U.S. patent application number 13/954736 was filed with the patent office on 2013-12-26 for polymorphic, crystalline and mesophase forms of sodium 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio) acetate, and uses thereof.
This patent application is currently assigned to Ardea Biosciences, Inc.. The applicant listed for this patent is Ardea Biosciences, Inc.. Invention is credited to Gabriel GALVIN, Jean-Luc GIRARDET, Irina ZAMANSKY.
Application Number | 20130345271 13/954736 |
Document ID | / |
Family ID | 44306123 |
Filed Date | 2013-12-26 |
United States Patent
Application |
20130345271 |
Kind Code |
A1 |
ZAMANSKY; Irina ; et
al. |
December 26, 2013 |
POLYMORPHIC, CRYSTALLINE AND MESOPHASE FORMS OF SODIUM
2-(5-BROMO-4-(4-CYCLOPROPYLNAPHTHALEN-1-YL)-4H-1,2,4-TRIAZOL-3-YLTHIO)
ACETATE, AND USES THEREOF
Abstract
Crystalline polymorphs and solid mesophase forms of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate are described. In addition, pharmaceutical compositions and
uses of such compositions for the treatment of a variety of
diseases and conditions are provided.
Inventors: |
ZAMANSKY; Irina; (Oceanside,
CA) ; GALVIN; Gabriel; (San Diego, CA) ;
GIRARDET; Jean-Luc; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ardea Biosciences, Inc. |
San Diego |
CA |
US |
|
|
Assignee: |
Ardea Biosciences, Inc.
San Diego
CA
|
Family ID: |
44306123 |
Appl. No.: |
13/954736 |
Filed: |
July 30, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13375607 |
Feb 9, 2012 |
8524754 |
|
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PCT/US2011/020233 |
Jan 5, 2011 |
|
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13954736 |
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61293602 |
Jan 8, 2010 |
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Current U.S.
Class: |
514/384 ;
548/263.8 |
Current CPC
Class: |
A61P 19/06 20180101;
A61P 13/12 20180101; A61P 13/00 20180101; C07D 249/12 20130101 |
Class at
Publication: |
514/384 ;
548/263.8 |
International
Class: |
C07D 249/12 20060101
C07D249/12 |
Claims
1.-9. (canceled)
10. A crystalline polymorph of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate: ##STR00016## characterized by peaks at 4.22, 8.51, and
16.95.degree. 2.theta..+-.0.1.degree. 2.theta..
11. The crystalline polymorph of claim 10, further characterized by
a peak at 12.80.degree. 2.theta..+-.0.1.degree. 2.theta..
12. The crystalline polymorph of claim 10 that exhibits an x-ray
powder diffraction pattern substantially the same as the x-ray
powder diffraction pattern shown in FIG. 5.
13. The crystalline polymorph of claim 10, characterized by an
endothermic point onset, as determined by differential scanning
calorimetry at about 173.degree. C.
14. The crystalline polymorph of claim 13 characterized by a
differential scanning calorimetry pattern substantially the same as
the differential scanning calorimetry pattern shown in FIG. 6.
15. (canceled)
16. A solid pharmaceutical composition comprising: an effective
amount of the crystalline polymorph of claim 10 as an active
ingredient; and at least one excipient or carrier.
17. A method for treating or preventing hyperuricemia, or a disease
caused by elevated uric acid levels, comprising administering an
effective amount of the crystalline polymorph of claim 10.
18. A method for treating or preventing gout comprising
administering an effective amount of the crystalline polymorph of
claim 10.
19.-46. (canceled)
47. A solid pharmaceutical composition comprising: an effective
amount of the crystalline polymorph of claim 13 as an active
ingredient; and at least one excipient or carrier.
48. A method for treating or preventing hyperuricemia, or a disease
caused by elevated uric acid levels, comprising administering an
effective amount of the crystalline polymorph of claim 13.
49. A method for treating or preventing gout comprising
administering an effective amount of the crystalline polymorph of
claim 13.
Description
CROSS REFERENCE
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/293,602, filed Jan. 8, 2010 which is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to polymorphic, crystalline
and mesophase forms of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, which decreases uric acid levels.
BACKGROUND OF THE INVENTION
[0003] Gout is associated with elevated levels of uric acid that
crystallize and deposit in joints, tendons, and surrounding
tissues. Gout is marked by recurrent attacks of red, tender, hot,
and/or swollen joints.
SUMMARY OF THE INVENTION
[0004] Described herein are crystal polymorphs, mesophases, and
other forms of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate:
##STR00001##
[0005] One aspect described herein are crystalline polymorphs of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate characterized by peaks at 4.90, 9.83, and 25.29.degree.
2.theta..+-.0.1.degree. 2.theta.. In further embodiment, such a
crystalline polymorph is further characterized by at least two
further peaks at 6.86, 8.41, 10.13, 17.92, and
23.10.degree.2.theta..+-.0.1.degree. 2.theta.. In yet still further
embodiments, the crystalline polymorph exhibits an x-ray powder
diffraction pattern substantially the same as the x-ray powder
diffraction pattern shown in FIG. 1. In a related aspect described
herein are crystalline polymorphs of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, characterized by an endothermic point onset, as determined by
differential scanning calorimetry at about 62.degree. C. In a
further embodiment, the crystalline polymorph is characterized by a
differential scanning calorimetry pattern substantially the same as
the differential scanning calorimetry pattern shown in FIG. 2. In
another related aspect described herein is the crystalline
polymorph Form A. In a related aspect described herein are solid
pharmaceutical compositions comprising an effective amount of the
crystalline polymorph characterized by the aforementioned
diffraction patterns, an effective amount of the crystalline
polymorph characterized by the aforementioned differential scanning
calorimetry patterns, or an effective amount of the crystalline
polymorph Form A, as an active ingredient; and at least one
excipient or carrier. A method for treating or preventing
hyperuricemia or a disease caused by elevated uric acid levels,
comprising administering, to a subject in need, an effective amount
of the crystalline polymorph characterized by the aforementioned
diffraction patterns, an effective amount of the crystalline
polymorph characterized by the aforementioned differential scanning
calorimetry patterns, or an effective amount of the crystalline
polymorph Form A. A method for treating or preventing gout,
comprising administering, to a subject in need, an effective amount
of the crystalline polymorph characterized by the aforementioned
diffraction patterns, an effective amount of the crystalline
polymorph characterized by the aforementioned differential scanning
calorimetry patterns, or an effective amount of the crystalline
polymorph Form A.
[0006] One aspect described herein are crystalline polymorphs of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate characterized by peaks at 4.22, 8.51, and 16.95.degree.
2.theta..+-.0.1.degree. 2.theta.. In further embodiment, such a
crystalline polymorph is further characterized by a peak at
12.80.degree. 2.theta..+-.0.1.degree. 2.theta.. In yet still
further embodiments, the crystalline polymorph exhibits an x-ray
powder diffraction pattern substantially the same as the x-ray
powder diffraction pattern shown in FIG. 5. In a related aspect
described herein are crystalline polymorphs of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3--
ylthio)acetate, characterized by an endothermic point onset, as
determined by differential scanning calorimetry at about
173.degree. C. In a further embodiment, the crystalline polymorph
is characterized by a differential scanning calorimetry pattern
substantially the same as the differential scanning calorimetry
pattern shown in FIG. 6. In another related aspect described herein
is the crystalline polymorph Form B. In a related aspect described
herein are solid pharmaceutical compositions comprising an
effective amount of the crystalline polymorph characterized by the
aforementioned diffraction patterns, an effective amount of the
crystalline polymorph characterized by the aforementioned
differential scanning calorimetry patterns, or an effective amount
of the crystalline polymorph Form B, as an active ingredient; and
at least one excipient or carrier. A method for treating or
preventing hyperuricemia or a disease caused by elevated uric acid
levels, comprising administering, to a subject in need, an
effective amount of the crystalline polymorph characterized by the
aforementioned diffraction patterns, an effective amount of the
crystalline polymorph characterized by the aforementioned
differential scanning calorimetry patterns, or an effective amount
of the crystalline polymorph Form B. A method for treating or
preventing gout, comprising administering, to a subject in need, an
effective amount of the crystalline polymorph characterized by the
aforementioned diffraction patterns, an effective amount of the
crystalline polymorph characterized by the aforementioned
differential scanning calorimetry patterns, or an effective amount
of the crystalline polymorph Form B.
[0007] One aspect described herein are crystalline polymorphs of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate characterized by an x-ray powder diffraction pattern
substantially the same as the x-ray powder diffraction pattern
shown in FIG. 7. In a related aspect described herein are
crystalline polymorphs of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, characterized by a differential scanning calorimetry pattern
substantially the same as the differential scanning calorimetry
pattern shown in FIG. 8. In another related aspect described herein
is the crystalline polymorph Form B'. In a related aspect described
herein are solid pharmaceutical compositions comprising an
effective amount of the crystalline polymorph characterized by the
aforementioned diffraction patterns, an effective amount of the
crystalline polymorph characterized by the aforementioned
differential scanning calorimetry patterns, or an effective amount
of the crystalline polymorph Form B', as an active ingredient; and
at least one excipient or carrier. A method for treating or
preventing hyperuricemia or a disease caused by elevated uric acid
levels, comprising administering, to a subject in need, an
effective amount of the crystalline polymorph characterized by the
aforementioned diffraction patterns, an effective amount of the
crystalline polymorph characterized by the aforementioned
differential scanning calorimetry patterns, or an effective amount
of the crystalline polymorph Form B'. A method for treating or
preventing gout, comprising administering, to a subject in need, an
effective amount of the crystalline polymorph characterized by the
aforementioned diffraction patterns, an effective amount of the
crystalline polymorph characterized by the aforementioned
differential scanning calorimetry patterns, or an effective amount
of the crystalline polymorph Form B'.
[0008] One aspect described herein are crystalline polymorphs of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate characterized by peaks at 6.9, 10.1 and 22.6.degree.
2.theta..+-.0.1.degree. 2.theta.. In further embodiments, the
crystalline polymorph is further characterized by at least two
peaks at 23.3, 23.9, 25.2, 28.3 or 29.0.degree.
2.theta..+-.0.1.degree. 2.theta.. In yet still further embodiments,
the crystalline polymorph exhibits an x-ray powder diffraction
pattern substantially the same as the x-ray powder diffraction
pattern shown in FIG. 9. In another related aspect described herein
is the crystalline polymorph Form C. In a related aspect described
herein are solid pharmaceutical compositions comprising an
effective amount of the crystalline polymorph characterized by the
aforementioned diffraction patterns, or an effective amount of the
crystalline polymorph Form C, as an active ingredient; and at least
one excipient or carrier. A method for treating or preventing
hyperuricemia or a disease caused by elevated uric acid levels,
comprising administering, to a subject in need, an effective amount
of the crystalline polymorph characterized by the aforementioned
diffraction patterns, or an effective amount of the crystalline
polymorph Form C. A method for treating or preventing gout,
comprising administering, to a subject in need, an effective amount
of the crystalline polymorph characterized by the aforementioned
diffraction patterns, or an effective amount of the crystalline
polymorph Form C.
[0009] One aspect described herein are crystalline polymorphs of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate characterized by peaks at 10.3, 17.8 and 25.2.degree.
2.theta..+-.0.1.degree. 2.theta.. In yet still further embodiments,
the crystalline polymorph exhibits an x-ray powder diffraction
pattern substantially the same as the x-ray powder diffraction
pattern shown in FIG. 10. In another related aspect described
herein is the crystalline polymorph Form D. In a related aspect
described herein are solid pharmaceutical compositions comprising
an effective amount of the crystalline polymorph characterized by
the aforementioned diffraction patterns, or an effective amount of
the crystalline polymorph Form D, as an active ingredient; and at
least one excipient or carrier. A method for treating or preventing
hyperuricemia or a disease caused by elevated uric acid levels,
comprising administering, to a subject in need, an effective amount
of the crystalline polymorph characterized by the aforementioned
diffraction patterns, or an effective amount of the crystalline
polymorph Form D. A method for treating or preventing gout,
comprising administering, to a subject in need, an effective amount
of the crystalline polymorph characterized by the aforementioned
diffraction patterns, or an effective amount of the crystalline
polymorph Form D.
[0010] One aspect described herein are crystalline polymorphs of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate characterized by at least three peaks at 10.5, 22.9, 23.2 or
24.6.degree. 2.theta..+-.0.1.degree. 2.theta.. In yet still further
embodiments, the crystalline polymorph exhibits an x-ray powder
diffraction pattern substantially the same as the x-ray powder
diffraction pattern shown in FIG. 11. In another related aspect
described herein is the crystalline polymorph Form E. In a related
aspect described herein are solid pharmaceutical compositions
comprising an effective amount of the crystalline polymorph
characterized by the aforementioned diffraction patterns, or an
effective amount of the crystalline polymorph Form E, as an active
ingredient; and at least one excipient or carrier. A method for
treating or preventing hyperuricemia or a disease caused by
elevated uric acid levels, comprising administering, to a subject
in need, an effective amount of the crystalline polymorph
characterized by the aforementioned diffraction patterns, or an
effective amount of the crystalline polymorph Form E. A method for
treating or preventing gout, comprising administering, to a subject
in need, an effective amount of the crystalline polymorph
characterized by the aforementioned diffraction patterns, or an
effective amount of the crystalline polymorph Form E.
[0011] In further aspects are a solid mesophase form of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, that exhibits an x-ray powder diffraction substantially the
same as the x-ray powder diffraction pattern shown in FIG. 12, FIG.
13, FIG. 14, or FIG. 15. In further embodiments are solid
pharmaceutical compositions comprising an effective amount of any
of the aforementioned solid mesophase forms of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, or a combination thereof; and at least one excipient or
carrier. In a further embodiments are methods for treating or
preventing hyperuricemia or a disease caused by elevated uric acid
levels, comprising administering an effective amount of any of the
aforementioned solid mesophase forms, or a combination thereof. In
a further embodiment are methods for treating or preventing gout,
comprising administering an effective amount of any of the
aforementioned solid mesophase forms, or a combination thereof.
[0012] In a further aspect are solid pharmaceutical compositions
comprising an effective amount of at least two of the
aforementioned crystalline polymorph or solid mesophase forms of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate; and at least one excipient or carrier.
