recovery period,
arising from motion sickness, arising from morning sickness, and
arising from inner ear disturbances and infections. However, it is
believed that the compound of Formula I is most advantageously
employed in the provision of anti-nausea and/or anti-emesis
treatment for delayed onset nausea and/or emesis associated with
chemotherapy treatments, radiation treatments, and arising during a
post-operative period. In some embodiments it is preferred to
provide a combination of a salt of the compound of Formula I
prepared in accordance with the present invention, or a
pharmaceutical composition containing the salt, and other
therapeutic agents, for example, a chemotherapeutic agent, for
example, temozolomide and cisplatin, preferably temozolomide.
[0048] As used herein a combination includes: physically combined
therapeutic agents in a pharmaceutical composition for
administering in a single dosage form; a medicament or kit
containing multiple therapeutic agents in one or more containers;
and providing therapy that includes providing a therapeutically
effective level of the compound of Formula I and other therapeutic
agents, for example, by contemporaneous or simultaneous
administration, as described herein, of more than one therapeutic
agent. When a kit combination is provided, generally multiple
medicaments are supplied in a form that will provide, upon
administration to a patient in need of such therapy, a
therapeutically effective amount of the active pharmaceutical
ingredient(s) contained therein.
[0049] Coadministration can be carried out by contemporaneous
administration of additional therapeutic agents, that is,
administering a second medicament before, during, or after
administration of a medicament comprising one or more of the salt
forms of the present invention, where the second medicament
contains one or more additional therapeutic agents in one or more
additional dosage forms. Coadministration of additional therapeutic
agents can also be carried out by simultaneous administration of
multiple therapeutic agents contained in a single dosage form. An
example of the latter administration scheme is a capsule dosage
form containing one or more salts of the present invention together
with one or more additional therapeutic agents, for example, a 5
HT-3 inhibitor, or a chemotherapeutic agent, for example,
temozolomide. In some dosage forms containing more than one
therapeutic agent it is preferred to prepare the formulation
contained in the dosage form by introducing an admixture of all
therapeutic agents into the formulation in place of the single drug
substance, for example, an admixture of all of the drug substances
to be included in the dosage form in place of a salt of the present
invention.
[0050] Whether administered as a separate medicament, or included
in the formulation of the present invention, when utilized it is
preferred for the 5HT3 receptor antagonist to be selected from
ondensetron, granisetron, palonosetron, dolasetron, and
tropisetron, and when utilized, whether as a separate medicament or
included in the formulation of the present invention, it is
preferred for the corticosteroid to be selected from
dexamethasone.
[0051] The present formulation can also contain additional
therapeutic agents, for example, chemotherapeutic agents, for
example, temozolomide, providing a single medicament for
administering chemotherapeutic treatment and relief and/or
prevention of nausea and/or vomiting associated with such
chemotherapeutic agent administration. Examples of dosage levels of
temozolomide are described in U.S. Pat. No. 5,939,098 (the '098
patent), issued Aug. 17, 1999, European Patent 085834181 (the '341
patent), Grant date Oct. 24, 2001, and published U.S. patent
application no. 2006/0100188, published May 11, 2006 (the '188
publication). Each of the '098 patent and '341 patent describes
coadministration of temozolomide with a 5HT3 inhibitor to provide
therapy for immediate onset nausea and vomiting associated with
chemotherapy. The '188 publication, in Tables 1 and 2 (pages 2 to 3
therein) describes detailed dosing regimens for dosing
temozolomide.
[0052] It is believed also that this medicament may be useful in
the treatment of other conditions amenable to treatment by
administration of an NK-1 inhibitor, including, but not limited to,
cough, morning sickness, and nausea and/or vomiting arising from
motion sickness.
[0053] In addition to the compounds of the present invention being
useful in the provision of anti-nausea and anti-emesis treatment,
the salt forms disclosed herein have processing advantages related
to their improved solubility in polar solvents in comparison to the
free base form of the compound which are beneficial in the
provision of useful medicaments. Moreover, each of the toyslate and
hydrochloride salts have one or more crystalline forms which
provide the compound of Formula I in a form having the following
advantages compared to amorphous forms of the compound: lower
impurity content and more consistent product quality i.e., more
consistent physical characteristics including more consistent
color, rate of dissolution and ease of handling; as well as a
longer term stability when incorporated into a medicament.
[0054] As described in detail below, each of the crystalline salt
forms of the compound of Formula I described herein can readily be
distinguished from one another and from amorphous forms by
examination of one or more of the characteristic X-ray Diffraction
patterns (see FIGS. 1, 5, 6, 9, and 12 to 14), the characteristic
infrared spectra (see FIGS. 3, 8, 11, 16, and 18) and the
analytical Differential Scanning Calorimetry (DSC) thermograms
(FIGS. 4, 19, 20, and 21) of the respective salt forms.
[0055] The inventors have surprisingly discovered that
diazaspirodecan-2-ones of Formula I contain can be precipitated by
inorganic acids selected from p-toluenesulfonic acid
##STR00004##
to form the tosylate salts of the compound of Formula I, and
hydrochloric acid (HCl), to form hydrochloride salts of the
compound of Formula I, for example, the hydrochloride monohydrate
of Formula II. Unexpectedly, these salts can be precipitated in a
crystalline solid form which optionally includes one or more
solvent molecules in the crystal structure for each molecule of the
protonated compound of Formula I present in the crystal structure.
Examples of suitable solvent molecules which the inventors have
found can form a part of the crystal structure are water, hexane
and acetonitrile.
[0056] The salts of the present invention offer a number of
surprising advantages over the free base in their physical
properties, for example, the ability to mill, micronize and
solubilize the compound. It has been found that the salts of the
present invention are thermodynamically robust in addition to
having desirable solubility and handling characteristics, thus
providing the compound of Formula I in a salt form which is easily
incorporated into a medicament and which is stable under a wide
variety of environmental conditions.
[0057] As is known, therapeutic agents typically display poor
absorption rates when they have an aqueous solubility of less than
about 10 mg/ml over a pH range of from about pH 1 to about pH 7.
Moreover, when orally administered therapeutic agents display a
solubility of less than about 1 mg/ml within this pH range,
typically such agents exhibit dissolution-rate limited absorption
since solubility and absorption are related in orally administered
medicaments. Accordingly, the improved solubility properties of
these salts are important for the provision of an orally
administered form of a medicament designed to deliver the compound
of Formula I as a therapeutic agent. Some salts of the invention
display advantageous physical properties in addition to these
desirable improved solubility properties, as described in detail
below.
