U.S. patent application number 15/537331 was filed with the patent office on 2019-04-04 for solid forms comprising (1e, 4e)-2-amino-n,n-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3h-benzo[b]- azepine-4-carboxamide, compositions thereof, and uses thereof.
This patent application is currently assigned to Celgene Corporation. The applicant listed for this patent is Celgene Corporation. Invention is credited to Marie G. BEAUCHAMPS, Antonio C. FERRETTI, Timothy D. FITZPATRICK, Anthony FRANK, Ying LI, Xiaoling LU, Hon-Wah MAN.
Application Number | 20190100512 15/537331 |
Document ID | / |
Family ID | 56127832 |
Filed Date | 2019-04-04 |
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United States Patent
Application |
20190100512 |
Kind Code |
A1 |
MAN; Hon-Wah ; et
al. |
April 4, 2019 |
SOLID FORMS COMPRISING (1E,
4E)-2-AMINO-N,N-DIPROPYL-8-(4-(PYRROLIDINE-1-CARBONYL)PHENYL)-3H-BENZO[B]-
AZEPINE-4-CARBOXAMIDE, COMPOSITIONS THEREOF, AND USES THEREOF
Abstract
Provided herein are compositions including the crystalline forms
of (1E,
4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]
azepine-4-carboxamide ("Compound A"), methods of making the
crystalline forms, and methods of using the crystalline forms for
the treatment of diseases, including, for example, cancer.
Inventors: |
MAN; Hon-Wah; (Princeton,
NJ) ; FITZPATRICK; Timothy D.; (Kirkland, WA)
; FRANK; Anthony; (Easton, PA) ; LI; Ying;
(Millburn, NJ) ; LU; Xiaoling; (Whippany, NJ)
; BEAUCHAMPS; Marie G.; (Randolph, NJ) ; FERRETTI;
Antonio C.; (Summit, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Celgene Corporation |
Summit |
NJ |
US |
|
|
Assignee: |
Celgene Corporation
Summit
NJ
|
Family ID: |
56127832 |
Appl. No.: |
15/537331 |
Filed: |
December 15, 2015 |
PCT Filed: |
December 15, 2015 |
PCT NO: |
PCT/US15/65755 |
371 Date: |
June 16, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62092764 |
Dec 16, 2014 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 2200/13 20130101;
C07D 403/10 20130101; C07D 223/16 20130101; A61K 45/06 20130101;
A61P 35/00 20180101 |
International
Class: |
C07D 403/10 20060101
C07D403/10; A61P 35/00 20060101 A61P035/00 |
Claims
1. A crystalline form of the compound of formula (I):
##STR00004##
2. The crystalline form of the compound of claim 1, wherein said
crystalline form comprises an unsolvated crystalline form.
3-88. (canceled)
89. The crystalline form of the compound of formula (I) of claim 2,
wherein said crystalline form is characterized by an X-ray powder
diffraction pattern comprising angle 2 .theta. peaks at about
11.9.+-.0.2, 16.4.+-.0.2, 18.5.+-.0.2, 20.9.+-.0.2, 21.2.+-.0.2,
21.6.+-.0.2, 23.0.+-.0.2, 23.5.+-.0.2, 24.2.+-.0.2, and
27.4.+-.0.2, wherein said x-ray powder diffraction spectrum is
obtained using a Cu K.alpha. radiation source (1.54 .ANG.).
90. The crystalline form of the compound of formula (I) of claim
89, characterized by an endothermic event with an onset temperature
of about 199.degree. C. and about 211.degree. C. as measured by
differential scanning calorimetry.
91. The crystalline form of the compound of formula (I) of claim 2,
wherein said crystalline form is characterized by an X-ray powder
diffraction pattern comprising angle 2 .theta. peaks at about
11.0.+-.0.2, 14.9.+-.0.2, 18.0.+-.0.2, 19.1.+-.0.2, 21.0.+-.0.2,
and 22.8.+-.0.2, wherein said x-ray powder diffraction spectrum is
obtained using a Cu K.alpha. radiation source (1.54 .ANG.).
92. The crystalline form of the compound of formula (I) of claim
91, characterized by an endothermic event with an onset temperature
of about 211.degree. C. as determined by differential scanning
calorimetry.
93. The crystalline form of the compound of formula (I) of claim 2,
wherein said crystalline form is characterized by an X-ray powder
diffraction pattern comprising angle 2 .theta. peaks at about
12.0.+-.0.2, 13.4.+-.0.2, 15.7.+-.0.2, 16.4.+-.0.2, 18.4.+-.0.2,
19.5.+-.0.2, 21.5.+-.0.2, 22.4.+-.0.2, 22.8.+-.0.2, 23.5.+-.0.2,
and 24.2.+-.0.2, wherein said x-ray powder diffraction spectrum is
obtained using a Cu K.alpha. radiation source (1.54 .ANG.).
94. The crystalline form of the compound of formula (I) of claim
93, characterized by an endothermic event with an onset temperature
of about 206.degree. C. as determined by differential scanning
calorimetry.
95. The crystalline form of the compound of formula (I) of claim 2,
wherein said crystalline form is characterized by an X-ray powder
diffraction pattern comprising angle 2 .theta. peaks at about
11.0.+-.0.2, 15.3.+-.0.2, 15.6.+-.0.2, 17.5.+-.0.2, 18.9.+-.0.2,
20.0.+-.0.2, 21.1.+-.0.2, 22.1.+-.0.2, 24.6.+-.0.2, 25.1.+-.0.2,
and 26.5.+-.0.2, wherein said x-ray powder diffraction spectrum is
obtained using a Cu K.alpha. radiation source (1.54 .ANG.).
96. The crystalline form of the compound of claim 1, wherein said
crystalline form comprises a solvated crystalline form.
97. The crystalline form of the compound of claim 96, wherein said
solvated crystalline form is selected from the group consisting of
1,4-dioxane solvate, dichloromethane solvate, chlorobenzene
solvate, and trifluoroethanol solvate.
98. The 1,4-dioxane solvate of claim 97, wherein said crystalline
form is characterized by an X-ray powder diffraction pattern
comprising angle 2 .theta. peaks at about 10.7.+-.0.2, 15.2.+-.0.2,
15.5.+-.0.2, 17.5.+-.0.2, 18.6.+-.0.2, 19.7.+-.0.2, 20.9.+-.0.2,
21.8.+-.0.2, 24.2.+-.0.2, 24.7.+-.0.2, and 26.4.+-.0.2, wherein
said x-ray powder diffraction spectrum is obtained using a Cu
K.alpha. radiation source (1.54 .ANG.).
99. The 1,4-dioxane solvate of claim 98, characterized by an
endothermic event with an onset temperature of about 94.degree. C.
and about 193.degree. C. as determined by differential scanning
calorimetry.
100. The dichloromethane solvate of claim 97, wherein said
crystalline form is characterized by an X-ray powder diffraction
pattern comprising angle 2 .theta. peaks at about 15.6.+-.0.2,
22.0.+-.0.2, and 23.7.+-.0.2, wherein said x-ray powder diffraction
spectrum is obtained using a Cu K.alpha. radiation source (1.54
.ANG.).
101. The dichloromethane solvate of claim 100, characterized by an
endothermic event with an onset temperature of about 205.degree. C.
as determined by differential scanning calorimetry.
102. The chlorobenzene solvate of claim 97, wherein said
crystalline form is characterized by an X-ray powder diffraction
pattern comprising angle 2 .theta. peaks at about 8.8.+-.0.2,
17.7.+-.0.2, and 21.4.+-.0.2, wherein said x-ray powder diffraction
spectrum is obtained using a Cu K.alpha. radiation source (1.54
.ANG.).
103. The trifluoroethanol solvate of claim 97, wherein said
crystalline form is characterized by an X-ray powder diffraction
pattern comprising angle 2 .theta. peaks at about 4.6.+-.0.2,
4.8.+-.0.2, 15.3.+-.0.2, 16.6.+-.0.2, 18.1.+-.0.2, and 22.9.+-.0.2,
wherein said x-ray powder diffraction spectrum is obtained using a
Cu K.alpha. radiation source (1.54 .ANG.).
104. The trifluoroethanol solvate of claim 103, characterized by an
endothermic event with an onset temperature of about 206.degree. C.
as determined by differential scanning calorimetry.
105. The trifluoroethanol solvate of claim 97, wherein said
crystalline form is characterized by an X-ray powder diffraction
pattern comprising angle 2 .theta. peaks at about 12.3.+-.0.2,
14.8.+-.0.2, 16.4.+-.0.2, 18.5.+-.0.2, 19.3.+-.0.2, 19.6.+-.0.2,
20.3.+-.0.2, 21.1.+-.0.2, 22.1.+-.0.2, 22.5.+-.0.2, 23.2.+-.0.2,
24.1.+-.0.2, 25.4.+-.0.2, and 28.2.+-.0.2, wherein said x-ray
powder diffraction spectrum is obtained using a Cu K.alpha.
radiation source (1.54 .ANG.).
106. The trifluoroethanol solvate of claim 105, characterized by an
endothermic event with an onset temperature of about 110.degree. C.
as determined by differential scanning calorimetry.
107. A pharmaceutical composition comprising a crystalline form of
the compound of formula (I) of claim 1 and a pharmaceutically
acceptable excipient.
108. A method of agonizing Toll-like receptor 8 (TLR8), said method
comprising contacting TLR8 with an effective amount of a
crystalline form of the compound formula (I) of claim 1, wherein
said effective amount agonizes said TLR8.
109. A method of treating cancer, said method comprising
administering a therapeutically effective amount of a crystalline
form of the compound formula (I) of claim 1, to a subject in need
thereof, thereby treating said cancer.
Description
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 62/092,764, filed Dec. 16, 2014, which is
hereby incorporated by reference in its entirety and for all
purposes.
FIELD
[0002] Provided herein are compositions of the crystalline forms of
(1E,
4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]
azepine-4-carboxamide ("Compound A"), methods of making the
crystalline forms, and methods of using the crystalline forms for
the treatment of diseases, including, for example, cancer.
BACKGROUND
[0003] There is an enormous variety of cancers which are described
in detail in the medical literature. Examples include cancers of
the lung, colon, liver, kidneys, bladder, ovaries, prostate,
breast, head and neck, brain, blood and intestine. The incidence of
cancer continues to climb as the general population ages, as new
cancers develop, and as susceptible populations (e.g., people
infected with AIDS or excessively exposed to sunlight) grow. To
that end, there is a need in the art for additional molecular
targets for effective anti-cancer therapies.
[0004] Despite availability of a variety of anti-cancer and
chemotherapeutic agents, many of these therapies have drawbacks.
Stockdale, Medicine, vol. 3, Rubenstein and Federman, eds., ch. 12,
sect. 10, 1998. For example, many chemotherapeutic agents are
toxic, and chemotherapy causes significant, and often acute
dangerous side effects including severe nausea, bone marrow
depression, and immunosuppression. In fact, even with
administration of combinations of chemotherapeutic agents, many
tumor cells are resistant or develop resistance to such
chemotherapeutic agents. Further, it is well recognized that
specific polymorphic crystalline forms of therapeutic agents,
including anti-cancer agents are effective while other forms of the
same compound may have reduced or little-to-no activity. Thus,
identification of polymorphic forms offers improved activity of
anti-cancer and chemotherapeutic agents.
[0005] The available options for the treatment of cancer are
limited. Toll-like receptors (TLRs) are a class of critical
transmembrane proteins with known involvement in the regulation of
the innate immune system. TLRs are also implicated in the onset and
progression of many cancers. TLRs modulate specific signaling
molecules, including NFKB, and represent a potential target for
anti-cancer agents in the treatment of cancer. A tremendous demand
therefore exists for new methods and compositions that can be used
to treat patients with cancer. Described herein are solutions to
these and other problems in the art.
BRIEF SUMMARY
[0006] Provided herein are crystalline forms of the compound having
formula (I).
##STR00001##
((1E,
4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-be-
nzo[b]azepine-4-carboxamide ("Compound A")). The crystalline form
can be an unsolvated or solvated crystalline form of the compound
of formula (I).
[0007] Also provided herein are compositions including the
crystalline forms of the compound of formula (I) described herein,
methods of making the crystalline forms, and methods of using the
crystalline forms for the treatment of diseases, including, for
example, cancer.
[0008] Further provided herein are methods of agonizing a Toll-like
receptor using the crystalline forms of the compound of formula (I)
described herein. In one aspect the method includes agonizing a
Toll-like receptor (TLR8) by contacting TLR8 with an effective
amount of a crystalline form of the compound formula (I) described
herein, wherein the effective amount agonizes the TLR8.
[0009] Also provided herein are methods of treating cancer using
crystalline forms of the compound of formula (I) described herein.
In one aspect, the method includes treating cancer by administering
a therapeutically effective amount of a crystalline form of the
compound formula (I) described herein to a subject in need thereof,
thereby treating the cancer. Further, the crystalline forms of the
compound of formula (I) and pharmaceutical compositions comprising
the same can be used for methods of treating cancer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1. Illustrates the structure of Compound A
[0011] FIG. 2. Illustrates the .sup.1H NMR spectrum of assay
determination of starting material. The internal standard is
hydrochinone dimethylether (HQDE).
[0012] FIG. 3. Illustrates the microscopy picture of Starting
material. The bar indicates 250 .mu.m.
[0013] FIG. 4. Illustrates the overlay of 7 forms tested by HPLC
with Compound A at 5.78 min. From bottom to top: blank, C2_1,
A1_10, C3_1, C3 2, A1_5, A1_6 and A2_1 (corresponding to Experiment
Nos. of Table 1-3).
[0014] FIG. SA.illlustrates one microscopy picture of different
screening samples of form A. FIG. 5B illlustrates another
microscopy picture of different screening samples of form A. FIG.
5C illlustrates another microscopy picture of different screening
samples of form A. FIG. 5D illlustrates another microscopy picture
of different screening samples of form A. All pictures taken with
crossed polarized filters. The bar indicates approximately 250
.mu.m.
[0015] FIG. 6. Illustrates the .sup.1H NMR of Form A.
[0016] FIG. 7. Illustrates the DSC of crude sample (Form A) with
two melting endotherms: 202.degree. C. (peak, Form A) and
212.degree. C. (peak, likely Form G).
[0017] FIG. 8. Illustrates the TGA with SDTA curve of Form A
showing a weight loss of approximately 0.28% w/w up to the first
melting endotherm.
[0018] FIG. 9A illustrates a microscopy picture of Form B (Table 1
experiment A1_10) taken with crossed polarization filters. FIG. 9B
illustrates a microscopy picture of Form B taken without
polarization. The bar indicates approximately 250 .mu.m.
[0019] FIG. 10. Illustrates the .sup.1H NMR of form B (Table 1
experiment A1_10) showing at 3.7 ppm 2 protons from compound and 8
protons from dioxane.
[0020] FIG. 11. Illustrates the DSC of form B (Table 1 experiment
A1_10) with two endotherms. The endotherm of about 100.degree. C.
likely corresponds to dioxane release.
[0021] FIG. 12. Illustrates the TGA with SDTA curve of form B
(Table 1 experiment A1_10) showing a weight loss of about 10% w/w
around 100.degree. C. and steady weight loss after this first
step.
[0022] FIG. 13. Illustrates the .sup.1H NMR overlay of material
after ACN slurry (bottom, ca. 0.9 eq) and after drying off ACN
(bottom) and crude 3 (top).
[0023] FIG. 14. Illustrates the overlay of isolated material: top:
completely dried (form C, crude 3#1), middle: gently dried (crude
2#1) and wet cake (bottom, crude 1#1).
[0024] FIG. 15. Illustrates the DSC of form C/J mixture (crude 2#1)
containing approximately 0.9 eq ACN which causes an endotherm at
about 100.degree. C.
[0025] FIG. 16. Illustrates the DSC of form C (pure).
[0026] FIG. 17A illustrates the microscopy picture of form D (Table
2 experiment B1_1) showing hedgehog-like crystal agglomerates using
crossed polarization filters. FIG. 17B illustrates the microscopy
picture of form D (Table 2 experiment B1_1) showing hedgehog-like
crystal agglomerates without using polarization. The bar indicates
approximately 250 .mu.m.
[0027] FIG. 18. Illustrates the .sup.1H NMR of Form D.
[0028] FIG. 19. Illustrates the DSC of form D (Table 3 experiment
C3 2) with two endotherm/exotherm combinations at about 140.degree.
C. and about 160.degree. C. (both not integrated) and a melting
endotherm at about 209.degree. C. (peak).
[0029] FIG. 20. Illustrates the TGA with SDTA curve of form D
(Table 3 experiment C3 2) showing a weight loss up to 150.degree.
C. of about 13% w/w (mono solvate would correspond to approximately
16% w/w).
[0030] FIG. 21A illustrates the microscopy picture of form E (Table
1 experiment A1_5) showing needle-like crystals using crossed
polarization filters. FIG. 21B illustrates the microscopy picture
of form E (Table 1 experiment A1_5) showing needle-like crystals
without polarization. The bar indicates approximately 250
.mu.m.
[0031] FIG. 22A illustrates the microscopy picture of form F (Table
1 experiment A1_6) showing the border of the solidified oil with
crossed polarization filters. FIG. 22B illustrates the microscopy
picture of form F (Table 1 experiment A1_6) showing the border of
the solidified oil without polarization. The bar indicates
approximately 250 .mu.m.
[0032] FIG. 23. Illustrates the .sup.1H NMR of form F.
[0033] FIG. 24. Illustrates the DSC of form F (Table 1 experiment
A1_6) with an endotherm/exotherm combination at about 100.degree.
C. (not integrated) and a melting endotherm at about 209.degree. C.
(peak).
[0034] FIG. 25. Illustrates the TGA with SDTA curve of form F
(Table 1 experiment A1_6) showing a weight loss up to 160.degree.
C. of about 14% w/w (mono solvate would correspond to approximately
18% w/w).
[0035] FIG. 26A illustrates the microscopy pictures of form G
(Table 1 experiment A2_1, A2_10) showing hedgehog-like crystal
agglomerates with crossed polarization filters. FIG. 26B
illustrates the microscopy pictures of form G showing the needle
forming form G with crossed polarization filters. FIG. 26C
illustrates the microscopy pictures of form G showing hedgehog-like
crystal agglomerates without polarization. The red bar indicates
about 250 .mu.m. FIG. 26D illustrates the microscopy pictures of
form G showing the needle forming form G without polarization.
[0036] FIG. 27. Illustrates the .sup.1H NMR of form G.
[0037] FIG. 28. Illustrates the DSC of form G (Table 1 experiment
A2_1) with a melting endotherm at around 209.5.degree. C.
(peak).
[0038] FIG. 29. Illustrates the TGA with SDTA curve of form G
(Table 1 experiment A2_1) showing a weight loss up to 120.degree.
C. (18 min) of about 3.7% w/w which corresponds about the expected
amount of isopropanol in the sample.
[0039] FIG. 30A illustrates the microscopy picture of form H (Table
2 experiment B2 2) showing crystals with bipyramidal habit with
crossed polarization filters. FIG. 30B illustrates the microscopy
picture of form H (Table 2 experiment B2_2) showing crystals with
bipyramidal habit without polarization. The bar indicates about 250
.mu.m.
[0040] FIG. 31. Illustrates the .sup.1H NMR of form G.
[0041] FIG. 32A illustrates the microscopy picture of form I
showing crystals without defined habit (after breaking the block)
with crossed polarization filters. FIG. 32B illustrates the
microscopy picture of form I showing crystals without defined habit
(after breaking the block) with crossed polarization filters
without polarization. The bar indicates about 250 .mu.m.
[0042] FIG. 33. Illustrates the .sup.1H NMR of form I.
[0043] FIG. 34. Illustrates the DSC with SDTA curve of form I with
an endotherm at around 110.degree. C. corresponding to a weight
loss of 19.8% w/w.
[0044] FIG. 35. Illustrates the XRPD of form J.
[0045] FIG. 36. Illustrates the DSC of form J. An exotherm form
conversion around 130.degree. C. and a melting point at 212.degree.
C. (peak) which likely represents form G.
[0046] FIG. 37. Illustrates the form diagram of the 4 identified
crystalline forms. Conversions in italics indicate unverified
pathways.
[0047] FIG. 38. Illustrates the XRPD pattern of evaporation series
(Ax_y-experiments). 9 digit number corresponds to the LIMS-Sample/
ID given in Table 1.
[0048] FIG. 39. Illustrates the XRPD pattern of
cooling/precipitation series (Bx_y-experiments). 9 digit number
corresponds to the LIMS-Sample/ID given in Table 2.
[0049] FIG. 40. Illustrates the XRPD pattern of slurry series
(Cx_y-experiments, part 1). 9 digit number corresponds to the
LIMS-Sample/ID given in Table 3.
[0050] FIG. 41. Illustrates the XRPD pattern of slurry series
(Cx_y-experiments, part 1). 9 digit number corresponds to the
LIMS-Sample/ID given in Table 3.
[0051] FIG. 42. Illustrates the XRPD of form A
[0052] FIG. 43. Illustrates the XRPD of form B.
[0053] FIG. 44. Illustrates the XRPD of form C.
[0054] FIG. 45. Illustrates the XRPD of form D.
[0055] FIG. 46. Illustrates the XRPD of form E.
[0056] FIG. 47. Illustrates the XRPD of form F.
[0057] FIG. 48. Illustrates the XRPD of form G.
[0058] FIG. 49. Illustrates the XRPD of form H.
[0059] FIG. 50. Illustrates the XRPD of form I.
DETAILED DESCRIPTION
[0060] Generally, the nomenclature used herein and the laboratory
procedures in organic chemistry, medicinal chemistry, and
pharmacology described herein are those well known and commonly
employed in the art. Unless defined otherwise, all technical and
scientific terms used herein generally have the same meaning as
commonly understood by one of ordinary skill in the art to which
this disclosure belongs.
[0061] The terms "(1E,
4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]-
azepine-4-carboxamide" and "Compound A" refer to a compound having
the structure:
##STR00002##
as disclosed in U.S. patent application Ser. No. 2012/0082658, the
entirety of which is incorporated herein by reference.
[0062] As used herein and unless otherwise specified, the term
"crystalline" and related terms used herein, when used to describe
a compound, substance, modification, material, component or
product, unless otherwise specified, mean that the compound,
substance, modification, material, component or product is
substantially crystalline as determined by X-ray diffraction. See,
e.g., Remington: The Science and Practice of Pharmacy, 21st
edition, Lippincott, Williams and Wilkins, Baltimore, Md. (2005);
The United States Pharmacopeia, 23rd ed., 1843-1844 (1995).
[0063] As used herein and unless otherwise specified, the term
"crystal forms," "crystalline forms" and related terms herein refer
to solid forms that are crystalline. Crystal forms include
single-component crystal forms and multiple-component crystal
forms, and include, but are not limited to, polymorphs, solvates,
hydrates, and/or other molecular complexes. In certain embodiments,
a crystal form of a substance may be substantially free of
amorphous forms and/or other crystal forms. In certain embodiments,
a crystal form of a substance may contain less than about 1%, 2%,
3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%
or 50% of one or more amorphous forms and/or other crystal forms on
a weight basis. In certain embodiments, a crystal form of a
substance may be physically and/or chemically pure. In certain
embodiments, a crystal form of a substance may be about 99%, 98%,
97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and/or
chemically pure.
[0064] As used herein and unless otherwise specified, the terms
"polymorphs," "polymorphic forms" and related terms herein, refer
to two or more crystal forms that consist essentially of the same
molecule, molecules, and/or ions. Like different crystal forms,
different polymorphs may have different physical properties such
as, e.g., melting temperature, heat of fusion, solubility,
dissolution properties and/or vibrational spectra, as a result of
the arrangement or conformation of the molecules and/or ions in the
crystal lattice. The differences in physical properties may affect
pharmaceutical parameters such as storage stability,
compressibility and density (important in formulation and product
manufacturing), and dissolution rate (an important factor in
bioavailability). Differences in stability can result from changes
in chemical reactivity (e.g., differential oxidation, such that a
dosage form discolors more rapidly when including one polymorph
than when including another polymorph) or mechanical changes
(e.g.,, tablets crumble on storage as a kinetically favored
polymorph converts to thermodynamically more stable polymorph) or
both (e.g., tablets of one polymorph are more susceptible to
breakdown at high humidity). As a result of solubility/dissolution
differences, some solid-state transitions may result in lack of
potency or, at the other extreme, toxicity. In addition, the
physical properties may be important in processing (e.g. one
polymorph might be more likely to form solvates or might be
difficult to filter and wash free of impurities, and particle shape
and size distribution might be different between polymorphs).
[0065] As used herein and unless otherwise specified, the terms
"solvate" and "solvated," refer to a crystal form of a substance
formed from the association of one or more solvent molecules to a
compound provided herein. The term "solvate" includes "hydrates"
(e.g., a mono-hydrate, dihydrate, trihydrate, tetrahydrate and the
like, compound described herein where the solvent includes water).
A hydrate includes a compound provided herein or a salt thereof
that further includes a stoichiometric or non-stoichiometric amount
of water bound by non-covalent intermolecular forces. "Polymorphs
of solvates" refers to the existence of more than one crystal form
for a particular solvate composition. Similarly, "polymorphs of
hydrates" refers to the existence of more than one crystal form for
a particular hydrate composition. The term "desolvated solvate," as
used herein, refers to a crystal form of a substance which may be
prepared by removing the solvent from a solvate.
[0066] As used herein and unless otherwise specified, the terms
"amorphous," and "amorphous form," and related terms used herein,
refer that the substance, component or product in question is not
substantially crystalline as determined by X-ray diffraction. The
term "amorphous form" describes a disordered solid form, i.e., a
solid form lacking long range crystalline order. In embodiments, an
amorphous form of a substance may be substantially free of other
amorphous forms and/or crystal forms. In embodiments, an amorphous
form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%,
10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more other
amorphous forms and/or crystal forms on a weight basis. In
embodiments, an amorphous form of a substance may be physically
and/or chemically pure. In embodiments, an amorphous form of a
substance is about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or
90% physically and/or chemically pure.
[0067] Techniques for characterizing crystal forms and amorphous
forms include those known and described in the art, such as, but
not limited to, thermal gravimetric analysis (TGA), differential
scanning calorimetry (DSC), X-ray powder diffractometry (XRPD),
single-crystal X-ray diffractometry, vibrational spectroscopy,
e.g., infrared (IR) and Raman spectroscopy, solid-state and
solution nuclear magnetic resonance (NMR) spectroscopy, optical
microscopy, hot stage optical microscopy, scanning electron
microscopy (SEM), electron crystallography and quantitative
analysis, particle size analysis (PSA), surface area analysis,
solubility measurements, dissolution measurements, elemental
analysis and Karl Fischer analysis. Characteristic unit cell
parameters may be determined using one or more techniques such as,
but not limited to, X-ray diffraction and neutron diffraction,
including single-crystal diffraction and powder diffraction.
Techniques useful for analyzing powder diffraction data include
profile refinement, such as Rietveld refinement, which may be used,
e.g., to analyze diffraction peaks associated with a single phase
in a sample including more than one solid phase. Other methods
useful for analyzing powder diffraction data include unit cell
indexing, which allows one of skill in the art to determine unit
cell parameters from a sample including crystalline powder.
[0068] The term "pharmaceutically acceptable salts" is meant to
include salts of the active compounds that are prepared with
relatively nontoxic acids or bases, depending on the particular
substituents found on the compounds described herein. When
compounds of the present invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable acid addition salts include metallic
salts made from aluminum, calcium, lithium, magnesium, potassium,
sodium and zinc or organic salts made from lysine,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. Suitable non-toxic acids include, but are not limited to,
inorganic and organic acids such as acetic, alginic, anthranilic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,
formic, fumaric, furoic, galacturonic, gluconic, glucuronic,
glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic,
maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,
pantothenic, phenylacetic, phosphoric, propionic, salicylic,
stearic, succinic, sulfanilic, sulfuric, tartaric acid, and
p-toluenesulfonic acid. Specific non-toxic acids include
hydrochloric, hydrobromic, phosphoric, sulfuric, and
methanesulfonic acids. Examples of specific salts thus include
hydrochloride and mesylate salts.
[0069] A "pharmaceutically acceptable excipient," comprises a
substance that aids the administration of an active agent to a
subject or modifies the absorption by a subject upon
administration. A pharmaceutically acceptable excipient typically
has no significant adverse toxicological effect on the patient.
Examples of pharmaceutically acceptable excipients include, but are
not limited to, water, NaCl (including salt solutions), normal
saline solutions, sucrose, glucose, binders, fillers,
disintegrants, lubricants, coatings, sweeteners, flavors, alcohols,
oils, gelatins, carbohydrates such as lactose, amylose or starch,
fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine,
and colors, and the like. One of skill in the art will recognize
that other pharmaceutical excipients known in the art are useful in
the present invention.