[0013] In a further aspect are methods for treating or preventing
hyperuricemia or a disease caused by elevated uric acid levels,
comprising administering an effective amount of at least two of the
aforementioned crystalline polymorph or solid mesophase forms of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate; and at least one excipient or carrier.
INCORPORATION BY REFERENCE
[0014] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawings.
[0016] FIG. 1 represents an illustrative X-ray Powder Diffraction
Pattern of Polymorph Form A.
[0017] FIG. 2 represents an illustrative Differential Scanning
calorimetry pattern of Polymorph Form A.
[0018] FIG. 3 represents an illustrative infrared spectrum of
Polymorph Form A.
[0019] FIG. 4 represents an illustrative Raman spectrum of
Polymorph Form A.
[0020] FIG. 5 represents an illustrative X-ray Powder Diffraction
Pattern of Polymorph Form B.
[0021] FIG. 6 represents an illustrative Differential Scanning
calorimetry pattern of Polymorph Form B.
[0022] FIG. 7 represents an illustrative X-ray Powder Diffraction
Pattern of Polymorph Form B'.
[0023] FIG. 8 represents an illustrative Differential Scanning
calorimetry pattern of Polymorph Form B'.
[0024] FIG. 9 represents an illustrative X-ray Powder Diffraction
Pattern C.
[0025] FIG. 10 represents an illustrative X-ray Powder Diffraction
Pattern D.
[0026] FIG. 11 represents an illustrative X-ray Powder Diffraction
Pattern E.
[0027] FIG. 12 represents an illustrative X-ray Powder Diffraction
Pattern of Mesophase 1.
[0028] FIG. 13 represents an illustrative Cyclic Differential
Scanning calorimetry Pattern of Mesophase 1.
[0029] FIG. 14 represents an illustrative X-ray Powder Diffraction
Pattern of Mesophase 2.
[0030] FIG. 15 represents an illustrative X-ray Powder Diffraction
Pattern of Mesophase 3.
DETAILED DESCRIPTION OF THE INVENTION
[0031] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
[0032] The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described. All documents, or portions of documents, cited in
the application including, without limitation, patents, patent
applications, articles, books, manuals, and treatises are hereby
expressly incorporated by reference in their entirety for any
purpose.
[0033] The present invention relates to polymorphic, crystalline
and mesophase forms of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, which decreases uric acid levels.
[0034] The term "polymorph Form A" refers to a crystalline form of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate that exhibits an x-ray powder diffraction pattern
substantially the same as that shown in FIG. 1, and a differential
scanning calorimetry profile substantially the same as that shown
in FIG. 2.
[0035] The term "polymorph Form B" refers to a crystalline form of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate that exhibits an x-ray powder diffraction pattern
substantially the same as that shown in FIG. 5, and a differential
scanning calorimetry profile substantially the same as that shown
in FIG. 6.
[0036] The term "polymorph Form B'" refers to a crystalline form of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate that exhibits an x-ray powder diffraction pattern
substantially the same as that shown in FIG. 7, and a differential
scanning calorimetry profile substantially the same as that shown
in FIG. 8.
[0037] Three other crystalline forms exhibit x-ray powder
diffraction patterns C, D and E substantially the same as those
shown in FIGS. 9, 10 and 11 respectively. Three solid mesophase
forms 1, 2 and 3 exhibit x-ray powder diffraction patterns
substantially the same as those shown in FIGS. 12, 14 and 15
respectively.
[0038] The present invention also relates to methods for treating
or preventing diseases, comprising administering an effective
amount of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylt-
hio)acetate, as the crystalline polymorph Form A, the crystalline
polymorph Form B, the crystalline polymorph Form B', the
crystalline form displaying XRPD pattern C, the crystalline form
displaying XRPD pattern D, the crystalline form displaying XRPD
pattern E, the solid mesophase form 1, the solid mesophase form 2,
the solid mesophase form 3 or a combination thereof.
[0039] The present invention also relates to solid pharmaceutical
composition, comprising, as an active ingredient, an effective
amount of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylt-
hio)acetate, as the crystalline polymorph Form A, the crystalline
polymorph Form B, the crystalline polymorph Form B', the
crystalline form displaying XRPD pattern C, the crystalline form
displaying XRPD pattern D, the crystalline form displaying XRPD
pattern E, the solid mesophase form 1, the solid mesophase form 2,
the solid mesophase form 3 or a combination thereof.
[0040] Also described are processes for the preparation of the
crystalline polymorph Form A, the crystalline polymorph Form B, the
crystalline polymorph Form B', the crystalline form displaying XRPD
pattern C, the crystalline form displaying XRPD pattern D, the
crystalline form displaying XRPD pattern E, the solid mesophase
form 1, the solid mesophase form 2, the solid mesophase form 3 of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate.
[0041] In certain instances, the crystalline polymorphs of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate were found to exhibit increased stability in comparison to the
amorphous solid state form of the carboxylic acid. In some
instances, improved stability of the crystalline polymorphs of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate provides for the preparation of pharmaceutical dosage forms
displaying reduced variability in the dosage present in a given
dosage form, reduction in the presence of impurities in the final
pharmaceutical product, and an improved shelf life of formulated
dosage forms when compared to the pharmaceutical dosage form
prepared with the amorphous solid state form of the carboxylic
acid. In some embodiments, a polymorph described herein (e.g., Form
A or Form B or Form B') demonstrates no degradation (e.g., less
than 0.01%, less than 0.1%, less than 0.5% by wt.) (i) for at least
3 months under accelerated conditions (e.g., 40.degree. C.-75% RH),
for at least 4 months under accelerated conditions (e.g.,
40.degree. C.-75% RH), for at least 5 months under accelerated
conditions (e.g., 40.degree. C.-75% RH), for at least 6 months
under accelerated conditions (e.g., 40.degree. C.-75% RH), for at
least 9 months under accelerated conditions (e.g., 40.degree.
C.-75% RH), for at least 12 months under accelerated conditions
(e.g., 40.degree. C.-75% RH), and/or (ii) for at least 12 months
under long-term conditions (e.g., 25.degree. C.-60% RH), for at
least 18 months under long-term conditions (e.g., 25.degree. C.-60%
RH), for at least 24 months under long-term conditions (e.g.,
25.degree. C.-60% RH).
Sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylth-
io)acetate
[0042] Described herein are various polymorphic, crystalline and
mesophase forms of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate which decreases uric acid levels, (see for example US patent
publication 2009/0197825, US patent publication 2010/0056464 and US
patent publication 2010/0056465). Details of clinical studies
involving sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylt-
hio)acetate have been described in International patent application
PCT/US2010/052958.
Polymorph Form A
[0043] In one embodiment, sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate polymorph Form A exhibits an x-ray powder diffraction pattern
characterized by the diffraction pattern summarized in Table 1A or
Table 1B. In some embodiments, provided herein is a polymorph of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 3 peaks of (.+-.0.1.degree. 2.theta.) of
Table 1A or 1B. In certain embodiments, provided herein is a
polymorph of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 4 peaks of (.+-.0.1.degree. 2.theta.) of
Table 1A or 1B, at least 5 peaks of (.+-.0.1.degree. 2.theta.) of
Table 1A or 1B, at least 6 peaks of (+0.1.degree. 2.theta.) of
Table 1A or 1B, at least 8 peaks of (.+-.0.1.degree. 2.theta.) of
Table 1A or 1B, at least 10 peaks of (.+-.0.1.degree. 2.theta.) of
Table 1A, at least 15 peaks of (.+-.0.1.degree. 2.theta.) of Table
1A, at least 20 peaks of (+0.1.degree. 2.theta.) of Table 1A, at
least 25 peaks of (.+-.0.1.degree. 2.theta.) of Table 1A, or at
least 30 peaks of (.+-.0.1.degree. 2.theta.) of Table 1A.
TABLE-US-00001 TABLE 1A .degree.2.theta. d space (.ANG.) Intensity
(%) 4.90 .+-. 0.10 18.027 .+-. 0.375 71 6.86 .+-. 0.10 12.891 .+-.
0.191 100 8.41 .+-. 0.10 10.512 .+-. 0.126 61 9.83 .+-. 0.10 8.996
.+-. 0.092 63 10.13 .+-. 0.10 8.730 .+-. 0.087 97 10.60 .+-. 0.10
8.346 .+-. 0.079 16 11.92 .+-. 0.10 7.424 .+-. 0.063 45 12.32 .+-.
0.10 7.183 .+-. 0.059 45 12.57 .+-. 0.10 7.041 .+-. 0.056 45 13.07
.+-. 0.10 6.772 .+-. 0.052 42 14.01 .+-. 0.10 6.322 .+-. 0.045 21
14.48 .+-. 0.10 6.118 .+-. 0.042 35 14.80 .+-. 0.10 5.988 .+-.
0.041 23 15.15 .+-. 0.10 5.850 .+-. 0.039 52 16.28 .+-. 0.10 5.444
.+-. 0.033 18 16.70 .+-. 0.10 5.309 .+-. 0.032 20 16.90 .+-. 0.10
5.246 .+-. 0.031 22 17.92 .+-. 0.10 4.950 .+-. 0.028 70 18.64 .+-.
0.10 4.761 .+-. 0.025 36 20.88 .+-. 0.10 4.255 .+-. 0.020 42 21.35
.+-. 0.10 4.163 .+-. 0.019 25 21.68 .+-. 0.10 4.099 .+-. 0.019 18
22.42 .+-. 0.10 3.966 .+-. 0.018 38 23.10 .+-. 0.10 3.850 .+-.
0.017 55 23.54 .+-. 0.10 3.780 .+-. 0.016 20 23.95 .+-. 0.10 3.715
.+-. 0.015 37 24.67 .+-. 0.10 3.609 .+-. 0.014 44 25.29 .+-. 0.10
3.522 .+-. 0.014 68 26.38 .+-. 0.10 3.379 .+-. 0.013 33 26.96 .+-.
0.10 3.307 .+-. 0.012 33 27.63 .+-. 0.10 3.229 .+-. 0.012 22 28.36
.+-. 0.10 3.147 .+-. 0.011 29 29.07 .+-. 0.10 3.072 .+-. 0.010
35
TABLE-US-00002 TABLE 1B .degree.2.theta. d space (.ANG.) Intensity
(%) 4.90 .+-. 0.10 18.027 .+-. 0.375 71 6.86 .+-. 0.10 12.891 .+-.
0.191 100 8.41 .+-. 0.10 10.512 .+-. 0.126 61 9.83 .+-. 0.10 8.996
.+-. 0.092 63 10.13 .+-. 0.10 8.730 .+-. 0.087 97 17.92 .+-. 0.10
4.950 .+-. 0.028 70 23.10 .+-. 0.10 3.850 .+-. 0.017 55 25.29 .+-.
0.10 3.522 .+-. 0.014 68
[0044] In one embodiment provided herein, the polymorph form A of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate is characterized by x-ray powder diffraction pattern peaks at
4.90, 9.83, and 25.29.degree. 2.theta..+-.0.1.degree. 2.theta.. In
further embodiments, the polymorph form A is further characterized
by at least one peak appearing at 6.86, 8.41, 10.13, 17.92, and
23.10.degree. 2.theta..+-.0.1.degree. 2.theta.. In further
embodiments, the polymorph form A is further characterized by at
least two peaks appearing at 6.86, 8.41, 10.13, 17.92, and
23.10.degree. 2.theta..+-.0.1.degree. 2.theta.. In yet still
further embodiments, the polymorph exhibits an x-ray powder
diffraction pattern substantially the same as the x-ray powder
diffraction pattern shown in FIG. 1.
Polymorph Form B
[0045] In one embodiment, sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate polymorph Form B exhibits an x-ray powder diffraction pattern
characterized by the diffraction pattern summarized in Table 2A or
2B. In some embodiments, provided herein is a polymorph of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 2 peaks of (+0.1.degree. 2.theta.) of
Table 2A or 2B. In certain embodiments, provided herein is a
polymorph of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 3 peaks of (+0.1.degree. 2.theta.) of
Table 2A or 2B, at least 4 peaks of (+0.1.degree. 2.theta.) of
Table 2A or 2B, at least 5 peaks of (+0.1.degree. 2.theta.) of
Table 2A, at least 6 peaks of (+0.1.degree. 2.theta.) of Table 2A,
at least 8 peaks of (+0.1.degree. 2.theta.) of Table 2A, at least
10 peaks of (+0.1.degree. 2.theta.) of Table 2A, at least 12 peaks
of (.+-.0.1.degree. 2.theta.) of Table 2A, at least 14 peaks of
(.+-.0.1.degree. 2.theta.) of Table 2A, or at least 16 peaks of
(.+-.0.1.degree. 2.theta.) of Table 2A.
TABLE-US-00003 TABLE 2 .degree.2.theta. d space (.ANG.) Intensity
(%) A 4.22 .+-. 0.10 20.939 .+-. 0.508 100 8.51 .+-. 0.10 10.392
.+-. 0.123 79 12.80 .+-. 0.10 6.917 .+-. 0.054 40 13.97 .+-. 0.10
6.337 .+-. 0.045 20 14.46 .+-. 0.10 6.126 .+-. 0.042 21 16.19 .+-.
0.10 5.475 .+-. 0.034 23 16.95 .+-. 0.10 5.231 .+-. 0.031 45 18.40
.+-. 0.10 4.821 .+-. 0.026 22 19.13 .+-. 0.10 4.639 .+-. 0.024 26
19.48 .+-. 0.10 4.558 .+-. 0.023 24 20.03 .+-. 0.10 4.433 .+-.
0.022 25 21.28 .+-. 0.10 4.176 .+-. 0.019 23 22.56 .+-. 0.10 3.942
.+-. 0.017 32 22.90 .+-. 0.10 3.883 .+-. 0.017 27 23.53 .+-. 0.10
3.781 .+-. 0.016 24 25.64 .+-. 0.10 3.474 .+-. 0.013 28 27.27 .+-.
0.10 3.271 .+-. 0.012 18 28.17 .+-. 0.10 3.168 .+-. 0.011 15 28.72
.+-. 0.10 3.108 .+-. 0.011 19 B 4.22 .+-. 0.10 20.939 .+-. 0.508
100 8.51 .+-. 0.10 10.392 .+-. 0.123 79 12.80 .+-. 0.10 6.917 .+-.