[0058] In general, a salt of the invention may be prepared from a
compound of Formula I and an acid selected from toluenesulfonic
acid and hydrochloric acid in accordance with the following
procedure: [0059] i) with stirring, a 0.1 g quantity of the
compound of Formula I (approximately 0.2 mMol) and an equivalent
amount (i.e. 0.2 mMol) of the selected acid is dissolved in about 3
ml of anhydrous ethanol contained in a vessel; [0060] ii) with
continued stirring, anhydrous diethylether is added dropwise to the
mixture until it becomes cloudy; [0061] iii) an amount of anhydrous
ethanol just sufficient to clear the cloudiness is added to the
cloudy mixture (typically several drops); [0062] iv) the stirring
is discontinued and the vessel is covered with aluminum foil
containing vent holes and left to stand quiescent for 24 to 48
hours during which time solids will precipitate; [0063] v) at the
end of the quiescent period the solids are recovered by filtration,
washed with solvent, and then dried first in the air for a period
of from about 1 to about 18 hours and then vacuum dried at ambient
temperature under house vacuum overnight, yielding the salt of the
compound of Formula I.
[0064] For some salts, solvate forms of various crystals are
prepared in accordance with the following general procedure. A
sample of the salt prepared by reactive crystallization in
accordance with the above procedure, or recrystallization of a salt
initially precipitated as an amorphous material utilizing the
above-described general procedure and subsequently crystallized by
seeding a slurry of the amorphous salt, is weighed into a vial,
typically from about 10 mg to about 50 mg. A solvent selected to
from ethanol, isopropanol, acetonitrile, water, toluene, ethyl
acetate, methylene chloride and hexane, in an amount sufficient to
completely immerse the solids is added to the vial. The solids and
solvent are stirred under ambient conditions a period of time
sufficient to provide solvate crystals, for example, for about
seven days. When solvate crystals have been prepared, a sample of
the suspended solvate crystals is dropped onto a sample holder for
use in a powder X-ray diffraction spectrometer and air dried. These
samples are then analyzed by X-ray spectroscopy according to
procedures described herein. Additional procedures for preparing
inventive salts of the compounds of Formula I are described and
exemplified below.
Analytical Procedures
[0065] Each of the crystalline salt forms of the compound of
Formula I is characterized by one or more techniques including
X-ray powder diffraction spectroscopy (PXRD), Infared Spectroscopy
(IR), and Raman Spectroscopy (Raman). Selected salt forms of
compound I were also analyzed by differential scanning calorimetry
(DSC), and/or further characterized by physical methods including
solubility studies and stability studies.
X-Ray Powder Diffraction Spectroscopy
[0066] X-ray powder diffraction spectroscopy was obtained on
samples using one of the following procedures. For the solvates
prepared in accordance with the above-described procedure, analysis
was carried out on a Rigaku spectrometer according to the following
procedure.
[0067] For analysis of samples obtained using a Rigaku Minitlex
spectrometer, the following procedure was employed (PXRD method I).
Specimens analyzed by PXRD method I were lightly packed onto a
low-background plate. The specimens were exposed to the room
environment with ambient temperature and humidity. The Rigaku
spectrometer was equipped with a six-plate carousel that rotated
the specimen at 54 rpm, minimizing preferred orientations of the
crystals in the sample studied. The Rigaku spectrometer was
equipped also with a copper K.alpha. radiation source utilized
without a K.alpha.2 filter. The spectrometer was equipped also with
a variable divergence slit and 0.3 mm receiving slit. Scan range
was carried out from 2.0 to 40.degree.2.theta.. Instrument
calibration was verified using the Cu K.alpha.1 peak for the 111
plane. During scanning, the step size was 0.02 degrees over step
durations of 0.6 seconds. Data analysis was accomplished using Jade
Plus (release 5.0.26) analysis software. The data ware smoothed
with a Savitzky-Golay parabolic filter at 11 points. Typically "d"
spacing values are accurate to within .+-.0.04 A.
[0068] X-ray Powder Diffraction spectroscopy analysis was obtained
for some samples using a Bruker D8 diffractometer manufactured in
2002 (PXRD method II). The Bruker diffractometer was equipped with
a parallel optic configuration utilizing a GOBEL beam focusing
mirror and a PSD detector equipped with a fixed radial soller slit.
The Bruker diffractometer was used with an Anton Paar TTK450
temperature stage. The radiation source is copper (K.alpha.). The
divergence slits are fixed at 0.6 mm. The Bruker diffractometer
utilized a top-loading brass block sample holder. PSD fast scan was
used to scan from 4.0.degree. to 39.9.degree.. To obtain a
diffraction pattern, specimens were loaded onto the sample holder
and leveled with a glass microscope slide. The sample chamber
temperature was set at 25.degree. C., 30.degree. C. or 120.degree.
C., under ambient humidity and not purged with nitrogen and not
under vacuum. Instrument calibration was verified using mica
standards. During scanning, the step size was 0.013 degrees to 0.02
degrees over step durations of 0.5 to 10 seconds. Data analysis was
accomplished using EVA analysis software, version 7.0.0.1, supplied
by Bruker.RTM. written by SOCABIM.RTM.. The data were smoothed by
the software at 0.1 to 0.15.
[0069] Except for those solvate samples prepared in accordance with
the above-described procedure, samples for analysis by X-ray Powder
Diffraction ("PXRD"), were subjected to minimal preparation to
prevent any form changes. Sample particles were lightly packed into
the sample holder to insure that they formed a smooth surface and
did not clump together. No solvents, drying or other preparation
steps were used for other than the solvate samples prepared in
accordance with the procedure described above.
Infrared Spectroscopy
[0070] Samples were characterized utilizing attenuated total
reflectance (ATR) infrared spectroscopy using a Nicolet Instruments
NEXUS 670 FTIR equipped with an Avatar Smart Miracle Attenuated
Total Reflectrance (ATR) sample compartment. Spectra were collected
utilizing the following parameters: DTGS KBr Detector; KBr beam
splitter; scanning range 600 cm-1 to 4000 cm-1; aperture setting
100; resolution 2; 100 scans/sample. The analysis was carried out
by collecting a background spectrum, then placing reference
standard or particulate sample (typically 3 mg to 5 mg of sample)
on the ATR crystal and applying force to the sample with the
instrument's pressure arm in accordance with the manufacturers
recommendations. A spectrum of the specimen (reference or sample)
was then obtained as a ratio of the background and specimen spectra
utilizing the manufacturers proprietary software.
[0071] Raman Spectroscopy
[0072] Raman spectroscopic analysis (Raman) of the hydrochloride
and tosylate salts of the invention was performed on a Thermo
Electron Nicolet Almega Dispersive Raman spectrometer in
high-resolution mode. Samples were contained in NMR sample tubes
and spectra were obtained under the following conditions: Scanning
range 4000 cm-1 to 90 cm-1; Exposure time 1.0 second; 100 sample
and 100 background exposures; Excitation Laser at 785 nm/100% power
level/parallel laser polarization; Grating 1200 lines/mm; 100
micron slit; Camera temperature -50.degree. C.
Differential Scanning Calorimetry
[0073] Calorimetric studies were conducted utilizing a modulated
Differential Scanning Calorimeter (DSC) from TA instruments. DSC
scans were run at a heating rate of 10 C/min. in an open aluminum
pan under nitrogen flowing at a rate of 40 ml/min.