[0070] As used herein, "administer" or "administration" refers to
the act of physically delivering a substance as it exists outside
the body into a patient. Administration includes all forms known in
the art for delivering therapeutic agents, including but not
limited to oral, topical, mucosal, injections, intradermal,
intravenous, intramuscular delivery or other method of physical
delivery described herein or known in the art (e.g., implantation
of a slow-release device, such as a mini-osmotic pump to a subject;
liposomal formulations; buccal; sublingual; palatal; gingival;
nasal; vaginal; rectal; intra-arteriole; intraperitoneal;
intraventricular; intracranial; or transdermal). When a disease,
disorder or condition, or a symptom thereof, is treated,
administration of the substance typically occurs after the onset of
disease, disorder or condition or symptoms thereof When a disease,
disorder or condition, or symptoms thereof, are being prevented,
administration of the substance typically occurs before the onset
of the disease, disorder or condition or symptoms thereof.
[0071] As used herein the terms "treat," "treating" and "treatment"
contemplate an action that occurs while a patient is suffering from
the specified disease or disorder, which reduces the severity or
symptoms of the disease or disorder, or retards or slows the
progression or symptoms of the disease or disorder.
[0072] The terms "patient," "subject," "patient in need thereof,"
and "subject in need thereof" are herein used interchangeably and
refer to a living organism suffering from or prone to a disease or
condition that can be treated by administration of a composition
described herein. Non-limiting examples of organisms include
humans, other mammals, bovines, rats, mice, dogs, monkeys, goat,
sheep, cows, deer, and other non-mammalian animals. In specific
embodiments, a patient is human.
[0073] The term "cancer" is used in accordance with its plain
ordinary meaning and refers to all types of neoplasms and malignant
or benign tumors found in mammals. "Cancer" as used herein refers
to leukemia, carcinomas and sarcomas. Exemplary cancers include
acute myeloid leukemia ("AML"), chronic myelogenous leukemia
("CML"), and cancer of the brain, breast, pancreas, colon, liver,
kidney, lung, non-small cell lung, melanoma, ovary, sarcoma, and
prostate. Additional examples include, cervix cancers, stomach
cancers, head & neck cancers, uterus cancers, mesothelioma,
metastatic bone cancer, Medulloblastoma, Hodgkin's Disease,
Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, ovarian
cancer, rhabdomyosarcoma, primary thrombocytosis, primary
macroglobulinemia, primary brain tumors, cancer, malignant
pancreatic insulanoma, malignant carcinoid, urinary bladder cancer,
premalignant skin lesions, testicular cancer, lymphomas, thyroid
cancer, neuroblastoma, esophageal cancer, genitourinary tract
cancer, malignant hypercalcemia, endometrial cancer, adrenal
cortical cancer, and neoplasms of the endocrine and exocrine
pancreas. In preferred embodiments, the cancer is colon carcinoma,
ovarian cancer, breast cancer, head and neck cancer, renal cancer,
bladder cancer, hepatocellular cancer, or lymphoma.
[0074] "Anti-cancer agent" is used in accordance with its plain and
ordinary meaning and refers to a composition (e.g., a
chemotherapeutic agent) that inhibits the growth or proliferation
of cells. An anti-cancer agent may be an agent approved by the FDA
or similar regulatory agency of a country other than the USA, for
treating cancer.
[0075] An "effective amount" is an amount sufficient to accomplish
a stated purpose (e.g., achieve the effect for which it is
administered, treat, manage, or prevent a disease, reduce enzyme
activity, increase enzyme activity, or reduce one or more symptoms
of a disease or condition). The term "therapeutically effective
amount" of a compound refers to the amount of the compound that,
when administered, is sufficient to treat, manage or prevent one or
more of the symptoms of a disease, disorder, or condition being
treated. The term also refers to the amount of the compound that is
sufficient to elicit a biological or medical response of a
biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,
tissue, system, animal, or human, which is being sought by a
researcher, veterinarian, medical doctor, or clinician. The term
encompasses an amount of the compound that improves overall
therapy, reduces, or avoids symptoms or causes of a disease,
disorder, or condition, or enhances the therapeutic efficacy of
another therapeutic agent.
[0076] Crystalline Forms:
[0077] Provided herein are crystalline forms of a compound having
the formula
##STR00003##
[0078] The crystalline form can be an unsolvated crystalline form
(e.g., a crystal form substantially without solvent) or a solvated
crystalline form. The crystalline form of the compound of formula
(I) can be obtained using techniques known in the art, including
but not limited to, evaporative screening, cooling and
precipitation screening, or slurry screening. Crystals of the
crystalline forms of the compound of formula (I) can be obtained
from solvents and techniques set forth in, for example, Table 1,
Table 2, or Table 3. The crystalline form can be an unsolvated
crystalline form. The crystalline form can be a solvated form. The
crystalline form can include a form described herein within the
Examples set forth below (e.g., Form A, Form B, Form C, Form D,
Form E, Form F, Form G, Form H, Form I, or Form J). Thus, in
embodiments, the crystalline form described herein can be referred
to by its present solvation state (i.e., solvated or unsolvated),
by its alphanumeric Form name, or a combination thereof The
crystalline form, can, in embodiments, be an unsolvated crystalline
form corresponding to Form A, Form C, Form G, or Form H. The
crystalline form, can, in embodiments, be a solvated crystalline
form corresponding to Form B, Form D, Form E, Form F, or Form
I.
[0079] The crystalline form of the compound of formula (I) can be
characterized by X-ray powder diffraction (XRPD). The crystalline
form of the compound of formula (I) can be characterized by a XRPD
pattern that includes angle 2 .theta. peaks (i.e., degrees 2
.theta.) at about 11.9.+-.0.3, 16.4.+-.0.3, 18.5.+-.0.3,
20.9.+-.0.3, 21.2.+-.0.3, 21.6.+-.0.3, 23.0.+-.0.3, 23.5.+-.0.3,
24.2.+-.0.3, and 27.4.+-.0.3. All values for angle 2 .theta. peaks
set forth herein (e.g., angle 2 .theta. values for Form A, Form B,
Form C, Form D, Form E, Form F, Form G, Form H, Form I, or Form J)
are obtained by using a Cu K.alpha. radiation source (1.54 .ANG.).
Further, the angle 2 .theta. values described herein should be
understood to include variances associated with X-ray diffraction
spectroscopy. The XRPD pattern of the crystalline form of the
compound of formula (I) can further include angle 2 .theta. peaks
at about 8.7.+-.0.3, 9.2.+-.0.3, 10.8.+-.0.3, 14.8.+-.0.3,
15.5.+-.0.3, 17.7.+-.0.3, 19.9.+-.0.3, 20.4.+-.0.3, 22.0.+-.0.3,
22.4.+-.0.3, 25.9.+-.0.3, 26.3.+-.0.3, 26.8.+-.0.3, 27.0.+-.0.3,
28.0.+-.0.3, 28.9.+-.0.3, and 29.8.+-.0.3.
[0080] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 8.7.+-.0.3, 9.2.+-.0.3, 10.8.+-.0.3,
11.9.+-.0.3, 14.8.+-.0.3, 15.5.+-.0.3, 16.4.+-.0.3, 17.7.+-.0.3,
18.5.+-.0.3, 19.9.+-.0.3, 20.4.+-.0.3, 20.9.+-.0.3, 21.2.+-.0.3,
21.6.+-.0.3, 22.0.+-.0.3, 22.4.+-.0.3, 23.0.+-.0.3, 23.5.+-.0.3,
24.2.+-.0.3, 25.9.+-.0.3, 26.3.+-.0.3, 26.8.+-.0.3, 27.0.+-.0.3,
27.4.+-.0.3, 28.0.+-.0.3, 28.9.+-.0.3, and 29.8.+-.0.3.
[0081] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 11.9.+-.0.2,
16.4.+-.0.2, 18.5.+-.0.2, 20.9.+-.0.2, 21.2.+-.0.2, 21.6.+-.0.2,
23.0.+-.0.2, 23.5.+-.0.2, 24.2.+-.0.2, and 27.4.+-.0.2. The XRPD
pattern of the crystalline form of the compound of formula (I) can
further include angle 2 .theta. peaks at about 8.7.+-.0.2,
9.2.+-.0.2, 10.8.+-.0.2, 14.8.+-.0.2, 15.5.+-.0.2, 17.7.+-.0.2,
19.9.+-.0.2, 20.4.+-.0.2, 22.0.+-.0.2, 22.4.+-.0.2, 25.9.+-.0.2,
26.3.+-.0.2, 26.8.+-.0.2, 27.0.+-.0.2, 28.0.+-.0.2, 28.9.+-.0.2,
and 29.8.+-.0.2.
[0082] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 8.7.+-.0.2, 9.2.+-.0.2, 10.8.+-.0.2,
11.9.+-.0.2, 14.8.+-.0.2, 15.5.+-.0.2, 16.4.+-.0.2, 17.7.+-.0.2,
18.5.+-.0.2, 19.9.+-.0.2, 20.4.+-.0.2, 20.9.+-.0.2, 21.2.+-.0.2,
21.6.+-.0.2, 22.0.+-.0.2, 22.4.+-.0.2, 23.0.+-.0.2, 23.5.+-.0.2,
24.2.+-.0.2, 25.9.+-.0.2, 26.3.+-.0.2, 26.8.+-.0.2, 27.0.+-.0.2,
27.4.+-.0.2, 28.0.+-.0.2, 28.9.+-.0.2, and 29.8.+-.0.2.
[0083] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 11.9.+-.0.1,
16.4.+-.0.1, 18.5.+-.0.1, 20.9.+-.0.1, 21.2.+-.0.1, 21.6.+-.0.1,
23.0.+-.0.1, 23.5.+-.0.1, 24.2.+-.0.1, and 27.4.+-.0.1. The XRPD
pattern of the crystalline form of the compound of formula (I) can
further include angle 2 .theta. peaks at about 8.7.+-.0.1,
9.2.+-.0.1, 10.8.+-.0.1, 14.8.+-.0.1, 15.5.+-.0.1, 17.7.+-.0.1,
19.9.+-.0.1, 20.4.+-.0.1, 22.0.+-.0.1, 22.4.+-.0.1, 25.9.+-.0.1,
26.3.+-.0.1, 26.8.+-.0.1, 27.0.+-.0.1, 28.0.+-.0.1, 28.9.+-.0.1,
and 29.8.+-.0.1.
[0084] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 8.7.+-.0.1, 9.2.+-.0.1,
10.8.+-.0.1,11.9.+-.0.1,14.8.+-.0.1,15.5.+-.0.1,16.4.+-.0.1,17.7.+-.0.1,1-
8.5.+-.0.1, 19.9.+-.0.1, 20.4.+-.0.1, 20.9.+-.0.1, 21.2.+-.0.1,
21.6.+-.0.1, 22.0.+-.0.1, 22.4.+-.0.1, 23.0.+-.0.1, 23.5.+-.0.1,
24.2.+-.0.1, 25.9.+-.0.1, 26.3.+-.0.1, 26.8.+-.0.1, 27.0.+-.0.1,
27.4.+-.0.1, 28.0.+-.0.1, 28.9.+-.0.1, and 29.8.+-.0.1.
[0085] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 11.9, 16.4,
18.5, 20.9, 21.2, 21.6, 23.0, 23.5, 24.2, and 27.4. The XRPD
pattern of the crystalline form of the compound of formula (I) can
further include angle 2 .theta. peaks at about 8.7, 9.2, 10.8,
14.8, 15.5, 17.7, 19.9, 20.4, 22.0, 22.4, 25.9, 26.3, 26.8, 27.0,
28.0, 28.9, and 29.8.
[0086] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 8.7, 9.2, 10.8, 11.9, 14.8, 15.5, 16.4,
17.7, 18.5, 19.9, 20.4, 20.9, 21.2, 21.6, 22.0, 22.4, 23.0, 23.5,
24.2, 25.9, 26.3, 26.8, 27.0, 27.4, 28.0, 28.9, and 29.8.
[0087] In certain embodiments, the crystalline form of the compound
of formula (I) is characterized by a XRPD pattern corresponding
substantially to FIG. 42.
[0088] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 7.40.+-.0.3, 5.40.+-.0.3, 4.78.+-.0.3,
4.24.+-.0.3, 4.17.+-.0.3, 4.09.+-.0.3, 3.86.+-.0.3, 3.77.+-.0.3,
3.68.+-.0.3, 3.25.+-.0.3. The d spacing values described herein
should be understood to include variances associated with X-ray
diffraction spectroscopy. All values for d spacings set forth
herein (e.g., d spacings for Form A, Form B, Form C, Form D, Form
E, Form F, Form G, Form H, Form I, or Form J) are obtained by using
a Cu K.alpha. radiation source (1.54 .ANG.). The XRPD pattern of
the crystalline form of the compound of formula (I) can further
include d spacings at about 10.20.+-.0.3, 9.58.+-.0.3, 8.18.+-.0.3,
5.98.+-.0.3, 5.70.+-.0.3, 5.01.+-.0.3, 4.45.+-.0.3, 4.34.+-.0.3,
4.02.+-.0.3, 3.97.+-.0.3, 3.43.+-.0.3, 3.38.+-.0.3, 3.32.+-.0.3,
3.29.+-.0.3, 3.17.+-.0.3, 3.08.+-.0.3, and 2.99.+-.0.3.
[0089] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 10.20.+-.0.3, 7.40.+-.0.3, 9.58.+-.0.3,
8.18.+-.0.3, 5.98.+-.0.3, 5.70.+-.0.3, 5.40.+-.0.3, 5.01.+-.0.3,
4.78.+-.0.3, 4.45.+-.0.3, 4.34.+-.0.3, 4.24.+-.0.3, 4.17.+-.0.3,
4.09.+-.0.3, 4.02.+-.0.3, 3.97.+-.0.3, 3.86.+-.0.3, 3.77.+-.0.3,
3.68.+-.0.3, 3.43.+-.0.3, 3.38.+-.0.3, 3.32.+-.0.3, 3.29.+-.0.3,
3.25.+-.0.3, 3.17.+-.0.3, 3.08.+-.0.3, and 2.99.+-.0.3.
[0090] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 7.40.+-.0.2, 5.40.+-.0.2, 4.78.+-.0.2,
4.24.+-.0.2, 4.17.+-.0.2, 4.09.+-.0.2, 3.86.+-.0.2, 3.77.+-.0.2,
3.68.+-.0.2, 3.25.+-.0.2. The XRPD pattern of the crystalline form
of the compound of formula (I) can further include d spacings at
about 10.20.+-.0.2, 9.58.+-.0.2, 8.18.+-.0.2, 5.98.+-.0.2,
5.70.+-.0.2, 5.01.+-.0.2, 4.45.+-.0.2, 4.34.+-.0.2, 4.02.+-.0.2,
3.97.+-.0.2, 3.43.+-.0.2, 3.38.+-.0.2, 3.32.+-.0.2, 3.29.+-.0.2,
3.17.+-.0.2, 3.08.+-.0.2, and 2.99.+-.0.2.
[0091] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 10.20.+-.0.2, 7.40.+-.0.2, 9.58.+-.0.2,
8.18.+-.0.2, 5.98.+-.0.2, 5.70.+-.0.2, 5.40.+-.0.2, 5.01.+-.0.2,
4.78.+-.0.2, 4.45.+-.0.2, 4.34.+-.0.2, 4.24.+-.0.2, 4.17.+-.0.2,
4.09.+-.0.2, 4.02.+-.0.2, 3.97.+-.0.2, 3.86.+-.0.2, 3.77.+-.0.2,
3.68.+-.0.2, 3.43.+-.0.2, 3.38.+-.0.2, 3.32.+-.0.2, 3.29.+-.0.2,
3.25.+-.0.2, 3.17.+-.0.2, 3.08.+-.0.2, and 2.99.+-.0.2.
[0092] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 7.40.+-.0.1, 5.40.+-.0.1, 4.78.+-.0.1,
4.24.+-.0.1, 4.17.+-.0.1, 4.09.+-.0.1, 3.86.+-.0.1, 3.77.+-.0.1,
3.68.+-.0.1, 3.25.+-.0.1. The XRPD pattern of the crystalline form
of the compound of formula (I) can further included spacings at
about 10.20.+-.0.1, 9.58.+-.0.1, 8.18.+-.0.1, 5.98.+-.0.1,
5.70.+-.0.1, 5.01.+-.0.1, 4.45.+-.0.1, 4.34.+-.0.1, 4.02.+-.0.1,
3.97.+-.0.1, 3.43.+-.0.1, 3.38.+-.0.1, 3.32.+-.0.1, 3.29.+-.0.1,
3.17.+-.0.1, 3.08.+-.0.1, and 2.99.+-.0.1.
[0093] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 10.20.+-.0.1, 7.40.+-.0.1, 9.58.+-.0.1,
8.18.+-.0.1, 5.98.+-.0.1, 5.70.+-.0.1, 5.40.+-.0.1, 5.01.+-.0.1,
4.78.+-.0.1, 4.45.+-.0.1, 4.34.+-.0.1, 4.24.+-.0.1, 4.17.+-.0.1,
4.09.+-.0.1, 4.02.+-.0.1, 3.97.+-.0.1, 3.86.+-.0.1, 3.77.+-.0.1,
3.68.+-.0.1, 3.43.+-.0.1, 3.38.+-.0.1, 3.32.+-.0.1, 3.29.+-.0.1,
3.25.+-.0.1, 3.17.+-.0.1, 3.08.+-.0.1, and 2.99.+-.0.1.
[0094] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 7.40, 5.40, 4.78, 4.24, 4.17, 4.09, 3.86, 3.77,
3.68, 3.25. The XRPD pattern of the crystalline form of the
compound of formula (I) can further included spacings at about
10.20, 9.58, 8.18, 5.98, 5.70, 5.01, 4.45, 4.34, 4.02, 3.97, 3.43,
3.38, 3.32, 3.29, 3.17, 3.08, and 2.99.
[0095] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 10.20, 7.40, 9.58, 8.18, 5.98, 5.70, 5.40, 5.01,
4.78, 4.45, 4.34, 4.24, 4.17, 4.09, 4.02, 3.97, 3.86, 3.77, 3.68,
3.43, 3.38, 3.32, 3.29, 3.25, 3.17, 3.08, and 2.99.
[0096] The crystalline form of the compound of formula (I) can be
Form A, where Form A is characterized by the XRPD pattern described
above or by a XRPD pattern corresponding substantially to FIG.
42.
[0097] Melting points set forth herein are determined using DSC and
reported as the peak. Crystalline forms described herein of the
compound of formula (I) can be can have a melting point of about
200.degree. C. to about 215.degree. C. Crystalline forms described
herein of the compound of formula (I) can be can have a melting
point of about 200.degree. C. to about 210.degree. C. Crystalline
forms described herein of the compound of formula (I) can be can
have a melting point of about 200.degree. C. to about 205.degree.
C. Crystalline forms described herein of the compound of formula
(I) can be can have a melting point of about 200.degree. C. to
about 204.degree. C. Crystalline forms described herein of the
compound of formula (I) can be can have a melting point of about
200.degree. C. to about 203.degree. C. Crystalline forms described
herein of the compound of formula (I) can be can have a melting
point of about 200.degree. C. to about 202.degree. C. Crystalline
forms described herein of the compound of formula (I) can be can
have a melting point of about 202.degree. C. to about 215.degree.
C. Crystalline forms described herein of the compound of formula
(I) can be can have a melting point of about 202.degree. C. to
about 210.degree. C. Crystalline forms described herein of the
compound of formula (I) can be can have a melting point of about
202.degree. C. to about 205.degree. C. Crystalline forms described
herein of the compound of formula (I) can be can have a melting
point of about 205.degree. C. to about 215.degree. C. Crystalline
forms described herein of the compound of formula (I) can be can
have a melting point of about 205.degree. C. to about 210.degree.
C. The Crystalline forms described herein of the compound of
formula (I) can be can have a melting point of about 208.degree. C.
to about 212.degree. C.
[0098] The crystalline form of the compound of formula (I) (e.g.,
Form A) can include an endothermic event with an onset temperature
of about 199.degree. C. and about 211.degree. C. as measured by
differential scanning calorimetry (DSC). The crystalline form of
the compound of formula (I) (e.g., Form A) can be characterized by
a DSC plot set forth in FIG. 7. The crystalline form of the
compound of formula (I) can have a melting point of about
202.degree. C. The crystalline form of the compound of formula (I)
can be Form A, where Form A has a melting point of about
202.degree. C.
[0099] The crystalline forms of the compound of formula (I)
described herein can be further characterized by TGA as described
herein. In embodiments, the crystalline form of the compound of
formula (I) (e.g., Form A) can have a mass loss of about 0.28% when
heated from about 25.degree. C. to about 180.degree. C. as measured
by TGA. The crystalline form of the compound of formula (I) can be
stable between about 0.degree. C. to about 60.degree. C. Form A can
be stable between about 0.degree. C. to about 60.degree. C.
[0100] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 10.7.+-.0.3,
15.2.+-.0.3, 15.5.+-.0.3, 17.5.+-.0.3, 18.6.+-.0.3, 19.7.+-.0.3,
20.9.+-.0.3, 21.8.+-.0.3, 24.2.+-.0.3, 24.7.+-.0.3, and
26.4.+-.0.3. The XRPD pattern of the crystalline form of the
compound of formula (I) can further include angle 2 .theta. peaks
at about 6.3.+-.0.3, 12.5.+-.0.3, 15.9.+-.0.3, 16.6.+-.0.3,
18.2.+-.0.3, 18.9.+-.0.3, 22.3.+-.0.3, 22.7.+-.0.3, 23.1.+-.0.3,
24.9.+-.0.3, 25.3.+-.0.3, 26.0.+-.0.3, 27.2.+-.0.3, 29.4.+-.0.3,
30.0.+-.0.3, 30.9.+-.0.3, 31.8.+-.0.3, and 35.4.+-.0.3.
[0101] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 6.3.+-.0.3, 10.7.+-.0.3, 15.2.+-.0.3,
15.5.+-.0.3, 12.5.+-.0.3, 15.9.+-.0.3, 16.6.+-.0.3, 17.5.+-.0.3,
18.2.+-.0.3, 18.6.+-.0.3, 18.9.+-.0.3, 19.7.+-.0.3, 20.9.+-.0.3,
21.8.+-.0.3, 22.3.+-.0.3, 22.7.+-.0.3, 23.1.+-.0.3, 24.2.+-.0.3,
24.7.+-.0.3, 24.9.+-.0.3, 25.3.+-.0.3, 26.0.+-.0.3, 26.4.+-.0.3,
27.2.+-.0.3, 29.4.+-.0.3, 30.0.+-.0.3, 30.9.+-.0.3, 31.8.+-.0.3,
and 35.4.+-.0.3.
[0102] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 10.7.+-.0.2,
15.2.+-.0.2, 15.5.+-.0.2, 17.5.+-.0.2, 18.6.+-.0.2, 19.7.+-.0.2,
20.9.+-.0.2, 21.8.+-.0.2, 24.2.+-.0.2, 24.7.+-.0.2, and
26.4.+-.0.2. The XRPD pattern of the crystalline form of the
compound of formula (I) can further include angle 2 .theta. peaks
at about 6.3.+-.0.2, 12.5.+-.0.2, 15.9.+-.0.2, 16.6.+-.0.2,
18.2.+-.0.2, 18.9.+-.0.2, 22.3.+-.0.2, 22.7.+-.0.2, 23.1.+-.0.2,
24.9.+-.0.2, 25.3.+-.0.2, 26.0.+-.0.2, 27.2.+-.0.2, 29.4.+-.0.2,
30.0.+-.0.2, 30.9.+-.0.2, 31.8.+-.0.2, and 35.4.+-.0.2.
[0103] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 6.3.+-.0.2, 10.7.+-.0.2, 15.2.+-.0.2,
15.5.+-.0.2, 12.5.+-.0.2, 15.9.+-.0.2, 16.6.+-.0.2, 17.5.+-.0.2,
18.2.+-.0.2, 18.6.+-.0.2, 18.9.+-.0.2, 19.7.+-.0.2, 20.9.+-.0.2,
21.8.+-.0.2, 22.3.+-.0.2, 22.7.+-.0.2, 23.1.+-.0.2, 24.2.+-.0.2,
24.7.+-.0.2, 24.9.+-.0.2, 25.3.+-.0.2, 26.0.+-.0.2, 26.4.+-.0.2,
27.2.+-.0.2, 29.4.+-.0.2, 30.0.+-.0.2, 30.9.+-.0.2, 31.8.+-.0.2,
and 35.4.+-.0.2.
[0104] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 10.7.+-.0.1,
15.2.+-.0.1, 15.5.+-.0.1, 17.5.+-.0.1, 18.6.+-.0.1, 19.7.+-.0.1,
20.9.+-.0.1, 21.8.+-.0.1, 24.2.+-.0.1, 24.7.+-.0.1, and
26.4.+-.0.1. The XRPD pattern of the crystalline form of the
compound of formula (I) can further include angle 2 .theta. peaks
at about 6.3.+-.0.1, 12.5.+-.0.1, 15.9.+-.0.1, 16.6.+-.0.1,
18.2.+-.0.1, 18.9.+-.0.1, 22.3.+-.0.1, 22.7.+-.0.1, 23.1.+-.0.1,
24.9.+-.0.1, 25.3.+-.0.1, 26.0.+-.0.1, 27.2.+-.0.1, 29.4.+-.0.1,
30.0.+-.0.1, 30.9.+-.0.1, 31.8.+-.0.1, and 35.4.+-.0.2.
[0105] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 6.3.+-.0.1, 10.7.+-.0.1,
15.2.+-.0.1,15.5.+-.0.1,12.5.+-.0.1,15.9.+-.0.1,16.6.+-.0.1,17.5.+-.0.1,1-
8.2.+-.0.1, 18.6.+-.0.1, 18.9.+-.0.1, 19.7.+-.0.1, 20.9.+-.0.1,
21.8.+-.0.1, 22.3.+-.0.1, 22.7.+-.0.1, 23.1.+-.0.1, 24.2.+-.0.1,
24.7.+-.0.1, 24.9.+-.0.1, 25.3.+-.0.1, 26.0.+-.0.1, 26.4.+-.0.1,
27.2.+-.0.1, 29.4.+-.0.1, 30.0.+-.0.1, 30.9.+-.0.1, 31.8.+-.0.1,
and 35.4.+-.0.1.
[0106] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 10.7, 15.2,
15.5, 17.5, 18.6, 19.7, 20.9, 21.8, 24.2, 24.7, and 26.4. The XRPD
pattern of the crystalline form of the compound of formula (I) can
further include angle 2 .theta. peaks at about 6.3, 12.5, 15.9,
16.6, 18.2, 18.9, 22.3, 22.7, 23.1, 24.9, 25.3, 26.0, 27.2, 29.4,
30.0, 30.9, 31.8, and 35.4.
[0107] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 6.3, 10.7, 15.2, 15.5, 12.5, 15.9, 16.6,
17.5, 18.2, 18.6, 18.9, 19.7, 20.9, 21.8, 22.3, 22.7, 23.1, 24.2,
24.7, 24.9, 25.3, 26.0, 26.4, 27.2, 29.4, 30.0, 30.9, 31.8, and
35.4.
[0108] In certain embodiments, the crystalline form of the compound
of formula (I) is characterized by a XRPD pattern corresponding
substantially to FIG. 43.
[0109] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 8.23.+-.0.3, 5.80.+-.0.3, 5.70.+-.0.3,
5.06.+-.0.3, 4.77.+-.0.3, 4.50.+-.0.3, 4.24.+-.0.3, 4.10.+-.0.3,
3.67.+-.0.3, 3.59.+-.0.3, and 3.37.+-.0.3. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 14.10.+-.0.3, 7.05.+-.0.3,
5.58.+-.0.3, 5.34.+-.0.3, 4.88.+-.0.3, 4.69.+-.0.3, 3.99.+-.0.3,
3.91.+-.0.3, 3.85.+-.0.3, 3.57.+-.0.3, 3.51.+-.0.3, 3.42.+-.0.3,
3.27.+-.0.3, 3.03.+-.0.3, 2.97.+-.0.3, 2.89.+-.0.3, 2.80.+-.0.3,
and 2.53.+-.0.3.
[0110] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 14.10.+-.0.3, 8.23.+-.0.3, 7.05.+-.0.3,
5.80.+-.0.3, 5.70.+-.0.3, 5.58.+-.0.3, 5.34.+-.0.3, 5.06.+-.0.3,
4.88.+-.0.3, 4.77.+-.0.3, 4.69.+-.0.3, 4.50.+-.0.3, 4.24.+-.0.3,
4.10.+-.0.3, 3.99.+-.0.3, 3.91.+-.0.3, 3.85.+-.0.3, 3.67.+-.0.3,
3.59.+-.0.3, 3.57.+-.0.3, 3.51.+-.0.3, 3.42.+-.0.3, 3.37.+-.0.3,
3.27.+-.0.3, 3.03.+-.0.3, 2.97.+-.0.3, 2.89.+-.0.3, 2.80.+-.0.3,
and 2.53.+-.0.3.
[0111] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 8.23.+-.0.2, 5.80.+-.0.2, 5.70.+-.0.2,
5.06.+-.0.2, 4.77.+-.0.2, 4.50.+-.0.2, 4.24.+-.0.2, 4.10.+-.0.2,
3.67.+-.0.2, 3.59.+-.0.2, and 3.37.+-.0.2. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 14.10.+-.0.2, 7.05.+-.0.2,
5.58.+-.0.2, 5.34.+-.0.2, 4.88.+-.0.2, 4.69.+-.0.2, 3.99.+-.0.2,
3.91.+-.0.2, 3.85.+-.0.2, 3.57.+-.0.2, 3.51.+-.0.2, 3.42.+-.0.2,
3.27.+-.0.2, 3.03.+-.0.2, 2.97.+-.0.2, 2.89.+-.0.2, 2.80.+-.0.2,
and 2.53.+-.0.2.