0.054 40 16.95 .+-. 0.10 5.231 .+-. 0.031 45
[0046] In one embodiment provided herein, the polymorph form B of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate is characterized by x-ray powder diffraction pattern peaks at
4.22, 8.51, and 16.95.degree. 2.theta..+-.0.1.degree. 2.theta.. In
a further embodiment, the polymorph form B is further characterized
by a peak appearing at 12.80.degree. 2.theta..+-.0.1.degree.
2.theta.. In yet still further embodiments, the polymorph exhibits
an x-ray powder diffraction pattern substantially the same as the
x-ray powder diffraction pattern shown in FIG. 5.
Polymorph Form B'
[0047] In one embodiment, sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate polymorph Form B' exhibits an x-ray powder diffraction pattern
characterized by the diffraction pattern summarized in FIG. 7.
Polymorph Form C
[0048] In one embodiment, sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate polymorph Form C exhibits an x-ray powder diffraction pattern
characterized by the diffraction pattern summarized in Table 3A or
3B. In some embodiments, provided herein is a polymorph of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 3 peaks of (.+-.0.1.degree. 2.theta.) of
Table 3A or 3B. In certain embodiments, provided herein is a
polymorph of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 4 peaks of (.+-.0.1.degree. 2.theta.) of
Table 3A or 3B, at least 5 peaks of (.+-.0.1.degree. 2.theta.) of
Table 3A or 3B, at least 6 peaks of (.+-.0.1.degree. 2.theta.) of
Table 3A or 3B, at least 8 peaks of (.+-.0.1.degree. 2.theta.) of
Table 3A or 3B, at least 10 peaks of (.+-.0.1.degree. 2.theta.) of
Table 3A, at least 15 peaks of (+0.1.degree. 2.theta.) of Table 3A,
at least 20 peaks of (+0.1.degree. 2.theta.) of Table 3A, or at
least 25 peaks of (.+-.0.1.degree. 2.theta.) of Table 3A.
TABLE-US-00004 TABLE 3 .degree.2.theta. d space (.ANG.) Intensity
(%) A 6.9 .+-. 0.1 12.774 .+-. 0.187 100 7.7 .+-. 0.1 11.512 .+-.
0.152 6 8.2 .+-. 0.1 10.809 .+-. 0.134 6 8.6 .+-. 0.1 10.306 .+-.
0.121 10 10.1 .+-. 0.1 8.758 .+-. 0.087 88 11.0 .+-. 0.1 8.014 .+-.
0.073 24 12.5 .+-. 0.1 7.059 .+-. 0.057 32 13.1 .+-. 0.1 6.779 .+-.
0.052 26 14.0 .+-. 0.1 6.308 .+-. 0.045 14 15.4 .+-. 0.1 5.746 .+-.
0.037 10 16.7 .+-. 0.1 5.315 .+-. 0.032 12 17.6 .+-. 0.1 5.051 .+-.
0.029 34 18.4 .+-. 0.1 4.827 .+-. 0.026 23 19.1 .+-. 0.1 4.656 .+-.
0.024 11 19.8 .+-. 0.1 4.480 .+-. 0.022 13 20.2 .+-. 0.1 4.388 .+-.
0.022 20 21.1 .+-. 0.1 4.215 .+-. 0.020 19 21.8 .+-. 0.1 4.081 .+-.
0.019 42 22.6 .+-. 0.1 3.941 .+-. 0.017 87 23.3 .+-. 0.1 3.811 .+-.
0.016 74 23.9 .+-. 0.1 3.726 .+-. 0.015 80 25.2 .+-. 0.1 3.534 .+-.
0.014 84 26.4 .+-. 0.1 3.376 .+-. 0.013 40 27.1 .+-. 0.1 3.295 .+-.
0.012 34 28.3 .+-. 0.1 3.158 .+-. 0.011 66 29.0 .+-. 0.1 3.075 .+-.
0.010 70 B 6.9 .+-. 0.1 12.774 .+-. 0.187 100 10.1 .+-. 0.1 8.758
.+-. 0.087 88 22.6 .+-. 0.1 3.941 .+-. 0.017 87 23.3 .+-. 0.1 3.811
.+-. 0.016 74 23.9 .+-. 0.1 3.726 .+-. 0.015 80 25.2 .+-. 0.1 3.534
.+-. 0.014 84 28.3 .+-. 0.1 3.158 .+-. 0.011 66 29.0 .+-. 0.1 3.075
.+-. 0.010 70
[0049] In one embodiment provided herein, the polymorph form C of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate is characterized by x-ray powder diffraction pattern peaks at
6.9, 10.1, and 22.6.degree. 2.theta..+-.0.1.degree. 2.theta.. In
further embodiments, the polymorph form C is further characterized
by at least one peak appearing at 23.3, 23.9, 25.2, 28.3, and
29.0.degree. 2.theta..+-.0.1.degree. 2.theta.. In further
embodiments, the polymorph form C is further characterized by at
least two peaks appearing at 23.3, 23.9, 25.2, 28.3, and
29.0.degree. 2.theta..+-.0.1.degree. 2.theta.. In yet still further
embodiments, the polymorph exhibits an x-ray powder diffraction
pattern substantially the same as the x-ray powder diffraction
pattern shown in FIG. 9.
Polymorph Form D
[0050] In one embodiment, sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate polymorph Form D exhibits an x-ray powder diffraction pattern
characterized by the diffraction pattern summarized in Table 4A or
4B. In some embodiments, provided herein is a polymorph of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 2 peaks of (.+-.0.1.degree. 2.theta.) of
Table 4A or 4B. In certain embodiments, provided herein is a
polymorph of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 3 peaks of (.+-.0.1.degree. 2.theta.) of
Table 3A or 3B, at least 4 peaks of (.+-.0.1.degree. 2.theta.) of
Table 3A, at least 5 peaks of (.+-.0.1.degree. 2.theta.) of Table
3A, at least 6 peaks of (.+-.0.1.degree. 2.theta.) of Table 3A, at
least 8 peaks of (+0.1.degree. 2.theta.) of Table 3A, at least 10
peaks of (.+-.0.1.degree. 2.theta.) of Table 3A, at least 15 peaks
of (.+-.0.1.degree. 2.theta.) of Table 3A, or at least 20 peaks of
(.+-.3.1.degree. 2.theta.) of Table 3A.
TABLE-US-00005 TABLE 4 .degree.2.theta. d space (.ANG.) Intensity
(%) A 6.1 .+-. 0.1 14.585 .+-. 0.244 20 6.5 .+-. 0.1 13.599 .+-.
0.212 10 6.9 .+-. 0.1 12.737 .+-. 0.186 11 7.3 .+-. 0.1 12.177 .+-.
0.170 31 10.3 .+-. 0.1 8.605 .+-. 0.084 100 12.6 .+-. 0.1 7.048
.+-. 0.056 29 12.9 .+-. 0.1 6.842 .+-. 0.053 23 17.8 .+-. 0.1 4.994
.+-. 0.028 43 18.1 .+-. 0.1 4.896 .+-. 0.027 21 20.7 .+-. 0.1 4.287
.+-. 0.021 22 21.9 .+-. 0.1 4.062 .+-. 0.018 26 22.5 .+-. 0.1 3.959
.+-. 0.017 38 23.0 .+-. 0.1 3.874 .+-. 0.017 16 23.3 .+-. 0.1 3.815
.+-. 0.016 20 23.6 .+-. 0.1 3.764 .+-. 0.016 21 24.3 .+-. 0.1 3.663
.+-. 0.015 31 25.2 .+-. 0.1 3.531 .+-. 0.014 66 26.0 .+-. 0.1 3.425
.+-. 0.013 23 27.3 .+-. 0.1 3.267 .+-. 0.012 14 27.9 .+-. 0.1 3.198
.+-. 0.011 11 28.5 .+-. 0.1 3.132 .+-. 0.011 32 28.9 .+-. 0.1 3.087
.+-. 0.010 29 29.7 .+-. 0.1 3.012 .+-. 0.010 18 B 10.3 .+-. 0.1
8.605 .+-. 0.084 100 17.8 .+-. 0.1 4.994 .+-. 0.028 43 25.2 .+-.
0.1 3.531 .+-. 0.014 66
[0051] In one embodiment provided herein, the polymorph form D of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate is characterized by x-ray powder diffraction pattern peaks at
10.3, 17.8, and 25.2.degree. 2.theta..+-.0.1.degree. 2.theta.. In
yet still further embodiments, the polymorph exhibits an x-ray
powder diffraction pattern substantially the same as the x-ray
powder diffraction pattern shown in FIG. 10.
Polymorph Form E
[0052] In one embodiment, sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate polymorph Form E exhibits an x-ray powder diffraction pattern
characterized by the diffraction pattern summarized in Table 5. In
some embodiments, provided herein is a polymorph of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 2 peaks of (.+-.0.1.degree. 2.theta.) of
Table 5A or 5B. In certain embodiments, provided herein is a
polymorph of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate comprising at least 3 peaks of (+0.1.degree. 2.theta.) of
Table 5A or 5B, at least 4 peaks of (+0.1.degree. 2.theta.) of
Table 5A or 5B, at least 5 peaks of (.+-.0.1.degree. 2.theta.) of
Table 5A or 5B, at least 6 peaks of (.+-.0.1.degree. 2.theta.) of
Table 5A or 5B, at least 8 peaks of (.+-.0.1.degree. 2.theta.) of
Table 5A or 5B, at least 10 peaks of (.+-.0.1.degree. 2.theta.) of
Table 5A, at least 15 peaks of (.+-.0.1.degree. 2.theta.) of Table
5A, at least 20 peaks of (+0.1.degree. 2.theta.) of Table 5A, at
least 25 peaks of (+0.1.degree. 2.theta.) of Table 5A, or at least
30 peaks of (.+-.0.1.degree. 2.theta.) of Table 5A.
TABLE-US-00006 TABLE 5 .degree.2.theta. d space (.ANG.) Intensity
(%) A 6.8 .+-. 0.1 13.038 .+-. 0.195 38 7.6 .+-. 0.1 11.694 .+-.
0.157 17 8.5 .+-. 0.1 10.378 .+-. 0.123 20 10.0 .+-. 0.1 8.828 .+-.
0.089 21 10.5 .+-. 0.1 8.425 .+-. 0.081 100 11.3 .+-. 0.1 7.844
.+-. 0.070 32 12.2 .+-. 0.1 7.243 .+-. 0.060 38 12.9 .+-. 0.1 6.863
.+-. 0.053 33 13.3 .+-. 0.1 6.647 .+-. 0.050 15 13.8 .+-. 0.1 6.417
.+-. 0.047 14 14.7 .+-. 0.1 6.026 .+-. 0.041 7 15.5 .+-. 0.1 5.724
.+-. 0.037 13 15.8 .+-. 0.1 5.623 .+-. 0.036 15 16.2 .+-. 0.1 5.471
.+-. 0.034 7 16.6 .+-. 0.1 5.328 .+-. 0.032 11 17.1 .+-. 0.1 5.198
.+-. 0.030 28 17.5 .+-. 0.1 5.068 .+-. 0.029 45 19.4 .+-. 0.1 4.566
.+-. 0.023 9 20.2 .+-. 0.1 4.405 .+-. 0.022 16 21.1 .+-. 0.1 4.215
.+-. 0.020 26 21.8 .+-. 0.1 4.081 .+-. 0.019 32 22.4 .+-. 0.1 3.973
.+-. 0.018 33 22.9 .+-. 0.1 3.890 .+-. 0.017 64 23.2 .+-. 0.1 3.834
.+-. 0.016 70 23.8 .+-. 0.1 3.739 .+-. 0.016 49 24.6 .+-. 0.1 3.616
.+-. 0.015 60 25.7 .+-. 0.1 3.472 .+-. 0.013 34 26.2 .+-. 0.1 3.396
.+-. 0.013 44 27.2 .+-. 0.1 3.283 .+-. 0.012 26 28.1 .+-. 0.1 3.176
.+-. 0.011 45 28.7 .+-. 0.1 3.115 .+-. 0.011 35 29.1 .+-. 0.1 3.071
.+-. 0.010 32 29.5 .+-. 0.1 3.028 .+-. 0.010 43 30.0 .+-. 0.1 2.979
.+-. 0.010 36 B 10.5 .+-. 0.1 8.425 .+-. 0.081 100 22.9 .+-. 0.1
3.890 .+-. 0.017 64 23.2 .+-. 0.1 3.834 .+-. 0.016 70 24.6 .+-. 0.1
3.616 .+-. 0.015 60
[0053] In one embodiment provided herein, the polymorph form E of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate is characterized by x-ray powder diffraction pattern peaks at
10.5, 22.9, 23.2, and 24.6.degree. 2.theta..+-.0.1.degree.
2.theta.. In yet still further embodiments, the polymorph exhibits
an x-ray powder diffraction pattern substantially the same as the
x-ray powder diffraction pattern shown in FIG. 11.
[0054] In certain embodiments, any of the polymorphs described
herein (e.g., Form A) optionally comprises (or is intermixed or in
combination with) a certain amount of amorphous sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate. In some embodiments, the amorphous component of the polymorph
(e.g., Form A) or polymorph combination comprises less than 50 wt.
% of the polymorph or polymorph combination, less than 25 wt. % of
the polymorph or polymorph combination, less than 15 wt. % of the
polymorph or polymorph combination, less than 10 wt. % of the
polymorph or polymorph combination, or less than 5 wt. % of the
polymorph or polymorph combination.
Hydrates
[0055] In certain embodiments, provided herein is a sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate hydrate. In some embodiments, provided herein the sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate hydrate is crystalline. In still further embodiments, the
crystalline
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate hydrate comprises
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate and water in a mol ratio of between 1:1 to 1:5. In some
embodiments, the crystalline
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate hydrate comprises
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate and water in a mol ratio of between 1:1.5 and 1:3.5, or
between 1:1.8 to 1:3, or between 1:2 and 1:2.8, or about 1:2, or
about 1:2.5. In some embodiments, provided herein is a sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate hydrate comprising at least 5 wt. % water. In certain
embodiments, provided herein is a sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate hydrate comprising at least 9 wt. % water, 9-15 wt. % water,
10-13 wt. % water, 5-25 wt. % water, or the like.