[0074] Solubility tests were conducted by placing an excess of the
compound in an aliquot of the solvent of interest and allowing the
slurry to equilibrate under the selected temperature conditions
(typically ambient). When the solvent was water, pH was adjusted to
the desired value with hydrochloric acid and sodium hydroxide. When
the slurry mixture had equilibrated, the excess solids were
centrifuged (water) or filtered (all other solvents) from the
supernatant and the amount of compound which had been dissolved was
quantified utilizing HPLC analysis of diluted aliquots of the
supernatant liquid. Pharmaceutical grade solvents were
employed.
[0075] Chemical stability tests were carried out on aliquots of the
salt form of interest by placing a accurately weighed sample of the
salt form of the compound of Formula I into a polyethylene bag. The
bagged samples were enclosed in fiberboard tubes fitted with metal
caps which were stored under the indicated conditions of humidity
and temperature for the indicated time. Analysis was carried out by
dissolving the contents of a vial and quantifying the amount of
solute utilizing HPLC analysis. Where noted the aliquots were
stored in capped amber vials under the conditions noted instead of
polyethylene bags.
Examples
[0076] Hydrochloride and tosylate salt forms of the compound of
Formula I were prepared as described below. As discussed below,
each of the salt forms of the compound of Formula I were also
characterized by various spectroscopic techniques including X-ray
Powder Diffraction Spectoscopy, Infrared Spectroscopy, and Raman
Spectroscopy, using the techniques described in detail above.
Selected salt forms were analyzed for stability, solubility and
other improved physical properties, including, for some salts,
analysis by differential scanning calorimetry (DSC). Unless noted
to the contrary, all reactive crystallizations, recrystallization,
and slurry procedures described herein were carried out in
commercially available solvents of the specified grade (generally
pharmaceutical or food grade unless otherwise specified) and used
as received (unless otherwise specified).
[0077] Preparation of the compound of Formula I (free base)
suitable for use in the preparation of salts of the compound of
Formula I described in the following examples was obtained either
from the methods disclosed in the '320 patent or by the procedure
described herein employing the compound of Formula III.
[0078] One suitable procedure for preparing the compound of Formula
i,
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one, for use in the preparation of
the salts described herein, is described in the above-mentioned
U.S. Pat. No. 7,049,320 (the '320 patent), utilizing as a precursor
to the compound of Formula I, the compound 61 (see the '320 patent
at col. 98, line 1 to col. 100, line 10), which is incorporated
herein by reference in its entirety. The compound of Formula I for
use in the preparation of salts in accordance with the present
invention may also suitably be prepared in accordance with the
procedures described in the application filed under Attorney's
docket no. CD06628US01 on Mar. 22, 2007, comprising precipitating
the mesylate salt of the compound of Formula III by treating a
toluene solution of the compound of Formula III with methyl
sulfonic acid. Simultaneous cyclization and nitrate reduction of
the compound of Formula III is carried out by treating the compound
of Formula III with acetic acid in the presence of zinc metal to
provide the free base of the compound of Formula I.
##STR00005##
[0079] The following example illustrates the foregoing process for
converting the compound of Formula III into the compound of Formula
I. Into a vessel was placed 8.14 Kg of the mesylate salt of the
compound of Formula III (obtained by precipitation of the mesylate
salt of the compound of Formula III, prepared in accordance with
procedures described in the patent application filed under
Attorney's docket no. CD06228L01US on Mar. 20, 2007). With
stirring, the salt of the compound of Formula III was dissolved in
82 L of concentrated acetic acid, and the temperature of the
solution was adjusted to be from about 25.degree. C. to about
30.degree. C. In a separate reactor 12.2 Kg of zinc dust was placed
under an inert nitrogen atmosphere by purging and venting the
reactor 3 times. The zinc dust was then covered with 42 L of
concentrated acetic acid during which the inert atmosphere was
maintained. While maintaining the inert atmosphere, the zinc
dust/acetic acid mixture was stirred to maintain substantially all
of the zinc dust in suspension and slow addition of the acetic acid
solution of the compound of Formula III was begun at a rate which
maintained the temperature in the reaction vessel at no more than
about 60.degree. C. After all of the solution of the compound of
Formula III had been added the reaction vessel temperature was
maintained at a temperature of from about 55.degree. C. to about
60.degree. C. The reaction mixture temperature was maintained and
vigorous stirring was continued to maintain suspension of the zinc
until samples of the reaction mixture indicated that substantially
all of the compound of Formula III was consumed.
[0080] When sampling indicated that the reaction had run to
completion (less than about 5 mole % of uncyclized material present
in the reaction mixture), the reaction mixture was cooled to a
temperature of from about 30.degree. C. to about 20.degree. C. When
the reaction mixture had cooled it was filtered through about 4.12
Kg of filteraid (Hyflo). The filter cake was washed with two 70 L
aliquots of toluene which were combined with the filtrate
previously obtained. The combined wash and filtrate was vacuum
distilled at a pressure of from about 80 mbar to about 120 mbar and
a temperature of from about 30.degree. C. to about 60.degree. C.
The residue thus obtained was maintained under an inert atmosphere
and redissolved in 41 L of toluene at ambient temperature.
[0081] The toluene solution of the residue was sequentially washed
45 L of 2N HCl aqueous solution followed by 80 L of 9 wt. % aqueous
sodium carbonate (8 kg Na.sub.2CO.sub.3 in 82 L H.sub.2O) followed
by two successive 22 L aliquots of 10 wt % aqueous sodium chloride
(2.2 Kg NaCl in 21 L H.sub.2O). After completing the washing
regime, the toluene supernatant solution was filtered through a 0.2
micron inline filter. The filter was rinsed with an additional 4 L
of toluene which was combined with the supernatant liquid
containing the free base compound of Formula I.
Provision of Hydrochloride Monohydrate Salt Form I Directly from
the Formula III Compound Reaction Mixture
[0082] The supernatant containing the free base compound of Formula
I prepared from the compound of Formula III, as described above,
was placed into a reactor and maintained at a temperature of from
about 20.degree. C. to about 25.degree. C. Seed crystals of the
hydrochloride monohydrate salt of the compound of Formula I were
added to the supernatant in an amount of about 0.004 kg. After the
solution had been seeded, 1.7 L of concentrated aqueous
hydrochloric acid (37%) and 1.2 L of ethanol containing about 5
vol. % isopropanol (Fine Spirit.RTM. obtained from Thommen) were
added over a period of about 20 minutes. The mixture was agitated
for about 30 minutes. Agitation was continued and the mixture was
cooled and maintained between a temperature of from 0.degree. C. to
about 5.degree. C. The cold mixture was agitated for an additional
35 minutes. At the end of the agitation period the crystals thus
obtained were isolated by vacuum filtration through a No. 148
filter and washed with 5 successive 5 L aliquots of a 1:1 (vol:vol)
mixture of toluene and methyl tertiary butyl ether (MTBE) followed
by a final wash comprising one 10 L aliquot of MTBE.