[0112] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 14.10.+-.0.2, 8.23.+-.0.2, 7.05.+-.0.2,
5.80.+-.0.2, 5.70.+-.0.2, 5.58.+-.0.2, 5.34.+-.0.2, 5.06.+-.0.2,
4.88.+-.0.2, 4.77.+-.0.2, 4.69.+-.0.2, 4.50.+-.0.2, 4.24.+-.0.2,
4.10.+-.0.2, 3.99.+-.0.2, 3.91.+-.0.2, 3.85.+-.0.2, 3.67.+-.0.2,
3.59.+-.0.2, 3.57.+-.0.2, 3.51.+-.0.2, 3.42.+-.0.2, 3.37.+-.0.2,
3.27.+-.0.2, 3.03.+-.0.2, 2.97.+-.0.2, 2.89.+-.0.2, 2.80.+-.0.2,
and 2.53.+-.0.2.
[0113] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 8.23.+-.0.1, 5.80.+-.0.1, 5.70.+-.0.1,
5.06.+-.0.1, 4.77.+-.0.1, 4.50.+-.0.1, 4.24.+-.0.1, 4.10.+-.0.1,
3.67.+-.0.1, 3.59.+-.0.1, and 3.37.+-.0.1. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 14.10.+-.0.1, 7.05.+-.0.1,
5.58.+-.0.1, 5.34.+-.0.1, 4.88.+-.0.1, 4.69.+-.0.1, 3.99.+-.0.1,
3.91.+-.0.1, 3.85.+-.0.1, 3.57.+-.0.1, 3.51.+-.0.1, 3.42.+-.0.1,
3.27.+-.0.1, 3.03.+-.0.1, 2.97.+-.0.1, 2.89.+-.0.1, 2.80.+-.0.1,
and 2.53.+-.0.1.
[0114] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 14.10.+-.0.1, 8.23.+-.0.1, 7.05.+-.0.1,
5.80.+-.0.1, 5.70.+-.0.1, 5.58.+-.0.1, 5.34.+-.0.1, 5.06.+-.0.1,
4.88.+-.0.1, 4.77.+-.0.1, 4.69.+-.0.1, 4.50.+-.0.1, 4.24.+-.0.1,
4.10.+-.0.1, 3.99.+-.0.1, 3.91.+-.0.1, 3.85.+-.0.1, 3.67.+-.0.1,
3.59.+-.0.1, 3.57.+-.0.1, 3.51.+-.0.1, 3.42.+-.0.1, 3.37.+-.0.1,
3.27.+-.0.1, 3.03.+-.0.1, 2.97.+-.0.1, 2.89.+-.0.1, 2.80.+-.0.1,
and 2.53.+-.0.1.
[0115] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 8.23, 5.80, 5.70, 5.06, 4.77, 4.50, 4.24, 4.10,
3.67, 3.59, and 3.37. The XRPD pattern of the crystalline form of
the compound of formula (I) can be further characterized by d
spacings at about 14.10, 7.05, 5.58, 5.34, 4.88, 4.69, 3.99, 3.91,
3.85, 3.57, 3.51, 3.42, 3.27, 3.03, 2.97, 2.89, 2.80, and 2.53.
[0116] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 14.10, 8.23, 7.05, 5.80, 5.70, 5.58, 5.34, 5.06,
4.88, 4.77, 4.69, 4.50, 4.24, 4.10, 3.99, 3.91, 3.85, 3.67, 3.59,
3.57, 3.51, 3.42, 3.37, 3.27, 3.03, 2.97, 2.89, 2.80, and 2.53.
[0117] The crystalline form of the compound of formula (I) can be
Form B, where Form B is characterized by the XRPD pattern described
above or by FIG. 43.
[0118] The crystalline form of the compound of formula (I) (e.g.,
Form B) can include an endothermic event with an onset temperature
of about 94.degree. C. and about 193.degree. C. as determined by
DSC. The crystalline form of the compound of formula (I) (e.g.,
Form B) can be characterized by a DSC plot set forth in FIG. 11.
The crystalline form of the compound of formula (I) can have a
melting point of about 204.degree. C. The crystalline form of the
compound of formula (I) can be Form B, where Form B has a melting
point of about 204.degree. C.
[0119] Form B can have a mass loss of about 12% when heated from
about 80.degree. C. to about 140.degree. C. Form B can be a
solvated crystalline form, where Form B is a 1,4-dioxane
solvate.
[0120] In some embodiments, the crystalline form of the compound of
formula (I) includes angle 2 .theta. peaks (i.e., degrees 2
.theta.) at about 11.0.+-.0.3, 14.9.+-.0.3, 18.0.+-.0.3,
19.1.+-.0.3, 21.0.+-.0.3, and 22.8.+-.0.3. The XRPD pattern of the
crystalline form of the compound of formula (I) can further include
angle 2 .theta. peaks at about 5.6.+-.0.3, 8.9.+-.0.3, 9.6.+-.0.3,
10.6.+-.0.3, 13.5.+-.0.3, 14.4.+-.0.3, 15.3.+-.0.3, 16.1.+-.0.3,
16.9.+-.0.3, 17.2.+-.0.3, 20.3.+-.0.3, 21.7.+-.0.3, 22.1.+-.0.3,
23.5.+-.0.3, 23.9.+-.0.3, 24.7.+-.0.3, 26.8.+-.0.3, 27.3.+-.0.3,
and 29.1.+-.0.3.
[0121] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 5.6.+-.0.3, 8.9.+-.0.3, 9.6.+-.0.3,
10.6.+-.0.3, 11.0.+-.0.3, 13.5.+-.0.3, 14.4.+-.0.3, 14.9.+-.0.3,
15.3.+-.0.3, 16.1.+-.0.3, 16.9.+-.0.3, 17.2.+-.0.3, 18.0.+-.0.3,
19.1.+-.0.3, 20.3.+-.0.3, 21.0.+-.0.321.7.+-.0.3, 22.1.+-.0.3,
22.8.+-.0.3, 23.5.+-.0.3, 23.9.+-.0.3, 24.7.+-.0.3, 26.8.+-.0.3,
27.3.+-.0.3, and 29.1.+-.0.3.
[0122] In some embodiments, the crystalline form of the compound of
formula (I) includes angle 2 .theta. peaks (i.e., degrees 2
.theta.) at about 11.0.+-.0.2, 14.9.+-.0.2, 18.0.+-.0.2,
19.1.+-.0.2, 21.0.+-.0.2, and 22.8.+-.0.2. The XRPD pattern of the
crystalline form of the compound of formula (I) can further include
angle 2 .theta. peaks at about 5.6.+-.0.2, 8.9.+-.0.2, 9.6.+-.0.2,
10.6.+-.0.2, 13.5.+-.0.2, 14.4.+-.0.2, 15.3.+-.0.2, 16.1.+-.0.2,
16.9.+-.0.2, 17.2.+-.0.2, 20.3.+-.0.2, 21.7.+-.0.2, 22.1.+-.0.2,
23.5.+-.0.2, 23.9.+-.0.2, 24.7.+-.0.2, 26.8.+-.0.2, 27.3.+-.0.2,
and 29.1.+-.0.2.
[0123] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 5.6.+-.0.2, 8.9.+-.0.2, 9.6.+-.0.2,
10.6.+-.0.2, 11.0.+-.0.2, 13.5.+-.0.2, 14.4.+-.0.2, 14.9.+-.0.2,
15.3.+-.0.2, 16.1.+-.0.2, 16.9.+-.0.2, 17.2.+-.0.2, 18.0.+-.0.2,
19.1.+-.0.2, 20.3.+-.0.2, 21.0.+-.0.221.7.+-.0.2, 22.1.+-.0.2,
22.8.+-.0.2, 23.5.+-.0.2, 23.9.+-.0.2, 24.7.+-.0.2, 26.8.+-.0.2,
27.3.+-.0.2, and 29.1.+-.0.2.
[0124] In some embodiments, the crystalline form of the compound of
formula (I) includes angle 2 .theta. peaks (i.e., degrees 2
.theta.) at about 11.0.+-.0.1, 14.9.+-.0.1, 18.0.+-.0.1,
19.1.+-.0.1, 21.0.+-.0.1, and 22.8.+-.0.1. The XRPD pattern of the
crystalline form of the compound of formula (I) can further include
angle 2 .theta. peaks at about 5.6.+-.0.1, 8.9.+-.0.1,
9.6.+-.0.1,10.6.+-.0.1,13.5.+-.0.1,14.4.+-.0.1,15.3.+-.0.1,16.1.+-.0.1,16-
.9.+-.0.1, 17.2.+-.0.1, 20.3.+-.0.1, 21.7.+-.0.1, 22.1.+-.0.1,
23.5.+-.0.1, 23.9.+-.0.1, 24.7.+-.0.1, 26.8.+-.0.1, 27.3.+-.0.1,
and 29.1.+-.0.1.
[0125] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 5.6.+-.0.1, 8.9.+-.0.1, 9.6.+-.0.1,
10.6.+-.0.1, 11.0.+-.0.1, 13.5.+-.0.1, 14.4.+-.0.1, 14.9.+-.0.1,
15.3.+-.0.1, 16.1.+-.0.1, 16.9.+-.0.1, 17.2.+-.0.1, 18.0.+-.0.1,
19.1.+-.0.1, 20.3.+-.0.1, 21.0.+-.0.1, 21.7.+-.0.1, 22.1.+-.0.1,
22.8.+-.0.1, 23.5.+-.0.1, 23.9.+-.0.1, 24.7.+-.0.1, 26.8.+-.0.1,
27.3.+-.0.1, and 29.1.+-.0.1.
[0126] In some embodiments, the crystalline form of the compound of
formula (I) includes angle 2 .theta. peaks (i.e., degrees 2
.theta.) at about 11.0, 14.9, 18.0, 19.1, 21.0, and 22.8. The XRPD
pattern of the crystalline form of the compound of formula (I) can
further include angle 2 .theta. peaks at about 5.6, 8.9, 9.6, 10.6,
13.5, 14.4, 15.3, 16.1, 16.9, 17.2, 20.3, 21.7, 22.1, 23.5, 23.9,
24.7, 26.8, 27.3, and 29.1.
[0127] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 5.6, 8.9, 9.6, 10.6, 11.0, 13.5, 14.4,
14.9, 15.3, 16.1, 16.9, 17.2, 18.0, 19.1, 20.3, 21.0, 21.7, 22.1,
22.8, 23.5, 23.9, 24.7, 26.8, 27.3, and 29.
[0128] In certain embodiments, the crystalline form of the compound
of formula (I) is characterized by a XRPD pattern corresponding
substantially to FIG. 44.
[0129] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 8.05.+-.0.3, 5.94.+-.0.3, 4.91.+-.0.3,
4.63.+-.0.3, 4.22.+-.0.3, and 3.89.+-.0.3. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 15.71.+-.0.3, 9.97.+-.0.3,
9.22.+-.0.3, 8.33.+-.0.3, 6.55.+-.0.3, 6.16.+-.0.3, 5.77.+-.0.3,
5.50.+-.0.3, 5.25.+-.0.3, 5.15.+-.0.3, 4.36.+-.0.3, 4.09.+-.0.3,
4.01.+-.0.3, 3.78.+-.0.3, 3.71.+-.0.3, 3.60.+-.0.3, 3.32.+-.0.3,
3.26.+-.0.3, and 3.07.+-.0.3.
[0130] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 15.71.+-.0.3, 9.97.+-.0.3, 9.22.+-.0.3,
8.33.+-.0.3, 8.05.+-.0.3, 6.55.+-.0.3, 6.16.+-.0.3, 5.94.+-.0.3,
5.77.+-.0.3, 5.50.+-.0.3, 5.25.+-.0.3, 5.15.+-.0.3, 4.91.+-.0.3,
4.63.+-.0.3, 4.36.+-.0.3, 4.22.+-.0.3, 4.09.+-.0.3, 4.01.+-.0.3,
3.89.+-.0.3, 3.78.+-.0.3, 3.71.+-.0.3, 3.60.+-.0.3, 3.32.+-.0.3,
3.26.+-.0.3, and 3.07.+-.0.3.
[0131] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 8.05.+-.0.2, 5.94.+-.0.2, 4.91.+-.0.2,
4.63.+-.0.2, 4.22.+-.0.2, and 3.89.+-.0.2. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 15.71.+-.0.2, 9.97.+-.0.2,
9.22.+-.0.2, 8.33.+-.0.2, 6.55.+-.0.2, 6.16.+-.0.2, 5.77.+-.0.2,
5.50.+-.0.2, 5.25.+-.0.2, 5.15.+-.0.2, 4.36.+-.0.2, 4.09.+-.0.2,
4.01.+-.0.2, 3.78.+-.0.2, 3.71.+-.0.2, 3.60.+-.0.2, 3.32.+-.0.2,
3.26.+-.0.2, and 3.07.+-.0.2.
[0132] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 15.71.+-.0.2, 9.97.+-.0.2, 9.22.+-.0.2,
8.33.+-.0.2, 8.05.+-.0.2, 6.55.+-.0.2, 6.16.+-.0.2, 5.94.+-.0.2,
5.77.+-.0.2, 5.50.+-.0.2, 5.25.+-.0.2, 5.15.+-.0.2, 4.91.+-.0.2,
4.63.+-.0.2, 4.36.+-.0.2, 4.22.+-.0.2, 4.09.+-.0.2, 4.01.+-.0.2,
3.89.+-.0.2, 3.78.+-.0.2, 3.71.+-.0.2, 3.60.+-.0.2, 3.32.+-.0.2,
3.26.+-.0.2, and 3.07.+-.0.2.
[0133] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 8.05.+-.0.1, 5.94.+-.0.1, 4.91.+-.0.1,
4.63.+-.0.1, 4.22.+-.0.1, and 3.89.+-.0.1. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 15.71.+-.0.1, 9.97.+-.0.1,
9.22.+-.0.1, 8.33.+-.0.1, 6.55.+-.0.1, 6.16.+-.0.1, 5.77.+-.0.1,
5.50.+-.0.1, 5.25.+-.0.1, 5.15.+-.0.1, 4.36.+-.0.1, 4.09.+-.0.1,
4.01.+-.0.1, 3.78.+-.0.1, 3.71.+-.0.1, 3.60.+-.0.1, 3.32.+-.0.1,
3.26.+-.0.1, and 3.07.+-.0.1.
[0134] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 15.71.+-.0.1, 9.97.+-.0.1, 9.22.+-.0.1,
8.33.+-.0.1, 8.05.+-.0.1, 6.55.+-.0.1, 6.16.+-.0.1, 5.94.+-.0.1,
5.77.+-.0.1, 5.50.+-.0.1, 5.25.+-.0.1, 5.15.+-.0.1, 4.91.+-.0.1,
4.63.+-.0.1, 4.36.+-.0.1, 4.22.+-.0.1, 4.09.+-.0.1, 4.01.+-.0.1,
3.89.+-.0.1, 3.78.+-.0.1, 3.71.+-.0.1, 3.60.+-.0.1, 3.32.+-.0.1,
3.26.+-.0.1, and 3.07.+-.0.1.
[0135] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 8.05, 5.94, 4.91, 4.63, 4.22, and 3.89. The XRPD
pattern of the crystalline form of the compound of formula (I) can
be further characterized by d spacings at about 15.71, 9.97, 9.22,
8.33, 6.55, 6.16, 5.77, 5.50, 5.25, 5.15, 4.36, 4.09, 4.01, 3.78,
3.71, 3.60, 3.32, 3.26, and 3.07.
[0136] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 15.71.+-.0.2, 9.97.+-.0.2, 9.22.+-.0.2,
8.33.+-.0.2, 8.05.+-.0.2, 6.55.+-.0.2, 6.16.+-.0.2, 5.94.+-.0.2,
5.77.+-.0.2, 5.50.+-.0.2, 5.25.+-.0.2, 5.15.+-.0.2, 4.91.+-.0.2,
4.63.+-.0.2, 4.36.+-.0.2, 4.22.+-.0.2, 4.09.+-.0.2, 4.01.+-.0.2,
3.89.+-.0.2, 3.78.+-.0.2, 3.71.+-.0.2, 3.60.+-.0.2, 3.32.+-.0.2,
3.26.+-.0.2, and 3.07.+-.0.2.
[0137] The crystalline form of the compound of formula (I) can be
Form C, where Form C is characterized by the XRPD pattern described
above or by FIG. 44.
[0138] The crystalline form of the compound of formula (I) (e.g.,
Form C) can include an endothermic event et temperature of about
211.degree. C. as determined by DSC. The crystalline form of the
compound of formula (I) (e.g., Form C) can be characterized by a
DSC plot set forth in FIG. 16. The crystalline form of the compound
of formula (I) can have a melting point of about 213.degree. C. The
crystalline form of the compound of formula (I) can be Form C,
where Form C has a melting point of about 213.degree. C.
[0139] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 15.6.+-.0.2,
22.0.+-.0.2, and 23.7.+-.0.2. The XRPD pattern of the crystalline
form of the compound of formula (I) can further include angle 2
.theta. peaks at about 6.6.+-.0.2, 7.8.+-.0.2, 9.0.+-.0.2,
10.6.+-.0.2, 13.7.+-.0.2, 14.7.+-.0.2, 16.3.+-.0.2, 17.1.+-.0.2,
18.1.+-.0.2, 18.2.+-.0.2, 18.8.+-.0.2, 19.1.+-.0.2, 19.7.+-.0.2,
20.7.+-.0.2, 21.2.+-.0.2, 22.5.+-.0.2, 25.0.+-.0.2, 26.6.+-.0.2,
27.6.+-.0.2, and 28.7.+-.0.2.
[0140] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 6.6.+-.0.2, 7.8.+-.0.2, 9.0.+-.0.2,
10.6.+-.0.2, 13.7.+-.0.2, 14.7.+-.0.2, 15.6.+-.0.2, 16.3.+-.0.2,
17.1.+-.0.2, 18.1.+-.0.2, 18.2.+-.0.2, 18.8.+-.0.2, 19.1.+-.0.2,
19.7.+-.0.2, 20.7.+-.0.2, 21.2.+-.0.2, 22.0.+-.0.2, 22.5.+-.0.2,
23.7.+-.0.2, 25.0.+-.0.2, 26.6.+-.0.2, 27.6.+-.0.2, and
28.7.+-.0.2.
[0141] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 15.6.+-.0.1,
22.0.+-.0.1, and 23.7.+-.0.1. The XRPD pattern of the crystalline
form of the compound of formula (I) can further include angle 2
.theta. peaks at about 6.6.+-.0.1, 7.8.+-.0.1,
9.0.+-.0.1,10.6.+-.0.1,13.7.+-.0.1,14.7.+-.0.1,16.3.+-.0.1,17.1.+-.0.1,18-
.1.+-.0.1, 18.2.+-.0.1, 18.8.+-.0.1, 19.1.+-.0.1, 19.7.+-.0.1,
20.7.+-.0.1, 21.2.+-.0.1, 22.5.+-.0.1, 25.0.+-.0.1, 26.6.+-.0.1,
27.6.+-.0.1, and 28.7.+-.0.1.
[0142] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 6.6.+-.0.1, 7.8.+-.0.1, 9.0.+-.0.1,
10.6.+-.0.1, 13.7.+-.0.1, 14.7.+-.0.1, 15.6.+-.0.1, 16.3.+-.0.1,
17.1.+-.0.1, 18.1.+-.0.1, 18.2.+-.0.1, 18.8.+-.0.1, 19.1.+-.0.1,
19.7.+-.0.1, 20.7.+-.0.1, 21.2.+-.0.1, 22.0.+-.0.1, 22.5.+-.0.1,
23.7.+-.0.1, 25.0.+-.0.1, 26.6.+-.0.1, 27.6.+-.0.1, and
28.7.+-.0.1.
[0143] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 15.6, 22.0, and
23.7. The XRPD pattern of the crystalline form of the compound of
formula (I) can further include angle 2 .theta. peaks at about 6.6,
7.8, 9.0, 10.6, 13.7, 14.7, 16.3, 17.1, 18.1, 18.2, 18.8, 19.1,
19.7, 20.7, 21.2, 22.5, 25.0, 26.6, 27.6, and 28.7.
[0144] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 6.6, 7.8, 9.0, 10.6, 13.7, 14.7, 15.6,
16.3, 17.1, 18.1, 18.2, 18.8, 19.1, 19.7, 20.7, 21.2, 22.0, 22.5,
23.7, 25.0, 26.6, 27.6, and 28.7.
[0145] In certain embodiments, the crystalline form of the compound
of formula (I) is characterized by a XRPD pattern corresponding
substantially to FIG. 45.
[0146] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 5.66.+-.0.3, 4.02.+-.0.3, and 3.75.+-.0.3. The
XRPD pattern of the crystalline form of the compound of formula (I)
can be further characterized by d spacings at about 13.46.+-.0.3,
11.38.+-.0.3, 9.79.+-.0.3, 8.37.+-.0.3, 6.43.+-.0.3, 6.02.+-.0.3,
5.44.+-.0.3, 5.18.+-.0.3, 4.90.+-.0.3, 4.86.+-.0.3, 4.72.+-.0.3,
4.64.+-.0.3, 4.50.+-.0.3, 4.29.+-.0.3, 4.19.+-.0.3, 3.94.+-.0.3,
3.55.+-.0.3, 3.34.+-.0.3, 3.22.+-.0.3, and 3.10.+-.0.3.
[0147] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 13.46.+-.0.3, 11.38.+-.0.3, 9.79.+-.0.3,
8.37.+-.0.3, 6.43.+-.0.3, 6.02.+-.0.3, 5.66.+-.0.3, 5.44.+-.0.3,
5.18.+-.0.3, 4.90.+-.0.3, 4.86.+-.0.3, 4.72.+-.0.3, 4.64.+-.0.3,
4.50.+-.0.3, 4.29.+-.0.3, 4.19.+-.0.3, 4.02.+-.0.3, 3.94.+-.0.3,
3.75.+-.0.3, 3.55.+-.0.3, 3.34.+-.0.3, 3.22.+-.0.3, and
3.10.+-.0.3.
[0148] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 5.66.+-.0.2, 4.02.+-.0.2, and 3.75.+-.0.2. The
XRPD pattern of the crystalline form of the compound of formula (I)
can be further characterized by d spacings at about 13.46.+-.0.2,
11.38.+-.0.2, 9.79.+-.0.2, 8.37.+-.0.2, 6.43.+-.0.2, 6.02.+-.0.2,
5.44.+-.0.2, 5.18.+-.0.2, 4.90.+-.0.2, 4.86.+-.0.2, 4.72.+-.0.2,
4.64.+-.0.2, 4.50.+-.0.2, 4.29.+-.0.2, 4.19.+-.0.2, 3.94.+-.0.2,
3.55.+-.0.2, 3.34.+-.0.2, 3.22.+-.0.2, and 3.10.+-.0.2.
[0149] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 13.46.+-.0.2, 11.38.+-.0.2, 9.79.+-.0.2,
8.37.+-.0.2, 6.43.+-.0.2, 6.02.+-.0.2, 5.66.+-.0.2, 5.44.+-.0.2,
5.18.+-.0.2, 4.90.+-.0.2, 4.86.+-.0.2, 4.72.+-.0.2, 4.64.+-.0.2,
4.50.+-.0.2, 4.29.+-.0.2, 4.19.+-.0.2, 4.02.+-.0.2, 3.94.+-.0.2,
3.75.+-.0.2, 3.55.+-.0.2, 3.34.+-.0.2, 3.22.+-.0.2, and
3.10.+-.0.2.
[0150] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 5.66.+-.0.1, 4.02.+-.0.1, and 3.75.+-.0.1. The
XRPD pattern of the crystalline form of the compound of formula (I)
can be further characterized by d spacings at about 13.46.+-.0.1,
11.38.+-.0.1, 9.79.+-.0.1, 8.37.+-.0.1, 6.43.+-.0.1, 6.02.+-.0.1,
5.44.+-.0.1, 5.18.+-.0.1, 4.90.+-.0.1, 4.86.+-.0.1, 4.72.+-.0.1,
4.64.+-.0.1, 4.50.+-.0.1, 4.29.+-.0.1, 4.19.+-.0.1, 3.94.+-.0.1,
3.55.+-.0.1, 3.34.+-.0.1, 3.22.+-.0.1, and 3.10.+-.0.1.
[0151] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 13.46.+-.0.1, 11.38.+-.0.1, 9.79.+-.0.1,
8.37.+-.0.1, 6.43.+-.0.1, 6.02.+-.0.1, 5.66.+-.0.1, 5.44.+-.0.1,
5.18.+-.0.1, 4.90.+-.0.1, 4.86.+-.0.1, 4.72.+-.0.1, 4.64.+-.0.1,
4.50.+-.0.1, 4.29.+-.0.1, 4.19.+-.0.1, 4.02.+-.0.1, 3.94.+-.0.1,
3.75.+-.0.1, 3.55.+-.0.1, 3.34.+-.0.1, 3.22.+-.0.1, and
3.10.+-.0.1.
[0152] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 5.66, 4.02, and 3.75. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 13.46, 11.38, 9.79, 8.37,
6.43, 6.02, 5.44, 5.18, 4.90, 4.86, 4.72, 4.64, 4.50, 4.29, 4.19,
3.94, 3.55, 3.34, 3.22, and 3.10.
[0153] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 13.46, 11.38, 9.79, 8.37, 6.43, 6.02, 5.66, 5.44,
5.18, 4.90, 4.86, 4.72, 4.64, 4.50, 4.29, 4.19, 4.02, 3.94, 3.75,
3.55, 3.34, 3.22, and 3.10.
[0154] The crystalline form of the compound of formula (I) can be
Form D, where Form D is characterized by the XRPD pattern described
above or by FIG. 45.
[0155] The crystalline form of the compound of formula (I) (e.g.,
Form D) can include an endothermic event with an onset temperature
of about 205.degree. C. as determined by DSC. The crystalline form
of the compound of formula (I) can be characterized by a DSC plot
set forth in FIG. 19. The crystalline form of the compound of
formula (I) can have a melting point of about 209.degree. C. The
crystalline form of the compound of formula (I) can be Form D,
where Form D has a melting point of about 209.degree. C.
[0156] The crystalline form of the compound of formula (I) (e.g.,
Form D) can have a mass loss of about 13% when heated from about
35.degree. C. to about 153.degree. C. Form D can be a solvated
crystalline form, where Form D is a dichloromethane solvate.
[0157] In some embodiments, the crystalline form of the compound of
formula (I) can be characterized by a XRPD pattern that includes
angle 2 .theta. peaks (i.e., degrees 2 .theta.) at about
8.8.+-.0.3, 17.7.+-.0.3, and 21.4.+-.0.3. The XRPD pattern of the
crystalline form of the compound of formula (I) can further include
angle 2 .theta. peaks at about 5.4.+-.0.3, 9.3.+-.0.3, 12.1.+-.0.3,
13.4.+-.0.3, 13.8.+-.0.3, 18.0.+-.0.3, 16.5.+-.0.3, 18.3.+-.0.3,
18.9.+-.0.3, 19.5.+-.0.3, 22.2.+-.0.3, 22.6.+-.0.3, 22.9.+-.0.3,
23.3.+-.0.3, 23.5.+-.0.3, 24.4.+-.0.3, 26.2.+-.0.3, 26.8.+-.0.3,
27.8.+-.0.3, and 29.3.+-.0.3.
[0158] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 5.4.+-.0.3, 8.8.+-.0.3, 9.3.+-.0.3,
12.1.+-.0.3, 13.4.+-.0.3, 13.8.+-.0.3, 17.7.+-.0.3, 18.0.+-.0.3,
16.5.+-.0.3, 18.3.+-.0.3, 18.9.+-.0.3, 19.5.+-.0.3, 21.4.+-.0.3,
22.2.+-.0.3, 22.6.+-.0.3, 22.9.+-.0.3, 23.3.+-.0.3, 23.5.+-.0.3,
24.4.+-.0.3, 26.2.+-.0.3, 26.8.+-.0.3, 27.8.+-.0.3, and
29.3.+-.0.3.
[0159] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 8.8.+-.0.2,
17.7.+-.0.2, and 21.4.+-.0.2. The XRPD pattern of the crystalline
form of the compound of formula (I) can further include angle 2
.theta. peaks at about 5.4.+-.0.2, 9.3.+-.0.2, 12.1.+-.0.2,
13.4.+-.0.2, 13.8.+-.0.2, 18.0.+-.0.2, 16.5.+-.0.2, 18.3.+-.0.2,
18.9.+-.0.2, 19.5.+-.0.2, 22.2.+-.0.2, 22.6.+-.0.2, 22.9.+-.0.2,
23.3.+-.0.2, 23.5.+-.0.2, 24.4.+-.0.2, 26.2.+-.0.2, 26.8.+-.0.2,
27.8.+-.0.2, and 29.3.+-.0.2.