Particle Size
[0056] In certain embodiments, provided herein is a sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate polymorph particle (e.g., crystalline, or comprising a
crystalline component). In some embodiments, provided herein is a
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate polymorph (e.g., crystalline, or comprising a crystalline
component) having a particle size of about 5-50 microns. In some
embodiments, the average particle size is at least 10 microns,
15-50 microns, 15-35 microns, 35-45 microns, 35-40 microns, about
40 microns, or the like. In some embodiments, particles of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (e.g., crystalline, or comprising a crystalline component,
such as a polymorph of Form A) having an average diameter of
greater than 5 or 10 microns have improved stability parameters
compared to smaller diameters. In some embodiments, provided herein
or used in any composition or method described herein is a sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate polymorph that is not micronized.
[0057] Uric acid is the result of the oxidation of xanthine.
Disorders of uric acid metabolism include, but are not limited to,
polycythemia, myeloid metaplasia, gout, a recurrent gout attack,
gouty arthritis, hyperuricaemia, hypertension, a cardiovascular
disease, coronary heart disease, Lesch-Nyhan syndrome,
Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidney
failure, joint inflammation, arthritis, urolithiasis, plumbism,
hyperparathyroidism, psoriasis or sarcoidosis.
DEFINITIONS
[0058] The term "subject", as used herein in reference to
individuals suffering from a disorder, and the like, encompasses
mammals and non-mammals. Examples of mammals include, but are not
limited to, any member of the Mammalian class: humans, non-human
primates such as chimpanzees, and other apes and monkey species;
farm animals such as cattle, horses, sheep, goats, swine; domestic
animals such as rabbits, dogs, and cats; laboratory animals
including rodents, such as rats, mice and guinea pigs, and the
like. Examples of non-mammals include, but are not limited to,
birds, fish and the like. In one embodiment of the methods and
compositions provided herein, the mammal is a human.
[0059] The terms "effective amount", "therapeutically effective
amount" or "pharmaceutically effective amount" as used herein,
refer to an amount of at least one agent or compound being
administered that is sufficient to treat or prevent the particular
disease or condition. The result can be reduction and/or
alleviation of the signs, symptoms, or causes of a disease, or any
other desired alteration of a biological system. For example, an
"effective amount" for therapeutic uses is the amount of the
composition comprising a compound as disclosed herein required to
provide a clinically significant decrease in a disease. An
appropriate "effective" amount in any individual case may be
determined using techniques, such as a dose escalation study.
[0060] The term "substantially the same as" as used herein, refers
to a powder x-ray diffraction pattern or differential scanning
calorimetry pattern that may be non-identical to those depicted
herein, but that falls within the limits of experimental error,
when considered by one of ordinary skill in the art.
[0061] "Representative Peaks" are the prominent peaks of an x-ray
powder diffraction pattern. Note that prominent peaks are
identified only if multiple XRPD patterns from multiple
diffractometers are available and the effects of both particle
statistics (reproducibility among XRPD patterns) and preferred
orientation (consistency of relative intensity among XRPD patterns)
are negligible.
[0062] "Characteristic peaks" are a subset of Representative Peaks
and are used to differentiate one crystalline polymorph or form
from another crystalline polymorph or form. Characteristic peaks
may be determined by evaluating which representative peaks, if any,
are present in one crystalline polymorph of a compound against all
other known crystalline polymorphs of that compound. Not all
crystalline polymorphs of a compound necessarily have at least one
characteristic peak.
Modulating URAT-1 Activity
[0063] The invention also relates to methods of modulating URAT-1
activity by contacting URAT-1 with an amount of a polymorphic,
crystalline or mesophase form of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, as described herein, sufficient to modulate the activity of
URAT-1. Modulate can be inhibiting or activating URAT-1 activity.
In some embodiments, the invention provides methods of inhibiting
URAT-1 activity by contacting URAT-1 with an amount of a
polymorphic, crystalline or mesophase form of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, as described herein, sufficient to inhibit the activity of
URAT-1. In some embodiments, the invention provides methods of
inhibiting URAT-1 activity in a solution by contacting said
solution with an amount of a polymorphic, crystalline or mesophase
form of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, as described herein sufficient to inhibit the activity of
URAT-1 in said solution. In some embodiments, the invention
provides methods of inhibiting URAT-1 activity in a cell by
contacting said cell with an amount of a polymorphic, crystalline
or mesophase form of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, as described herein, sufficient to inhibit the activity of
URAT-1 in said cell. In some embodiments, the invention provides
methods of inhibiting URAT-1 activity in a tissue by contacting
said tissue with an amount of a polymorphic, crystalline or
mesophase form of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, as described herein, sufficient to inhibit the activity of
URAT-1 in said tissue. In some embodiments, the invention provides
methods of inhibiting URAT-1 activity in blood by contacting the
blood with an amount of a polymorphic, crystalline or mesophase
form of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, as described herein, sufficient to inhibit the activity of
URAT-1 in blood. In some embodiments, the invention provides
methods of inhibiting URAT-1 activity in plasma by contacting the
plasma with an amount of a polymorphic, crystalline or mesophase
form of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, as described herein, sufficient to inhibit the activity of
URAT-1 in plasma. In some embodiments, the invention provides
methods of inhibiting URAT-1 activity in an animal by contacting
said animal with an amount of a polymorphic, crystalline or
mesophase form of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, as described herein sufficient to inhibit the activity of
URAT-1 in said animal. In some embodiments, the invention provides
methods of inhibiting URAT-1 activity in a mammal by contacting
said mammal with an amount of a polymorphic, crystalline or
mesophase form of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, as described herein sufficient to inhibit the activity of
URAT-1 in said mammal. In some embodiments, the invention provides
methods of inhibiting URAT-1 activity in a human by contacting said
human with an amount of a polymorphic, crystalline or mesophase
form of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, as described herein, sufficient to inhibit the activity of
URAT-1 in said human.
Pharmaceutical Compositions
[0064] Described herein are pharmaceutical compositions comprising
an effective amount of a polymorphic, crystalline or mesophase form
of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylt-
hio)acetate, as described herein. In some embodiments, the
pharmaceutical compositions comprise an effective amount of a
polymorphic, crystalline or mesophase form of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, as described herein, and at least one pharmaceutically
acceptable carrier. In some embodiments the pharmaceutical
compositions are for the treatment of disorders. In some
embodiments the pharmaceutical compositions are for the treatment
of disorders in a mammal. In some embodiments the pharmaceutical
compositions are for the treatment of disorders in a human. In some
embodiments the pharmaceutical compositions are for the treatment
or prophylaxis of disorders of uric acid metabolism. In some
embodiments the pharmaceutical compositions are for the treatment
or prophylaxis of hyperuricemia. In some embodiments the
pharmaceutical compositions are for the treatment or prophylaxis of
gout.
Modes of Administration, Formulations and Dosage Forms
[0065] Described herein are pharmaceutical compositions comprising
a polymorphic, crystalline or mesophase form of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate, as described herein. The compound, compound forms and
compositions described herein may be administered either alone or
in combination with pharmaceutically acceptable carriers,
excipients or diluents, in a pharmaceutical composition, according
to standard pharmaceutical practice. Administration can be effected
by any method that enables delivery of the compounds to the site of
action. These methods include, though are not limited to delivery
via enteral routes (including oral, gastric or duodenal feeding
tube, rectal suppository and rectal enema), parenteral routes
(injection or infusion, including intraarterial, intracardiac,
intradermal, intraduodenal, intramedullary, intramuscular,
intraosseous, intraperitoneal, intrathecal, intravascular,
intravenous, intravitreal, epidural and subcutaneous),
inhalational, transdermal, transmucosal, sublingual, buccal and
topical (including epicutaneous, dermal, enema, eye drops, ear
drops, intranasal, vaginal) administration, although the most
suitable route may depend upon for example the condition and
disorder of the recipient. Those of skill in the art will be
familiar with administration techniques that can be employed with
the compounds and methods of the invention. By way of example only,
the compounds, compound forms and compositions described herein can
be administered locally to the area in need of treatment, by for
example, local infusion during surgery, topical application such as
creams or ointments, injection, catheter, or implant, said implant
made for example, out of a porous, non-porous, or gelatinous
material, including membranes, such as sialastic membranes, or
fibers. The administration can also be by direct injection at the
site of a diseased tissue or organ.
[0066] The pharmaceutical compositions described herein may, for
example, be in a form suitable for oral administration as a tablet,
capsule, pill, powder, sustained release formulations, solution,
suspension, for parenteral injection as a sterile solution,
suspension or emulsion, for topical administration as an ointment
or cream or for rectal administration as a suppository. The
pharmaceutical composition may be in unit dosage forms suitable for
single administration of precise dosages. The pharmaceutical
composition will include a conventional pharmaceutical carrier or
excipient and a compound according to the invention as an active
ingredient. In addition, it may include other medicinal or
pharmaceutical agents, carriers, adjuvants, etc.
[0067] The formulations may conveniently be presented in unit
dosage form and may be prepared by any of the methods in the art of
pharmacy. All methods include the step of bringing into association
a compound or compound form of the subject invention or a
pharmaceutically acceptable salt, ester, prodrug or solvate thereof
("active ingredient") with the carrier which constitutes one or
more accessory ingredients. In general, the formulations are
prepared by uniformly and intimately bringing into association the
active ingredient with liquid carriers or finely divided solid
carriers or both and then, if necessary, shaping the product into
the desired formulation. Methods of preparing various
pharmaceutical compositions with a specific amount of active
compound are known, or will be apparent, to those skilled in this
art.
Doses
[0068] The amount of pharmaceutical compositions administered will
firstly be dependent on the mammal being treated. In the instances
where pharmaceutical compositions are administered to a human
subject, the daily dosage will normally be determined by the
prescribing physician with the dosage generally varying according
to the age, sex, diet, weight, general health and response of the
individual patient, the severity of the patient's symptoms, the
precise indication or condition being treated, the severity of the
indication or condition being treated, time of administration,
route of administration, the disposition of the composition, rate
of excretion, drug combination, and the discretion of the
prescribing physician. Also, the route of administration may vary
depending on the condition and its severity. The pharmaceutical
composition may be in unit dosage form. In such form, the
preparation is subdivided into unit doses containing appropriate
quantities of the active component, e.g., an effective amount to
achieve the desired purpose. Determination of the proper dosage for
a particular situation is within the skill of the art. For
convenience, the total daily dosage may be divided and administered
in portions during the day if desired. The amount and frequency of
administration will be regulated according to the judgment of the
attending clinician (physician) considering such factors as
described above. Thus the amount of pharmaceutical composition to
be administered may vary widely. Administration may occur in an
amount of between about 0.001 mg/kg of body weight to about 100
mg/kg of body weight per day (administered in single or divided
doses), or at least about 0.1 mg/kg of body weight per day. A
particular therapeutic dosage can include, e.g., from about 0.01 mg
to about 7000 mg of compound, or, e.g., from about 0.05 mg to about
2500 mg. In other embodiments a particular therapeutic dosage is
selected from about 200 mg, about 300 mg, about 400 mg, about 500
mg, about 600 mg, or about 700 mg. The quantity of active compound
in a unit dose of preparation may be varied or adjusted from about
0.1 mg to 1000 mg, from about 1 mg to 300 mg, or 10 mg to 200 mg,
according to the particular application. In other embodiments a
particular unit dosage is selected from 100 mg, 200 mg or 300 mg.
In some instances, dosage levels below the lower limit of the
aforesaid range may be more than adequate, while in other cases
still larger doses may be employed without causing any harmful side
effect, e.g. by dividing such larger doses into several small doses
for administration throughout the day. In combinational
applications in which the compound is not the sole therapy, it may
be possible to administer lesser amounts of compound and still have
therapeutic or prophylactic effect.
Combination Therapies
[0069] The compounds and compound forms described herein may be
administered as a sole therapy or in combination with another
therapy or therapies.
[0070] By way of example only, if one of the side effects
experienced by a patient upon receiving a compound or compound form
as described herein is hypertension, then it may be appropriate to
administer an anti-hypertensive agent in combination with the
compound. Or, by way of example only, the therapeutic effectiveness
of a compound or compound form as described herein may be enhanced
by administration of an adjuvant (i.e., by itself the adjuvant may
only have minimal therapeutic benefit, but in combination with
another therapeutic agent, the overall therapeutic benefit to the
patient is enhanced). Or, by way of example only, the benefit
experienced by a patient may be increased by administering a
compound or compound form as described herein with another
therapeutic agent (which also includes a therapeutic regimen) that
also has therapeutic benefit. Regardless of the disease, disorder
or condition being treated, the overall benefit experienced by the
patient may simply be additive of the two therapeutic agents or the
patient may experience a synergistic benefit.
[0071] In the instances where the compounds or compound forms as
described herein are administered with other therapeutic agents,
they need not be administered in the same pharmaceutical
composition as other therapeutic agents, and may, because of
different physical and chemical characteristics, be administered by
a different route. For example, the compound or compound form as
described herein may be administered orally to generate and
maintain good blood levels thereof, while the other therapeutic
agent may be administered intravenously. The determination of the
mode of administration and the advisability of administration,
where possible, in the same pharmaceutical composition, is well
within the knowledge of the skilled clinician. The initial
administration can be made, e.g., according to established
protocols known in the art, and then, based upon the observed
effects, the dosage, modes of administration and times of
administration can be modified by the skilled clinician.
[0072] The compounds, compound forms and compositions described
herein (and where appropriate other chemotherapeutic agent) may be
administered concurrently (e.g., simultaneously, essentially
simultaneously or within the same treatment protocol) sequentially
or separately, depending upon the nature of the disease, the
condition of the patient, and the actual choice of other
chemotherapeutic agent to be administered. For combinational
applications and uses, the compounds, compound forms and
compositions described herein and the chemotherapeutic agent need
not be administered simultaneously or essentially simultaneously.
Thus, the compounds, compound forms and compositions as described
herein may be administered first followed by the administration of
the chemotherapeutic agent; or the chemotherapeutic agent may be
administered first followed by the administration of the compounds,
compound forms and compositions as described herein. This alternate
administration may be repeated during a single treatment protocol.