[0083] The precipitated monohydrate hydrochloride form I salt
crystals were recovered from the filter and dried in a vacuum oven
at a temperature of from about 40.degree. C. to about 45.degree. C.
until the desired residual solvent (MTBE, ethanol, toluene and
water) values were obtained.
Hydrochloride Salts of the Compound of Formula I
[0084] It was found that the amorphous hydrochloride salt for of
the compound of Formula I, prepared by treating a solution of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I)
with hydrochloric acid, in accordance with the general procedure
described above, could be converted to three crystalline forms of a
salt of the compound of Formula I.
The Crystalline Monohydrate Hydrochloride Salt Form I of the
Compound of Formula I
[0085] Crystalline monohydrate hydrochloride form I salt was
prepared directly from the compound of Formula I by dissolving one
equivalent of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I
prepared in accordance with the procedures described in the '320
patent) in a minimum of ethanol or methanol, and adding one
equivalent of hydrochloric acid to the solution. Following the
addition of HCl, water was added dropwise to the solution with
stirring until crystals of the monohydrate hydrochloride salt form
of the compound of Formula I dropped out of the solution. The
crystals were separated from the supernatant liquid by filtration,
washed with ethanol and vacuum dried.
[0086] Whether the HCl salt is obtained by precipitation of the
free base of the compound of Formula I provided directly from
reaction of the compound of Formula III described above, or
provided by the procedures described in the '320 patent, or
provided in another manner, a hydrochloride salt of the compound of
Formula I can be recrystallized in accordance with the following
procedure to provide the monohydrate hydrochloride crystal form I
in accordance with the following procedure. Into a vessel was
added, under a nitrogen blanket, 14.54 Kg of the monohydrate
hydrochloride salt form I of the compound of Formula I prepared as
described above. The crystals were suspended by adding a mixture
consisting of: 35 L of Fine Spirits.RTM. (ethanol with 5 wt %
isopropanol); 35 L water; 0.3 L concentrated HCl (37%) with
agitation. The suspension was heated to reflux (approximately
78.degree. C. to 85.degree. C.) with continued to agitation. When
the solution was clear it was filtered through a No. 3 filter into
a second vessel. The filter was rinsed with a water/ethanol mixture
consisting of 10 L of fine Spirits.RTM. and 32 L of water at a
temperature of from about 60.degree. C. to about 70.degree. C. and
the rinse was added to the filtrate solution. The temperature of
the combined rinse and filtrate was stabilized at 73.degree. C.
(.+-.1.degree. C.) and 0.115 kg of monohydrate hydrochloride salt
form I seed crystals were added with agitation. With continued
agitation the temperature was maintained at about 73.degree. C. for
about 20 minutes additional. The solution was subsequently cooled
at a rate of from about 0.5.degree. C./min to a temperature between
0.degree. C. and 5.degree. C. and maintained at this temperature
with agitation for 33 minutes while a thick suspension gradually
formed. At the end of this time period the crystals were separated
from the suspension by filtration through a No. 110 filter. The
filter was washed with 14.5 L of an ethanol/water mixture (40.60,
ethanol:water by vol) which had been chilled and maintained at a
temperature between 0.degree. C. and 5.degree. C. The crystals were
recovered from the filter and dried for about 15 hours in a vacuum
drier with the temperature maintained between 35.degree. C. and
40.degree. C.
[0087] With reference to FIGS. 1 to 4, the monohydrate
hydrochloride salt form I of the compound of Formula I prepared
above was analyzed by X-ray, Infrared, and Raman spectroscopy and
by DSC, as described above. Table VIII, below, lists 12
characteristic peaks of the X-ray Powder Diffraction spectrum shown
in FIG. 1, expressed in diffraction angle expressed in degrees 2
theta (.degree.2.theta.), the corresponding "d" spacing in
angstroms (A), and relative intensities of the signal ("RI") in the
following notation: S=strong, M=medium, W=weak; V=Very and
D=diffuse:
TABLE-US-00008 TABLE VIII Diffraction Angle D spacing relative
(.degree.2.THETA., .+-.0.2) (A, .+-.0.04) intensity 12.9 6.65 VW
16.1 5.49 M 18.4 4.83 M 18.7 4.74 W 19.8 4.48 W 21.6 4.11 S 22.8
3.89 VWD 23.5 3.78 M 24.0 3.70 WD 28.2 3.16 VW 34.3 2.62 VW 35.1
2.56 VW
Of the peaks characteristic of the monohydrate hydrochloride salt
of the compound of Formula I shown in Table VIII, the eight most
characteristic peaks are those appearing at diffraction angles (in
.degree.2.theta.) equal to 12.9, 16.1, 18.4, 18.7, 19.8, 21.6,
23.5, and 24.0, and the four most characteristic peaks are those
appearing at diffraction angles (in .degree.2.theta.) equal to
16.1, 18.4, 21.6, and 23.5.
[0088] FIG. 2 illustrates a transmission Infrared Spectrum of the
crystalline monohydrate hydrochloride form I salt of the compound
of Formula I, obtained in accordance with the above-described
procedures. The 12 most characteristic peaks of the crystalline
monohydrate hydrochloride form I salt shown in FIG. 2 are listed in
Table IX, below, and in an adjacent column, the relative absorption
intensity of each listed peak utilizing the notation: S=Strong,
M=Moderate, W=Weak.
TABLE-US-00009 TABLE IX Absorption Wave No. relative Peak
(cm.sup.-1) intensity 1 1693 M 2 1377 W 3 1277 S 4 1167 S 5 1141 S
6 1130 S 7 1094 M 8 897 W 9 842 W 10 772 W 11 703 S 12 682 S
Of the characteristic peaks shown in Table IX, the 8 most
characteristic peaks of the compound are those appearing at 1693,
1277, 1167, 1141, 1130, 1094, 703, and 682 reciprocal centimeters
(cm.sup.-1), and the four most characteristic peaks are those
appearing at 1693, 1277, 1167, and 682 cm.sup.-1.
[0089] FIG. 3 illustrates a Raman spectrum of the monohydrate
hydrochloride form I salt of the compound of Formula I. The 12 most
characteristic scattering peaks of the spectrum in FIG. 3 are
listed (in reciprocal centimeters, cm.sup.-1) in Table X (below).
In a column adjacent to the listed peaks, the relative absorption
intensity of each peak is indicated in the notation: S=Strong;
M=Moderate; W=Weak; V=Very; B=Broad.
TABLE-US-00010 TABLE X Scattering Wave No. relative Peak
(cm.sup.-1) intensity 1 3695 W 2 3690 W 3 3625 WB 4 1604 MB 5 1371
WB 6 1218 WB 7 1032 M 8 997 S 9 827 WB 10 732 VW 11 698 S 12 616
M
Of the characteristic peaks shown in Table X, the 8 most
characteristic peaks of the compound are those appearing at 3695,
3690, 3625, 1604, 1032, 997, 724, and 616 cm.sup.-1, and the four
most characteristic peaks are those appearing at 3695, 1032, 997,
and 724 cm.sup.-1.
