U.S. patent application number 17/393496 was filed with the patent office on 2022-07-14 for morphic forms of 4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-- 7h-pyrrolo[2,3-d]pyrimidine-5-carboxamide and uses thereof.
The applicant listed for this patent is Chimerix, Inc.. Invention is credited to Aaron Leigh DOWNEY, Venkat LAKSHMANAN, Roy W. WARE.
Application Number | 20220220146 17/393496 |
Document ID | / |
Family ID | 1000006198424 |
Filed Date | 2022-07-14 |
United States Patent
Application |
20220220146 |
Kind Code |
A1 |
WARE; Roy W. ; et
al. |
July 14, 2022 |
MORPHIC FORMS OF
4-AMINO-7-(3,4-DIHYDROXY-5-(HYDROXYMETHYL)TETRAHYDROFURAN-2-YL)-2-METHYL--
7H-PYRROLO[2,3-d]PYRIMIDINE-5-CARBOXAMIDE AND USES THEREOF
Abstract
The present disclosure relates to crystalline morphic forms of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.
The morphic form can be a stable hemihydrate crystalline form.
Inventors: |
WARE; Roy W.; (Durham,
NC) ; LAKSHMANAN; Venkat; (Durham, NC) ;
DOWNEY; Aaron Leigh; (Durham, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Chimerix, Inc. |
Durham |
NC |
US |
|
|
Family ID: |
1000006198424 |
Appl. No.: |
17/393496 |
Filed: |
August 4, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16645876 |
Mar 10, 2020 |
11111264 |
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PCT/US18/52180 |
Sep 21, 2018 |
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17393496 |
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62561355 |
Sep 21, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 2200/13 20130101;
C07H 19/14 20130101 |
International
Class: |
C07H 19/14 20060101
C07H019/14 |
Claims
1.-17. (canceled)
18. A crystalline Form ("Form B") of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide,
wherein the Form has a powder X-ray diffraction pattern comprising
a peak at a diffraction angle (2.theta.) of about 22.9, wherein
said powder X-ray diffraction pattern is obtained using Cu
K.alpha.1 X-rays at a wavelength of 1.5406 .ANG..
19-25. (canceled)
26. A method of treating a viral infection in a subject in need
thereof, comprising administering to the subject a therapeutically
effective amount of a crystalline form of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.
27. The method of claim 26, wherein the crystalline form is a
crystalline hemihydrate form.
28. The method of claim 26, wherein the viral infection is selected
from norovirus, human cytomegalovirus, BK virus, Epstein-Barr
virus, adenovirus, JC virus, SV40, MC virus, KI virus, WU virus,
vaccinia, herpes simplex virus 1, herpes simplex virus 2, human
herpes virus 6, human herpes virus 8, hepatitis B virus, hepatitis
C virus, varicella zoster virus, variola major, variola minor,
smallpox, cowpox, camelpox, monkeypox, poliovirus, picornaviridae,
paramyxoviridae, ebola virus, Marburg virus, influenza,
enterovirus, papilloma virus, West Nile virus, yellow fever virus,
foot-and-mouth disease virus, Rift Valley fever virus, and other
flavivirus, arenavirus, bunyavirus, alphavirus, human
immunodeficiency virus, and any combination thereof.
29.-32. (canceled)
33. A method of preparing a crystalline hemihydrate form of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
comprising: recrystallizing the
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
from a solvent system comprising 1-propanol and 0.01 M aqueous
NaOH.
34. The method of claim 33, wherein the solvent system comprises
1-propanol and 0.01 M aqueous NaOH at a volume ratio of 1:2.
35. The method of claim 33, wherein the
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
is dissolved in the solvent system comprising 1-propanol and 0.01 M
aqueous NaOH at a temperature of about 90.degree. C. to produce a
solution.
36. The method of claim 35, wherein the solution is cooled to about
80.degree. C. and stirred for about an hour.
37. The method of claim 35, wherein the solution is seeded with the
morphic form of claim 3.
38. The method of claim 37, wherein the seed comprises about 1% of
the amount of Compound 1 in the solution.
39. The method of claim 36, wherein the solution is further cooled
to a temperature of about 5.degree. C.
40. The method of claim 39, wherein the solution is stirred at
about 5.degree. C. for about 4 hours.
41. The method of claim 39, wherein the cooling rate is about
5K/hour.
42. The method of claim 33, wherein the crystallized
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
is further washed with water.
43. The method of claim 33, wherein the crystallized
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
is over 99% pure.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/645,876, filed Mar. 10, 2020, which is a U.S. National Phase
application, filed under 35 U.S.C. .sctn. 371, of International
Application No. PCT/US2018/052180, filed Sep. 21, 2018, which
claims priority to, and the benefit of, U.S. Provisional Patent
Application No. 62/561,355, filed Sep. 21, 2017, the contents of
each of which are incorporated by reference in their
entireties.
FIELD OF THE INVENTION
[0002] The present disclosure relates to crystalline morphic forms
of 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo
[2,3-d]pyrimidine-5-carboxamide. The morphic form can be a stable
hemihydrate crystalline form (e.g., Form A).
BACKGROUND OF THE INVENTION
[0003] Viral infections can have serious adverse effects on
individuals and society as a whole. In addition to fatal viral
infections such as Ebola, even non-fatal infections can have
serious societal and economic consequences. For example, human
noroviruses (NV) are the most common cause of epidemic acute
gastroenteritis worldwide with an estimated 19-21 million cases
each year in the United States including 56,000-71,000
hospitalizations and 570-800 deaths (Hall et al., Emerg. Infect.
Dis. 2013 August; 19(8):1198-205).
[0004] 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo
[2,3-d]pyrimidine-5-carboxamide (Compound 1) is an antiviral
drug.
SUMMARY OF THE INVENTION
[0005] The present disclosure provides morphic forms of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo
[2,3-d]pyrimidine-5-carboxamide (Compound 1). In some embodiments,
the present disclosure provides stable crystalline hemihydrate
morphic forms of Compound 1. In some embodiments, the hemihydrate
form is the most stable form of Compound 1.
[0006] In one aspect, the present disclosure provides crystalline
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
hemihydrate.
[0007] In another aspect, the present disclosure provides
crystalline
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
hemihydrate in substantially pure form.
[0008] In another aspect, the present disclosure provides a
crystalline hemihydrate form ("Form A") of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
wherein said form has an X-ray diffraction pattern comprising a
peak at a diffraction angle (2.theta.) of about 26.2 (e.g., at
26.2.+-.0.20 .degree.2.theta.; at 26.2.+-.0.15 .degree.2.theta.; at
26.2.+-.0.10 .degree.2.theta.; at 26.2.+-.0.05 .degree.2.theta.; at
26.2.+-.0.01 .degree.2.theta.; or at 26.2 .degree.2.theta.). In
some embodiments, said powder X-ray diffraction pattern is obtained
using Cu K.alpha.1 X-rays at a wavelength of 1.5406 .ANG..
[0009] In another aspect, the present disclosure provides a method
of preparing a crystalline hemihydrate form (e.g., "Form A") of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
comprising: recrystallizing the
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
from a solvent having a water activity of at least about 0.18
(e.g., about 0.1, about 0.15, about 0.20, about 0.21, about 0.22,
about 0.23, about 0.24, about 0.25, about 0.26, about 0.27, about
0.28, about 0.29, or about 0.30).
[0010] In another aspect, the present disclosure provides a
crystalline Form (i.e., "Form B") of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
wherein said form has an X-ray diffraction pattern comprising a
peak at a diffraction angle (2.theta.) of about 22.9 (e.g., at
22.9.+-.0.20 .degree.2.theta.; at 22.9.+-.0.15 .degree.2.theta.; at
22.9.+-.0.10 .degree.2.theta.; at 22.9.+-.0.05 .degree.2.theta.; at
22.9.+-.0.01 .degree.2.theta.; or at 22.9 .degree.2.theta.). In
some embodiments, said powder X-ray diffraction pattern is obtained
using Cu K.alpha.1 X-rays at a wavelength of 1.5406 .ANG..
[0011] In another aspect, the present disclosure provides a
crystalline Form (i.e., "Form C") of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
wherein said form has an X-ray diffraction pattern comprising a
peak at a diffraction angle (2.theta.) of about 22.4 (e.g., at
22.4.+-.0.20 .degree.2.theta.; at 22.4.+-.0.15 .degree.2.theta.; at
22.4.+-.0.10 .degree.2.theta.; at 22.4.+-.0.05 .degree.2.theta.; at
22.4.+-.0.01 .degree.2.theta.; or at 22.4 .degree.2.theta.). In
some embodiments, said powder X-ray diffraction pattern is obtained
using Cu K.alpha.1 X-rays at a wavelength of 1.5406 .ANG..
[0012] In another aspect, the present disclosure provides a
crystalline Form (i.e., "Form D") of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
wherein said form has an X-ray diffraction pattern comprising a
peak at a diffraction angle (2.theta.) of about 26.6 (e.g., at
26.6.+-.0.20 .degree.2.theta.; at 26.6.+-.0.15 .degree.2.theta.; at
26.6.+-.0.10 .degree.2.theta.; at 26.6.+-.0.05 .degree.2.theta.; at
26.6.+-.0.01 .degree.2.theta.; or at 26.6 .degree.2.theta.). In
some embodiments, said powder X-ray diffraction pattern is obtained
using Cu K.alpha.1 X-rays at a wavelength of 1.5406 .ANG..
[0013] In another aspect, the present disclosure provides a
crystalline Form (i.e., "Form E") of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
wherein said form has an X-ray diffraction pattern comprising a
peak at a diffraction angle (2.theta.) of about 10.9 (e.g., at
10.9.+-.0.20 .degree.2.theta.; at 10.9.+-.0.15 .degree.2.theta.; at
10.9.+-.0.10 .degree.2.theta.; at 10.9.+-.0.05 .degree.2.theta.; at
10.9.+-.0.01 .degree.2.theta.; or at 10.9.degree. 20) and/or about
26.5 (e.g., at 26.5.+-.0.20 .degree.2.theta.; at 26.5.+-.0.15
.degree.2.theta.; at 26.5.+-.0.10 .degree.2.theta.; at 26.5.+-.0.05
.degree.2.theta.; at 26.5.+-.0.01 .degree.2.theta.; or at 26.5
.degree.2.theta.). In some embodiments, said powder X-ray
diffraction pattern is obtained using Cu K.alpha.1 X-rays at a
wavelength of 1.5406 .ANG..
[0014] In another aspect, the present disclosure provides a
crystalline Form (i.e., "Form F") of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
wherein said form has an X-ray diffraction pattern comprising a
peak at a diffraction angle (2.theta.) of about 15.0 (e.g., at
15.0.+-.0.20 .degree.2.theta.; at 15.0.+-.0.15 .degree.2.theta.; at
15.0.+-.0.10 .degree.2.theta.; at 15.0.+-.0.05 .degree.2.theta.; at
15.0.+-.0.01 .degree.2.theta.; or at 15.0.degree. 20) and/or about
22.8 (e.g., at 22.8.+-.0.20 .degree.2.theta.; at 22.8.+-.0.15
.degree.2.theta.; at 22.8 0.10 .degree.2.theta.; at 22.8.+-.0.05
.degree.2.theta.; at 22.8.+-.0.01 .degree.2.theta.; or at 22.8
.degree.2.theta.). In some embodiments, said powder X-ray
diffraction pattern is obtained using Cu K.alpha.1 X-rays at a
wavelength of 1.5406 .ANG..
[0015] In another aspect, the present disclosure provides a
crystalline Form (i.e., "Form G") of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
wherein said form has an X-ray diffraction pattern comprising a
peak at a diffraction angle (2.theta.) of about 22.8 (e.g., at
22.8.+-.0.20 .degree.2.theta.; at 22.8.+-.0.15 .degree.2.theta.; at
22.8.+-.0.10 .degree.2.theta.; at 22.8.+-.0.05 .degree.2.theta.; at
22.8.+-.0.01 .degree.2.theta.; or at 22.8 .degree.2.theta.). In
some embodiments, said powder X-ray diffraction pattern is obtained
using Cu K.alpha.1 X-rays at a wavelength of 1.5406 .ANG..
[0016] In some embodiments, the present disclosure provides a
mixture comprising a crystalline form (e.g., Form A) and further
comprising one or more additional morphic forms. In some
embodiments, the mixture comprises Form A and Form B; in some
embodiments, the mixture comprises Form A and Form C; in some
embodiments, the mixture comprises Form A and Form D; in some
embodiments, the mixture comprises Form A and Form E; in some
embodiments, the mixture comprises Form A and Form F; in some
embodiments, the mixture comprises Form A and Form G. In some
embodiments, the mixture comprises Form A and more than one
additional morphic form selected from Form B, C, D, E, F and G.
[0017] In another aspect, the present disclosure provides a
pharmaceutical composition comprising a crystalline form (e.g.,
Form A) of 4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
and a pharmaceutically acceptable carrier. In some embodiments, the
pharmaceutical composition further comprises Form B. In some
embodiments, the pharmaceutical composition further comprises Form
C. In some embodiments, the pharmaceutical composition further
comprises Form D. In some embodiments, the pharmaceutical
composition further comprises Form E. In some embodiments, the
pharmaceutical composition further comprises Form F. In some
embodiments, the pharmaceutical composition further comprises Form
G.
[0018] In another aspect, the present disclosure provides a method
of treating a viral infection in a subject in need thereof,
comprising administering to the subject a therapeutically effective
amount of a crystalline form (e.g., Form A) of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.
In some embodiments, the method comprises administering Form A, B,
C, D, E, F and/or G.
[0019] In another aspect, the present disclosure provides the use
of crystalline form (e.g., Form A) of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
in the manufacture of a medicament for the treatment of a viral
infection. In some embodiments, Form A, B, C, D, E, F and/or G is
used.
[0020] In another aspect, the present disclosure provides the use
of crystalline form (e.g., Form A) of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
for the treatment of a viral infection. In some embodiments, Form
A, B, C, D, E, F and/or G is used.
[0021] In some embodiments, the crystalline Form A has X-ray
diffraction pattern comprising peaks at a diffraction angle
(2.theta.) of about 23.2 and/or 26.5. In some embodiments, the
crystalline Form A has an X-ray diffraction pattern comprising
X-peaks at a diffraction angle (2.theta.) of about 10.7, 11.6,
12.2, 15.3, and/or 18.6.
[0022] In some embodiments, the crystalline Form A is further
characterized by an endothermic peak at about 231.degree. C. as
measured by differential scanning calorimetry. In some embodiments,
the endothermic peak represents an energy input of about 173
J/g.
[0023] In some embodiments, the crystalline Form A is further
characterized by a mass loss of about 2.4% between a temperature of
about 110.degree. C. and 220.degree. C. as measured by
thermogravimetric analysis.
[0024] In some embodiments, the crystalline Form A is further
characterized by a PXRD pattern substantially similar to that set
forth in FIG. 1A. In some embodiments, the crystalline Form A is
further characterized by a PXRD pattern substantially similar to
that set forth in FIG. 1B.
[0025] In some embodiments, the crystalline Form A is further
characterized by a TG-FTIR profile substantially similar to that
set forth in FIG. 8. In some embodiments, the crystalline Form A is
further characterized by a DSC profile substantially similar to
that set forth in FIG. 15.
[0026] In some embodiments, the crystalline Form A is further
characterized by a DVS profile substantially similar to that set
forth in FIG. 20A. In some embodiments, the crystalline Form A is
characterized by a DVS profile substantially similar to that set
forth in FIG. 20B.
[0027] In some embodiments, the crystalline Form A is substantially
non-hygroscopic.
[0028] In some embodiments, the crystalline Form A is
recrystallized from a solvent having a water activity of at least
about 0.2.
[0029] In some embodiments, the crystalline
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
(e.g., Form A) is used to treat a viral infection selected from
norovirus, human cytomegalovirus, BK virus, Epstein-Barr virus,
adenovirus, JC virus, SV40, MC virus, KI virus, WU virus, vaccinia,
herpes simplex virus 1, herpes simplex virus 2, human herpes virus
6, human herpes virus 8, hepatitis B virus, hepatitis C virus,
varicella zoster virus, variola major, variola minor, smallpox,
cowpox, camelpox, monkeypox, poliovirus, picornaviridae,
paramyxoviridae, ebola virus, Marburg virus, influenza,
enterovirus, papilloma virus, West Nile virus, yellow fever virus,
foot-and-mouth disease virus, Rift Valley fever virus, and other
flavivirus, arenavirus, bunyavirus, alphavirus, human
immunodeficiency virus, and any combination thereof. In some
embodiments, the viral infection is norovirus. In some embodiments,
a compound and/or morphic form (e.g., Form A) is used in the
manufacture of a medicament for the treatment of one of the
above-viral infections. In some embodiments, a compound and/or
morphic form (e.g., Form A) is used for the treatment of one of the
above-viral infections. In some embodiments, the present disclosure
teaches a compound and/or morphic Form (e.g., Form A) for use in
treating any one of the above-viral infections.
[0030] In another aspect, the present disclosure provides a method
of preparing a crystalline hemihydrate form of
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
comprising: recrystallizing the
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
from a solvent system comprising 1-propanol and 0.01 M aqueous
NaOH. In some embodiments, the solvent system comprises 1-propanol
and 0.01 M aqueous NaOH at a volume ratio of 1:2.
[0031] In some embodiments, the
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
is dissolved in the solvent system comprising 1-propanol and 0.01 M
aqueous NaOH at a temperature of about 90.degree. C. to produce a
solution. In some embodiments, the solution is cooled to about
80.degree. C. and stirred (e.g., for about an hour).
[0032] In some embodiments, the solution is seeded with Compound 1,
Form A, for example at a temperature of about 80.degree. C. In some
cases, the solution can be seeded before the solution is cooled
(e.g., to about 80.degree. C.). In some cases, the solution can be
seeded after the solution is cooled (e.g., to about 80.degree. C.).
In some cases, the solution is not seeded. In some embodiments, the
seed comprises about 1% of the amount of Compound 1 in the
solution.
[0033] In some embodiments, the solution is further cooled to a
temperature of about 5.degree. C. In some embodiments, the solution
is stirred at about 5.degree. C. for about 4 hours. In some
embodiments, the cooling rate is about 5K/hour. In some
embodiments, cooling the solution can result in a suspension (e.g.,
comprising solid crystalline Compound 1 (e.g., Form A)). In some
embodiments, the suspension is filtered to isolate the crystalline
Compound 1 (e.g., Form A).
[0034] In some embodiments, the crystallized
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
is further washed with water. In some embodiments, the crystallized
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)
tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide
is over 99% pure.
BRIEF DESCRIPTION OF THE FIGURES
[0035] FIG. 1A is a PXRD pattern of a sample of Compound 1, Form A
taken in reflection geometry.
[0036] FIG. 1B is a PXRD pattern of a sample of Compound 1, Form A
taken in transmission geometry.
[0037] FIG. 2A is a PXRD pattern of two samples of Compound 1, Form
B taken in transmission geometry.
[0038] FIG. 2B is a PXRD pattern of a sample of Compound 1, Form B,
taken in transmission geometry.
[0039] FIG. 3 is a PXRD pattern of a sample of Compound 1, Form C
taken in transmission geometry.
[0040] FIG. 4 is a PXRD pattern of a sample of Compound 1, Form D
taken in transmission geometry.
[0041] FIG. 5A is a PXRD pattern of two samples of Compound 1, Form
E taken in transmission geometry.
[0042] FIG. 5B is a PXRD pattern of a sample of Compound 1, Form E,
taken in transmission geometry.
[0043] FIG. 6 is a PXRD pattern of a sample of Compound 1, Form F
taken in transmission geometry between 0 .degree.2.theta. and 40
.degree.2.theta..
[0044] FIG. 7 is a PXRD pattern of a sample of Compound 1, Form G
taken in transmission geometry between 0 .degree.2.theta. and 40
.degree.2.theta..
[0045] FIG. 8 is a TG-FTIR diagram of a sample of Compound 1, Form
A.
[0046] FIG. 9A is a TG-FTIR diagram of a first sample of Compound
1, Form B.
[0047] FIG. 9B is a TG-FTIR diagram of a second sample of Compound
1, Form B.
[0048] FIG. 10 is a TG-FTIR diagram of a sample of Compound 1, Form
C.
[0049] FIG. 11 is a TG-FTIR diagram of a sample of Compound 1, Form
D.
[0050] FIG. 12 is a TG-FTIR diagram of a sample of Compound 1, Form
E.
[0051] FIG. 13 is a TG-FTIR diagram of a sample of Compound 1, Form
F.
[0052] FIG. 14 is a TG-FTIR diagram of a sample of Compound 1, Form
G.
[0053] FIG. 15 is a DSC diagram of a sample of Compound 1, Form
A.
[0054] FIG. 16 is a DSC diagram of a sample of Compound 1, Form
B.
[0055] FIG. 17 is a DSC diagram of a sample of Compound 1, Form
C.
[0056] FIG. 18 is a DSC diagram of a sample of Compound 1, Form
D.
[0057] FIG. 19 is a DSC diagram of a sample of Compound 1, Form
E.
[0058] FIG. 20A is a DVS diagram of a sample of Compound 1, Form A
as a function of time and the applied change in relative
humidity.
[0059] FIG. 20B is a DVS diagram of a sample of Compound 1, Form A
as a function of the applied relative humidity.
[0060] FIG. 21A is a DVS diagram of a sample of Compound 1, Form B
as a function of time and the applied change in relative
humidity.
[0061] FIG. 21B is a DVS diagram of a sample of Compound 1, Form B
as a function of the applied relative humidity.
[0062] FIG. 22A is a DVS diagram of a sample of Compound 1, Form D
as a function of time and the applied change in relative
humidity.
[0063] FIG. 22B is a DVS diagram of a sample of Compound 1, Form D
as a function of the applied relative humidity.
[0064] FIG. 23A is a DVS diagram of a sample of Compound 1, Form E
as a function of time and the applied change in relative
humidity.
[0065] FIG. 23B is a DVS diagram of a sample of Compound 1, Form E
as a function of the applied relative humidity.
[0066] FIG. 24 is an ORTEP plot of the structure of Compound 1,
Form A.
[0067] FIG. 25 is a plot showing the results of the metastable zone
width (MSZW) experiments using a solvent of 1-PrOH/0.01M NaOH 1:2
(v/v) at a heating and cooling rate of 3K/hour.
[0068] FIG. 26 is a TG-FTIR plot of the solid recovered from
Experiment No. 29 in Example 6.
[0069] FIG. 27 is a TG-FTIR plot of the solid recovered from
Experiment No. 30 in Example 6.
DETAILED DESCRIPTION OF THE INVENTION
[0070] As set forth herein, Compound 1 is an antiviral agent that
is effective against a number of viral indications. This disclosure
provides stable morphic forms of Compound 1 that can be used as
pharmaceutical agents. In some embodiments, one or more morphic
forms (e.g., Form A) can be formulated into a pharmaceutical
composition.
Definitions
[0071] "ORTEP" is understood to mean Oak Ridge Thermal Ellipsoid
Plot.
[0072] "PXRD" is understood to mean powder X-ray diffraction.
Unless otherwise specified, all PXRD peaks and patterns are given
in .degree.2.theta. using Cu K.alpha.1 radiation at a wavelength of
1.5406 .ANG..
[0073] "Preferred orientation effects" refer to variable peak
intensities or relative intensity differences between different
PXRD measurements of the same samples that can be due to the
orientation of the particles. Without wishing to be bound by
theory, in PXRD it can be desirable to have a sample in which
particles are oriented randomly (e.g., a powder). However, it can
be difficult or in some cases impossible to achieve truly random
particle orientations in practice. As particle size increases, the
randomness of particle orientation can decrease, leading to
increased challenges with achieving a preferred orientation.
Without wishing to be bound by theory, a smaller particle size can
reduce technical challenges associated with preferred orientation
and allow for more accurate representation of peaks. However, one
of skill in the art will understand how to reduce or mitigate
preferred orientation effects, and will recognize preferred
orientation effects that can exist even between two different
measurements of the same sample. For instance, in some embodiments,
differences in resolution or relative peak intensities can be
attributed to preferred orientation effects.
[0074] As used herein, the term "treat," "treating," or "treatment"
herein, is meant decreasing the symptoms, markers, and/or any
negative effects of a condition in any appreciable degree in a
patient who currently has the condition. In some embodiments,
treatment can be administered to a subject who exhibits only early
signs of the condition for the purpose of decreasing the risk of
developing the disease, disorder, and/or condition (e.g., a viral
indication).
[0075] As used herein, the term "prevent," "prevention," or
"preventing" refers to any method to partially or completely
preclude or delay the onset of one or more symptoms or features of
a disease, disorder, and/or condition. Prevention treatment can be
administered to a subject who does not exhibit signs of a disease,
disorder, and/or condition. Prevention can apply to subjects who
are at risk of developing or acquiring a certain disease. For
instance, a subject can be at risk of developing or acquiring a
certain disease when they are in close proximity to others who
suffer from (e.g., exhibit symptoms of) the disease. That is, one
can be exposed to a disease by being in close proximity to another
individual who suffers from a disease and thus increase one's risk
of acquiring the disease. For example, hospital workers can be at
risk of developing or acquiring a certain disease when treating
others who suffer from the disease. Hospital patients can also be
at risk of developing or acquiring a disease from other patients
who suffer from the disease. Accordingly, a compound and/or form
disclosed herein can be used for the prevention of a disease in
subjects who are spending extended periods of time in close contact
with others. For example, norovirus can be spread when individuals
are in close contact to one or more persons suffering from
norovirus, such as aboard a cruise ship, at an amusement park, on a
college campus, or at the Olympic village. Likewise, for instance,
influenza can be spread when individuals are in close contact to
one or more persons suffering from influenza (e.g., aboard an
airplane).
[0076] The term "therapeutically effective amount", as used herein,
refers to an amount of a pharmaceutical agent to treat or
ameliorate an identified disease or condition, or to exhibit a
detectable therapeutic effect. The effect can be detected by any
assay method known in the art. The precise therapeutically
effective amount for a subject will depend upon the subject's body
weight, size, and health; the nature and extent of the condition;
and the therapeutic or combination of therapeutics selected for
administration. Therapeutically effective amounts for a given
situation can be determined by routine experimentation that is
within the skill and judgment of the clinician.
[0077] The term "prophylactically effective amount", as used
herein, refers to an amount of a pharmaceutical agent to prevent or
delay onset of an identified disease or condition, or to exhibit a
detectable inhibitory effect. A prophylactically effective amount
can provide prophylaxis for an identified disease or condition. The
effect can be detected by any assay method known in the art. The
precise prophylactically effective amount for a subject will depend
upon the subject's body weight, size, and health; the nature and
extent of the condition; and the therapeutic or combination of
therapeutics selected for administration. Prophylactically
effective amounts for a given situation can be determined by
routine experimentation that is within the skill and judgment of
the clinician.
[0078] As used herein, "subject" means a human or animal (in the
case of an animal, the subject can be a mammal). In one aspect, the
subject is a human. In one aspect, the subject is a male. In one
aspect, the subject is a female.
[0079] The term "about" is used herein to mean approximately, in
the region of, roughly or around. When the term "about" is used in
conjunction with a numerical range, it modifies that range by
extending the boundaries above and below the numerical values set
forth. In general, the term "about" is used herein to modify a
numerical value above and below the stated value by a variance of
20%. When used in the context of XRPD peak values, the term "about"
can indicate a peak value .+-.0.20; .+-.0.15; .+-.0.10; .+-.0.05;
or .+-.0.01 .degree.2.theta.. In some embodiments, when used in the
context of XRPD peak values "about" can indicate a peak value at
substantially exactly the disclosed peak value.
Compounds of the Disclosure
Formula 1
[0080] As used herein, "Formula I" is understood to encompass all
diastereomers of
4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl--
7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, and pharmaceutically
acceptable salts and solvates thereof. The structure of Formula I
is shown below:
##STR00001##
[0081] In some embodiments, a compound of Formula I can be
4-amino-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-
-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide ("Compound
1"), or a pharmaceutically acceptable salt solvate, or isomers
(e.g., enantiomers and diastereomers) thereof. The structure of
Compound 1 is shown below:
##STR00002##
[0082] As set forth below, an investigation of the polymorphic
forms of Compound 1 identified seven unique morphic forms,
identified as Form A, Form B, Form C, Form D, Form E, Form F, and
Form G. Characterization data for each of the morphic forms is
given below. Without wishing to be bound by theory, Form A was
found to be the most stable and least hygroscopic of the forms
identified.
[0083] Exemplary acid addition salts for incorporation with
Compound 1 (e.g., Compound 1 Form A) include acetates, ascorbates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, fumarates,
hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,
methanesulfonates, naphthalenesulfonates, nitrates, oxalates,
phosphates, propionates, salicylates, succinates, sulfates,
tartarates, thiocyanates, toluenesulfonates (also known as
tosylates), and the like. Additionally, acids which are generally
considered suitable for the formation of pharmaceutically useful
salts from basic pharmaceutical compounds are discussed, for
example, by P. Stahl et al, Camille G. (eds.) Handbook of
Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:
Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences
(1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics
(1986) 33 201-217; Anderson et al, The Practice of Medicinal
Chemistry (1996), Academic Press, New York; and in The Orange Book
(Food & Drug Administration, Washington, D.C. on their
website). These disclosures are incorporated herein by reference
thereto. In some embodiments, Formula I encompasses a hydrochloride
salt of Compound 1.
[0084] Exemplary basic salts include ammonium salts, alkali metal
salts such as sodium, lithium, and potassium salts, alkaline earth
metal salts such as calcium and magnesium salts, salts with organic
bases (for example, organic amines) such as dicyclohexylamines,
t-butyl amines, and salts with amino acids such as arginine, lysine
and the like. Basic nitrogen-containing groups may be quarternized
with agents such as lower alkyl halides (e.g., methyl, ethyl, and
butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.,
dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g.,
decyl, lauryl, and stearyl chlorides, bromides and iodides),
aralkyl halides (e.g., benzyl and phenethyl bromides), and
others.
[0085] All such acid salts and base salts are intended to be
pharmaceutically acceptable salts within the scope of the
invention.
Form A
[0086] Form A of Compound 1 was characterized as a hemihydrate
morphic form of Compound 1. Morphic Form A of compound 1 can be
prepared by crystallization from a number of organic solvent/water
mixtures. The solvent/water mixtures can have various water
activities. For example, morphic Form A was recovered from solvent
systems that had a water activity of at least 0.2. In some
embodiments, morphic Form A was recovered from solvent systems that
had a water activity of 0.18. Accordingly, the present disclosure
presents a method of preparing morphic Form A of Compound 1
comprising recrystallizing from a solvent system with a water
activity of at least 0.18 (e.g., 0.19, 0.20, 0.21, 0.22, 0.23,
0.24, 0.25, or above 0.25). For instance, recrystallization from
water; THF:water 1:1; acetone:water 4:1; DMA:water 1:1; DMF:water
1:1; DMSO:water 1:1; methanol:water 9:1; and methanol:water 95:5
were all found to yield morphic Form A. The final temperature of
the recrystallization solvents can be room temperature (e.g., about
25.degree. C.).
[0087] Other morphic Forms described herein (e.g., Form B and Form
E) were found to convert to morphic Form A under appropriate
conditions (e.g., at room temperature, about 25.degree. C.). For
example, Forms B and E transformed into Form A at about 25.degree.
C. and above about 50% relative humidity (e.g., during water vapor
sorption experiments).
[0088] Two unique PXRD patterns are shown in FIG. 1A and FIG. 1B,
respectively. FIG. 1A is a PXRD pattern of a sample of Compound 1,
Form A taken in reflection mode. FIG. 1A was obtained using a
Bruker D8 Advance powder X-ray diffractometer using Cu K.alpha.
radiation and Bragg-Brentano reflection geometry. FIG. 1B is a PXRD
pattern of a sample of Compound 1, Form A taken in transmission
mode. FIG. 1B was obtained using a Stoe Stadi P powder X-ray
diffractometer using Cu K.alpha.1 radiation and transmission
geometry. As shown in FIG. 1A and FIG. 1i, the main differences
between the two patterns are the relative intensities of the peaks.
Without wishing to be bound by theory, the differences in the
relative intensities can be due to preferred orientation effects
(i.e., different particle shapes and/or sizes).
[0089] In some embodiments, morphic Form A can be characterized by
the PXRD peaks set forth below in Table 1. For example, morphic
Form A can be characterized by a PXRD peak at about 26.2
.degree.2.theta. (e.g., 26.2.+-.0.2 .degree.2.theta.; 26.2.+-.0.1
.degree.2.theta.; or 26.2.+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). Form A can further be characterized by PXRD peaks at
about 23.2 .degree.2.theta. and/or 26.5 .degree.2.theta. (e.g.,
.+-.0.2 .degree.2.theta., 0.1 .degree.2.theta., or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). Form A can be further
characterized by PXRD peaks at about 10.7 .degree.2.theta., 11.6
.degree.2.theta., 12.2 .degree.2.theta., 15.3 .degree.2.theta.,
and/or 18.6 .degree.2.theta. (e.g., .+-.0.2 .degree.2.theta., 0.1
.degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0090] In some embodiments, Form A can be characterized by PXRD
peaks at about 26.2 .degree.2.theta. and about 23.2
.degree.2.theta. (e.g., .+-.0.2 .degree.2.theta., 0.1
.degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form A can be characterized by
PXRD peaks at about 26.2 .degree.2.theta. and about 26.5
.degree.2.theta. (e.g., .+-.0.2 .degree.2.theta., .+-.0.1
.degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form A can be characterized by
PXRD peaks at about 26.2 .degree.2.theta., 23.2 .degree.2.theta.,
and about 26.5 .degree.2.theta. (e.g., .+-.0.2 .degree.2.theta.,
0.1 .degree.2.theta., or 0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0091] In some embodiments, Form A can be characterized by PXRD
peaks at about 10.7 .degree.2.theta., about 26.2 .degree.2.theta.,
about 23.2 .degree.2.theta., and about 26.5 .degree.2.theta. (e.g.,
.+-.0.2 .degree.2.theta., 0.1 .degree.2.theta., or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form A can be characterized by PXRD peaks at about 11.6
.degree.2.theta., about 26.2 .degree.2.theta., about 23.2
.degree.2.theta., and about 26.5 .degree.2.theta. (e.g., .+-.0.2
.degree.2.theta., 0.1 .degree.2.theta., or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form A can be characterized by PXRD peaks at about 12.2
.degree.2.theta., about 26.2 .degree.2.theta., about 23.2
.degree.2.theta., and about 26.5 .degree.2.theta. (e.g., .+-.0.2
.degree.2.theta., 0.1 .degree.2.theta., or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form A can be characterized by PXRD peaks at about 15.3
.degree.2.theta., about 26.2 .degree.2.theta., about 23.2
.degree.2.theta., and about 26.5 .degree.2.theta. (e.g., .+-.0.2
.degree.2.theta., 0.1 .degree.2.theta., or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form A can be characterized by PXRD peaks at about 18.6
.degree.2.theta., about 26.2 .degree.2.theta., about 23.2
.degree.2.theta., and about 26.5 .degree.2.theta. (e.g., .+-.0.2
.degree.2.theta., 0.1 .degree.2.theta., or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0092] In some embodiments, Form A is characterized by PXRD peaks
at about 15.9 .degree.2.theta. and about 23.8 .degree.2.theta.