The determination of the order of administration, and the number of
repetitions of administration of each therapeutic agent during a
treatment protocol, is well within the knowledge of the skilled
physician after evaluation of the disease being treated and the
condition of the patient. For example, the chemotherapeutic agent
may be administered first, especially if it is a cytotoxic agent,
and then the treatment continued with the administration of the
compounds, compound forms and compositions as described herein
followed, where determined advantageous, by the administration of
the chemotherapeutic agent, and so on until the treatment protocol
is complete. Thus, in accordance with experience and knowledge, the
practicing physician can modify each administration protocol for
treatment according to the individual patient's needs, as the
treatment proceeds. The attending clinician, in judging whether
treatment is effective at the dosage administered, will consider
the general well-being of the patient as well as more definite
signs such as relief of disease-related symptoms. Relief of
disease-related symptoms such as pain, and improvement in overall
condition can also be used to help judge effectiveness of
treatment.
[0073] Specific, non-limiting examples of possible combination
therapies include use of the compounds and compositions described
herein with Febuxostat, Allopurinol, Probenacid, Sulfinpyrazone,
Losartan, Fenofibrate, Benzbromarone or PNP-inhibitors (such as,
but not limited to Forodesine, BCX-1777 or BCX-4208). This list
should not be construed to be closed, but should instead serve as
an illustrative example common to the relevant therapeutic area at
present. Moreover, combination regimens may include a variety of
routes of administration, including but not limited to oral,
intravenous, intraocular, subcutaneous, dermal, and inhaled
topical.
Diseases
[0074] Described herein are methods of treating a disease or
disorder in an individual suffering from said disease or disorder
comprising administering to said individual an effective amount of
a polymorph, crystalline form or mesophase as described herein of
sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate.
[0075] The invention extends to the use of the compounds and
compound forms described herein in the manufacture of a medicament
for treating a disease or disorder.
[0076] In some embodiments, the disease or disorder is
hyperuricemia. In certain instances, hyperuricemia is characterized
by higher than normal blood levels of uric acid, sustained over
long periods of time. In certain instances, increased blood urate
levels may be due to enhanced uric acid production (-10-20%) and/or
reduced renal excretion (-80-90%) of uric acid. In certain
instances, causes of hyperuricemia may include obesity/weight gain,
excessive alcohol use, excessive dietary purine intake (foods such
as shellfish, fish roe, scallops, peas lentils, beans and red meat,
particularly offal--brains, kidneys, tripe, liver), certain
medications, including low-dose aspirin, diuretics, niacin,
cyclosporine, pyrazinamide, ethambutol, some high blood pressure
drugs and some cancer chemotherapeutics, immunosuppressive and
cytotoxic agents, specific disease states, particularly those
associated with a high cell turnover rate (such as malignancy,
leukemia, lymphoma or psoriasis), and also including high blood
pressure, hemoglobin diseases, hemolytic anemia, sickle cell
anemia, various nephropathies, myeloproliferative and
lymphoproliferative diseases, hyperparathyroidism, renal disease,
conditions associated with insulin resistance and diabetes
mellitus, and in transplant recipients, and possibly heart disease,
inherited enzyme defects, abnormal kidney function (e.g. increased
ATP turn over, reduced glomerular urate filtration) and exposure to
lead (plumbism or "saturnine gout").
[0077] In certain instances, hyperuricemia may be asymptomatic,
though is associated with the following conditions: gout, gouty
arthritis, uric acid stones in the urinary tract (urolithiasis),
deposits of uric acid in the soft tissue (tophi), deposits of uric
acid in the kidneys (uric acid nephropathy), and impaired kidney
function, possibly leading to chronic and acute renal failure.
[0078] In further or additional embodiments, the disease or
disorder is gout, which is a condition that results from uric acid
crystals depositing in tissues of the body. It is often related to
an inherited abnormality in the body's ability to process uric
acid, but may also be exacerbated by a diet high in purines.
Defective uric acid processing may lead to elevated levels of uric
acid in the blood causing recurring attacks of joint inflammation
(arthritis), uric acid deposits in and around the joints,
tophaceous gout, the formation of tophi, decreased kidney function,
and kidney stones. Approximately 3-5 million people in the United
States suffer from attacks of gout with attacks 6 to 9 times more
common in men than in women (see Sanders and Wortmann, "Harrison's
Principles of Internal Medicine", 16th Edition; 2005; Food and Drug
Administration (FDA) Advisory Committee Meeting, Terkeltaub
presentation, June 2004; Terkeltaub, "Gout", N Engl J Med., 349,
1647-55, 2003). In certain instances, gout is one of the most
common forms of arthritis, accounting for approximately 5% of all
arthritis cases. In certain instances, kidney failure and
urolithiasis occur in 10-18% of individuals with gout and are
common sources of morbidity and mortality from the disease.
[0079] Gout is associated with hyperuricemia. In certain instances,
individuals suffering from gout excrete approximately 40% less uric
acid than nongouty individuals for any given plasma urate
concentration. In certain instances, urate levels increase until
the saturation point is reached. In certain instances,
precipitation of urate crystals occurs when the saturation point is
reached. In certain instances, these hardened, crystallized
deposits (tophi) form in the joints and skin, causing joint
inflammation (arthritis). In certain instances, deposits are be
made in the joint fluid (synovial fluid) and/or joint lining
(synovial lining). Common areas for these deposits are the large
toe, feet, ankles and hands (less common areas include the ears and
eyes). In certain instances, the skin around an affected joint
becomes red and shiny with the affected area being tender and
painful to touch. In certain instances, gout attacks increase in
frequency. In certain instances, untreated acute gout attacks lead
to permanent joint damage and disability. In certain instances,
tissue deposition of urate leads to: acute inflammatory arthritis,
chronic arthritis, deposition of urate crystals in renal parenchyma
and urolithiasis. In certain instances, the incidence of gouty
arthritis increases 5 fold in individuals with serum urate levels
of 7 to 8.9 mg/dL and up to 50 fold in individuals with levels
>9 mg/dL (530 .mu.mol/L). In certain instances, individuals with
gout develop renal insufficiency and end stage renal disease (i.e.,
"gouty nephropathy"). In certain instances, gouty nephropathy is
characterized by a chronic interstitial nephropathy, which is
promoted by medullary deposition of monosodium urate.
[0080] In certain instances, gout includes painful attacks of
acute, monarticular, inflammatory arthritis, deposition of urate
crystals in joints, deposition of urate crystals in renal
parenchyma, urolithiasis (formation of calculus in the urinary
tract), and nephrolithiasis (formation of kidney stones). In
certain instances, secondary gout occurs in individuals with
cancer, particularly leukemia, and those with other blood diseases
(e.g. polycythemia, myeloid metaplasia, etc).
[0081] In certain instances, attacks of gout develop very quickly,
frequently the first attack occurring at night. In certain
instances, symptoms include sudden, severe joint pain and extreme
tenderness in the joint area, joint swelling and shiny red or
purple skin around the joint. In certain instances, the attacks are
infrequent lasting 5-10 days, with no symptoms between episodes. In
certain instances, attacks become more frequent and last longer,
especially if the disease is not controlled. In certain instances,
episodes damage the affected joint(s) resulting in stiffness,
swelling, limited motion and/or persistent mild to moderate
pain.
[0082] Plumbism or "saturnine gout," is a lead-induced
hyperuricemia that results from lead inhibition of tubular urate
transport causing decreased renal excretion of uric acid. In
certain instances, more than 50% of individuals suffering from lead
nephropathy suffer from gout. In certain instances, acute attacks
of saturnine gout occur in the knee more frequently than the big
toe. In certain instances, renal disease is more frequent and more
severe in saturnine gout than in primary gout. In certain
instances, treatment consists of excluding the individual from
further exposure to lead, the use of chelating agents to remove
lead, and control of acute gouty arthritis and hyperuricaemia. In
certain instances, saturnine gout is characterized by less frequent
attacks than primary gout. In certain instances, lead-associated
gout occurs in pre-menopausal women, an uncommon occurrence in non
lead-associated gout.
[0083] In certain instances, Lesch-Nyhan syndrome (LNS or Nyhan's
syndrome) affects about one in 100,000 live births. In certain
instances, LNS is caused by a genetic deficiency of the enzyme
hypoxanthine-guanine phosphoribosyltransferase (HGPRT). In certain
instances, LNS is an X-linked recessive disease. In certain
instances, LNS is present at birth in baby boys. In certain
instances, the disease leads to severe gout, poor muscle control,
and moderate mental retardation, which appear in the first year of
life. In certain instances, the disease also results in
self-mutilating behaviors (e.g., lip and finger biting, head
banging) beginning in the second year of life. In certain
instances, the disease also results in gout-like swelling in the
joints and severe kidney problems. In certain instances, the
disease leads neurological symptoms include facial grimacing,
involuntary writhing, and repetitive movements of the arms and legs
similar to those seen in Huntington's disease. The prognosis for
individuals with LNS is poor. In certain instances, the life
expectancy of an untreated individual with LNS is less than about 5
years. In certain instances, the life expectancy of a treated
individual with LNS is greater than about 40 years of age.
[0084] In certain instances, hyperuricemia is found in individuals
with cardiovascular disease (CVD) and/or renal disease. In certain
instances, hyperuricemia is found in individuals with
prehypertension, hypertension, increased proximal sodium
reabsorption, microalbuminuria, proteinuria, kidney disease,
obesity, hypertriglyceridemia, low high-density lipoprotein
cholesterol, hyperinsulinemia, hyperleptinemia,
hypoadiponectinemia, peripheral, carotid and coronary artery
disease, atherosclerosis, congestive heart failure, stroke, tumor
lysis syndrome, endothelial dysfunction, oxidative stress, elevated
renin levels, elevated endothelin levels, and/or elevated
C-reactive protein levels. In certain instances, hyperuricemia is
found in individuals with obesity (e.g., central obesity), high
blood pressure, hyperlipidemia, and/or impaired fasting glucose. In
certain instances, hyperuricemia is found in individuals with
metabolic syndrome. In certain instances, gouty arthritis is
indicative of an increased risk of acute myocardial infarction. In
some embodiments, administration of a compound described herein to
an individual are useful for decreasing the likelihood of a
clinical event associated with a disease or condition linked to
hyperuricemia, including, but not limited to, prehypertension,
hypertension, increased proximal sodium reabsorption,
microalbuminuria, proteinuria, kidney disease, obesity,
hypertriglyceridemia, low high-density lipoprotein cholesterol,
hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, peripheral,
carotid and coronary artery disease, atherosclerosis, congestive
heart failure, stroke, tumor lysis syndrome, endothelial
dysfunction, oxidative stress, elevated renin levels, elevated
endothelin levels, and/or elevated C-reactive protein levels.
[0085] In some embodiments, a compound or compound form as
described herein is administered to an individual suffering from a
disease or condition requiring treatment with a diuretic. In some
embodiments, a compound or compound form as described herein is
administered to an individual suffering from a disease or condition
requiring treatment with a diuretic, wherein the diuretic causes
renal retention of urate. In some embodiments, the disease or
condition is congestive heart failure or essential
hypertension.
[0086] In some embodiments, administration of a compound or
compound form as described herein to an individual is useful for
improving motility or improving quality of life.
[0087] In some embodiments, administration of a compound or
compound form as described herein to an individual is useful for
treating or decreasing the side effects of cancer treatment.
[0088] In some embodiments, administration of a compound or
compound form as described herein to an individual is useful for
decreasing kidney toxicity of cis-platin.
[0089] In certain instances, gout is treated by lowering the
production of uric acid. In certain instances, gout is treated by
increasing the excretion of uric acid. In certain instances, gout
is treated by URAT 1, xanthine oxidase, xanthine dehydrogenase,
xanthine oxidoreductase, a purine nucleoside phosphorylase (PNP)
inhibitor, a uric acid transporter (URAT) inhibitor, a glucose
transporter (GLUT) inhibitor, a GLUT-9 inhibitor, a solute carrier
family 2 (facilitated glucose transporter), member 9 (SLC2A9)
inhibitor, an organic anion transporter (OAT) inhibitor, an OAT-4
inhibitor, or combinations thereof. In general, the goals of gout
treatment are to i) reduce the pain, swelling and duration of an
acute attack, and ii) prevent future attacks and joint damage. In
certain instances, gout attacks are treated successfully using a
combination of treatments. In certain instances, gout is one of the
most treatable forms of arthritis.
[0090] i) Treating the gout attack. In certain instances, the pain
and swelling associated with an acute attack of gout can be
addressed with medications such as acetaminophen, steroids,
nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropic
hormone (ACTH) or colchicine. In certain instances, proper
medication controls gout within 12 to 24 hours and treatment is
stopped after a few days. In certain instances, medication is used
in conjunction with rest, increased fluid intake, ice-packs,
elevation and/or protection of the affected area/s. In certain
instances, the aforementioned treatments do not prevent recurrent
attacks and they do not affect the underlying diseases of abnormal
uric acid metabolism.
[0091] ii) Preventing future attacks. In certain instances,
reducing serum uric acid levels below the saturation level is the
goal for preventing further gout attacks. In some cases, this is
achieved by decreasing uric acid production (e.g. allopurinol), or
increasing uric acid excretion with uricosuric agents (e.g.
probenecid, sulfinpyrazone, benzbromarone).
[0092] In certain instances, allopurinol inhibits uric acid
formation, resulting in a reduction in both the serum and urinary
uric acid levels and becomes fully effective after 2 to 3
months.
##STR00002##
[0093] In certain instances, allopurinol is a structural analogue
of hypoxanthine, (differing only in the transposition of the carbon
and nitrogen atoms at positions 7 and 8), which inhibits the action
of xanthine oxidase, the enzyme responsible for the conversion of
hypoxanthine to xanthine, and xanthine to uric acid. In certain
instances, it is metabolized to the corresponding xanthine
analogue, alloxanthine (oxypurinol), which is also an inhibitor of
xanthine oxidase. In certain instances, alloxanthine, though more
potent in inhibiting xanthine oxidase, is less pharmaceutically
acceptable due to low oral bioavailability. In certain instances,
fatal reactions due to hypersensitivity, bone marrow suppression,
hepatitis, and vasculitis have been reported with Allopurinol. In
certain instances, the incidence of side effects may total 20% of
all individuals treated with the drug. Treatment for diseases of
uric acid metabolism has not evolved significantly in the following
two decades since the introduction of allopurinol.