[0160] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 5.4.+-.0.2, 8.8.+-.0.2, 9.3.+-.0.2,
12.1.+-.0.2, 13.4.+-.0.2, 13.8.+-.0.2, 17.7.+-.0.2, 18.0.+-.0.2,
16.5.+-.0.2, 18.3.+-.0.2, 18.9.+-.0.2, 19.5.+-.0.2, 21.4.+-.0.2,
22.2.+-.0.2, 22.6.+-.0.2, 22.9.+-.0.2, 23.3.+-.0.2, 23.5.+-.0.2,
24.4.+-.0.2, 26.2.+-.0.2, 26.8.+-.0.2, 27.8.+-.0.2, and
29.3.+-.0.2.
[0161] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 8.8.+-.0.1,
17.7.+-.0.1, and 21.4.+-.0.1. The XRPD pattern of the crystalline
form of the compound of formula (I) can further include angle 2
.theta. peaks at about 5.4.+-.0.1, 9.3.+-.0.1, 12.1.+-.0.1,
13.4.+-.0.1, 13.8.+-.0.1, 18.0.+-.0.1, 16.5.+-.0.1, 18.3.+-.0.1,
18.9.+-.0.1, 19.5.+-.0.1, 22.2.+-.0.1, 22.6.+-.0.1, 22.9.+-.0.1,
23.3.+-.0.1, 23.5.+-.0.1, 24.4.+-.0.1, 26.2.+-.0.1, 26.8.+-.0.1,
27.8.+-.0.1, and 29.3.+-.0.1.
[0162] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 5.4.+-.0.1, 8.8.+-.0.1, 9.3.+-.0.1,
12.1.+-.0.1, 13.4.+-.0.1, 13.8.+-.0.1, 17.7.+-.0.1, 18.0.+-.0.1,
16.5.+-.0.1, 18.3.+-.0.1, 18.9.+-.0.1, 19.5.+-.0.1, 21.4.+-.0.1,
22.2.+-.0.1, 22.6.+-.0.1, 22.9.+-.0.1, 23.3.+-.0.1, 23.5.+-.0.1,
24.4.+-.0.1, 26.2.+-.0.1, 26.8.+-.0.1, 27.8.+-.0.1, and
29.3.+-.0.1.
[0163] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 8.8, 17.7, and
21.4. The XRPD pattern of the crystalline form of the compound of
formula (I) can further include angle 2 .theta. peaks at about 5.4,
9.3, 12.1, 13.4, 13.8, 18.0, 16.5, 18.3, 18.9, 19.5, 22.2, 22.6,
22.9, 23.3, 23.5, 24.4, 26.2, 26.8, 27.8, and 29.3.
[0164] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 5.4, 8.8, 9.3, 12.1, 13.4, 13.8, 17.7,
18.0, 16.5, 18.3, 18.9, 19.5, 21.4, 22.2, 22.6, 22.9, 23.3, 23.5,
24.4, 26.2, 26.8, 27.8, and 29.3.
[0165] In certain embodiments, the crystalline form of the compound
of formula (I) is characterized by a XRPD pattern corresponding
substantially to FIG. 46.
[0166] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 10.01.+-.0.3, 4.99.+-.0.3, and 4.14.+-.0.3. The
XRPD pattern of the crystalline form of the compound of formula (I)
can be further characterized by d spacings at about 16.41.+-.0.3,
9.46.+-.0.3, 7.30.+-.0.3, 6.61.+-.0.3, 6.40.+-.0.3, 5.52.+-.0.3,
5.38.+-.0.3, 4.83.+-.0.3, 4.67.+-.0.3, 4.55.+-.0.3, 3.99.+-.0.3,
3.93,.+-.0.3 3.87.+-.0.3, 3.81.+-.0.3, 3.77.+-.0.3, 3.64.+-.0.3,
3.40.+-.0.3, 3.32.+-.0.3, and 3.04.+-.0.3.
[0167] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 16.41.+-.0.3, 10.01.+-.0.3, 9.46.+-.0.3,
7.30.+-.0.3, 6.61.+-.0.3, 6.40.+-.0.3, 5.52.+-.0.3, 5.38.+-.0.3,
4.99.+-.0.3, 4.83.+-.0.3, 4.67.+-.0.3, 4.55.+-.0.3, 4.14.+-.0.3,
3.99.+-.0.3, 3.93,.+-.0.3 3.87.+-.0.3, 3.81.+-.0.3, 3.77.+-.0.3,
3.64.+-.0.3, 3.40.+-.0.3, 3.32.+-.0.3, and 3.04.+-.0.3.
[0168] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 10.01.+-.0.2, 4.99.+-.0.2, and 4.14.+-.0.2. The
XRPD pattern of the crystalline form of the compound of formula (I)
can be further characterized by d spacings at about 16.41.+-.0.2,
9.46.+-.0.2, 7.30.+-.0.2, 6.61.+-.0.2, 6.40.+-.0.2, 5.52.+-.0.2,
5.38.+-.0.2, 4.83.+-.0.2, 4.67.+-.0.2, 4.55.+-.0.2, 3.99.+-.0.2,
3.93,.+-.0.2 3.87.+-.0.2, 3.81.+-.0.2, 3.77.+-.0.2, 3.64.+-.0.2,
3.40.+-.0.2, 3.32.+-.0.2, and 3.04.+-.0.2.
[0169] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 16.41.+-.0.2, 10.01.+-.0.2, 9.46.+-.0.2,
7.30.+-.0.2, 6.61.+-.0.2, 6.40.+-.0.2, 5.52.+-.0.2, 5.38.+-.0.2,
4.99.+-.0.2, 4.83.+-.0.2, 4.67.+-.0.2, 4.55.+-.0.2, 4.14.+-.0.2,
3.99.+-.0.2, 3.93,.+-.0.2 3.87.+-.0.2, 3.81.+-.0.2, 3.77.+-.0.2,
3.64.+-.0.2, 3.40.+-.0.2, 3.32.+-.0.2, and 3.04.+-.0.2.
[0170] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 10.01.+-.0.1, 4.99.+-.0.1, and 4.14.+-.0.1. The
XRPD pattern of the crystalline form of the compound of formula (I)
can be further characterized by d spacings at about 16.41.+-.0.1,
9.46.+-.0.1, 7.30.+-.0.1, 6.61.+-.0.1, 6.40.+-.0.1, 5.52.+-.0.1,
5.38.+-.0.1, 4.83.+-.0.1, 4.67.+-.0.1, 4.55.+-.0.1, 3.99.+-.0.1,
3.93,.+-.0.1 3.87.+-.0.1, 3.81.+-.0.1, 3.77.+-.0.1, 3.64.+-.0.1,
3.40.+-.0.1, 3.32.+-.0.1, and 3.04.+-.0.1.
[0171] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 16.41.+-.0.1, 10.01.+-.0.1, 9.46.+-.0.1,
7.30.+-.0.1, 6.61.+-.0.1, 6.40.+-.0.1, 5.52.+-.0.1, 5.38.+-.0.1,
4.99.+-.0.1, 4.83.+-.0.1, 4.67.+-.0.1, 4.55.+-.0.1, 4.14.+-.0.1,
3.99.+-.0.1, 3.93,.+-.0.1 3.87.+-.0.1, 3.81.+-.0.1, 3.77.+-.0.1,
3.64.+-.0.1, 3.40.+-.0.1, 3.32.+-.0.1, and 3.04.+-.0.1.
[0172] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 10.01, 4.99, and 4.14. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 16.41, 9.46, 7.30, 6.61, 6.40,
5.52, 5.38, 4.83, 4.67, 4.55, 3.99, 3.93, 3.87, 3.81, 3.77, 3.64,
3.40, 3.32, and 3.04.
[0173] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 16.41, 10.01, 9.46, 7.30, 6.61, 6.40, 5.52, 5.38,
4.99, 4.83, 4.67, 4.55, 4.14, 3.99, 3.93, 3.87, 3.81, 3.77, 3.64,
3.40, 3.32, and 3.04.
[0174] The crystalline form of the compound of formula (I) can be
Form E, where Form E is characterized by the XRPD pattern described
above or by FIG. 46.
[0175] Form E can be a solvated crystalline form, where Form E is a
chlorobenzene solvate.
[0176] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 4.6.+-.0.3,
4.8.+-.0.3, 15.3.+-.0.3, 16.6.+-.0.3, 18.1.+-.0.3, and 22.9.+-.0.3.
The XRPD pattern of the crystalline form of the compound of formula
(I) can further include angle 2 .theta. peaks at about 7.3.+-.0.3,
8.1.+-.0.3, 9.7.+-.0.3, 11.0.+-.0.3, 12.2.+-.0.3, 13.8.+-.0.3,
14.8.+-.0.3, 16.1.+-.0.3, 17.5.+-.0.3, 17.9.+-.0.3, 18.5.+-.0.3,
19.8.+-.0.3, 20.2.+-.0.3, 20.8.+-.0.3, 21.5.+-.0.3, 22.2.+-.0.3,
23.4.+-.0.3, 24.0.+-.0.3, 24.8.+-.0.3, 25.2.+-.0.3, 25.8.+-.0.3,
27.5.+-.0.3, 27.9.+-.0.3, and 31.9.+-.0.3.
[0177] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 4.6.+-.0.3, 4.8.+-.0.3, 7.3.+-.0.3,
8.1.+-.0.3, 9.7.+-.0.3, 11.0.+-.0.3, 12.2.+-.0.3, 13.8.+-.0.3,
14.8.+-.0.3, 15.3.+-.0.3, 16.1.+-.0.3, 16.6.+-.0.3, 17.5.+-.0.3,
17.9.+-.0.3, 18.1.+-.0.3, 18.5.+-.0.3, 19.8.+-.0.3, 20.2.+-.0.3,
20.8.+-.0.3, 21.5.+-.0.3, 22.2.+-.0.3, 22.9.+-.0.3, 23.4.+-.0.3,
24.0.+-.0.3, 24.8.+-.0.3, 25.2.+-.0.3, 25.8.+-.0.3, 27.5.+-.0.3,
27.9.+-.0.3, and 31.9.+-.0.3.
[0178] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 4.6.+-.0.2,
4.8.+-.0.2, 15.3.+-.0.2, 16.6.+-.0.2, 18.1.+-.0.2, and 22.9.+-.0.2.
The XRPD pattern of the crystalline form of the compound of formula
(I) can further include angle 2 .theta. peaks at about 7.3.+-.0.2,
8.1.+-.0.2, 9.7.+-.0.2, 11.0.+-.0.2, 12.2.+-.0.2, 13.8.+-.0.2,
14.8.+-.0.2, 16.1.+-.0.2, 17.5.+-.0.2, 17.9.+-.0.2, 18.5.+-.0.2,
19.8.+-.0.2, 20.2.+-.0.2, 20.8.+-.0.2, 21.5.+-.0.2, 22.2.+-.0.2,
23.4.+-.0.2, 24.0.+-.0.2, 24.8.+-.0.2, 25.2.+-.0.2, 25.8.+-.0.2,
27.5.+-.0.2, 27.9.+-.0.2, and 31.9.+-.0.2.
[0179] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 4.6.+-.0.2, 4.8.+-.0.2, 7.3.+-.0.2,
8.1.+-.0.2, 9.7.+-.0.2, 11.0.+-.0.2, 12.2.+-.0.2, 13.8.+-.0.2,
14.8.+-.0.2, 15.3.+-.0.2, 16.1.+-.0.2, 16.6.+-.0.2, 17.5.+-.0.2,
17.9.+-.0.2, 18.1.+-.0.2, 18.5.+-.0.2, 19.8.+-.0.2, 20.2.+-.0.2,
20.8.+-.0.2, 21.5.+-.0.2, 22.2.+-.0.2, 22.9.+-.0.2, 23.4.+-.0.2,
24.0.+-.0.2, 24.8.+-.0.2, 25.2.+-.0.2, 25.8.+-.0.2, 27.5.+-.0.2,
27.9.+-.0.2, and 31.9.+-.0.2.
[0180] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 4.6.+-.0.1,
4.8.+-.0.1, 15.3.+-.0.1, 16.6.+-.0.1, 18.1.+-.0.1, and 22.9.+-.0.1.
The XRPD pattern of the crystalline form of the compound of formula
(I) can further include angle 2 .theta. peaks at about 7.3.+-.0.1,
8.1.+-.0.1, 9.7.+-.0.1, 11.0.+-.0.1, 12.2.+-.0.1, 13.8.+-.0.1,
14.8.+-.0.1, 16.1.+-.0.1, 17.5.+-.0.1, 17.9.+-.0.1, 18.5.+-.0.1,
19.8.+-.0.1, 20.2.+-.0.1, 20.8.+-.0.1, 21.5.+-.0.1, 22.2.+-.0.1,
23.4.+-.0.1, 24.0.+-.0.1, 24.8.+-.0.1, 25.2.+-.0.1, 25.8.+-.0.1,
27.5.+-.0.1, 27.9.+-.0.1, and 31.9.+-.0.1.
[0181] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 4.6.+-.0.1, 4.8.+-.0.1, 7.3.+-.0.1,
8.1.+-.0.1, 9.7.+-.0.1, 11.0.+-.0.1, 12.2.+-.0.1, 13.8.+-.0.1,
14.8.+-.0.1, 15.3.+-.0.1, 16.1.+-.0.1, 16.6.+-.0.1, 17.5.+-.0.1,
17.9.+-.0.1, 18.1.+-.0.1, 18.5.+-.0.1, 19.8.+-.0.1, 20.2.+-.0.1,
20.8.+-.0.1, 21.5.+-.0.1, 22.2.+-.0.1, 22.9.+-.0.1, 23.4.+-.0.1,
24.0.+-.0.1, 24.8.+-.0.1, 25.2.+-.0.1, 25.8.+-.0.1, 27.5.+-.0.1,
27.9.+-.0.1, and 31.9.+-.0.1.
[0182] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 4.6, 4.8, 15.3,
16.6, 18.1, and 22.9. The XRPD pattern of the crystalline form of
the compound of formula (I) can further include angle 2 .theta.
peaks at about 7.3, 8.1, 9.7, 11.0, 12.2, 13.8, 14.8, 16.1, 17.5,
17.9, 18.5, 19.8, 20.2, 20.8, 21.5, 22.2, 23.4, 24.0, 24.8, 25.2,
25.8, 27.5, 27.9, and 31.9.
[0183] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 4.6.+-.0.2, 4.8.+-.0.2, 7.3.+-.0.2,
8.1.+-.0.2, 9.7.+-.0.2, 11.0.+-.0.2, 12.2.+-.0.2, 13.8.+-.0.2,
14.8.+-.0.2, 15.3.+-.0.2, 16.1.+-.0.2, 16.6.+-.0.2, 17.5.+-.0.2,
17.9.+-.0.2, 18.1.+-.0.2, 18.5.+-.0.2, 19.8.+-.0.2, 20.2.+-.0.2,
20.8.+-.0.2, 21.5.+-.0.2, 22.2.+-.0.2, 22.9.+-.0.2, 23.4.+-.0.2,
24.0.+-.0.2, 24.8.+-.0.2, 25.2.+-.0.2, 25.8.+-.0.2, 27.5.+-.0.2,
27.9.+-.0.2, and 31.9.+-.0.2.
[0184] In certain embodiments, the crystalline form of the compound
of formula (I) is characterized by a XRPD pattern corresponding
substantially to FIG. 47.
[0185] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 19.27.+-.0.3, 18.31.+-.0.3, 5.77.+-.0.3,
5.33.+-.0.3, 4.65.+-.0.3, and 3.88.+-.0.3. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 12.06.+-.0.3, 10.96.+-.0.3,
9.11.+-.0.3, 8.02.+-.0.3, 7.22.+-.0.3, 6.39.+-.0.3, 5.98.+-.0.3,
5.51.+-.0.3, 5.07.+-.0.3, 4.95.+-.0.3, 4.78.+-.0.3, 4.52.+-.0.3,
4.39.+-.0.3, 4.26.+-.0.3, 4.12.+-.0.3, 4.00.+-.0.3, 3.80.+-.0.3,
3.69.+-.0.3, 3.61.+-.0.3, 3.53.+-.0.3, 3.45.+-.0.3, 3.24.+-.0.3,
3.19.+-.0.3, and 2.80.+-.0.3.
[0186] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 19.27.+-.0.3, 18.31.+-.0.3, 12.06.+-.0.3,
10.96.+-.0.3, 9.11.+-.0.3, 8.02.+-.0.3, 7.22.+-.0.3, 6.39.+-.0.3,
5.98.+-.0.3, 5.77.+-.0.3, 5.51.+-.0.3, 5.33.+-.0.3, 5.07.+-.0.3,
4.95.+-.0.3, 4.78.+-.0.3, 4.65.+-.0.3, 4.52.+-.0.3, 4.39.+-.0.3,
4.26.+-.0.3, 4.12.+-.0.3, 4.00.+-.0.3, 3.88.+-.0.3, 3.80.+-.0.3,
3.69.+-.0.3, 3.61.+-.0.3, 3.53.+-.0.3, 3.45.+-.0.3, 3.24.+-.0.3,
3.19.+-.0.3, and 2.80.+-.0.3.
[0187] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 19.27.+-.0.2, 18.31.+-.0.2, 5.77.+-.0.2,
5.33.+-.0.2, 4.65.+-.0.2, and 3.88.+-.0.2. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 12.06.+-.0.2, 10.96.+-.0.2,
9.11.+-.0.2, 8.02.+-.0.2, 7.22.+-.0.2, 6.39.+-.0.2, 5.98.+-.0.2,
5.51.+-.0.2, 5.07.+-.0.2, 4.95.+-.0.2, 4.78.+-.0.2, 4.52.+-.0.2,
4.39.+-.0.2, 4.26.+-.0.2, 4.12.+-.0.2, 4.00.+-.0.2, 3.80.+-.0.2,
3.69.+-.0.2, 3.61.+-.0.2, 3.53.+-.0.2, 3.45.+-.0.2, 3.24.+-.0.2,
3.19.+-.0.2, and 2.80.+-.0.2.
[0188] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 19.27.+-.0.2, 18.31.+-.0.2, 12.06.+-.0.2,
10.96.+-.0.2, 9.11.+-.0.2, 8.02.+-.0.2, 7.22.+-.0.2, 6.39.+-.0.2,
5.98.+-.0.2, 5.77.+-.0.2, 5.51.+-.0.2, 5.33.+-.0.2, 5.07.+-.0.2,
4.95.+-.0.2, 4.78.+-.0.2, 4.65.+-.0.2, 4.52.+-.0.2, 4.39.+-.0.2,
4.26.+-.0.2, 4.12.+-.0.2, 4.00.+-.0.2, 3.88.+-.0.2, 3.80.+-.0.2,
3.69.+-.0.2, 3.61.+-.0.2, 3.53.+-.0.2, 3.45.+-.0.2, 3.24.+-.0.2,
3.19.+-.0.2, and 2.80.+-.0.2.
[0189] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 19.27.+-.0.1, 18.31.+-.0.1, 5.77.+-.0.1,
5.33.+-.0.1, 4.65.+-.0.1, and 3.88.+-.0.1. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 12.06.+-.0.1, 10.96.+-.0.1,
9.11.+-.0.1, 8.02.+-.0.1, 7.22.+-.0.1, 6.39.+-.0.1, 5.98.+-.0.1,
5.51.+-.0.1, 5.07.+-.0.1, 4.95.+-.0.1, 4.78.+-.0.1, 4.52.+-.0.1,
4.39.+-.0.1, 4.26.+-.0.1, 4.12.+-.0.1, 4.00.+-.0.1, 3.80.+-.0.1,
3.69.+-.0.1, 3.61.+-.0.1, 3.53.+-.0.1, 3.45.+-.0.1, 3.24.+-.0.1,
3.19.+-.0.1, and 2.80.+-.0.1.
[0190] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 19.27.+-.0.1, 18.31.+-.0.1, 12.06.+-.0.1,
10.96.+-.0.1, 9.11.+-.0.1, 8.02.+-.0.1, 7.22.+-.0.1, 6.39.+-.0.1,
5.98.+-.0.1, 5.77.+-.0.1, 5.51.+-.0.1, 5.33.+-.0.1, 5.07.+-.0.1,
4.95.+-.0.1, 4.78.+-.0.1, 4.65.+-.0.1, 4.52.+-.0.1, 4.39.+-.0.1,
4.26.+-.0.1, 4.12.+-.0.1, 4.00.+-.0.1, 3.88.+-.0.1, 3.80.+-.0.1,
3.69.+-.0.1, 3.61.+-.0.1, 3.53.+-.0.1, 3.45.+-.0.1, 3.24.+-.0.1,
3.19.+-.0.1, and 2.80.+-.0.1.
[0191] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 19.27, 18.31, 5.77, 5.33, 4.65, and 3.88. The
XRPD pattern of the crystalline form of the compound of formula (I)
can be further characterized by d spacings at about 12.06, 10.96,
9.11, 8.02, 7.22, 6.39, 5.98, 5.51, 5.07, 4.95, 4.78, 4.52, 4.39,
4.26, 4.12, 4.00, 3.80, 3.69, 3.61, 3.53, 3.45, 3.24, 3.19, and
2.80.
[0192] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 19.27, 18.31, 12.06, 10.96, 9.11, 8.02, 7.22,
6.39, 5.98, 5.77, 5.51, 5.33, 5.07, 4.95, 4.78, 4.65, 4.52, 4.39,
4.26, 4.12, 4.00, 3.88, 3.80, 3.69, 3.61, 3.53, 3.45, 3.24, 3.19,
and 2.80.
[0193] The crystalline form of the compound of formula (I) can be
Form F, where Form F is characterized by the XRPD pattern described
above or by FIG. 47.
[0194] The crystalline form of the compound of formula (I) (e.g.,
Form F) can include an endothermic event with an onset temperature
of about 206.degree. C. as determined by DSC. The crystalline form
of the compound of formula (I) can be characterized by a DSC plot
set forth in FIG. 24. The crystalline form of the compound of
formula (I) can have a melting point of about 209.degree. C. The
crystalline form of the compound of formula (I) can be Form F,
where Form F has a melting point of about 209.degree. C.
[0195] The crystalline form of the compound of formula (I) (e.g.,
Form F) can have a mass loss of about 14% when heated from about
40.degree. C. to about 170.degree. C. Form F can be a solvated
crystalline form, where Form F is a trifluoroethanol solvate.
[0196] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 12.0.+-.0.3,
13.4.+-.0.3, 15.7.+-.0.3, 16.4.+-.0.3, 18.4.+-.0.3, 19.5.+-.0.3,
21.5.+-.0.3, 22.4.+-.0.3, 22.8.+-.0.3, 23.5.+-.0.3, and
24.2.+-.0.3. The XRPD pattern of the crystalline form of the
compound of formula (I) can further include angle 2 .theta. peaks
at about 9.4.+-.0.3, 10.2.+-.0.3, 11.3.+-.0.3, 12.9.+-.0.3,
14.7.+-.0.3, 17.1.+-.0.3, 17.7.+-.0.3, 19.0.+-.0.3, 20.1.+-.0.3,
20.5.+-.0.3, 21.8.+-.0.3, 25.1.+-.0.3, 25.9.+-.0.3, 26.2.+-.0.3,
28.7.+-.0.3, 27.2.+-.0.3, 28.5.+-.0.3, 29.3.+-.0.3, and
33.8.+-.0.3.
[0197] T In some embodiments, the crystalline form of the compound
of formula (I) is characterized by a XRPD pattern that includes
angle 2 .theta. peaks at about 9.4.+-.0.3,
10.2.+-.0.3,11.3.+-.0.3,12.0.+-.0.3,12.9.+-.0.3,13.4.+-.0.3,14.7.+-.0.3,1-
5.7.+-.0.3, 16.4.+-.0.3, 17.1.+-.0.3, 17.7.+-.0.3, 18.4.+-.0.3,
19.0.+-.0.3, 19.5.+-.0.3, 20.1.+-.0.3, 20.5.+-.0.3, 21.5.+-.0.3,
21.8.+-.0.3, 25.1.+-.0.3, 22.4.+-.0.3, 22.8.+-.0.3, 23.5.+-.0.3,
24.2.+-.0.3, 25.9.+-.0.3, 26.2.+-.0.3, 28.7.+-.0.3, 27.2.+-.0.3,
28.5.+-.0.3, 29.3.+-.0.3, and 33.8.+-.0.3.
[0198] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 12.0.+-.0.2,
13.4.+-.0.2, 15.7.+-.0.2, 16.4.+-.0.2, 18.4.+-.0.2, 19.5.+-.0.2,
21.5.+-.0.2, 22.4.+-.0.2, 22.8.+-.0.2, 23.5.+-.0.2, and
24.2.+-.0.2. The XRPD pattern of the crystalline form of the
compound of formula (I) can further include angle 2 .theta. peaks
at about 9.4.+-.0.2, 10.2.+-.0.2, 11.3.+-.0.2, 12.9.+-.0.2,
14.7.+-.0.2, 17.1.+-.0.2, 17.7.+-.0.2, 19.0.+-.0.2, 20.1.+-.0.2,
20.5.+-.0.2, 21.8.+-.0.2, 25.1.+-.0.2, 25.9.+-.0.2, 26.2.+-.0.2,
28.7.+-.0.2, 27.2.+-.0.2, 28.5.+-.0.2, 29.3.+-.0.2, and
33.8.+-.0.2.
[0199] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 9.4.+-.0.2, 10.2.+-.0.2, 11.3.+-.0.2,
12.0.+-.0.2, 12.9.+-.0.2, 13.4.+-.0.2, 14.7.+-.0.2, 15.7.+-.0.2,
16.4.+-.0.2, 17.1.+-.0.2, 17.7.+-.0.2, 18.4.+-.0.2, 19.0.+-.0.2,
19.5.+-.0.2, 20.1.+-.0.2, 20.5.+-.0.2, 21.5.+-.0.2, 21.8.+-.0.2,
25.1.+-.0.2, 22.4.+-.0.2, 22.8.+-.0.2, 23.5.+-.0.2, 24.2.+-.0.2,
25.9.+-.0.2, 26.2.+-.0.2, 28.7.+-.0.2, 27.2.+-.0.2, 28.5.+-.0.2,
29.3.+-.0.2, and 33.8.+-.0.2.
[0200] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 12.0.+-.0.1,
13.4.+-.0.1, 15.7.+-.0.1, 16.4.+-.0.1, 18.4.+-.0.1, 19.5.+-.0.1,
21.5.+-.0.1, 22.4.+-.0.1, 22.8.+-.0.1, 23.5.+-.0.1, and
24.2.+-.0.1. The XRPD pattern of the crystalline form of the
compound of formula (I) can further include angle 2 .theta. peaks
at about 9.4.+-.0.1, 10.2.+-.0.1, 11.3.+-.0.1, 12.9.+-.0.1,
14.7.+-.0.1, 17.1.+-.0.1, 17.7.+-.0.1, 19.0.+-.0.1, 20.1.+-.0.1,
20.5.+-.0.1, 21.8.+-.0.1, 25.1.+-.0.1, 25.9.+-.0.1, 26.2.+-.0.1,
28.7.+-.0.1, 27.2.+-.0.1, 28.5.+-.0.1, 29.3.+-.0.1, and
33.8.+-.0.1.
[0201] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 9.4.+-.0.1, 10.2.+-.0.1, 11.3.+-.0.1,
12.0.+-.0.1, 12.9.+-.0.1, 13.4.+-.0.1, 14.7.+-.0.1, 15.7.+-.0.1,
16.4.+-.0.1, 17.1.+-.0.1, 17.7.+-.0.1, 18.4.+-.0.1, 19.0.+-.0.1,
19.5.+-.0.1, 20.1.+-.0.1, 20.5.+-.0.1, 21.5.+-.0.1, 21.8.+-.0.1,
25.1.+-.0.1, 22.4.+-.0.1, 22.8.+-.0.1, 23.5.+-.0.1, 24.2.+-.0.1,
25.9.+-.0.1, 26.2.+-.0.1, 28.7.+-.0.1, 27.2.+-.0.1, 28.5.+-.0.1,
29.3.+-.0.1, and 33.8.+-.0.1.
[0202] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 12.0, 13.4,
15.7, 16.4, 18.4, 19.5, 21.5, 22.4, 22.8, 23.5, and 24.2. The XRPD
pattern of the crystalline form of the compound of formula (I) can
further include angle 2 .theta. peaks at about 9.4, 10.2, 11.3,
12.9, 14.7, 17.1, 17.7, 19.0, 20.1, 20.5, 21.8, 25.1, 25.9, 26.2,
28.7, 27.2, 28.5, 29.3, and 33.8.
[0203] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 9.4, 10.2, 11.3, 12.0, 12.9, 13.4, 14.7,
15.7, 16.4, 17.1, 17.7, 18.4, 19.0, 19.5, 20.1, 20.5, 21.5, 21.8,
25.1, 22.4, 22.8, 23.5, 24.2, 25.9, 26.2, 28.7, 27.2, 28.5, 29.3,
and 33.8.
[0204] In certain embodiments, the crystalline form of the compound
of formula (I) is characterized by a XRPD pattern corresponding
substantially to FIG. 48.