[0090] FIG. 22 presents a proton NMR spectra of the monohydrate
hydrochloride form I salt of the compound of Formula I obtained by
analyzing a solution of about 12 mg/ml of the salt dissolved in
deuterated dimethyl sulfoxide. The spectrum was obtained by
analyzing the solution with a Varian INOVA-500 NMR spectrometer at
25.degree. C. Table XI lists the characteristic peaks of the
spectrum in ppm relative to TMS. The region from 7.3 ppm to 8.0 ppm
has the peaks expected for a mono-substituted aromatic ring and a
symmetrical tri-substituted aromatic ring. The region from 8.5 ppm
to 10.8 ppm is consistent with three amine peaks, including the
protonated amine forming the HCl salt. The region between 2.8 and
4.8 ppm is consistent with five aliphatic protons proximal to a
nitrogen or oxygen. The region between 1.3 ppm and 2.6 ppm is
consistent with the remaining eight aliphatic protons and the
doublet at 1.4 ppm is consistent with the methyl group.
TABLE-US-00011 TABLE XI Table 1 H-NMR Assignments Chemical Shift
Proton (PPM) 1-NH 8.56 Br H3s 2.15, 2,24 m, m H4s 1.67, 1.88 m, m
H6s 2.88, 3.22 d of d (10 H, 13 Hz) d (13 Hz), 7NH.sub.2.sup.+
Cl.sup.- 9.63, 10.62 m, d (12 Hz), d of d (10 Hz, 12 Hz) H92 2.19,
2.49 m, d (14.5 Hz) H10s 1.39, 1.79 m, d (13.5 Hz) H12, 12' 7.58 d
(7.5 Hz) H13, 13' 7.44 M H14 7.40 M H15s 3.36, 4.30 d (10 Hz), d
(10 Hz) H16 4.65 q (6.4 Hz) H17s 1.41 d (6.4 Hz) H19, 19' 7.66 S
H21 7.92 S
[0091] The crystalline monohydrate hydrochloride form I salt of the
compound of Formula I was analyzed by differential scanning
calorimetric in accordance with the procedures described above.
FIG. 4 illustrates the DSC thermogram obtained from this analysis.
The DSC thermogram of FIG. 4 contains a broad endotherm centered at
approximately 101.degree. C., a second endotherm centered at
approximately 150.degree. C., and a third endotherm centered at
approximately 207.degree. C. The first endotherm corresponds to
dehydration of the crystalline monohydrate form I, producing the
corresponding anhydrous hydrochloride form I salt. The the second
endotherm corresponds to the melting of the anhydrous form I salt
(about 150.degree. C.), which in melting decomposes to produce
anhydrous hydrochloride form 1 salt. The third endotherm at
approximately 207.degree. C. corresponds to the anhydrous form II
salt melting point.
[0092] The inventors have found that when the monohydrate
hydrochloride form I salt was dehydrated at a temperature below the
decomposition point of the anhydrous hydrochloride form I salt,
subsequent storage of anhydrous form I salt under ambient
conditions of temperature and humidity returns the crystals to the
monohydrate form. Stability test in accordance with the
above-described procedure showed that the monohydrate hydrochloride
form I salt of the compound of Formula I does not decompose or
dehydrate under conditions of ambient temperature and at relative
humidity of from about 5% relative humidity to about 95% relative
humidity.
[0093] A sample of the anhydrous form I salt was prepared by
heating the monohydrate hydrochloride form I salt of the compound
of Formula I under flowing nitrogen at a temperature above
70.degree. C. The anhydrous form I salt was analyzed by X-ray
Powder Diffraction Spectroscopy. FIG. 5 illustrates an X-ray Powder
Diffraction Spectrum of the anhydrous hydrochloride form I salt of
the compound of Formula I. Table XII, below, lists 12
characteristic peaks of the spectrum shown in FIG. 5 by diffraction
angle expressed in degrees 2 theta (.degree.2.theta.), the
corresponding "d" spacing in angstroms (A), and relative
intensities of the signal (`RI`) in the following notation:
S=strong, M=medium, W=weak; V=Very and D=diffuse:
TABLE-US-00012 TABLE XII Diffraction Angle d spacing relative
(.degree.2.theta., .+-.0.2) (A, .+-.0.04) intensity 10.8 8.21 VW
12.9 6.86 S 13.7 6.45 W 14.3 6.18 S 15.4 5.75 S 17.3 5.13 S 18.0
4.91 W 19.9 4.47 M 20.2 4.38 S 22.0 4.03 W 23.0 3.86 M 24.0 3.70
S
Of the peaks characteristic of the anhydrous form I hydrochloride
salt of the compound of Formula I shown in Table XII, the eight
most characteristic peaks are those appearing at diffraction angles
(in .degree.2.theta.) equal to 12.9, 14.3, 15.4, 17.3, 19.9, 20.2,
23.0, and 24.0, and the four most characteristic peaks are those
appearing at diffraction angles (in .degree.2.theta.) equal to
12.9, 15.4, 17.3, and 20.2.
[0094] FIG. 6 illustrates an X-ray Powder Diffraction spectrum of
the anhydrous hydrochloride form II salt of the compound of Formula
I prepared by heating the anhydrous form I hydrochloride salt above
its decomposition point. Table XIII, below, lists 12 characteristic
peaks of the X-ray Powder Diffraction spectrum shown in FIG. 6 by
diffraction angle expressed in degrees 2 theta (.degree.2.theta.),
the corresponding "d" spacing in angstroms (A), and relative
intensities of the signal ("RI") in the following notation:
S=strong, M=medium, W=weak; B=Broad, V=Very and D=diffuse:
TABLE-US-00013 TABLE XIII Diffraction Angle d spacing relative
(.degree.2 .THETA., .+-.0.2) (A, .+-.0.04) intensity 7.0 12.70 M
9.0 9.87 S 10.4 8.48 M 11.3 7.85 M 12.6 7.00 S 13.7 6.47 MD 17.3
5.13 WD 20.2 4.39 S 22.4 3.96 M 22.8 3.90 M 23.2 3.83 M 23.7 3.75
M
Of the peaks characteristic of the anhydrous form II hydrochloride
salt of the compound of Formula I shown in Table XIII, the eight
most characteristic peaks are those appearing at diffraction angles
(in .degree.2.theta.) equal to 7.0, 9.0, 10.4, 12.6, 13.7, 17.3,
20.2, and 22.4, and the four most characteristic peaks are those
appearing at diffraction angles (in .degree.2.theta.) equal to 7.0,
9.0, 12.6, and 20.2.
[0095] FIG. 7 illustrates a transmission infrared spectrum of the
crystalline anhydrous hydrochloride form II salt form of the
compound of Formula I obtained in accordance with the procedures
described above. The 12 most characteristic peaks of the
crystalline monohydrate are listed in Table XIV, below, and in an
adjacent column, the relative absorption intensity of each listed
peak utilizing the notation: S=Strong, M=Moderate, W=Weak.