[0094] In certain instances, uricosuric agents (e.g., probenecid,
sulfinpyrazone, and benzbromarone) increase uric acid excretion. In
certain instances, probenecid causes an increase in uric acid
secretion by the renal tubules and, when used chronically,
mobilizes body stores of urate. In certain instances, 25-50% of
individuals treated with probenecid fail to achieve reduction of
serum uric acid levels <6 mg/dL. In certain instances,
insensitivity to probenecid results from drug intolerance,
concomitant salicylate ingestion, and renal impairment. In certain
instances, one-third of the individuals develop intolerance to
probenecid. In certain instances, administration of uricosuric
agents also results in urinary calculus, gastrointestinal
obstruction, jaundice and anemia.
[0095] Successful treatment aims to reduce both the pain associated
with acute gout flare and long-term damage to the affected joints
(Emerson, "The Management of Gout", N Engl J Med., 334(7), 445-451,
1996). Therapeutic goals include providing rapid and safe pain
relief, preventing further attacks, preventing the formation of
tophi and subsequent arthritis, and avoiding exacerbating other
medical conditions. Initiation of treatment depends upon the
underlying causes of hyperuricemia, such as renal function, diet,
and medications. While gout is a treatable condition, there are
limited treatments available for managing acute and chronic gout
and a number of adverse effects are associated with current
therapies. Medication treatment of gout includes pain management,
prevention or decrease in joint inflammation during an acute gouty
attack, and chronic long-term therapy to maintain decreased serum
uric acid levels.
[0096] Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective
anti-inflammatory medications for acute gout but are frequently
associated with irritation of the gastrointestinal (GI) system,
ulceration of the stomach and intestines, and occasionally
intestinal bleeding (Schlesinger, "Management of Acute and Chronic
Gouty Arthritis Present State-of-the-Art"; Medications; 64 (21),
2399-2416, 2004; Pascual and Sivera, "Therapeutic advances in
gout"; Curr Opin Rheumatol., March; 19(2), 122-7, 2007). Colchicine
for acute gout is most commonly administered orally as tablets
(every 1-2 hours until there is significant improvement in pain or
the patient develops GI side effects such as severe diarrhea,
nausea and vomiting), or intravenously. Corticosteroids, given in
short courses, can be administered orally or injected directly into
the inflamed joint.
[0097] Medications are available for reducing blood uric acid
levels that either increase renal excretion of uric acid by
inhibiting re-uptake or reduce production of uric acid by blockade
of xanthine oxidase. These medicines are generally not initiated
until after the inflammation from acute gouty arthritis has
subsided because they may intensify the attack. If they are already
being taken prior to the attack, they are continued and only
adjusted after the attack has resolved. Since many subjects with
elevated blood uric acid levels may not develop gouty attacks or
kidney stones, the decision for prolonged treatment with uric
acid-lowering medications is individualized.
Kits
[0098] The compounds, compound forms, compositions and methods
described herein provide kits for the treatment of diseases and
disorders, such as the ones described herein. These kits comprise a
compound, compound form, compounds, compound forms or compositions
described herein in a container and, optionally, instructions
teaching the use of the kit according to the various methods and
approaches described herein. Such kits may also include
information, such as scientific literature references, package
insert materials, clinical trial results, and/or summaries of these
and the like, which indicate or establish the activities and/or
advantages of the composition, and/or which describe dosing,
administration, side effects, drug interactions, or other
information useful to the health care provider. Such information
may be based on the results of various studies, for example,
studies using experimental animals involving in vivo models and
studies based on human clinical trials. Kits described herein can
be provided, marketed and/or promoted to health providers,
including physicians, nurses, pharmacists, formulary officials, and
the like. Kits may also, in some embodiments, be marketed directly
to the consumer.
[0099] Provided in certain embodiments, are compositions or kits
comprising sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (e.g., a polymorph thereof, such as Form A), a double low
density polyethylene plastic bag, and an HDPE container. In further
embodiments, the composition or kit further comprises a foil bag
(e.g., an anhydrous foil bag, such as a heat sealed anhydrous foil
bag). In some embodiments, the composition or kit further comprises
a desiccant; in still other embodiments, a desiccant is not
necessary and/or present. In some instances, such packing improves
the stability of the sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (e.g., Form A).
[0100] The compounds, compound forms and pharmaceutical
compositions described herein may be utilized for diagnostics and
as research reagents. For example, the compounds, compound forms
and pharmaceutical compositions, either alone or in combination
with other compounds, can be used as tools in differential and/or
combinatorial analyses to elucidate expression patterns of genes
expressed within cells and tissues. As one non-limiting example,
expression patterns within cells or tissues treated with one or
more compounds are compared to control cells or tissues not treated
with compounds and the patterns produced are analyzed for
differential levels of gene expression as they pertain, for
example, to disease association, signaling pathway, cellular
localization, expression level, size, structure or function of the
genes examined. These analyses can be performed on stimulated or
unstimulated cells and in the presence or absence of other
compounds which affect expression patterns.
[0101] Besides being useful for human treatment, the compounds,
compound forms and pharmaceutical compositions described herein are
also useful for veterinary treatment of companion animals (e.g.
dogs, cats), exotic animals and farm animals (e.g. horses),
including mammals, rodents, and the like.
[0102] The examples and preparations provided below further
illustrate and exemplify the compounds of the present invention and
methods of preparing such compounds. It is to be understood that
the scope of the present invention is not limited in any way by the
scope of the following examples and preparations.
EXAMPLES
I Preparation of Compounds
Example 1
Preparation of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate
[0103] Sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate was prepared according to previously described procedures (see
US patent publication 2009/0197825) and as outlined below.
##STR00003##
[0104] Aqueous sodium hydroxide solution (1M, 2.0 mL, 2.0 mmol) was
added dropwise over 5 min to a solution of
2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid (810 mg, 2.0 mmol) in ethanol (10 mL) at 10.degree. C. The
mixture was stirred at 10.degree. C. for a further 10 min. Volatile
solvents were removed in vacuo to dryness to provide sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate as a solid (850 mg, 100%).
Example 2
Preparation of
2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid
[0105]
2-(5-Bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylth-
io)acetic acid was prepared according to previously described
procedures (see US patent publication 2009/0197825) and as outlined
below.
##STR00004##
Sodium hydroxide solution (2M aqueous, 33.7 mL, 67 mmol, 2 eq) was
added to a suspension of
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)-N--
(2-chloro-4-sulfamoylphenyl)acetamide (prepared by previously
published procedures, see US 2009/0197825; 20 g, 34 mmol) in
ethanol (200 mL) and the mixture heated at reflux for 4 hours.
Charcoal (10 g) was added, the mixture stirred at room temperature
for 12 hours and the charcoal removed by filtration. The charcoal
was washed several times with ethanol and the filtrate then
concentrated. Water (200 mL) was added and then concentrated to
approx. one third volume to remove all ethanol. Water (200 mL) and
ethyl acetate (250 mL) were added, the mixture stirred vigorously
for 15 min and the organic layer removed. The aqueous layer was
cooled to 0.degree. C. and acidified by treatment with HCl (1N)
resulting in the formation of a cloudy oily precipitate. The
mixture was extracted with ethyl acetate (3.times.) and the
combined organic extracts dried over sodium sulfate and
concentrated to give
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid as an off white solid (11.2 g, 82%).
##STR00005## ##STR00006##
Step A: 1-Cyclopropylnaphthalene
##STR00007##
[0107] Cyclopropylmagnesium bromide (150 mL, 0.5M in
tetrahydrofuran) was slowly added to a solution of
1-bromonaphthalene (10 g, 50 mmol) and
[1,3-bis(diphenylphosphino)propane]dichloro nickel (11) in
tetrahydrofuran (10 mL) stirred at 0.degree. C., and the reaction
mixture stirred at room temperature for 16 hours. The solvent was
removed under reduced pressure and ethyl acetate and aqueous
ammonium chloride were added. After extraction, the organic layer
was dried over sodium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography to yield 1-cyclopropylnaphthalene (6.4 g, 76%).
Step B: 1-Cyclopropyl-4-nitronaphthalene
##STR00008##
[0109] Sodium nitrite (30 mL) was slowly added (over 2 hours) to
1-cyclopropylnaphthalene (6.4 g, 38 mmol) stirred at 0.degree. C.
The reaction mixture was stirred at 0.degree. C. for an extra 30
min and then slowly poured into ice. Water was added, followed by
ethyl acetate. After extraction, the organic layer was washed with
aqueous sodium hydroxide (1%) and water, dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
purified by silica gel chromatography to yield
1-cyclopropyl-4-nitronaphthalene (5.2 g, 64%).
Step C: 1-Amino-4-cyclopropylnaphthalene
##STR00009##
[0111] A solution of 1-cyclopropyl-4-nitronaphthalene (5 g, 23
mmol) in ethanol (200 mL) was stirred under hydrogen in the
presence of Pd/C (10% net, 1.8 g). The reaction mixture was shaken
overnight, filtered over celite, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography to
yield 1-amino-4-cyclopropylnaphthalene (3.1 g, 73%).
Step D: 1-Cyclopropyl-4-isothiocvanatonaphthalene
##STR00010##
[0113] Thiophosgene (1.1 g, 9.7 mmol) was added to a stirred
solution of 1-amino-4-cyclopropylnaphthalene (1.8 g, 9.7 mmol) and
diisopropylethylamine (2 eq) in dichloromethane (50 mL) at
0.degree. C. The reaction mixture was stirred for 5 min at
0.degree. C. and then aqueous HCl (1% solution) was added. The
organic layer was separated, washed with brine, dried over sodium
sulfate, filtered and the solvent removed under reduced pressure.
Hexane was added, and the resulting precipitate was filtered. The
solvent was evaporated to yield
1-cyclopropyl-4-isothiocyanatonaphthalene (1.88 g, 86%).
Step E:
5-Amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-3-thiol
##STR00011##
[0115] A mixture of aminoguanidine hydrochloride (3.18 g, 29 mmol),
1-cyclopropyl-4-isothiocyanato naphthalene (3.24 g, 14 mmol) and
diisopropylethylamine (3 eq) in DMF (20 mL) was stirred at
50.degree. C. for 15 hours. The solvent was removed under reduced
pressure, toluene added, and the solvent was evaporated again.
Sodium hydroxide solution (2M, 30 mL) was added and the reaction
mixture heated at 50.degree. C. for 60 hours. The reaction mixture
was filtered and the filtrate neutralized with aqueous HCl (2M).
The mixture was re-filtered and the solvent removed under reduced
pressure. The residue was purified by silica gel chromatography to
yield
5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-3-thiol
(2.0 g, 49%).
Step F: Methyl
2-(5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate
##STR00012##
[0117] Methyl 2-chloroacetate (0.73 mL, 8.3 mmol) was added
dropwise over 5 min to a suspension of
5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-3-thiol
(2.24 g, 7.9 mmol) and potassium carbonate (1.21 g, 8.7 mmol) in
DMF (40 mL) at room temperature. The reaction was stirred at room
temperature for 24 h and slowly poured into a stirred ice-cold
water solution. The tan precipitate was collected by vacuum
filtration and dried under high vacuum at 50.degree. C. for 16 h in
the presence of P.sub.2O.sub.5 to yield methyl
2-(5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (2.24 g, 80%).
Step G: Methyl
2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate
##STR00013##
[0119] Sodium nitrite (2.76 g, 40 mmol) was added to a solution of
methyl
2-(5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (0.71 g, 2 mmol) and benzyltriethylammonium chloride (1.63 g,
6 mmol) in bromoform (10 mL). Dichloroacetic acid (0.33 mL, 4 mmol)
was then added and the reaction mixture stirred at room temperature
for 3 h. The mixture was directly loaded onto a 7-inch column of
silica gel, packed with dichloromethane (DCM). The column was first
eluted with DCM until all bromoform eluted, then eluted with
acetone/DCM (5:95) to give methyl
2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (713 mg, 85%).
Step H:
2-(5-Bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylt-
hio)acetic acid
##STR00014##
[0121] A solution of lithium hydroxide (98 mg, 4.1 mmol) in water
(10 mL) was added dropwise over 5 min to a solution of methyl
2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (1.14 g, 2.7 mmol) in ethanol (10 mL) and THF (10 mL) at
0.degree. C. The mixture was stirred at 0.degree. C. for a further
45 min and then neutralized to pH 7 by the addition of 0.5N HCl
solution at 0.degree. C. The resulting mixture was concentrated in
vacuo to 1/5th of its original volume, then diluted with water
(.about.20 mL) and acidified to pH 2-3 by the addition of 0.5N HCl
to produce a sticky solid. (If the product comes out as an oil
during acidification, extraction with dichloromethane is
recommended.) The tan solid was collected by vacuum filtration and
dried under high vacuum at 50.degree. C. for 16 h in the presence
of P.sub.2O.sub.5 to yield
2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tic acid (1.02 g, 93%).
II Preparation and Analysis of Various Polymorphic, Crystalline and
Mesophase Forms General Solvent Techniques
[0122] Solvents:
[0123] Solvents were either HPLC grade or ACS grade.
[0124] Evaporation:
[0125] Solvents were added to weighed solids and heated, agitated
and/or sonicated to facilitate dissolution as required. The
resulting solutions were filtered into clean containers and left
uncovered (fast evaporation) or with a loose cap (slow evaporation)
in a laboratory fume hood under ambient conditions or on a stir
plate at ambient, elevated or sub-ambient temperatures. Samples
were evaporated until no solvent was visible, generally to
dryness.
[0126] Slurry:
[0127] Slurries were prepared by adding enough solids to a given
solvent or solvent mixture so that excess solids were present. The
mixture was then stirred in a sealed vial (unless it was
evaporation slurry) at ambient, elevated, or sub-ambient
temperatures. The solids were isolated by vacuum or positive
pressure filtration or solvent decantation. Low solubility solvents
slurries were spiked with a small volume of high solubility solvent
to encourage conversion. Elevated temperature slurries seeking
increased solid yield and/or crystallization initiation were slow
cooled by shutting off the heat.
[0128] Trituration:
[0129] Samples that generated oil and/or gel were scratched/scraped
with a dental pick or spatula to encourage crystallization.
Polymorphic Forms A, B and B'
[0130] Three polymorphic forms of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate were prepared.