[0205] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 7.35.+-.0.3, 6.61.+-.0.3, 5.62.+-.0.3,
5.38.+-.0.3, 4.82.+-.0.3, 4.54.+-.0.3, 4.13.+-.0.3, 3.95.+-.0.3,
3.89.+-.0.3, 3.78.+-.0.3, and 3.67.+-.0.3. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 9.44.+-.0.3, 8.63.+-.0.3,
7.79.+-.0.3, 6.84.+-.0.3, 6.01.+-.0.3, 5.16.+-.0.3, 5.01.+-.0.3,
4.66.+-.0.3, 4.41.+-.0.3, 4.32.+-.0.3, 4.06.+-.0.3, 3.53.+-.0.3,
3.43.+-.0.3, 3.39.+-.0.3, 3.34.+-.0.3, 3.27.+-.0.3, 3.12.+-.0.3,
3.04.+-.0.3, and 2.64.+-.0.3.
[0206] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 9.44.+-.0.3, 8.63.+-.0.3, 7.79.+-.0.3,
7.35.+-.0.3, 6.84.+-.0.3, 6.61.+-.0.3, 6.01.+-.0.3, 5.62.+-.0.3,
5.38.+-.0.3, 5.16.+-.0.3, 5.01.+-.0.3, 4.82.+-.0.3, 4.66.+-.0.3,
4.54.+-.0.3, 4.41.+-.0.3, 4.32.+-.0.3, 4.13.+-.0.3, 4.06.+-.0.3,
3.95.+-.0.3, 3.89.+-.0.3, 3.78.+-.0.3, 3.67.+-.0.3, 3.53.+-.0.3,
3.43.+-.0.3, 3.39.+-.0.3, 3.34.+-.0.3, 3.27.+-.0.3, 3.12.+-.0.3,
3.04.+-.0.3, and 2.64.+-.0.3.
[0207] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 7.35.+-.0.2, 6.61.+-.0.2, 5.62.+-.0.2,
5.38.+-.0.2, 4.82.+-.0.2, 4.54.+-.0.2, 4.13.+-.0.2, 3.95.+-.0.2,
3.89.+-.0.2, 3.78.+-.0.2, and 3.67.+-.0.2. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 9.44.+-.0.2, 8.63.+-.0.2,
7.79.+-.0.2, 6.84.+-.0.2, 6.01.+-.0.2, 5.16.+-.0.2, 5.01.+-.0.2,
4.66.+-.0.2, 4.41.+-.0.2, 4.32.+-.0.2, 4.06.+-.0.2, 3.53.+-.0.2,
3.43.+-.0.2, 3.39.+-.0.2, 3.34.+-.0.2, 3.27.+-.0.2, 3.12.+-.0.2,
3.04 .+-.0.2, and 2.64.+-.0.2.
[0208] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 9.44.+-.0.2, 8.63.+-.0.2, 7.79.+-.0.2,
7.35.+-.0.2, 6.84.+-.0.2, 6.61.+-.0.2, 6.01.+-.0.2, 5.62.+-.0.2,
5.38.+-.0.2, 5.16.+-.0.2, 5.01.+-.0.2, 4.82.+-.0.2, 4.66.+-.0.2,
4.54.+-.0.2, 4.41.+-.0.2, 4.32.+-.0.2, 4.13.+-.0.2, 4.06.+-.0.2,
3.95.+-.0.2, 3.89.+-.0.2, 3.78.+-.0.2, 3.67.+-.0.2, 3.53.+-.0.2,
3.43.+-.0.2, 3.39.+-.0.2, 3.34.+-.0.2, 3.27.+-.0.2, 3.12.+-.0.2,
3.04.+-.0.2, and 2.64.+-.0.2.
[0209] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 7.35.+-.0.1, 6.61.+-.0.1, 5.62.+-.0.1,
5.38.+-.0.1, 4.82.+-.0.1, 4.54.+-.0.1, 4.13.+-.0.1, 3.95.+-.0.1,
3.89.+-.0.1, 3.78.+-.0.1, and 3.67.+-.0.1. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 9.44.+-.0.1, 8.63.+-.0.1,
7.79.+-.0.1, 6.84.+-.0.1, 6.01.+-.0.1, 5.16.+-.0.1, 5.01.+-.0.1,
4.66.+-.0.1, 4.41.+-.0.1, 4.32.+-.0.1, 4.06.+-.0.1, 3.53.+-.0.1,
3.43.+-.0.1, 3.39.+-.0.1, 3.34.+-.0.1, 3.27.+-.0.1, 3.12.+-.0.1,
3.04.+-.0.1, and 2.64.+-.0.1.
[0210] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 9.44.+-.0.1, 8.63.+-.0.1, 7.79.+-.0.1,
7.35.+-.0.1, 6.84.+-.0.1, 6.61.+-.0.1, 6.01.+-.0.1, 5.62.+-.0.1,
5.38.+-.0.1, 5.16.+-.0.1, 5.01.+-.0.1, 4.82.+-.0.1, 4.66.+-.0.1,
4.54.+-.0.1, 4.41.+-.0.1, 4.32.+-.0.1, 4.13.+-.0.1, 4.06.+-.0.1,
3.95.+-.0.1, 3.89.+-.0.1, 3.78.+-.0.1, 3.67.+-.0.1, 3.53.+-.0.1,
3.43.+-.0.1, 3.39.+-.0.1, 3.34.+-.0.1, 3.27.+-.0.1, 3.12.+-.0.1,
3.04.+-.0.1, and 2.64.+-.0.1.
[0211] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 7.35, 6.61, 5.62, 5.38, 4.82, 4.54, 4.13, 3.95,
3.89, 3.78, and 3.67. The XRPD pattern of the crystalline form of
the compound of formula (I) can be further characterized by d
spacings at about 9.44, 8.63, 7.79, 6.84, 6.01, 5.16, 5.01, 4.66,
4.41, 4.32, 4.06, 3.53, 3.43, 3.39, 3.34, 3.27, 3.12, 3.04, and
2.64.
[0212] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 9.44, 8.63, 7.79, 7.35, 6.84, 6.61, 6.01, 5.62,
5.38, 5.16, 5.01, 4.82, 4.66, 4.54, 4.41, 4.32, 4.13, 4.06, 3.95,
3.89, 3.78, 3.67, 3.53, 3.43, 3.39, 3.34, 3.27, 3.12, 3.04, and
2.64.
[0213] The crystalline form of the compound of formula (I) can be
Form G, where Form G is characterized by the XRPD pattern described
above or by FIG. 48.
[0214] The crystalline form of the compound of formula (I) (e.g.,
Form G) can include an endothermic event with an onset temperature
of about 206.degree. C. as determined by DSC. The crystalline form
of the compound of formula (I) can be characterized by a DSC plot
set forth in FIG. 28. The crystalline form of the compound of
formula (I) can have a melting point of about 210.degree. C. The
crystalline form of the compound of formula (I) can be Form G,
where Form G has a melting point of about 210.degree. C.
[0215] The crystalline form of the compound of formula (I) (e.g.,
Form G) can have a mass loss of about 3.7% heated from about
25.degree. C. to about 115.degree. C.
[0216] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 11.0.+-.0.3,
15.3.+-.0.3, 15.6.+-.0.3, 17.5.+-.0.3, 18.9.+-.0.3, 20.0.+-.0.3,
21.1.+-.0.3, 22.1.+-.0.3, 24.6.+-.0.3, 25.1.+-.0.3, and
26.5.+-.0.3. The XRPD pattern of the crystalline form of the
compound of formula (I) can further include angle 2 .theta. peaks
at about 6.3.+-.0.3, 12.7.+-.0.3, 15.9.+-.0.3, 18.2.+-.0.3,
18.6.+-.0.3, 22.6.+-.0.3, 23.2.+-.0.3, 24.2.+-.0.3, 25.7.+-.0.3,
27.0.+-.0.3, 27.5.+-.0.3, 29.5.+-.0.3, 29.9.+-.0.3, 30.5.+-.0.3,
31.5.+-.0.3, 32.2.+-.0.3, 34.6.+-.0.3, 35.1.+-.0.3, and
35.6.+-.0.3.
[0217] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 6.3.+-.0.3, 11.0.+-.0.3, 12.7.+-.0.3,
15.3.+-.0.3, 15.6.+-.0.3, 15.9.+-.0.3, 17.5.+-.0.3, 18.2.+-.0.3,
18.6.+-.0.3, 18.9.+-.0.3, 20.0.+-.0.3, 21.1.+-.0.3, 22.1.+-.0.3,
22.6.+-.0.3, 23.2.+-.0.3, 24.2.+-.0.3, 24.6.+-.0.3, 25.1.+-.0.3,
25.7.+-.0.3, 26.5.+-.0.3, 27.0.+-.0.3, 27.5.+-.0.3, 29.5.+-.0.3,
29.9.+-.0.3, 30.5.+-.0.3, 31.5.+-.0.3, 32.2.+-.0.3, 34.6.+-.0.3,
35.1.+-.0.3, and 35.6.+-.0.3.
[0218] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 11.0.+-.0.2,
15.3.+-.0.2, 15.6.+-.0.2, 17.5.+-.0.2, 18.9.+-.0.2, 20.0.+-.0.2,
21.1.+-.0.2, 22.1.+-.0.2, 24.6.+-.0.2, 25.1.+-.0.2, and
26.5.+-.0.2. The XRPD pattern of the crystalline form of the
compound of formula (I) can further include angle 2 .theta. peaks
at about 6.3.+-.0.2, 12.7.+-.0.2, 15.9.+-.0.2, 18.2.+-.0.2,
18.6.+-.0.2, 22.6.+-.0.2, 23.2.+-.0.2, 24.2.+-.0.2, 25.7.+-.0.2,
27.0.+-.0.2, 27.5.+-.0.2, 29.5.+-.0.2, 29.9.+-.0.2, 30.5.+-.0.2,
31.5.+-.0.2, 32.2.+-.0.2, 34.6.+-.0.2, 35.1.+-.0.2, and
35.6.+-.0.2.
[0219] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 6.3.+-.0.2, 11.0.+-.0.2, 12.7.+-.0.2,
15.3.+-.0.2, 15.6.+-.0.2, 15.9.+-.0.2, 17.5.+-.0.2, 18.2.+-.0.2,
18.6.+-.0.2, 18.9.+-.0.2, 20.0.+-.0.2, 21.1.+-.0.2, 22.1.+-.0.2,
22.6.+-.0.2, 23.2.+-.0.2, 24.2.+-.0.2, 24.6.+-.0.2, 25.1.+-.0.2,
25.7.+-.0.2, 26.5.+-.0.2, 27.0.+-.0.2, 27.5.+-.0.2, 29.5.+-.0.2,
29.9.+-.0.2, 30.5.+-.0.2, 31.5.+-.0.2, 32.2.+-.0.2, 34.6.+-.0.2,
35.1.+-.0.2, and 35.6.+-.0.2.
[0220] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 11.0.+-.0.1,
15.3.+-.0.1, 15.6.+-.0.1, 17.5.+-.0.1, 18.9.+-.0.1, 20.0.+-.0.1,
21.1.+-.0.1, 22.1.+-.0.1, 24.6.+-.0.1, 25.1.+-.0.1, and
26.5.+-.0.1. The XRPD pattern of the crystalline form of the
compound of formula (I) can further include angle 2 .theta. peaks
at about 6.3.+-.0.1, 12.7.+-.0.1, 15.9.+-.0.1, 18.2.+-.0.1,
18.6.+-.0.1, 22.6.+-.0.1, 23.2.+-.0.1, 24.2.+-.0.1, 25.7.+-.0.1,
27.0.+-.0.1, 27.5.+-.0.1, 29.5.+-.0.1, 29.9.+-.0.1, 30.5.+-.0.1,
31.5.+-.0.1, 32.2.+-.0.1, 34.6.+-.0.1, 35.1.+-.0.1, and
35.6.+-.0.1.
[0221] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 6.3.+-.0.1, 11.0.+-.0.1, 12.7.+-.0.1,
15.3.+-.0.1, 15.6.+-.0.1, 15.9.+-.0.1, 17.5.+-.0.1, 18.2.+-.0.1,
18.6.+-.0.1, 18.9.+-.0.1, 20.0.+-.0.1, 21.1.+-.0.1, 22.1.+-.0.1,
22.6.+-.0.1, 23.2.+-.0.1, 24.2.+-.0.1, 24.6.+-.0.1, 25.1.+-.0.1,
25.7.+-.0.1, 26.5.+-.0.1, 27.0.+-.0.1, 27.5.+-.0.1, 29.5.+-.0.1,
29.9.+-.0.1, 30.5.+-.0.1, 31.5.+-.0.1, 32.2.+-.0.1, 34.6.+-.0.1,
35.1.+-.0.1, and 35.6.+-.0.1.
[0222] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 11.0, 15.3,
15.6, 17.5, 18.9, 20.0, 21.1, 22.1, 24.6, 25.1, and 26.5. The XRPD
pattern of the crystalline form of the compound of formula (I) can
further include angle 2 .theta. peaks at about 6.3, 12.7, 15.9,
18.2, 18.6, 22.6, 23.2, 24.2, 25.7, 27.0, 27.5, 29.5, 29.9, 30.5,
31.5, 32.2, 34.6, 35.1, and 35.6.
[0223] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 6.3, 11.0, 12.7, 15.3, 15.6, 15.9, 17.5,
18.2, 18.6, 18.9, 20.0, 21.1, 22.1, 22.6, 23.2, 24.2, 24.6, 25.1,
25.7, 26.5, 27.0, 27.5, 29.5, 29.9, 30.5, 31.5, 32.2, 34.6, 35.1,
and 35.6.
[0224] In certain embodiments, the crystalline form of the compound
of formula (I) is characterized by a XRPD pattern corresponding
substantially to FIG. 49.
[0225] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 8.03.+-.0.3, 5.80.+-.0.3, 5.69.+-.0.3,
5.05.+-.0.3, 4.69.+-.0.3, 4.44.+-.0.3, 4.21.+-.0.3, 4.02.+-.0.3,
3.61.+-.0.3, 3.55.+-.0.3, and 3.35.+-.0.3. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 13.92.+-.0.3, 6.96.+-.0.3,
5.55.+-.0.3, 4.87.+-.0.3, 4.77.+-.0.3, 3.93.+-.0.3, 3.82.+-.0.3,
3.67.+-.0.3, 3.46.+-.0.3, 3.29.+-.0.3, 3.24.+-.0.3, 3.02.+-.0.3,
2.98.+-.0.3, 2.92.+-.0.3, 2.83.+-.0.3, 2.77.+-.0.3, 2.58.+-.0.3,
2.55.+-.0.3, and 2.52.+-.0.3.
[0226] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 13.92.+-.0.3, 8.03.+-.0.3, 6.96.+-.0.3,
5.80.+-.0.3, 5.69.+-.0.3, 5.55.+-.0.3, 5.05.+-.0.3, 4.87.+-.0.3,
4.77.+-.0.3, 4.69.+-.0.3, 4.44.+-.0.3, 4.21.+-.0.3, 4.02.+-.0.3,
3.93.+-.0.3, 3.82.+-.0.3, 3.67.+-.0.3, 3.61.+-.0.3, 3.55.+-.0.3,
3.46.+-.0.3, 3.35.+-.0.3, 3.29.+-.0.3, 3.24.+-.0.3, 3.02.+-.0.3,
2.98.+-.0.3, 2.92.+-.0.3, 2.83.+-.0.3, 2.77.+-.0.3, 2.58.+-.0.3,
2.55.+-.0.3, and 2.52.+-.0.3.
[0227] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 8.03.+-.0.2, 5.80.+-.0.2, 5.69.+-.0.2,
5.05.+-.0.2, 4.69.+-.0.2, 4.44.+-.0.2, 4.21.+-.0.2, 4.02.+-.0.2,
3.61.+-.0.2, 3.55.+-.0.2, and 3.35.+-.0.2. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 13.92.+-.0.2, 6.96.+-.0.2,
5.55.+-.0.2, 4.87.+-.0.2, 4.77.+-.0.2, 3.93.+-.0.2, 3.82.+-.0.2,
3.67.+-.0.2, 3.46.+-.0.2, 3.29.+-.0.2, 3.24.+-.0.2, 3.02.+-.0.2,
2.98.+-.0.2, 2.92.+-.0.2, 2.83.+-.0.2, 2.77.+-.0.2, 2.58.+-.0.2,
2.55.+-.0.2, and 2.52.+-.0.2.
[0228] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 13.92.+-.0.2, 8.03.+-.0.2, 6.96.+-.0.2,
5.80.+-.0.2, 5.69.+-.0.2, 5.55.+-.0.2, 5.05.+-.0.2, 4.87.+-.0.2,
4.77.+-.0.2, 4.69.+-.0.2, 4.44.+-.0.2, 4.21.+-.0.2, 4.02.+-.0.2,
3.93.+-.0.2, 3.82.+-.0.2, 3.67.+-.0.2, 3.61.+-.0.2, 3.55.+-.0.2,
3.46.+-.0.2, 3.35.+-.0.2, 3.29.+-.0.2, 3.24.+-.0.2, 3.02.+-.0.2,
2.98.+-.0.2, 2.92.+-.0.2, 2.83.+-.0.2, 2.77.+-.0.2, 2.58.+-.0.2,
2.55.+-.0.2, and 2.52.+-.0.2.
[0229] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 8.03.+-.0.1, 5.80.+-.0.1, 5.69.+-.0.1,
5.05.+-.0.1, 4.69.+-.0.1, 4.44.+-.0.1, 4.21.+-.0.1, 4.02.+-.0.1,
3.61.+-.0.1, 3.55.+-.0.1, and 3.35.+-.0.1. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 13.92.+-.0.1, 6.96.+-.0.1,
5.55.+-.0.1, 4.87.+-.0.1, 4.77.+-.0.1, 3.93.+-.0.1, 3.82.+-.0.1,
3.67.+-.0.1, 3.46.+-.0.1, 3.29.+-.0.1, 3.24.+-.0.1, 3.02.+-.0.1,
2.98.+-.0.1, 2.92.+-.0.1, 2.83.+-.0.1, 2.77.+-.0.1, 2.58.+-.0.1,
2.55.+-.0.1, and 2.52.+-.0.1.
[0230] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 13.92.+-.0.1, 8.03.+-.0.1, 6.96.+-.0.1,
5.80.+-.0.1, 5.69.+-.0.1, 5.55.+-.0.1, 5.05.+-.0.1, 4.87.+-.0.1,
4.77.+-.0.1, 4.69.+-.0.1, 4.44.+-.0.1, 4.21.+-.0.1, 4.02.+-.0.1,
3.93.+-.0.1, 3.82.+-.0.1, 3.67.+-.0.1, 3.61.+-.0.1, 3.55.+-.0.1,
3.46.+-.0.1, 3.35.+-.0.1, 3.29.+-.0.1, 3.24.+-.0.1, 3.02.+-.0.1,
2.98.+-.0.1, 2.92.+-.0.1, 2.83.+-.0.1, 2.77.+-.0.1, 2.58.+-.0.1,
2.55.+-.0.1, and 2.52.+-.0.1.
[0231] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 8.03, 5.80, 5.69, 5.05, 4.69, 4.44, 4.21, 4.02,
3.61, 3.55, and 3.35. The XRPD pattern of the crystalline form of
the compound of formula (I) can be further characterized by d
spacings at about 13.92, 6.96, 5.55, 4.87, 4.77, 3.93, 3.82, 3.67,
3.46, 3.29, 3.24, 3.02, 2.98, 2.92, 2.83, 2.77, 2.58, 2.55, and
2.52.
[0232] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 13.92, 8.03, 6.96, 5.80, 5.69, 5.55, 5.05, 4.87,
4.77, 4.69, 4.44, 4.21, 4.02, 3.93, 3.82, 3.67, 3.61, 3.55, 3.46,
3.35, 3.29, 3.24, 3.02, 2.98, 2.92, 2.83, 2.77, 2.58, 2.55, and
2.52.
[0233] The crystalline form of the compound of formula (I) can be
Form H, where Form H is characterized by the XRPD pattern described
above or by FIG. 49.
[0234] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 12.3.+-.0.3,
14.8.+-.0.3, 16.4.+-.0.3, 18.5.+-.0.3, 19.3.+-.0.3, 19.6.+-.0.3,
20.3.+-.0.3, 21.1.+-.0.3, 22.1.+-.0.3, 22.5.+-.0.3, 23.2.+-.0.3,
24.1.+-.0.3, 25.4.+-.0.3, and 28.2.+-.0.3. The XRPD pattern of the
crystalline form of the compound of formula (I) can further include
angle 2 .theta. peaks at about 4.6.+-.0.3, 8.7.+-.0.3, 8.3.+-.0.3,
9.1.+-.0.3, 10.3.+-.0.3, 11.0.+-.0.3, 13.5.+-.0.3, 14.0.+-.0.3,
15.4.+-.0.3, 17.1.+-.0.3, 24.8.+-.0.3, 27.2.+-.0.3, 27.7.+-.0.3,
29.4.+-.0.3, 30.2.+-.0.3, and 37.2.+-.0.3.
[0235] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 4.6.+-.0.3, 8.7.+-.0.3, 8.3.+-.0.3,
9.1.+-.0.3, 10.3.+-.0.3, 11.0.+-.0.3, 12.3.+-.0.3, 13.5.+-.0.3,
14.0.+-.0.3, 14.8.+-.0.3, 15.4.+-.0.3, 16.4.+-.0.3, 17.1.+-.0.3,
18.5.+-.0.3, 19.3.+-.0.3, 19.6.+-.0.3, 20.3.+-.0.3, 21.1.+-.0.3,
22.1.+-.0.3, 22.5.+-.0.3, 23.2.+-.0.3, 24.1.+-.0.3, 24.8.+-.0.3,
25.4.+-.0.3, 27.2.+-.0.3, 27.7.+-.0.3, 28.2.+-.0.3, 29.4.+-.0.3,
30.2.+-.0.3, and 37.2.+-.0.3.
[0236] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 12.3.+-.0.2,
14.8.+-.0.2, 16.4.+-.0.2, 18.5.+-.0.2, 19.3.+-.0.2, 19.6.+-.0.2,
20.3.+-.0.2, 21.1.+-.0.2, 22.1.+-.0.2, 22.5.+-.0.2, 23.2.+-.0.2,
24.1.+-.0.2, 25.4.+-.0.2, and 28.2.+-.0.2. The XRPD pattern of the
crystalline form of the compound of formula (I) can further include
angle 2 .theta. peaks at about 4.6.+-.0.2, 8.7.+-.0.2, 8.3.+-.0.2,
9.1.+-.0.2, 10.3.+-.0.2, 11.0.+-.0.2, 13.5.+-.0.2, 14.0.+-.0.2,
15.4.+-.0.2, 17.1.+-.0.2, 24.8.+-.0.2, 27.2.+-.0.2, 27.7.+-.0.2,
29.4.+-.0.2, 30.2.+-.0.2, and 37.2.+-.0.2.
[0237] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 4.6.+-.0.2, 8.7.+-.0.2, 8.3.+-.0.2,
9.1.+-.0.2, 10.3.+-.0.2, 11.0.+-.0.2, 12.3.+-.0.2, 13.5.+-.0.2,
14.0.+-.0.2, 14.8.+-.0.2, 15.4.+-.0.2, 16.4.+-.0.2, 17.1.+-.0.2,
18.5.+-.0.2, 19.3.+-.0.2, 19.6.+-.0.2, 20.3.+-.0.2, 21.1.+-.0.2,
22.1.+-.0.2, 22.5.+-.0.2, 23.2.+-.0.2, 24.1.+-.0.2, 24.8.+-.0.2,
25.4.+-.0.2, 27.2.+-.0.2, 27.7.+-.0.2, 28.2.+-.0.2, 29.4.+-.0.2,
30.2.+-.0.2, and 37.2.+-.0.2.
[0238] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 12.3.+-.0.1,
14.8.+-.0.1, 16.4.+-.0.1, 18.5.+-.0.1, 19.3.+-.0.1, 19.6.+-.0.1,
20.3.+-.0.1, 21.1.+-.0.1, 22.1.+-.0.1, 22.5.+-.0.1, 23.2.+-.0.1,
24.1.+-.0.1, 25.4.+-.0.1, and 28.2.+-.0.1. The XRPD pattern of the
crystalline form of the compound of formula (I) can further include
angle 2 .theta. peaks at about 4.6.+-.0.1, 8.7.+-.0.1, 8.3.+-.0.1,
9.1.+-.0.1, 10.3.+-.0.1, 11.0.+-.0.1, 13.5.+-.0.1, 14.0.+-.0.1,
15.4.+-.0.1, 17.1.+-.0.1, 24.8.+-.0.1, 27.2.+-.0.1, 27.7.+-.0.1,
29.4.+-.0.1, 30.2.+-.0.1, and 37.2.+-.0.1.
[0239] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 4.6.+-.0.1, 8.7.+-.0.1, 8.3.+-.0.1,
9.1.+-.0.1, 10.3.+-.0.1, 11.0.+-.0.1, 12.3.+-.0.1, 13.5.+-.0.1,
14.0.+-.0.1, 14.8.+-.0.1, 15.4.+-.0.1, 16.4.+-.0.1, 17.1.+-.0.1,
18.5.+-.0.1, 19.3.+-.0.1, 19.6.+-.0.1, 20.3.+-.0.1, 21.1.+-.0.1,
22.1.+-.0.1, 22.5.+-.0.1, 23.2.+-.0.1, 24.1.+-.0.1, 24.8.+-.0.1,
25.4.+-.0.1, 27.2.+-.0.1, 27.7.+-.0.1, 28.2.+-.0.1, 29.4.+-.0.1,
30.2.+-.0.1, and 37.2.+-.0.1.
[0240] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks (i.e., degrees 2 .theta.) at about 12.3, 14.8,
16.4, 18.5, 19.3, 19.6, 20.3, 21.1, 22.1, 22.5, 23.2, 24.1, 25.4,
and 28.2. The XRPD pattern of the crystalline form of the compound
of formula (I) can further include angle 2 .theta. peaks at about
4.6, 8.7, 8.3, 9.1, 10.3, 11.0, 13.5, 14.0, 15.4, 17.1, 24.8, 27.2,
27.7, 29.4, 30.2, and 37.2.
[0241] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes angle
2 .theta. peaks at about 4.6, 8.7, 8.3, 9.1, 10.3, 11.0, 12.3,
13.5, 14.0, 14.8, 15.4, 16.4, 17.1, 18.5, 19.3, 19.6, 20.3, 21.1,
22.1, 22.5, 23.2, 24.1, 24.8, 25.4, 27.2, 27.7, 28.2, 29.4, 30.2,
and 37.2.
[0242] In certain embodiments, the crystalline form of the compound
of formula (I) is characterized by a XRPD pattern corresponding
substantially to FIG. 50.
[0243] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 7.17.+-.0.3, 5.96.+-.0.3, 5.41.+-.0.3,
4.79.+-.0.3, 4.59.+-.0.3, 4.51.+-.0.3, 4.37.+-.0.3, 4.21.+-.0.3,
4.01.+-.0.3, 3.95.+-.0.3, 3.83.+-.0.3, 3.68.+-.0.3, 3.50.+-.0.3,
and 3.15.+-.0.3. The XRPD pattern of the crystalline form of the
compound of formula (I) can be further characterized by d spacings
at about 19.19.+-.0.3, 13.10.+-.0.3, 10.69.+-.0.3, 9.71.+-.0.3,
8.54.+-.0.3, 8.02.+-.0.3, 6.54.+-.0.3, 6.33.+-.0.3, 5.75.+-.0.3,
5.18.+-.0.3, 3.58.+-.0.3, 3.28.+-.0.3, 3.22.+-.0.3, 3.03.+-.0.3,
2.95.+-.0.3, and 2.41.+-.0.3.
[0244] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 19.19.+-.0.3, 13.10.+-.0.3, 10.69.+-.0.3,
9.71.+-.0.3, 8.54.+-.0.3, 8.02.+-.0.3, 7.17.+-.0.3, 6.54.+-.0.3,
6.33.+-.0.3, 5.96.+-.0.3, 5.75.+-.0.3, 5.41.+-.0.3, 5.18.+-.0.3,
4.79.+-.0.3, 4.59.+-.0.3, 4.51.+-.0.3, 4.37.+-.0.3, 4.21.+-.0.3,
4.01.+-.0.3, 3.95.+-.0.3, 3.83.+-.0.3, 3.68.+-.0.3, 3.58.+-.0.3,
3.50.+-.0.3, 3.28.+-.0.3, 3.22.+-.0.3, 3.15.+-.0.3, 3.03.+-.0.3,
2.95.+-.0.3, 2.41.+-.0.3.
[0245] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 7.17.+-.0.2, 5.96.+-.0.2, 5.41.+-.0.2,
4.79.+-.0.2, 4.59.+-.0.2, 4.51.+-.0.2, 4.37.+-.0.2, 4.21.+-.0.2,
4.01.+-.0.2, 3.95.+-.0.2, 3.83.+-.0.2, 3.68.+-.0.2, 3.50.+-.0.2,
and 3.15.+-.0.2. The XRPD pattern of the crystalline form of the
compound of formula (I) can be further characterized by d spacings
at about 19.19.+-.0.2, 13.10.+-.0.2, 10.69.+-.0.2, 9.71.+-.0.2,
8.54.+-.0.2, 8.02.+-.0.2, 6.54.+-.0.2, 6.33.+-.0.2, 5.75.+-.0.2,
5.18.+-.0.2, 3.58.+-.0.2, 3.28.+-.0.2, 3.22.+-.0.2, 3.03.+-.0.2,
2.95.+-.0.2, and 2.41.+-.0.2.