(e.g., .+-.0.2 .degree.2.theta., 0.1 .degree.2.theta., or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0093] In some embodiments, Form A is characterized by PXRD peaks
at about 10.7 .degree.2.theta., about 11.6 .degree.2.theta., and
about 12.2 .degree.2.theta. (e.g., .+-.0.2 .degree.2.theta., 0.1
.degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form A is characterized by PXRD
peaks at about 10.7 .degree.2.theta., about 11.6 .degree.2.theta.,
about 12.2 .degree.2.theta., and about 15.3 .degree.2.theta. (e.g.,
.+-.0.2 .degree.2.theta., 0.1 .degree.2.theta., or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form A is characterized by a single peak at about 11.6
.degree.2.theta. (e.g., .+-.0.2 .degree.2.theta., .+-.0.1
.degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0094] In some embodiments, Form A is characterized by PXRD peaks
at about 10.7 .degree.2.theta., about 11.6 .degree.2.theta., about
12.2 .degree.2.theta., about 15.3 .degree.2.theta., and about 15.9
.degree.2.theta. (e.g., .+-.0.2 .degree.2.theta., 0.1
.degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form A is characterized by PXRD
peaks at about 10.7 .degree.2.theta., about 11.6 .degree.2.theta.,
about 12.2 .degree.2.theta., about 15.3 .degree.2.theta., and about
16.3 .degree.2.theta. (e.g., .+-.0.2 .degree.2.theta., .+-.0.1
.degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form A is characterized by PXRD
peaks at about 10.7 .degree.2.theta., about 11.6 .degree.2.theta.,
about 12.2 .degree.2.theta., about 15.3 .degree.2.theta., about
15.9 .degree.2.theta. and about 16.3 .degree.2.theta. (e.g.,
.+-.0.2 .degree.2.theta., 0.1 .degree.2.theta., or 0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form A is characterized by PXRD peaks at about 10.7
.degree.2.theta., about 11.6 .degree.2.theta., about 12.2
.degree.2.theta., about 15.3 .degree.2.theta., and about 18.6
.degree.2.theta. (e.g., .+-.0.2 .degree.2.theta., 0.1
.degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form A is characterized by PXRD
peaks at about 10.7 .degree.2.theta., about 11.6 .degree.2.theta.,
about 12.2 .degree.2.theta., about 15.3 .degree.2.theta., about
15.9 .degree.2.theta., about 16.3 .degree.2.theta. and about 18.6
.degree.2.theta. (e.g., .+-.0.2 .degree.2.theta., 0.1
.degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form A is characterized by PXRD
peaks at about 10.7 .degree.2.theta., about 11.6 .degree.2.theta.,
about 12.2 .degree.2.theta., about 15.3 .degree.2.theta., about
15.9 .degree.2.theta., and about 18.6 .degree.2.theta. (e.g.,
.+-.0.2 .degree.2.theta., 0.1 .degree.2.theta., or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form A is characterized by PXRD peaks at about 10.7
.degree.2.theta., about 11.6 .degree.2.theta., about 12.2
.degree.2.theta., about 15.3 .degree.2.theta., about 16.3
.degree.2.theta. and about 18.6 .degree.2.theta. (e.g., .+-.0.2
.degree.2.theta., 0.1 .degree.2.theta., or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0095] In some embodiments, Form A can be characterized by PXRD
peaks at about 10.7 .degree.2.theta., about 23.2 .degree.2.theta.,
about 26.2 .degree.2.theta., and about 26.5 .degree.2.theta. (e.g.,
.+-.0.2 .degree.2.theta., 0.1 .degree.2.theta., or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form A can be characterized by PXRD peaks at about 10.7
.degree.2.theta., about 11.6 .degree.2.theta., about 23.2
.degree.2.theta., about 26.2 .degree.2.theta., and about 26.5
.degree.2.theta. (e.g., .+-.0.2 .degree.2.theta., 0.1
.degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form A can be characterized by
PXRD peaks at about 10.7 .degree.2.theta., about 11.6
.degree.2.theta., about 12.2 .degree.2.theta., about 23.2
.degree.2.theta., about 26.2 .degree.2.theta., and about 26.5
.degree.2.theta. (e.g., .+-.0.2 .degree.2.theta., 0.1
.degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form A can be characterized by
PXRD peaks at about 10.7 .degree.2.theta., about 11.6
.degree.2.theta., about 12.2 .degree.2.theta., about 15.3
.degree.2.theta., about 23.2 .degree.2.theta., about 26.2
.degree.2.theta., and about 26.5 .degree.2.theta. (e.g., .+-.0.2
.degree.2.theta., 0.1 .degree.2.theta., or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form A can be characterized by PXRD peaks at about 10.7
.degree.2.theta., about 11.6 .degree.2.theta., about 12.2
.degree.2.theta., about 15.3 .degree.2.theta., about 18.6
.degree.2.theta., about 23.2 .degree.2.theta., about 26.2
.degree.2.theta., and about 26.5 .degree.2.theta. (e.g., .+-.0.2
.degree.2.theta., 0.1 .degree.2.theta., or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0096] Accordingly, in some embodiments, morphic Form A is
characterized by one, two, three, four, five, six, seven or eight
peaks selected from about 10.7, 11.6, 12.2, 15.3, 18.6, 23.2, 26.2,
and 26.5 .degree.2.theta. (e.g., .+-.0.2 .degree.2.theta., 0.1
.degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form A is characterized by
one peak selected from about 10.7, 11.6, 12.2, 15.3, 18.6, 23.2,
26.2, and 26.5 .degree.2.theta. (e.g., .+-.0.2 .degree.2.theta.,
0.1 .degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form A is characterized by
two peaks selected from about 10.7, 11.6, 12.2, 15.3, 18.6, 23.2,
26.2, and 26.5 .degree.2.theta. (e.g., .+-.0.2 .degree.2.theta.,
0.1 .degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form A is characterized by
three peaks selected from about 10.7, 11.6, 12.2, 15.3, 18.6, 23.2,
26.2, and 26.5 .degree.2.theta. (e.g., .+-.0.2 .degree.2.theta.,
0.1 .degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form A is characterized by
four peaks selected from about 10.7, 11.6, 12.2, 15.3, 18.6, 23.2,
26.2, and 26.5 .degree.2.theta. (e.g., .+-.0.2 .degree.2.theta.,
0.1 .degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form A is characterized by
five peaks selected from about 10.7, 11.6, 12.2, 15.3, 18.6, 23.2,
26.2, and 26.5 .degree.2.theta. (e.g., .+-.0.2 .degree.2.theta.,
.+-.0.1 .degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form A is characterized by
six peaks selected from about 10.7, 11.6, 12.2, 15.3, 18.6, 23.2,
26.2, and 26.5 .degree.2.theta. (e.g., .+-.0.2 .degree.2.theta.,
.+-.0.1 .degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form A is characterized by
seven peaks selected from about 10.7, 11.6, 12.2, 15.3, 18.6, 23.2,
26.2, and 26.5 .degree.2.theta. (e.g., .+-.0.2 .degree.2.theta.,
.+-.0.1 .degree.2.theta., or .+-.0.0'.degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form A is characterized by
eight peaks selected from about 10.7, 11.6, 12.2, 15.3, 18.6, 23.2,
26.2, and 26.5 .degree.2.theta. (e.g., .+-.0.2 .degree.2.theta.,
.+-.0.1 .degree.2.theta., or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
TABLE-US-00001 TABLE 1 Representative PXRD Peaks for Morphic Form A
(Cu K.alpha.1 radiation) d value Angle (.degree.20) (.ANG.)
Intensity 8.8 10.02 vw 10.7 8.26 m 11.6 7.66 m 12.2 7.26 m 13.7
6.44 w 15.3 5.80 m 15.9 5.57 w 16.3 5.44 w 16.6 5.35 vw 17.4 5.10
vw 17.7 5.00 w 17.9 4.94 vw 18.5 4.80 vw 18.6 4.76 m 20.6 4.31 w
20.9 4.25 vw 21.5 4.12 w 22.1 4.01 vw 22.7 3.91 w 23.2 3.83 s 23.5
3.78 vw 23.8 3.74 w 24.0 3.70 vw 24.3 3.66 vw 25.0 3.56 vw 25.2
3.54 vw 25.6 3.47 vw 26.2 3.39 vs 26.5 3.36 s 27.1 3.29 w 27.3 3.26
vw 27.7 3.22 vw 27.9 3.20 w 28.7 3.11 vw 28.9 3.08 w 29.6 3.01 vw
29.9 2.98 vw 30.3 2.95 vw 30.8 2.90 vw 31.2 2.86 vw 31.6 2.83 vw
31.9 2.80 vw 32.2 2.78 vw 32.9 2.72 vw 33.5 2.67 vw 34.0 2.63 vw
34.2 2.62 vw 34.8 2.57 vw 35.4 2.54 vw 35.6 2.52 vw 35.9 2.50 w
36.1 2.49 vw 36.5 2.46 vw 36.8 2.44 vw 37.2 2.42 vw 37.8 2.38 vw
38.3 2.35 vw 38.5 2.34 vw 39.0 2.31 vw 39.7 2.27 vw
[0097] FIG. 8 is a TG-FTIR diagram of a sample of Compound 1, Form
A. FIG. 8 was obtained using a Netzsch TG 209, over the range of
25.degree. C. to 300.degree. C. The scanning speed was 10.degree.
C. per minute. FIG. 8 shows a mass loss step between about
110.degree. C. and about 220.degree. C. of about 2.4% (e.g., about
2.35%). Without wishing to be bound by theory, this mass loss can
be attributable to a loss of water. In some embodiments, Form A is
characterized by a mass loss of about 2.4% between about
110.degree. C. and about 220.degree. C. (e.g., as measured by
TG-FTIR). FIG. 8 shows a second mass loss step between about
220.degree. C. and about 245.degree. C. of about 0.5% (e.g., about
0.54%). Without wishing to be bound by theory, this mass loss step
can be attributed to the loss of additional water and trace amounts
of DMF. In some embodiments, Form A is characterized by a mass loss
of about 0.5% between about 220.degree. C. and about 245.degree.
C.
[0098] Without wishing to be bound by theory, the amount of water
lost is very close to the theoretical water content of about 2.7%
(e.g., about 2.71%) for a hemihydrate, further providing support
that morphic Form A is a hemihydrate. Moreover, without wishing to
be bound by theory, the high temperature necessary for dehydration
suggests that water is strongly bound in the crystalline lattice of
Form A, which suggests a very stable hemihydrate. Accordingly, in
some embodiments, the present disclosure provides a morphic form
(e.g., a hemihydrate form) of Compound 1 that is highly stable. In
some embodiments, the water content of Form A is about 2.4% (w/w)
or about 2.7 (w/w).
[0099] FIG. 15 is a DSC diagram of a sample of Compound 1, Form A.
FIG. 15 was obtained using a DSC Q2000 V24.3 with a hermetically
closed gold sample pan. The heating rate was 10.degree. C. per
minute. As shown in FIG. 15, Form A revealed an endothermal peak
with a peak temperature of about 231.degree. C. (173 J/g) (e.g.,
about 231.2.degree. C. (173.21 J/g)). Accordingly, in some
embodiments, Form A is characterized by a DVS curve with an
endothermal peak with a peak temperature of about 231.degree. C.
(173 J/g). In some embodiments, Form A is characterized by a DVS
curve with a single endothermal peak (e.g., at about 231.degree. C.
(173 J/g)). In some embodiments, Form A is characterized by a DVS
curve with no exothermic peak.
[0100] FIG. 20A is a DVS diagram of a sample of Compound 1, Form A
as a function of time and the applied change in relative humidity.
Line A represents the relative weight of the sample at each
relative humidity. Line B represents the applied relative humidity
(i.e., the applied measurement program). FIG. 20B is a DVS diagram
of a sample of Compound 1, Form A as a function of the applied
relative humidity. FIG. 20A and FIG. 20B were obtained using a
Sorptions Prufsystem ProUmid system using a scan rate of 5%
relative humidity per hour at a temperature of 25.degree. C.
[0101] As shown in FIG. 20A and FIG. 20B, the DVS analysis of Form
A showed only small desorption (0% R.H.: .ltoreq.0.1% m/m) and
adsorption (95% R.H.: .+-.0.1% m/m) of water. Without wishing to be
bound by theory, these data demonstrate that Form A is stable and
is non-hygroscopic. Additionally, PXRD measurement of the sample
post-DVS showed the same pattern as the sample before DVS.
Accordingly, in some embodiments, Form A is non-hygroscopic, and
does not convert to other forms in the presence of high relative
humidity.
Stability
[0102] In some embodiments, morphic Form A is less hygroscopic than
other identified morphic forms (e.g., forms B-G). For example, FIG.
20A and FIG. 20B show that Form A showed only small adsorption or
desorption of water as a function of relative humidity. In
contrast, as shown below, other morphic Forms (e.g., Form B, Form D
and Form E) exhibited greater fluctuations in mass as a function of
relative humidity, suggesting that these morphic forms are more
hygroscopic than Form A. These results also suggest that morphic
Form A is the least hygroscopic morphic form of any of the forms
identified in this disclosure.
[0103] Additionally, as set forth in Example 5, all seven of the
morphic forms identified herein (i.e., Form A, Form B, Form C, Form
D, Form E, Form F, and Form G) were stirred for four days in a 1:1
mixture of DMF:water; and a 95:5 mixture of methanol:water. After
each experiment, PXRD of all of the samples returned only morphic
Form A. Accordingly, without wishing to be bound by theory, morphic
Form A is the most thermodynamically stable morphic form of all of
the morphic forms identified herein.
Single Crystal Structure of the Form A Hemihydrate
[0104] The single crystal structure of Form A was elucidated using
X-ray diffraction. The data allowed for the absolute configuration
to be determined. Without wishing to be bound by theory, the
molecule crystallizes in the triclinic space group P1 with two
molecules of Compound 1 and one molecule of water in the asymmetric
unit. One molecule of water is found in the asymmetric unit
together with two molecules of Compound 1, which, without wishing
to be bound by theory, likely confirms that the structure is a
hemihydrate.
[0105] FIG. 24 is an ORTEP plot of the structure of Compound 1,
Form A. FIG. 24 gives labels for all non-hydrogen atoms. As shown
in FIG. 24, a molecule of water is associated with one of the
equivalents of Compound 1 (2402) in the asymmetric unit cell.
Molecule 2402 is hydrogen-bound to the other molecule of Compound 1
(2401). Referring again to FIG. 24, Bond distances and angles are
as expected and all possible hydrogen bond donors and acceptors
form hydrogen bonds.
[0106] The structure refined without problems and converged at an
R-value of 2.24% applying a 2a cutoff with a weighted R-value using
all data of 2.55%. More details about the data collection, the
structure solution, and refinement can be found in Table 2, below.
The structure is ordered and only the displacement parameters of
the water molecule are slightly larger than those for the rest of
the atoms in the structure.
TABLE-US-00002 TABLE 2 Data Collection of Crystal Structure of Form
A Formula 2(C.sub.13H.sub.17N.sub.5O.sub.5) H.sub.2O Formula weight
664.63 Z, calculated density 1, 1.589 Mg*m.sup.-3 F(000) 350
Description and size of crystal Colorless plate, 002*0.13*0.16
mm.sup.3 Absorption Coefficient (mm.sup.-1) 1.070 Min/max
transmission 0.87/0.98 Temperature (K) 123 Radiation (wavelength)
CuK.sub.a (.lamda. = 1.54178 .ANG.) Crystal System, space group
Triclinic, P1 a/.ANG. 8.1005(6) b/.ANG. 8.7599(6) c/.ANG.
11.1948(8) .alpha./.degree. 69.537 (2) .beta./.degree. 69.349(2)
.gamma./.degree. 79.041(3) V/.ANG..sup.3 694.60(9) Min/max
.THETA./.degree. 4.434/68.875 Number of collected reflections 15445
Number of independent reflections 4651 (merging r = 0.024) Number
of observed reflections 4596 (I > 2.sigma. (I)) Number of
refined parameters 489 R 0.0224 (I > 2.sigma. (I)) Rw 0.0255
(all data) Goodness of fit 1.1272 Flack parameter 0.10(9) Min/max
density in difference map -0.16/0.16
Exemplary Crystallization Protocol for Preparation of Form A
[0107] Example 6 below outlines the development of a robust
crystallization process for the preparation of Form A of Compound 1
on an industrially relevant (e.g., 20-g or greater than 20-g)
scale. As set forth in Example 6 below, it was found that
crystallizing Compound 1 in a solvent system comprising 1-propanol
and 0.01 M aqueous NaOH, e.g., at a ratio of 1:2 (v/v) effectively
removed common impurities present in an initial sample of Compound
1, Form A. For example, crystallizing from 1-propanol and 0.01 M
aqueous NaOH at a ratio of 1:2 (v/v) effectively removed residual
benzoic acid and Impurity No. 1 which can be, for example, present
in samples of Compound 1, (e.g., Compound 1, Form A) as a result of
synthetic process (for example as set forth in U.S. Pat. No.
9,701,706, the contents of which are hereby incorporated by
reference in their entirety). Accordingly, crystallizing Compound 1
using a mixture of 1-propanol and 0.01 M aqueous NaOH at a ratio of
1:2 (v/v) can result in highly pure (e.g., greater than 99% pure)
samples of Compound 1, Form A. The crystallization conditions were
also found to produce Compound 1, Form A in well-formed, plate-like
particles, and at a high yield (e.g., 88%). Furthermore, residual
content of the solvent (1-propanol) was found to be low (e.g., less
than 0.1% m/m) after recrystallizing using a mixture of 1-propanol
and 0.01 M aqueous NaOH at a ratio of 1:2 (v/v).
[0108] The present disclosure teaches a recrystallization protocol
for Compound 1 to give a crystalline form of Compound 1 (e.g., Form
A). The present disclosure differs from the teachings of U.S. Pat.
No. 9,701,706, which teaches that a suspension of Compound 1 was
slurried in water and filtered to give a powder-like solid. As set
forth in U.S. Pat. No. 9,701,706, Compound 1 was produced at a
purity of 98.84%. As set forth in Example 6, suspension
equilibration as taught by U.S. Pat. No. 9,701,706 is not effective
to eliminate the main impurities found in crude samples of Compound
1, such as benzoic acid, Impurity No. 1 and Impurity No. 2.
[0109] The present disclosure teaches highly pure compositions of
Compound 1, for example by purification from 1-propanol and 0.01 M
aqueous NaOH at a ratio of 1:2 (v/v). The present disclosure
teaches compositions comprising Compound 1 that are greater than
99% pure (e.g., 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%,
99.8%, 99.9%, or 99.99%). The present disclosure teaches
compositions that contain less than 0.1% benzoic acid (e.g., less
than 0.09%, less than 0.08%, less than 0.07%, less than 0.06%, less
than 0.05%, less than 0.04%, less than 0.03%, less than 0.02%, or
less than 0.01%). The present disclosure also teaches compositions
that contain less than 0.1% of Impurity No. 1 (e.g., less than
0.09%, less than 0.08%, less than 0.07%, less than 0.06%, less than
0.05%, less than 0.04%, less than 0.03%, less than 0.02%, or less
than 0.01%). The present disclosure teaches compositions that
contain less than 1% of Impurity No. 2 (e.g., less than 0.9%, less
than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less
than 0.4%, less than 0.3%, less than 0.2%, or less than 0.1%).
[0110] Additionally, morphic Form A can be substantially free of
solvent impurities. For example, Form A can be substantially free
of methanol (e.g., Form A can contain less than 0.9%, less than
0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than
0.4%, less than 0.3%, less than 0.2%, or less than 0.1% methanol).
For example, Form A can be substantially free of ethanol (e.g.,
Form A can contain less than 0.9%, less than 0.8%, less than 0.7%,
less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%,
less than 0.2%, or less than 0.1% ethanol). For example, Form A can
be substantially free of 1-propanol, (e.g., Form A can contain less
than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less
than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less
than 0.1% of 1-propanol). Form A can be substantially free of
2-propanol, (e.g., Form A can contain less than 0.9%, less than
0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than
0.4%, less than 0.3%, less than 0.2%, or less than 0.1% of
2-propanol). For example, Form A can be substantially free of DMSO
(e.g., Form A can contain less than 0.9%, less than 0.8%, less than
0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than
0.3%, less than 0.2%, or less than 0.1% DMSO).
[0111] The high purity of the compositions of the present
disclosure has advantages over the teachings of U.S. Pat. No.
9,701,706. For example, impurities such as benzoic acid and
Impurity Nos. 1 and 2 are undesirable for incorporation in a
pharmaceutical composition. For instance, impurities such as
benzoic acid and Impurity Nos. 1 and 2 can be toxic, and can cause
unwanted side effects when ingested (e.g., as part of a
pharmaceutical formulation).
[0112] As set forth in Example 6 below, a sample of Compound 1,
Form A was found to contain three main impurities left over from
the synthetic process (see e.g., U.S. Pat. No. 9,701,706). The
impurities were benzoic acid, Impurity No. 1 and Impurity No. 2
(the structures of which are shown below in Example 6). As outlined
in Example 6, Compound 1 was dissolved at 90.degree. C. in
1-propanol/0.01M aqueous NaOH (1:2 v/v). The solvent volume for
dissolution of 1 g of Compound 1 at 90.degree. C. was 12.5 mL.
Without wishing to be bound by theory, this solvent volume can be
acceptable for crystal production at an industrial (e.g., greater
than 20-g) scale. After cooling to 80.degree. C., the solution
became supersaturated and was seeded using 1% m/m of Compound 1,
Form A, cooled to 5.degree. C. and filtered. Suspensions thus
obtained were found to be easy to stir and easy to filter.
[0113] As set forth in Example 6, Compound 1, Form A crystallized
in well-formed plate-like particles with a particle size of between
about 50 m and 250 m at a yield of 88%. The residual content of
1-propanol was less than 0.1% (m/m). Furthermore, crystallization
from 1-propanol/0.01M aqueous NaOH (1:2 v/v) effectively removed
the impurities of benzoic acid and Impurity No. 1, and partially
removed the content of Impurity No. 2.
[0114] Accordingly, the present disclosure provides a process for
the preparation of Compound 1, Form A comprising recrystallizing
Compound 1 using a mixture of 1-propanol and 0.01 M aqueous NaOH,
e.g. at a ratio of 1:2 (v/v). In some embodiments, Compound 1 can
be dissolved in the mixture of 1-propanol and 0.01 M aqueous NaOH
at a ratio of 1:2 (v/v) at a temperature of about 90.degree. C.
(e.g., about 110.degree. C.; about 100.degree. C.; about 90.degree.
C.; about 80.degree. C.; about 70.degree. C.). In some embodiments,
the solution of Compound 1 in the mixture of 1-propanol and 0.01 M
aqueous NaOH at a ratio of 1:2 (v/v) can be cooled to about
80.degree. C. (e.g., about 100.degree. C.; about 90.degree. C.;
about 80.degree. C.; about 70.degree. C.; about 60.degree. C.). In
some embodiments, this cooling results in supersaturation. In some
embodiments, the solution of Compound 1 (e.g., the cooled solution)
can be seeded with Compound 1, Form A. In some embodiments, the
seed crystal is itself suspended in a solution (e.g., water;
1-propanol and 0.01 M aqueous NaOH at a ratio of 1:2 (v/v)). In
some embodiments, the seed crystal is about 1% m/m of the amount of
Compound 1 dissolved in the 1-propanol and 0.01 M aqueous NaOH at a
ratio of 1:2 (v/v). For example, the seed crystal can be about
0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%,
about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 2%, about 3%,
about 4%, or about 5%). In some embodiments, crystallizing Compound
1 from 1-propanol and 0.01 M aqueous NaOH at a ratio of 1:2 (v/v)
can result in a highly pure sample of Compound 1, Form A (e.g.,
greater than about 90% pure; greater than about 91% pure; greater
than about 92% pure; greater than about 93% pure; greater than
about 94% pure; greater than about 95% pure; greater than about 96%
pure; greater than about 97% pure; greater than about 98% pure;
greater than about 99% pure; greater than about 99.9% pure; or
greater than about 99.99% pure).
[0115] In some embodiments, highly pure Compound 1 (e.g., 99% pure,
99.1% pure, 99.2% pure, 99.3% pure, 99.4% pure, 99.5% pure, 99.6%
pure, 99.7% pure, 99.8% pure, 99.9% pure, or 99.99% pure) can be
incorporated into a pharmaceutical composition. For example, the
pharmaceutical composition can comprise highly pure Compound 1 and
a pharmaceutically acceptable carrier.
[0116] In some embodiments, the present disclosure provides a
method of treatment of a viral infection comprising administering
to a subject in need thereof a highly pure sample of Compound 1
(e.g., 99% pure, 99.1% pure, 99.2% pure, 99.3% pure, 99.4% pure,
99.5% pure, 99.6% pure, 99.7% pure, 99.8% pure, 99.9% pure, or
99.99% pure). In some embodiments, the method comprises
administering to the subject a pharmaceutical composition
comprising a highly pure sample of Compound 1.
[0117] In some embodiments, a highly pure sample of Compound 1
(e.g., 99% pure, 99.1% pure, 99.2% pure, 99.3% pure, 99.4% pure,
99.5% pure, 99.6% pure, 99.7% pure, 99.8% pure, 99.9% pure, or
99.99% pure) can be used for the treatment or prevention of a viral
infection. In some embodiments, a highly pure sample of Compound 1
(e.g., 99% pure, 99.1% pure, 99.2% pure, 99.3% pure, 99.4% pure,
99.5% pure, 99.6% pure, 99.7% pure, 99.8% pure, 99.9% pure, or
99.99% pure) can be used in the manufacture of a medicament for the
treatment or prevention of a viral infection.
[0118] In some embodiments, the solution and/or suspension of
Compound 1 in the mixture of 1-propanol and 0.01 M aqueous NaOH,
e.g. at a ratio of 1:2 (v/v) is stirred. The stirring can be at a
rate of about 500 rpm, and can ensure that Compound 1 does not
spontaneously crystallize to an appreciable degree before
seeding.
[0119] As set forth in Example 6, although many crystallization
conditions were identified that can produce Form A, 1-propanol and
0.01 M aqueous NaOH at a ratio of 1:2 (v/v) was able to dissolve
Compound 1 using less total solvent than other solvent systems
tested. In some embodiments, this can enable larger amounts of
Compound 1 (e.g., Form A) to be produced or processed per batch of
solvent. Additionally, this solvent system was able to dissolve
Compound 1 over a broad temperature range, enabling a higher yield
of Form A (e.g., 88% or greater) while still maintaining a high
(e.g., greater than 99%) purity. Additionally, solutions comprising
Compound 1 in 1-propanol and 0.01 M aqueous NaOH at a ratio of 1:2
(v/v) were found to be easy to stir and filter (e.g., did not
exhibit extensive stickiness when stirring and filtering).
Furthermore, the crystallization was able to remove many of the
common impurities (e.g., benzoic acid, Impurity Nos. 1 and 2) that
can be found in samples of Compound 1, Form A. Additionally,
stirring the solution and/or suspension can ensure that Compound 1
does not spontaneously crystallize to an appreciable degree before
seeding, which can ensure higher purity of the resulting morphic
form (e.g., Form A). Furthermore, the solvents that are used (i.e.,
1-propanol and 0.01 M NaOH are considered class 3 solvents for
their low toxicity. That is, according to FDA guidelines, class 3
solvents may be regarded as less toxic and of lower risk to human
health. These solvents exhibit no known risk to human health at
levels normally accepted in pharmaceuticals. For example, according
to FDA guidelines, the acceptable level of 1-propanol is 5,000 ppm.
Accordingly, the solvents used are safer than other common organic
solvents.
[0120] The present disclosure provides a morphic Form A of Compound
1 that has advantages over other forms of Compound 1. For example,
Form A can be highly pure; Form A can be more stable than other
morphic forms; and Form A can be non-hygroscopic. Preparation of
Form A can also be straightforward, as suspensions and/or solutions
of Form A can be easy to stir and filter, and Form A can be
prepared from substantially non-toxic solvents.
Form B
[0121] Morphic Form B of Compound 1 was characterized as a methanol
hemisolvate of Compound 1. Morphic Form B can be prepared by
crystallization of Compound 1 from methanol (e.g., substantially
pure methanol) by cooling a solution of Compound 1 in methanol.
[0122] FIG. 2A is a PXRD pattern of two samples of Compound 1, Form
B taken in transmission mode. Both of the PXRD patterns in FIG. 2A
were obtained using a Stoe Stadi P powder X-ray diffractometer
using Cu K.alpha.1 radiation and transmission geometry. FIG. 2B is
a PXRD pattern of Form B measured from 4 to 34
.degree.2.theta..
[0123] In some embodiments, morphic Form B can be characterized by
the PXRD peaks set forth below in Table 3. For example, morphic
Form B can be characterized by a PXRD peak at about 22.9
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). Form B can further be characterized by PXRD peaks at
about 4.9 .degree.2.theta., 10.9 .degree.2.theta., 13.3
.degree.2.theta., 18.4 .degree.2.theta., 20.9 .degree.2.theta.,
and/or 26.1 .degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). Form B can further be characterized by PXRD peaks at
about 13.6 .degree.2.theta., 15.1 .degree.2.theta., 17.5
.degree.2.theta., 19.0 .degree.2.theta., 19.5 .degree.2.theta.,
20.0 .degree.2.theta., 20.3 .degree.2.theta., 20.4
.degree.2.theta., 23.3 .degree.2.theta., and/or 25.7
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0124] In some embodiments, Form B can be characterized by PXRD
peaks at about 4.9 .degree.2.theta., about 10.9 .degree.2.theta.,
and about 13.3 .degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form B can be characterized by
PXRD peaks at about 10.9 .degree.2.theta., about 13.3
.degree.2.theta., and about 18.4 .degree.2.theta., (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form B can be characterized by PXRD peaks at about 13.3
.degree.2.theta., about 18.4 .degree.2.theta., and about 20.9
.degree.2.theta., (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form B can be characterized by
PXRD peaks at about 18.4 .degree.2.theta., about 20.9
.degree.2.theta., and about 22.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form B can be characterized by PXRD peaks at about 20.9
.degree.2.theta., about 22.9 .degree.2.theta., and about 26.1
.degree.2.theta., (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0125] In some embodiments, Form B can be characterized by PXRD
peaks at about 22.9 .degree.2.theta. and about 4.9 .degree.2.theta.
(.+-.0.2 .degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form B can be characterized by PXRD peaks at about 22.9
.degree.2.theta., about 4.9 .degree.2.theta., and about 10.9
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form B can be characterized by
PXRD peaks at about 22.9 .degree.2.theta., about 4.9
.degree.2.theta., about 10.9 .degree.2.theta., and about 13.3
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form B can be characterized by
PXRD peaks at about 22.9 .degree.2.theta., about 4.9
.degree.2.theta., about 10.9 .degree.2.theta., about 13.3
.degree.2.theta., and about 18.4 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form B can be characterized by PXRD peaks at about 22.9
.degree.2.theta., about 4.9 .degree.2.theta., about 10.9
.degree.2.theta., about 13.3 .degree.2.theta., about 18.4
.degree.2.theta., and about 20.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form B can be characterized by PXRD peaks at about 22.9
.degree.2.theta., about 4.9 .degree.2.theta., about 10.9
.degree.2.theta., about 13.3 .degree.2.theta., about 18.4
.degree.2.theta., about 20.9 .degree.2.theta., and about 26.1
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form B can further be
characterized by PXRD peaks at about 23.3 and/or 25.7
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or 0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0126] In some embodiments, Form B can be characterized by PXRD
peaks at about 22.9 .degree.2.theta., about 4.9 .degree.2.theta.,
about 10.9 .degree.2.theta., about 13.3 .degree.2.theta., about
13.6 .degree.2.theta., about 18.4 .degree.2.theta., about 20.9
.degree.2.theta., and about 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form B can be characterized by PXRD peaks at about 22.9
.degree.2.theta., about 4.9 .degree.2.theta., about 10.9
.degree.2.theta., about 13.3 .degree.2.theta., about 13.6
.degree.2.theta., about 15.1 .degree.2.theta., about 18.4
.degree.2.theta., about 20.9 .degree.2.theta., and about 26.1
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form B can be characterized by
PXRD peaks at about 22.9 .degree.2.theta., about 4.9
.degree.2.theta., about 10.9 .degree.2.theta., about 13.3
.degree.2.theta., about 13.6 .degree.2.theta., about 15.1
.degree.2.theta., about 17.5 .degree.2.theta., about 18.4
.degree.2.theta., about 20.9 .degree.2.theta., and about 26.1
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form B can be characterized by
PXRD peaks at about 22.9 .degree.2.theta., about 4.9
.degree.2.theta., about 10.9 .degree.2.theta., about 13.3
.degree.2.theta., about 13.6 .degree.2.theta., about 15.1
.degree.2.theta., about 17.5 .degree.2.theta., about 18.4
.degree.2.theta., about 19.0 .degree.2.theta., about 20.9
.degree.2.theta., and about 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form B can be characterized by PXRD peaks at about 22.9
.degree.2.theta., about 4.9 .degree.2.theta., about 10.9
.degree.2.theta., about 13.3 .degree.2.theta., about 13.6
.degree.2.theta., about 15.1 .degree.2.theta., about 17.5
.degree.2.theta., about 18.4 .degree.2.theta., about 19.0
.degree.2.theta., about 19.5 .degree.2.theta., about 20.9
.degree.2.theta., and about 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form B can be characterized by PXRD peaks at about 22.9
.degree.2.theta., about 4.9 .degree.2.theta., about 10.9
.degree.2.theta., about 13.3 .degree.2.theta., about 13.6
.degree.2.theta., about 15.1 .degree.2.theta., about 17.5
.degree.2.theta., about 18.4 .degree.2.theta., about 19.0
.degree.2.theta., about 19.5 .degree.2.theta., about 20.0
.degree.2.theta., about 20.9 .degree.2.theta., and about 26.1
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form B can be characterized by
PXRD peaks at about 22.9 .degree.2.theta., about 4.9
.degree.2.theta., about 10.9 .degree.2.theta., about 13.3
.degree.2.theta., about 13.6 .degree.2.theta., about 15.1
.degree.2.theta., about 17.5 .degree.2.theta., about 18.4
.degree.2.theta., about 19.0 .degree.2.theta., about 19.5
.degree.2.theta., about 20.0 .degree.2.theta., about 20.3
.degree.2.theta., about 20.9 .degree.2.theta., and about 26.1
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form B can be characterized by
PXRD peaks at about 22.9 .degree.2.theta., about 4.9
.degree.2.theta., about 10.9 .degree.2.theta., about 13.3
.degree.2.theta., about 13.6 .degree.2.theta., about 15.1
.degree.2.theta., about 17.5 .degree.2.theta., about 18.4
.degree.2.theta., about 19.0 .degree.2.theta., about 19.5
.degree.2.theta., about 20.0 .degree.2.theta., about 20.3
.degree.2.theta., about 20.4 .degree.2.theta., about 20.9
.degree.2.theta., and about 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form B can be characterized by PXRD peaks at about 22.9
.degree.2.theta., about 4.9 .degree.2.theta., about 10.9
.degree.2.theta., about 13.3 .degree.2.theta., about 13.6
.degree.2.theta., about 15.1 .degree.2.theta., about 17.5
.degree.2.theta., about 18.4 .degree.2.theta., about 19.0
.degree.2.theta., about 19.5 .degree.2.theta., about 20.0
.degree.2.theta., about 20.3 .degree.2.theta., about 20.4
.degree.2.theta., about 20.9 .degree.2.theta., about 23.3
.degree.2.theta., and about 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or 0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form B can be characterized by PXRD peaks at about 22.9
.degree.2.theta., about 4.9 .degree.2.theta., about 10.9
.degree.2.theta., about 13.3 .degree.2.theta., about 13.6
.degree.2.theta., about 15.1 .degree.2.theta., about 17.5
.degree.2.theta., about 18.4 .degree.2.theta., about 19.0
.degree.2.theta., about 19.5 .degree.2.theta., about 20.0
.degree.2.theta., about 20.3 .degree.2.theta., about 20.4
.degree.2.theta., about 20.9 .degree.2.theta., about 23.3
.degree.2.theta., about 25.7 .degree.2.theta., and about 26.1
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0127] In some embodiments, morphic Form B is characterized by one
peak selected from about 4.9 .degree.2.theta., 10.9
.degree.2.theta., 13.3 .degree.2.theta., 13.6 .degree.2.theta.,
15.1 .degree.2.theta., 17.5 .degree.2.theta., 18.4
.degree.2.theta., 19.0 .degree.2.theta., 19.5 .degree.2.theta.,
20.0 .degree.2.theta., 20.3 .degree.2.theta., 20.4
.degree.2.theta., 20.9 .degree.2.theta., 22.9 .degree.2.theta.,
23.3 .degree.2.theta., 25.7 .degree.2.theta., and 26.1
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form B is characterized by
two peaks selected from about 4.9 .degree.2.theta., 10.9
.degree.2.theta., 13.3 .degree.2.theta., 13.6 .degree.2.theta.,
15.1 .degree.2.theta., 17.5 .degree.2.theta., 18.4
.degree.2.theta., 19.0 .degree.2.theta., 19.5 .degree.2.theta.,
20.0 .degree.2.theta., 20.3 .degree.2.theta., 20.4
.degree.2.theta., 20.9 .degree.2.theta., 22.9 .degree.2.theta.,
23.3 .degree.2.theta., 25.7 .degree.2.theta., and 26.1
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form B is characterized by
three peaks selected from about 4.9 .degree.2.theta., 10.9
.degree.2.theta., 13.3 .degree.2.theta., 13.6 .degree.2.theta.,
15.1 .degree.2.theta., 17.5 .degree.2.theta., 18.4
.degree.2.theta., 19.0 .degree.2.theta., 19.5 .degree.2.theta.,
20.0 .degree.2.theta., 20.3 .degree.2.theta., 20.4
.degree.2.theta., 20.9 .degree.2.theta., 22.9 .degree.2.theta.,
23.3 .degree.2.theta., 25.7 .degree.2.theta., and 26.1
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or 0.0 .degree.2.theta.; Cu K.alpha.1 radiation).
In some embodiments, morphic Form B is characterized by four peaks
selected from about 4.9 .degree.2.theta., 10.9 .degree.2.theta.,
13.3 .degree.2.theta., 13.6 .degree.2.theta., 15.1
.degree.2.theta., 17.5 .degree.2.theta., 18.4 .degree.2.theta.,
19.0 .degree.2.theta., 19.5 .degree.2.theta., 20.0
.degree.2.theta., 20.3 .degree.2.theta., 20.4 .degree.2.theta.,
20.9 .degree.2.theta., 22.9 .degree.2.theta., 23.3
.degree.2.theta., 25.7 .degree.2.theta., and 26.1 .degree.2.theta.
(.+-.0.2 .degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form B is characterized by five peaks selected from about
4.9 .degree.2.theta., 10.9 .degree.2.theta., 13.3 .degree.2.theta.,
13.6 .degree.2.theta., 15.1 .degree.2.theta., 17.5
.degree.2.theta., 18.4 .degree.2.theta., 19.0 .degree.2.theta.,
19.5 .degree.2.theta., 20.0 .degree.2.theta., 20.3
.degree.2.theta., 20.4 .degree.2.theta., 20.9 .degree.2.theta.,
22.9 .degree.2.theta., 23.3 .degree.2.theta., 25.7
.degree.2.theta., and 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form B is characterized by six peaks selected from about
4.9 .degree.2.theta., 10.9 .degree.2.theta., 13.3 .degree.2.theta.,
13.6 .degree.2.theta., 15.1 .degree.2.theta., 17.5
.degree.2.theta., 18.4 .degree.2.theta., 19.0 .degree.2.theta.,
19.5 .degree.2.theta., 20.0 .degree.2.theta., 20.3
.degree.2.theta., 20.4 .degree.2.theta., 20.9 .degree.2.theta.,
22.9 .degree.2.theta., 23.3 .degree.2.theta., 25.7
.degree.2.theta., and 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form B is characterized by seven peaks selected from about
4.9.degree. 20, 10.9 .degree.2.theta., 13.3 .degree.2.theta., 13.6
.degree.2.theta., 15.1 .degree.2.theta., 17.5 .degree.2.theta.,
18.4 .degree.2.theta., 19.0 .degree.2.theta., 19.5
.degree.2.theta., 20.0 .degree.2.theta., 20.3 .degree.2.theta.,
20.4 .degree.2.theta., 20.9 .degree.2.theta., 22.9
.degree.2.theta., 23.3 .degree.2.theta., 25.7 .degree.2.theta., and
26.1 .degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form B is characterized by
eight peaks selected from about 4.9 .degree.2.theta., 10.9
.degree.2.theta., 13.3 .degree.2.theta., 13.6 .degree.2.theta.,
15.1 .degree.2.theta., 17.5 .degree.2.theta., 18.4
.degree.2.theta., 19.0 .degree.2.theta., 19.5 .degree.2.theta.,
20.0 .degree.2.theta., 20.3 .degree.2.theta., 20.4
.degree.2.theta., 20.9 .degree.2.theta., 22.9 .degree.2.theta.,
23.3 .degree.2.theta., 25.7 .degree.2.theta., and 26.1
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or 0.0 .degree.2.theta.; Cu K.alpha.1 radiation).