TABLE-US-00014 TABLE XIV Absorption Wave No. relative Peak
(cm.sup.-1) intensity 1 1694 M 2 1597 W 3 1383 W 4 1276 S 5 1066 M
6 1020 S 7 1102 S 8 898 M 9 843 M 10 768 M 11 704 S 12 682 S
Of the characteristic peaks shown in Table XIV, the 8 most
characteristic peaks of the compound are those appearing at 1694,
1597, 1276, 1166, 1120, 898, 704 and 682 reciprocal centimeters
(cm.sup.-1), and the four most characteristic peaks are those
appearing at 1694, 1276, 898, and 682 cm.sup.-1.
[0096] FIG. 8 illustrates a Raman spectrum of the anhydrous
hydrochloride form II salt form of the compound of Formula I
obtained in accordance with the above described procedures. Table
XV, below, lists the 12 most characteristic scattering peaks (in
reciprocal centimeters, cm.sup.-1) of the compound shown in the
spectrum of FIG. 8. In a column adjacent to the listed peaks, the
relative absorption intensity of each peak is indicated in the
notation: S=Strong; M=Moderate; W=Weak; V=Very; B=Broad.
TABLE-US-00015 TABLE XV Scattering Wave No. relative Peak
(cm.sup.-1) intensity 1 1694 W 2 1607 M 3 1456 W 4 1382 W 5 1033 M
6 1001 S 7 903 W 8 829 W 9 729 W 10 618 W 11 527 WB 12 277 W
Of the characteristic peaks shown in Table XV, the 8 most
characteristic peaks of the compound are those appearing at 1694,
1607, 1456, 1382, 1001, 729, 618, and 277 cm.sup.-1, and the four
most characteristic peaks are those appearing at 1607, 1001, 729,
and 277 cm.sup.-1.
[0097] When examined for solubility in accordance with the
above-described procedure, it was found that the monohydrate
hydrochloride form I salt of the compound of Formula I had aqueous
solubility, at pH of 4 or less (more acidic), of at least about 1.0
mg/ml, and had the indicated solubilities at ambient temperatures
in the pharmaceutical solvents shown below in Table XVI.
TABLE-US-00016 TABLE XVI Solubility (mg/ml, Solvent ambient
conditions) Ethanol 185 Propylene Glycol 160 PEG 400 .TM. 20
Glycerin 16
[0098] The stability of the crystalline monohydrate hydrochloride
salt form of the compound of Formula I was also examined using the
procedure described above for samples contained in polyethylene
bags by exposing samples to the following conditions: (a) 60%
relative humidity (RH) at 4.degree. C. for twelve months, at
25.degree. C. for eighteen months, and at 50.degree. C. for one
month; (b) 40.degree. C. and 75% relative humidity (RH) for twelve
weeks; and (c) 70.degree. C. at ambient humidity for one hour.
Samples of the crystalline monohydrate hydrochloride form I salt
were also tested for one cycle of ICH UV/Vis fight stress
conditions. These tests demonstrated that the crystalline
monohydrate hydrochloride form I salt of the compound of Formula I
is stable at room temperature between about 5% and about 95%
relative humidity, is stable up to about 70.degree. C., and is
stable under light stress conditions.
Tosylate Salts of the Compound of Formula I
[0099] In accordance with the processes described herein, four
forms of a tosylate salt of the compound of Formula I have been
prepared.
Tosylate Form I Salt
[0100] Crystalline tosylate form I salt of the compound of Formula
I was prepared by dissolving 1 g of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) and
380 mg of p-tolyenesulfonic acid in 4 ml of anhydrous ethanol
contained in a vial. Into this solution was added 30 ml of
anhydrous diethyl ether. The mixture was titrated with additional
drops of ethanol until it was clear. The vial containing the
mixture was covered (with a vented covering) and left to stand
quiescent under ambient conditions for 48 hours during which time
crystals of the tosylate form I salt of the compound of Formula I
precipitated. The precipitated crystals were isolate by filtration,
washed with an aliquot of diethyl ether and dried in air. The
crystals were subsequently collected and dried under house vacuum
overnight.
[0101] With reference to FIGS. 9 to 11 and 19, the tosylate form I
salt form of the compound of Formula I thus obtained was
characterized by X-ray Powder Diffraction, Infrared, and Raman
spectroscopic techniques and by DSC, as in accordance with the
procedures described above. Table XVII, below, lists 12
characteristic peaks of the X-ray Powder Diffraction spectrum shown
in FIG. 9, expressed in diffraction angle expressed in degrees 2
theta (.degree.2.theta.) values are shown as +/-0.02
(.degree.2.theta.)), the corresponding "d" spacing in angstroms
(A), shown +/-0.04 A, and relative intensities of the signal ("RI")
in the following notation: S=strong. M=medium, W=weak; B=Broad,
V=Very and D=diffuse:
TABLE-US-00017 TABLE XVII Diffraction Angle d spacing relative
(.degree.2 .theta., .+-.0.2) (A, .+-.0.04) intensity 9.4 9.36 M 9.9
8.91 W 12.8 6.92 M 14.4 6.14 W 15.1 5.86 M 18.0 4.93 M 20.0 4.43 S
21.0 4.22 S 21.7 4.09 S 23.5 3.78 M 25.3 3.51 S 28.5 3.13 M
Of the peaks characteristic of the the tosylate form I salt form of
the compound of Formula I shown in Table XVII, the eight most
characteristic peaks are those appearing at diffraction angles (in
.degree.2.theta.) equal to 9.4, 12.8, 15.1, 18.0, 20.0, 21.0, 21.7,
and 25.3, and the four most characteristic peaks are those
appearing at diffraction angles (In .degree.2.theta.) equal to 9.4,
20.0, 21.0, and 25.3.
[0102] FIG. 10 illustrates a transmission infrared spectrum of the
tosylate form I salt form of the compound of Formula I obtained
utilizing the procedure described above. Table XVIII, below, lists
the 12 most characteristic peaks of the crystalline tosylate form I
salt, and in an adjacent column, the relative absorption intensity
of each listed peak is identified utilizing the notation: S=Strong,
M=Moderate, W=Weak, V=Very.
TABLE-US-00018 TABLE XVIII Absorption Wave No. relative Peak
(cm.sup.-1) intensity 1 1668 M 2 1275 S 3 1249 M 4 1177 M 5 1157 S
6 1125 S 7 1032 S 8 1009 S 9 899 M 10 817 M 11 770 M 12 681 S
Of the characteristic peaks shown in Table XVIII, the 8 most
characteristic peaks of the compound are those appearing at 1668,
1275, 1157, 1125, 1032, 1009, 899, and 681 reciprocal centimeters
(cm.sup.-1), and the four most characteristic peaks are those
appearing at 1275, 1125, 1032, and 681 cm.sup.-1.