[0246] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 19.19.+-.0.2, 13.10.+-.0.2, 10.69.+-.0.2,
9.71.+-.0.2, 8.54.+-.0.2, 8.02.+-.0.2, 7.17.+-.0.2, 6.54.+-.0.2,
6.33.+-.0.2, 5.96.+-.0.2, 5.75.+-.0.2, 5.41.+-.0.2, 5.18.+-.0.2,
4.79.+-.0.2, 4.59.+-.0.2, 4.51.+-.0.2, 4.37.+-.0.2, 4.21.+-.0.2,
4.01.+-.0.2, 3.95.+-.0.2, 3.83.+-.0.2, 3.68.+-.0.2, 3.58.+-.0.2,
3.50.+-.0.2, 3.28.+-.0.2, 3.22.+-.0.2, 3.15.+-.0.2, 3.03.+-.0.2,
2.95.+-.0.2, 2.41.+-.0.2.
[0247] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 7.17.+-.0.1, 5.96.+-.0.1, 5.41.+-.0.1,
4.79.+-.0.1, 4.59.+-.0.1, 4.51.+-.0.1, 4.37.+-.0.1, 4.21.+-.0.1,
4.01.+-.0.1, 3.95.+-.0.1, 3.83.+-.0.1, 3.68.+-.0.1, 3.50.+-.0.1,
and 3.15.+-.0.1. The XRPD pattern of the crystalline form of the
compound of formula (I) can be further characterized by d spacings
at about 19.19.+-.0.1, 13.10.+-.0.1, 10.69.+-.0.1, 9.71.+-.0.1,
8.54.+-.0.1, 8.02.+-.0.1, 6.54.+-.0.1, 6.33.+-.0.1, 5.75.+-.0.1,
5.18.+-.0.1, 3.58.+-.0.1, 3.28.+-.0.1, 3.22.+-.0.1, 3.03.+-.0.1,
2.95.+-.0.1, and 2.41.+-.0.1.
[0248] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 19.19.+-.0.1, 13.10.+-.0.1, 10.69.+-.0.1,
9.71.+-.0.1, 8.54.+-.0.1, 8.02.+-.0.1, 7.17.+-.0.1, 6.54.+-.0.1,
6.33.+-.0.1, 5.96.+-.0.1, 5.75.+-.0.1, 5.41.+-.0.1, 5.18.+-.0.1,
4.79.+-.0.1, 4.59.+-.0.1, 4.51.+-.0.1, 4.37.+-.0.1, 4.21.+-.0.1,
4.01.+-.0.1, 3.95.+-.0.1, 3.83.+-.0.1, 3.68.+-.0.1, 3.58.+-.0.1,
3.50.+-.0.1, 3.28.+-.0.1, 3.22.+-.0.1, 3.15.+-.0.1, 3.03.+-.0.1,
2.95.+-.0.1, 2.41.+-.0.1.
[0249] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 7.17, 5.96, 5.41, 4.79, 4.59, 4.51, 4.37, 4.21,
4.01, 3.95, 3.83, 3.68, 3.50, and 3.15. The XRPD pattern of the
crystalline form of the compound of formula (I) can be further
characterized by d spacings at about 19.19, 13.10, 10.69, 9.71,
8.54, 8.02, 6.54, 6.33, 5.75, 5.18, 3.58, 3.28, 3.22, 3.03, 2.95,
and 2.41.
[0250] In some embodiments, the crystalline form of the compound of
formula (I) is characterized by a XRPD pattern that includes d
spacings at about 19.19, 13.10, 10.69, 9.71, 8.54, 8.02, 7.17,
6.54, 6.33, 5.96, 5.75, 5.41, 5.18, 4.79, 4.59, 4.51, 4.37, 4.21,
4.01, 3.95, 3.83, 3.68, 3.58, 3.50, 3.28, 3.22, 3.15, 3.03, 2.95,
2.41.
[0251] The crystalline form of the compound of formula (I) can be
Form I, where Form I is characterized by the XRPD pattern described
above or by FIG. 50.
[0252] The crystalline form of the compound of formula (I) (e.g.,
Form I) can include an endothermic event with an onset temperature
of about 110.degree. C. as determined by DSC. The crystalline form
of the compound of formula (I) (e.g., Form I) can be characterized
by a DSC plot set forth in FIG. 34.
[0253] The crystalline form of the compound of formula (I) (e.g.,
Form I) can have a mass loss of 20% when heated from about
25.degree. C. to about 180.degree. C. Form I can be a solvated
crystalline form, where Form I is a trifluoroethanol solvate.
[0254] The crystalline form of the compound of formula (I) (e.g.,
Form J) can include an exothermic event with an onset temperature
of about 130.degree. C. as determined by DSC. The crystalline form
of the compound of formula (I) (e.g., Form I) can be characterized
by a DSC plot set forth in FIG. 36.
[0255] The crystalline form of the compound of formula (I) can have
a loss of about 19.8% when heated from about 25.degree. C. to about
180.degree. C. The crystalline form of the compound of formula (I)
can be Form J, where Form J has a loss of about 19.8% when heated
from about 25.degree. C. to about 180.degree. C.
[0256] The crystalline form of the compound of formula (I) can be
Form J, where Form J is characterized by the XRPD pattern described
above or by FIG. 35.
[0257] The crystalline forms of the compound of formula (I),
including those described herein (e.g., Form A, B, C, D, E, F, G,
H, I, or J) can interconvert. In certain embodiments, a crystalline
form of the compound of formula (I) as described herein converts to
Form A, where Form A is as described herein. The crystalline forms
can interconvert as set forth in FIG. 37.
[0258] Methods of Agonizing TLRs
[0259] Further provided herein are methods of agonizing Toll-like
receptors (TLRs) by contacting a toll-like receptor with an
effective amount of a crystalline form of the compound of formula
(I) described herein, where the effective amount agonizes the TLR.
The TLR can be Toll-like receptor 8 (TLR8). The TLR can be in a
cell where the cell is an immune response cell. The cell can be a
myeloid dendritic cell, a monocyte cell, or a natural killer cell.
The cell can be a myeloid dendritic cell. The cell can be a
monocyte cell. The cell can be a natural killer cell. The cell can
be part of an organism (e.g., a mammal). The organism can be a
human. The crystalline form can be in solution as part of a dose,
for example, by administration through intravenous
administration.
[0260] Also provided herein are methods of modulating the level,
activity, or function of a protein associated with a disease (e.g.
cancer). The method includes contacting the protein (e.g. TLR) with
an effective amount of a compound, or pharmaceutically acceptable
salt thereof, as described herein.
[0261] Methods of Treating
[0262] Provided herein are methods of treating cancer using a
crystalline form of the compound of formula (I) described herein.
In one aspect, the method includes treating cancer by administering
a therapeutically effective amount of a crystalline form of the
compound of formula (I) described herein to a subject in need
thereof, thereby treating the cancer. The cancer can be a solid
tumor cancer or lymphoma as described herein. The cancer can be
colon carcinoma, ovarian cancer, breast cancer, head and neck
cancer, renal cancer, bladder cancer, hepatocellular cancer, or
lymphoma. The cancer can be colon carcinoma. The cancer can be
ovarian cancer. The cancer can be breast cancer. The cancer can be
head and neck cancer. The cancer can be renal cancer. The cancer
can be bladder cancer. The cancer can be hepatocellular cancer. The
cancer can be lymphoma. The cancer can be treated by agonizing a
TLR (e.g., TLR8) as described herein. The method of treating cancer
can further include co-administering an anti-cancer agent described
herein.
[0263] Depending on the cancer to be treated and the subject's
condition (e.g., age, current symptoms, current health), a compound
described herein, e.g., Compound A or a pharmaceutically acceptable
salt thereof, may be administered by oral, parenteral (e.g.,
intramuscular, intraperitoneal, intravenous, CIV, intracistemal
injection or infusion, subcutaneous injection, or implant),
inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g.,
transdermal or local) routes of administration.
[0264] Compounds described herein, e.g., Compound A or a
pharmaceutically acceptable salt thereof, may be formulated, alone
or together, in suitable dosage unit with pharmaceutically
acceptable excipients, carriers, adjuvants and vehicles described
herein and for which are appropriate for the desired route of
administration.
[0265] In certain embodiments, a compound described herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
prepared for administration by injection (e.g., intravenous,
subcutaneous, intramuscular, etc.). In embodiments, the
pharmaceutical composition is prepared for intravenous
administrations. In certain embodiments, the pharmaceutical
composition includes a pharmaceutically acceptable excipient
described herein and is formulated in aqueous solution, such as
water or physiologically compatible buffers such as Hanks's
solution, Ringer's solution, or physiological saline buffer. In
certain embodiments, other ingredients are included (e.g.,
ingredients that aid in solubility or serve as preservatives). In
certain embodiments, injectable suspensions are prepared using
appropriate liquid carriers, suspending agents and the like.
Certain pharmaceutical compositions for injection are presented in
unit dosage form, e.g., in ampoules or in multi-dose containers.
Certain pharmaceutical compositions for injection are suspensions,
solutions or emulsions in oily or aqueous vehicles, and may contain
formulatory agents such as suspending, stabilizing and/or
dispersing agents. Certain solvents suitable for use in
pharmaceutical compositions for injection include, but are not
limited to, lipophilic solvents and fatty oils, such as sesame oil,
synthetic fatty acid esters, such as ethyl oleate or triglycerides,
and liposomes. Aqueous injection suspensions may contain substances
that increase the viscosity of the suspension, such as sodium
carboxymethyl cellulose, sorbitol, or dextran. Optionally, such
suspensions may also contain suitable stabilizers or agents that
increase the solubility of the pharmaceutical agents to allow for
the preparation of highly concentrated solutions.
[0266] The excipient can be liquid or solid and is selected, with
the planned manner of administration in mind, so as to provide for
the desired bulk, consistency, etc., when combined with a compound
described herein in formulating a pharmaceutical composition
contemplated herein. In certain embodiments, compositions can be
administered to the patient in a single dosage comprising a
therapeutically effective amount of a compound described herein.
The compound can be a crystalline compound having form A as
described herein.
[0267] In some embodiments, the compositions can be administered to
the patient in multiple doses that include a therapeutically
effective amount of a compound described herein, e.g., Compound A
or a pharmaceutically acceptable salt thereof
[0268] In some embodiments, the compositions can be administered to
the patient in a single, daily dosage form, once per day. In other
embodiments, the compositions can be administered to the patient
two or more (i.e., two, three, four or more) times per day, or as
needed according to the particular treatment regimen designed by
the patient's physician.
[0269] The amount of the compositions administered each time
throughout the treatment period can be the same. Alternatively, the
amount administered each time during the treatment period can vary
(e.g., the amount administered at a given time can be more or less
than the amount administered previously). For example, doses given
later in therapy can be lower than those administered during the
acute phase (i.e., earlier stages) of treatment. Appropriate dosing
schedules depending on the specific circumstances will be apparent
to persons of ordinary skill in the art.
[0270] In other embodiments where treatment includes more than one
dose, the doses administered during the entirety of the treatment
are all equal (i.e., the same concentration of compound is
administered in each dose). In certain embodiments, the doses
administered during the treatment are not all the same amount
(e.g., the amount can increase or decrease during treatment). In
certain such embodiments, the doses increase over time. In certain
embodiments, the doses decrease over time. Increasing dose over the
course of treatment can, in embodiments, mitigate undesired side
effects.
[0271] In certain embodiments, dose, dose frequency, and duration
are adjusted to result in a therapeutically effective concentration
of the compounds described herein in a subject. In certain
embodiments the plasma concentration is maintained above the
minimal effective concentration (MEC). In certain embodiments,
compounds described herein (e.g., in a pharmaceutical composition)
are administered with a dosage regimen (i.e., a combination of
doses designed to achieve one or more desired effects) designed to
maintain a concentration above the MEC for 10-90% of the time,
between 30-90% of the time, or between 50-90% of the time.
[0272] In certain embodiments, dose, dose frequency, and duration
of the induction phase may be selected to achieve a desired effect,
e.g., a therapeutic effect, within a specified time period. In
certain embodiments, it is desirable to achieve a desired effect as
quickly as possible. In such embodiments, early intervention by
administration of high dose and/or high dose frequency of compounds
described herein may be desirable.
[0273] In certain embodiments, it is desirable to mitigate an
undesired side effect. In certain embodiments, early intervention
by administration of a low dose and/or low dose frequency and/or
long duration may be desirable. In embodiments, early intervention
by administration with a low dose and/or low dose frequency and/or
long duration mitigates undesired side effects. For example, early
intervention by administration with relatively low doses, may
result in better tolerance of the pharmaceutical agent. Such
embodiments may include gradual increases of dose over time.
[0274] In certain embodiments, doses, dose frequency, and duration
of the induction phase may be selected to achieve an acceptable
safety profile. For example, in certain embodiments, such variables
may be selected to mitigate toxicity of the pharmaceutical
composition. In certain such embodiments, doses increase over
time.
[0275] In certain embodiments, the treatment includes
administration of one, two, three, four, five, six, seven, eight,
nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen,
seventeen, eighteen, nineteen, twenty, or more than twenty
doses.
[0276] In certain embodiments, subjects are monitored for effects
(therapeutic and/or toxic effects) and doses, dose frequency,
and/or duration of treatment may be adjusted based on the results
of such monitoring. It will be recognized by one of ordinary skill
in the art that doses, dose frequency, and duration of treatment
may be manipulated independently to achieve a desired effect.
[0277] Combinational Therapies
[0278] One or more additional therapies, such as additional active
ingredients (e.g., compounds described herein or pharmaceutically
acceptable salts thereof, or anti-cancer agents), can be used in
combination. In certain embodiments, one or more additional
anti-cancer agents described herein are used in combination with
compounds described herein, e.g., Compound A or a pharmaceutically
acceptable salt thereof
[0279] Anti-cancer agents include, but are not limited to:
abraxane; ace-11; acivicin; aclarubicin; acodazole hydrochloride;
acronine; adozelesin; aldesleukin; altretamine; ambomycin;
ametantrone acetate; amrubicin; amsacrine; anastrozole;
anthramycin; asparaginase; asperlin; azacitidine; azetepa;
azotomycin; batimastat; benzodepa; bicalutamide; bisantrene
hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;
brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;
caracemide; carbetimer; carboplatin; carmustine; carubicin
hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor);
chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol
mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin;
daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine;
dezaguanine mesylate; diaziquone; docetaxel; doxorubicin;
doxorubicin hydrochloride; droloxifene; droloxifene citrate;
dromostanolone propionate; duazomycin; edatrexate; eflornithine
hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;
epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;
estramustine; estramustine phosphate sodium; etanidazole;
etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;
fazarabine; fenretinide; floxuridine; fludarabine phosphate;
fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;
gemcitabine; gemcitabine hydrochloride; herceptin; hydroxyurea;
idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin;
irinotecan; irinotecan hydrochloride; lanreotide acetate;
lapatinib; letrozole; leuprolide acetate; liarozole hydrochloride;
lometrexol sodium; lomustine; losoxantrone hydrochloride;
masoprocol; maytansine; mechlorethamine hydrochloride; megestrol
acetate; melengestrol acetate; melphalan; menogaril;
mercaptopurine; methotrexate; methotrexate sodium; metoprine;
meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin;
mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;
pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
piposulfan; piroxantrone hydrochloride; plicamycin; plomestane;
porflmer sodium; porfiromycin; prednimustine; procarbazine
hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
riboprine; romidepsin; safingol; safingol hydrochloride; semustine;
simtrazene; sparfosate sodium; sparsomycin; spirogermanium
hydrochloride; spiromustine; spiroplatin; stem cell treatments such
as PDA-001; streptonigrin; streptozocin; sulofenur; talisomycin;
tecogalan sodium; taxotere; tegafur; teloxantrone hydrochloride;
temoporfin; teniposide; teroxirone; testolactone; thiamiprine;
thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene
citrate; trestolone acetate; triciribine phosphate; trimetrexate;
trimetrexate glucuronate; triptorelin; tubulozole hydrochloride;
uracil mustard; uredepa; vapreotide; verteporfin; vinblastine
sulfate; vincristine sulfate; vindesine; vindesine sulfate;
vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate;
vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate;
vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.
[0280] Other anti-cancer drugs include, but are not limited to:
20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;
aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin;
ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; b-FGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; capecitabine; carboxamide-amino-triazole;
carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived
inhibitor; carzelesin; casein kinase inhibitors (ICOS);
castanospermine; cecropin B; cetrorelix; chlorins;
chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl
spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;
doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen;
ecomustine; edelfosine; edrecolomab; eflornithine; elemene;
emitefur; epirubicin; epristeride; estramustine analogue; estrogen
agonists; estrogen antagonists; etanidazole; etoposide phosphate;
exemestane; fadrozole; fazarabine; fenretinide; filgrastim;
finasteride; flavopiridol; flezelastine; fluasterone; fludarabine;
fluorodaunorunicin hydrochloride; forfenimex; formestane;
fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;
galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;
glutathione inhibitors; hepsulfam; heregulin; hexamethylene
bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;
idramantone; ilmofosine; ilomastat; imatinib (e.g., GLEEVEC.RTM..),
imiquimod; immunostimulant peptides; insulin-like growth factor-1
receptor inhibitor; interferon agonists; interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic
peptides; maitansine; mannostatin A; marimastat; masoprocol;
maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors;
menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF
inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
Erbitux, human chorionic gonadotrophin; monophosphoryl lipid
A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;
mycaperoxide B; mycobacterial cell wall extract; myriaporone;
N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;
naloxone+pentazocine; napavin; naphterpin; nartograstim;
nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin;
nitric oxide modulators; nitroxide antioxidant; nitrullyn;
oblimersen (GENASENSE.RTM.); O.sub.6-benzylguanine; octreotide;
okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;
oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;
oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel
derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;
panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;
peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;
perflubron; perfosfamide; perillyl alcohol; phenazinomycin;
phenylacetate; phosphatase inhibitors; picibanil; pilocarpine
hydrochloride; pirarubicin; piritrexim; placetin A; placetin B;
plasminogen activator inhibitor; platinum complex; platinum
compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rohitukine; romurtide; roquinimex;
rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;
sargramostim; Sdi 1 mimetics; semustine; senescence derived
inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; sizofuran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stipiamide; stromelysin inhibitors;
sulfinosine; superactive vasoactive intestinal peptide antagonist;
suradista; suramin; swainsonine; tallimustine; tamoxifen
methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;
tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;
tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;
thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin
receptor agonist; thymotrinan; thyroid stimulating hormone; tin
ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin;
toremifene; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; velaresol; veramine;
verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0281] Specific additional active agents include, but are not
limited to, oblimersen (GENASENSE.RTM.), remicade, docetaxel,
celecoxib, melphalan, dexamethasone (DECADRON.RTM.), steroids,
gemcitabine, cisplatinum, temozolomide, etoposide,
cyclophosphamide, temodar, carboplatin, procarbazine, gliadel,
tamoxifen, topotecan, methotrexate, ARISA.RTM., taxol, taxotere,
fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon
alpha, pegylated interferon alpha (e.g., PEG INTRON-A),
capecitabine, cisplatin, thiotepa, fludarabine, carboplatin,
liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel,
vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic
acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate,
arsenic trioxide, vincristine, doxorubicin (DOXIL.RTM.),
paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate
(EMCYT), sulindac, and etoposide.
[0282] In certain embodiments the additional active agent is a
taxol, gemcitabine, or cisplatin (including cisplatin derivatives
such as, for example, carboplatin or oxaliplatin). In other
embodiments, the additional active agent is etoposide, tamoxifen,
taxotere, or cytarabine. In still other embodiments, the additional
active agent is pacilitaxel, tamoxifen, or taxol. In another
embodiment, the additional active agent is daunorubicin, prdisone,
doxorubicin, or adriamycin.
[0283] As used herein, the terms "in combination" and
"co-administration" are used interchangeably and include the use of
more than one therapy (e.g., one or more prophylactic and/or
therapeutic agents). However, the use of the terms does not
restrict the order in which therapies (e.g., compounds described
herein and anti-cancer agents) are administered to a patient with a
disease or disorder. A first therapy (e.g., a compound described
herein, including pharmaceutically acceptable salts thereof) can be
administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45
minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48
hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with,
or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45
minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48
hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a
second therapy (e.g., an anti-cancer agent) to the subject. Triple
therapy is also contemplated herein (e.g., a compound described
herein and two anti-cancer agents described herein).
[0284] Anti-cancer agents can be administered prior to,
concurrently with, or subsequent to the administration of compounds
described herein, e.g., Compound A or a pharmaceutically acceptable
salt thereof. Administration of one or more of the compounds
provided herein and one or more second active agents to a patient
can occur simultaneously or sequentially by the same or different
routes of administration. The suitability of a particular route of
administration employed for a particular active agent will depend
on the active agent itself (e.g., whether it can be administered
orally without decomposing prior to entering the blood stream) and
the cancer being treated.
[0285] The route of administration of the compounds provided herein
can be independent of the route of administration of a second
therapy. In one embodiment, the compounds provided herein are
administered orally. In another embodiment, the compounds provided
herein are administered intravenously. Thus, in accordance with
these embodiments, the compounds provided herein can be
administered orally or intravenously, and the second therapy can be
administered orally, parenterally, intraperitoneally,
intravenously, intraarterially, transdermally, sublingually,
intramuscularly, rectally, transbuccally, intranasally,
liposomally, via inhalation, vaginally, intraoccularly, via local
delivery by catheter or stent, subcutaneously, intraadiposally,
intraarticularly, intrathecally, or in a slow release dosage form.
In certain embodiments, a compound provided herein and a second
therapy are administered by the same mode of administration, e.g.,
orally or by IV. In another embodiment, a compound provided herein
is administered by one mode of administration, e.g., by IV, whereas
the second agent (e.g., an anticancer agent) is administered by
another mode of administration, e.g., orally.
[0286] In one embodiment, the second active agent is administered
intravenously or subcutaneously and once or twice daily in an
amount of from about 1 to about 1000 mg, from about 5 to about 500
mg, from about 10 to about 350 mg, or from about 50 to about 200
mg. The specific amount of the second active agent will depend on
the specific agent used, the type of disease being treated or
managed, the severity and stage of disease, and the amount of the
first active agent, and any optional additional active agents
concurrently administered to the patient. In certain embodiments,
the second active agent is oblimersen (GENASENSE.RTM.), GM-CSF,
G-CSF, SCF, EPO, taxotere, irinotecan, dacarbazine, transretinoic
acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone,
vincristine, doxorubicin, COX-2 inhibitor, IL2, IL8, IL18, IFN,
Ara-C, vinorelbine, or a combination thereof
[0287] In certain embodiments, GM-CSF, G-CSF, SCF or EPO is
administered subcutaneously during about five days in a four or six
week cycle in an amount ranging from about 1 to about 750
mg/m2/day, from about 25 to about 500 mg/m2/day, from about 50 to
about 250 mg/m2/day, or from about 50 to about 200 mg/m2/day. In
certain embodiments, GM-CSF may be administered in an amount of
from about 60 to about 500 mcg/m2 intravenously over 2 hours or
from about 5 to about 12 mcg/m2/day subcutaneously. In certain
embodiments, G-CSF may be administered subcutaneously in an amount
of about 1 mcg/kg/day initially and can be adjusted depending on
rise of total granulocyte counts. The maintenance dose of G-CSF may
be administered in an amount of about 300 (in smaller patients) or
480 mcg subcutaneously. In certain embodiments, EPO may be
administered subcutaneously in an amount of 10,000 Unit 3 times per
week.
[0288] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
administered with gemcitabine and cisplatinum to patients with
locally advanced or metastatic transitional cell bladder
cancer.
[0289] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
administered with methotrexate, cyclophosphamide, taxane, abraxane,
lapatinib, herceptin, aromatase inhibitors, selective estrogen
modulators, estrogen receptor antagonists, and/or PLX3397
(Plexxikon) to patients with metastatic breast cancer.
[0290] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
administered with gemcitabine to patients with recurrent or
metastatic head or neck cancer.
[0291] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
administered to patients with colon cancer in combination with
ARISA.RTM., avastatin, taxol, and/or taxotere.
[0292] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
administered with capecitabine and/or PLX4032 (Plexxikon) to
patients with refractory colorectal cancer or patients who fail
first line therapy or have poor performance in colon or rectal
adenocarcinoma.
[0293] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt, thereof, is
administered in combination with fluorouracil, leucovorin, and
irinotecan to patients with Dukes C & D colorectal cancer or to
patients who have been previously treated for metastatic colorectal
cancer.
[0294] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
administered to patients with refractory colorectal cancer in
combination with capecitabine, xeloda, and/or CPT-11.
[0295] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
administered with capecitabine and irinotecan to patients with
refractory colorectal cancer or to patients with unresectable or
metastatic colorectal carcinoma.
[0296] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
administered alone or in combination with interferon alpha or
capecitabine to patients with unresectable or metastatic
hepatocellular carcinoma; or with cisplatin and thiotepa to
patients with primary or metastatic liver cancer.
[0297] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
administered in combination with ABT-737 (Abbott Laboratories)
and/or obatoclax (GX15-070) to patients with lymphoma and other
blood cancers.
[0298] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt, thereof, is
administered alone or in combination with a second active
ingredient such as vinblastine or fludarabine to patients with
various types of lymphoma, including, but not limited to, Hodgkin's
lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma,
cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or
relapsed or refractory low grade follicular lymphoma.
[0299] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
administered to patients with various types or stages of ovarian
cancer such as peritoneal carcinoma, papillary serous carcinoma,
refractory ovarian cancer or recurrent ovarian cancer, in
combination with taxol, carboplatin, doxorubicin, gemcitabine,
cisplatin, xeloda, paclitaxel, dexamethasone, or a combination
thereof
[0300] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
administered to patients with various types or stages of renal cell
cancer, in combination with capecitabine, IFN, tamoxifen, IL-2,
GM-CSF, Celebrex.RTM., or a combination thereof
[0301] In certain embodiments, a compound provided herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
administered to patients with various types or stages of solid
tumors in combination with celebrex, etoposide, cyclophosphamide,
docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a
combination thereof.
[0302] In such embodiments, the compound described herein, e.g.,
Compound A or a pharmaceutically acceptable salt thereof, is
administered intravenously.
[0303] Also encompassed herein is a method of increasing the dosage
of an anti-cancer drug or agent that can be safely and effectively
administered to a patient, which includes administering to the
patient (e.g., a human) a compound provided herein, or a
pharmaceutically acceptable salts thereof. Patients that can
benefit by this method are those likely to suffer from an adverse
effect associated with anti-cancer drugs for treating a specific
cancer of the breast. The administration of a compound provided
herein, or pharmaceutically acceptable salt thereof, in
embodiments, alleviates or reduces adverse effects which are of
such severity that it would otherwise limit the amount of
anti-cancer drug.
[0304] In one embodiment, a compound provided herein, or
pharmaceutically acceptable salt thereof is administered orally and
daily in an amount ranging from about 0.1 to about 150 mg, from
about 1 to about 50 mg, or from about 2 to about 25 mg, prior to,
during, or after the occurrence of the adverse effect associated
with the administration of an anti-cancer drug to a patient. In one
embodiment, a compound provided herein, or pharmaceutically
acceptable salt thereof is administered orally and daily in an
amount ranging from about 0.1 to about 50 mg, or from about 2 to
about 50 mg, prior to, during, or after the occurrence of the
adverse effect associated with the administration of an anti-cancer
drug to a patient. In one embodiment, a compound provided herein,
or pharmaceutically acceptable salt thereof is administered orally
and daily in an amount ranging from about 1 to about 50 mg, or from
about 2 to about 50 mg, prior to, during, or after the occurrence
of the adverse effect associated with the administration of an
anti-cancer drug to a patient. In one embodiment, a compound
provided herein, or pharmaceutically acceptable salt thereof is
administered orally and daily in an amount ranging from about 0.1
to about 25 mg, prior to, during, or after the occurrence of the
adverse effect associated with the administration of an anti-cancer
drug to a patient. In one embodiment, a compound provided herein,
or pharmaceutically acceptable salt thereof is administered orally
and daily in an amount ranging about 1 to about 25 mg, prior to,
during, or after the occurrence of the adverse effect associated
with the administration of an anti-cancer drug to a patient. In
certain embodiments, one or more of the compounds provided herein,
or pharmaceutically acceptable salts thereof, are administered in
combination with specific agents such as heparin, aspirin,
coumadin, or G-CSF to avoid adverse effects that are associated
with anti-cancer drugs such as but not limited to neutropenia or
thrombocytopenia.
[0305] In another embodiment, encompassed herein is a method of
treating, preventing and/or managing cancer, by administering one
or more of the compounds provided herein, or pharmaceutically
acceptable salts thereof, in conjunction with (e.g. before, during,
or after) conventional therapy including, but not limited to,
surgery, immunotherapy, biological therapy, radiation therapy, or
other non-drug based therapy presently used to treat, prevent or
manage cancer. The combined use of the compound provided herein and
conventional therapy may provide a unique treatment regimen that is
unexpectedly effective in certain patients. Without being limited
by theory, it is believed that the compounds provided herein may
provide additive or synergistic effects when given concurrently
with conventional therapy.