In some embodiments, morphic Form B is characterized by nine peaks
selected from about 4.9 .degree.2.theta., 10.9 .degree.2.theta.,
13.3 .degree.2.theta., 13.6 .degree.2.theta., 15.1
.degree.2.theta., 17.5 .degree.2.theta., 18.4 .degree.2.theta.,
19.0 .degree.2.theta., 19.5 .degree.2.theta., 20.0
.degree.2.theta., 20.3 .degree.2.theta., 20.4 .degree.2.theta.,
20.9 .degree.2.theta., 22.9 .degree.2.theta., 23.3
.degree.2.theta., 25.7 .degree.2.theta., and 26.1 .degree.2.theta.
(.+-.0.2 .degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form B is characterized by ten peaks selected from about
4.9 .degree.2.theta., 10.9 .degree.2.theta., 13.3 .degree.2.theta.,
13.6 .degree.2.theta., 15.1 .degree.2.theta., 17.5
.degree.2.theta., 18.4 .degree.2.theta., 19.0 .degree.2.theta.,
19.5 .degree.2.theta., 20.0 .degree.2.theta., 20.3
.degree.2.theta., 20.4 .degree.2.theta., 20.9 .degree.2.theta.,
22.9 .degree.2.theta., 23.3 .degree.2.theta., 25.7
.degree.2.theta., and 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form B is characterized by eleven peaks selected from about
4.9 .degree.2.theta., 10.9 .degree.2.theta., 13.3 .degree.2.theta.,
13.6 .degree.2.theta., 15.1 .degree.2.theta., 17.5
.degree.2.theta., 18.4 .degree.2.theta., 19.0 .degree.2.theta.,
19.5 .degree.2.theta., 20.0 .degree.2.theta., 20.3
.degree.2.theta., 20.4 .degree.2.theta., 20.9 .degree.2.theta.,
22.9 .degree.2.theta., 23.3 .degree.2.theta., 25.7
.degree.2.theta., and 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form B is characterized by twelve peaks selected from about
4.9 .degree.2.theta., 10.9 .degree.2.theta., 13.3 .degree.2.theta.,
13.6 .degree.2.theta., 15.1 .degree.2.theta., 17.5
.degree.2.theta., 18.4 .degree.2.theta., 19.0 .degree.2.theta.,
19.5 .degree.2.theta., 20.0 .degree.2.theta., 20.3
.degree.2.theta., 20.4 .degree.2.theta., 20.9 .degree.2.theta.,
22.9 .degree.2.theta., 23.3 .degree.2.theta., 25.7
.degree.2.theta., and 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form B is characterized by thirteen peaks selected from
about 4.9 .degree.2.theta., 10.9 .degree.2.theta., 13.3
.degree.2.theta., 13.6 .degree.2.theta., 15.1 .degree.2.theta.,
17.5 .degree.2.theta., 18.4 .degree.2.theta., 19.0
.degree.2.theta., 19.5 .degree.2.theta., 20.0 .degree.2.theta.,
20.3 .degree.2.theta., 20.4 .degree.2.theta., 20.9
.degree.2.theta., 22.9 .degree.2.theta., 23.3 .degree.2.theta.,
25.7 .degree.2.theta., and 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or 0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form B is characterized by fourteen peaks selected from
about 4.9 .degree.2.theta., 10.9 .degree.2.theta., 13.3
.degree.2.theta., 13.6 .degree.2.theta., 15.1 .degree.2.theta.,
17.5 .degree.2.theta., 18.4 .degree.2.theta., 19.0
.degree.2.theta., 19.5 .degree.2.theta., 20.0 .degree.2.theta.,
20.3 .degree.2.theta., 20.4 .degree.2.theta., 20.9
.degree.2.theta., 22.9 .degree.2.theta., 23.3 .degree.2.theta.,
25.7 .degree.2.theta., and 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form B is characterized by fifteen peaks selected from
about 4.9 .degree.2.theta., 10.9 .degree.2.theta., 13.3
.degree.2.theta., 13.6 .degree.2.theta., 15.1 .degree.2.theta.,
17.5 .degree.2.theta., 18.4 .degree.2.theta., 19.0
.degree.2.theta., 19.5 .degree.2.theta., 20.0 .degree.2.theta.,
20.3 .degree.2.theta., 20.4 .degree.2.theta., 20.9
.degree.2.theta., 22.9 .degree.2.theta., 23.3 .degree.2.theta.,
25.7 .degree.2.theta., and 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form B is characterized by sixteen peaks selected from
about 4.9 .degree.2.theta., 10.9 .degree.2.theta., 13.3
.degree.2.theta., 13.6 .degree.2.theta., 15.1 .degree.2.theta.,
17.5 .degree.2.theta., 18.4 .degree.2.theta., 19.0
.degree.2.theta., 19.5 .degree.2.theta., 20.0 .degree.2.theta.,
20.3 .degree.2.theta., 20.4 .degree.2.theta., 20.9
.degree.2.theta., 22.9 .degree.2.theta., 23.3 .degree.2.theta.,
25.7 .degree.2.theta., and 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form B is characterized by seventeen peaks selected from
about 4.9 .degree.2.theta., 10.9 .degree.2.theta., 13.3
.degree.2.theta., 13.6 .degree.2.theta., 15.1 .degree.2.theta.,
17.5 .degree.2.theta., 18.4 .degree.2.theta., 19.0
.degree.2.theta., 19.5 .degree.2.theta., 20.0 .degree.2.theta.,
20.3 .degree.2.theta., 20.4 .degree.2.theta., 20.9
.degree.2.theta., 22.9 .degree.2.theta., 23.3 .degree.2.theta.,
25.7 .degree.2.theta., and 26.1 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0128] Accordingly, in some embodiments, morphic Form B is
characterized by one, two, three, four, five, six, seven, eight,
nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen or
seventeen peaks selected from about 4.9, 10.9, 13.3, 13.6, 15.1,
17.5, 18.4, 19.0, 19.5, 20.0, 20.3, 20.4, 20.9, 22.9, 23.3, 25.7,
and 26.1 .degree.2.theta. (Cu K.alpha.1 radiation).
TABLE-US-00003 TABLE 3 Representative PXRD Peaks of Morphic Form B
(Cu K.alpha.1 radiation) Angle (.degree.20) d value (.ANG.)
Intensity 4.9 17.89 s 6.6 13.38 w 8.8 10.02 vw 9.9 8.91 w 10.1 8.74
w 10.9 8.15 s 11.4 7.78 w 11.7 7.56 w 12.2 7.25 w 13.3 6.66 s 13.6
6.50 m 14.0 6.32 w 14.3 6.19 w 14.4 6.13 w 14.8 5.96 w 15.1 5.85 m
15.5 5.72 vw 16.2 5.46 vw 16.6 5.34 w 17.0 5.22 w 17.5 5.07 m 17.7
5.01 w 18.0 4.94 w 18.4 4.83 s 19.0 4.68 m 19.5 4.54 m 20.0 4.44 m
20.3 4.37 m 20.4 4.34 m 20.9 4.25 s 21.1 4.21 w 21.4 4.16 w 21.7
4.09 w 21.9 4.06 w 22.2 4.00 w 22.4 3.97 w 22.9 3.89 vs 23.3 3.81 m
23.9 3.71 vw 24.3 3.66 vw 24.6 3.62 vw 25.5 3.49 w 25.7 3.46 m 26.1
3.41 s 26.8 3.33 vw 27.2 3.27 w 27.8 3.21 vw 28.2 3.16 vw 28.9 3.09
w 29.0 3.07 w 29.5 3.02 vw 30.2 2.96 w 30.5 2.92 w 30.9 2.89 vw
31.2 2.86 vw 31.6 2.83 vw 32.0 2.79 vw 32.8 2.73 w 33.1 2.70 w 33.5
2.67 vw 33.9 2.64 vw 34.7 2.58 vw 35.2 2.55 vw 35.6 2.52 vw 35.8
2.51 vw 36.0 2.49 vw 36.3 2.47 vw 37.3 2.41 vw 37.8 2.38 vw 38.5
2.33 w 39.9 2.26 vw
[0129] FIG. 9A is a TG-FTIR diagram of a first sample of Compound
1, Form B prepared as set forth in Example 1, Experiment 9. FIG. 9B
is a TG-FTIR diagram of a second sample of Compound 1, Form B
prepared as set forth in Example 1, Experiment 10. FIG. 9A and FIG.
9B was obtained using a Netzsch TG 209, over the range of
25.degree. C. to 300.degree. C. The scanning speed was 10.degree.
C. per minute.
[0130] As shown in FIG. 9A and FIG. 9B, morphic Form B shows a mass
change between of about 4.9% (e.g., about 4.81%; about 4.93%) about
100.degree. C. and about 215.degree. C. Without wishing to be bound
by theory, this mass change is attributed to loss of methanol and
trace water. Accordingly, in some embodiments, morphic Form B
contains about 4.9% methanol (w/w). In some embodiments, morphic
Form B is characterized by a mass loss of about 4.9% between about
100.degree. C. and about 215.degree. C. (e.g., as measured by
TG-FTIR).
[0131] FIG. 16 is a DSC diagram of a sample of Compound 1, Form B.
FIG. 16 was obtained using a DSC Q2000 V24.3 with a hermetically
closed gold sample pan. The heating rate was 10.degree. C. per
minute. The DSC diagram shows an insert between about 155.degree.
C. and 205.degree. C.
[0132] As shown in FIG. 16, morphic Form B exhibited endothermic
peaks at about 177.degree. C. (20 J/g) (e.g., about 177.2.degree.
C. (20.30 J/g)); about 190.degree. C. (17 J/g) (e.g., about
190.0.degree. C. (16.86 J/g)); and about 231.degree. C. (122 J/g)
(e.g., about 230.5.degree. C. (121.53 J/g)). Morphic Form B also
exhibited an exothermic peak at about 191.degree. C. (8 J/g) (e.g.,
about 191.2.degree. C. (7.85 J/g)). Accordingly, in some
embodiments, morphic Form B shows peaks above about 170.degree. C.
In some embodiments, morphic Form B is characterized by a DSC
diagram exhibiting an endothermic peak at about 177.degree. C. (20
J/g) (e.g., about 177.2.degree. C. (20.30 J/g)). In some
embodiments, morphic Form B is characterized by a DSC diagram
exhibiting an endothermic peak at about 190.degree. C. (17 J/g)
(e.g., about 190.0.degree. C. (16.86 J/g)). In some embodiments,
morphic Form B is characterized by a DSC diagram exhibiting an
endothermic peak at about 231.degree. C. (122 J/g) (e.g., about
230.5.degree. C. (121.53 J/g)). In some embodiments, morphic Form B
is characterized by a DSC diagram exhibiting endothermic peaks at
about 177.degree. C. (20 J/g) (e.g., about 177.2.degree. C. (20.30
J/g)); about 190.degree. C. (17 J/g) (e.g., about 190.0.degree. C.
(16.86 J/g)); and about 231.degree. C. (122 J/g) (e.g., about
230.5.degree. C. (121.53 J/g)). In some embodiments, morphic Form B
is characterized by a DSC diagram exhibiting an exothermic peak at
about 191.degree. C. (8 J/g) (e.g., about 191.2.degree. C. (7.85
J/g)).
[0133] FIG. 21A is a DVS diagram of a sample of Compound 1, Form B
as a function of time and the applied change in relative humidity.
Line A represents the relative weight of the sample at each
relative humidity. Line B represents the applied relative humidity
(i.e., the applied measurement program). FIG. 21B is a DVS diagram
of a sample of Compound 1, Form B as a function of the applied
relative humidity. FIG. 21A and FIG. 21B were obtained using a
Sorptions Prufsystem ProUmid system using a scan rate of 5%
relative humidity per hour at a temperature of 25.degree. C. As
shown in FIGS. 21A and 21B, the mass of the sample of morphic Form
B was found to fluctuate as a function of relative humidity.
Without wishing to be bound by theory, this suggests that morphic
Form B is hygroscopic. Additionally, Form B was found to transform
in to Form A under the conditions of the DVS. Accordingly, in some
embodiments, Form B can be converted to Form A under conditions of
high relative humidity (e.g., at about 25.degree. C. and about 50%
relative humidity or above, for instance under conditions of
dynamic water vapor sorption experiments).
Form C
[0134] Morphic Form C of Compound 1 was characterized as an ethanol
hemisolvate of Compound 1. In some embodiments, morphic Form C can
be prepared by crystallization of Compound 1 from ethanol (e.g.,
substantially pure ethanol) by cooling a solution of Compound 1 in
ethanol.
[0135] FIG. 3 is a PXRD pattern of a sample of Compound 1, Form C
taken in transmission mode. FIG. 3 was obtained using a Stoe Stadi
P powder X-ray diffractometer using Cu K.alpha.1 radiation and
transmission geometry.
[0136] In some embodiments, morphic Form C can be characterized by
the PXRD peaks set forth below in Table 4. For example, morphic
Form C can be characterized by a PXRD peak at about 22.4
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). Morphic Form C can further be characterized by a PXRD
peak at about 4.9 .degree.2.theta., 10.7 .degree.2.theta., 13.2
.degree.2.theta., 17.4 .degree.2.theta., 19.4 .degree.2.theta.,
20.5 .degree.2.theta., 22.8 .degree.2.theta., 25.2
.degree.2.theta., and/or 25.6, .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). Morphic Form C can
further be characterized by a PXRD peak at about 6.6
.degree.2.theta., 11.2 .degree.2.theta., 13.5 .degree.2.theta.,
14.2 .degree.2.theta., 14.8 .degree.2.theta., 16.5
.degree.2.theta., 16.7 .degree.2.theta., 18.5 .degree.2.theta.,
19.0 .degree.2.theta., 19.7 .degree.2.theta., 20.3
.degree.2.theta., 21.0 .degree.2.theta., 25.4 .degree.2.theta.,
and/or 26.7 .degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0137] In some embodiments, morphic Form C can be characterized by
PXRD peaks at about 4.9 .degree.2.theta., about 10.7
.degree.2.theta., and about 13.2 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by PXRD peaks at about 10.7
.degree.2.theta., about 13.2 .degree.2.theta., and about 17.4
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form C can be
characterized by PXRD peaks at about 13.2 .degree.2.theta., about
17.4 .degree.2.theta., and about 19.4 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by PXRD peaks at about 17.4
.degree.2.theta., about 19.4 .degree.2.theta., and about 20.5
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form C can be
characterized by PXRD peaks at about 19.4 .degree.2.theta., about
20.5 .degree.2.theta., and about 22.4 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by PXRD peaks at about 20.5
.degree.2.theta., about 22.4 .degree.2.theta., and about 22.8
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form C can be
characterized by PXRD peaks at about 22.4 .degree.2.theta., about
22.8 .degree.2.theta., and about 25.2 .degree.2.theta.
(.+-.0.2.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by PXRD peaks at about 22.8
.degree.2.theta., about 25.2 .degree.2.theta., and about 25.6
.degree.2.theta. (.+-.0.2.degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0138] In some embodiments, morphic Form C can be characterized by
a PXRD peak at about 22.4 .degree.2.theta. and about 4.9
.degree.2.theta. (.+-.0.2.degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form C can be
characterized by a PXRD peak at about 22.4 .degree.2.theta. about
4.9 .degree.2.theta., and about 10.7 .degree.2.theta.
(.+-.0.2.degree.2.theta.; 0.1 .degree.2.theta.; or 0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by a PXRD peak at about 22.4
.degree.2.theta. about 4.9 .degree.2.theta., about 10.7
.degree.2.theta., and about 13.2 .degree.2.theta.
(.+-.0.2.degree.2.theta.; .+-.0.1 .degree.2.theta.; or 0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by a PXRD peak at about 22.4
.degree.2.theta. about 4.9 .degree.2.theta., about 10.7
.degree.2.theta., about 13.2 .degree.2.theta., and about 17.4
.degree.2.theta. (.+-.0.2.degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form C can be
characterized by a PXRD peak at about 22.4 .degree.2.theta. about
4.9 .degree.2.theta., about 10.7 .degree.2.theta., about 13.2
.degree.2.theta., about 17.4 .degree.2.theta., and about 19.4
.degree.2.theta. (.+-.0.2.degree.2.theta.; .+-.0.1
.degree.2.theta.; or 0.0 .degree.2.theta.; Cu K.alpha.1 radiation).
In some embodiments, morphic Form C can be characterized by a PXRD
peak at about 22.4 .degree.2.theta. about 4.9 .degree.2.theta.,
about 10.7 .degree.2.theta., about 13.2 .degree.2.theta., about
17.4 .degree.2.theta., about 19.4 .degree.2.theta., and about 20.5
.degree.2.theta. (.+-.0.2.degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form C can be
characterized by a PXRD peak at about 22.4 .degree.2.theta. about
4.9 .degree.2.theta., about 10.7 .degree.2.theta., about 13.2
.degree.2.theta., about 17.4 .degree.2.theta., about 19.4
.degree.2.theta., about 20.5 .degree.2.theta., and about 22.8
.degree.2.theta. (.+-.0.2.degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form C can be
characterized by a PXRD peak at about 22.4 .degree.2.theta. about
4.9 .degree.2.theta., about 10.7 .degree.2.theta., about 13.2
.degree.2.theta., about 17.4 .degree.2.theta., about 19.4
.degree.2.theta., about 20.5 .degree.2.theta., about 22.8
.degree.2.theta., and about 25.2 .degree.2.theta.
(.+-.0.2.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by a PXRD peak at about 22.4
.degree.2.theta. about 4.9 .degree.2.theta., about 10.7
.degree.2.theta., about 13.2 .degree.2.theta., about 17.4
.degree.2.theta., about 19.4 .degree.2.theta., about 20.5
.degree.2.theta., about 22.8 .degree.2.theta., about 25.2
.degree.2.theta., and about 25.6 .degree.2.theta.
(.+-.0.2.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0139] In some embodiments, morphic Form C can be characterized by
a PXRD peak at about 22.4 .degree.2.theta. about 4.9
.degree.2.theta., about 6.6 .degree.2.theta., about 10.7
.degree.2.theta., about 13.2 .degree.2.theta., about 17.4
.degree.2.theta., about 19.4 .degree.2.theta., about 20.5
.degree.2.theta., about 22.8 .degree.2.theta., about 25.2
.degree.2.theta., and about 25.6 .degree.2.theta.
(.+-.0.2.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by a PXRD peak at about 22.4
.degree.2.theta. about 4.9 .degree.2.theta., about 6.6
.degree.2.theta., about 10.7 .degree.2.theta., about 11.2
.degree.2.theta., about 13.2 .degree.2.theta., about 17.4
.degree.2.theta., about 19.4 .degree.2.theta., about 20.5
.degree.2.theta., about 22.8 .degree.2.theta., about 25.2
.degree.2.theta., and about 25.6 .degree.2.theta.
(.+-.0.2.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by a PXRD peak at about 22.4
.degree.2.theta. about 4.9 .degree.2.theta., about 6.6
.degree.2.theta., about 10.7 .degree.2.theta., about 11.2
.degree.2.theta., about 13.2 .degree.2.theta., about 13.5
.degree.2.theta., about 17.4 .degree.2.theta., about 19.4
.degree.2.theta., about 20.5 .degree.2.theta., about 22.8
.degree.2.theta., about 25.2 .degree.2.theta., and about 25.6
.degree.2.theta. (.+-.0.2.degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form C can be
characterized by a PXRD peak at about 22.4 .degree.2.theta. about
4.9 .degree.2.theta., about 6.6 .degree.2.theta., about 10.7
.degree.2.theta., about 11.2 .degree.2.theta., about 13.2
.degree.2.theta., about 13.5 .degree.2.theta., about 14.2
.degree.2.theta., about 17.4 .degree.2.theta., about 19.4
.degree.2.theta., about 20.5 .degree.2.theta., about 22.8
.degree.2.theta., about 25.2 .degree.2.theta., and about 25.6
.degree.2.theta. (.+-.0.2.degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form C can be
characterized by a PXRD peak at about 22.4 .degree.2.theta. about
4.9 .degree.2.theta., about 6.6 .degree.2.theta., about 10.7
.degree.2.theta., about 11.2 .degree.2.theta., about 13.2
.degree.2.theta., about 13.5 .degree.2.theta., about 14.2
.degree.2.theta., about 14.8 .degree.2.theta., about 17.4
.degree.2.theta., about 19.4 .degree.2.theta., about 20.5
.degree.2.theta., about 22.8 .degree.2.theta., about 25.2
.degree.2.theta., and about 25.6 .degree.2.theta.
(.+-.0.2.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by a PXRD peak at about 22.4
.degree.2.theta. about 4.9 .degree.2.theta., about 6.6
.degree.2.theta., about 10.7 .degree.2.theta., about 11.2
.degree.2.theta., about 13.2 .degree.2.theta., about 13.5
.degree.2.theta., about 14.2 .degree.2.theta., about 14.8
.degree.2.theta., about 16.5 .degree.2.theta., about 17.4
.degree.2.theta., about 19.4 .degree.2.theta., about 20.5
.degree.2.theta., about 22.8 .degree.2.theta., about 25.2
.degree.2.theta., and about 25.6 .degree.2.theta.
(.+-.0.2.degree.2.theta.; .+-.0.1 .degree.2.theta.; or 0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by a PXRD peak at about 22.4
.degree.2.theta. about 4.9 .degree.2.theta., about 6.6
.degree.2.theta., about 10.7 .degree.2.theta., about 11.2
.degree.2.theta., about 13.2 .degree.2.theta., about 13.5
.degree.2.theta., about 14.2 .degree.2.theta., about 14.8
.degree.2.theta., about 16.5 .degree.2.theta., about 16.7
.degree.2.theta., about 17.4 .degree.2.theta., about 19.4
.degree.2.theta., about 20.5 .degree.2.theta., about 22.8
.degree.2.theta., about 25.2 .degree.2.theta., and about 25.6
.degree.2.theta. (.+-.0.2.degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form C can be
characterized by a PXRD peak at about 22.4 .degree.2.theta. about
4.9 .degree.2.theta., about 6.6 .degree.2.theta., about 10.7
.degree.2.theta., about 11.2 .degree.2.theta., about 13.2
.degree.2.theta., about 13.5 .degree.2.theta., about 14.2
.degree.2.theta., about 14.8 .degree.2.theta., about 16.5
.degree.2.theta., about 16.7 .degree.2.theta., about 17.4
.degree.2.theta., about 18.5 .degree.2.theta., about 19.4
.degree.2.theta., about 20.5 .degree.2.theta., about 22.8
.degree.2.theta., about 25.2 .degree.2.theta., and about 25.6
.degree.2.theta. (.+-.0.2.degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form C can be
characterized by a PXRD peak at about 22.4 .degree.2.theta. about
4.9 .degree.2.theta., about 6.6 .degree.2.theta., about 10.7
.degree.2.theta., about 11.2 .degree.2.theta., about 13.2
.degree.2.theta., about 13.5 .degree.2.theta., about 14.2
.degree.2.theta., about 14.8 .degree.2.theta., about 16.5
.degree.2.theta., about 16.7 .degree.2.theta., about 17.4
.degree.2.theta., about 18.5 .degree.2.theta., about 19.0
.degree.2.theta., about 19.4 .degree.2.theta., about 20.5
.degree.2.theta., about 22.8 .degree.2.theta., about 25.2
.degree.2.theta., and about 25.6 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by a PXRD peak at about 22.4
.degree.2.theta. about 4.9 .degree.2.theta., about 6.6
.degree.2.theta., about 10.7 .degree.2.theta., about 11.2
.degree.2.theta., about 13.2 .degree.2.theta., about 13.5
.degree.2.theta., about 14.2 .degree.2.theta., about 14.8
.degree.2.theta., about 16.5 .degree.2.theta., about 16.7
.degree.2.theta., about 17.4 .degree.2.theta., about 18.5
.degree.2.theta., about 19.0 .degree.2.theta., about 19.4
.degree.2.theta., about 19.7 .degree.2.theta., about 20.5
.degree.2.theta., about 22.8 .degree.2.theta., about 25.2
.degree.2.theta., and about 25.6 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by a PXRD peak at about 22.4
.degree.2.theta. about 4.9 .degree.2.theta., about 6.6
.degree.2.theta., about 10.7 .degree.2.theta., about 11.2
.degree.2.theta., about 13.2 .degree.2.theta., about 13.5
.degree.2.theta., about 14.2 .degree.2.theta., about 14.8
.degree.2.theta., about 16.5 .degree.2.theta., about 16.7
.degree.2.theta., about 17.4 .degree.2.theta., about 18.5
.degree.2.theta., about 19.0 .degree.2.theta., about 19.4
.degree.2.theta., about 19.7 .degree.2.theta., about 20.3
.degree.2.theta., about 20.5 .degree.2.theta., about 22.8
.degree.2.theta., about 25.2 .degree.2.theta., and about 25.6
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form C can be
characterized by a PXRD peak at about 22.4 .degree.2.theta. about
4.9 .degree.2.theta., about 6.6 .degree.2.theta., about 10.7
.degree.2.theta., about 11.2 .degree.2.theta., about 13.2
.degree.2.theta., about 13.5 .degree.2.theta., about 14.2
.degree.2.theta., about 14.8 .degree.2.theta., about 16.5
.degree.2.theta., about 16.7 .degree.2.theta., about 17.4
.degree.2.theta., about 18.5 .degree.2.theta., about 19.0
.degree.2.theta., about 19.4 .degree.2.theta., about 19.7
.degree.2.theta., about 20.3 .degree.2.theta., about 20.5
.degree.2.theta., about 21.0 .degree.2.theta., about 22.8
.degree.2.theta., about 25.2 .degree.2.theta., and about 25.6
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form C can be
characterized by a PXRD peak at about 22.4 .degree.2.theta. about
4.9 .degree.2.theta., about 6.6 .degree.2.theta., about 10.7
.degree.2.theta., about 11.2 .degree.2.theta., about 13.2
.degree.2.theta., about 13.5 .degree.2.theta., about 14.2
.degree.2.theta., about 14.8 .degree.2.theta., about 16.5
.degree.2.theta., about 16.7 .degree.2.theta., about 17.4
.degree.2.theta., about 18.5 .degree.2.theta., about 19.0
.degree.2.theta., about 19.4 .degree.2.theta., about 19.7
.degree.2.theta., about 20.3 .degree.2.theta., about 20.5
.degree.2.theta., about 21.0 .degree.2.theta., about 22.8
.degree.2.theta., about 25.2 .degree.2.theta., about 25.4
.degree.2.theta., and about 25.6 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form C can be characterized by a PXRD peak at about 22.4
.degree.2.theta. about 4.9 .degree.2.theta., about 6.6
.degree.2.theta., about 10.7 .degree.2.theta., about 11.2
.degree.2.theta., about 13.2 .degree.2.theta., about 13.5
.degree.2.theta., about 14.2 .degree.2.theta., about 14.8
.degree.2.theta., about 16.5 .degree.2.theta., about 16.7
.degree.2.theta., about 17.4 .degree.2.theta., about 18.5
.degree.2.theta., about 19.0 .degree.2.theta., about 19.4
.degree.2.theta., about 19.7 .degree.2.theta., about 20.3
.degree.2.theta., about 20.5 .degree.2.theta., about 21.0
.degree.2.theta., about 22.8 .degree.2.theta., about 25.2
.degree.2.theta., about 25.4 .degree.2.theta., about 25.6
.degree.2.theta., and about 26.7 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0140] Accordingly, in some embodiments, Form C can be
characterized by one, two, three, four, five, six, seven, eight,
nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen,
seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two,
twenty-three or twenty-four PXRD peaks selected from about 4.9,
6.6, 10.7, 11.2, 13.2, 13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5,
19.0, 19.4, 19.7, 20.3, 20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6,
and 26.7 .degree.2.theta. (Cu K.alpha.1 radiation). In some
embodiments, Form C can be characterized by one PXRD peak selected
from about 4.9, 6.6, 10.7, 11.2, 13.2, 13.5, 14.2, 14.8, 16.5,
16.7, 17.4, 18.5, 19.0, 19.4, 19.7, 20.3, 20.5, 21.0, 22.8, 22.4,
25.2, 25.4, 25.6, and 26.7 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form C can be characterized by two PXRD peaks selected from about
4.9, 6.6, 10.7, 11.2, 13.2, 13.5, 14.2, 14.8, 16.5, 16.7, 17.4,
18.5, 19.0, 19.4, 19.7, 20.3, 20.5, 21.0, 22.8, 22.4, 25.2, 25.4,
25.6, and 26.7 .degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form C can be characterized by
three PXRD peaks selected from about 4.9, 6.6, 10.7, 11.2, 13.2,
13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5, 19.0, 19.4, 19.7, 20.3,
20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6, and 26.7 .degree.2.theta.
(.+-.0.2 .degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form C can be characterized by four PXRD peaks selected from about
4.9, 6.6, 10.7, 11.2, 13.2, 13.5, 14.2, 14.8, 16.5, 16.7, 17.4,
18.5, 19.0, 19.4, 19.7, 20.3, 20.5, 21.0, 22.8, 22.4, 25.2, 25.4,
25.6, and 26.7 .degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form C can be characterized by
five PXRD peaks selected from about 4.9, 6.6, 10.7, 11.2, 13.2,
13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5, 19.0, 19.4, 19.7, 20.3,
20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6, and 26.7 .degree.2.theta.
(.+-.0.2 .degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form C can be characterized by six PXRD peaks selected from about
4.9, 6.6, 10.7, 11.2, 13.2, 13.5, 14.2, 14.8, 16.5, 16.7, 17.4,
18.5, 19.0, 19.4, 19.7, 20.3, 20.5, 21.0, 22.8, 22.4, 25.2, 25.4,
25.6, and 26.7 .degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form C can be characterized by
seven PXRD peaks selected from about 4.9, 6.6, 10.7, 11.2, 13.2,
13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5, 19.0, 19.4, 19.7, 20.3,
20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6, and 26.7 .degree.2.theta.
(.+-.0.2 .degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form C can be characterized by eight PXRD peaks selected from about
4.9, 6.6, 10.7, 11.2, 13.2, 13.5, 14.2, 14.8, 16.5, 16.7, 17.4,
18.5, 19.0, 19.4, 19.7, 20.3, 20.5, 21.0, 22.8, 22.4, 25.2, 25.4,
25.6, and 26.7 .degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form C can be characterized by
nine PXRD peaks selected from about 4.9, 6.6, 10.7, 11.2, 13.2,
13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5, 19.0, 19.4, 19.7, 20.3,
20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6, and 26.7 .degree.2.theta.
(.+-.0.2 .degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form C can be characterized by ten PXRD peaks selected from about
4.9, 6.6, 10.7, 11.2, 13.2, 13.5, 14.2, 14.8, 16.5, 16.7, 17.4,
18.5, 19.0, 19.4, 19.7, 20.3, 20.5, 21.0, 22.8, 22.4, 25.2, 25.4,
25.6, and 26.7 .degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form C can be characterized by
eleven PXRD peaks selected from about 4.9, 6.6, 10.7, 11.2, 13.2,
13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5, 19.0, 19.4, 19.7, 20.3,
20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6, and 26.7 .degree.2.theta.
(.+-.0.2 .degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form C can be characterized by twelve PXRD peaks selected from
about 4.9, 6.6, 10.7, 11.2, 13.2, 13.5, 14.2, 14.8, 16.5, 16.7,
17.4, 18.5, 19.0, 19.4, 19.7, 20.3, 20.5, 21.0, 22.8, 22.4, 25.2,
25.4, 25.6, and 26.7 .degree.2.theta. (.+-.0.2 .degree.2.theta.;
.+-.0.1 .degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form C can be characterized by
thirteen PXRD peaks selected from about 4.9, 6.6, 10.7, 11.2, 13.2,
13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5, 19.0, 19.4, 19.7, 20.3,
20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6, and 26.7 .degree.2.theta.
(.+-.0.2 .degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form C can be characterized by fourteen PXRD peaks selected from
about 4.9, 6.6, 10.7, 11.2, 13.2, 13.5, 14.2, 14.8, 16.5, 16.7,
17.4, 18.5, 19.0, 19.4, 19.7, 20.3, 20.5, 21.0, 22.8, 22.4, 25.2,
25.4, 25.6, and 26.7 .degree.2.theta. (.+-.0.2 .degree.2.theta.;
.+-.0.1 .degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form C can be characterized by
fifteen PXRD peaks selected from about 4.9, 6.6, 10.7, 11.2, 13.2,
13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5, 19.0, 19.4, 19.7, 20.3,
20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6, and 26.7 .degree.2.theta.
(.+-.0.2 .degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form C can be characterized by sixteen PXRD peaks selected from
about 4.9, 6.6, 10.7, 11.2, 13.2, 13.5, 14.2, 14.8, 16.5, 16.7,
17.4, 18.5, 19.0, 19.4, 19.7, 20.3, 20.5, 21.0, 22.8, 22.4, 25.2,
25.4, 25.6, and 26.7 .degree.2.theta. (.+-.0.2 .degree.2.theta.;
.+-.0.1 .degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form C can be characterized by
seventeen PXRD peaks selected from about 4.9, 6.6, 10.7, 11.2,
13.2, 13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5, 19.0, 19.4, 19.7,
20.3, 20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6, and 26.7
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form C can be characterized by
eighteen PXRD peaks selected from about 4.9, 6.6, 10.7, 11.2, 13.2,
13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5, 19.0, 19.4, 19.7, 20.3,
20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6, and 26.7 .degree.2.theta.
(.+-.0.2 .degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form C can be characterized by nineteen PXRD peaks selected from
about 4.9, 6.6, 10.7, 11.2, 13.2, 13.5, 14.2, 14.8, 16.5, 16.7,
17.4, 18.5, 19.0, 19.4, 19.7, 20.3, 20.5, 21.0, 22.8, 22.4, 25.2,
25.4, 25.6, and 26.7 .degree.2.theta. (.+-.0.2 .degree.2.theta.;
.+-.0.1 .degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form C can be characterized by
twenty PXRD peaks selected from about 4.9, 6.6, 10.7, 11.2, 13.2,
13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5, 19.0, 19.4, 19.7, 20.3,
20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6, and 26.7 .degree.2.theta.
(.+-.0.2 .degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
Form C can be characterized by twenty-one PXRD peaks selected from
about 4.9, 6.6, 10.7, 11.2, 13.2, 13.5, 14.2, 14.8, 16.5, 16.7,
17.4, 18.5, 19.0, 19.4, 19.7, 20.3, 20.5, 21.0, 22.8, 22.4, 25.2,
25.4, 25.6, and 26.7 .degree.2.theta. (.+-.0.2 .degree.2.theta.;
.+-.0.1 .degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form C can be characterized by
twenty-two PXRD peaks selected from about 4.9, 6.6, 10.7, 11.2,
13.2, 13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5, 19.0, 19.4, 19.7,
20.3, 20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6, and 26.7
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form C can be characterized by
twenty-three PXRD peaks selected from about 4.9, 6.6, 10.7, 11.2,
13.2, 13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5, 19.0, 19.4, 19.7,
20.3, 20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6, and 26.7
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, Form C can be characterized by
twenty-four PXRD peaks selected from about 4.9, 6.6, 10.7, 11.2,
13.2, 13.5, 14.2, 14.8, 16.5, 16.7, 17.4, 18.5, 19.0, 19.4, 19.7,
20.3, 20.5, 21.0, 22.8, 22.4, 25.2, 25.4, 25.6, and 26.7
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
TABLE-US-00004 TABLE 4 Representative PXRD Peaks for Morphic Form C
(CuK.alpha.1 radiation) d value Angle (.degree.20) (.ANG.)
Intensity 4.9 18.17 s 6.6 13.44 m 9.8 9.06 w 10.1 8.75 w 10.7 8.25
s 11.2 7.93 m 11.6 7.61 w 12.0 7.37 w 13.2 6.70 s 13.5 6.55 m 14.0
6.34 w 14.2 6.22 m 14.6 6.06 w 14.8 5.97 m 15.3 5.80 vw 16.2 5.47
vw 16.5 5.36 m 16.7 5.30 m 17.1 5.17 w 17.4 5.10 s 17.8 4.98 w 18.5
4.79 m 19.0 4.66 m 19.4 4.57 s 19.7 4.50 m 20.0 4.43 w 20.3 4.37 m
20.5 4.32 5 20.8 4.27 w 21.0 4.22 m 21.5 4.13 w 21.6 4.10 w 21.8
4.07 w 22.1 4.03 w 22.4 3.96 vs 22.8 3.89 s 23.1 3.85 vw 23.3 3.82
w 23.7 3.75 vw 24.1 3.68 w 24.4 3.65 vw 24.5 3.63 vw 25.2 3.54 s
25.4 3.51 m 25.6 3.48 s 26.1 3.41 w 26.7 3.34 m 26.9 3.31 w 27.2
3.27 vw 27.6 3.23 w 28.1 3.17 vw 28.6 3.12 w 29.3 3.04 vw 29.7 3.00
w 30.1 2.97 vw 30.4 2.94 vw 31.1 2.88 vw 31.2 2.86 vw 31.8 2.81 w
32.0 2.79 w 32.5 2.76 vw 32.7 2.74 w 32.9 2.72 w 33.4 2.68 w 33.6
2.67 w 33.8 2.65 vw 34.2 2.62 vw 34.6 2.59 w 35.1 2.55 vw 35.4 2.53
vw 36.0 2.49 vw 37.1 2.42 vw 37.4 2.40 vw 37.7 2.38 vw 38.0 2.37 vw
38.4 2.34 vw 39.6 2.28 vw
[0141] FIG. 10 is a TG-FTIR diagram of a sample of Compound 1, Form
C. FIG. 10 was obtained using a Netzsch TG 209, over the range of
25.degree. C. to 300.degree. C. The scanning speed was 10.degree.