##STR00015##
Example 3A
Preparation of crystalline polymorph Form A of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate
[0131] Deionized water (0.5 mL) was added to a stirred suspension
of amorphous sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (1.00 g containing 1.8 wt % water) and ethyl acetate (4 mL)
producing a bi-phasic mixture, which was stirred at room
temperature for 18 hours. The resulting slurry was filtered under
vacuum and the solids washed with ethyl acetate (2.times.10 mL).
The filter cake was dried in vacuo at 18-20.degree. C. with a
nitrogen sweep for 4.5 hours to give 0.78 g sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylt-
hio)acetate containing 13.0 wt % water (70.3% recovery, anhydrous
basis). The isolated solid was designated Form A.
Example 3B
Analysis of crystalline polymorph Form A of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate
[0132] X-Ray Powder Diffraction
[0133] One Panalytical and one Inel XRPD pattern were analyzed. The
reproducibility and relative peak intensities were in good
agreement between the x-ray powder diffraction patterns, indicating
good particle and orientation statistics. The XRPD pattern for Form
A is shown in FIG. 1; observed and representative peaks in the XRPD
pattern are shown in the tables below:
TABLE-US-00007 Form A Observed .degree.2.theta. d space (.ANG.)
Intensity (%) 4.90 .+-. 0.10 18.027 .+-. 0.375 71 6.86 .+-. 0.10
12.891 .+-. 0.191 100 8.41 .+-. 0.10 10.512 .+-. 0.126 61 9.83 .+-.
0.10 8.996 .+-. 0.092 63 10.13 .+-. 0.10 8.730 .+-. 0.087 97 10.60
.+-. 0.10 8.346 .+-. 0.079 16 11.92 .+-. 0.10 7.424 .+-. 0.063 45
12.32 .+-. 0.10 7.183 .+-. 0.059 45 12.57 .+-. 0.10 7.041 .+-.
0.056 45 13.07 .+-. 0.10 6.772 .+-. 0.052 42 14.01 .+-. 0.10 6.322
.+-. 0.045 21 14.48 .+-. 0.10 6.118 .+-. 0.042 35 14.80 .+-. 0.10
5.988 .+-. 0.041 23 15.15 .+-. 0.10 5.850 .+-. 0.039 52 16.28 .+-.
0.10 5.444 .+-. 0.033 18 16.70 .+-. 0.10 5.309 .+-. 0.032 20 16.90
.+-. 0.10 5.246 .+-. 0.031 22 17.92 .+-. 0.10 4.950 .+-. 0.028 70
18.64 .+-. 0.10 4.761 .+-. 0.025 36 20.88 .+-. 0.10 4.255 .+-.
0.020 42 21.35 .+-. 0.10 4.163 .+-. 0.019 25 21.68 .+-. 0.10 4.099
.+-. 0.019 18 22.42 .+-. 0.10 3.966 .+-. 0.018 38 23.10 .+-. 0.10
3.850 .+-. 0.017 55 23.54 .+-. 0.10 3.780 .+-. 0.016 20 23.95 .+-.
0.10 3.715 .+-. 0.015 37 24.67 .+-. 0.10 3.609 .+-. 0.014 44 25.29
.+-. 0.10 3.522 .+-. 0.014 68 26.38 .+-. 0.10 3.379 .+-. 0.013 33
26.96 .+-. 0.10 3.307 .+-. 0.012 33 27.63 .+-. 0.10 3.229 .+-.
0.012 22 28.36 .+-. 0.10 3.147 .+-. 0.011 29 29.07 .+-. 0.10 3.072
.+-. 0.010 35
TABLE-US-00008 Form A Representative .degree.2.theta. d space
(.ANG.) Intensity (%) 4.90 .+-. 0.10 18.027 .+-. 0.375 71 6.86 .+-.
0.10 12.891 .+-. 0.191 100 8.41 .+-. 0.10 10.512 .+-. 0.126 61 9.83
.+-. 0.10 8.996 .+-. 0.092 63 10.13 .+-. 0.10 8.730 .+-. 0.087 97
17.92 .+-. 0.10 4.950 .+-. 0.028 70 23.10 .+-. 0.10 3.850 .+-.
0.017 55 25.29 .+-. 0.10 3.522 .+-. 0.014 68
The differential scanning calorimetry trace for Form A is shown in
FIG. 2. The infrared absorption spectrum of Form A is shown in FIG.
3. The Raman spectrum of Form A is shown in FIG. 4.
[0134] Form A of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate was tested under various conditions to determine thermodynamic
stability. No degradation of packaged Form A was observed for 6
months under accelerated conditions (40.degree. C.-75% RH).
Moreover, no degradation of packaged Form A was observed for 12
months under long term conditions (25.degree. C.-60% RH). Packaging
was in a double low density polyethylene plastic bag inside a heat
sealed anhydrous foil bag in an HDPE container. The stability
results of Form A demonstrated an improvement over the solid state
amorphous free acid.
Example 4A
Preparation of crystalline polymorph Form B of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate
[0135] Preparation i:
[0136] A mixture of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (3.02 g, Form A) and water-saturated ethyl acetate (6 mL) was
stirred at 45-50.degree. C. for 16 hours producing a bi-phasic
mixture, which was gradually cooled to room temperature over 2
hours and stirred for an additional 21 hours to give a uniform
suspension. The suspension was vacuum filtered, washed with ethyl
acetate and the filter cake dried in vacuo at 18-20.degree. C. with
a nitrogen sweep for 2 hours to give 2.77 g sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-y-
lthio)acetate containing 12.9 wt % water (91.7% recovery, anhydrous
basis).
[0137] Preparation ii:
[0138] Sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (Form A) was stirred at .about.50.degree. C. in
water-saturated ethyl acetate (0.5 mL) overnight, converting the
solids to oil. The oil was scratched with a dental pick and left to
stir at ambient temperature. After .about.3 days, optical
microscopy indicated crystalline solids. The liquid was removed by
decantation and the solids isolated. The isolated solids were
designated Form B.
Example 4B
Analysis of crystalline polymorph Form B of Sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate
[0139] X-Ray Powder Diffraction
[0140] One Panalytical and one Inel XRPD pattern were analyzed. The
reproducibility and relative peak intensities were in good
agreement between the x-ray powder diffraction patterns, indicating
good particle and orientation statistics. The XRPD pattern for Form
B is shown in FIG. 5; observed and representative peaks in the XRPD
pattern are shown in the tables below:
TABLE-US-00009 Form B Observed .degree.2.theta. d space (.ANG.)
Intensity (%) 4.22 .+-. 0.10 20.939 .+-. 0.508 100 8.51 .+-. 0.10
10.392 .+-. 0.123 79 12.80 .+-. 0.10 6.917 .+-. 0.054 40 13.97 .+-.
0.10 6.337 .+-. 0.045 20 14.46 .+-. 0.10 6.126 .+-. 0.042 21 16.19
.+-. 0.10 5.475 .+-. 0.034 23 16.95 .+-. 0.10 5.231 .+-. 0.031 45
18.40 .+-. 0.10 4.821 .+-. 0.026 22 19.13 .+-. 0.10 4.639 .+-.
0.024 26 19.48 .+-. 0.10 4.558 .+-. 0.023 24 20.03 .+-. 0.10 4.433
.+-. 0.022 25 21.28 .+-. 0.10 4.176 .+-. 0.019 23 22.56 .+-. 0.10
3.942 .+-. 0.017 32 22.90 .+-. 0.10 3.883 .+-. 0.017 27 23.53 .+-.
0.10 3.781 .+-. 0.016 24 25.64 .+-. 0.10 3.474 .+-. 0.013 28 27.27
.+-. 0.10 3.271 .+-. 0.012 18 28.17 .+-. 0.10 3.168 .+-. 0.011 15
28.72 .+-. 0.10 3.108 .+-. 0.011 19
TABLE-US-00010 Form B Representative .degree.2.theta. d space
(.ANG.) Intensity (%) 4.22 .+-. 0.10 20.939 .+-. 0.508 100 8.51
.+-. 0.10 10.392 .+-. 0.123 79 12.80 .+-. 0.10 6.917 .+-. 0.054 40
16.95 .+-. 0.10 5.231 .+-. 0.031 45
[0141] The differential scanning calorimetry trace for Form B is
shown in FIG. 6.
Example 5A
Preparation of crystalline polymorph Form B' of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl
thio)acetate
[0142] Sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate (Form B containing 12.9 wt % water) was dried under vacuum at
ambient temperature for 1-3 days resulting in an off-white solid,
designated as form B'.
Example 5B
Analysis of crystalline polymorph Form B' of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate
[0143] The x-ray powder diffraction pattern for Form B', shown in
FIG. 7, resembles that of Form B, however with non-uniform peak
shifts between the patterns, suggesting a different solvation state
of the same polymorph. The differential scanning calorimetry trace
of Form B' is shown in FIG. 8.
Stability of crystalline polymorph sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate
[0144] The crystalline polymorphs of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate were found to exhibit increased stability in comparison to the
amorphous solid state form of the carboxylic acid. The improved
stability of the crystalline polymorphs of sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate provides for the preparation of pharmaceutical dosage forms
displaying reduced variability in the dosage present in a given
dosage form, reduction in the presence of impurities in the final
pharmaceutical product, and an improved shelf life of formulated
dosage forms when compared to the pharmaceutical dosage form
prepared with the amorphous solid state form of the carboxylic
acid.
Unique Crystalline X-Ray Powder Diffraction Patterns C, D and E
Example 6
Sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylth-
io)acetate generated three additional unique crystalline x-ray
powder diffraction patterns--patterns C, D and E, prepared as
follows:
[0145] Pattern C: fast evaporation from methanol at .about.97%
relative humidity. Pattern D: cold crystallization from
ethanol/water. Pattern E: cold crystallization from
2-propanol/water.
Example 6A
Sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylth-
io)acetate displaying unique crystalline x-ray powder diffraction
pattern C
[0146] A portion of Form A was dissolved in methanol, followed by
fast evaporation at 97% relative humidity. One Bruker XRPD pattern
was analyzed for this material, and preferred orientation and
particle statistic effects assessed through evaluation of the two
dimensional scattering pattern. Consistent, uninterrupted rings
devoid of spots suggest good particle and orientation statistics.
XRPD pattern C is shown in FIG. 9; observed and representative
peaks in the XRPD pattern are shown in the table below:
TABLE-US-00011 .degree.2.theta. d space (.ANG.) Intensity (%)
Pattern C Observed 6.9 .+-. 0.1 12.774 .+-. 0.187 100 7.7 .+-. 0.1
11.512 .+-. 0.152 6 8.2 .+-. 0.1 10.809 .+-. 0.134 6 8.6 .+-. 0.1
10.306 .+-. 0.121 10 10.1 .+-. 0.1 8.758 .+-. 0.087 88 11.0 .+-.
0.1 8.014 .+-. 0.073 24 12.5 .+-. 0.1 7.059 .+-. 0.057 32 13.1 .+-.
0.1 6.779 .+-. 0.052 26 14.0 .+-. 0.1 6.308 .+-. 0.045 14 15.4 .+-.
0.1 5.746 .+-. 0.037 10 16.7 .+-. 0.1 5.315 .+-. 0.032 12 17.6 .+-.
0.1 5.051 .+-. 0.029 34 18.4 .+-. 0.1 4.827 .+-. 0.026 23 19.1 .+-.
0.1 4.656 .+-. 0.024 11 19.8 .+-. 0.1 4.480 .+-. 0.022 13 20.2 .+-.
0.1 4.388 .+-. 0.022 20 21.1 .+-. 0.1 4.215 .+-. 0.020 19 21.8 .+-.
0.1 4.081 .+-. 0.019 42 22.6 .+-. 0.1 3.941 .+-. 0.017 87 23.3 .+-.
0.1 3.811 .+-. 0.016 74 23.9 .+-. 0.1 3.726 .+-. 0.015 80 25.2 .+-.
0.1 3.534 .+-. 0.014 84 26.4 .+-. 0.1 3.376 .+-. 0.013 40 27.1 .+-.
0.1 3.295 .+-. 0.012 34 28.3 .+-. 0.1 3.158 .+-. 0.011 66 29.0 .+-.
0.1 3.075 .+-. 0.010 70 Pattern C Representative 6.9 .+-. 0.1
12.774 .+-. 0.187 100 10.1 .+-. 0.1 8.758 .+-. 0.087 88 22.6 .+-.
0.1 3.941 .+-. 0.017 87 23.3 .+-. 0.1 3.811 .+-. 0.016 74 23.9 .+-.
0.1 3.726 .+-. 0.015 80 25.2 .+-. 0.1 3.534 .+-. 0.014 84 28.3 .+-.
0.1 3.158 .+-. 0.011 66 29.0 .+-. 0.1 3.075 .+-. 0.010 70
Example 6B
Preparation of Sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate displaying unique crystalline x-ray powder diffraction pattern
D
[0147] A portion of Form A was crystallized in a freezer from an
ethanol/water (1/1) solution. One Bruker XRPD pattern was analyzed
for this material, and preferred orientation and particle statistic
effects assessed through evaluation of the two dimensional
scattering pattern. Consistent, uninterrupted rings devoid of spots
suggest good particle and orientation statistics. XRPD pattern D is
shown in FIG. 10; observed and representative peaks in the XRPD
pattern are shown in the table below:
TABLE-US-00012 .degree.2.theta. d space (.ANG.) Intensity (%)
Pattern D Observed 6.1 .+-. 0.1 14.585 .+-. 0.244 20 6.5 .+-. 0.1
13.599 .+-. 0.212 10 6.9 .+-. 0.1 12.737 .+-. 0.186 11 7.3 .+-. 0.1
12.177 .+-. 0.170 31 10.3 .+-. 0.1 8.605 .+-. 0.084 100 12.6 .+-.
0.1 7.048 .+-. 0.056 29 12.9 .+-. 0.1 6.842 .+-. 0.053 23 17.8 .+-.
0.1 4.994 .+-. 0.028 43 18.1 .+-. 0.1 4.896 .+-. 0.027 21 20.7 .+-.
0.1 4.287 .+-. 0.021 22 21.9 .+-. 0.1 4.062 .+-. 0.018 26 22.5 .+-.
0.1 3.959 .+-. 0.017 38 23.0 .+-. 0.1 3.874 .+-. 0.017 16 23.3 .+-.
0.1 3.815 .+-. 0.016 20 23.6 .+-. 0.1 3.764 .+-. 0.016 21 24.3 .+-.