[0306] As discussed elsewhere herein, encompassed herein is a
method of reducing, treating and/or preventing adverse or undesired
effects associated with conventional therapy including, but not
limited to, surgery, chemotherapy, radiation therapy, hormonal
therapy, biological therapy and immunotherapy. Compounds provided
herein, or pharmaceutically acceptable salts thereof and other
active ingredient can be administered to a patient prior to,
during, or after the occurrence of the adverse effect associated
with conventional therapy.
[0307] In certain embodiments, the compounds provided herein, or
pharmaceutically acceptable salts thereof are cyclically
administered to a patient. Cycling therapy involves the
administration of an active agent for a period of time, followed by
a rest for a period of time, and repeating this sequential
administration. Cycling therapy can reduce the development of
resistance to one or more of the therapies, avoid, or reduce the
side effects of one of the therapies, and/or improves the efficacy
of the treatment.
[0308] Consequently, in certain embodiments, one or more of the
compounds provided herein are administered daily in a single or
divided doses in, for example, a four to six week cycle with a rest
period of about a week or two weeks. The cycling method further
allows the frequency, number, and length of dosing cycles to be
increased. Thus, encompassed herein in certain embodiments is the
administration of a compound provided herein or pharmaceutically
acceptable salts thereof, for more cycles than are typical when it
is administered alone. In certain embodiments the compounds
provided herein, or pharmaceutically acceptable salts thereof, are
administered for a greater number of cycles that would typically
cause dose-limiting toxicity in a patient to whom a second active
ingredient is not also being administered.
[0309] In one embodiment, the compounds provided herein are
administered daily and continuously for about three or four weeks
at a dose of from about 0.1 to about 150 mg/d followed by a break
of one or two weeks. In one embodiment, the compounds provided
herein are administered daily and continuously for about three or
four weeks at a dose of from about 1 to about 150 mg/d followed by
a break of one or two weeks. In one embodiment, the compounds
provided herein are administered daily and continuously for about
three or four weeks at a dose of from about 0.1 to about 50 mg/d
followed by a break of one or two weeks. In one embodiment, the
compounds provided herein are administered daily and continuously
for about three or four weeks at a dose of from about 1 to about 50
mg/d followed by a break of one or two weeks.
[0310] In another embodiment, a compound provided herein and a
second active ingredient are administered orally, with
administration of the compound provided herein occurring 30 to 60
minutes prior to a second active ingredient, during a cycle of four
to six weeks. In certain embodiments, the combination of the
compound provided herein and a second active ingredient is
administered by intravenous infusion over about 90 minutes every
cycle. In certain embodiments, one cycle comprises the
administration from about 0.1 to about 150 mg/day of the compound
provided herein and from about 50 to about 200 mg/m2/day of a
second active ingredient daily for three to four weeks and then one
or two weeks of rest. In certain embodiments, the number of cycles
during which the combinatorial treatment is administered to a
patient is ranging from about one to about 24 cycles, from about
two to about 16 cycles, or from about four to about three
cycles.
[0311] Single unit dosage forms provided herein are suitable for
oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or
rectal), parenteral (e.g., subcutaneous, intravenous, bolus
injection, intramuscular, or intraarterial), topical (e.g., eye
drops or other ophthalmic preparations), transdermal, or
transcutaneous administration to a patient. Examples of dosage
forms include, but are not limited to: tablets; caplets; capsules,
such as soft elastic gelatin capsules; cachets; troches; lozenges;
dispersions; suppositories; powders; aerosols (e.g., nasal sprays
or inhalers); gels; liquid dosage forms suitable for oral or
mucosal administration to a patient, including suspensions (e.g.,
aqueous or non-aqueous liquid suspensions, oil-in-water emulsions,
or a water-in-oil liquid emulsions), solutions, and elixirs; liquid
dosage forms suitable for parenteral administration to a patient;
eye drops or other ophthalmic preparations suitable for topical
administration; and sterile solids (e.g., crystalline or amorphous
solids) that can be reconstituted to provide liquid dosage forms
suitable for parenteral administration to a patient.
[0312] The composition, shape, and type of dosage forms provided
herein may vary depending on their use. For example, a dosage form
used in the acute treatment of a disease may contain larger amounts
of one or more of the active ingredients than a dosage form used in
the chronic treatment of the same disease. Similarly, a parenteral
dosage form may contain smaller amounts of one or more of the
active ingredients than an oral dosage form used to treat the same
disease. See, e.g., Remington's Pharmaceutical Sciences, 18th ed.,
Mack Publishing, Easton Pa. (1990).
[0313] Whether a particular excipient is suitable for incorporation
into a pharmaceutical composition or dosage form provided herein
depends on a variety of factors, including, but not limited to, the
route of administration. For example, oral dosage forms such as
tablets may contain excipients not suited for use in parenteral
dosage forms. The suitability of a particular excipient may also
depend on the specific active ingredients in the dosage form. For
example, the decomposition of some active ingredients may be
accelerated by some excipients such as lactose, or when exposed to
water. Active ingredients that comprise primary or secondary amines
are particularly susceptible to such accelerated decomposition.
Consequently, encompassed herein are pharmaceutical compositions
and dosage forms that contain little, if any, lactose. As used
herein, the term "lactose-free" means that the amount of lactose
present, if any, is insufficient to substantially increase the
degradation rate of an active ingredient.
[0314] Lactose-free compositions provided herein can comprise
excipients that are listed, for example, in the U.S. Pharmacopeia
(USP) 25 NF20 (2002). In certain embodiments, lactose-free
compositions comprise active ingredients, a binder/filler, and a
lubricant in pharmaceutically compatible and pharmaceutically
acceptable amounts. In certain embodiments, lactose-free dosage
forms comprise active ingredients, microcrystalline cellulose,
pre-gelatinized starch, and magnesium stearate.
[0315] Encompassed herein are pharmaceutical compositions and
dosage forms that comprise one or more compounds that reduce the
rate by which an active ingredient will decompose. Such compounds,
which are referred to herein as "stabilizers," include, but are not
limited to, antioxidants such as ascorbic acid, pH buffers, or salt
buffers.
[0316] Like the amounts and types of excipients, the amounts and
specific types of active ingredients in a dosage form may differ
depending on factors such as, but not limited to, the route by
which it is to be administered to patients. In certain embodiments,
the dosage forms provided herein comprise one or more of the
compounds provided herein, or pharmaceutically acceptable salts
thereof, in an amount ranging from about 0.10 to about 1000 mg,
from about 0.10 to about 500 mg, from about 0.10 to about 200 mg,
from about 0.10 to about 150 mg, from about 0.10 to about 100 mg,
or from about 0.10 to about 50 mg. In certain embodiments, the
dosage forms provided herein comprise one or more of the compounds
provided herein, or pharmaceutically acceptable salts thereof, in
an amount of about 0.1, about 1, about 2, about 5, about 7.5, about
10, about 12.5, about 15, about 17.5, about 20, about 25, about 50,
about 100, about 150, or about 200 mg.
[0317] In certain embodiments, pharmaceutical compositions provided
herein that are suitable for oral administration are formulated as
discrete dosage forms, examples of which include, but are not
limited to, tablets (e.g., chewable tablets), caplets, capsules,
and liquids (e.g., flavored syrups). Such dosage forms contain
predetermined amounts of active ingredients and may be prepared by
some known methods of pharmacy. See generally, Remington's
Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa.
(1990).
[0318] In certain embodiments, the oral dosage forms provided
herein are prepared by combining the active ingredients in an
intimate admixture with at least one excipient according to
conventional pharmaceutical compounding techniques. Excipients can
take a wide variety of forms depending on the form of preparation
desired for administration. For example, excipients suitable for
use in oral liquid or aerosol dosage forms include, but are not
limited to, water, glycols, oils, alcohols, flavoring agents,
preservatives, and coloring agents. Examples of excipients suitable
for use in solid oral dosage forms (e.g., powders, tablets,
capsules, and caplets) include, but are not limited to, starches,
sugars, micro-crystalline cellulose, diluents, granulating agents,
lubricants, binders, and disintegrating agents.
[0319] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or nonaqueous techniques. Such dosage
forms may be prepared by some known methods of pharmacy. In certain
embodiments, pharmaceutical compositions and dosage forms are
prepared by uniformly and intimately admixing the active
ingredients with liquid carriers, finely divided solid carriers, or
both, and then shaping the product into the desired presentation if
necessary.
[0320] In certain embodiments, a tablet is prepared by compression
or molding. In certain embodiments, compressed tablets are be
prepared by compressing in a suitable machine the active
ingredients in a free-flowing form, e.g., powder or granules,
optionally mixed with an excipient. In certain embodiments, molded
tablets are made by molding in a suitable machine a mixture of a
powdered compound moistened with an inert liquid diluent.
[0321] Examples of excipients that can be used in oral dosage forms
provided herein include, but are not limited to, binders, fillers,
disintegrants, and lubricants. Binders suitable for use in
pharmaceutical compositions and dosage forms provided herein
include, but are not limited to, corn starch, potato starch, or
other starches, gelatin, natural and synthetic gums such as acacia,
sodium alginate, alginic acid, other alginates, powdered
tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl
cellulose, cellulose acetate, carboxymethyl cellulose calcium,
sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl
cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose,
(e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and
mixtures thereof.
[0322] Suitable forms of microcrystalline cellulose include, but
are not limited to, AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581,
AVICEL-PH-105 (FMC Corporation, American Viscose Division, Avicel
Sales, Marcus Hook, Pa.), and mixtures thereof. An specific binder
is a mixture of microcrystalline cellulose and sodium carboxymethyl
cellulose (e.g., AVICEL RC-581). Suitable anhydrous or low moisture
excipients or additives include AVICEL-PH-103.TM. and Starch 1500
LM.
[0323] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms provided herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. In certain embodiments, the binder or filler
in pharmaceutical compositions provided herein is present in from
about 50 to about 99 weight percent of the pharmaceutical
composition or dosage form.
[0324] Disintegrants are used in the compositions provided herein
to provide tablets the ability to disintegrate when exposed to an
aqueous environment. Tablets that contain too much disintegrant may
disintegrate in storage, while those that contain too little may
not disintegrate at a desired rate or under the desired conditions.
Thus, a sufficient amount of disintegrant that is neither too much
nor too little to detrimentally alter the release of the active
ingredients should be used to form solid oral dosage forms provided
herein. The amount of disintegrant used varies based upon the type
of formulation. In certain embodiments, the pharmaceutical
compositions provided herein comprise from about 0.5 to about 15
weight percent or from about 1 to about 5 weight percent of
disintegrant.
[0325] Disintegrants that are suitable for use in pharmaceutical
compositions and dosage forms provided herein include, but are not
limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, potato or tapioca
starch, other starches, pre-gelatinized starch, other starches,
clays, other algins, other celluloses, gums, and mixtures
thereof
[0326] Lubricants that are suitable for use in pharmaceutical
compositions and dosage forms provided herein include, but are not
limited to, calcium stearate, magnesium stearate, mineral oil,
light mineral oil, glycerin, sorbitol, mannitol, polyethylene
glycol, other glycols, stearic acid, sodium lauryl sulfate, talc,
hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,
sunflower oil, sesame oil, olive oil, corn oil, and soybean oil),
zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures
thereof. Additional lubricants include, but are not limited to, a
syloid silica gel (AEROSIL200, W.R. Grace Co., Baltimore, Md.), a
coagulated aerosol of synthetic silica (Degussa Co. of Plano,
Tex.), CAB-O-SIL (a pyrogenic silicon dioxide, Cabot Co. of Boston,
Mass.), and mixtures thereof. In certain embodiments, if used at
all, lubricants are used in an amount of less than about 1 weight
percent of the pharmaceutical compositions or dosage forms into
which they are incorporated.
[0327] In certain embodiments, provided herein is a solid oral
dosage form, comprising one or more of the compounds provided
herein, or pharmaceutically acceptable salts thereof; and one or
more excipients selected from anhydrous lactose, microcrystalline
cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous
silica, and gelatin.
[0328] In certain embodiments, provided herein is a solid oral
dosage form, comprising one or more of the compounds provided
herein, or pharmaceutically acceptable salts thereof; and anhydrous
lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic
acid, colloidal anhydrous silica, and gelatin.
[0329] In certain embodiments, the active ingredients provided
herein are administered by controlled release means or by delivery
devices. Examples include, but are not limited to, those described
in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123;
4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543,
5,639,476, 5,354,556, and 5,733,566, each of which is incorporated
herein by reference in its entirety. In certain embodiments, such
dosage forms are be used to provide slow or controlled-release of
one or more active ingredients using, for example,
hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Encompassed herein are single unit dosage forms suitable for oral
administration, including, but not limited to, tablets, capsules,
gelcaps, and caplets that are adapted for controlled-release.
[0330] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0331] Most controlled-release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release of other amounts of drug to maintain this level
of therapeutic or prophylactic effect over an extended period of
time. In order to maintain this constant level of drug in the body,
the drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
[0332] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
patients' natural defenses against contaminants, parenteral dosage
forms are preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0333] Some suitable vehicles that can be used to provide
parenteral dosage forms provided herein include, but are not
limited to: Water for Injection USP; aqueous vehicles such as, but
not limited to, Sodium Chloride Injection, Ringer's Injection,
Dextrose Injection, Dextrose and Sodium Chloride Injection, and
Lactated Ringer's Injection; water-miscible vehicles such as, but
not limited to, ethyl alcohol, polyethylene glycol, and
polypropylene glycol; and non-aqueous vehicles such as, but not
limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl
oleate, isopropyl myristate, and benzyl benzoate.
[0334] Topical and mucosal dosage forms provided herein include,
but are not limited to, sprays, aerosols, solutions, emulsions,
suspensions, eye drops or other ophthalmic preparations, or other
forms known to one of skill in the art. See, e.g., Remington's
Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing,
Easton Pa. (1980 & 1990); and Introduction to Pharmaceutical
Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985).
Dosage forms suitable for treating mucosal tissues within the oral
cavity can be formulated as mouthwashes or as oral gels.
[0335] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide topical and mucosal dosage
forms encompassed herein depend on the particular tissue to which a
given pharmaceutical composition or dosage form will be applied.
With that fact in mind, in certain embodiments, the excipients
include, but are not limited to, water, acetone, ethanol, ethylene
glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,
isopropyl palmitate, mineral oil, and mixtures thereof to form
solutions, emulsions or gels, which are non-toxic and
pharmaceutically acceptable. Moisturizers or humectants can also be
added to pharmaceutical compositions and dosage forms if desired.
Additional examples of such ingredients can be found, for example,
in Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack
Publishing, Easton Pa. (1980 & 1990).
EXAMPLES
Example 1
General Chemistry and Technique Description
[0336] Melting Point by DSC. Differential scanning calorimetry was
performed with power compensation using a DSC-systems (DSC
822e--Mettler Toledo)/analytical micro balance. An accurately
weighed amount of sample (typically 1-5 mg), was placed in a clean
and dry aluminum crucible and closed with an aluminum cap with a
hole. A second crucible was the reference crucible.
[0337] Conditions: starting temperature: 20.degree. C.; heating
rate: 10.degree. C./min final temperature: 300.degree. C.;
atmosphere: N.sub.2 (flow 20 mL/min)
[0338] TGA Volatile Components. Thermogravimetry was performed
using a TGA 851e apparatus that included an oven, oven temperature
sensor and sample temperature sensor/aluminum oxide pan/analytical
micro balance. An empty aluminum oxide pan was used to collect the
background curve, after which an accurately weighed amount of
sample (10 mg) was placed in a clean and dry pan. The measurement
was done as described above.
[0339] Conditions: starting temperature: 25.degree. C.; heating
rate: 5.degree. C./min final temperature: 300.degree. C.;
atmosphere: N2 (flow 50 mL/min)
[0340] .sup.1H NMR was performed using a Bruker AVANCE 400 MHz with
DMSO-D.sub.6 or CDCl.sub.3 as solvent and either Tetramethylsilane
(TMS) or solvent peak as the internal standard. Decoupling was
performed using inverse gate decoupling. Assays were determined
using the ACD/Spec Manager 9 software suite by comparing
integration areas of the compound with those of an internal
standard (typically hydrochinondimethylether).
[0341] Light Microscopy with Hot Stage was performed with an
Olympus BX41 with Di-Li 5MP camera and grab&measure software. A
Hotstage Mettler Toledo FP90 with FP 82 heating table was used.
Samples were prepared with brushes onto object holders. Observation
was done using unpolarized light or polarized light using two
polarization filters at 40, 100, 200 or 400.times. magnification.
Images were taken by software and exported as JPEG, (scale is only
approximate and not validated).
[0342] X-Ray powder diffraction was performed with a MiniFlex by
Rigaku Corporation using silicon low background sample holders
(diameter 24 mm, pit 0.2 mm) and Cu, 1=1.54056 .ANG., 15 kV tubes.
Samples were ground with mortar and pestle when a sufficient amount
was isolated, which lead to consistent results, less preferred
orientation and better handling of material with huge particle
size. Solid was positioned on a sample holder prepared with grease
and flattened with a disc of glass
[0343] Method: Angle: 2 .theta.=2.degree. to 2 .theta.=40.degree.;
Sampling width 0.02 [2 .theta.]; Measurement time: 75 minutes.
[0344] For purity estimation and determination of the solubility in
solution a generic in-house HPLC method was used. HPLC was
performed using a Phenomenex Luna 3 pm C18 (50.times.4.6 mm) column
and detected with a DAD detector, recording at 214 nm.
[0345] Diluent: 0.5 mg/mL in ACN/H.sub.2O 1:1+1% TFA
[0346] Eluents: A="H.sub.2O+0.05% CF.sub.3COOH";
B="CH.sub.3CN+0.05% CF.sub.3COOH"
[0347] Method: Injection: 5 .mu.L; Flow: 1.0 mL/min
TABLE-US-00001 Min Eluents 0.00 % A = 70.0 % B = 30.0 0.10 % A =
70.0 % B = 30.0 15.1 % A = 5.0 % B = 95.0 16.1 % A = 5.0 % B = 95.0
17.1 % A = 70.0 % B = 30.0 12.1 % A = 70.0 % B = 30.0
Example 2
Screening Techniques
[0348] The polymorphism screening was performed using an approach
to find kinetically preferred polymorphs as well as
thermodynamically preferred or in other words more stable
polymorphs. The kinetically preferred polymorphs were examined
using evaporation and cooling crystallizations. Thermodynamically
preferred polymorphs were examined using slurry type
experiments.
[0349] The forms described herein are assigned to sequential
capital letters (e.g., A, B, C . . . ). The starting material used
for screening was a pale yellow to beige solid. NMR assay of the
material was found to be 95.6% w/w and HPLC indicated 99.07% a/a.
The material appeared crystalline by microscopy (FIG. 3) as well as
by XRPD which showed a mixture of Forms A and G.
[0350] DSC indicated a melting point of around 202.degree. C. with
a second melting event around 211.degree. C. TGA with SDTA curve
indicated a weight loss of around 0.2% w/w up to the endothermic
events as well as further weight loss during melting/form
conversion which probably is due to beginning degradation.
[0351] Screening. The screening was done in 3 series:
A--evaporation, B--fast cooling and C--slurries. Experiments struck
through indicate that these experiments were not performed because
of low solubility of the starting material. The experiment name is
provided in each table.
Evaporation screening. For the evaporation experiments
approximately 40 mg starting material was suspended/dissolved in
each of the solvents listed (up to 4 mL) per Table 1. Solvents were
chosen to have a high diversity, e.g., in polarity, protic/aprotic,
acceptability according to ICH guidelines.
[0352] Experiments where no dissolution occurred at room
temperature were heated to maximum 60.degree. C. and in case still
no dissolution occurred were filtered at elevated temperature to
obtain a more concentrated starting solution. The solutions were
evaporated in a drying oven starting at 25.degree. C. and 850 mbar
with a constant flow of nitrogen decreasing vacuum after 3 days 750
mbar. After 5 days remaining solutions were concentrated using a
nitrogen stream. The resulting solids were examined visually and in
cases where a sufficient amount of solid was obtained X-ray powder
diffraction was performed.
TABLE-US-00002 TABLE 1 Evaporation Experiments. Experiment
Dissolved After Optical LIMS- LIMS- No. .sup.1 Solvent Heating
Impression Comment Form Task/ID Sample/ID .sup.1 A1_1 .sup. .sup.1
heptane -- -- -- -- A1_2 methyl no film -- -- cyclohexane A1_3
toluene no film/spots Too few -- A1_4 THF yes yellow -- A G
305062099 200664726 A1_5 chlorobenzene no yellow -- E 305062101
200664727 A1_6 trifluoroethanol yes oil.fwdarw.wax -- F 305062103
200664728 A1_7 acetone no beige -- A 305062105 200664729 A1_8 MEK
no oil/spots -- Am.sup.2 A 305062107 200664730 A1_9 MIBK no film --
-- A1_10 dioxane no beige -- B 305062109 200664731 A2_1 2-propanol
no beige -- G 305062111 200664732 A2_2 1-propanol no beige -- G
305062113 200664733 A2_3 ethanol no film/spots -- A 305062115
200664734 A2_4 methanol yes beige -- A G 305062117 200664735 A2_5
methyl acetate no film/spots -- Am.sup.2 X.sup.3 305062119
200664736 A2_6 ethyl acetate no film -- -- A2_7 isopropyl acetate
no film -- -- .sup.1 A2_8 .sup. .sup.1 diethylether -- -- -- --
AS_9 TBME no film -- -- AS_10 2-Me-THF no yellow -- G 305062121
200664737 A3_1 ACN no crystals -- A C 305062123 200664738 A3_2 DCM
yes film/spots -- A 305062125 200664739 A3_3 DMSO yes yellow -- A
305063649 200664904 .sup.1 A3_4 .sup. .sup.1 NMP no -- -- -- A3_5
EtOAc wet no film/spots -- Am.sup.2 305062127 200664740 A3_6
acetone/water 1/2 no beige -- A 305062129 200664741 A3_7 EtOH/water
1/1 yes brown -- A X.sup.3 305062131 200664742 A3_8 EtOH/water 3/1
yes beige -- A 305062133 200664743 A3_9 IPA/water 3/1 yes
film/spots -- A 305062135 200664744 A3_10 HOAc/water 1/1 yes oil --
-- A4_1 water no film too few -- .sup.1 Experiments were not
performed due to low solubility. Form X indicates additional
reflexes that do not correspond to any other observed form.
.sup.2Am indicates Amorphous. .sup.3X indicates additional reflexes
not corresponding to other observed forms
TABLE-US-00003 TABLE 2 Cooling/precipitation experiments. T.sub.max
in .degree. C. Experiment Vol Tmax[.degree. C.]/ Anti- Vol Optical
LIMS- LIMS- No. Solvent (mL) solution? solvent (mL) impression Form
Task/ID Sample/ID B1_1 DCM 0.5 60/yes MCH 3 solid D 305073328
200666054 B1_2 IPA/water 3/1 1 60/yes none -- solid A 305073330
200666055 B1_3 EtOH/water 3/1 1 60/yes none -- solid A 305073332
200666056 B1_4 IPA 2 60/yes none -- solid A 305073334 200666057
B1_5 IPA +/ACN 0.5/0.5 60/yes none -- solid A 305073336 200666058
B1_6 MeOH 0.5 60/yes none -- solid A 305073338 200666059 B1_7 DCM +
TBME 0.5 60/yes TBME 4 solid G 305073340 200666060 B1_8 1-propanol
0.5/0.5 60/yes none -- solid H 305073342 200666061 B1_9 1-propanol
+ TBME 1 60/yes TBME 2 solid A 305073344 200666062 B1_10 1-propanol
+ hept 1 60/yes Heptane 2 solid A 305073346 200666063 B2_1
1-propanol + water 1 60/yes water 2 solid A 305073348 200666064
B2_2 THF 4 60/yes none -- solid H 305073350 200666065 B2_3 MEK 4
60/no none -- solution -- B2_4 acetone 4 60/no none -- solid A
305073353 200666066 B2_5 DCM/MeOH + TBME 0.2/0.25 r.t./yes TBME 3.5
solid A G 305073355 200666067 B2_6 MeOH + water 0.5 60/yes water 2
solid A 305073357 200666068 B2_7 EtOAc (wet) 4 60/no none --
solution -- B2_8 MEK (wet) 0.9 60/yes none -- solid A 305073361
200666070 B2_9 ACN/MeOH + ACN 0.2/0.2 60/yes ACN 2 solution --
B2_10 Tol/MeOH 7/3 + Hep 0.2 60/yes Heptane 2 solid A 305073365
200666072 B3_1 DMSO + water 0.4 60/yes water 0.75 solid A 305074841
200666266 B3_2 DMSO + TBME 0.4 60/yes TBME 3 solid A 305074843
200666269 B3_3 NMP + TBME 0.4 60/yes TBME 3.5 solid A 305074845
200666270 B3_4 NMP + water 0.4 60/yes water 2 solid A 305074843
200666271 B3_5 THF + water 0.5/0.1 60/yes water 1.5 Oil > solid
A 305074849 200666272 -- indicates no form observed.
TABLE-US-00004 TABLE 3 Slurry screening. * solubility determined by
HPLC. Experiment Optical HPLC ML LIMS- LIMS- No. Solvent Solution?
impression mg/mL (% a/a) Form Task/ID Sample/ID C1_1 heptane no
beige 0.02 100.00 A G 305054045 200663995 C1_2 MCH no beige 0.08
100.00 A G 305054047 200663996 C1_3 toluene no beige 0.45 87.28 A G
305054049 200663997 C1_4 THF no beige 5.71 94.83 A 305054051
200663998 C1_5 chlorobenzene no beige 1.81 92.35 A 305054053
200663999 C1_6 trifluoroethanol yes solution >130 96.33 -- C1_7
acetone no beige 1.37 81.66 A 305054055 200664000 C1_8 MEK no beige
3.67 92.40 A 305054057 200664001 C1_9 MIBK no beige 0.79 87.53 A G
305054059 200664002 C1_10 dioxane no beige 5.10 95.50 B A 305054061
200664003 C2_1 2-propanol no beige 6.86 97.18 A 305054063 200664004
C2_2 1-propanol no beige 12.00 95.28 A 305054065 200664005 C2_3
ethanol no beige 11.60 94.59 A 305054067 200664006 C2_4 methanol no
beige 29.84 97.52 A 305054069 200664007 C2_5 methyl acetate no
beige 0.94 85.37 A 305054071 200664008 C2_6 ethyl acetate no beige
0.57 77.59 A 305054073 200664009 C2_7 iPrOAc no beige 0.60 86.13 A
G 305054075 200664010 C2_8 diethylether no beige 0.02 70.74 A
305054077 200664011 C2_9 TBME no beige 0.16 86.76 A G 305054079
200664012 C2_10 2-Me-THF no beige 1.03 88.83 A 305054081 200664013
C3_1 ACN no beige 0.81 84.74 C J 305054083 200664014 C3_2 DCM no
beige >70 98.32 D 305054085 200664015 C3_3 DMSO no yellow 28.82
95.03 A 305054087 200664016 C3_4 NMP no yellow 52.32 94.79 A
Am.sup.1 305054089 200664017 C3_5 EtOAc wet no beige 2.69 84.49 A
305054091 200664018 C3_6 ac/water 1/2 no beige 0.48 74.20 A
305054093 200664019 C3_7 EtOH/water 1/1 no beige 3.22 86.64 A
305054095 200664020 C3_8 EtOH/water 3/1 no beige 20.96 96.08 A
305054097 200664021 C3_9 IPA/water 3/1 no beige 16.88 96.20 A
305054099 200664022 C3_10 HOAc/water 1/1 yes solution >100 98.11
-- C4_1 water no beige 0.04 89.74 A G 305054101 200664023 .sup.1 Am
indicates Amorphous. -- indicates no form observed. 2 digits after
decimal point are provided to show minimal amounts in low
solubilizing solvents. Italicized numbers indicate concentration
was too high and above linearity.
[0353] Slurry Screening. The slurry experiments were performed by
taking approximately 40 mg starting material and slurrying in each
of the solvent mixtures as detailed Table 3 using a magnetic stir
bar. Solvents were chosen as described to have a high diversity
(e.g., in polarity, protic/aprotic). The solvents were not
necessarily selected for pharmaceutical suitability in regards to
ICH guidelines. Only as much solvent or mixtures as needed to
slurry/suspend the material was used--starting from 200 .mu.L to a
maximum of 2 mL. The slurries were stirred for 5 days. The
suspensions were filtered and the filter cake slightly dried to not
destroy potential solvates and subjected to XRPD. In case
suspensions started to run through the filter the suspensions were
dried using a nitrogen stream. As the solubility was tested in the
solvents, the evaporated solvent provides a small amount of solid
compared to the material suspended (i.e., the slurry form still
should be dominant).
[0354] Screening results and promotion to next phase. After
identification of different forms per XRPD during the screening
phase the individual forms were checked (evaporation and cooling
screening) by microscopy. HPLC was performed once per form to
confirm identity and to get an idea about purity. NMR was done to
check for residual solvents and to confirm identity. If sufficient
material was left DSC and TGA were also performed to confirm NMR
residual solvent results stability. After this first
characterization phase further scale-up experiments were
performed.