C. per minute. As shown in FIG. 10, Form C exhibited a mass change
of about 6.6% (e.g., about 6.62%) between about 100 and about
200.degree. C. Without wishing to be bound by theory, this is
proposed to be due to a loss of ethanol. Accordingly, in some
embodiments, morphic Form C contains about 6.6% ethanol (w/w).
Accordingly, in some embodiments, morphic Form C is characterized
by a mass loss of about 6.6% between about 100 and about
200.degree. C. (e.g., as measured by TG-FTIR).
[0142] FIG. 17 is a DSC diagram of a sample of Compound 1, Form C.
FIG. 17 was obtained using a DSC Q2000 V24.3 with a hermetically
closed gold sample pan. The heating rate was 10.degree. C. per
minute. The DSC diagram shows an insert between about 120.degree.
C. and 225.degree. C. for greater detail. As shown in FIG. 17, Form
C exhibited endotherms with peaks at about 151.degree. C. (21 J/g)
(e.g., about 151.0.degree. C. (21.01 J/g)); about 187.degree. C.
(11 J/g) (e.g., about 186.8.degree. C. (10.55 J/g)); about
223.degree. C. (7 J/g) (e.g., about 223.2.degree. C. (6.77 J/g));
and about 231.degree. C. (120 J/g) (e.g., about 231.4.degree. C.
(120.16 J/g)). Form C also exhibited exotherms with troughs at
about 190.degree. C. (4 J/g) (e.g., about 189.5.degree. C. (3.75
J/g)) and about 224.degree. C. (1 J/g) (e.g., about 224.4.degree.
C. (0.75 J/g)). Accordingly, in some embodiments, morphic Form C
exhibits DSC peaks above about 150.degree. C.
[0143] In some embodiments, Form C is characterized by a DSC
diagram exhibiting an endothermic peak at about 151.degree. C. (21
J/g) (e.g., about 151.0.degree. C. (21.01 J/g)). In some
embodiments, Form C is characterized by a DSC diagram exhibiting an
endothermic peak at about 187.degree. C. (11 J/g) (e.g., about
186.8.degree. C. (10.55 J/g)). In some embodiments, Form C is
characterized by a DSC diagram exhibiting an endothermic peak at
about 223.degree. C. (7 J/g) (e.g., about 223.2.degree. C. (6.77
J/g)). In some embodiments, Form C is characterized by a DSC
diagram exhibiting an endothermic peak at about 231.degree. C. (120
J/g) (e.g., about 231.4.degree. C. (6.77 J/g)). In some
embodiments, Form C is characterized by a DSC diagram exhibiting an
endothermic peak at about 151.0.degree. C. (21.01 J/g)); about
187.degree. C. (11 J/g) (e.g., about 186.8.degree. C. (10.55 J/g));
about 223.degree. C. (7 J/g) (e.g., about 223.2.degree. C. (6.77
J/g)); and about 231.degree. C. (120 J/g) (e.g., about
231.4.degree. C. (120.16 J/g)).
[0144] In some embodiments, Form C is characterized by a DSC
diagram exhibiting an exothermic peak at about 190.degree. C. (4
J/g) (e.g., about 189.5.degree. C. (3.75 J/g)). In some
embodiments, Form C is characterized by a DSC diagram exhibiting an
exothermic peak at about 224.degree. C. (1 J/g) (e.g., about
224.4.degree. C. (0.75 J/g)). In some embodiments, Form C is
characterized by a DSC diagram exhibiting an exothermic peak at
about 190.degree. C. (4 J/g) (e.g., about 189.5.degree. C. (3.75
J/g)) and about 224.degree. C. (1 J/g) (e.g., about 224.4.degree.
C. (0.75 J/g)).
Form D
[0145] Morphic Form D of Compound 1 was characterized as a first
substantially anhydrous morphic form of Compound 1. In some
embodiments, morphic Form D can be prepared by heating the
hemihydrate morphic Form A under a flow of dry nitrogen to about
200.degree. C.
[0146] FIG. 4 is a PXRD pattern of a sample of Compound 1, Form D
taken in transmission mode. FIG. 4 was obtained using a Stoe Stadi
P powder X-ray diffractometer using Cu K.alpha.1 radiation and
transmission geometry.
[0147] In some embodiments, morphic Form D can be characterized by
the PXRD peaks set forth below in Table 5. For example, morphic
Form D can be characterized by a PXRD peak at about 26.6
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). Form D can further be characterized by PXRD peaks at
about 10.7 .degree.2.theta., 11.5 .degree.2.theta., 12.3
.degree.2.theta., 15.4 .degree.2.theta., 18.8 .degree.2.theta.,
23.6 .degree.2.theta., and/or 26.8 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). Form D can further be
characterized by peaks at about 11.7 .degree.2.theta., 13.8
.degree.2.theta., and/or 16.4 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0148] In some embodiments, morphic Form D can be characterized by
PXRD peaks at about 10.7 .degree.2.theta., about 11.5
.degree.2.theta., and about 12.3 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form D can be characterized by PXRD peaks at about 11.5
.degree.2.theta., about 12.3 .degree.2.theta., and about 15.4
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form D can be
characterized by PXRD peaks at about 12.3 .degree.2.theta., about
15.4 .degree.2.theta., and about 18.8 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form D can be characterized by PXRD peaks at about 15.4
.degree.2.theta., about 18.8 .degree.2.theta., and about 23.6
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form D can be
characterized by PXRD peaks at about 18.8 .degree.2.theta., about
23.6 .degree.2.theta., and about 26.6 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form D can be characterized by PXRD peaks at about 23.6
.degree.2.theta., about 26.6 .degree.2.theta., and about 26.8
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0149] In some embodiments, morphic Form D can be characterized by
PXRD peaks at about 26.6 .degree.2.theta. and about 10.7
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form D can be
characterized by PXRD peaks at about 26.6 .degree.2.theta., about
10.7 .degree.2.theta. and about 11.5 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or 0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form D can be characterized by PXRD peaks at about 26.6
.degree.2.theta., about 10.7 .degree.2.theta., about 11.5
.degree.2.theta., and about 12.3 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form D can be characterized by PXRD peaks at about 26.6
.degree.2.theta., about 10.7 .degree.2.theta., about 11.5
.degree.2.theta., about 12.3 .degree.2.theta., and about 15.4
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form D can be
characterized by PXRD peaks at about 26.6 .degree.2.theta., about
10.7 .degree.2.theta., about 11.5 .degree.2.theta., about 12.3
.degree.2.theta., about 15.4 .degree.2.theta., and about 18.8
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form D can be
characterized by PXRD peaks at about 26.6 .degree.2.theta., about
10.7 .degree.2.theta., about 11.5 .degree.2.theta., about 12.3
.degree.2.theta., about 15.4 .degree.2.theta., about 18.8
.degree.2.theta., and about 23.6 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form D can be characterized by PXRD peaks at about 26.6
.degree.2.theta., about 10.7 .degree.2.theta., about 11.5
.degree.2.theta., about 12.3 .degree.2.theta., about 15.4
.degree.2.theta., about 18.8 .degree.2.theta., about 23.6
.degree.2.theta., and about 26.8 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0150] In some embodiments, morphic Form D can be characterized by
PXRD peaks at about 26.6 .degree.2.theta., about 10.7
.degree.2.theta., about 11.5 .degree.2.theta., about 11.7
.degree.2.theta., about 12.3 .degree.2.theta., about 15.4
.degree.2.theta., about 18.8 .degree.2.theta., about 23.6
.degree.2.theta., and about 26.8 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form D can be characterized by PXRD peaks at about 26.6
.degree.2.theta., about 10.7 .degree.2.theta., about 11.5
.degree.2.theta., about 11.7 .degree.2.theta., about 12.3
.degree.2.theta., about 13.8 .degree.2.theta., about 15.4
.degree.2.theta., about 18.8 .degree.2.theta., about 23.6
.degree.2.theta., and about 26.8 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form D can be characterized by PXRD peaks at about 26.6
.degree.2.theta., about 10.7 .degree.2.theta., about 11.5
.degree.2.theta., about 11.7 .degree.2.theta., about 12.3
.degree.2.theta., about 13.8 .degree.2.theta., about 15.4
.degree.2.theta., about 16.4, about 18.8 .degree.2.theta., about
23.6 .degree.2.theta., and about 26.8 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0151] Accordingly, in some embodiments, morphic Form D can be
characterized by one, two, three, four, five, six, seven, eight,
nine, ten, or eleven PXRD peaks selected from the group consisting
of about 10.7 .degree.2.theta., 11.5 .degree.2.theta., 11.7
.degree.2.theta., 12.3 .degree.2.theta., 13.8 .degree.2.theta.,
15.4 .degree.2.theta., 16.4 .degree.2.theta., 18.8
.degree.2.theta., 23.6 .degree.2.theta., 26.6 .degree.2.theta., and
26.8 .degree.2.theta. (Cu K.alpha.1 radiation). In some
embodiments, morphic Form D can be characterized by one, PXRD peak
selected from the group consisting of about 10.7 .degree.2.theta.,
11.5 .degree.2.theta., 11.7 .degree.2.theta., 12.3
.degree.2.theta., 13.8 .degree.2.theta., 15.4 .degree.2.theta.,
16.4 .degree.2.theta., 18.8 .degree.2.theta., 23.6
.degree.2.theta., 26.6 .degree.2.theta., and 26.8 .degree.2.theta.
(Cu K.alpha.1 radiation). In some embodiments, morphic Form D can
be characterized by two PXRD peaks selected from the group
consisting of about 10.7 .degree.2.theta., 11.5 .degree.2.theta.,
11.7 .degree.2.theta., 12.3 .degree.2.theta., 13.8
.degree.2.theta., 15.4 .degree.2.theta., 16.4 .degree.2.theta.,
18.8 .degree.2.theta., 23.6 .degree.2.theta., 26.6
.degree.2.theta., and 26.8 .degree.2.theta. (Cu K.alpha.1
radiation). In some embodiments, morphic Form D can be
characterized by three PXRD peaks selected from the group
consisting of about 10.7 .degree.2.theta., 11.5 .degree.2.theta.,
11.7 .degree.2.theta., 12.3 .degree.2.theta., 13.8
.degree.2.theta., 15.4 .degree.2.theta., 16.4 .degree.2.theta.,
18.8 .degree.2.theta., 23.6 .degree.2.theta., 26.6
.degree.2.theta., and 26.8 .degree.2.theta. (Cu K.alpha.1
radiation). In some embodiments, morphic Form D can be
characterized by four PXRD peaks selected from the group consisting
of about 10.7 .degree.2.theta., 11.5 .degree.2.theta., 11.7
.degree.2.theta., 12.3 .degree.2.theta., 13.8 .degree.2.theta.,
15.4 .degree.2.theta., 16.4 .degree.2.theta., 18.8
.degree.2.theta., 23.6 .degree.2.theta., 26.6 .degree.2.theta., and
26.8 .degree.2.theta. (Cu K.alpha.1 radiation). In some
embodiments, morphic Form D can be characterized by five PXRD peaks
selected from the group consisting of about 10.7 .degree.2.theta.,
11.5 .degree.2.theta., 11.7 .degree.2.theta., 12.3
.degree.2.theta., 13.8 .degree.2.theta., 15.4 .degree.2.theta.,
16.4 .degree.2.theta., 18.8 .degree.2.theta., 23.6
.degree.2.theta., 26.6 .degree.2.theta., and 26.8 .degree.2.theta.
(Cu K.alpha.1 radiation). In some embodiments, morphic Form D can
be characterized by six PXRD peaks selected from the group
consisting of about 10.7 .degree.2.theta., 11.5 .degree.2.theta.,
11.7 .degree.2.theta., 12.3 .degree.2.theta., 13.8
.degree.2.theta., 15.4 .degree.2.theta., 16.4 .degree.2.theta.,
18.8 .degree.2.theta., 23.6 .degree.2.theta., 26.6
.degree.2.theta., and 26.8 .degree.2.theta. (Cu K.alpha.1
radiation). In some embodiments, morphic Form D can be
characterized by seven PXRD peaks selected from the group
consisting of about 10.7 .degree.2.theta., 11.5 .degree.2.theta.,
11.7 .degree.2.theta., 12.3 .degree.2.theta., 13.8
.degree.2.theta., 15.4 .degree.2.theta., 16.4 .degree.2.theta.,
18.8 .degree.2.theta., 23.6 .degree.2.theta., 26.6
.degree.2.theta., and 26.8 .degree.2.theta. (Cu K.alpha.1
radiation). In some embodiments, morphic Form D can be
characterized by eight PXRD peaks selected from the group
consisting of about 10.7 .degree.2.theta., 11.5 .degree.2.theta.,
11.7 .degree.2.theta., 12.3 .degree.2.theta., 13.8
.degree.2.theta., 15.4 .degree.2.theta., 16.4 .degree.2.theta.,
18.8 .degree.2.theta., 23.6 .degree.2.theta., 26.6
.degree.2.theta., and 26.8 .degree.2.theta. (Cu K.alpha.1
radiation). In some embodiments, morphic Form D can be
characterized by nine PXRD peaks selected from the group consisting
of about 10.7 .degree.2.theta., 11.5 .degree.2.theta., 11.7
.degree.2.theta., 12.3 .degree.2.theta., 13.8 .degree.2.theta.,
15.4 .degree.2.theta., 16.4 .degree.2.theta., 18.8
.degree.2.theta., 23.6 .degree.2.theta., 26.6 .degree.2.theta., and
26.8 .degree.2.theta. (Cu K.alpha.1 radiation). In some
embodiments, morphic Form D can be characterized by ten PXRD peaks
selected from the group consisting of about 10.7 .degree.2.theta.,
11.5 .degree.2.theta. 11.7 .degree.2.theta., 12.3 .degree.2.theta.,
13.8 .degree.2.theta., 15.4 .degree.2.theta., 16.4
.degree.2.theta., 18.8 .degree.2.theta., 23.6 .degree.2.theta.,
26.6 .degree.2.theta. and 26.8 .degree.2.theta. (Cu K.alpha.1
radiation). In some embodiments, morphic Form D can be
characterized by eleven PXRD peaks selected from the group
consisting of about 10.7 .degree.2.theta., 11.5 .degree.2.theta.,
11.7 .degree.2.theta., 12.3 .degree.2.theta., 13.8 .degree.2.theta.
15.4 .degree.2.theta., 16.4 .degree.2.theta., 18.8
.degree.2.theta., 23.6 .degree.2.theta., 26.6 .degree.2.theta., and
26.8 .degree.2.theta. (Cu K.alpha.1 radiation).
TABLE-US-00005 TABLE 5 Representative PXRD Peaks for Morphic Form D
(Cu K.alpha.1 radiation) Angle (.degree.20) d value (.ANG.)
Intensity 8.9 9.94 vw 10.7 8.29 s 11.5 7.67 s 11.7 7.54 m 12.3 7.17
s 13.8 6.41 m 15.4 5.76 s 15.9 5.55 w 16.4 5.40 m 16.8 5.27 vw 17.4
5.08 w 17.8 4.97 w 18.1 4.91 vw 18.6 4.78 w 18.8 4.72 s 20.4 4.34 w
21.1 4.22 vw 21.4 4.14 w 22.7 3.92 w 23.2 3.84 vw 23.6 3.77 s 24.1
3.70 w 24.3 3.66 vw 25.2 3.53 vw 25.6 3.48 vw 25.8 3.45 vw 26.6
3.35 vs 26.8 3.32 s 27.0 3.30 w 27.8 3.20 w 28.1 3.18 vw 29.4 3.04
w 29.9 2.99 vw 30.4 2.94 vw 30.7 2.91 vw 31.0 2.88 w 31.9 2.81 vw
32.2 2.78 vw 32.4 2.76 vw 33.1 2.70 w 33.5 2.68 vw 33.9 2.64 vw
34.3 2.62 vw 34.8 2.58 vw 35.3 2.54 vw 35.9 2.50 w 36.4 2.46 w 37.6
2.39 vw 39.8 2.26 vw
[0152] FIG. 11 is a TG-FTIR diagram of a sample of Compound 1, Form
D. FIG. 11 was obtained using a Netzsch TG 209, over the range of
25.degree. C. to 300.degree. C. The scanning speed was 10.degree.
C. per minute. As shown in FIG. 11, Form D exhibited a mass loss of
about 0.2% (e.g., about 0.24%) between about 100.degree. C. and
about 210.degree. C. Without wishing to be bound by theory, this is
proposed to be due to a loss of water. Form D also exhibited a mass
loss of about 0.300 (e.g., about 0.34%) between about 210.degree.
C. and about 250.degree. C. Without wishing to be bound by theory,
this is proposed to be due to a loss of DMF. Accordingly, in some
embodiments, morphic Form D contains about 0.2% water (w/w). In
some embodiments, morphic Form D contains about 0.3% DMF (w/w). In
some embodiments, Form D contains less than 0.2% water. In some
embodiments, Form D is substantially anhydrous. In some
embodiments, Form D is characterized by a mass loss of about 0.3%
between about 210.degree. C. and about 250.degree. C. (e.g., as
measured by TG-FTIR). In some embodiments, Form D is characterized
by a mass loss of about 0.2% between about 100.degree. C. and about
210.degree. C. (e.g., as measured by TG-FTIR).
[0153] FIG. 18 is a DSC diagram of a sample of Compound 1, Form D.
FIG. 18 was obtained using a DSC Q2000 V24.3 with a hermetically
closed gold sample pan. The heating rate was 10.degree. C. per
minute. As shown in FIG. 18, Form D exhibited an endotherm with a
peak at about 229.degree. C. (157 J/g) (e.g., about 229.0.degree.
C. (156.93 J/g)). Accordingly, in some embodiments morphic Form D
is characterized by a DSC diagram exhibiting a peak at about
229.degree. C. (157 J/g).
[0154] FIG. 22A is a DVS diagram of a sample of Compound 1, Form D
as a function of time and the applied change in relative humidity.
Line A represents the relative weight of the sample at each
relative humidity. Line B represents the applied relative humidity
(i.e., the applied measurement program). FIG. 22B is a DVS diagram
of a sample of Compound 1, Form D as a function of the applied
relative humidity. FIG. 22A and FIG. 22B were obtained using a
Sorptions Prufsystem ProUmid system using a scan rate of 5%
relative humidity per hour at a temperature of 25.degree. C. As
shown in FIG. 22A and FIG. 22B, the relative sample weight of Form
D changed as a function of the relative humidity of the
environment. Without wishing to be bound by theory, this suggests
that Form D is hygroscopic (e.g., more hygroscopic than Form A). In
some embodiments, Form D is slightly hygroscopic.
Form E
[0155] Morphic Form E of Compound 1 was characterized as a second
substantially anhydrous morphic form of Compound 1. In some
embodiments, morphic Form E can be prepared by heating the methanol
hemisolvate morphic Form B under a flow of dry nitrogen to about
200.degree. C.
[0156] FIG. 5A is a PXRD pattern of two samples of Compound 1, Form
E taken in transmission mode. Both of the PXRD patterns in FIG. 5
were obtained using a Stoe Stadi P powder X-ray diffractometer
using Cu K.alpha.1 radiation and transmission geometry. FIG. 5B is
a PXRD pattern of Form E measured from 4 to 34
.degree.2.theta..
[0157] In some embodiments, morphic Form E can be characterized by
the PXRD peaks set forth below in Table 6. For example, morphic
Form E can be characterized by PXRD peaks at about 10.9
.degree.2.theta. and/or 26.5 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). Morphic Form E can
further be characterized by a PXRD peak at about 14.4
.degree.2.theta., 17.8 .degree.2.theta., and/or 18.5
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or 0.0 .degree.2.theta.; Cu K.alpha.1 radiation).
Morphic Form E can further be characterized by a PXRD peak at about
10.7 .degree.2.theta., 12.1 .degree.2.theta., 16.2
.degree.2.theta., 16.8 .degree.2.theta., 22.5 .degree.2.theta.,
24.5 .degree.2.theta., and/or 26.2 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0158] In some embodiments, morphic Form E can be characterized by
PXRD peaks at about 10.9 .degree.2.theta., about 14.4
.degree.2.theta., and about 17.8 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form E can be characterized by PXRD peaks at about 14.4
.degree.2.theta., about 17.8 .degree.2.theta., and about 18.5
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form E can be
characterized by PXRD peaks at about 17.8 .degree.2.theta., about
18.5 .degree.2.theta., and about 26.5 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0159] In some embodiments, morphic Form E can be characterized by
PXRD peaks at about 10.9 .degree.2.theta. and about 26.5
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form E can be
characterized by PXRD peaks at about 10.9 .degree.2.theta., about
14.4 .degree.2.theta., and about 26.5 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form E can be characterized by PXRD peaks at about 10.9
.degree.2.theta., about 14.4 .degree.2.theta., about 17.8
.degree.2.theta., and about 26.5 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form E can be characterized by PXRD peaks at about 10.9
.degree.2.theta., about 14.4 .degree.2.theta., about 17.8
.degree.2.theta., about 18.5 .degree.2.theta., and about 26.5
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0160] In some embodiments, morphic Form E can be characterized by
PXRD peaks at about 10.7 .degree.2.theta., about 10.9
.degree.2.theta., about 14.4 .degree.2.theta., about 17.8
.degree.2.theta., about 18.5 .degree.2.theta., and about 26.5
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form E can be
characterized by PXRD peaks at about 10.7 .degree.2.theta., about
10.9 .degree.2.theta., about 12.1 .degree.2.theta., about 14.4
.degree.2.theta., about 17.8 .degree.2.theta., about 18.5
.degree.2.theta., and about 26.5 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form E can be characterized by PXRD peaks at about 10.7
.degree.2.theta., about 10.9 .degree.2.theta., about 12.1
.degree.2.theta., about 14.4 .degree.2.theta., about 16.2
.degree.2.theta., about 17.8 .degree.2.theta., about 18.5
.degree.2.theta., and about 26.5 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form E can be characterized by PXRD peaks at about 10.7
.degree.2.theta., about 10.9 .degree.2.theta., about 12.1
.degree.2.theta., about 14.4 .degree.2.theta., about 16.2
.degree.2.theta., about 16.8 .degree.2.theta., about 17.8
.degree.2.theta., about 18.5 .degree.2.theta., and about 26.5
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form E can be
characterized by PXRD peaks at about 10.7 .degree.2.theta., about
10.9 .degree.2.theta., about 12.1 .degree.2.theta., about 14.4
.degree.2.theta., about 16.2 .degree.2.theta., about 16.8
.degree.2.theta., about 17.8 .degree.2.theta., about 18.5
.degree.2.theta., about 22.5 .degree.2.theta., and about 26.5
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form E can be
characterized by PXRD peaks at about 10.7 .degree.2.theta., about
10.9 .degree.2.theta., about 12.1 .degree.2.theta., about 14.4
.degree.2.theta., about 16.2 .degree.2.theta., about 16.8
.degree.2.theta., about 17.8 .degree.2.theta., about 18.5
.degree.2.theta., about 22.5 .degree.2.theta., about 24.5
.degree.2.theta., and about 26.5 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form E can be characterized by PXRD peaks at about 10.7
.degree.2.theta., about 10.9 .degree.2.theta., about 12.1
.degree.2.theta., about 14.4 .degree.2.theta., about 16.2
.degree.2.theta., about 16.8 .degree.2.theta., about 17.8
.degree.2.theta., about 18.5 .degree.2.theta., about 22.5
.degree.2.theta., about 24.5 .degree.2.theta., about 26.2
.degree.2.theta., and about 26.5 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0161] Accordingly, in some embodiments, morphic Form E can be
characterized by one, two, three, four, five, six, seven, eight,
nine, ten, eleven, or twelve PXRD peaks selected from about 10.7,
10.9, 12.1, 14.4, 16.2, 16.8, 17.8, 18.5, 22.5, 24.5, 26.2, and
26.5 .degree.2.theta. (Cu K.alpha.1 radiation). In some
embodiments, morphic Form E can be characterized by one PXRD peak
selected from about 10.7, 10.9, 12.1, 14.4, 16.2, 16.8, 17.8, 18.5,
22.5, 24.5, 26.2, and 26.5 .degree.2.theta. (Cu K.alpha.1
radiation). In some embodiments, morphic Form E can be
characterized by two PXRD peaks selected from about 10.7, 10.9,
12.1, 14.4, 16.2, 16.8, 17.8, 18.5, 22.5, 24.5, 26.2, and 26.5
.degree.2.theta. (Cu K.alpha.1 radiation). In some embodiments,
morphic Form E can be characterized by three PXRD peaks selected
from about 10.7, 10.9, 12.1, 14.4, 16.2, 16.8, 17.8, 18.5, 22.5,
24.5, 26.2, and 26.5 .degree.2.theta. (Cu K.alpha.1 radiation). In
some embodiments, morphic Form E can be characterized by four PXRD
peaks selected from about 10.7, 10.9, 12.1, 14.4, 16.2, 16.8, 17.8,
18.5, 22.5, 24.5, 26.2, and 26.5 .degree.2.theta. (Cu K.alpha.1
radiation). In some embodiments, morphic Form E can be
characterized by five PXRD peaks selected from about 10.7, 10.9,
12.1, 14.4, 16.2, 16.8, 17.8, 18.5, 22.5, 24.5, 26.2, and 26.5
.degree.2.theta. (Cu K.alpha.1 radiation). In some embodiments,
morphic Form E can be characterized by six PXRD peaks selected from
about 10.7, 10.9, 12.1, 14.4, 16.2, 16.8, 17.8, 18.5, 22.5, 24.5,
26.2, and 26.5 .degree.2.theta. (Cu K.alpha.1 radiation). In some
embodiments, morphic Form E can be characterized by seven PXRD
peaks selected from about 10.7, 10.9, 12.1, 14.4, 16.2, 16.8, 17.8,
18.5, 22.5, 24.5, 26.2, and 26.5 .degree.2.theta. (Cu K.alpha.1
radiation). In some embodiments, morphic Form E can be
characterized by eight PXRD peaks selected from about 10.7, 10.9,
12.1, 14.4, 16.2, 16.8, 17.8, 18.5, 22.5, 24.5, 26.2, and 26.5
.degree.2.theta. (Cu K.alpha. radiation). In some embodiments,
morphic Form E can be characterized by nine PXRD peaks selected
from about 10.7, 10.9, 12.1, 14.4, 16.2, 16.8, 17.8, 18.5, 22.5,
24.5, 26.2, and 26.5 .degree.2.theta. (Cu K.alpha.1 radiation). In
some embodiments, morphic Form E can be characterized by ten PXRD
peaks selected from about 10.7, 10.9, 12.1, 14.4, 16.2, 16.8, 17.8,
18.5, 22.5, 24.5, 26.2, and 26.5 .degree.2.theta. (Cu K.alpha.1
radiation). In some embodiments, morphic Form E can be
characterized by eleven PXRD peaks selected from about 10.7, 10.9,
12.1, 14.4, 16.2, 16.8, 17.8, 18.5, 22.5, 24.5, 26.2, and 26.5
.degree.2.theta. (Cu K.alpha.1 radiation). In some embodiments,
morphic Form E can be characterized by twelve PXRD peaks selected
from about 10.7, 10.9, 12.1, 14.4, 16.2, 16.8, 17.8, 18.5, 22.5,
24.5, 26.2, and 26.5 .degree.2.theta. (Cu K.alpha.1 radiation).
TABLE-US-00006 TABLE 6 Representative PXRD Peaks for Morphic Form E
(Cu K.alpha.1 radiation) Angle (.degree.2.theta.) d value (.ANG.)
Intensity 8.9 9.93 w 10.7 8.28 m 10.9 8.12 vs 12.1 7.34 m 13.3 6.63
w 13.7 6.45 vw 14.4 6.13 s 14.9 5.95 w 15.4 5.75 vw 16.2 5.47 m
16.4 5.40 w 16.8 5.28 m 17.5 5.07 vw 17.8 4.97 s 18.5 4.79 s 19.2
4.62 w 19.5 4.55 vw 20.0 4.44 w 20.4 4.34 w 21.8 4.08 w 21.9 4.06 w
22.5 3.94 m 23.0 3.87 w 23.5 3.78 w 24.2 3.67 vw 24.5 3.63 m 25.1
3.55 w 25.7 3.47 w 26.2 3.40 m 26.5 3.36 vs 26.8 3.32 w 27.7 3.22 w
27.9 3.19 w 29.5 3.03 w 30.1 2.96 vw 30.5 2.93 w 30.8 2.90 vw 31.1
2.88 w 31.5 2.83 w 32.4 2.76 vw 33.1 2.70 w 33.7 2.65 vw 34.5 2.60
vw 35.1 2.56 vw 36.0 2.50 vw 36.2 2.48 vw 36.7 2.44 vw 38.1 2.36 vw
38.3 2.35 vw 38.9 2.32 vw 39.9 2.26 vw
[0162] FIG. 12 is a TG-FTIR diagram of a sample of Compound 1, Form
E. FIG. 12 was obtained using a Netzsch TG 209, over the range of
25.degree. C. to 300.degree. C. The scanning speed was 10.degree.
C. per minute. As shown in FIG. 12, Form E shows a mass change of
about 0.4% (e.g., about 0.36%) between about 50.degree. C. and
about 215.degree. C. Without wishing to be bound by theory, this is
proposed to be due to a loss of trace water. Accordingly, in some
embodiments, morphic Form E contains about 0.4% water (w/w).
Accordingly, in some embodiments, morphic Form E is characterized
by a mass loss of about 0.4% between about 50.degree. C. and about
215.degree. C. (e.g., as measured by TG-FTIR).
[0163] FIG. 19 is a DSC diagram of a sample of Compound 1, Form E.
FIG. 19 was obtained using a DSC Q2000 V24.3 with a hermetically
closed gold sample pan. The heating rate was 10.degree. C. per
minute. As shown in FIG. 19, Form E shows an endotherm with a peak
at about 237.degree. C. (143 J/g) (e.g., about 236.5.degree. C.
(142.83 J/g)). Accordingly, in some embodiments, morphic Form E is
characterized by a DSC diagram exhibiting a DSC peak at about
237.degree. C. (143 J/g).
[0164] FIG. 23A is a DVS diagram of a sample of Compound 1, Form E
as a function of time and the applied change in relative humidity.
Line A represents the relative weight of the sample at each
relative humidity. Line B represents the applied relative humidity
(i.e., the applied measurement program). FIG. 23B is a DVS diagram
of a sample of Compound 1, Form E as a function of the applied
relative humidity. FIG. 23A and FIG. 23B were obtained using a
Sorptions Prufsystem ProUmid system using a scan rate of 5%
relative humidity per hour at a temperature of 25.degree. C.
[0165] As shown in FIG. 23A and FIG. 23B, the mass of Form E
fluctuated as a function of the relative humidity of the
environment. Without wishing to be bound by theory, this suggests
that Form E is hygroscopic (e.g., more hygroscopic than morphic
Form A). Additionally, it was found that under the conditions of
the DVS analysis, morphic Form E was transformed into Form A.
Accordingly, in some embodiments, morphic Form E can be converted
to Form A in the presence of high relative humidity, for example at
about 25.degree. C. and about 50% relative humidity or above (e.g.,
under the conditions of dynamic water vapor sorption
experiments).
Form F
[0166] Morphic Form F of Compound 1 was preliminarily characterized
as a 2-propanol solvate form of Compound 1. In some embodiments,
morphic Form F can be prepared dissolving Compound 1 in DMSO and
precipitating Compound 1 at room temperature using 2-propanol.
[0167] FIG. 6 is a PXRD pattern of a sample of Compound 1, Form F
taken in transmission mode. FIG. 6 was obtained using a Stoe Stadi
P powder X-ray diffractometer using Cu K.alpha.1 radiation and
transmission geometry.
[0168] In some embodiments, morphic Form F can be characterized by
the PXRD peaks set forth below in Table 7. For example, Form F can
be characterized by PXRD peaks at about 15.0 and/or 22.8
.degree.2.theta. (Cu K.alpha.1 radiation). Form F can further be
characterized by PXRD peaks at about 7.1 .degree.2.theta., 11.3 20,
12.9 20, 14.3 20, 17.4 20, 19.7 .degree.2.theta., and/or 23.2
.degree.2.theta. (Cu K.alpha.1 radiation). Form F can further be
characterized by PXRD peaks at about 8.4 .degree.2.theta., 13.7
.degree.2.theta., 18.7 .degree.2.theta., 19.5 .degree.2.theta.,
20.5 .degree.2.theta., 24.4 .degree.2.theta. and/or 28.9
.degree.2.theta. (Cu K.alpha.1 radiation).
[0169] In some embodiments, morphic Form F can be characterized by
PXRD peaks at about 7.1 .degree.2.theta., about 11.3
.degree.2.theta., and about 12.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F can be characterized by PXRD peaks at about 11.3
.degree.2.theta., about 12.9 .degree.2.theta., and about 14.3
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F can be
characterized by PXRD peaks at about 12.9 .degree.2.theta., about
14.3 .degree.2.theta., and about 15.0 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F can be characterized by PXRD peaks at about 14.3
.degree.2.theta., about 15.0 .degree.2.theta., and about 17.4
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F can be
characterized by PXRD peaks at about 15.0 .degree.2.theta., about
17.4 .degree.2.theta., and about 19.7 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F can be characterized by PXRD peaks at about 17.4
.degree.2.theta., about 19.7 .degree.2.theta., and about 22.8
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F can be
characterized by PXRD peaks at about 19.7 .degree.2.theta., about
22.8 .degree.2.theta., and about 23.2 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0170] In some embodiments, morphic Form F can be characterized by
PXRD peaks at about 15.0 .degree.2.theta. and about 22.8
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F can be
characterized by PXRD peaks at about 7.1 .degree.2.theta., about
15.0 .degree.2.theta. and about 22.8 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or 0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F can be characterized by PXRD peaks at about 7.1
.degree.2.theta., about 11.3 .degree.2.theta., about 15.0
.degree.2.theta. and about 22.8 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or 0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F can be characterized by PXRD peaks at about 7.1
.degree.2.theta., about 11.3 .degree.2.theta., about 12.9
.degree.2.theta., about 15.0 .degree.2.theta. and about 22.8
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F can be
characterized by PXRD peaks at about 7.1 .degree.2.theta., about
11.3 .degree.2.theta., about 12.9 .degree.2.theta., about 14.3
.degree.2.theta., about 15.0 .degree.2.theta. and about 22.8
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F can be
characterized by PXRD peaks at about 7.1 .degree.2.theta., about
11.3 .degree.2.theta., about 12.9 .degree.2.theta., about 14.3
.degree.2.theta., about 15.0 .degree.2.theta., about 17.4
.degree.2.theta., and about 22.8 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F can be characterized by PXRD peaks at about 7.1
.degree.2.theta., about 11.3 .degree.2.theta., about 12.9
.degree.2.theta., about 14.3 .degree.2.theta., about 15.0
.degree.2.theta., about 17.4 .degree.2.theta., about 19.7
.degree.2.theta., and about 22.8 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F can be characterized by PXRD peaks at about 7.1
.degree.2.theta., about 11.3 .degree.2.theta., about 12.9
.degree.2.theta., about 14.3 .degree.2.theta., about 15.0
.degree.2.theta., about 17.4 .degree.2.theta., about 19.7
.degree.2.theta., about 22.8 .degree.2.theta., and about 23.2
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0171] In some embodiments, morphic Form F can be characterized by
PXRD peaks at about 7.1 .degree.2.theta., about 8.4
.degree.2.theta., about 11.3 .degree.2.theta., about 12.9
.degree.2.theta., about 14.3 .degree.2.theta., about 15.0
.degree.2.theta., about 17.4 .degree.2.theta., about 19.7
.degree.2.theta., about 22.8 .degree.2.theta., and about 23.2
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F can be
characterized by PXRD peaks at about 7.1 .degree.2.theta., about
8.4 .degree.2.theta., about 11.3 .degree.2.theta., about 12.9
.degree.2.theta., about 13.7 .degree.2.theta., about 14.3
.degree.2.theta., about 15.0 .degree.2.theta., about 17.4
.degree.2.theta., about 19.7 .degree.2.theta., about 22.8
.degree.2.theta., and about 23.2 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F can be characterized by PXRD peaks at about 7.1
.degree.2.theta., about 8.4 .degree.2.theta., about 11.3
.degree.2.theta., about 12.9 .degree.2.theta., about 13.7
.degree.2.theta., about 14.3 .degree.2.theta., about 15.0
.degree.2.theta., about 17.4 .degree.2.theta., about 18.7
.degree.2.theta., about 19.7 .degree.2.theta., about 22.8
.degree.2.theta., and about 23.2 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F can be characterized by PXRD peaks at about 7.1
.degree.2.theta., about 8.4 .degree.2.theta., about 11.3
.degree.2.theta., about 12.9 .degree.2.theta., about 13.7
.degree.2.theta., about 14.3 .degree.2.theta., about 15.0
.degree.2.theta., about 17.4 .degree.2.theta., about 18.7
.degree.2.theta., about 19.5 .degree.2.theta., about 19.7
.degree.2.theta., about 22.8 .degree.2.theta., and about 23.2
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F can be
characterized by PXRD peaks at about 7.1 .degree.2.theta., about
8.4 .degree.2.theta., about 11.3 .degree.2.theta., about 12.9
.degree.2.theta., about 13.7 .degree.2.theta., about 14.3
.degree.2.theta., about 15.0 .degree.2.theta., about 17.4
.degree.2.theta., about 18.7 .degree.2.theta., about 19.5
.degree.2.theta., about 19.7 .degree.2.theta., about 20.5
.degree.2.theta., about 22.8 .degree.2.theta., and about 23.2
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F can be
characterized by PXRD peaks at about 7.1 .degree.2.theta., about
8.4 .degree.2.theta., about 11.3 .degree.2.theta., about 12.9
.degree.2.theta., about 13.7 .degree.2.theta., about 14.3
.degree.2.theta., about 15.0 .degree.2.theta., about 17.4
.degree.2.theta., about 18.7 .degree.2.theta., about 19.5
.degree.2.theta., about 19.7 .degree.2.theta., about 20.5
.degree.2.theta., about 22.8 .degree.2.theta., about 23.2
.degree.2.theta., and about 24.4 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F can be characterized by PXRD peaks at about 7.1
.degree.2.theta., about 8.4 .degree.2.theta., about 11.3
.degree.2.theta., about 12.9 .degree.2.theta., about 13.7
.degree.2.theta., about 14.3 .degree.2.theta., about 15.0
.degree.2.theta., about 17.4 .degree.2.theta., about 18.7
.degree.2.theta., about 19.5 .degree.2.theta., about 19.7
.degree.2.theta., about 20.5 .degree.2.theta., about 22.8
.degree.2.theta., about 23.2 .degree.2.theta., about 24.4
.degree.2.theta., and about 28.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0172] Accordingly, in some embodiments, morphic Form F is
characterized by one, two, three, four, five, six, seven, eight,
nine, ten, eleven, twelve, thirteen, fourteen, fifteen or sixteen
peaks selected from about 7.1, 8.4, 11.3, 12.9, 13.7, 14.3, 15.0,
17.4, 18.7, 19.5, 19.7, 20.5, 22.8, 23.2, 24.4, and 28.9
.degree.2.theta. (Cu K.alpha.1 radiation).