[0103] FIG. 11 illustrates a Raman spectrum of the tosylate form I
salt form of the compound of Formula I. Table XIX, below, lists the
12 most characteristic scattering peaks of the compound (in
reciprocal centimeters, (cm.sup.-1)). Listed in an adjacent column
beside each peak listed in Table XI, the relative absorption
intensity of each peak is indicated in the notation: S=Strong;
M=Moderate; W=Weak; V=Very; B=Broad.
TABLE-US-00019 TABLE XIX Scattering Wave No. relative Peak
(cm.sup.-1) intensity 1 3695 W 2 3690 W 3 3250 M 4 1602 MB 5 1371 W
6 1117 W 7 1026 M 8 996 S 9 793 MB 10 727 VW 11 632 M 12 615 VW
Of the characteristic peaks shown in Table XIX, the 8 most
characteristic peaks of the compound are those appearing at 3695,
3250, 1117, 1026, 996, 793, 727, and 615 cm.sup.-1, and the four
most characteristic peaks are those appearing at 3250, 1117, 996,
and 727 cm.sup.-1.
[0104] The crystalline tosylate form I salt form of the compound of
Formula I was analyzed by differential scanning calorimetry using
the procedure described above. FIG. 19 illustrates the DSC
thermogram thereby obtained. The DSC thermogram contains a single
sharp endotherm centered at approximately 218.degree. C., which is
the melting point of the crystalline tosylate form I salt form of
the compound of Formula I.
[0105] When examined for solubility in accordance with the
above-described procedure, it was found that the tosylate form I
salt of the compound of Formula I has aqueous solubility, at pH of
4 or less (more acidic), of at least 0.38 mg/ml, and had the
following solubilities at ambient temperatures in the
pharmaceutical solvents shown below in Table XX.
TABLE-US-00020 TABLE XX Solvent Solubility (mg/ml, ambient
conditions) Ethanol 75 Propylene Glycol 20 PEG 400 .TM. 1.8
Glycerin 2.5
[0106] The stability of the crystalline tosylate form I salt form
of the compound of Formula I was examined by placing weighed
amounts of the salt into clear glass vials and storing them under
the indicated conditions. Periodically a vial was removed and the
contents examined for decomposition of the compound. Accordingly,
samples of the tosylate form I salt were exposed to the following
conditions: (a) 40.degree. C. and 75% relative humidity (RH) for
four weeks; (b) 50.degree. C. and ambient relative humidity for
four weeks; and (c) 70.degree. C. for one hour. Samples of the
tosylate form I salt were separately tested for one cycle of ICH
UV/Vis light stress conditions. These tests illustrate that the
crystalline tosylate form I salt form of the compound of Formula I
is stable under all tested conditions.
Tosylate Form II Salt
[0107] Utilizing the general slurry procedures described herein,
tosylate form II salt of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one (the tosylate form II salt of
the compound of Formula I) was prepared by slurrying in
acetonitrile (ACN) the crystalline tosylate form I salt prepared in
accordance with the procedure described above. With reference to
FIGS. 12, 15 and 16, the crystalline tosylate form II salt form of
the compound of Formula I was characterized by X-ray Powder
Diffraction, Infrared, and Raman spectroscopies and analyzed by
DSC.
[0108] FIG. 12 shows the X-ray Powder Diffraction Spectrum of the
crystalline tosylate form II salt form of the compound of Formula
I, obtained using the general procedure described herein. Table
XXI, below, lists 12 characteristic peaks of the X-ray Powder
Diffraction spectrum shown in FIG. 12. Table XXI lists the
characteristic peaks by diffraction angle expressed in degrees 2
theta (.degree.2.theta.), the corresponding "d" spacing in
angstroms (A), and relative intensities of the signal ("RI") in the
following notation: S=strong, M=medium, W=weak; B=Broad, V=Very and
D=diffuse:
TABLE-US-00021 TABLE XXI Diffraction Angle d spacing relative
(.degree.2 .THETA., .+-.0.2) (A, .+-.0.04) intensity 5.0 17.66 S
9.1 9.73 W 10.0 8.80 S 13.2 6.70 M 13.6 6.52 M 14.9 5.96 M 15.0
5.85 S 18.2 4.88 M 19.7 4.49 S 23.0 3.87 M 24.7 3.60 M 25.7 3.46
M
[0109] Of the peaks shown in Table XXI characteristic of the
crystalline tosylate form II salt form of the compound of Formula
I, the eight most characteristic peaks are those appearing at
diffraction angles (in .degree.2.theta.) equal to 5.0, 9.1, 10.0,
13.2, 13.6, 14.9, 19.7 and 23.0, and the four most characteristic
peaks are those appearing at diffraction angles (in
.degree.2.theta.) equal to 5.0, 10.0, 13.6, and 19.7.
[0110] FIG. 15 illustrates a transmission infrared spectrum of the
crystalline tosylate form II salt form of the compound of Formula
I, obtained using the procedure described above. Table XXII, below,
lists the 12 most characteristic peaks of the spectrum of
crystalline tosylate form II salt shown in FIG. 15, and in an
adjacent column beside each of the listed peaks, represents the
relative absorption intensity of each listed peak utilizing the
notation: S=Strong, M=Moderate, W=Weak, B=Broad, V=Very.
TABLE-US-00022 TABLE XXII Absorption Wave No. relative Peak
(cm.sup.-1) intensity 1 1671 MB 2 1625 MB 3 1276 S 4 1158 MB 5 1119
SB 6 1032 S 7 1010 S 8 898 S 9 816 M 10 770 M 11 705 M 12 680 S
Of the characteristic peaks shown in Table XXII, the 8 most
characteristic peaks of the compound are those appearing at 1671,
1625, 1276, 1158, 1119, 1032, 1010, 898, 816, 770, 705, and 680
reciprocal centimeters (cm.sup.-1), and the four most
characteristic peaks are those appearing at 1671, 1276, 1119, and
680 cm.sup.-1.
[0111] FIG. 16 illustrates a Raman spectrum of the crystalline
tosylate form II salt form of the compound of Formula I obtained
using the procedure described above. Table XXIII lists the 12 most
characteristic scattering peaks shown in FIG. 16 (In reciprocal
centimeters, cm.sup.-1). In a column adjacent to the listed peaks,
Table XXIII represents the relative absorption intensity of each
peak in the notation: S=Strong; M=Moderate; W=Weak; V=Very;
B=Broad.
TABLE-US-00023 TABLE XXIII Scattering Wave No. relative Peak
(cm.sup.-1) intensity 1 1608 WB 2 1446 WB 3 1212 WB 4 1126 M 5 1037
M 6 1003 M 7 802 MB 8 731 WB 9 637 WB 10 290 WB 11 233 VWB 12 152
S
Of the characteristic peaks shown in Table XXIII, the 8 most
characteristic peaks of the compound are those appearing at 1608,
1126, 1037, 1003, 802, 731, 290, 152 cm.sup.-1, and the four most
characteristic peaks are those appearing at 1126, 1037, 1003, and
802 cm.sup.-1.