0.1 3.663 .+-. 0.015 31 25.2 .+-. 0.1 3.531 .+-. 0.014 66 26.0 .+-.
0.1 3.425 .+-. 0.013 23 27.3 .+-. 0.1 3.267 .+-. 0.012 14 27.9 .+-.
0.1 3.198 .+-. 0.011 11 28.5 .+-. 0.1 3.132 .+-. 0.011 32 28.9 .+-.
0.1 3.087 .+-. 0.010 29 29.7 .+-. 0.1 3.012 .+-. 0.010 18 Pattern D
Representative 10.3 .+-. 0.1 8.605 .+-. 0.084 100 17.8 .+-. 0.1
4.994 .+-. 0.028 43 25.2 .+-. 0.1 3.531 .+-. 0.014 66
Example 6C
Preparation of Sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)ace-
tate displaying unique crystalline x-ray powder diffraction pattern
E
[0148] Preparation i:
[0149] A portion of Form A was mixed with ethanol and water (1/1)
to form a slurry, which then underwent slow evaporation/fast
evaporation in a cold room.
[0150] Preparation ii:
[0151] A portion of Form A was mixed with isopropyl alcohol and
water (9/1) to form a slurry, which was slow cooled from 50.degree.
C., and then underwent slow evaporation/fast evaporation in a
refrigerator. One Bruker pattern was analyzed for this material,
and preferred orientation and particle statistic effects assessed
through evaluation of the two dimensional scattering pattern.
Consistent, uninterrupted rings devoid of spots suggest good
particle and orientation statistics. XRPD pattern E is shown in
FIG. 11; observed and representative peaks in the XRPD pattern are
shown in the table below:
TABLE-US-00013 .degree.2.theta. d space (.ANG.) Intensity (%)
Pattern E Observed 6.8 .+-. 0.1 13.038 .+-. 0.195 38 7.6 .+-. 0.1
11.694 .+-. 0.157 17 8.5 .+-. 0.1 10.378 .+-. 0.123 20 10.0 .+-.
0.1 8.828 .+-. 0.089 21 10.5 .+-. 0.1 8.425 .+-. 0.081 100 11.3
.+-. 0.1 7.844 .+-. 0.070 32 12.2 .+-. 0.1 7.243 .+-. 0.060 38 12.9
.+-. 0.1 6.863 .+-. 0.053 33 13.3 .+-. 0.1 6.647 .+-. 0.050 15 13.8
.+-. 0.1 6.417 .+-. 0.047 14 14.7 .+-. 0.1 6.026 .+-. 0.041 7 15.5
.+-. 0.1 5.724 .+-. 0.037 13 15.8 .+-. 0.1 5.623 .+-. 0.036 15 16.2
.+-. 0.1 5.471 .+-. 0.034 7 16.6 .+-. 0.1 5.328 .+-. 0.032 11 17.1
.+-. 0.1 5.198 .+-. 0.030 28 17.5 .+-. 0.1 5.068 .+-. 0.029 45 19.4
.+-. 0.1 4.566 .+-. 0.023 9 20.2 .+-. 0.1 4.405 .+-. 0.022 16 21.1
.+-. 0.1 4.215 .+-. 0.020 26 21.8 .+-. 0.1 4.081 .+-. 0.019 32 22.4
.+-. 0.1 3.973 .+-. 0.018 33 22.9 .+-. 0.1 3.890 .+-. 0.017 64 23.2
.+-. 0.1 3.834 .+-. 0.016 70 23.8 .+-. 0.1 3.739 .+-. 0.016 49 24.6
.+-. 0.1 3.616 .+-. 0.015 60 25.7 .+-. 0.1 3.472 .+-. 0.013 34 26.2
.+-. 0.1 3.396 .+-. 0.013 44 27.2 .+-. 0.1 3.283 .+-. 0.012 26 28.1
.+-. 0.1 3.176 .+-. 0.011 45 28.7 .+-. 0.1 3.115 .+-. 0.011 35 29.1
.+-. 0.1 3.071 .+-. 0.010 32 29.5 .+-. 0.1 3.028 .+-. 0.010 43 30.0
.+-. 0.1 2.979 .+-. 0.010 36 Pattern E Representative 10.5 .+-. 0.1
8.425 .+-. 0.081 100 22.9 .+-. 0.1 3.890 .+-. 0.017 64 23.2 .+-.
0.1 3.834 .+-. 0.016 70 24.6 .+-. 0.1 3.616 .+-. 0.015 60
Mesophase patterns 1, 2 and 3
Example 7A
Sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylth-
io)acetate displaying Mesophase pattern 1
[0152] Solids isolated via various procedures outlined below,
produced a mesophase material, designated as mesophase 1 (mesophase
indicates an X-ray amorphous pattern with relatively few
reflections, suggesting limited order in the solids), which shows a
strong broad reflection at .about.4.degree. 2.theta., but no
birefringence by optical microscopy: [0153] a) evaporation from
methanol, ethanol, acetone, methyl ethyl ketone, methyl ethyl
ketone+heptanes or water; [0154] b) vacuum drying Form A; [0155] c)
vacuum drying a mixture of Form A and pattern C at ambient
temperature for .about.23 hours; [0156] d) precipitation from an
acetonitrile slurry; [0157] e) precipitation from slurries of Form
A and Form B' in 2-propanol, prepared at ambient and cold room
temperatures (.about.2-8.degree. C.).
[0158] The x-ray powder diffraction pattern of Mesophase Pattern 1
is shown in FIG. 12.
[0159] The cyclic differential scanning calorimetry trace of
Mesophase Pattern 1 is shown in FIG. 13.
Example 7B
Sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylth-
io)acetate displaying Mesophase pattern 2
[0160] Mesophase pattern 2 solids were prepared by precipitation
from 2-propanol/ethanol, and exhibits a strong sharp reflection at
.about.3.degree. 2.theta. and various potential weak broad
reflections.
[0161] The x-ray powder diffraction pattern of Mesophase Pattern 2
is shown in FIG. 14.
Example 7C
Sodium
2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylth-
io)acetate displaying Mesophase pattern 3
[0162] Mesophase pattern 3 solids were prepared by evaporation
under vapor stress. Dichloromethane and tetrahydrofuran solutions
were evaporated at .about.97% relative humidity initially
generating oils, which gradually exhibited partial crystallization
and eventual stiffened to a gel.
[0163] The x-ray powder diffraction pattern of Mesophase Pattern 3
is shown in FIG. 15. Note that crystalline solids signals may be
obscured by the gel.
Example 8
Karl Fischer Water Content Determination
[0164] Coulometric Karl Fischer (KF) analysis for water
determination was performed using a Mettler Toledo DL39 KF
titrator. A blank titration was carried out prior to analysis. The
sample was prepared under a dry nitrogen atmosphere; where
.about.1-13 mg of the sample were dissolved in approximately 1 mL
dry Hydranal--Coulomat AD in a pre-dried vial. The entire solution
was added to the Karl Fischer coulometer through a septum and mixed
for 10 seconds. The sample was then titrated by means of a
generator electrode, which produces iodine by electrochemical
oxidation (2I.sup.-.fwdarw.I.sub.2+2c.sup.-). Samples were run in
duplicate; the mean values are shown below, measured to the nearest
tenth of a percent.
TABLE-US-00014 Karl Fisher analysis (% wt water) Form A 10.2%
(Average of two lots) Form B' 2.3%
III Instrument Techniques
Example 9
X-Ray Powder Diffraction (XRPD)
[0165] X-ray powder diffraction patterns were collected using an
Inel XRG-3000 diffractometer equipped with a curved position
sensitive detector with a 20 range of 120.degree.. An incident beam
of Cu K.alpha. radiation (40 kV, 30 mA) was used to collect data in
real time at a resolution of 0.03.degree. 2.theta.. Prior to the
analysis, a silicon standard (NIST SRM 640c) was analyzed to verify
the Si 111 peak position. Samples were prepared for analysis by
packing them into thin-walled glass capillaries. Each capillary was
mounted onto a goniometer head and rotated during data acquisition.
The monochromator slit was set at 5 mm by 160 .mu.m.
[0166] Alternatively, X-ray powder diffraction patterns were
collected using a Bruker D-8 Discover diffractometer and Bruker's
General Detector System (GADDS, v. 4.1.20). An incident microbeam
of Cu K.alpha. radiation was produced using a fine-focus tube (40
kV, 40 mA), a Gobel mirror, and a 0.5 mm double-pinhole collimator.
Prior to the analysis, a silicon standard (NIST SRM 640c) was
analyzed to verify the Si 111 peak position. The sample was packed
between 3 .mu.m thick films to form a portable, disc-shaped
specimen. The prepared specimen was loaded in a holder secured to a
translation stage. A video camera and laser were used to position
the area of interest to intersect the incident beam in transmission
geometry. The incident beam was scanned and rastered to optimize
orientation statistics. A beam-stop was used to minimize air
scatter from the incident beam. Diffraction patterns were collected
using a Hi-Star area detector located 15 cm from the sample and
processed using GADDS. The intensity in the GADDS image of the
diffraction pattern was integrated using a step size of
0.04.degree. 2.theta.. The integrated patterns display diffraction
intensity as a function of 2.theta..
[0167] Or, X-ray powder diffraction patterns were collected using a
Panalytical X'Pert Pro diffractometer. An incident beam of Cu
K.alpha. radiation was produced using an Optix long, fine-focus
source. An elliptically graded multilayer mirror was used to focus
the Cu K.alpha. X-rays of the source through the specimen and onto
the detector. Data were collected and analyzed using X'Pert Pro
Data Collector software (v. 2.2b). Prior to the analysis, a silicon
specimen (NIST SRM 640c) was analyzed to verify the Si 111 peak
position. The specimen was sandwiched between 3 .mu.m thick films,
analyzed in transmission geometry, and rotated to optimize
orientation statistics. A beam-stop was used to minimize the
background generated by air scattering. Soller slits were used for
the incident and diffracted beams to minimize axial divergence.
Diffraction patterns were collected using a scanning
position-sensitive detector (X'Celerator) located 240 mm from the
specimen.
[0168] Peaks within the range of up to about 30.degree. 2.theta.
are listed in the tables, although different rounding algorithms
were used to round each peak to the nearest 0.1.degree. or
0.01.degree. 2.theta., depending upon the instrument used to
collect the data and/or the inherent peak resolution. The location
of the peaks along the x-axis (.degree. 2.theta.) in the tables
were automatically determined using PatternMatch.TM. 3.0.1 and
rounded to one or two significant figures after the decimal point
based upon the above criteria. Peak position variabilities are
given to within +0.1.degree. 2.theta. based upon recommendations
outlined in United States Pharmacopeia, USP 32, NF 27, Vol. 1, pg.
392, 2009. The wavelength used to calculate d-spacings was 1.541874
.ANG., a weighted average of the Cu-K.sub..alpha.1 and
Cu-K.sub..alpha.2 wavelengths. Variability associated with
d-spacing estimates was calculated from the USP recommendation, at
each d-spacing.
[0169] If multiple diffraction patterns are available, then
assessments of particle statistics (PS) and/or preferred
orientation (PO) are possible. Reproducibility among XRPD patterns
from multiple samples analyzed on a single diffractometer indicates
that the particle statistics are adequate. Consistency of relative
intensity among XRPD patterns from multiple diffractometers
indicates good orientation statistics. Alternatively, the observed
XRPD pattern may be compared with a calculated XRPD pattern based
upon a single crystal structure, if available. Two-dimensional
scattering patterns using area detectors can also be used to
evaluate PS/PO. If the effects of both PS and PO are determined to
be negligible, then the XRPD pattern is representative of the
powder average intensity for the sample and prominent peaks may be
identified as Representative Peaks.
[0170] Characteristic peaks are a subset of Representative Peaks
and are used to differentiate one crystalline polymorph from
another crystalline polymorph. Characteristic peaks are determined
by evaluating which representative peaks, if any, are present in
one crystalline polymorph of a compound against all other known
crystalline polymorphs of that compound to within .+-.0.1.degree.
2.theta.. Not all crystalline polymorphs of a compound necessarily
have at least one characteristic peak.
Example 10
Differential Scanning Calorimetry (DSC)
[0171] Differential scanning calorimetry was performed using a TA
Instruments Q2000 differential scanning calorimeter. Temperature
calibration was performed using NIST traceable indium metal. The
sample was placed into an aluminum DSC pan, and the weight was
accurately recorded. The pan was covered with a lid, and the lid
was crimped. A weighed, crimped aluminum pan was placed on the
reference side of the cell. The sample cell was equilibrated at the
initial temperature and heated under a nitrogen purge. To measure
glass transition temperature (T.sub.g) the sample cell was first
equilibrated at -30.degree. C., and then heated under nitrogen gas
at a rate of 10.degree. C./min, cycling three times to 90.degree.
C. Each cycle, the sample cell was allowed to cool and equilibrate
at -30.degree. C. The sample cell was then heated at 10.degree.
C./min to a final temperature of 250.degree. C.
Example 11
Infrared Spectroscopy (IR)
[0172] IR spectra were acquired on a Magna-IR 860.RTM. Fourier
transform infrared (FT-IR) spectrophotometer (Thermo Nicolet)
equipped with an Ever-Glo mid/far IR source, an extended range
potassium bromide (KBr) beamsplitter, and a deuterated triglycine
sulfate (DTGS) detector. Wavelength verification was performed
using NIST SRM 1921b (polystyrene). A diffuse reflectance accessory
(the Collector.TM., Thermo Spectra-Tech) was used for sampling.
Sample preparation consisted of physically mixing the sample with
KBr, placing the sample into a 13 mm diameter cup and leveling the
material. The background data set was acquired with KBr powder. A
Log 1/R(R=reflectance) spectrum was obtained by taking a ratio of
these two data sets against each other and then converting to
Kubelka-Munk units.
Example 12
FT-Raman Spectroscopy
[0173] Raman spectra were acquired on a FT-Raman 960 spectrometer
(Thermo Nicolet) equipped with an indium gallium arsenide (InGaAs)
detector. Wavelength verification was performed using sulfur and
cyclohexane. Each sample was prepared for analysis by placing the
sample into a glass tube and positioning the tube in a gold-coated
tube holder. The sample was irradiated with a Nd:YVO.sub.4 laser
(1064 nm excitation wavelength).
* * * * *