[0173] In some embodiments, morphic Form F is characterized by one
peak selected from about 7.1 .degree.2.theta., 8.4
.degree.2.theta., 11.3 .degree.2.theta., 12.9 .degree.2.theta.,
13.7 .degree.2.theta., 14.3 .degree.2.theta., 15.0
.degree.2.theta., 17.4 .degree.2.theta., 18.7 .degree.2.theta.,
19.5 .degree.2.theta., 19.7 .degree.2.theta., 20.5
.degree.2.theta., 22.8 .degree.2.theta., 23.2 .degree.2.theta.,
24.4 .degree.2.theta., and 28.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or 0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F is characterized by two peaks selected from about
7.1 .degree.2.theta., 8.4 .degree.2.theta., 11.3 .degree.2.theta.,
12.9 .degree.2.theta., 13.7 .degree.2.theta., 14.3
.degree.2.theta., 15.0 .degree.2.theta., 17.4 .degree.2.theta.,
18.7 .degree.2.theta., 19.5 .degree.2.theta., 19.7
.degree.2.theta., 20.5 .degree.2.theta., 22.8 .degree.2.theta.,
23.2 .degree.2.theta., 24.4 .degree.2.theta., and 28.9
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F is characterized by
three peaks selected from about 7.1 .degree.2.theta., 8.4
.degree.2.theta., 11.3 .degree.2.theta., 12.9 .degree.2.theta.,
13.7 .degree.2.theta., 14.3 .degree.2.theta., 15.0
.degree.2.theta., 17.4 .degree.2.theta., 18.7 .degree.2.theta.,
19.5 .degree.2.theta., 19.7 .degree.2.theta., 20.5
.degree.2.theta., 22.8 .degree.2.theta., 23.2 .degree.2.theta.,
24.4 .degree.2.theta., and 28.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F is characterized by four peaks selected from about
7.1 .degree.2.theta., 8.4 .degree.2.theta., 11.3 .degree.2.theta.,
12.9 .degree.2.theta., 13.7 .degree.2.theta., 14.3
.degree.2.theta., 15.0 .degree.2.theta., 17.4 .degree.2.theta.,
18.7 .degree.2.theta., 19.5 .degree.2.theta., 19.7
.degree.2.theta., 20.5 .degree.2.theta., 22.8 .degree.2.theta.,
23.2 .degree.2.theta., 24.4 .degree.2.theta., and 28.9
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F is characterized by
five peaks selected from about 7.1 .degree.2.theta., 8.4
.degree.2.theta., 11.3 .degree.2.theta., 12.9 .degree.2.theta.,
13.7 .degree.2.theta., 14.3 .degree.2.theta., 15.0
.degree.2.theta., 17.4 .degree.2.theta., 18.7 .degree.2.theta.,
19.5 .degree.2.theta., 19.7 .degree.2.theta., 20.5
.degree.2.theta., 22.8 .degree.2.theta., 23.2 .degree.2.theta.,
24.4 .degree.2.theta., and 28.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F is characterized by six peaks selected from about
7.1 .degree.2.theta., 8.4 .degree.2.theta., 11.3 .degree.2.theta.,
12.9 .degree.2.theta., 13.7 .degree.2.theta., 14.3
.degree.2.theta., 15.0 .degree.2.theta., 17.4 .degree.2.theta.,
18.7 .degree.2.theta., 19.5 .degree.2.theta., 19.7
.degree.2.theta., 20.5 .degree.2.theta., 22.8 .degree.2.theta.,
23.2 .degree.2.theta., 24.4 .degree.2.theta., and 28.9
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F is characterized by
seven peaks selected from about 7.1 .degree.2.theta., 8.4
.degree.2.theta., 11.3 .degree.2.theta., 12.9 .degree.2.theta.,
13.7 .degree.2.theta., 14.3 .degree.2.theta., 15.0
.degree.2.theta., 17.4 .degree.2.theta., 18.7 .degree.2.theta.,
19.5 .degree.2.theta., 19.7 .degree.2.theta., 20.5
.degree.2.theta., 22.8 .degree.2.theta., 23.2 .degree.2.theta.,
24.4 .degree.2.theta., and 28.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F is characterized by eight peaks selected from about
7.1 .degree.2.theta., 8.4 .degree.2.theta., 11.3 .degree.2.theta.,
12.9 .degree.2.theta., 13.7 .degree.2.theta., 14.3
.degree.2.theta., 15.0 .degree.2.theta., 17.4 .degree.2.theta.,
18.7 .degree.2.theta., 19.5 .degree.2.theta., 19.7
.degree.2.theta., 20.5 .degree.2.theta., 22.8 .degree.2.theta.,
23.2 .degree.2.theta., 24.4 .degree.2.theta., and 28.9
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or 0.0 .degree.2.theta.; Cu K.alpha.1 radiation).
In some embodiments, morphic Form F is characterized by nine peaks
selected from about 7.1 .degree.2.theta., 8.4 .degree.2.theta.,
11.3 .degree.2.theta., 12.9 .degree.2.theta., 13.7
.degree.2.theta., 14.3 .degree.2.theta., 15.0 .degree.2.theta.,
17.4 .degree.2.theta., 18.7 .degree.2.theta., 19.5
.degree.2.theta., 19.7 .degree.2.theta., 20.5 .degree.2.theta.,
22.8 .degree.2.theta., 23.2 .degree.2.theta., 24.4
.degree.2.theta., and 28.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F is characterized by ten peaks selected from about
7.1 .degree.2.theta., 8.4 .degree.2.theta., 11.3 .degree.2.theta.,
12.9 .degree.2.theta., 13.7 .degree.2.theta., 14.3
.degree.2.theta., 15.0 .degree.2.theta., 17.4 .degree.2.theta.,
18.7 .degree.2.theta., 19.5 .degree.2.theta., 19.7
.degree.2.theta., 20.5 .degree.2.theta., 22.8 .degree.2.theta.,
23.2 .degree.2.theta., 24.4 .degree.2.theta., and 28.9
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or 0.0 .degree.2.theta.; Cu K.alpha.1 radiation).
In some embodiments, morphic Form F is characterized by eleven
peaks selected from about 7.1 .degree.2.theta., 8.4
.degree.2.theta., 11.3 .degree.2.theta., 12.9 .degree.2.theta.,
13.7 .degree.2.theta., 14.3 .degree.2.theta., 15.0
.degree.2.theta., 17.4 .degree.2.theta., 18.7 .degree.2.theta.,
19.5 .degree.2.theta., 19.7 .degree.2.theta., 20.5
.degree.2.theta., 22.8 .degree.2.theta., 23.2 .degree.2.theta.,
24.4 .degree.2.theta., and 28.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F is characterized by twelve peaks selected from about
7.1 .degree.2.theta., 8.4 .degree.2.theta., 11.3 .degree.2.theta.,
12.9 .degree.2.theta., 13.7 .degree.2.theta., 14.3
.degree.2.theta., 15.0 .degree.2.theta., 17.4 .degree.2.theta.,
18.7 .degree.2.theta., 19.5 .degree.2.theta., 19.7
.degree.2.theta., 20.5 .degree.2.theta., 22.8 .degree.2.theta.,
23.2 .degree.2.theta., 24.4 .degree.2.theta., and 28.9
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F is characterized by
thirteen peaks selected from about 7.1 .degree.2.theta., 8.4
.degree.2.theta., 11.3 .degree.2.theta., 12.9 .degree.2.theta.,
13.7 .degree.2.theta., 14.3 .degree.2.theta., 15.0
.degree.2.theta., 17.4 .degree.2.theta., 18.7 .degree.2.theta.,
19.5 .degree.2.theta., 19.7 .degree.2.theta., 20.5
.degree.2.theta., 22.8 .degree.2.theta., 23.2 .degree.2.theta.,
24.4 .degree.2.theta., and 28.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or 0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F is characterized by fourteen peaks selected from
about 7.1 .degree.2.theta., 8.4 .degree.2.theta., 11.3
.degree.2.theta., 12.9 .degree.2.theta., 13.7 .degree.2.theta.,
14.3 .degree.2.theta., 15.0 .degree.2.theta., 17.4
.degree.2.theta., 18.7 .degree.2.theta., 19.5 .degree.2.theta.,
19.7 .degree.2.theta., 20.5 .degree.2.theta., 22.8
.degree.2.theta., 23.2 .degree.2.theta., 24.4 .degree.2.theta., and
28.9 .degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or 0.0 .degree.2.theta.; Cu K.alpha.1 radiation).
In some embodiments, morphic Form F is characterized by fifteen
peaks selected from about 7.1 .degree.2.theta., 8.4
.degree.2.theta., 11.3 .degree.2.theta., 12.9 .degree.2.theta.,
13.7 .degree.2.theta., 14.3 .degree.2.theta., 15.0
.degree.2.theta., 17.4 .degree.2.theta., 18.7 .degree.2.theta.,
19.5 .degree.2.theta., 19.7 .degree.2.theta., 20.5
.degree.2.theta., 22.8 .degree.2.theta., 23.2 .degree.2.theta.,
24.4 .degree.2.theta., and 28.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F is characterized by sixteen peaks selected from
about 7.1 .degree.2.theta., 8.4 .degree.2.theta., 11.3
.degree.2.theta., 12.9 .degree.2.theta., 13.7 .degree.2.theta.,
14.3 .degree.2.theta., 15.0 .degree.2.theta., 17.4
.degree.2.theta., 18.7 .degree.2.theta., 19.5 .degree.2.theta.,
19.7 .degree.2.theta., 20.5 .degree.2.theta., 22.8
.degree.2.theta., 23.2 .degree.2.theta., 24.4 .degree.2.theta., and
28.9 .degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-..+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
TABLE-US-00007 TABLE 7 Representative PXRD Peaks for Morphic Form F
(Cu K.alpha.1 radiation) Angle (.degree.2.theta.) d value (.ANG.)
Intensity 7.1 12.37 s 8.4 10.52 m 9.8 9.03 w 10.4 8.49 w 11.3 7.81
s 12.1 7.28 vw 12.4 7.12 w 12.9 6.84 s 13.7 6.48 m 14.3 6.19 s 15.0
5.90 vs 16.8 5.26 w 17.4 5.08 s 17.9 4.94 w 18.2 4.88 w 18.4 4.81 w
18.7 4.75 m 19.0 4.67 w 19.5 4.54 m 19.7 4.50 s 20.5 4.33 m 21.1
4.20 w 21.5 4.14 w 22.0 4.03 w 22.8 3.90 vs 23.2 3.83 s 23.6 3.76 w
24.4 3.64 m 24.8 3.58 w 26.1 3.41 w 26.4 3.37 w 27.5 3.24 w 28.2
3.16 w 28.9 3.08 m 29.3 3.05 w 30.3 2.94 w 31.1 2.88 vw 32.0 2.80 w
32.5 2.75 w 32.7 2.73 w 34.1 2.63 w 34.4 2.60 vw 36.4 2.46 w
[0174] FIG. 13 is a TG-FTIR diagram of a sample of Compound 1, Form
F. FIG. 13 was obtained using a Netzsch TG 209, over the range of
25.degree. C. to 300.degree. C. The scanning speed was 10.degree.
C. per minute. As shown in FIG. 13, Form F has a mass loss change
of about 2.5% (e.g., about 2.55%) between about 40.degree. C. and
about 150.degree. C. Without wishing to be bound by theory, this
mass loss is proposed to be due to the loss of DMSO. Form F also
shows a mass loss of about 4.500 (e.g., about 4.45%) between about
150.degree. C. and about 220.degree. C. Without wishing to be bound
by theory, this is proposed to be due to a loss of 2-propanol.
Accordingly, in some embodiments, morphic Form F contains DMSO
and/or 2-propanol. Accordingly, in some embodiments, morphic Form F
is characterized by a mass loss of about 2.5% between about
40.degree. C. and about 150.degree. C. (e.g., as measured by
TG-FTIR). In some embodiments, morphic Form F is characterized by a
mass loss of about 4.5% between about 150.degree. C. and about
220.degree. C. (e.g., as measured by TG-FTIR).
Form G
[0175] Morphic Form G of Compound 1 was preliminarily characterized
as a DMSO solvate form of Compound 1. In some embodiments, morphic
Form G can be prepared dissolving Compound 1 in DMSO and
precipitating Compound 1 at room temperature using acetone. Without
wishing to be bound by theory, form F and Form G show similar XRPD
patterns but contain different solvents. Accordingly, without
wishing to be bound by theory, Form F and Form G are isomorphous
solvates.
[0176] FIG. 7 is a PXRD pattern of a sample of Compound 1, Form G
taken in transmission mode. FIG. 7 was obtained using a Stoe Stadi
P powder X-ray diffractometer using Cu K.alpha.1 radiation and
transmission geometry.
[0177] In some embodiments, morphic Form G can be characterized by
the PXRD peaks set forth below in Table 8. For example, morphic
Form G can be characterized by a PXRD peak at about 22.8
.degree.2.theta. (Cu K.alpha.1 radiation). Morphic Form G can
further be characterized by PXRD peaks at about 7.1
.degree.2.theta., 11.3 .degree.2.theta., 12.9 .degree.2.theta.,
14.3 .degree.2.theta., 15.0 .degree.2.theta., 23.2
.degree.2.theta., and/or 24.4 .degree.2.theta. (Cu K.alpha.1
radiation). Morphic Form G can further be characterized by PXRD
peaks at about 8.4 .degree.2.theta., 13.7 .degree.2.theta., 17.4
.degree.2.theta., 19.5 .degree.2.theta., 19.7 .degree.2.theta.,
20.5 .degree.2.theta., and/or 28.9 .degree.2.theta. (Cu K.alpha.1
radiation).
[0178] In some embodiments, morphic Form F can be characterized by
PXRD peaks at about 7.1 .degree.2.theta., about 11.3
.degree.2.theta., and about 12.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F can be characterized by PXRD peaks at about 11.3
.degree.2.theta., about 12.9 .degree.2.theta., and about 14.3
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F can be
characterized by PXRD peaks at about 12.9 .degree.2.theta., about
14.3 .degree.2.theta., and about 15.0 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F can be characterized by PXRD peaks at about 14.3
.degree.2.theta., about 15.0 .degree.2.theta., and about 22.8
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form F can be
characterized by PXRD peaks at about 15.0 .degree.2.theta., about
22.8 .degree.2.theta., and about 23.2 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form F can be characterized by PXRD peaks at about 22.8
.degree.2.theta., about 23.2 .degree.2.theta., and about 24.4
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0179] In some embodiments, morphic Form G can be characterized by
PXRD peaks at about 22.8 .degree.2.theta. and about 7.1
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form G can be
characterized by PXRD peaks at about 22.8 .degree.2.theta., about
7.1 .degree.2.theta., and about 11.3 .degree.2.theta. (.+-.0.2
.degree.2.theta.; 0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form G can be characterized by PXRD peaks at about 22.8
.degree.2.theta., about 7.1 .degree.2.theta., about 11.3
.degree.2.theta., and about 12.9 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form G can be characterized by PXRD peaks at about 22.8
.degree.2.theta., about 7.1 .degree.2.theta., about 11.3
.degree.2.theta., about 12.9 .degree.2.theta., and about 14.3
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form G can be
characterized by PXRD peaks at about 22.8 .degree.2.theta., about
7.1 .degree.2.theta., about 11.3 .degree.2.theta., about 12.9
.degree.2.theta., about 14.3 .degree.2.theta., and about 15.0
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form G can be
characterized by PXRD peaks at about 22.8 .degree.2.theta., about
7.1 .degree.2.theta., about 11.3 .degree.2.theta., about 12.9
.degree.2.theta., about 14.3 .degree.2.theta., about 15.0
.degree.2.theta., and about 23.2 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form G can be characterized by PXRD peaks at about 22.8
.degree.2.theta., about 7.1 .degree.2.theta., about 11.3
.degree.2.theta., about 12.9 .degree.2.theta., about 14.3
.degree.2.theta., about 15.0 .degree.2.theta., about 23.2
.degree.2.theta., and about 24.4 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation).
[0180] In some embodiments, morphic Form G can be characterized by
PXRD peaks at about 22.8 .degree.2.theta., about 7.1
.degree.2.theta., about 8.4 .degree.2.theta., about 11.3
.degree.2.theta., about 12.9 .degree.2.theta., about 14.3
.degree.2.theta., about 15.0 .degree.2.theta., about 23.2
.degree.2.theta., and about 24.4 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form G can be characterized by PXRD peaks at about 22.8
.degree.2.theta., about 7.1 .degree.2.theta., about 8.4
.degree.2.theta., about 11.3 .degree.2.theta., about 12.9
.degree.2.theta., about 13.7 .degree.2.theta., about 14.3
.degree.2.theta., about 15.0 .degree.2.theta., about 23.2
.degree.2.theta., and about 24.4 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form G can be characterized by PXRD peaks at about 22.8
.degree.2.theta., about 7.1 .degree.2.theta., about 8.4
.degree.2.theta., about 11.3 .degree.2.theta., about 12.9
.degree.2.theta., about 13.7 .degree.2.theta., about 14.3
.degree.2.theta., about 15.0 .degree.2.theta., about 17.4
.degree.2.theta., about 23.2 .degree.2.theta., and about 24.4
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form G can be
characterized by PXRD peaks at about 22.8 .degree.2.theta., about
7.1 .degree.2.theta., about 8.4 .degree.2.theta., about 11.3
.degree.2.theta., about 12.9 .degree.2.theta., about 13.7
.degree.2.theta., about 14.3 .degree.2.theta., about 15.0
.degree.2.theta., about 17.4 .degree.2.theta., about 19.5
.degree.2.theta., about 23.2 .degree.2.theta., and about 24.4
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation). In some embodiments, morphic Form G can be
characterized by PXRD peaks at about 22.8 .degree.2.theta., about
7.1 .degree.2.theta., about 8.4 .degree.2.theta., about 11.3
.degree.2.theta., about 12.9 .degree.2.theta., about 13.7
.degree.2.theta., about 14.3 .degree.2.theta., about 15.0
.degree.2.theta., about 17.4 .degree.2.theta., about 19.5
.degree.2.theta., about 19.7 .degree.2.theta., about 23.2
.degree.2.theta., and about 24.4 .degree.2.theta. (.+-.0.2
.degree.2.theta.; .+-.0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form G can be characterized by PXRD peaks at about 22.8
.degree.2.theta., about 7.1 .degree.2.theta., about 8.4
.degree.2.theta., about 11.3 .degree.2.theta., about 12.9
.degree.2.theta., about 13.7 .degree.2.theta., about 14.3
.degree.2.theta., about 15.0 .degree.2.theta., about 17.4
.degree.2.theta., about 19.5 .degree.2.theta., about 19.7
.degree.2.theta., about 20.5 .degree.2.theta., about 23.2
.degree.2.theta., and about 24.4 .degree.2.theta. (.+-.0.2
.degree.2.theta.; 0.1 .degree.2.theta.; or .+-.0.0
.degree.2.theta.; Cu K.alpha.1 radiation). In some embodiments,
morphic Form G can be characterized by PXRD peaks at about 22.8
.degree.2.theta., about 7.1 .degree.2.theta., about 8.4
.degree.2.theta., about 11.3 .degree.2.theta., about 12.9
.degree.2.theta., about 13.7 .degree.2.theta., about 14.3
.degree.2.theta., about 15.0 .degree.2.theta., about 17.4
.degree.2.theta., about 19.5 .degree.2.theta., about 19.7
.degree.2.theta., about 20.5 .degree.2.theta., about 23.2
.degree.2.theta., about 24.4 .degree.2.theta., and about 28.9
.degree.2.theta. (.+-.0.2 .degree.2.theta.; .+-.0.1
.degree.2.theta.; or .+-.0.0 .degree.2.theta.; Cu K.alpha.1
radiation).
[0181] Accordingly, in some embodiments, morphic Form G is
characterized by one, two, three, four, five, six, seven, eight,
nine, ten, eleven, twelve, thirteen, or fourteen PXRD peaks
selected from about 7.1, 8.4, 11.3, 12.9, 13.7, 14.3, 15.0, 17.4,
19.5, 19.7, 20.5, 22.8, and 23.2 .degree.2.theta. (Cu K.alpha.1
radiation). In some embodiments, morphic Form G is characterized by
one PXRD peak selected from about 7.1, 8.4, 11.3, 12.9, 13.7, 14.3,
15.0, 17.4, 19.5, 19.7, 20.5, 22.8, and 23.2 .degree.2.theta. (Cu
K.alpha.1 radiation). In some embodiments, morphic Form G is
characterized by two PXRD peaks selected from about 7.1, 8.4, 11.3,
12.9, 13.7, 14.3, 15.0, 17.4, 19.5, 19.7, 20.5, 22.8, and 23.2
.degree.2.theta. (Cu K.alpha.1 radiation). In some embodiments,
morphic Form G is characterized by three PXRD peaks selected from
about 7.1, 8.4, 11.3, 12.9, 13.7, 14.3, 15.0, 17.4, 19.5, 19.7,
20.5, 22.8, and 23.2 .degree.2.theta. (Cu K.alpha.1 radiation). In
some embodiments, morphic Form G is characterized by four PXRD
peaks selected from about 7.1, 8.4, 11.3, 12.9, 13.7, 14.3, 15.0,
17.4, 19.5, 19.7, 20.5, 22.8, and 23.2 .degree.2.theta. (Cu
K.alpha.1 radiation). In some embodiments, morphic Form G is
characterized by five PXRD peaks selected from about 7.1, 8.4,
11.3, 12.9, 13.7, 14.3, 15.0, 17.4, 19.5, 19.7, 20.5, 22.8, and
23.2 .degree.2.theta. (Cu K.alpha.1 radiation). In some
embodiments, morphic Form G is characterized by six PXRD peaks
selected from about 7.1, 8.4, 11.3, 12.9, 13.7, 14.3, 15.0, 17.4,
19.5, 19.7, 20.5, 22.8, and 23.2 .degree.2.theta. (Cu K.alpha.1
radiation). In some embodiments, morphic Form G is characterized by
seven PXRD peaks selected from about 7.1, 8.4, 11.3, 12.9, 13.7,
14.3, 15.0, 17.4, 19.5, 19.7, 20.5, 22.8, and 23.2 .degree.2.theta.
(Cu K.alpha.1 radiation). In some embodiments, morphic Form G is
characterized by eight PXRD peaks selected from about 7.1, 8.4,
11.3, 12.9, 13.7, 14.3, 15.0, 17.4, 19.5, 19.7, 20.5, 22.8, and
23.2 .degree.2.theta. (Cu K.alpha.1 radiation). In some
embodiments, morphic Form G is characterized by nine PXRD peaks
selected from about 7.1, 8.4, 11.3, 12.9, 13.7, 14.3, 15.0, 17.4,
19.5, 19.7, 20.5, 22.8, and 23.2 .degree.2.theta. (Cu K.alpha.1
radiation). In some embodiments, morphic Form G is characterized by
ten PXRD peaks selected from about 7.1, 8.4, 11.3, 12.9, 13.7,
14.3, 15.0, 17.4, 19.5, 19.7, 20.5, 22.8, and 23.2 .degree.2.theta.
(Cu K.alpha.1 radiation). In some embodiments, morphic Form G is
characterized by eleven PXRD peaks selected from about 7.1, 8.4,
11.3, 12.9, 13.7, 14.3, 15.0, 17.4, 19.5, 19.7, 20.5, 22.8, and
23.2 .degree.2.theta. (Cu K radiation). In some embodiments,
morphic Form G is characterized by twelve PXRD peaks selected from
about 7.1, 8.4, 11.3, 12.9, 13.7, 14.3, 15.0, 17.4, 19.5, 19.7,
20.5, 22.8, and 23.2 .degree.2.theta. (Cu K.alpha.1 radiation). In
some embodiments, morphic Form G is characterized by thirteen PXRD
peaks selected from about 7.1, 8.4, 11.3, 12.9, 13.7, 14.3, 15.0,
17.4, 19.5, 19.7, 20.5, 22.8, and 23.2 .degree.2.theta. (Cu K03
radiation). In some embodiments, morphic Form G is characterized by
fourteen PXRD peaks selected from about 7.1, 8.4, 11.3, 12.9, 13.7,
14.3, 15.0, 17.4, 19.5, 19.7, 20.5, 22.8, and 23.2 .degree.2.theta.
(Cu K.alpha.1 radiation).
TABLE-US-00008 TABLE 8 Representative PXRD Peaks for Morphic Form G
(Cu K.alpha.1 radiation) Angle (.degree.2.theta.) d value (.ANG.)
Intensity 7.1 12.37 s 8.4 10.52 m 8.8 10.03 vw 9.8 9.03 w 10.4 8.48
w 11.3 7.81 s 12.1 7.28 w 12.4 7.12 vw 12.9 6.85 s 13.7 6.48 m 13.9
6.38 vw 14.3 6.19 s 15.0 5.89 s 15.8 5.59 vw 16.8 5.27 vw 17.4 5.08
m 17.9 4.94 w 18.2 4.88 w 18.4 4.81 w 18.7 4.75 w 19.0 4.68 w 19.2
4.62 w 19.5 4.54 m 19.7 4.50 m 20.5 4.33 m 20.9 4.24 vw 21.1 4.20 w
21.5 4.13 w 22.0 4.03 w 22.8 3.90 vs 23.2 3.83 s 23.6 3.76 w 24.4
3.64 s 24.8 3.58 w 25.3 3.52 vw 25.8 3.45 vw 26.1 3.41 w 26.4 3.37
w 26.8 3.32 vw 27.5 3.24 vw 27.9 3.20 vw 28.2 3.16 w 28.9 3.08 m
29.3 3.05 w 30.0 2.98 vw 30.3 2.95 w 31.0 2.88 vw 31.9 2.80 w 32.5
2.76 w 32.8 2.73 w 33.2 2.69 vw 34.1 2.63 w 34.4 2.60 vw 34.7 2.58
vw 35.9 2.50 vw 36.4 2.47 w 36.7 2.45 w 37.3 2.41 vw 38.8 2.32
vw
[0182] FIG. 14 is a TG-FTIR diagram of a sample of Compound 1, Form
G. FIG. 14 was obtained using a Netzsch TG 209, over the range of
25.degree. C. to 300.degree. C. The scanning speed was 10.degree.
C. per minute. As shown in FIG. 14, Form G exhibited a mass loss of
about 7.5% (e.g., about 7.48%) between about 40.degree. C. and
about 150.degree. C. Without wishing to be bound by theory, this
mass loss is preliminarily proposed to be due to the loss of
4-hydroxy-4-methyl-2-pentanone. Form G also exhibited a mass loss
of about 6.1% (e.g., about 6.07%) between about 150.degree. C. and
about 260.degree. C. Without wishing to be bound by theory, this is
proposed to be due to a loss of DMSO. Accordingly, in some
embodiments, morphic Form G contains water and/or DMSO.
Accordingly, in some embodiments, morphic Form G is characterized
by a mass loss of about 7.5% between about 40.degree. C. and about
150.degree. C. (e.g., as measured by TG-FTIR). In some embodiments,
morphic Form G is characterized by a mass loss of about 6.1%
between about 150.degree. C. and about 260.degree. C. (e.g., as
measured by TG-FTIR).
Methods of Use
Disease Indications
[0183] The present disclosure provides treatment of a viral
infection with a compound and/or morphic form (e.g., Compound 1
Form A) disclosed herein and pharmaceutically acceptable salts
thereof. The compounds and morphic forms encompassed by Formula I
(e.g., Compound 1, Form A) can be used in treating, and/or in the
manufacture of a medicament for treating at least one virus
selected from but not limited to ssRNA viruses. In some
embodiments, the virus can be a norovirus, human cytomegalovirus
(HCMV), BK virus (BKV), Epstein-Barr virus (EBV), adenovirus, JC
virus (JCV), SV40, MC virus (MCV), KI virus (KIV), WU virus (WUV),
vaccinia, herpes simplex virus 1 (HSV-1), herpes simplex virus 2
(HSV-2), human herpes virus 6 (HHV-6), human herpes virus 8
(HHV-8), hepatitis B virus, hepatitis C virus, varicella zoster
virus (VZV), variola major, variola minor, smallpox, cowpox,
camelpox, monkeypox, poliovirus, picornaviridae (e.g., rhinovirus),
paramyxoviridae (e.g., respiratory syncytial virus, RSV), ebola
virus, Marburg virus, Epstein-Barr virus (EBV), influenza,
enterovirus (e.g., EV68 and EV71, papilloma virus, West Nile virus,
yellow fever virus, foot-and-mouth disease virus, Rift Valley fever
virus, and other flavivirus, arenavirus, bunyavirus, alphavirus,
and human immunodeficiency virus (HIV) infections, and any
combination thereof. In some embodiments, the virus is a norovirus.
In some embodiments, the method of treatment comprises
administering to a subject in need thereof a therapeutically
effective amount of a compound and/or morphic form (e.g., Compound
1 Form A) disclosed herein and pharmaceutically acceptable salts
thereof.
[0184] In some embodiments, the present disclosure provides a
method of treatment of Marburg virus infection or Marburg virus
infection-associated disease or disorder, by oral administration to
a subject in need thereof a therapeutically effective dose of a
compound of Formula I, (e.g., Compound 1, Form A) or a
pharmaceutically acceptable salt thereof. In some embodiments, the
therapeutically effective amount of a compound of Formula I (e.g.,
Compound 1, Form A) is administered as a pharmaceutical composition
comprising a pharmaceutically acceptable carrier.
[0185] In some embodiments the present disclosure provides a method
of treatment of Ebola virus infection or Ebola virus
infection-associated disease or disorder, by oral administration to
a subject in need thereof a therapeutically effective dose of a
compound of Formula I, (e.g., Compound 1, Form A) or a
pharmaceutically acceptable salt thereof. In some embodiments, the
therapeutically effective amount of a compound of Formula I (e.g.,
Compound 1, Form A) is administered as a pharmaceutical composition
comprising a pharmaceutically acceptable carrier.
[0186] In some embodiments the present disclosure provides a method
of treatment of influenza virus infection or influenza virus
infection-associated disease or disorder, by oral administration to
a subject in need thereof a therapeutically effective dose of a
compound of Formula I, (e.g., Compound 1, Form A) or a
pharmaceutically acceptable salt thereof. In some embodiments, the
therapeutically effective amount of a compound of Formula I (e.g.,
Compound 1, Form A) is administered as a pharmaceutical composition
comprising a pharmaceutically acceptable carrier.
[0187] In some embodiments the present disclosure provides a method
of treatment of norovirus virus infection or norovirus virus
infection-associated disease or disorder, by oral administration to
a subject in need thereof a therapeutically effective dose of a
compound of Formula I, (e.g., Compound 1, Form A) or a
pharmaceutically acceptable salt thereof. In some embodiments, the
therapeutically effective amount of a compound of Formula I (e.g.,
Compound 1, Form A) is administered as a pharmaceutical composition
comprising a pharmaceutically acceptable carrier.
[0188] In some embodiments the present disclosure provides a method
of treatment of picornaviridae virus infection or picornaviridae
virus-infection associated disease or disorder, by oral
administration to a subject in need thereof a therapeutically
effective dose of a compound of Formula I, (e.g., Compound 1, Form
A) or a pharmaceutically acceptable salt thereof. In some
embodiments, the therapeutically effective amount of a compound of
Formula I (e.g., Compound 1, Form A) is administered as a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier.
[0189] In some embodiments the present disclosure provides a method
of treatment paramyxoviridae virus infection or paramyxoviridae
virus infection-associated disease or disorder, by oral
administration to a subject in need thereof a therapeutically
effective dose of a compound of Formula I, (e.g., Compound 1, Form
A) or a pharmaceutically acceptable salt thereof. In some
embodiments, the therapeutically effective amount of a compound of
Formula I (e.g., Compound 1, Form A) is administered as a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier.
[0190] In some embodiments of the present disclosure provides a
method of treatment of enterovirus infection or enterovirus
infection-associated disease or disorder, by oral administration to
a subject in need thereof of a therapeutically effective dose of a
compound of Formula I, (e.g., Compound 1, Form A) or a
pharmaceutically acceptable salt thereof. In some embodiments, the
therapeutically effective amount of a compound of Formula I (e.g.,
Compound 1, Form A) is administered as a pharmaceutical composition
comprising a pharmaceutically acceptable carrier.
[0191] In one of the embodiments, a compound of Formula I, (e.g.,
Compound 1, Form A) can be used to treat norovirus. In another
embodiments, a compound of Formula I, (e.g., Compound 1, Form A)
can be used to treat norovirus associated with specific genotypes
such as those in genogroups I, II and IV, VI and VII which are
known to infect humans (Phan et al., J. Med. Virol. 2007 September;
79(9): 1388-1400).
[0192] In some embodiments the present disclosure provides a method
of treatment of a viral infection, (e.g., norovirus virus infection
or norovirus virus infection associated disease or disorder;
influenza virus infection or influenza virus infection associated
disease or disorder), by oral administration to a subject in need
thereof a pharmaceutical composition of a therapeutically effective
dose of a compound of Formula I, (e.g., Compound 1, Form A) or a
pharmaceutically acceptable salt thereof.
[0193] The present disclosure provides prevention and/or
prophylaxis of a viral infection with a compound and/or morphic
form (e.g., Compound 1 Form A) disclosed herein and
pharmaceutically acceptable salts thereof. The compounds and
morphic forms encompassed by Formula I (e.g., Compound 1, Form A)
can be used in prevention and/or prophylaxis; and/or in the
manufacture of a medicament for prevention and/or prophylaxis at
least one virus selected from but not limited to ssRNA viruses. In
some embodiments, the virus can be a norovirus, human
cytomegalovirus (HCMV), BK virus (BKV), Epstein-Barr virus (EBV),
adenovirus, JC virus (JCV), SV40, MC virus (MCV), KI virus (KIV),
WU virus (WUV), vaccinia, herpes simplex virus 1 (HSV-1), herpes
simplex virus 2 (HSV-2), human herpes virus 6 (HHV-6), human herpes
virus 8 (HHV-8), hepatitis B virus, hepatitis C virus, varicella
zoster virus (VZV), variola major, variola minor, smallpox, cowpox,
camelpox, monkeypox, poliovirus, picornaviridae (e.g., rhinovirus),
paramyxoviridae (e.g., respiratory syncytial virus, RSV), ebola
virus, Marburg virus, Epstein-Barr virus (EBV), influenza,
enterovirus (e.g., EV68 and EV71, papilloma virus, West Nile virus,
yellow fever virus, foot-and-mouth disease virus, Rift Valley fever
virus, and other flavivirus, arenavirus, bunyavirus, alphavirus,
and human immunodeficiency virus (HIV) infections, and any
combination thereof. In some embodiments, the virus is a norovirus.
In some embodiments, the method of prevention and/or prophylaxis
comprises administering to a subject in need thereof a
prophylactically effective amount of a compound and/or morphic form
(e.g., Compound 1 Form A) disclosed herein and pharmaceutically
acceptable salts thereof.
[0194] In some embodiments, the present disclosure provides a
method of prevention and/or prophylaxis of Marburg virus infection
or Marburg virus infection-associated disease or disorder, by oral
administration to a subject in need thereof a prophylactically
effective dose of a compound of Formula I, (e.g., Compound 1, Form
A) or a pharmaceutically acceptable salt thereof. In some
embodiments, the prophylactically effective amount of a compound of
Formula I (e.g., Compound 1, Form A) is administered as a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier. In some embodiments, prevention and/or prophylaxis of
Marburg virus infection or Marburg virus infection-associated
disease or disorder can comprises delaying the onset of Marburg
virus infection or Marburg virus infection-associated disease or
disorder.
[0195] In some embodiments the present disclosure provides a method
of prevention and/or prophylaxis of Ebola virus infection or Ebola
virus infection-associated disease or disorder, by oral
administration to a subject in need thereof a pharmaceutical
composition of a prophylactically effective dose of a compound of
Formula I, (e.g., Compound 1, Form A) or a pharmaceutically
acceptable salt thereof. In some embodiments, the prophylactically
effective amount of a compound of Formula I (e.g., Compound 1, Form
A) is administered as a pharmaceutical composition comprising a
pharmaceutically acceptable carrier. In some embodiments,
prevention and/or prophylaxis of Ebola virus infection or Ebola
virus infection-associated disease or disorder can comprises
delaying the onset of Ebola virus infection or Ebola virus
infection-associated disease or disorder.
[0196] In some embodiments the present disclosure provides a method
of prevention and/or prophylaxis of influenza virus infection or
influenza virus infection-associated disease or disorder, by oral
administration to a subject in need thereof a prophylactically
effective dose of a compound of Formula I, (e.g., Compound 1, Form
A) or a pharmaceutically acceptable salt thereof. In some
embodiments, the prophylactically effective amount of a compound of
Formula I (e.g., Compound 1, Form A) is administered as a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier. In some embodiments, prevention and/or prophylaxis of
influenza virus infection or influenza virus infection-associated
disease or disorder can comprises delaying the onset of influenza
virus infection or influenza virus infection-associated disease or
disorder.