[0355] Scale-up and more detailed Characterization of Forms. All
six forms were tested by HPLC to ensure that none of the forms is a
false positive, e.g., degradation. An overlay of the chromatograms
is shown in FIG. 4. All samples showed at least 96% a/a by HPLC
with no new impurities (except for solvents e.g., chlorobenzene)
compared to the starting material. Form J identified after the
screening phase was verified by NMR which confirmed identity.
Example 3
Form Characterization
[0356] Form A. Form A was present in the starting material used for
the screening and occurred in nearly all screening experiments.
Form A was the most often obtained form and Form A is likely the
thermodynamically most stable form from 0 to 60.degree. C.
[0357] The crystal habit of Form A appeared to vary widely (FIG.
5A, 5B, 5C, and 5D) from agglomerates of fine needles (brushlike),
undefined forms (stone knife form), rod-like needles or almost
cubic crystals. XRPD (FIG. 42) shows a well resolved pattern with
probably nice crystallinity. The .sup.1H NMR (FIG. 6) does not show
any residual solvents for Form A except for the water signal which
is not suitable for quantification.
[0358] Thermal analysis showed 2 melting events for Form A (FIG. 7)
at 201 .degree. C. (peak) and 208.degree. C. (peak) where the
latter likely corresponds to the melting point of Form G.
[0359] TGA (FIG. 8) with SDTA curve shows a similar curve as DSC
with two endotherms and only 0.28% w/w weight loss up to the first
melting endotherm. The increasing weight loss around melting points
indicated thermal degradation.
[0360] Scale-up procedure. Removal of solvates can require
repetition of the given procedure. 200 mg starting material was
suspended in acetone (1 mL) and the suspension stirred for 48 h.
The suspension was filtered and the solid dried in vacuum.
[0361] Form B. Form B was obtained from tested screening
experiments and from slurry in 1,4-dioxane and evaporation from
1,4-dioxane. Form B is a 1,4-dioxane solvate as confirmed by NMR
(FIG. 10), which shows 1 eq of 1,4-dioxane.
[0362] Form B was nicely crystalline under the microscope (FIG. 9A
and 9B) but does not appear to have a clear crystal habit. XRPD of
Form B (FIG. 43) shows good intensity of reflexes which can be at
least partially come from nicely crystalline material. NMR showed
approximately one equivalent of dioxane in the solid isolated from
the evaporation experiment (Table 1, A1_10).
[0363] DSC (FIG. 11) showed an endotherm around 100.degree. C. that
corresponds to dioxane evaporation. The corresponding weight drop
can be observed in TGA (FIG. 12). The second endotherm in DSC
around does not appear to correspond to an event in TGA. The weight
loss necessary for 1 eq of dioxane (about 16% w/w) was only reached
around 180.degree. C. but the SDTA curve does not show the lower
nor the higher endotherm observed in DSC. Without being bound by
any particular theory, the second endotherm may correspond to
remaining solvent released during melt of the partially desolvated
solid.
[0364] Scale-up procedure. 80 mg starting material was dissolved in
1,4-dioxane (12 mL) at 65.degree. C. The solution was cooled to
25.degree. C. and the solvent was slowly (ca. 6 h) evaporated by a
constant stream of nitrogen until a dry solid is obtained.
[0365] Form C. Initially Form C was found present in experiment
C3_1--likely in a pure form. After drying-out acetonitrile (FIG.
13: ACN at 2.02 ppm, confirmed by spiking ACN as signal was
expected at 2.10 ppm) from material showing this pattern a new
pattern could be observed where many reflexes almost vanished (the
reflexes present in Form J).
[0366] Several attempts were undertaken to generate Form C.
Slurries in ACN (up to 5 days) provided Form A. A prolonged slurry
(2 weeks) afforded a mixture of Form C and J.
[0367] The material from the screening as well as the scale-up
experiment contained ACN in the solid (FIG. 13) but could be dried
under vacuum at ambient temperature. The wet cake (paste: crude
1#1), the gently dried cake (crude 2#1) and the completely dried
cake (crude 3#1) were also checked by XRPD (FIG. 14): The reflexes
of Form J are vanishing (see e.g., at 7.5 2theta). The screening
sample A3_1 (evaporation from acetonitrile) converted to Form A
during drying.
[0368] DSC before drying the Form C/J mixture (FIG. 15) showed an
endotherm around 100.degree. C. that corresponds to ACN release and
Form conversion and the dried Form mixture showing Form C (FIG. 16)
was very similar to Form J.
[0369] Scale-up procedure. The following approach was used to
generate Form C. 200 mg starting material (Form A/G mixture) was
suspended in ACN and intensively stirred for 15 days. The
suspension was filtered and the solid dried in vacuum (max. vacuum,
ambient temperature) to give Form C.
[0370] Form D. Form D was isolated from the screening experiments,
using dichloromethane as solvent. The slurry and quick cooling
experiment but not the evaporation experiment led to Form D. Thus
Form D was likely a (weak) solvate as weak vacuum during drying led
to complete desolvation. XRPD (FIG. 45) of Form D is not well
resolved with relatively broad reflexes. Additionally either an
amorphous halo appears to be present or due to low sample amount
the measurement does show high background noise.
[0371] NMR (FIG. 18) showed one equivalent of dichloromethane at
5.3 ppm. DSC (FIG. 19) and TGA (FIG. 20) correspond when it comes
to weight loss and the related endothermicity. Although not
integrated in DSC prior to the first endothermic event a steady
endotherm can be observed. After a first endotherm/exotherm a
second smaller one can be observed leading to a melting point
likely corresponding to Form G.
[0372] Scale-up procedure. 50 mg starting material was suspended in
dichloromethane (0.3 mL) and the suspension was stirred for 5 d.
The suspension was filtered and the solid gently dried in
vacuum.
[0373] Form E. Form E was observed from evaporation from
chlorobenzene. The scale-up experiments (evaporation from
chlorobenzene leading to Form G, slurry in chlorobenzene led to
Form A (even wet solid). A seeded crystallization in chlorobenzene
(targeted to deliver Form G) led to Form G with only traces of Form
E.
[0374] As the screening sample contained chlorobenzene in liquid
form (smell and visually confirmed) thermal analysis as TGA/DSC
were not performed. Also no NMR data was collected as residual
solvent and solvated chlorobenzene could not be distinguished. Form
E showed needle-like crystals under the microscope (FIG. 21A and
21B) and XRPD has narrow reflexes (FIG. 46).
[0375] The remaining screening sample was dried in vacuum (ambient
temperature) and the resulting solid was checked by XRPD and showed
conversion to Form G. Hence Form E is a chlorobenzene solvate.
[0376] Form F. Form F was obtained from evaporation from
trifluoroethanol. The material formed a solidified oil and no
crystal habit could be determined (FIG. 22A and 22B). NMR (FIG. 23)
revealed about 0.95 eq of trifluoroethanol (3.95 ppm) and XRPD
(FIG. 47) showed a crystalline material with not well resolved
reflexes. Without being bound by any particular theory, this may
arise from non-ideal crystallization out of an oil/resin with
residual amorphous/resin-like residue in the material.
[0377] DSC (FIG. 24) and TGA (FIG. 25) confirmed that Form F
contained a large amount of trifluoroethanol. Although TGA
indicated that less than 1 eq (about 0.8 eq) trifluoroethanol was
released, without being bound by any particular theory, this could
be because of the sample desolvating partially before starting the
measurement or because the solvent is not completely released from
the melt.
[0378] Form F is likely a mono trifluoroethanol solvate.
Evaporation of a trifluoroethanol solution also yields Form I.
[0379] Form G. Form G was present in the starting material used for
the screening. It occurred in many experiments during the screening
phase. The conversion to Form A in the slurry screening in most
solvents showed that Form G was less stable at 25.degree. C. in
comparison to Form A. Remaining Form A/G mixes indicated that a
certain level of solubility appeared necessary to improve form
conversion. Form G has a needle-like habit (FIG. 26A, 26B, 26C, and
26D) with a high tendency to form agglomerates.
[0380] NMR (FIG. 27) showed approximately 0.25 equivalents of
isopropanol, but Form G is not likely an isopropanol solvate. It
was also isolated from different solvents. During scale-up
experiments from isopropanol Karl-Fischer titration was also
performed and 0.5% w/w water found (approximately 0.1 eq).
[0381] Although XRPD (FIG. 47) does not appear to have well
separated reflexes, no pattern was observed that seemed to have
less amorphous halo.
[0382] Thermal analysis of Form G showed only one melting point
(peak: 209.5.degree. C.) in DSC (FIG. 28) but no clear
corresponding solvent loss in TGA (FIG. 29). Several attempts were
undertaken to generate Form G in slightly larger scale. Form G was
obtained by evaporating a solution in chlorobenzene at ambient
temperature. Evaporation, in some instances, afforded a mixture of
Form G and Form E. On 270 mg scale a solution in isopropanol
afforded Form A after evaporation. A seeded crystallization from
isopropanol with subsequent evaporation of the solvent led to Form
G in slightly larger scale.
[0383] Scale-up procedure. 100 mg starting material was dissolved
in isopropanol (4 mL) at 65.degree. C. and filtered over a syringe
filter. The solution was cooled to 25.degree. C. and the solvent
was slowly (ca. 6 h) evaporated by a constant stream of nitrogen
until a dry solid is obtained.
[0384] Form H. Form H was observed in cooling experiments,
including THF and isopropanol as solvents. The crystal habit of
Form F appears to be bipyramidal (FIG. 30A and 30B). Form H can be
obtained as a mixture with Form A in a seeded scale-up experiment
from THF. Drying off the remaining THF at ambient temperature led
to pure Form A. Although this could also have been a solid
transformation of a non-solvated form into another form, Form A is
more stable than Form H. The drying of the Form A/H mixture was
performed 5 days after the scale-up run which would correspond to a
quick form transition in case not the drying would have caused form
transition.
[0385] Pure Form H was available in small amounts from the THF
screening experiment (B2_2). Collected NMR data (FIG. 31) indicated
a THF content of approximately 2.4 equivalents. Form H cannot be a
THF solvate because it was obtained from isopropanol as well. The
detected THF either showed wet solid or that form H is a channel
solvate also possible with isopropanol.
[0386] Scale-up procedure. 50 mg starting material is dissolved in
4 mL THF at 65.degree. C. The solution is cooled to room
temperature. and the solvent evaporated with a constant stream of
vacuum at 850 mbar during >3 days.
[0387] A mixture of Form A and Form H was tested by XRPD after
drying off residual THF and only Form A was visible. Without being
bound by any particular theory, this may occur by a desolvation
effect of a potential channel solvate or by form conversion of a
kinetic form to the stable Form A.
[0388] Form I. Form I is likely a mono trifluoroethanol solvate as
indicated by NMR (FIG. 33) showing about 1.1 eq trifluoroethanol
and by TGA (FIG. 34). Insufficient material hindered additional
analytics.
[0389] Form J. The exotherm event in DSC (FIG. 36) indicated a
monotropic correlation to Form G which itself has an enantiotropic
relation to Form A. Hence Form J is less stable than Form A.
Example 4
Form Stability Analysis
[0390] Stability of forms. For the examination of the stability of
different forms the solvates were excluded. The identified solvates
are: [0391] Form B (1,4-dioxane) [0392] Form D (dichloromethane)
[0393] Form E (chlorobenzene) [0394] Form F (trifluoroethanol)
[0395] Form I (trifluoroethanol)
[0396] The following forms were regarded as potential real forms or
could not be identified as real solvates: [0397] Form A (obtained
in most screening experiments) [0398] Form C (Initially Form C
appeared to be an ACN solvate) [0399] Form G (present in starting
material) [0400] Form H (potentially a channel solvate) [0401] Form
J
[0402] Solubility data for Forms A and G was collected to determine
the most stable form from 0 to 60.degree. C. The screening results
confirmed Form A to be more stable than Form G at 20.degree. C. As
the most stable form also shows the lowest solubility, data for
both forms was collected in ethanol and MEK (at least two solvents
were selected to exclude any solvent/solvate effect).
TABLE-US-00005 TABLE 4 Solubility of Forms A and G in [mg/mL] after
40 min stirring. .degree. C. A/EtOH G/EtOH A/MEK G/MEK 0 4.7 7.6
1.8 2.6 22 11.7 15.8 2.4 3.1 60 32.1 36.9 3.7 4.6
[0403] As form conversions tend to happen faster at elevated
temperature at 60.degree. C., slurries were performed for the
starting material used for the screening (A/G mixture) during 18 h
at 60.degree. C. Both isolated samples showed pure Form A. The
difference in solubility at 60.degree. C. was much smaller than at
0.degree. C., and indicates either less difference in stability or
quicker form conversion at elevated temperature.
[0404] Form J. Forms J and C were identified as potential
non-solvates and their stability was investigated. Form J could be
eliminated as stable form because, in part, the DSC (FIG. 36)
indicated an exothermic form conversion around 140.degree. C. This
leads to a form melting at 210.degree. C., which likely represents
Form G and therefore represents a monotropic relation.
[0405] Form C. Form C was obtained by drying a Form C/J mixture.
The XRPD pattern appeared to contain traces of reflexes of Form J.
Slurries of Form C seeded with Form A (15% w/w) in ethanol and
acetone were performed during 18 h. The resulting solid was pure
Form A. This also confirmed the exothermic event observed in DSC
(FIG. 16) which indicated a monotropic relation to the form formed
in DSC around 130.degree. C. (melting point 210.degree. C., which,
as described herein, is likely Form G).
[0406] Solubility of Form A. To develop a Form A crystallization, a
series of solubility data points was collected (Table 5). An amount
of up to 15 mg was suspended in 150 .mu.L and the mixture stirred
for 2 days. Solubility was then determined by HPLC or by
calculation if a solution was observed.
TABLE-US-00006 TABLE 5 Solubility of Form A at 20.degree. C. and
40.degree. C. Solubility [mg/mL] Entry Solvent 20.degree. C.
40.degree. C. Comment 1 DMSO 21.6 50.9 -- 2 DMSO/TBME 1:1 v/v 17.2
44.6 -- 3 DMSO/EtOAc 1:1 v/v 15.0 36.9 -- 4 THF 3.7 7.7 -- 5
THF/H.sub.2O 8:2 v/v 38.6 >100 Clear solution with 10 vol of
solvent mix @ 40.degree. C. 6 THF/EtOH 8:2 v/v 13.4 27.8 -- 7
2-PrOH 4.5 9.59 -- 8 EtOH 8.50 24.0 -- 9 Toluene/MeOH 7:3 v/v
>100 >100 Clear solution with 10 vol of solvent mix. 10
Toluene/2-PrOH 7:3 23.1 45.9 -- v/v
Example 5
Summary
[0407] The screening successfully identified 10 forms of which the
following 5 forms were identified as solvates: [0408] Form B
(1,4-dioxane) [0409] Form D (dichloromethane) [0410] Form E
(chlorobenzene) [0411] Form F (trifluoroethanol) [0412] Form I
(trifluoroethanol)
[0413] The solubility and concurrent slurry experiments identified
Form A as the most stable form from 0.degree. C. to 60.degree. C.
Form G is an enantiotropic form of Form A (higher melting point
than Form A but at least above melting point of Form A more stable
than Form A) but the transition temperature is not known.
[0414] Form C and J are less stable than Forms A and G and are in a
monotropic correlation to Forms A and G.
[0415] While examples of certain particular embodiments are
provided herein, it will be apparent to those skilled in the art
that various changes and modifications may be made. Such
modifications are also intended to fall within the scope of the
appended claims.
TABLE-US-00007 TABLE 6 XRPD of form A Sample: 200672169 File:
305130227_CLGR14 Date: Aug. 7, 2014 09:26:55 Operator: BBO Comment:
Rough Memo: Si Sample Holder: No grinding Method: 2.sup.nd
differential Typical width: 0.250 deg. Min. height: 150.00 cps
Intensity (cps) 2theta (deg.) Peak no. 2theta Flex Width d-value
Intensity I/Io 1 8.660 0.188 10.2023 441 13 2 9.220 0.212 9.5838
798 23 3 10.800 0.188 8.1850 366 11 4 11.940 0.212 7.4060 2467 70 5
14.780 0.212 5.9887 615 18 6 15.520 0.188 5.7048 775 22 7 16.380
0.259 5.4071 3573 100 8 17.680 0.212 5.0124 617 18 9 18.520 0.188
4.7869 1159 33 10 19.900 0.235 4.4579 324 10 11 20.400 0.212 4.3498
826 24 12 20.920 0.165 4.2428 1646 47 13 21.240 0.188 4.1796 2303
65 14 21.680 0.212 4.0958 1183 34 15 22.040 0.141 4.0297 533 15 16
22.360 0.212 3.9727 850 24 17 22.980 0.235 3.8669 1130 32 18 23.520
0.188 3.7794 1316 37 19 24.160 0.400 3.6807 1746 49 20 25.880 0.212
3.4398 1062 30 21 26.320 0.212 3.3833 512 15 22 26.820 0.141 3.3214
596 17 23 27.000 0.212 3.2996 832 24 24 27.380 0.235 3.2547 1147 33
25 28.040 0.259 3.1796 644 19 26 28.900 0.212 3.0869 430 13 27
29.840 0.212 2.9917 363 11
TABLE-US-00008 TABLE 7 XRPD of form B Sample: 200664731 File:
305062109_CLGR14 Date: Jun. 26, 2014 16:36:13 Operator: BBO
Comment: Rough Memo: Si Sample Holder: slightly grinded Method:
2.sup.nd differential Typical width: 0.250 deg. Min. height: 150.00
cps Intensity (cps) 2theta (deg.) Peak no. 2theta Flex Width
d-value Intensity I/Io 1 6.260 0.188 14.1073 363 3 2 10.740 0.188
8.2306 2449 15 3 12.540 0.188 7.0530 394 3 4 15.240 0.165 5.8090
1061 7 5 15.520 0.235 5.7048 1876 12 6 15.860 0.165 5.5832 745 5 7
16.580 0.141 5.3424 357 3 8 17.480 0.165 5.0693 17038 100 9 18.160
0.188 4.8810 605 4 10 18.580 0.188 4.7716 1419 9 11 18.900 0.141
4.6915 626 4 12 19.700 0.188 4.5027 3186 19 13 20.900 0.212 4.2468
1290 8 14 21.820 0.212 4.1070 2602 16 15 22.260 0.259 3.9904 521 4
16 22.680 0.165 3.9174 428 3 17 23.080 0.212 3.8504 410 3 18 24.220
0.188 3.6717 2377 14 19 24.740 0.188 3.5957 1053 7 20 24.920 0.141
3.5701 814 5 21 25.320 0.188 3.5146 528 4 22 25.960 0.212 3.4294
876 6 23 26.380 0.188 3.3757 1505 9 24 27.180 0.282 3.2782 443 3 25
29.380 0.212 3.0375 650 4 26 30.020 0.235 2.9742 444 3 27 30.880
0.188 2.8933 356 3 28 31.820 0.141 2.8099 422 3 29 35.400 0.188
2.5335 736 5
TABLE-US-00009 TABLE 8 XRPD of form C Sample: 200676519 File:
305164001_CLGR14 Date: Aug. 27, 2014 16:51:03 Operator: BBO
Comment: Rough Memo: Si Sample Holder: slightly ground Method:
2.sup.nd differential Typical width: 0.250 deg. Min. height: 150.00
cps Intensity (cps) 2theta (deg.) Peak no. 2theta Flex Width
d-value Intensity I/Io 1 5.620 0.329 15.7123 428 13 2 8.860 0.282
9.9724 990 31 3 9.580 0.212 9.2245 508 16 4 10.600 0.141 8.3390 542
17 5 10.980 0.353 8.0513 1002 31 6 13.500 0.471 6.5536 791 25 7
14.360 0.235 6.1829 664 21 8 14.880 0.282 5.9487 1101 34 9 15.340
0.282 5.7713 722 22 10 16.100 0.306 5.5006 769 24 11 16.860 0.188
5.2543 653 20 12 17.200 0.306 5.1512 779 24 13 18.020 0.235 4.9186
1283 39 14 19.120 0.447 4.6380 1070 33 15 20.320 0.282 4.3667 858
27 16 21.020 0.259 4.2229 3292 100 17 21.680 0.212 4.0958 893 28 18
22.120 0.306 4.0153 759 24 19 22.800 0.282 3.8971 1556 48 20 23.480
0.259 3.7857 706 22 21 23.940 0.188 3.7140 641 17 22 24.700 0.238
3.6014 687 21 23 26.760 0.141 3.3287 448 14 24 27.320 0.353 3.2817
569 18 25 29.060 0.212 3.0702 441 14
TABLE-US-00010 TABLE 9 XRPD of form D 2theta (deg.) Peak no. 2theta
Flex Width d-value Intensity I/Io 1 6.560 0.282 13.4628 342 23 2
7.760 0.259 11.3834 752 50 3 9.020 0.329 9.7959 481 32 4 10.560
0.235 8.3705 389 26 5 13.740 0.306 6.4396 437 29 6 14.700 0.212
6.0211 379 25 7 15.620 0.306 5.6685 1368 90 8 16.280 0.165 5.4401
491 33 9 17.100 0.329 5.1811 462 31 10 18.060 0.141 4.9078 582 39
11 18.220 0.494 4.8650 651 43 12 18.780 0.188 4.7212 464 31 13
19.080 0.141 4.6476 415 28 14 19.680 0.471 4.5073 654 44 15 20.680
0.188 4.2915 791 53 16 21.180 0.165 4.1913 646 43 17 22.040 0.353
4.0297 1521 100 18 22.520 0.259 3.9449 842 56 19 23.700 0.635
3.7511 1321 87 20 25.000 0.141 3.5589 470 31 21 26.640 0.235 8.3494
418 28 22 27.620 0.400 3.2269 439 29 23 28.700 0.188 3.1079 409
27
TABLE-US-00011 TABLE 10 XRPD of form E 2theta (deg.) Peak no.
2theta Flex Width d-value Intensity I/Io 1 5.380 -- 16.4127 316 14
2 8.820 0.165 10.0176 2381 100 3 9.340 0.165 9.4610 729 31 4 12.100
-- 7.3084 269 12 5 13.380 0.188 6.6120 491 21 6 13.820 -- 6.4025
250 11 7 18.020 0.165 6.5278 391 17 8 16.480 0.165 5.3810 325 14 9
17.740 0.188 4.9958 954 41 10 18.320 0.306 4.8387 383 16 11 18.860
0.188 4.6768 448 19 12 19.480 0.188 4.5531 529 23 13 21.440 0.165
4.1411 938 40 14 22.240 0.188 3.9939 743 32 15 22.600 0.235 3.8311
744 32 16 22.920 0.141 3.8769 375 16 17 23.300 0.141 3.6145 405 18
18 23.540 0.235 3.7762 352 15 19 24.400 0.235 3.6450 761 32 20
26.160 0.188 3.4036 270 12 21 26.800 0.212 3.3238 554 24 22 27.820
0.188 3.2042 278 12 23 29.320 -- 3.0436 150 7
TABLE-US-00012 TABLE 11 XRPD of form F 2theta (deg.) Peak no.
2theta Flex Width d-value Intensity I/Io 1 4.580 0.235 19.2776 3884
100 2 4.820 0.188 18.3182 3087 80 3 7.320 0.250 12.0668 388 11 4
8.060 -- 10.9604 286 8 5 9.700 0.308 9.1106 442 12 6 11.020 --
8.0221 306 8 7 12.240 -- 7.2251 383 10 8 13.840 0.282 6.3933 437 12
9 14.800 0.212 5.9806 505 14 10 15.320 0.353 5.7788 1158 30 11
16.060 0.329 5.5142 896 24 12 16.600 0.424 5.3360 1290 34 13 17.460
0.282 5.0750 553 15 14 17.900 0.165 4.9513 473 13 15 18.520 0.259
4.7889 681 18 16 18.060 0.282 4.6525 1483 39 17 19.820 0.235 4.5209
709 19 18 20.200 0.259 4.3924 630 17 19 20.820 0.282 4.2830 631 17
20 21.520 0.259 4.1259 613 14 21 22.180 0.212 4.0048 488 13 22
22.880 0.353 3.8838 1372 38 23 23.380 0.282 3.8017 774 21 24 24.040
0.308 3.6968 443 12 25 24.840 0.282 3.6100 732 19 26 25.160 0.259
3.5366 554 15 27 25.800 0.400 3.4503 555 15 28 27.460 0.212 3.2454
418 11 29 27.880 0.259 3.1974 452 12 30 31.880 0.235 2.8048 427
12
TABLE-US-00013 TABLE 12 XRPD of form G 2theta (deg.) Peak no.
2theta Flex Width d-value Intensity I/Io 1 9.360 0.212 9.4408 673
23 2 10.240 0.235 8.6314 387 13 3 11.340 0.308 7.7965 606 20 4
12.020 0.259 7.3569 1071 38 5 12.920 0.212 6.8464 564 20 6 13.380
0.235 6.6120 1097 37 7 14.720 0.259 6.0130 822 31 8 15.740 0.235
5.6255 1178 39 9 16.440 0.259 5.3875 3038 100 10 17.140 0.212
5.1691 591 20 11 17.660 0.168 6.0180 739 25 12 18.360 0.235 4.8282
2105 70 13 19.000 0.235 4.6670 951 32 14 19.520 0.235 4.5439 1152
38 15 20.100 0.235 4.4140 739 25 16 20.520 0.212 4.3248 706 24 17
21.460 0.235 4.1373 1378 48 18 21.840 0.165 4.0681 592 20 19 22.440
0.308 3.9588 2180 73 20 22.800 0.235 3.8971 1455 48 21 23.460 0.329
3.7889 1954 65 22 24.200 0.212 3.6747 1123 37 23 25.140 0.353
3.5994 947 32 24 25.880 0.212 3.4398 558 19 25 26.220 0.282 3.3960
932 31 26 28.660 0.165 3.3409 640 22 27 27.240 0.141 3.2711 507 17
28 28.540 0.212 3.1250 402 14 29 29.300 0.282 3.0456 542 18 30
33.820 0.259 2.6408 420 14
TABLE-US-00014 TABLE 13 XRPD of form H 2theta (deg.) Peak no.
2theta Flex Width d-value Intensity I/Io 1 6.340 0.188 13.9295 465
8 2 11.000 0.188 8.0387 6647 100 3 12.700 0.212 6.9645 589 9 4
15.260 0.165 5.8014 1720 26 5 15.560 0.188 5.6902 2914 44 6 15.940
0.188 5.5554 728 11 7 17.540 0.212 5.0521 3708 56 8 18.200 0.165
4.8703 724 11 9 18.560 0.165 4.7718 804 13 10 18.880 0.188 4.8964
1852 28 11 19.960 0.212 4.4447 5860 89 12 21.080 0.141 4.2110 1011
16 13 22.080 0.188 4.0225 4809 73 14 22.580 0.141 3.9345 546 9 15
23.220 0.212 3.8275 594 9 16 24.180 0.165 3.6777 538 9 17 24.620
0.188 3.6129 3194 49 18 25.060 0.235 3.6505 1521 23 19 25.660 0.259
3.4688 541 9 20 26.520 0.188 3.3582 1249 19 21 27.040 0.188 3.2948
647 9 22 27.460 0.212 3.2454 600 10 23 29.480 0.235 3.0274 417 7 24
29.880 0.188 2.9878 887 14 25 30.500 0.188 2.9285 758 12 26 31.480
0.212 2.8395 449 7 27 32.180 0.188 2.7793 417 7 28 34.620 0.188
2.5888 427 7 29 35.120 0.235 2.5531 381 6 30 35.580 0.212 2.5211
548 9
TABLE-US-00015 TABLE 14 XRPD of form I 2theta (deg.) Peak no.
2theta Flex Width d-value Intensity I/Io 1 4.600 0.188 19.1938 447
8 2 8.740 0.165 13.1037 562 9 3 8.260 0.259 10.6954 433 7 4 9.100
0.212 9.7100 890 15 5 10.340 0.212 8.5481 804 13 6 11.020 0.188
8.0221 881 11 7 12.320 0.212 7.1784 1278 21 8 13.520 0.235 6.5438
528 9 9 13.980 0.235 6.3388 930 15 10 14.840 0.235 5.9646 1117 19
11 15.380 0.212 5.7564 923 15 12 16.360 0.212 5.4137 6268 100 13
17.080 0.235 5.1871 924 16 14 18.500 0.212 4.7920 2791 45 15 19.300
0.188 4.5952 1816 29 16 19.640 0.259 4.5164 1823 30 17 20.300 0.212
4.3710 1849 32 18 21.080 0.212 4.2110 2742 44 19 22.140 0.188
4.0117 3426 65 20 22.480 0.212 3.9518 6302 85 21 23.160 0.212
3.8373 3911 63 22 24.100 0.212 3.6897 2407 39 23 24.840 0.329
3.5814 945 16 24 25.380 0.235 3.5064 1097 18 25 27.160 0.235 3.2805
692 12 26 27.660 0.353 3.2224 902 15 27 28.240 0.212 3.1575 1030 17
28 29.360 0.259 3.0395 708 12 29 30.180 0.165 2.9588 707 12 30
37.180 -- 2.4162 673 10
* * * * *