[0112] The crystalline tosylate form II salt form of the compound
of Formula I was analyzed also by differential scanning
calorimetry, using the general procedure described above. The DSC
thermogram thus obtained is shown in FIG. 20. With reference to
FIG. 20, the DSC thermogram contains two broad endotherms, one
centered at approximately 52.degree. C., which is attributable to
loss of solvent of crystallization. The second broad endotherm,
centered at about 143.degree. C., is attributable to melting and
decomposition of the salt form remaining after driving off the
solvent.
Tosylate Form III Salt
[0113] Using the general slurrying procedure described herein, the
Tosylate salt form III of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) was
prepared by slurrying in hexane the crystalline tosylate salt form
I prepared as described above. With reference to FIGS. 13 and 21,
the crystalline tosylate form III salt form of the compound of
Formula I was characterized by X-ray Powder Diffraction
spectroscopy and analyzed by DSC using the above-described
procedures.
[0114] Table XXIV, below, lists 12 characteristic peaks of the
X-ray Powder Diffraction spectrum shown in FIG. 13, expressed in
diffraction angle expressed in degrees 2 theta (.degree.2.theta.),
the corresponding "d" spacing in angstroms (A), and relative
intensities of the signal ("RI") in the following notation:
S=strong, M=medium, B=Broad, W=weak; V=Very and D=diffuse:
TABLE-US-00024 TABLE XXIV Diffraction Angle d spacing relative
(.degree.2 .theta., .+-.0.2) (A, .+-.0.04) intensity 6.3 14.02 M
9.7 9.13 S 11.1 7.95 W 12.6 6.70 WB 15.1 5.85 WB 16.7 5.29 M 17.2
5.16 M 19.3 4.59 M 20.2 4.39 SB 20.7 4.29 SB 22.2 4.00 S 23.4 3.79
WB
Of the peaks shown in Table XXIV characteristic of the crystalline
tosylate form III salt form of the compound of Formula I, the eight
most characteristic peaks are those appearing at diffraction angles
(in .degree.2.theta.) equal to 6.3, 9.7, 12.6, 16.7, 17.2, 20.2,
20.7, and 22.2, and the four most characteristic peaks are those
appearing at diffraction angles (in .degree.2 .THETA.) equal to
6.3, 9.7, 20.2, and 22.2.
[0115] FIG. 21 illustrates the DSC thermogram obtained from DSC
analysis of the crystalline tosylate form III salt form of the
compound of Formula I, obtained using the procedure described
above. The DSC thermogram contains a broad endotherm centered at
approximately 130.degree. C., which is attributable to loss of
solvent of crystallization and decomposition of the crystalline
material remaining after solvent loss.
Tosylate Form IV Salt
[0116] Utilizing the general slurrying procedure described herein,
tosylate salt form IV of
(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph-
enyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) was
prepared by slurrying in tetrahydrofuran (THF) the crystalline
tosylate form I salt prepared as described above to provide the THF
solvate. With reference to FIGS. 14, 17 and 18, the crystalline
tosylate form IV salt form of the compound of Formula I was
characterized by X-ray Powder Diffraction, Infrared, and Raman
spectroscopies.
[0117] FIG. 14 illustrates an X-ray Powder Diffraction Spectrum of
the crystalline tosylate form IV salt form of the compound of
Formula I obtained using the general procedure described herein.
Table XXV, below, lists 12 characteristic peaks of the X-ray Powder
Diffraction spectrum shown in FIG. 14, expressed in diffraction
angle expressed in degrees 2 theta (.degree.2.theta.), the
corresponding "d" spacing in angstroms (A), and relative
intensities of the signal ("RI") in the following notation:
S=strong, M=medium, B=Broad, W=weak; V=Very and D=diffuse.
TABLE-US-00025 TABLE XXV Diffraction Angle d spacing relative
(.degree.2 .theta., .+-.0.2) (A, .+-.0.04) intensity 6.1 14.44 S
7.3 12.09 M 9.6 9.19 S 11.4 7.76 MB 13.3 6.66 M 16.0 5.53 M 16.9
5.25 S 17.5 5.06 M 18.8 4.73 MB 19.2 4.63 SB 20.9 4.26 S 22.2 4.03
S
Of the peaks shown in Table XXV characteristic of the crystalline
tosylate form II salt form of the compound of Formula I, the eight
most characteristic peaks are those appearing at diffraction angles
(in .degree.2.theta.) equal to 6.1, 7.3, 9.6, 13.3, 16.9, 18.8,
20.9 and 22.0, and the four most characteristic peaks are those
appearing at diffraction angles (in .degree.2.theta.) equal to 6.1,
9.6, 20.9 and 22.0.
[0118] FIG. 17 illustrates a transmission infrared spectrum of the
crystalline tosylate form IV salt form of the compound of Formula I
obtained using the procedure described herein. Table XXVI, below,
lists the 12 most characteristic peaks of the crystalline tosylate
form IV salt and in an adjacent column represents the relative
absorption intensity of each listed peak utilizing the notation:
S=Strong, M=Moderate, W=Weak, B=Broad, V=Very.
TABLE-US-00026 TABLE XXVI Absorption Wave No. relative Peak
(cm.sup.-1) intensity 1 1673 MB 2 1459 MB 3 1381 S 4 1277 MB 5 1172
SB 6 1121 S 7 1029 S 8 1007 S 9 898 M 10 820 M 11 767 M 12 665
S
Of the characteristic peaks shown in Table XXVI, the 8 most
characteristic peaks of the compound are those appearing at 1673,
1277, 1172, 1121, 1029, 1007, 898, and 665 reciprocal centimeters
(cm.sup.-1), and the four most characteristic peaks are those
appearing at 1277, 1121, 1007, and 665 cm.sup.-1.
[0119] FIG. 18 illustrates a Raman spectrum of the crystalline
tosylate form IV salt form of the compound of Formula I obtained
using the procedure described above. Table XXVII lists the 12 most
characteristic scattering peaks in the Raman spectra shown in FIG.
18, and in an adjacent column represents the intensity of each
listed peak in the notation: S=Strong; M=Moderate; W=Weak; V=Very;
B=Broad.
TABLE-US-00027 TABLE XXVII Scattering Wave No. relative Peak
(cm.sup.-1) intensity 1 1678 W 2 1604 M 3 1450 MB 4 1383 M 5 1207 M
6 1120 M 7 1003 S 8 800 M 9 730 W 10 620 WB 11 289 M 12 146 S
Of the characteristic peaks shown in Table XXVII, the 8 most
characteristic peaks of the compound are those appearing at 1604,
1450, 1383, 1207, 1120, 1003, 800, and 289 cm.sup.-1, and the four
most characteristic peaks are those appearing at 1604, 1003, 800,
and 289 cm.sup.-1.
* * * * *