[0197] In some embodiments the present disclosure provides a method
of prevention and/or prophylaxis of norovirus virus infection or
norovirus virus infection-associated disease or disorder, by oral
administration to a subject in need thereof a prophylactically
effective dose of a compound of Formula I, (e.g., Compound 1, Form
A) or a pharmaceutically acceptable salt thereof. In some
embodiments, the prophylactically effective amount of a compound of
Formula I (e.g., Compound 1, Form A) is administered as a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier. In some embodiments, prevention and/or prophylaxis of
norovirus virus infection or norovirus virus infection-associated
disease or disorder can comprises delaying the onset of norovirus
virus infection or norovirus virus infection-associated disease or
disorder.
[0198] In some embodiments the present disclosure provides a method
of prevention and/or prophylaxis of picornaviridae virus infection
or picornaviridae virus-infection associated disease or disorder,
by oral administration to a subject in need thereof a
prophylactically effective dose of a compound of Formula I, (e.g.,
Compound 1, Form A) or a pharmaceutically acceptable salt thereof.
In some embodiments, the prophylactically effective amount of a
compound of Formula I (e.g., Compound 1, Form A) is administered as
a pharmaceutical composition comprising a pharmaceutically
acceptable carrier. In some embodiments, prevention and/or
prophylaxis of picornaviridae virus infection or picornaviridae
virus infection-associated disease or disorder can comprises
delaying the onset of picornaviridae virus infection or
picornaviridae virus infection-associated disease or disorder.
[0199] In some embodiments the present disclosure provides a method
of prevention and/or prophylaxis paramyxoviridae virus infection or
paramyxoviridae virus infection-associated disease or disorder, by
oral administration to a subject in need thereof a prophylactically
effective dose of a compound of Formula I, (e.g., Compound 1, Form
A) or a pharmaceutically acceptable salt thereof. In some
embodiments, the prophylactically effective amount of a compound of
Formula I (e.g., Compound 1, Form A) is administered as a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier. In some embodiments, prevention and/or prophylaxis of
paramyxoviridae virus infection or paramyxoviridae virus
infection-associated disease or disorder can comprises delaying the
onset of paramyxoviridae virus infection or paramyxoviridae virus
infection-associated disease or disorder.
[0200] In some embodiments of the present disclosure provides a
method of prevention and/or prophylaxis of enterovirus infection or
enterovirus infection-associated disease or disorder, by oral
administration to a subject in need thereof of a prophylactically
effective dose of a compound of Formula I, (e.g., Compound 1, Form
A) or a pharmaceutically acceptable salt thereof. In some
embodiments, the prophylactically effective amount of a compound of
Formula I (e.g., Compound 1, Form A) is administered as a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier. In some embodiments, prevention and/or prophylaxis of
enterovirus virus infection or enterovirus virus
infection-associated disease or disorder can comprises delaying the
onset of enterovirus virus infection or enterovirus virus
infection-associated disease or disorder.
[0201] In one of the embodiments, a compound of Formula I, (e.g.,
Compound 1, Form A) can be used to prevent transmission of
norovirus. In another embodiments, a compound of Formula I, (e.g.,
Compound 1, Form A) can be used to prevent transmission of a
norovirus associated with specific genotypes such as those in
genogroups I, II and IV, VI and VII which are known to infect
humans (Phan et al., J. Med. Virol. 2007 September; 79(9):
1388-1400).
[0202] In some embodiments the present disclosure provides a method
of prevention and/or prophylaxis of a viral infection, (e.g.,
norovirus virus infection or norovirus virus infection associated
disease or disorder; influenza virus infection or influenza virus
infection associated disease or disorder), by oral administration
to a subject in need thereof a pharmaceutical composition of a
prophylactically effective dose of a compound of Formula I, (e.g.,
Compound 1, Form A) or a pharmaceutically acceptable salt
thereof.
[0203] In some embodiments the present disclosure provides a method
of prevention or delaying onset of a viral infection, (e.g.,
norovirus virus infection or norovirus virus infection associated
disease or disorder; influenza virus infection or influenza virus
infection associated disease or disorder), by oral administration
to a subject in need thereof a pharmaceutical composition of a
prophylactically effective dose of a compound of Formula I, (e.g.,
Compound 1, Form A) or a pharmaceutically acceptable salt thereof.
In some embodiments, the administration of a compound of Formula I
(e.g., Compound 1 Form A) can prevent transmission of an infection
such as a viral infection. For example, Compound 1 can be
administered to a subject who has not yet been infected with an
infection (e.g., a viral infection such as norovirus) but who is at
risk of developing an infection as a result of being in close
proximity to others who are infected with the viral infection. As
noted above, such situations can arise in, for instance, hospitals,
cruise ships, college campuses, the Olympic Village, airplanes,
airports and the like. As set forth herein, administration of a
compound of Formula I to a subject prior to the subject being
infected can prevent transmission of a viral infection to the
subject despite the subject being in close proximity to others with
the infection and thus being at higher risk for infection.
[0204] The present disclosure further provides a method of
prevention and/or prophylaxis of norovirus infection or a norovirus
infection associated disease or disorder, by orally administering
to a subject a prophylactically effective dose of a compound of
Formula I, (e.g., Compound 1, Form A) or a pharmaceutically
acceptable salt thereof, in combination with one or more antiviral
agent. In some embodiments, the prophylactically effective amount
of a compound of Formula I (e.g., Compound 1, Form A) is
administered as a pharmaceutical composition comprising a
pharmaceutically acceptable carrier.
[0205] In some embodiments, the method of prevention and/or
prophylaxis comprises administering a subject with a compound of
the disclosure prior to infection with the norovirus. As noted
above, a compound of Formula I can be administered to a subject
that is at risk for developing a norovirus infection, for example a
person who spends time in close proximity to someone infected with
norovirus. For instance, one may be at risk of being infected with
norovirus if one is a hospital worker or hospital patient in the
presence of another patient that is infected with norovirus.
Norovirus can also spread in other contexts such as college
campuses, cruise ships, airplanes, the Olympic Village, and the
like.
Dosage Regimens
[0206] The regimen of administration can affect what constitutes a
therapeutically and/or prophylactically effective amount. A
compound of Formula I, (e.g., Compound 1, Form A) or a
pharmaceutically acceptable salt thereof can be administered to the
subject either prior to or after the onset of a disease. Further,
several divided dosages, as well as staggered dosages can be
administered daily or sequentially, or the dose can be continuously
infused, or can be a bolus injection. Further, the dosages can be
proportionally increased or decreased as indicated by the
exigencies of the therapeutic or prophylactic situation. Further,
the dosages can be co-administered in combination with other
antiviral.
[0207] The dosage regimen utilizing a therapeutically and/or
prophylactically amount of a compound of the present disclosure
(e.g., Compound 1, Form A) can also be selected in accordance with
a variety of factors including type, species, age, weight, sex and
medical condition of the patient; the severity of the condition to
be treated; the route of administration; the renal and hepatic
function of the patient; and the particular compound or salt
thereof employed. An ordinarily skilled physician or veterinarian
can readily determine and prescribe the therapeutically and/or
prophylactically effective amount of the drug required to prevent,
counter or arrest the progress of the condition.
[0208] In some embodiments, the subject treated for a viral
infection (e.g., a norovirus infection or a norovirus infection
associated disease or disorder) is administered once or twice a
week with about 40 mg, 50 mg, 75 mg, 100 mg, 150 mg, 175 mg, 200
mg, or 250 mg of a compound of Formula I, (e.g., Compound 1, Form
A) or a pharmaceutically acceptable salt thereof. The present
disclosure provides treatment of a subject for norovirus infection
or norovirus infection associated disease or disorder by
administering to the subject once a week (QW) about 200 mg or twice
a week (BIW) about 100 mg of a compound of Formula I, (e.g.,
Compound 1, Form A) or a pharmaceutically acceptable salt thereof.
In one embodiment, the subject is treated twice a week (BIW) with
about 100 mg of the compound. In another embodiment, the subject is
treated once a week (QW) with about 200 mg, or twice a week (BIW)
with about 100 mg of the compound.
[0209] In some embodiments a compound of Formula I, (e.g., Compound
1, Form A) or a pharmaceutically acceptable salt thereof is
administered to the subject for prophylaxis and/or prevention of a
viral infection (e.g., a norovirus infection or a norovirus
infection associated disease or disorder) once or twice a week with
about 40 mg, 50 mg, 75 mg, 100 mg, 150 mg, 175 mg, 200 mg, or 250
mg of a compound of Formula I, (e.g., Compound 1, Form A) or a
pharmaceutically acceptable salt thereof. The present disclosure
provides prophylaxis and/or prevention of a norovirus infection or
norovirus infection associated disease or disorder in a subject by
administering to the subject once a week (QW) about 200 mg or twice
a week (BIW) about 100 mg of a compound of Formula I, (e.g.,
Compound 1, Form A) or a pharmaceutically acceptable salt thereof.
In one embodiment, the subject is administered twice a week (BIW)
with about 100 mg of the compound. In another embodiment, the
subject is administered once a week (QW) with about 200 mg, or
twice a week (BIW) with about 100 mg of the compound for the
prevention of an infection.
[0210] In an embodiment, a compound of Formula I, (e.g., Compound
1, Form A) or pharmaceutically acceptable salt thereof having a
purity of equal to or greater than about 91% (e.g., greater than
92%, greater than 93%, greater than 94%, greater than 95%, greater
than 96%, greater than 97%, greater than 98%, or greater than 99%)
is administered orally to a subject, for example, at a dosage of
about 0.01 mg/kg to about 10 mg/kg or more, e.g., up to 100 mg/kg,
or up to 400 mg/kg, or up to 1000 mg/kg for a therapeutic and/or
prophylactic effect.
[0211] In another embodiment, a compound of Formula I, (e.g.,
Compound 1, Form A) or pharmaceutically acceptable salt thereof
having a purity of equal to or greater than about 91% w/w (e.g.,
greater than about 99% w/w) is administered to a subject at a
dosage of about 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg, 1
mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg,
4.5 mg/kg, 5 mg/kg, 5.5 mg/kg, 6 mg/kg, 6.5 mg/kg, 7 mg/kg, 7.5
mg/kg, 8 mg/kg, 8.5 mg/kg, 9 mg/kg, 9.5 mg/kg, or 10 mg/kg or more
or any range therein for a therapeutic and/or prophylactic
effect.
[0212] Dosage and administration are adjusted to provide sufficient
levels of the active agent(s) or to maintain the desired (e.g.,
therapeutic and/or prophylactic) effect. Factors which can be taken
into account include the severity of the disease state, general
health of the subject, age, weight, and gender of the subject,
diet, time and frequency of administration, drug combination(s),
reaction sensitivities, and tolerance/response to therapy.
Long-acting pharmaceutical compositions can be administered every 3
to 4 days, every week, once every two weeks, or monthly depending
on half-life and clearance rate of the particular formulation.
[0213] In some embodiments, the administration of a compound of
Formula I (e.g., Compound 1 Form A) for the treatment and/or
prevention of a disease continues for ten total doses. For
instance, a compound of Formula I, (e.g., Compound 1, Form A) can
be administered at dosages of about 100 mg twice a week for five
weeks (i.e., ten total doses). Alternatively, a compound of Formula
I (e.g., Compound 1, Form A) can be administered with a loading
dose of about 200 mg followed by about 100 mg doses continuing
twice a week. In some embodiments, the administration continues for
ten total doses. For instance, a compound of Formula I, (e.g.,
Compound 1, Form A) can be administered at a loading dose of about
200 mg followed by nine additional about 100 mg doses twice a week
for a total of ten doses. In one of the embodiments, a compound of
Formula I, (e.g., Compound 1, Form A) can be dosed daily in the
range of about 20-200 mg/day or weekly in the range of about 200
mg-3000 mg.
[0214] In one or more embodiments a compound of the disclosure can
be useful at treating and/or preventing a viral infection such as a
norovirus infection or a norovirus-infection associated disease or
disorder. In some embodiments, treatment of the infection, e.g.,
norovirus infection, can comprise daily dosing, or dosing multiple
times per day. In some embodiments, the total treatment regimen
only lasts as long as the norovirus infection is active (e.g.,
between 1-3 days). In some embodiments, a compound of the
disclosure can be dosed multiple times per day for 1-3 days to
treat a norovirus infection.
[0215] In another embodiment, tablets or suspensions comprising a
compound of Formula I, (e.g., Compound 1, Form A) or a
pharmaceutically acceptable salt thereof can be administered at,
for instance, a dose of about 40-3000 mg daily. For instance, a
compound of Formula I can be administered BID, TID, QID (i.e., 4
times a day), q6h, q8h, q12h, once a week (QW) or twice a week
(BIW). In another embodiment, tablets or suspensions of a compound
of Formula I, (e.g., Compound 1, Form A) or a pharmaceutically
acceptable salt thereof can be administered at a dose of about
40-400 mg daily, BID, TID, QID (i.e., 4 times a day), q6h, q8h,
g12h, once a week (QW) or twice a week (BIW) for a therapeutic
and/or prophylactic effect.
[0216] In therapeutic and/or prophylactic applications, the dosages
of the pharmaceutical compositions disclosed herein vary depending
on the agent, the age, weight, and clinical condition of the
recipient patient, and the experience and judgment of the clinician
or practitioner administering the therapy, among other factors
affecting the selected dosage. Dosages can range from about 0.01
mg/kg to about 100 mg/kg. In preferred aspects, dosages can range
from about 0.1 mg/kg to about 10 mg/kg. In an aspect, the dose will
be in the range of about 1 mg to about 1 g; about 10 mg to about
500 mg; about 20 mg to about 400 mg; about 40 mg to about 400 mg;
or about 50 mg to about 400 mg, in single, divided, or continuous
doses (which dose can be adjusted for the patient's weight in kg,
body surface area in m.sup.2, and age in years). In certain
embodiments, the amount per dosage form can be about 0.1 mg to
about 3000 mg, e.g., about 0.1 mg, about 0.5 mg, about 1 mg, about
2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg,
about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg,
about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg,
about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg,
about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg,
about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500
mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about
1000 mg, about 1250 mg, 1500 mg, about 1750 mg, about 2000 mg,
about 2500 mg, or about 3000 mg. In one embodiment, the amount can
be about 20 mg. In one embodiment, the amount can be about 50 mg.
In another embodiment the dosage can be 100 mg. In another
embodiment the dose can be 500 mg.
[0217] In another embodiment, a compound of Formula I, (e.g.,
Compound 1, Form A) or pharmaceutically acceptable salts thereof
can be administered to a subject as a single dose for a therapeutic
and/or prophylactic effect. In another embodiment, a compound of
Formula I, (e.g., Compound 1, Form A) or pharmaceutically
acceptable salts thereof can be administered to a subject in
multiple doses. Multiple doses can be administered regularly, for
example, once every 12 hours, once a day, every 2 days, every 3
days, every 4 days, every 5 days, every 6 days, every 7 days, every
8 days, every 9 days, every 10 days, every 11 days, every 12 days,
every 13 days, every 14 days or every 15 days. For example, doses
can be administered twice per week. Moreover, each individual dose
can be administered with the same or a different dosage.
[0218] For example, a subject can be administered a compound of
Formula I, (e.g., Compound 1, Form A) or a pharmaceutically
acceptable salt thereof with a first dose of about 1-20 mg/kg
(e.g., about 1-1.1 mg/kg, about 1.1-1.2 mg/kg, about 1.2-1.3 mg/kg,
about 1.3-1.4 mg/kg, about 1.4-1.5 mg/kg, about 1.5-1.6 mg/kg,
about 1.6-1.7 mg/kg, about 1.7-1.8 mg/kg, about 1.8-1.9 mg/kg,
about 1.9-2.0 mg/kg, about 2.0-2.1 mg/kg, about 2.1-2.2 mg/kg,
about 2.2-2.3 mg/kg, about 2.3-2.4 mg/kg, about 2.4-2.5 mg/kg,
about 2.5-2.6 mg/kg, about 2.6-2.7 mg/kg, about 2.7-2.8 mg/kg,
about 2.8-2.9 mg/kg, about 2.9-3.0 mg/kg, about 3.0-3.1 mg/kg,
about 3.1-3.2 mg/kg, about 3.2-3.3 mg/kg, about 3.3-3.4 mg/kg,
about 3.4-3.5 mg/kg, about 3.5-3.6 mg/kg, about 3.6-3.7 mg/kg,
about 3.7-3.8 mg/kg, about 3.8-3.9 mg/kg, about 3.9-4.0 mg/kg,
about 4.0-5.0 mg/kg, about 5.0-6.0 mg/kg, about 6.0-7.0 mg/kg,
about 7.0-8.0 mg/kg, about 8.0-9.0 mg/kg, about 9.0-10.0 mg/kg, or
about 10-20 mg/kg) of a compound of Formula I, (e.g., Compound 1,
Form A) (or a pharmaceutically acceptable salt thereof) followed by
one or more additional doses at 1-4 mg/kg (e.g., about 1-1.1 mg/kg,
about 1.1-1.2 mg/kg, about 1.2-1.3 mg/kg, about 1.3-1.4 mg/kg,
about 1.4-1.5 mg/kg, about 1.5-1.6 mg/kg, about 1.6-1.7 mg/kg,
about 1.7-1.8 mg/kg, about 1.8-1.9 mg/kg, about 1.9-2.0 mg/kg,
about 2.0-2.1 mg/kg, about 2.1-2.2 mg/kg, about 2.2-2.3 mg/kg,
about 2.3-2.4 mg/kg, about 2.4-2.5 mg/kg, about 2.5-2.6 mg/kg,
about 2.6-2.7 mg/kg, about 2.7-2.8 mg/kg, about 2.8-2.9 mg/kg,
about 2.9-3.0 mg/kg, about 3.0-3.1 mg/kg, about 3.1-3.2 mg/kg,
about 3.2-3.3 mg/kg, about 3.3-3.4 mg/kg, about 3.4-3.5 mg/kg,
about 3.5-3.6 mg/kg, about 3.6-3.7 mg/kg, about 3.7-3.8 mg/kg,
about 3.8-3.9 mg/kg, or about 3.9-4.0 mg/kg) of a compound of
Formula I, (e.g., Compound 1, Form A) (or a pharmaceutically
acceptable salt thereof) in the same week or in the following week
for a therapeutic and/or prophylactic effect. For example, a
subject can be administered with a first dose of about 3 mg/kg
followed by one or more additional doses at about 1 mg/kg. For
example, a subject can be administered with a first dose of about 2
mg/kg followed by one or more additional doses at about 3 mg/kg.
For example, a subject can be administered with a first dose of 4
mg/kg followed by one or more additional doses at about 4
mg/kg.
[0219] Multiple doses can also be administered at variable time
intervals for a therapeutic and/or prophylactic effect. For
example, the first 2, 3, 4, 5, 6, 7, or 8 or more doses can be
administered at an interval of 6 days followed by additional doses
administered at an interval of 7 days. For example, the first 2, 3,
4, 5, 6, 7, or 8 or more doses can be administered at an interval
of 7 days followed by additional doses administered at an interval
of 3 days.
[0220] In one embodiment, a compound of Formula I, (e.g., Compound
1, Form A) or a pharmaceutically acceptable salt thereof can be
administered to a subject once a week at a dose of about 40-3000
mg, or twice a week at a dose of about 40-3000 mg for a therapeutic
and/or prophylactic effect.
[0221] In some embodiments, a compound of the present disclosure
(e.g., Compound 1 Form A) is administered daily, BID, TID, once a
week (QW), or twice a week (BIW) with about 40-3000 mg of a
compound of Formula I, (e.g., Compound 1, Form A) or a
pharmaceutically acceptable salt thereof for a therapeutic and/or
prophylactic effect. A pharmaceutical compositions of the present
disclosure can be administered daily, BID, TID, once a week (QW),
or twice a week (BIW) with about 40 mg, 50 mg, 75 mg, 100 mg, 150
mg, 175 mg, 200 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg,
400 mg, 450 mg, 500 mg, 500-600 mg, 600-700 mg, 700-800 mg, 800-900
mg, or 900-1000 mg, or twice a week (BIW) with about 40 mg, 50 mg,
75 mg, 100 mg, 150 mg, 175 mg, 200 mg, 250 mg, 275 mg, 300 mg, 325
mg, 350 mg, 375 mg, or 400 mg, 450 mg, 500 mg, 500-600 mg, 600-700
mg, 700-800 mg, 800-900 mg, or 900-1000 mg of a compound of Formula
I, (e.g., Compound 1, Form A) or a pharmaceutically acceptable salt
thereof.
[0222] The present disclosure provides a compound of Formula I,
(e.g., Compound 1, Form A) administered at a dose of about 1-100
mg/kg (e.g., 10-20 mg/kg, 20-50 mg/kg, 50-75 mg/kg, 75-100 mg/kg)
for a therapeutic and/or prophylactic effect.
Routes of Administration
[0223] A compound (e.g., Compound 1 Form A) of the present
disclosure, or a pharmaceutically acceptable salt, ester or
derivative thereof, can be administered orally, nasally,
intranasally, transdermally, pulmonary, inhalationally, buccally,
sublingually, intraperintoneally, subcutaneously, intramuscularly,
intravenously, rectally, intrapleurally, intrathecally and
parenterally. In one embodiment, the compound is administered
orally. One skilled in the art will recognize the advantages of
certain routes of administration.
[0224] Dosage forms for the topical or transdermal administration
of a compound of this disclosure include powders, sprays,
ointments, pastes, creams, lotions, gels, solutions, patches and
inhalants. In one embodiment, the active compound is mixed under
sterile conditions with a pharmaceutically acceptable carrier, and
with any preservatives, buffers or propellants that are
required.
[0225] For administration by inhalation, a compound of the
disclosure can be delivered in the form of an aerosol spray from
pressured container or dispenser, which can contain a suitable
propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
[0226] Systemic administration can also be by transmucosal or
transdermal means. For transmucosal or transdermal administration,
penetrants appropriate to the barrier to be permeated are used in
the formulation. Such penetrants are generally known in the art,
and include, for example, for transmucosal administration,
detergents, bile salts, and fusidic acid derivatives. Transmucosal
administration can be accomplished through the use of, e.g., nasal
sprays, rectal foam, or suppositories. For transdermal
administration, an active compound can be formulated into an
ointment, salve, gel, or cream as generally known in the art.
[0227] A pharmaceutical composition of the disclosure is formulated
to be compatible with its intended route of administration.
Examples of routes of administration include parenteral, e.g.,
intravenous, intradermal, subcutaneous, oral (e.g., inhalation),
transdermal (topical), and transmucosal administration. Solutions
or suspensions used for parenteral, intradermal, or subcutaneous
application can include the following components: a sterile diluent
such as water for injection, saline solution, fixed oils,
polyethylene glycols, glycerine, propylene glycol or other
synthetic solvents; antibacterial agents such as benzyl alcohol or
methyl parabens; antioxidants such as ascorbic acid or sodium
bisulfite; chelating agents such as ethylenediaminetetraacetic
acid; buffers such as acetates, citrates or phosphates, and agents
for the adjustment of tonicity such as sodium chloride or dextrose.
The pH can be adjusted with acids or bases, such as hydrochloric
acid or sodium hydroxide. The parenteral preparation can be
enclosed in ampoules, disposable syringes or multiple dose vials
made of glass or plastic.
Combination Therapy
[0228] The present disclosure provides methods of preventing or
treating a viral infection in a subject (e.g., a norovirus
infection). The methods comprise administering a subject a
therapeutically and/or prophylactically effective amount of a
compound (e.g., Compound 1, Form A) described herein. A compound
can be used in a monotherapy or combination therapy regime.
[0229] As used herein, "monotherapy" means or refers to the
administration of a single active or therapeutic compound (e.g.,
Compound 1, Form A) to a subject in need thereof. Preferably,
monotherapy will involve administration of a therapeutically and/or
prophylactically effective amount of an active compound. For
example, norovirus monotherapy with one of the compound of the
present disclosure, or a pharmaceutically acceptable salt, prodrug,
metabolite, analog or derivative thereof, to a subject in need of
treatment of norovirus. Monotherapy can be contrasted with
combination therapy, in which a combination of multiple active
compounds is administered, preferably with each component of the
combination present in a therapeutically and/or prophylactically
effective amount. In one aspect, monotherapy with a compound of the
present disclosure, or a pharmaceutically acceptable salt, prodrug,
metabolite, polymorph or solvate thereof, is more effective than
combination therapy in inducing a desired biological effect.
[0230] As used herein, "combination therapy" or "co-therapy"
includes the administration of a compound of the present
disclosure, or a pharmaceutically acceptable salt, prodrug,
metabolite, polymorph or solvate thereof, and at least a second
agent as part of a specific treatment regimen intended to provide
the beneficial effect from the co-action of these therapeutic
agents. The beneficial effect of the combination includes, but is
not limited to, pharmacokinetic or pharmacodynamic co-action
resulting from the combination of therapeutic agents.
Administration of these therapeutic agents in combination typically
is carried out over a defined time period (usually minutes, hours,
days or weeks depending upon the combination selected).
"Combination therapy" can be, but generally is not, intended to
encompass the administration of two or more of these therapeutic
agents as part of separate monotherapy regimens that incidentally
and arbitrarily result in the combinations of the present
disclosure.
[0231] "Combination therapy" is intended to embrace administration
of these therapeutic agents in a sequential manner, wherein each
therapeutic agent is administered at a different time, as well as
administration of these therapeutic agents, or at least two of the
therapeutic agents, in a substantially simultaneous manner.
Substantially simultaneous administration can be accomplished, for
example, by administering to the subject a single capsule having a
fixed ratio of each therapeutic agent or in multiple, single
capsules for each of the therapeutic agents. Sequential or
substantially simultaneous administration of each therapeutic agent
can be effected by any appropriate route including, but not limited
to, oral routes, intravenous routes, intramuscular routes, and
direct absorption through mucous membrane tissues. The therapeutic
agents can be administered by the same route or by different
routes. For example, a first therapeutic agent of the combination
selected can be administered by intravenous injection while the
other therapeutic agents of the combination can be administered
orally. Alternatively, for example, all therapeutic agents can be
administered orally or all therapeutic agents can be administered
by intravenous injection. The sequence in which the therapeutic
agents are administered is not narrowly critical.
[0232] In some embodiments, combination therapy embraces the
administration of a compound and/or morphic form of the present
disclosure (e.g., Compound 1, Form A) in temporal proximity with
another therapeutic agent. As used herein, "temporal proximity"
means that administration of one therapeutic agent (e.g., Compound
1 Form A) occurs within a time period before or after the
administration of another therapeutic agent, such that the
therapeutic effect of the one therapeutic agent overlaps with the
therapeutic effect of the another therapeutic agent. In some
embodiments, the therapeutic and/or prophylactic effect of the one
therapeutic agent completely overlaps with the therapeutic and/or
prophylactic effect of the another therapeutic agent. In some
embodiments, "temporal proximity" means that administration of one
therapeutic agent occurs within a time period before or after the
administration of another therapeutic agent, such that there is a
synergistic effect between the one therapeutic agent and the
another therapeutic agent. "Temporal proximity" can vary according
to various factors, including but not limited to, the age, gender,
weight, genetic background, medical condition, disease history, and
treatment history of the subject to which the therapeutic agents
are to be administered; the disease or condition to be treated or
ameliorated; the therapeutic outcome to be achieved; the dosage,
dosing frequency, and dosing duration of the therapeutic agents;
the pharmacokinetics and pharmacodynamics of the therapeutic
agents; and the route(s) through which the therapeutic agents are
administered. In some embodiments, "temporal proximity" means
within 15 minutes, within 30 minutes, within an hour, within two
hours, within four hours, within six hours, within eight hours,
within 12 hours, within 18 hours, within 24 hours, within 36 hours,
within 2 days, within 3 days, within 4 days, within 5 days, within
6 days, within a week, within 2 weeks, within 3 weeks, within 4
weeks, with 6 weeks, or within 8 weeks. In some embodiments,
multiple administration of one therapeutic agent can occur in
temporal proximity to a single administration of another
therapeutic agent. In some embodiments, temporal proximity can
change during a treatment cycle or within a dosing regimen.
[0233] "Combination therapy" also embraces the administration of
the therapeutic and/or prophylactic agents as described above in
further combination with other biologically active ingredients and
non-drug therapies. Where the combination therapy further comprises
a non-drug treatment, the non-drug treatment can be conducted at
any suitable time so long as a beneficial effect from the co-action
of the combination of the therapeutic agents and non-drug treatment
is achieved. For example, in appropriate cases, the beneficial
effect is still achieved when the non-drug treatment is temporally
removed from the administration of the therapeutic agents, perhaps
by days or even weeks.
[0234] In some embodiments the present disclosure provides a method
of treatment, prevention, or delaying on-set of a viral infection,
(e.g., norovirus virus infection or norovirus virus infection
associated disease or disorder; influenza virus infection or
influenza virus infection associated disease or disorder), by oral
administration to a subject in need thereof a compound of Formula
I, for instance a pharmaceutical composition of a therapeutically
effective dose of a compound of Formula I, (e.g., Compound 1, Form
A) or a pharmaceutically acceptable salt thereof in combination
with one or more antiviral agents.
[0235] In some embodiments the present disclosure provides a method
of treatment, prevention, or delaying on-set of picornaviridae
virus infection or picornaviridae virus infection associated
disease or disorder, by oral administration to a subject in need
thereof a pharmaceutical composition of a therapeutically effective
dose of a compound of Formula I, (e.g., Compound 1, Form A) or a
pharmaceutically acceptable salt thereof in combination with one or
more antiviral agents.
[0236] In some embodiments the present disclosure provides a method
of treatment, prevention, or delaying on-set of paramyxoviridae
virus infection or paramyxoviridae virus infection associated
disease or disorder, by oral administration to a subject in need
thereof a pharmaceutical composition of a therapeutically effective
dose of a compound of Formula I, (e.g., Compound 1, Form A) or a
pharmaceutically acceptable salt thereof in combination with one or
more antiviral agents.
[0237] In one embodiment, the method of treating, prevention and/or
prophylaxis of a viral infection, e.g., influenza virus or
norovirus infection or norovirus infection further comprises
administering at least one additional antiviral agent. In one
embodiment, the one additional antiviral agent is an adamantane. In
a further embodiment, the one additional antiviral agent is
amantadine or rimantadine. In another embodiment, the one
additional antiviral agent is a neuraminidase inhibitor (e.g.,
oseltamivir, zanamivir, laninamivir, and peramivir). In a further
embodiment, the one additional antiviral agent is oseltamivir or
zanamivir.
[0238] In some embodiments, the pharmaceutical composition of the
present disclosure (e.g., Compound 1, Form A) is administered in
combination with one or more compounds or compositions selected
from midazolam, cyclosporine A, tacrolimus, ganciclovir,
valganciclovir, foscavir, cidofovir, second-line anti-CMV drugs,
second-line anti-HCV drugs, foscarnet, filgrastim, pegfilgrastim,
corticosteroids such as budesonide, beclomethasone, and
broad-spectrum CYP inhibitor aminobenzotriazole or combinations
thereof.
[0239] In additional embodiments, the compound is for
administration in combination with at least one other
immunosuppressant agent. In one embodiment, the immunosuppressant
agent is concurrently or sequentially administered. The
immunosuppressant agents include but are not limited to Daclizumab,
Basiliximab, Tacrolimus, Sirolimus, Mycophenolate, Cyclosporine A,
Glucocorticoids, Anti-CD3 monoclonal antibodies, Antithymocyte
globulin, Anti-CD52 monoclonal antibodies, Azathioprine,
Everolimus, Dactinomycin, Cyclophosphamide, Platinum, Nitrosurea,
Methotrexate, Mercaptopurine, Muromonab, IFN gamma, Infliximab,
Etanercept, Adalimumab, Natalizumab, Fingolimod, and combinations
thereof.
[0240] A compound or composition provided herein can also be used
in combination with an enhancer agent, with other active
ingredients, or with an immunosuppressant agent. In certain
embodiments, a compound can be administered in combination, or
sequentially, with another therapeutic agent or an enhancer. Such
other therapeutic agents include those known for treatment,
prevention, or amelioration of one or more symptoms associated with
viral infections. It should be understood that any suitable
combination of a compound provided herein with one or more of the
above-mentioned therapeutic agent or enhancer and optionally one or
more further pharmacologically active substances are considered to
be within the scope of the present disclosure. In another
embodiment, a compound provided herein is administered prior to or
subsequent to the one or more additional active ingredients. In one
embodiment, two or more of the antiviral agents disclosed herein
are administered serially or in combination. The amount of some
enhancers can be selected using methods known in the art to enhance
the bioavailability of the anti-viral agent. Any amount can be used
that provides a desired response by some enhancers. The dosages can
range, in a non-limiting example, from 0.001 mg to about 3000 mg of
compound per kilogram of body weight per day, e.g., 0.01 to 500
mg/kg, or e.g., 0.1-20 mg/kg.
[0241] The pharmacokinetic behavior of a composition will vary
somewhat from subject to subject within a population. The numbers
described above for the compositions disclosed herein are based on
the average behavior in a population. The present disclosure is
intended to encompass compositions that on average fall within the
disclosed ranges, even though it is understood that certain
subjects can fall outside of the ranges.
[0242] The pharmaceutical compositions can be included in a
container, pack, or dispenser together with instructions for
administration. The present disclosure provides a kit including, in
addition to a pharmaceutical composition of a compound of the
disclosure, a container, pack, or dispenser together with
instructions for administration.
[0243] A compound of the present disclosure (e.g., Compound 1, Form
A), or a pharmaceutically acceptable salt, prodrug, metabolite,
analog or derivative thereof, can be administered in combination
with a second antiviral compound. For example, as noted above, a
composition of the present disclosure can include a compound as
described above in combination with one or more (e.g., 1, 2, 3)
additional active agents such as described in this section in
analogous manner as known in the art. Additional antiviral active
agents that can be used with a compound of the present disclosure
in carrying out the present methods include, but are not limited
to, those that target the M2 ion channel in influenza A viruses
(e.g., the adamantanes, such as amantadine and rimantadine); those
that inhibit viral uncoating following entry into the cell, agents
that block release of the newly formed virions from the surface of
infected cells (e.g., the neuraminidase inhibitors, such as
oseltamivir and zanamivir).
Methods for Preventing Disease or Disorder Due to Virus
Reactivation
[0244] The current disclosure also provides a method of preventing
a disease or disorder in a subject at risk of virus infection
reactivation, by orally administering to the subject a
pharmaceutical composition of a therapeutically effective dose of a
compound of Formula I, (e.g., Compound 1, Form A) or a
pharmaceutically acceptable salt thereof. As used herein, "viral
reactivation" is understood as a process by which a latent virus
switches to a lytic phase of replication.
[0245] In some embodiments, the virus at risk of reactivation can
be herpes simplex virus, varicella zoster virus, human
cytomegalovirus, human herpesvirus 6, human herpesvirus 7, Kaposi's
sarcoma-associated herpesvirus, JC virus, BK virus, parvovirus,
adenovirus, influenza, norovirus, EBV, ebola, picornaviridae,
paramyxoviridae, and Marburg virus. In some embodiments, the virus
at risk of reactivation can be influenza. In one embodiment, the
subject at risk of virus infection reactivation may be a subject
with a weakened immune system such as a stem cell transplant or
renal transplant recipient. In an embodiment, the subject may be a
post-hematopoietic stem cell transplant subject. In yet other
embodiments, the subject may be an islet cell transplant recipient,
bone marrow transplant recipient, endothelial cell transplant
recipient, epidermal cell transplant recipient, myoblast transplant
recipient, muscle derived stem cell recipient, and/or neural stem
cell transplant recipient.
[0246] Accordingly, administration (e.g., oral administration) of a
prophylactically effective amount of a compound of Formula I (e.g.,
Compound 1 Form A) to a subject with a latent viral infection can
prevent or delay onset of viral reactivation in a subject that is
at risk of viral reactivation.
Effect of Food
[0247] In some embodiments, the pharmaceutical composition of the
current embodiments, e.g., tablet or suspension, can be provided to
a subject when the subject is either fasted or in fed conditions.
In one embodiment, the composition comprising a compound of Formula
I, (e.g., Compound 1, Form A) (or a pharmaceutically acceptable
salt thereof) can be provided to a subject having an empty stomach,
e.g., after fasting for less than 24 hours but more than 12 hours,
more than 11 hours, more than 10 hours, more than 8 hours, or more
than 5 hours.
[0248] In other embodiments, the composition comprising a compound
of Formula I, (e.g., Compound 1, Form A) (or a pharmaceutically
acceptable salt thereof) can be provided to a subject in
combination with food or subsequent to having food. In one
embodiment, a compound of Formula I, (e.g., Compound 1, Form A) (or
a pharmaceutically acceptable salt thereof) can be taken by a
subject on an empty stomach.
Patient Population
[0249] In certain embodiments, a therapeutically and/or
prophylactically effective amount of a compound of Formula I,
(e.g., Compound 1, Form A) (or a pharmaceutically acceptable salt
thereof), a composition comprising a compound of Formula I, (e.g.,
Compound 1, Form A), or a combination therapy comprising a
composition of Formula I, (e.g., Compound 1, Form A) is
administered to a mammal in need thereof (e.g., a human) which is
about 1 to 6 months old, 6 to 12 months old, 1 to 5 years old, 5 to
10 years old, 10 to 15 years old, 15 to 20 years old, 20 to 25
years old, 25 to 30 years old, 30 to 35 years old, 35 to 40 years
old, 40 to 45 years old, 45 to 50 years old, 50 to 55 years old, 55
to 60 years old, 60 to 65 years old, 65 to 70 years old, 70 to 75
years old, 75 to 80 years old, 80 to 85 years old, 85 to 90 years
old, 90 to 95 years old, or 95 to 100 years old. In some
embodiments, the mammal is suffering from a viral infection (e.g.,
an ssRNA infection such as a norovirus infection).
[0250] In certain embodiments, a prophylactically effective amount
of a compound of Formula I, (e.g., Compound 1, Form A), a
composition comprising a compound of Formula I, (e.g., Compound 1,
Form A) or a combination therapy comprising a compound of Formula
I, (e.g., Compound 1, Form A) is administered to a human at risk
for developing a virus infection. In certain embodiments, a
compound of Formula I, (e.g., Compound 1, Form A) a composition
comprising a compound of Formula I, (e.g., Compound 1, Form A) or a
combination therapy comprising a compound of Formula I, (e.g.,
Compound 1, Form A) is administered to a human with a virus
infection. In certain embodiments, the patient is a human about 1
to 6 months old, 6 to 12 months old, 1 to 5 years old, 5 to 10
years old, 5 to 12 years old, 10 to 15 years old, 15 to 20 years
old, 13 to 19 years old, 20 to 25 years old, 25 to 30 years old, 20
to 65 years old, 30 to 35 years old, 35 to 40 years old, 40 to 45
years old, 45 to 50 years old, 50 to 55 years old, 55 to 60 years
old, 60 to 65 years old, 65 to 70 years old, 70 to 75 years old, 75
to 80 years old, 80 to 85 years old, 85 to 90 years old, 90 to 95
years old or 95 to 100 years old.
[0251] In some embodiments, a therapeutically and/or
prophylactically effective amount of a compound of Formula I,
(e.g., Compound 1, Form A), a composition comprising a compound of
Formula I, (e.g., Compound 1, Form A), or a combination therapy
comprising a compound of Formula I, (e.g., Compound 1, Form A) is
administered to a human infant. In other embodiments, a
therapeutically and/or prophylactically effective amount of a
compound of Formula I, (e.g., Compound 1, Form A), or a combination
therapy comprising a compound of Formula I, (e.g., Compound 1, Form
A) is administered to a human child. In other embodiments, a
therapeutically and/or prophylactically effective amount of a
compound of Formula I, (e.g., Compound 1, Form A), a composition
comprising a compound of Formula I, (e.g., Compound 1, Form A), or
a combination therapy comprising a compound of Formula I, (e.g.,
Compound 1, Form A) is administered to a human adult. In yet other
embodiments, a therapeutically and/or prophylactically effective
amount of a compound of Formula I, (e.g., Compound 1, Form A), a
composition comprising a compound of Formula I, (e.g., Compound 1,
Form A), or a combination therapy comprising a compound of Formula
I, (e.g., Compound 1, Form A) is administered to an elderly
human.
[0252] All percentages and ratios used herein, unless otherwise
indicated, are by weight. Other features and advantages of the
present disclosure are apparent from the different examples. The
provided examples illustrate different components and methodology
useful in practicing the present disclosure. The examples do not
limit the claimed disclosure. Based on the present disclosure the
skilled artisan can identify and employ other components and
methodology useful for practicing the present disclosure.
[0253] All patents, patent applications, and publications mentioned
herein are hereby incorporated by reference in their entireties.
However, where a patent, patent application, or publication
containing express definitions is incorporated by reference, those
express definitions should be understood to apply to the
incorporated patent, patent application, or publication in which
they are found, and not to the remainder of the text of this
application, in particular the claims of this application.
EXAMPLES
[0254] The disclosure is further illustrated by the following
examples, which are not to be construed as limiting this disclosure
in scope or spirit to the specific procedures herein described. It
is to be understood that the examples are provided to illustrate
certain embodiments and that no limitation to the scope of the
disclosure is intended thereby. It is to be further understood that
resort can be had to various other embodiments, modifications, and
equivalents thereof which can suggest themselves to those skilled
in the art without departing from the spirit of the present
disclosure and/or scope of the appended claims.
Abbreviations
TABLE-US-00009 [0255] a.sub.H2O Water activity aq. Aqueous DMA
N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO
Dimethylsulfoxide DSC Differential scanning calorimetry HPLC High
pressure liquid chromatography ICH International Conference on
Harmonization MeOH Methanol MSZW Metastable zone width NMR Nuclear
magnetic resonance 1-PrOH 1-propanol PXRD Powder X-ray diffraction
RH/r.h. Relative humidity RT r.t. Room temperature (22-26.degree.
C.) S Approximate solubility SC-XRD Single crystal X-ray
diffraction SEQ Suspension equilibration experiment Start. Mat.
Starting material T.sub.clear Temperature at which a clear solution
is obtained during heating T.sub.cloud Temperature at which a
solution starts to crystallize during cooling Temp. Temperature THF
Tetrahydrofuran TG-FTIR Thermogravimetry coupled to Fourier
transform infrared spectroscopy.
Experimental Procedures
[0256] Unless otherwise specified, the procedures used herein are
as set forth below.
Powder X-Ray Diffraction (PXRD)
[0257] When characterizing peaks (e.g., in the peak tables above),
intensities are given qualitatively: vw=very weak, w=weak,
m=medium, s=strong, vs=very strong. Unless otherwise specified, all
PXRD peaks and patterns are given in .degree.2.theta. using Cu
K.alpha. radiation at a wavelength of 1.5406 .ANG..
Reflection Mode
[0258] Measurements carried out with a Bruker D8 Advance powder
X-ray diffractometer used Cu K.alpha. radiation in the
Bragg-Brentano reflection geometry. Generally, the 2.theta. values
are accurate within 0.1-0.2.degree.. The relative peak intensities
can vary considerably for different samples of the same crystalline
form because of different preferred orientations of the crystals.
The samples were prepared without any special treatment other than
the application of slight pressure to achieve a flat surface.
Silicon single crystal sample holders of 0.1 mm, 0.5 mm or 1.0 mm
depth were used. The tube voltage and current were 40 kV and 40 mA,
respectively. The X-ray diffractometer is equipped with a LynxEye
detector. A variable divergence slit was used with a 3.degree.
window. The samples were rotated at 0.5 rps during the measurement.
PXRD standard measurements were carried out in the 2.theta. range
2.degree. to 500 with a total measuring time of about 10 minutes.
The step size was 0.02 .degree.2.theta. with a step time of 37
seconds.
Transmission Mode
[0259] The Stoe Stadi P diffractometer was equipped with a Mythen1K
Detector; Cu-Kai radiation; standard measurement conditions:
transmission; 40 kV and 40 mA tube power; curved Ge monochromator;
0.02 .degree.2.theta. step size, 48 s step time, 1.5-50.5
.degree.2.theta. scanning range; detector mode: step scan; 1
.degree.2.theta. detector step; standard sample preparation: 10 to
20 mg sample was placed between two acetate foils or Kapton foils;
sample holder: Stoe transmission sample holder; the sample was
rotated during the measurement.
Thermogravimetry Coupled to Infrared Spectroscopy (TG-FTIR)
[0260] TG-FTIR was performed on a Netzsch Thermo-Microbalance TG
209, which was coupled to a Bruker FT-IR Spectrometer Vector 22 or
IFS 28. The measurements were carried out with aluminum crucibles
with a micro pinhole under a nitrogen atmosphere and at a heating
rate of 10.degree. C./min over the range 25.degree. C. to
250.degree. C. or 300.degree. C.
Differential Scanning Calorimetry (DSC)
[0261] Differential scanning calorimetry was carried out with a TA
Instruments DSC Q2000 using hermetically sealed gold sample pans.
The heating rate was 10.degree. C. per minute.
Dynamic Vapor Sorption (DVS)
[0262] DVS measurements were performed with an SPS11-100n
"Sorptions Prufsystem" of Projekt Messtechnik", D-89077 Ulm
(Germany). About 20 to 100 mg of sample were put into an aluminum
sample pan. Humidity change rates of 5% per hour were used. The
applied measurement program is visualized in the figures.
Sonication
[0263] A laboratory ultrasound device 150 W was used.
Polarized Light Microscopy
[0264] Polarized light microscopic images were taken using a Leitz
microscope.
.sup.1HNMR
[0265] .sup.1HNMR spectra were recorded on a Bruker DPX 300
spectrometer. Solvent: deuterated DMSO or deuterated DMF.
pH Measurement
[0266] A Metrohm 780 pH meter equipped with an unitrode was used
for determination of pH values.
Solvents
[0267] For all experiments, Merck, Fluka, Sigma-Aldrich or Lab Scan
Analytical Services grade solvents were used.
HPLC
[0268] The HPLC method used in this study is described in the
Cambrex document No AP1-0548 V3. Compound 1 purity and most of the
impurities are given in area % at 280 nm and benzoic acid in area %
at 223 nm. Benzoic acid content in % w/w was not determined.
Example 1--Crystallization ExTeriments in Water and Organic
Solvent/Water Mixtures
[0269] Crystallization experiments in water, methanol, and a number
of organic solvent/water mixtures with different water activities
were conducted. As set forth below, the experiments revealed that
Form A was stable under water activity conditions between about 0.2
and 1.0. As shown below, Form A was formed from solvent systems
with a water activity of about 0.2 or above (e.g., about 0.18 or
above). Table 9 below gives a summary of crystallization
experiments and the resulting morphic form. As shown in Table 9,
the solvent:water ratios are given in terms of a volume:volume
(v/v) ratio. If the solubility at elevated temperature was A <20
mg/mL, the crystallization technique used was suspension
equilibration. Precise experimental procedures are given below.
TABLE-US-00010 TABLE 9 Crystallization Experiments in Water,
Methanol, and Organic Solvent/Water Mixtures Estimated Experiment
Solvent Water Crystal No. System Activity Crystallization Technique
Form 1 Water 1 Suspension equilibration 90.degree. C. (2 days) A
Cooling RT (2 hours) Suspension equilibration RT (2 hours) Filter
centrifugation 2 THF:Water 0.94 Cooling solution 60.degree. C. to
RT A 1:1 Suspension equilibration RT (4 days) Filter centrifugation
3 Acetone:Water 0.82 Suspension equilibration 54.degree. C. (3
days) A 4:1 Hot filtration and air drying (22.degree. C./36% RH) 4
DMA:Water 0.8 Cooling Solution 90.degree. C. to RT A 1:1 Suspension
equilibration RT (1 day) Filter centrifugation 5 DMF:Water 0.79
Cooling Solution 90.degree. C. to RT A 1:1 Suspension equilibration
RT (1 day) Filter centrifugation 6 DMSO:Water 0.68 Cooling Solution
90.degree. C. to RT A 1:1 Suspension equilibration RT (1 day)
Filter centrifugation 7 MeOH:Water 0.29 Suspension equilibration
54.degree. C. (3 days) A 9:1 Hot filtration and air drying
(22.degree. C./35% RH) 8 MeOH:Water 0.18 Suspension equilibration
54.degree. C. (3 days) A 95:5 Hot filtration and air drying
(22.degree. C./35% RH) 9, 10 MeOH <0.1 Cooling solution
60.degree. C. to RT B
[0270] Experiment No. 1:
[0271] 103 mg of a sample of Compound 1 was suspended at 90.degree.
C. in 5.0 mL of water (water activity 1.00). Weak suspension was
stirred at 90.degree. C. for 2 days. Weak suspension was cooled to
30.degree. C. in about 2 hours. Suspension was stirred at r.t. for
about 2 hours and centrifuged (filter centrifugation).
[0272] Experiment No. 2:
[0273] 106 mg of a sample of Compound 1 was dissolved at 60.degree.
C. in 2.5 mL of THF/water 1:1 v/v (water activity about 0.94).
Solution was cooled to r.t. and stirred at r.t. for 4 days. Weak
suspension was centrifuged (filter centrifugation).
[0274] Experiment No. 3:
[0275] 110 mg of a sample of Compound 1 was suspended at 60.degree.
C. in 5.0 mL of acetone/water 4:1 v/v (water activity about 0.82).
Suspension was cooled to 54.degree. C. and stirred at 54.degree. C.
for 3 days. Suspension was filtered (hot filtration) and air dried
(22.degree. C./36% r.h.).
[0276] Experiment No. 4:
[0277] 104 mg of a sample of Compound 1 was dissolved at 90.degree.
C. in 1.5 mL of DMA/water 1:1 v/v (water activity about 0.8).
Solution was cooled to r.t. and stirred at r.t. for 1 day.
Suspension was centrifuged (filter centrifugation).
[0278] Experiment No. 5:
[0279] 103 mg of a sample of Compound 1 was dissolved at 90.degree.
C. in 1.0 mL of DMF/water 1:1 v/v (water activity about 0.79).
Solution was cooled to r.t. and stirred at r.t. for 1 day.
Suspension was centrifuged (filter centrifugation).
[0280] Experiment No. 6:
[0281] 103 mg of a sample of Compound 1 was dissolved at 90.degree.
C. in 1.5 mL of DMSO/water 1:1 v/v (water activity about 0.68).
Solution was cooled to r.t. and stirred at r.t. for 1 day.
Suspension was centrifuged (filter centrifugation).
[0282] Experiment No. 7:
[0283] 110 mg of a sample of Compound 1 was suspended at 60.degree.
C. in 5.0 mL of methanol/water 9:1 v/v (water activity about 0.29).
Suspension was cooled to 54.degree. C. and stirred at 54.degree. C.
for 3 days. Suspension was filtered (hot filtration) and air dried
(22.degree. C./35% r.h.).
[0284] Experiment No. 8:
[0285] 110 mg of a sample of Compound 1 was suspended at 60.degree.
C. in 5.0 mL of methanol/water 95:5 v/v (water activity about
0.18). Suspension was cooled to 54.degree. C. and stirred at
54.degree. C. for 3 days. Suspension was filtered (hot filtration)
and air dried (22.degree. C./35% r.h.).
[0286] Experiment No. 9: Dissolution of a sample of Compound 1 was
in methanol at 60.degree. C., followed by partial evaporation of
the solvent and cooling the sample to room temperature.
[0287] Experiment No. 10:
[0288] Dissolution of a sample of Compound 1 was in methanol at
60.degree. C., followed by partial evaporation of the solvent and
cooling the sample to room temperature.
Example 2--Crystallization from Solutions in Organic Solvents
[0289] Crystallization by cooling of solutions of Compound 1 in
organic solvents as well as precipitation experiments by addition
of organic antisolvents to solutions in DMSO resulted in the
formation of solvates of Compound 1. Table 10 below gives a summary
of the experimental protocols, and the protocols are given in more
detail below.
TABLE-US-00011 TABLE 10 Crystallization from Solutions of Compound
1 in Organic Solvents Experiment No. Solvent Antisolvent Crystal
Form 11, 12, 13 Methanol None B (methanol hemisolvate) 14 Ethanol
None C (ethanol hemisolvate) 15 DMSO 2-propanol F (2-propanol
hemisolvate; preliminary) 16 DMSO acetone G (DMSO solvate;
preliminary)
[0290] Experiment No. 11:
[0291] 103 mg of a sample of Compound 1 was dissolved at 60.degree.
C. in 5.0 mL of methanol. Solution was cooled to r.t. and stirred
at r.t. for 3 days. Weak suspension was filtered and air dried
(22.degree. C./36% r.h.).
[0292] Experiment No. 12:
[0293] Dissolution of a sample of Compound 1 in methanol at
60.degree. C., followed by partial evaporation of the solvent and
cooling the sample to room temperature.
[0294] Experiment No. 13:
[0295] Dissolution of a sample of Compound 1 in methanol at
60.degree. C., followed by partial evaporation of the solvent and
cooling the sample to room temperature.
[0296] Experiment No. 14:
[0297] Dissolution of a sample of Compound 1 in ethanol at
80.degree. C., followed by partial evaporation of the solvent and
cooling the sample to room temperature.
[0298] Experiment No. 15:
[0299] Dissolution of a sample of Compound 1 in DMSO and
precipitation at room temperature using 2-propanol.
[0300] Experiment No. 16:
[0301] Dissolution of a sample of Compound 1 in DMSO and
precipitation at room temperature using acetone.
Example 3--Suspension Equilibration of Compound 1, Form A in
Organic Solvents
[0302] Compound 1, Form A was stirred in methanol at room
temperature for six days. After this period, the PXRD of a sample
of the suspension showed the presence of the hemihydrate. At least
90% of Form A was still present.
[0303] Additionally, Compound 1, Form A was stirred in acetonitrile
at a temperature ranging between 52.degree. C. and 75.degree. C.
for five days. The resulting crystalline material showed a PXRD
pattern similar to Compound 1, Form D. TG-FTIR of the sample showed
a reduced water content (to .ltoreq.1.6%).
[0304] As set forth above, transformations of Compound 1, Form A by
suspension equilibration was found to be slow.
Example 4--Additional Preparative Procedures
[0305] Additional synthetic protocols for various morphic Forms of
Compound 1 are given below.
Form A
[0306] Form A was prepared by suspension at equilibrium in THE at
25.degree. C. Form A was prepared by suspension equilibrium in
acetone at 52.degree. C. Form A was prepared by suspension
equilibrium in 2-propanol at 75.degree. C. and at 52.degree. C.
Form A was prepared by suspension at equilibrium in water at
25.degree. C. Form A was prepared by suspension at equilibrium in
THF:water (1:1, v/v) at 25.degree. C. Form A was prepared by
suspension at equilibrium in DMA:water (1:1, v/v) at 25.degree. C.
Form A was prepared by suspension at equilibrium in methanol:water
(9:1, v/v) at 25.degree. C.
[0307] Form A was also prepared by storing the mother liquor from
Experiment 2 (Example 1; Form A) and partially evaporating the
solvent. After 1 day, about 40% of the solvent had evaporated. The
suspension was centrifuged and filtered to produce Form A.
[0308] Form A was prepared by suspending 100 mg Compound 1 (Form A)
at 60.degree. C. in 5.0 mL THF. The suspension was cooled to
54.degree. C. and stirred at 54.degree. C. for 3 days. The
suspension was filtered and air dried at 22.degree. C. and 35%
relative humidity to give Form A.
[0309] Form A was prepared by treating the product of Experiment 9
(Example 1; Form B) under the conditions of dynamic vapor sorption
(DVS) from 50% relative humidity to 0% relative humidity to 95%
relative humidity to 50% relative humidity.
[0310] Form A was prepared by suspending 151.8 mg of Compound 1
(Form A) at room temperature (25.degree. C.) in 15.00 mL of 1M
aqueous HCl followed by addition of 15.00 mL of 1M aqueous NaOH.
The resulting solution was about pH 6. The sample was sonicated and
stirred at room temperature for about 2 hours. A suspension was
formed, resulting in Form A.
Forms A and C
[0311] A mixture of Form A and Form C was prepared by cooling a
solution of Compound 1 (Form A) in about 8 mL ethanol from
75.degree. C. to about 25.degree. C. (i.e., to room
temperature).
Form B
[0312] Form B was prepared by heating the product of Experiment 10
(Example 1; Form B) under dry nitrogen flow up to about 80.degree.
C.
Form D
[0313] Form D was prepared by heating a sample of Compound 1 (Form
A) under dry nitrogen flow up to about 200.degree. C. or about
207.degree. C. The same sample remained as Form D after the
conditions of dynamic vapor sorption from 50% relative humidity to
0% relative humidity to 95% relative humidity to 50% relative
humidity.
Form E
[0314] Form E was prepared by heating the product of Experiment 9
(Example 1; Form B) under a dry nitrogen flow up to about
200.degree. C. The product was converted to Form A under the
conditions of dynamic vapor sorption at 50% relative humidity to 0%
relative humidity to 95% relative humidity to 50% relative
humidity.
[0315] Form E was prepared by heating the product of Experiment 14
(Example 2; Form C) under dry nitrogen flow up to about 200.degree.
C.
[0316] Form E was prepared by heating the product of Experiment 10
(Example 1; Form B) under dry nitrogen flow up to about 200.degree.
C.
Example 5--Thermodynamic Stability
[0317] A mixture of Compound 1, Forms A, B, C, D, E, F and G was
stirred in DMF/water 1:1 v/v (water activity about 0.79). After
stirring the suspension for four days at room temperature PXRD
showed only the peaks of crystal form A.
[0318] A mixture of Compound 1, Forms A, B, C, D, E, F and G was
stirred in methanol/water 95:5 v/v (water activity about 0.18).
After stirring the suspension for four days at room temperature
PXRD showed only the peaks of crystal form A.
[0319] Accordingly, the above-results suggest that morphic Form A
is the most thermodynamically stable of the seven morphic forms
identified.
Example 6--Development of Large-Scale Crystallization Conditions
for Form A
[0320] This example explored suitable crystallization processes to
produce Compound 1, Form A on a multi-gram scale. Process
development investigated purity, yield, crystal form, residual
solvent content, and particle size distribution.
[0321] With the exception of the approximate solubility
investigations, all experiments set forth in this example began
with the same two hundred-gram sample of crude Compound 1. The
sample comprised Form A of Compound 1, and 1.4% total impurity.
Specifically, the sample comprised 0.57% benzoic acid (w/w); 0.44%
of Impurity No. 1 (by HPLC; RRT about 0.54); and 0.41% of Impurity
No. 2, (by HPLC; RRT about 1.13). The structure of Impurity Nos. 1
and 2 are shown below:
##STR00003##
Preliminary Investigations: Approximate Solubility Compound 1
[0322] To determine approximate solubility of Compound 1, solvent
was added in steps to the solid material (about 20 to 100 mg). The
solubility values were rough approximations. Therefore, these
values were used solely for the preliminary design of subsequent
crystallization experiments. The results of the approximate
solubility determinations are given in Table 11.
TABLE-US-00012 TABLE 11 Approximate solubility of Compound 1 in
Various Solvents Solubility [S, mg/mL] Solvent/Mixture RT
60.degree. C. Water <1.3 ~3 NaOH aq 1M ~60 ~95 NaOH aq 0.5M ~16
~38 NaOH aq 0.1M ~3 ~9 DMSO ~500 -- DMSO/water 1:1 v/v ~8 (~45 at
80.degree. C.) DMSO/NaOH aq 0.1M 1:1 v/v ~20 -- DMSO/water 1:2 v/v
~3 -- 2-Propanol/water 2:1 v/v ~6 -- 2-Propanol/water 1:1 v/v ~7 --
2-Propanol/NaOH aq 0.1M 1:1 v/v ~16 -- 2-Propanol/water 1:2 v/v ~5
(~31 at 70.degree. C.) 1-Propanol/water 2:1 v/v ~7 --
1-Propanol/water 1:2 v/v ~6 (~51 at 80.degree. C.) Ethanol 1.7 --
THF <1 -- THF/water 4:1 v/v ~15 -- THF/water 1:1 v/v ~22 --
THF/water 1:4 v/v ~6 --
[0323] Based on the preliminary investigations set forth above in
Table 11, the following potentially useful solvent systems for
crystallization of Form A were identified: (1) Aqueous 1M NaOH
(initial concentration of NaOH at 60.degree. C.) and aqueous 0.1 M
or 0.01M NaOH (final concentration of NaOH at room temperature);
(2) DMSO/aqueous NaOH 0.01 M 1:2 v/v (final concentration of NaOH
at room temperature); (3) 2-Propanol/aqueous NaOH 0.01 M 1:3 v/v
(final concentration of NaOH at room temperature); (4)
1-Propanol/aqueous NaOH 0.01 M 1:3 v/v (final concentration of NaOH
at room temperature); (5) Ethanol/aqueous NaOH 0.01 M 1:3 v/v
(final concentration of NaOH at room temperature); (6) DMSO/water
1:1 v/v; (7) 2-Propanol/water 1:2 v/v; (8) 1-Propanol/water 1:2
v/v; and (9) Water (or <0.01M NaOH).
Exact Solubility of Compound 1
[0324] The exact solubilities of Compound 1 Form A in selected
solvent systems were determined at 24.degree. C. and 60.degree. C.
About 100 mg of Compound 1 Form A were suspended in 2.0 mL of
solvent and stirred using a magnetic stirrer bar for 1 day at
24.degree. C. or 60.degree. C., followed by filter centrifugation
at the corresponding temperature. The concentration of Compound 1
was then determined by HPLC.
Exact Solubility of Compound 1 at 24.degree. C. and 60.degree.
C.
[0325] The exact solubilities of Form A in selected solvent systems
were determined at 24.degree. C. and 60.degree. C. About 100 mg of
Compound 1 were suspended in 2.0 mL of solvent and stirred using a
magnetic stirrer bar for 1 day at 24.degree. C. or 60.degree. C.,
followed by filter centrifugation at the corresponding temperature.
The concentration of Compound 1 was then determined by HPLC. The
results of the exact solubility determinations are given in Table
12.
TABLE-US-00013 TABLE 12 Exact solubility of Compound 1 in Various
Solvents Solubility [mg/mL] Solvent/Mixture 24.degree. C.
60.degree. C. NaOH aq 0.1M 2.8 8.0 NaOH aq 0.01M 0.81 -- DMSO/NaOH
aq 0.1M 1:2 v/v 12.5 -- DMSO/NaOH aq 0.01M 1:2 v/v 4.8 19.6
2-Propanol/NaOH aq 0.1M 1:3 v/v 14.1 -- 2-Propanol/NaOH aq 0.01M
1:3 v/v 5.2 16.9 1-Propanol/NaOH aq 0.1M 1:3 v/v 16.6 --
1-Propanol/NaOH aq 0.01M 1:3 v/v 6.8 25.9 Ethanol/NaOH aq 0.1M 1:3
v/v 9.0 -- Ethanol/NaOH aq 0.01M 1:3 v/v 3.3 15.3 2-Propanol/water
1:2 v/v -- 26.6 1-Propanol/water 1:2 v/v -- 30.9 DMSO/water 1:1 v/v
-- 18.7
HPLC Analysis for the Solutions of the Solubility Experiments
[0326] Most of the PLC chromatograms of the solutions of the exact
solubility determinations shown above in Table 12 exhibited higher
levels of the impurities benzoic acid, Impurity No. 1 and Impurity
No. 2 as shown below in Table 13. Without wising to be bound by
theory, this enrichment of the impurities in the solutions
indicates purification of crude Compound 1 during suspension
equilibration, especially at 60.degree. C. Without wising to be
bound by theory, it is likely that the enrichment of Impurity No. 1
is due to degradation only when using 0.1M NaOH over a period of 24
hours.
TABLE-US-00014 TABLE 13 HPLC Analysis for the Solutions of the
Exact Solubility Determinations Solvent/Mixture 24.degree. C. (area
%; 280 nm) 60.degree. C. (area %; 280 nm) Crude Compound 1 prior to
Compound 1: 99.08 -- solubility measurements benzoic acid (223 nm):
1.14 Impurity No. 1: 0.45 RRT 0.67: 0.02 Impurity No. 2: 0.41 NaOH
aq 0.1M Compound 1: 92.62 Compound 1: 70.21 benzoic acid (223 nm):
14.38 benzoic acid (223 nm): 4.29 Impurity No. 1: 5.12 Impurity No.
1: 28.79 RRT 0.67: 0.19 RRT 0.67: 0.08 Impurity No. 2: 1.52
Impurity No. 2: 0.72 NaOH aq 0.01M Compound 1: 86.56 -- benzoic
acid (223 nm): 36.65 Impurity No. 1: 7.43 RRT 0.67: 0.54 Impurity
No. 2: 3.59 DMSO/NaOH aq 0.1M 1:2 v/v Compound 1: 97.96 -- benzoic
acid (223 nm): 3.78 Impurity No. 1: 1.15 RRT 0.67: 0.05 Impurity
No. 2: 0.67 DMSO/NaOH aq 0.01M 1:2 v/v Compound 1: 96.87 Compound
1: 97.71 benzoic acid (223 nm): 9.28 benzoic acid (223 nm): 2.43
Impurity No. 1: 1.60 Impurity No. 1: 1.38 RRT 0.67: 0.10 RRT 0.67:
0.06 Impurity No. 2: 1.05 Impurity No. 2: 0.76 2-Propanol/NaOH aq
0.1M 1:3 v/v Compound 1: 98.04 -- benzoic acid (223 nm): 3.77
Impurity No. 1: 1.17 RRT 0.67: 0.06 Impurity No. 2: 0.62
2-Propanol/NaOH aq 0.01M 1:3 Compound 1: 96.38 Compound 1: 97.48
v/v benzoic acid (223 nm): 9.79 benzoic acid (223 nm): 2.90
Impurity No. 1: 1.93 Impurity No. 1: 1.64 RRT 0.67: 0.13 RRT 0.67:
0.06 Impurity No. 2: 1.24 Impurity No. 2: 0.72 1-Propanol/NaOH aq
0.1M 1:3 v/v Compound 1: 98.00 -- benzoic acid (223 nm): 3.35
Impurity No. 1: 1.16 RRT 0.67: 0.05 Impurity No. 2: 0.68
1-Propanol/NaOH aq 0.01M 1:3 Compound 1: 98.00 Compound 1: 97.83
v/v benzoic acid (223 nm): 6.57 benzoic acid (223 nm): 2.25
Impurity No. 1: 0.99 Impurity No. 1: 1.40 RRT 0.67: 0.07 RRT 0.67:
0.05 Impurity No. 2: 0.73 Impurity No. 2: 0.65 Ethanol/NaOH aq 0.1M
1:3 v/v Compound 1: 97.93 -- benzoic acid (223 nm): 5.45 Impurity
No. 1: 1.22 RRT 0.67: 0.05 Impurity No. 2: 0.62 Ethanol/NaOH aq
0.01M 1:3 v/v Compound 1: 95.00 Compound 1: 96.53 benzoic acid (223
nm): 10.74 benzoic acid (223 nm): 3.97 Impurity No. 1: 2.70
Impurity No. 1: 2.37 RRT 0.67: 0.21 RRT 0.67: 0.10 Impurity No. 2:
1.72 Impurity No. 2: 0.85 2-Propanol/water 1:2 v/v -- Compound 1:
98.60 benzoic acid (223 nm): 1.97 Impurity No. 1: 0.71 RRT 0.67:
0.05 Impurity No. 2: 0.58 1-Propanol/water 1:2 v/v -- Compound 1:
98.76 benzoic acid (223 nm): 2.08 Impurity No. 1: 0.61 RRT 0.67:
0.05 Impurity No. 2: 0.51 DMSO/water 1:1 v/v -- Compound 1: 98.21
benzoic acid (223 nm): 3.23 Impurity No. 1: 0.91 RRT 0.67: 0.06
Impurity No. 2: 0.71
PXRD of Solid Residues and HPLC Analysis for Selected Solid
Residues
[0327] The solid residues of the solubility determinations were
characterized by PXRD. All solid residues showed the pattern of
Compound 1 hemihydrate (Form A).
[0328] Selected solid residues after the solubility determinations
were also tested by HPLC (see Table 14). These characterizations
were performed in order to get a preliminary insight into
purification or degradation during suspension equilibration. All
the samples tested showed somewhat higher HPLC purities compared to
the crude Compound 1, including the solid residue of the solubility
determination in 0.1M NaOH at 60.degree. C. These results indicate
that suspension equilibration is not effective enough for
elimination of the main impurities.
TABLE-US-00015 TABLE 14 HPLC Analysis for Selected Solid Residues
of the Exact Solubility Determinations Solvent/Mixture 24.degree.
C. (area %; 280 nm) 60.degree. C. (area %; 280 nm) Crude Compound 1
prior to Compound 1: 99.08 -- solubility measurements benzoic acid
(223 nm): 1.14 Impurity No. 1: 0.45 RRT 0.67: 0.02 Impurity No. 2:
0.41 NaOH aq 0.1M Compound 1: 99.27 Compound 1: 99.32 benzoic acid
(223 nm): 0.11 benzoic acid (223 nm): 0.09 Impurity No. 1: 0.35
Impurity No. 1: 0.39 RRT 0.67: 0.02 RRT 0.67: 0.02 Impurity No. 2:
0.35 Impurity No. 2: 0.28 NaOH aq 0.01M Compound 1: 99.28 --
benzoic acid (223 nm): 0.15 Impurity No. 1: 0.34 RRT 0.67: 0.02
Impurity No. 2: 0.36 DMSO/NaOH aq 0.1M -- -- 1:2 v/v DMSO/NaOH aq
0.01M Compound 1: 99.38 Compound 1: 99.59 1:2 v/v benzoic acid (223
nm): 0.14 benzoic acid (223 nm): 0.07 Impurity No. 1: 0.30 Impurity
No. 1: 0.18 RRT 0.67: <0.01 RRT 0.67: <0.01 Impurity No. 2:
0.32 Impurity No. 2: 0.23 2-Propanol/NaOH aq -- -- 0.1M 1:3 v/v
2-Propanol/NaOH aq Compound 1: 99.34 Compound 1: 99.58 0.01M 1:3
v/v benzoic acid (223 nm): 0.12 benzoic acid (223 nm): 0.07
Impurity No. 1: 0.31 Impurity No. 1: 0.17 RRT 0.67: 0.02 RRT 0.67:
0.01 Impurity No. 2: 0.33 Impurity No. 2: 0.24 1-Propanol/NaOH aq
-- -- 0.1M 1:3 v/v 1-Propanol/NaOH aq Compound 1: 99.31 -- 0.01M
1:3 v/v benzoic acid (223 nm): 0.12 Impurity No. 1: 0.33 RRT 0.67:
0.02 Impurity No. 2: 0.34 Ethanol/NaOH aq 0.1M -- -- 1:3 v/v
Ethanol/NaOH aq 0.01M Compound 1: 99.42 Compound 1: 99.57 1:3 v/v
benzoic acid (223 nm): 0.10 benzoic acid (223 nm): 0.08 Impurity
No. 1: 0.27 Impurity No. 1: 0.17 RRT 0.67: <0.01 RRT 0.67:
<0.01 Impurity No. 2: 0.30 Impurity No. 2: 0.26 2-Propanol/water
1:2 v/v -- Compound 1: 99.49 benzoic acid (223 nm): 0.09 Impurity
No. 1: 0.24 RRT 0.67: 0.01 Impurity No. 2: 0.26 1-Propanol/water
1:2 v/v -- -- DMSO/water 1:1 v/v -- Compound 1: 99.45 benzoic acid
(223 nm): 0.11 Impurity No. 1: 0.25 RRT 0.67: 0.02 Impurity No. 2:
0.28
Small Scale Crystallization Experiments
[0329] Small scale crystallization experiments were carried out
using a Mettler Toledo MultiMax system with 50 mL glass vessels
equipped with magnetic stirrer bars and turbidity probes. For
vacuum filtration sintered glass funnels were used (porosity P4;
diameter 2.theta. mm or 73 mm).
First Iteration
[0330] The initially selected solvent systems for crystallization
experiments at the 10 mL to 20 mL scale are given in Table 15.
Without wishing to be bound by theory, these solvent systems were
chosen in view of the solubility measurements set forth above in
view of the following observations: (i) 1-Propanol/water 1:2 v/v
showed a workable solubility profile and allows using a broad
temperature range; (ii) Starting with 1-propanol/NaH aq 0.1M 1:3
v/v could be useful if the solubility at 60.degree. C. can be
significantly increased; (iii) Starting with DMSO/NaOH aq 0.1M 1:2
v/v might be useful if the solubility at 60.degree. C. can be
significantly increased; (iv) Starting with NaOH aq 1M at
60.degree. C. is close to the conditions used in the THF/aqueous
NaH process for hydrolysis after evaporation of THF. Detailed
experimental procedures are given below.
TABLE-US-00016 TABLE 15 Selected Solvent Systems for
Crystallization Experiments at to 10-mL to 20-mL Scale Process/
Solvent system Temperature Exp. No. Initial Final Initial Final
Seeding Cooling rate 17 1-PrOH/H2O 1-PrOH/H2O 80.degree. C.
10.degree. C. 60.degree. C. 80.degree. C. to 60.degree. C.: 1:2 v/v
1:2 v/v 20K/hour 60.degree. C. to 10.degree. C.: 5K/hour 18
1-PrOH/NaOH aq 1-PrOH/NaOH aq 60.degree. C. 10.degree. C.
60.degree. C. 5K/hour 0.1M 0.01M 1:3 v/v about 1:3 v/v (addition of
aqueous 1M acetic acid solution at 60.degree. C.). 19 DMSO/NaOH aq
DMSO/NaOH aq 60.degree. C. 10.degree. C. 60.degree. C. 5K/hour 0.1M
0.01M 1:2 v/v about 1:2 v/v (addition of aqueous 1M acetic acid
solution at 60.degree. C.). 20 NaOH aq 1M NaOH aq 0.01M 60.degree.
C. 10.degree. C. 60.degree. C. 5K/hour (addition of aqueous 1M
acetic acid solution at 60.degree. C.).
[0331] Experiment No. 17:
[0332] 971 mg of crude Compound 1 were suspended in 20 mL of
1-propanol/water 1:2 v/v, stirred using a magnetic stirrer and
heated to 80.degree. C. in 30 minutes. After stirring at 80.degree.
C. for about 2 minutes the solution formed was then cooled to
60.degree. C. with a cooling rate of 20K/hour. At 60.degree. C. the
solution was seeded with a suspension of 25 mg of crude Compound 1
in 1 mL of water. The weak suspension formed was stirred at
60.degree. C. for 5 minutes, cooled to 10.degree. C. with a cooling
rate of 5K/hour and then stirred overnight at 10.degree. C.
[0333] The easy-to-stir suspension was filtered using a sintered
glass funnel (porosity P4). The suspension was easy to filter. The
glass reactor was flushed with 5 mL of water and the washing
suspension was also filtered. The filter cake was again washed with
5 mL of water and air dried for 15 minutes by drawing ambient air
through the glass funnel. The off-white solid was then vacuum dried
at about 45.degree. C./about 20 mbar overnight. Yield (corrected
for seeding material): 797 mg (82.1%) and 99.59% pure by HPLC.
[0334] Experiment No. 18:
[0335] 1258 mg of crude Compound 1 were suspended in 20 mL of
1-propanol/0.1 M aq NaOH 1:3 v/v, stirred using a magnetic stirrer
and heated to 60.degree. C. in 30 minutes. Additional
1-propanol/0.1 M aq NaOH 1:3 v/v was added at 60.degree. C. in 2 mL
steps in about 20 minutes until a solution was formed (total volume
of 1-propanol/0.1 M aq NaOH 1:3 v/v: 36 mL). At 60.degree. C. a
total of 2.43 mL of 1M aq acetic acid solution was then added in
0.243 mL steps in about 20 minutes. After addition of 0.729 mL the
solution was seeded with a suspension of 26 mg sample of crude
Compound 1 in 1 mL of water resulting in a very weak suspension.
After complete addition of 1M aq acetic acid the weak suspension
formed was cooled to 10.degree. C. with a cooling rate of 5K/hour
and stirred overnight at 10.degree. C.
[0336] The easy-to-stir suspension was filtered using a sintered
glass funnel (porosity P4). The suspension was easy to filter. The
glass reactor was flushed with 5 mL of water and the washing
suspension was also filtered. The filter cake was washed with 5 mL
of water and air dried for 15 minutes by drawing ambient air
through the glass funnel. The off-white solid was then vacuum dried
at about 45.degree. C./about 20 mbar overnight. Yield (corrected
for seeding material): 1050 mg (83.5%) and 99.73% pure by HPLC.
[0337] Experiment No. 19:
[0338] 1020 mg sample of crude Compound 1 was suspended in 20 mL of
DMSO/0.1 M aq NaOH 1:2 v/v, stirred using a magnetic stirrer and
heated to 60.degree. C. in 30 minutes. Additional DMSO/0.1 M aq
NaOH 1:2 v/v was added at 60.degree. C. in 2 mL steps in about 20
minutes until a solution was formed (total volume of DMSO/0.1 M aq
NaOH 1:2 v/v: 31 mL). At 60.degree. C. a total of 1.86 mL of 1M aq
acetic acid solution was then added in 0.186 mL steps in about 20
minutes. After addition of 0.558 mL the solution was seeded with a
suspension of 25 mg crude Compound 1 in 1 mL of water resulting in
a very weak suspension. After complete addition of 1M aq acetic
acid the weak suspension formed was cooled to 10.degree. C. with a
cooling rate of 5K/hour and stirred overnight at 10.degree. C.
[0339] The easy-to-stir suspension was then filtered using a
sintered glass funnel (porosity P4). The suspension was easy to
filter. The glass reactor was flushed with 5 mL of water and the
washing suspension was also filtered. The filter cake was washed
with 5 mL of water and air dried for 15 minutes by drawing ambient
air through the glass funnel. The off-white solid was then vacuum
dried at about 45.degree. C./about 20 mbar overnight. Yield
(corrected for seeding material): 864 mg (84.7%) and 99.70% pure by
HPLC.
[0340] Experiment No. 20:
[0341] 914 mg sample of crude Compound 1 was suspended in 10 mL of
1M aq NaOH, stirred using a magnetic stirrer and heated to
60.degree. C. in 15 minutes. After stirring at 60.degree. C. for
about 2 minutes a clear solution was present. At 60.degree. C. a
total of 9.90 mL of 1M aq acetic acid solution was added in 0.99 mL
steps in about 20 minutes. After addition of 2.97 mL the solution
was seeded with a suspension of 25 mg of crude Compound 1 in 1 mL
of water resulting in a suspension. After complete addition of 1M
aq acetic acid the suspension formed was cooled to 10.degree. C.
with a cooling rate of 5K/hour and stirred overnight at 10.degree.
C.
[0342] The easy-to-stir suspension was then filtered using a
sintered glass funnel (porosity P4). The suspension was easy to
filter. The glass reactor was flushed with 5 mL of water and the
washing suspension was also filtered. The filter cake was washed
with 5 mL of water and air dried for 15 minutes by drawing ambient
air through the glass funnel. The off-white solid was then vacuum
dried at about 45.degree. C./about 20 mbar overnight. Yield
(corrected for seeding material): 813 mg (88.9%) and 99.52% pure by
HPLC.
[0343] The HPLC of samples from Exp. Nos. 17-20 showed that all
four processes significantly removed benzoic acid (<0.01 area
%). Impurity No. 1 was significantly reduced by Exp. Nos. 18 and 19
(<0.01 area %). The volume of solvent necessary to dissolve one
gram of Compound 1 was relatively high. For Exp. Nos. 17 and 20 the
volume of solvent was lower but Impurity No. 1 was only reduced to
a certain degree. The content of Impurity No. 2 was only partially
decreased by all four Experiments 17-20.
[0344] Without wishing to be bound by theory, a better method for
the reduction of the content of Impurity No. 1 seemed to be to use
a mixture of 1-propanol/0.01 M aqueous NaOH instead of
1-propanol/water, or to start with 1-propanol/0.1 M aq NaOH at
80.degree. C. instead of 60.degree. C. in order to reduce the
volume of solvent. Accordingly, two additional experiments were
carried out in the second iteration.
Second Iteration
[0345] Experiment No. 21:
[0346] 1007 mg of crude Compound 1 was suspended in 10 mL of
1-propanol/0.01 M aq NaOH 1:2 v/v, stirred using a magnetic stirrer
and heated to 80.degree. C. in 30 minutes. The suspension was then
stirred at 80.degree. C. for 10 minutes and additional
1-propanol/0.01 M aq NaOH 1:2 v/v was added at 80.degree. C. in
2-mL steps in about 10 minutes until a solution was formed (total
volume of 1-propanol/0.01 M aq NaOH 1:2 v/v: 20.0 mL). The solution
was then cooled to 60.degree. C. with a cooling rate of
20K/hour.
[0347] At 60.degree. C. the solution was seeded with a suspension
of 25 mg of crude Compound 1 in 1 mL of water. The very weak
suspension formed was stirred at 60.degree. C. for 20 minutes,
cooled to 10.degree. C. with a cooling rate of 5K/hour and then
stirred overnight at 10.degree. C.
[0348] The easy-to-stir suspension was filtered using a sintered
glass funnel (porosity P4). The suspension was easy to filter. The
glass reactor was flushed with 5 mL of water and the washing
suspension was also filtered. The filter cake was again washed with
5 mL of water and air dried for 15 minutes by drawing ambient air
through the glass funnel. The off-white solid was then vacuum dried
at about 45.degree. C./about 10 mbar overnight. Yield (corrected
for seeding material): 819 mg (81.3%) and 99.73% pure by HPLC.
[0349] Experiment No. 22:
[0350] 1260 mg of crude Compound 1 was suspended in 20 mL of
1-propanol/0.1 M aq NaOH 1:3 v/v, stirred using a magnetic stirrer
and heated to 80.degree. C. in 30 minutes. After stirring at
80.degree. C. for about 20 minutes the solution was cooled to
60.degree. C. with a cooling rate of 20K/hour. At 60.degree. C. a
total of 1.35 mL of 1M aq acetic acid solution was added in 0.135
mL steps in about 20 minutes. After addition of 0.405 mL the
solution was seeded with a suspension of 25 mg of crude Compound 1
in 1 mL of water resulting in a very weak suspension. After
complete addition of 1M aq acetic acid the weak suspension formed
was cooled to 10.degree. C. with a cooling rate of 5K/hour and
stirred overnight at 10.degree. C.
[0351] The easy-to-stir suspension was filtered using a sintered
glass funnel (porosity P4). The suspension was easy to filter. The
glass reactor was flushed with 5 mL of water and the washing
suspension was also filtered. The filter cake was washed with 5 mL
of water and air dried for 15 minutes by drawing ambient air
through the glass funnel. The off-white solid was then vacuum dried
at about 45.degree. C./about 10 mbar overnight. Yield (corrected
for seeding material): 1081 mg (85.8%) and 99.72% pure by HPLC.
[0352] Experiment No. 21 using 1-propanol/0.01 M aqueous NaOH 1:2
v/v instead of 1-propanol/water 1:2 v/v effectively reduced the
content of Impurity No. 1 to <0.01 area %. The volume of solvent
necessary to dissolve one gram of Compound 1 was 19.8 mL.
[0353] Experiment No. 22, starting at 80.degree. C. instead of
60.degree. C., allowed the volume of solvent to be decreased and
also effectively reduced the content of the Impurity No. 1 to
<0.01 area %. The volume of solvent necessary to dissolve one
gram of Compound 1 was 16.9 mL.
[0354] The two additional experiments 21 and 22 resulted in
significant reduction of Impurity No. 1. Without wishing to be
bound by theory, possible ways of attempting to further reduce the
volume of solvent seemed to be: (i) starting the 1-PrOH/0.01 M aq
NaOH 1:2 v/v process at temperatures around 95.degree. C.; (ii)
starting the 1-PrOH/0.01 M aq NaOH process at 80.degree. C. or
95.degree. C. using a ratio of 1:1 instead of 1:2; (iii) starting
the 1-PrOH/0.01 M aq NaOH 1:2 v/v process at 80.degree. C. and
adding DMSO to try to increase the solubility; (iv) starting the
1-PrOH/0.1 M aq NaOH process at 80.degree. C. using a ratio of 1:1
or 1:2 instead of 1:3. Accordingly, further experimentation was
carried out to evaluate ways to reduce the necessary volume of
solvent.
Third Iteration
[0355] Three additional experiments were carried out in attempt to
further reduce the necessary volume of solvent:
[0356] Experiment No. 23, Starting the I-PrOH 0.01 M Aq NaOH 1:2 v
v Process at 90.degree. C., Cooling to 60.degree. C., Seeding and
Cooling to 10.degree. C.:
[0357] 1010 mg of crude Compound 1 was suspended in 10 mL of
1-propanol/0.01 M aq NaOH 1:2 v/v, stirred using a magnetic stirrer
and heated to 90.degree. C. in 30 minutes. The suspension was then
stirred at 90.degree. C. for 3 minutes and additional
1-propanol/0.01 M aq NaOH 1:2 v/v was added at 90.degree. C. in
about 4 minutes until a solution was formed (total volume of
1-propanol/0.01 M aq NaOH 1:2 v/v: 12.5 mL). The solution was then
cooled to 60.degree. C. with a cooling rate of 20K/hour.
[0358] At 60.degree. C. the solution was seeded with a suspension
of 26 mg of crude Compound 1 in 1 mL of water. The very weak
suspension formed was stirred at 60.degree. C. for 5 minutes,
cooled to 10.degree. C. with a cooling rate of 5K/hour and then
stirred overnight at 10.degree. C.
[0359] The easy-to-stir suspension was filtered using a sintered
glass funnel (porosity P4). The suspension was easy to filter. The
glass reactor was flushed with 5 mL of water and the washing
suspension was also filtered. The filter cake was again washed with
5 mL of water and air dried for 15 minutes by drawing ambient air
through the glass funnel. The off-white solid was then vacuum dried
at about 45.degree. C./about 10 mbar overnight. Yield (corrected
for seeding material): 902 mg (89.3%) and 99.76% pure by HPLC.
[0360] Experiment No. 24, Starting the I-PrOH 0.01 M Aq NaOH
Process at 90.degree. C. Using a Ratio of 1:1 Instead of 1:2,
Cooling to 60.degree. C., Seeding and Cooling to 10.degree. C.:
[0361] 1006 mg of crude Compound 1 was suspended in 10 mL of
1-propanol/0.01 M aq NaOH 1:1 v/v, stirred using a magnetic stirrer
and heated to 90.degree. C. in 30 minutes. The suspension was then
stirred at 90.degree. C. for 3 minutes and additional
1-propanol/0.01 M aq NaOH 1:1 v/v was added at 90.degree. C. in
about 2 minutes until a solution was formed (total volume of
1-propanol/0.01 M aq NaOH 1:1 v/v: 12.0 mL). The solution was then
cooled to 60.degree. C. with a cooling rate of 20K/hour.
[0362] At 60.degree. C. the solution was seeded with a suspension
of 25 mg of crude Compound 1 in 1 mL of water. The very weak
suspension formed was stirred at 60.degree. C. for 6 minutes,
cooled to 10.degree. C. with a cooling rate of 5K/hour and then
stirred overnight at 10.degree. C.
[0363] The easy-to-stir suspension was filtered using a sintered
glass funnel (porosity P4). The suspension was easy to filter. The
glass reactor was flushed with 5 mL of water and the washing
suspension was also filtered. The filter cake was again washed with
5 mL of water and air dried for 15 minutes by drawing ambient air
through the glass funnel. The off-white solid was then vacuum dried
at about 45.degree. C./about 10 mbar overnight. Yield (corrected
for seeding material): 888 mg (88.3%) and 99.73% pure by HPLC.
[0364] Experiment No. 25, Starting the 1-PrOH 0.1 M Aq NaOH Process
at 90.degree. C. Using a Ratio of 1:1 Instead of 1:3, Cooling to
60.degree. C. Followed by Addition of 1M Aq Acetic Acid at
60.degree. C., Seeding and Cooling to 10.degree. C.:
[0365] 999 mg of crude Compound 1 was suspended in 10 mL of
1-propanol/0.1 M aq NaOH 1:1 v/v, stirred using a magnetic stirrer
and heated to 90.degree. C. in 30 minutes. At 90.degree. C. a
solution was formed. The solution was then cooled to 60.degree. C.
with a cooling rate of 20K/hour. At 60.degree. C. a total of 0.09
mL of 1M aq acetic acid solution was then added in 0.018 mL steps
in about 9 minutes. After addition of 0.036 mL the solution was
seeded with a suspension of 25 mg of crude Compound 1 in 1 mL of
water resulting in a very weak suspension. After complete addition
of 1M aq acetic acid the weak suspension formed was cooled to
10.degree. C. with a cooling rate of 5K/hour and stirred overnight
at 10.degree. C.
[0366] The easy-to-stir suspension was filtered using a sintered
glass funnel (porosity P4). The suspension was easy to filter. The
glass reactor was flushed with 5 mL of water and the washing
suspension was also filtered. The filter cake was washed with 5 mL
of water and air dried for 15 minutes by drawing ambient air
through the glass funnel. The off-white solid was then vacuum dried
at about 45.degree. C./about 20 mbar overnight. Yield (corrected
for seeding material): 870 mg (87.1%) and 99.71% pure by HPLC.
[0367] All three additional experiments (Experiment Nos. 23-25)
resulted in significant reduction of the volume of solvent and
significant reduction of Impurity No. 1. The volume of solvent
necessary to dissolve one gram of Compound 1 was significantly
decreased in all three experiments. In all three experiments the
suspensions were easy to stir and easy to filter. The yield for all
three experiments was high (Exp. No. 23: 89%/Exp. No. 24: 88%/Exp.
No. 25: 87%). PXRD showed the pattern of Compound 1 Form A. Benzoic
acid was significantly reduced by all three processes (<0.01
area %). Impurity No. 1 was significantly reduced by all three
processes (Exp. No. 23: 0.01 area %, Exp. No. 24: 0.01 area % and
Exp. No. 25: 0.03 area %). The content of Impurity No. 2 was
partially decreased (Exp. No. 23: 0.22 area %/Exp. No. 24: 0.26
area %/Exp. No. 25: 0.26 area %). Accordingly, it was decided to
use 1-propanol/0.01 M aq NaOH 1:2 v/v for additional medium scale
crystallization experiments.
Metastable Zone Width (MSZW)
[0368] Metastable zone width experiments were carried out using a
Mettler Toledo MultiMax system with 50 mL glass vessels equipped
with magnetic stirrer bars and turbidity probes. The MSZW
experiments investigated an appropriate temperature for seeding of
the crystallization experiments.
[0369] In order to further optimize the crystallization process at
medium scale, the metastable zone width was determined in the
selected solvent system 1-PrOH/0.01 M aq NaOH 1:2 v/v using four
different concentrations and two heating/cooling rates. The most
important conditions are given in Table 16 together with the
temperatures at which clear solutions were obtained during heating
(T.sub.clear), and the temperatures at which solutions started to
crystallize during cooling (T.sub.cloud). The results of the
experiments using a heating and cooling rate of 3K/hour are
depicted in FIG. 25. As shown in FIG. 25, T.sub.cloud is indicated
by squares, and T.sub.clear is indicated by diamonds.
TABLE-US-00017 TABLE 16 MSZW Experiments in 1-PrOH/0.01M aq NaOH
(1:2 v/v) Concentration (mg Compound 1/ T.sub.clear (.degree. C.)
T.sub.cloud (.degree. C.) mL solvent mixture) 10 K/h 3 K/h 10 K/h 3
K/h 50 73 73.6 22 48.2 60 79 78.6 51 56.9 70 83 82.6 60 67 80 86
87.1 66 71.8
[0370] 50 mg mL, 10 K/h: 499 mg of crude Compound 1 was suspended
in 10 mL of 1-propanol/0.01 M aq NaOH 1:2 v/v, stirred using a
magnetic stirrer and heated to 90.degree. C. with a heating rate of
10 K/hour. The solution formed was stirred at 90.degree. C. for 10
minutes and then cooled to 10.degree. C. with a cooling rate of
10K/hour.
[0371] 60 mg/mL, 10 K/h: 599 mg of crude Compound 1 was suspended
in 10 mL of 1-propanol/0.01 M aq NaOH 1:2 v/v, stirred using a
magnetic stirrer and heated to 90.degree. C. with a heating rate of
10 K/hour. The solution formed was stirred at 90.degree. C. for 10
minutes and then cooled to 10.degree. C. with a cooling rate of
10K/hour.
[0372] 70 mg mL, 10 K/h: 706 mg of crude Compound 1 was suspended
in 10 mL of 1-propanol/0.01 M aq NaOH 1:2 v/v, stirred using a
magnetic stirrer and heated to 90.degree. C. with a heating rate of
10 K/hour. The solution formed was stirred at 90.degree. C. for 10
minutes and then cooled to 10.degree. C. with a cooling rate of
10K/hour.
[0373] 80 mg mL, 10 K/h: 804 mg of crude Compound 1 was suspended
in 10 mL of 1-propanol/0.01 M aq NaOH 1:2 v/v, stirred using a
magnetic stirrer and heated to 90.degree. C. with a heating rate of
10 K/hour. The solution formed was stirred at 90.degree. C. for 10
minutes and then cooled to 10.degree. C. with a cooling rate of
10K/hour.
[0374] 50 mg mL, 3K/h: 502 mg of crude Compound 1 was suspended in
10 mL of 1-propanol/0.01 M aq NaOH 1:2 v/v, stirred using a
magnetic stirrer and heated to 90.degree. C. with a heating rate of
3 K/hour. The solution formed was stirred at 90.degree. C. for 10
minutes and then cooled to 10.degree. C. with a cooling rate of 3
K/hour.
[0375] 60 mg mL, 3K/h: 600 mg of crude Compound 1 was suspended in
10 mL of 1-propanol/0.01 M aq NaOH 1:2 v/v, stirred using a
magnetic stirrer and heated to 90.degree. C. with a heating rate of
3 K/hour. The solution formed was stirred at 90.degree. C. for 10
minutes and then cooled to 10.degree. C. with a cooling rate of 3
K/hour.
[0376] 70 mg mL, 3K/h: 699 mg of crude Compound 1 was suspended in
10 mL of 1-propanol/0.01 M aq NaOH 1:2 v/v, stirred using a
magnetic stirrer and heated to 90.degree. C. with a heating rate of
3 K/hour. The solution formed was stirred at 90.degree. C. for 10
minutes and then cooled to 10.degree. C. with a cooling rate of 3
K/hour.
[0377] 80 mg mL, 3K/h: 802 mg of crude Compound 1 was suspended in
10 mL of 1-propanol/0.01 M aq NaOH 1:2 v/v, stirred using a
magnetic stirrer and heated to 90.degree. C. with a heating rate of
3 K/hour. The solution formed was stirred at 90.degree. C. for 10
minutes and then cooled to 10.degree. C. with a cooling rate of
3K/hour.
[0378] Without wising to be bound by theory, these experiments show
that for the most concentrated system (800 mg Compound 1 in 10 mL
solvent mixture) an appropriate temperature for seeding is between
75.degree. C. and 80.degree. C.
Medium Scale Crystallization Experiments
[0379] Experiments involving medium scale reaction volumes (about
100 mL to 270 mL) were carried out using the Mettler-Toledo
MultiMax system equipped with a MultiMax six-necked glass reactor
(volume=300 mL, diameter 70 mm) inserted in a jacketed enclosure
along with a two-bladed metal impeller (diameter 40 mm), a
thermocouple for temperature control, and a turbidity probe. The
reactor contents temperature, T.sub.r, was used as the control
variable in the applied temperature programs. For vacuum filtration
sintered glass funnels were used (porosity P4; diameter 65 mm).
[0380] Five medium scale crystallization experiments were carried
out using the MultiMax system in order to further optimize the
crystallization process at a 20 g scale (Exp. Nos. 26-30). Without
wishing to be bound by theory, these experiments in general
confirmed the findings of the small scale crystallization
experiments regarding solvent selection, concentration, temperature
program and seeding. At the 20 g scale it was possible to improve
the stirring conditions in order to maintain the suspension over
the whole experiment, preventing lower purity deposits of solid
material on the glass wall of the reactor above the suspension.
Seeding conditions and final temperature were also
investigated.
[0381] The crystallization procedure of Exp. No. 29 was found to be
suitable for large scale crystallization. The key parameters for
the crystallization process for Compound 1 Form A at the 20-g scale
are given in below:
[0382] HPLC purity crude Compound 1: Compound 1: 99.08 area % (280
nm); Benzoic acid: 1.14 area % (223 nm); Impurity No. 1: 0.45 area
% (280 nm); Impurity No. 2: 0.41 area % (280 nm).
[0383] Solvent system: 1-PrOH/0.01 M aq NaOH 1:2 v/v pH: 12.0 to
12.2.
[0384] Concentration: 80 mg/mL.
[0385] Solvent volume: 12.5 mL/g Compound 1.
[0386] Start temperature: Room temperature (RT).
[0387] Heating rate (RT to 90.degree. C.) 30 K/hour.
[0388] Stirring time at 90.degree. C.; 15 minutes.
[0389] Cooling rate (90.degree. C. to 80.degree. C.): 15K/hour.
[0390] Stirring time at 80.degree. C. before seeding 10
minutes.
[0391] Seeding at 80.degree. C.; 0.01 g seeding material/g
dissolved Compound 1 (1% m/m) Plate-like particles average diameter
about 2.theta. .mu.m to 90 .mu.m.
[0392] Stirring at 80.degree. C. after seeding; 60 minutes
[0393] Cooling rate (80.degree. C. to 5.degree. C.): 5K/hour
[0394] Stirring time at 5.degree. C. before filtration: 4 hours
[0395] Filtration: Sintered glass funnel (porosity P4)
[0396] pH mother liquor: About 11.7
[0397] Washing: 2.times.20 mL water/20 g Compound 1
[0398] Air drying: 15 minutes at room temperature
[0399] Vacuum drying: 45.degree. C./10 mbar to 20
mbar/overnight
[0400] Yield: About 88%
[0401] HPLC benzoic acid: About 0.03 area % (223 nm)
[0402] HPLC Impurity No. 1: About 0.01 area % (280 nm)
[0403] HPLC Impurity No. 2: About 0.3 area % (280 nm)
[0404] PXRD: Compound 1 Form A
[0405] Residual 1-propanol (.sup.1H-NMR): <0.1% m/m
[0406] Microscopy: Plate-like particles about 50 m to 250 m.
[0407] Experiment No. 26
[0408] Experiment No. 26 tested seeding behavior at 75.degree. C.
at the 16 g scale as well as chemical stability when stirring
suspensions at 75.degree. C. for extended times.
[0409] 16.02 g of Compound 1 were placed in a 300 mL glass reactor
(diameter 70 mm) and 200 mL of 1-propanol/0.01 M NaOH aq 1:2 v/v
were added at room temperature. The suspension was stirred using a
two-bladed impeller (diameter 40 mm; 500 rpm) and heated to
90.degree. C. in 30 minutes. After stirring at 90.degree. C. for
about 15 minutes (500 rpm) the solution formed was cooled to
75.degree. C. with a cooling rate of 15K/hour and stirred at
75.degree. C. for 10 minutes.
[0410] At 75.degree. C. the solution was seeded with a suspension
of 158 mg of crude Compound 1 in 5 mL of water. The weak suspension
formed was stirred at 75.degree. C. overnight followed by hot
filtration (sintered glass funnel, porosity P4, diameter 65 mm; the
suspension was easy to filter). The glass reactor was flushed with
20 mL of water and the washing suspension was also filtered. The
filter cake was again washed with 20 mL of water and air dried for
20 minutes by drawing ambient air through the glass funnel.
[0411] The solid was then vacuum dried at about 45.degree. C./about
20 mbar. After drying for 3 days the solid product was 8.07 g of a
yellowish powder. Yield: 49.4% (corrected for seeding
material).
[0412] PXRD showed the pattern of Compound 1 Form A. Microscopy
revealed that very well-formed plate-like particles were produced.
HPLC of the resulting material showed a high purity of Compound 1
as shown in Table 17. Benzoic acid and Impurity No. 1 were
significantly reduced. The content of Impurity No. 2 was
decreased.
[0413] About 49% of dissolved Compound 1 crystallized at 75.degree.
C. after seeding. Compound 1 was found to be chemically stable even
after stirring of the suspension at 75.degree. C. overnight.
TABLE-US-00018 TABLE 17 HPLC Purity of Product of Experiment No. 26
Percent Area Compound 1 (280 nm) 99.84 Benzoic Acid (223 nm)
<0.01 Impurity No. 1 (280 nm) 0.01 Impurity No. 2 (280 nm)
0.15
[0414] Experiment No. 27
[0415] Experiment No. 27 tested seeding at 75.degree. C. and
cooling to 10.degree. C. as well as stirring speed 200 rpm. The
experiment also tested filtration behavior when cooling to
10.degree. C., and the HPLC purity of material suspended over the
whole experiment as well as deposits of solid material above the
suspension.
[0416] 16.00 g of crude Compound 1 were placed in a 300 mL glass
reactor (diameter 70 mm) and 200 mL of 1-propanol/0.01 M NaOH aq
1:2 v/v were added at room temperature. The suspension was stirred
using a two-bladed impeller (diameter 40 mm; 500 rpm) and heated to
90.degree. C. in 30 minutes. After stirring at 90.degree. C. for
about 15 minutes (200 rpm) the solution formed was cooled to
75.degree. C. with a cooling rate of 15K/hour and stirred at
75.degree. C. for 10 minutes.
[0417] At 75.degree. C. the solution was seeded with a suspension
of 156 mg of crude Compound 1 in 5 mL of water. The weak suspension
formed was stirred at 75.degree. C. for 10 minutes and cooled to
10.degree. C. with a cooling rate of 5K/hour, and then stirred at
10.degree. C. for 5 hours.
[0418] Because of the low stirring speed of 200 rpm it was hard to
maintain the suspension over the whole experiment. In addition, a
deposit of solid material above the suspension was observed (about
0.37 g) and separately characterized by HPLC. The suspension was
filtered using a sintered glass funnel (porosity P4; diameter 65
mm; the suspension was easy to filter). The filter cake was air
dried for 20 minutes by drawing ambient air through the glass
funnel.
[0419] The solid was then vacuum dried at about 45.degree. C./about
20 mbar. After drying for 3 days the solid product was 13.78 g of a
yellowish powder. Yield: 85.1% (corrected for seeding
material).
[0420] PXRD showed the pattern of Compound 1 Form A. Microscopy
revealed that very well-formed plate-like particles were produced.
The residual 1-propanol content estimated by .sup.1H-NMR was
<0.1% m/m. HPLC of the resulting material showed a high purity
of Compound 1. Benzoic acid and Impurity No. 1 were significantly
reduced. The content of Impurity No. 2 was decreased. However, the
solid deposit above the suspension showed a lower purity as shown
in Table 18.
[0421] Seeding at 75.degree. C. and cooling to 10.degree. C.
resulted in high yield. Stirring speed of 200 rpm was found to be
too low to maintain the suspension over the whole experiment. The
suspension was easy to filter at 10.degree. C. Benzoic acid and
Impurity No. 1 were significantly reduced; content of Impurity No.
2 decreased. Deposits of solid material above the suspension
exhibited lower purity.
TABLE-US-00019 TABLE 18 HPLC Purity of Product of Experiment No. 27
Recrystallized Deposit of solid material material above the (area
%) suspension (area %) Compound 1 (280 nm) 99.69 99.42 Benzoic acid
(223 nm) 0.02 0.20 Impurity No. 1 (280 nm) 0.03 0.17 Impurity No. 2
(280 nm) 0.28 0.40
[0422] Experiment No. 28 (Carried out in Parallel with Experiment
No. 27)
[0423] Experiment No. 28 tested seeding at 75.degree. C. and
cooling to 5.degree. C. at a stirring speed of 200 rpm. It also
tested filtration behavior when cooling to 5.degree. C., and HPLC
purity of material suspended over the whole experiment as well as
deposits of solid material above the suspension.
[0424] 16.01 g of crude Compound 1 were placed in a 300 mL glass
reactor (diameter 70 mm) and 200 mL of 1-propanol/0.01 M NaOH aq
1:2 v/v were added at room temperature. The suspension was stirred
using a two-bladed impeller (diameter 40 mm; 500 rpm) and heated to
90.degree. C. in 30 minutes. After stirring at 90.degree. C. for
about 15 minutes (200 rpm) the solution formed was cooled to
75.degree. C. with a cooling rate of 15K/hour and stirred at
75.degree. C. for 10 minutes.
[0425] At 75.degree. C. the solution was seeded with a suspension
of 158 mg of crude Compound 1 in 5 mL of water. The weak suspension
formed was stirred at 75.degree. C. for 10 minutes and cooled to
5.degree. C. with a cooling rate of 5K/hour, and then stirred at
5.degree. C. for 4 hours.
[0426] Because of the low stirring speed of 200 rpm it was hard to
maintain the suspension over the whole experiment. In addition, a
deposit of solid material above the suspension was observed (about
0.41 g) and separately characterized by HPLC. The suspension was
filtered using a sintered glass funnel (porosity P4; diameter 65
mm; the suspension was easy to filter). The filter cake was air
dried for 20 minutes by drawing ambient air through the glass
funnel.
[0427] The solid was then vacuum dried at about 45.degree. C./about
20 mbar. After drying for 3 days the solid product was 13.54 g of a
yellowish powder. Yield: 83.6% (corrected for seeding
material).
[0428] PXRD showed the pattern of Compound 1 Form A. Microscopy
revealed that very well-formed plate-like particles were produced.
The residual 1-propanol content estimated by .sup.1H-NMR was
<0.1% m/m.
[0429] HPLC of the resulting material showed a high Compound 1
purity. Benzoic acid and Impurity No. 1 were significantly reduced.
The content of Impurity No. 2 was decreased. However, the solid
deposit above the suspension showed a lower purity as shown in
Table 19.
[0430] Seeding at 75.degree. C. and cooling to 5.degree. C.
resulted in high yield. Stirring speed of 200 rpm was found to be
too low to maintain the suspension over the whole experiment. The
suspension was easy to filter at 5.degree. C. Benzoic acid and
Impurity No. 1 were significantly reduced; the content of Impurity
No. 2 decreased. Deposits of solid material above the suspension
exhibited lower purity.
TABLE-US-00020 TABLE 19 HPLC Purity of the Product of Experiment
No. 28 Recrystallized Deposit of solid material material above the
(area %) suspension (area %) Compound 1 (280 nm) 99.70 99.50
Benzoic acid (223 nm) 0.01 0.03 Impurity No. 1 (280 nm) 0.01 0.08
Impurity No. 2 (280 nm) 0.29 0.42
[0431] Experiment No. 29
[0432] Experiment No. 29 tested seeding at 80.degree. C. and
cooling to 5.degree. C. at a stirring speed of 500 rpm. It also
tested whether deposits of solid material above the suspension
could be prevented. The solid material was characterized by PXRD,
microscopy, .sup.1HNMR (residual 1-propanol) and TG-FTIR.
[0433] 20.98 g of crude Compound 1 were placed in a 300 mL glass
reactor (diameter 70 mm) and 262 mL of 1-propanol/0.01 M NaOH aq
1:2 v/v were added at room temperature. The suspension was stirred
using a two-bladed impeller (diameter 40 mm; 500 rpm) and heated to
90.degree. C. in 30 minutes. After stirring at 90.degree. C. for
about 15 minutes (500 rpm) the solution formed was cooled to
80.degree. C. with a cooling rate of 15K/hour and stirred at
80.degree. C. for 10 minutes.
[0434] At 80.degree. C. the solution was seeded with a suspension
of 209 mg of crude Compound 1 in 5 mL of water. The weak suspension
formed was stirred at 80.degree. C. for one hour and cooled to
5.degree. C. with a cooling rate of 5K/hour, and then stirred at
5.degree. C. for 4 hours.
[0435] The easy-to-stir suspension was filtered using a sintered
glass funnel (porosity P4; diameter 65 mm). The suspension was easy
to filter (mother liquor pH: 11.7). The glass reactor was flushed
with 20 mL of water and the washing suspension was also filtered.
The filter cake was again washed with 20 mL of water and air dried
for 20 minutes by drawing ambient air through the glass funnel.
[0436] The solid was then vacuum dried at about 45.degree. C./about
20 mbar. After drying overnight the solid product was 18.59 g and
after 4 days 18.58 g of a yellowish powder. Yield: 87.6% (corrected
for seeding material).
[0437] PXRD showed the pattern of Compound 1, Form A. Microscopy
revealed that very well-formed plate-like particles were produced.
The residual 1-propanol content estimated by .sup.1H-NMR was
<0.1% m/m. TG-FTIR showed a mass loss step in the temperature
range about 170.degree. C. to about 250.degree. C. of 2.6% which
was attributable to water, as shown in FIG. 26. HPLC showed a high
purity of Compound 1. Benzoic acid and Impurity No. 1 were
significantly reduced. The content of Impurity No. 2 was decreased
as shown in Table 20.
[0438] A stirring speed of 500 rpm maintained the suspension over
the whole experiment. An effective cooler was necessary in order to
prevent partial evaporation of the solvent at 90.degree. C. Seeding
at 80.degree. C. and cooling to 5.degree. C. resulted in high
yield. Seeding at 80.degree. C. is more appropriate because of the
lower supersaturation. Almost no deposits of solid material above
the suspension were observed. Benzoic acid and Impurity No. 1 were
significantly reduced; the content of Impurity No. 2 decreased.
[0439] The precise amount of sodium hydroxide at the beginning of
the crystallization experiment can affect the recrystallization. To
ensure consistency, the diluted sodium hydroxide solution can be
freshly prepared shortly before beginning the crystallization
experiment. The pH of the mother liquor of after filtration was
11.7, which is somewhat lower than the expected pH of a
1-propanol/0.01 M NaOH aq 1:2 v/v solution (pH about 12). This
could be due to the presence of 1-propanol and sodium salt
formation by acidic impurities. Another explanation could be
CO.sub.2 uptake from air and partial formation of NaHCO.sub.3. It
could also be because of the significantly lower pK.sub.a values of
benzoic acid and Impurity No. 1 compared to the pK.sub.a of
carbonic acid. Benzoic acid and Impurity No. 1 will can be
transformed into the sodium salts with NaHCO.sub.3. This
crystallization procedure was found to be suitable for large scale
experiments.
TABLE-US-00021 TABLE 20 HPLC Purity of Product of Experiment No. 29
Percent Area Compound 1 (280 nm) 99.71 Benzoic Acid (223 nm) 0.03
Impurity No. 1 (280 nm) <0.01 Impurity No. 2 (280 nm) 0.29
[0440] Experiment No. 30
[0441] Experiment No. 30 tested seeding at 75.degree. C. and
cooling to 5.degree. C. at a stirring speed of 500 rpm. It also
tested whether deposits of solid material above the suspension
could be prevented. The solid material was characterized by PXRD,
microscopy, .sup.1HNMR (residual 1-propanol) and TG-FTIR.
[0442] 21.62 g of crude Compound 1 were placed in a 300 mL glass
reactor (diameter 70 mm) and 270 mL of 1-propanol/0.01 M NaOH aq
1:2 v/v were added at room temperature. The suspension was stirred
using a two-bladed impeller (diameter 40 mm; 500 rpm) and heated to
90.degree. C. in 30 minutes. After stirring at 90.degree. C. for
about 15 minutes (500 rpm) the solution formed was cooled to
75.degree. C. with a cooling rate of 15K/hour and stirred at
75.degree. C. for 10 minutes.
[0443] At 75.degree. C. the solution was seeded with a suspension
of 213 mg of crude Compound 1 in 5 mL of water. The weak suspension
formed was stirred at 75.degree. C. for one hour and cooled to
5.degree. C. with a cooling rate of 5K/hour, and then stirred at
5.degree. C. for 6 hours.
[0444] The easy-to-stir suspension was filtered using a sintered
glass funnel (porosity P4; diameter 65 mm). The suspension was easy
to filter (mother liquor pH: 11.7) The glass reactor was flushed
with 20 mL of water and the washing suspension was also filtered.
The filter cake was again washed with 20 mL of water and air dried
for 20 minutes by drawing ambient air through the glass funnel.
[0445] The solid was then vacuum dried at about 45.degree. C./about
20 mbar. After drying for 3 days the solid product was 19.06 g of a
yellowish powder. Yield: 87.2% (corrected for seeding
material).
[0446] PXRD showed the pattern of Compound 1, Form A. Microscopy
revealed that very well-formed plate-like particles were produced.
The residual 1-propanol content estimated by .sup.1H-NMR was
<0.1% m/m. TG-FTIR showed a mass loss step in the temperature
range about 160.degree. C. to about 250.degree. C. of 2.6% which
was attributable to water (FIG. 27). HPLC showed a high Compound 1
purity (Table 21). Benzoic acid and Impurity No. 1 were
significantly reduced. The content of Impurity No. 2 was
decreased.
[0447] Seeding at 75.degree. C. and cooling to 5.degree. C.
resulted in high yield. A stirring speed of 500 rpm maintained the
suspension over the whole experiment. Benzoic acid and Impurity No.
1 were significantly reduced; the content of Impurity No. 2
decreased. Almost no deposits of solid material above the
suspension were observed. The results were the same as for
experiment No. 29. However, seeding at 80.degree. C. (as carried
out in experiment No. 29) reduced the probability of spontaneous
crystallization before seeding. Accordingly, seeing at 80.degree.
C. as set forth in Experiment No. 29 was found to be the most
robust method for the preparation of Form A on an industrial
scale.
TABLE-US-00022 TABLE 21 HPLC Purity of Product of Experiment No. 30
Percent Area Compound 1 (280 nm) 99.72 Benzoic Acid (223 nm) 0.02
Impurity No. 1 (280 nm) <0.01 Impurity No. 2 (280 nm) 0.28
EQUIVALENTS
[0448] While the present invention has been described in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and other variations thereof will be
apparent to those of ordinary skill in the art. All such
alternatives, modifications and variations are intended to fall
within the spirit and scope of the present invention.
* * * * *