U.S. patent application number 15/236283 was filed with the patent office on 2016-12-01 for crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzald- ehyde.
The applicant listed for this patent is Global Blood Therapeutics, Inc.. Invention is credited to Travis HOUSTON, Zhe LI, Stephan D. PARENT.
Application Number | 20160346263 15/236283 |
Document ID | / |
Family ID | 53774359 |
Filed Date | 2016-12-01 |
United States Patent
Application |
20160346263 |
Kind Code |
A1 |
LI; Zhe ; et al. |
December 1, 2016 |
CRYSTALLINE POLYMORPHS OF THE FREE BASE OF
2-HYDROXY-6-((2-(1-ISOPROPYL-1H-PYRAZOL-5-YL)PYRIDIN-3-YL)METHOXY)BENZALD-
EHYDE
Abstract
Disclosed are crystalline free base ansolvate forms of
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzald-
ehyde (or Compound 1), such as the free base Form I, Form II and
Material N. Also disclosed are crystalline free base solvates of
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzald-
ehyde (or Compound 1).
Inventors: |
LI; Zhe; (South San
Francisco, CA) ; PARENT; Stephan D.; (South San
Francisco, CA) ; HOUSTON; Travis; (South San
Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Global Blood Therapeutics, Inc. |
South San Francisco |
CA |
US |
|
|
Family ID: |
53774359 |
Appl. No.: |
15/236283 |
Filed: |
August 12, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14616548 |
Feb 6, 2015 |
9447071 |
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15236283 |
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61937404 |
Feb 7, 2014 |
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61937393 |
Feb 7, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/04 20180101; A61P
35/00 20180101; A61P 11/00 20180101; A61K 31/4439 20130101; C07D
401/04 20130101; A61P 25/28 20180101 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; C07D 401/04 20060101 C07D401/04 |
Claims
1.-20. (canceled)
21. A method of increasing oxygen affinity of hemoglobin S in a
patient in need thereof comprising administering to the patient in
need thereof a crystalline ansolvate of Compound 1: ##STR00011##
wherein the crystalline ansolvate is characterized by at least one
X-ray powder diffraction peak (Cu K.alpha. radiation) selected from
13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
22. The method of claim 21, wherein the crystalline ansolvate is
characterized by at least two X-ray powder diffraction peaks (Cu
K.alpha. radiation) selected from 13.37.degree., 14.37.degree.,
19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.).
23. The method of claim 21, wherein the crystalline ansolvate is
characterized by at least three powder diffraction peaks (Cu
K.alpha. radiation) selected from 13.37.degree., 14.37.degree.,
19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.).
24. The method of claim 21, wherein the crystalline ansolvate is
characterized by X-ray powder diffraction peaks (Cu K.alpha.
radiation) of 13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
25. The method of claim 21, wherein the crystalline ansolvate is
characterized by an X-ray powder diffraction pattern (Cu K.alpha.
radiation) substantially similar to that of FIG. 5.
26. The method of claim 21, wherein the crystalline ansolvate of
Compound 1 is substantially free of a solvated polymorph of
Compound 1.
27. The method of claim 21, wherein the crystalline ansolvate of
Compound 1 is characterized by X-ray powder diffraction peaks (Cu
K.alpha. radiation) of 13.37.degree., 14.37.degree., 19.95.degree.
and 23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.), and less
than about 25 mole %, 10 mole %, or 5 mole % of one or more of
crystalline Form I, Material N, or amorphous forms of Compound
1.
28. A method of increasing oxygen affinity of hemoglobin S in a
patient in need thereof comprising administering to the patient in
need thereof a pharmaceutical composition comprising a crystalline
ansolvate of Compound 1: ##STR00012## and at least one
pharmaceutically acceptable excipient, wherein the crystalline
ansolvate is characterized by at least one X-ray powder diffraction
peak (Cu K.alpha. radiation) selected from 13.37.degree.,
14.37.degree., 19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.).
29. The method of claim 28, wherein the crystalline ansolvate of
the pharmaceutical composition is characterized by at least two
X-ray powder diffraction peaks (Cu K.alpha. radiation) selected
from 13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
30. The method of claim 28, wherein the crystalline ansolvate of
the pharmaceutical composition is characterized by at least three
X-ray powder diffraction peaks (Cu K.alpha. radiation) selected
from 13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
31. The method of claim 28, wherein the crystalline ansolvate of
the pharmaceutical composition is characterized by X-ray powder
diffraction peaks (Cu K.alpha. radiation) of 13.37.degree.,
14.37.degree., 19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.).
32. The method of claim 28, wherein the crystalline ansolvate of
the pharmaceutical composition of Compound 1 is substantially free
of a solvated polymorph of Compound 1.
33. The method of claim 28, wherein the crystalline ansolvate of
the pharmaceutical composition is characterized by X-ray powder
diffraction peaks (Cu K.alpha. radiation) of 13.37.degree.,
14.37.degree., 19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.), and less than about 25 mole %, 10 mole %,
or 5 mole % of one or more of crystalline Form I, Material N, or
amorphous forms of Compound 1.
34. A method of treating sickle cell disease in a patient having
sickle cell disease comprising administering to the patient in need
thereof a crystalline ansolvate of Compound 1: ##STR00013## wherein
the crystalline ansolvate is characterized by at least one X-ray
powder diffraction peak (Cu K.alpha. radiation) selected from
13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
35. The method of claim 34, wherein the crystalline ansolvate is
characterized by at least two X-ray powder diffraction peaks (Cu
K.alpha. radiation) selected from 13.37.degree., 14.37.degree.,
19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.).
36. The method of claim 34, wherein the crystalline ansolvate is
characterized by at least three X-ray powder diffraction peaks (Cu
K.alpha. radiation) selected from 13.37.degree., 14.37.degree.,
19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.).
37. The method of claim 34, wherein the crystalline ansolvate is
characterized by X-ray powder diffraction peaks (Cu K.alpha.
radiation) of 13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
38. The method of claim 34, wherein the crystalline ansolvate is
characterized by an X-ray powder diffraction pattern (Cu K.alpha.
radiation) substantially similar to that of FIG. 5.
39. The method of claim 34, wherein the crystalline ansolvate of
Compound 1 is substantially free of a solvated polymorph of
Compound 1.
40. The method of claim 34, wherein the crystalline ansolvate of
Compound 1 is characterized by X-ray powder diffraction peaks (Cu
K.alpha. radiation) of 13.37.degree., 14.37.degree., 19.95.degree.
and 23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.), and less
than about 25 mole %, 10 mole %, or 5 mole % of one or more of
crystalline Form I, Material N, or amorphous forms of Compound
1.
41. A method of treating sickle cell disease in a patient having
sickle cell disease comprising administering to the patient in need
thereof a pharmaceutical composition comprising a crystalline
ansolvate of Compound 1: ##STR00014## and at least one
pharmaceutically acceptable excipient, wherein the crystalline
ansolvate of the pharmaceutical composition is characterized by at
least one X-ray powder diffraction peak (Cu K.alpha. radiation)
selected from 13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
42. The method of claim 41, wherein the crystalline ansolvate of
the pharmaceutical composition is characterized by at least two
X-ray powder diffraction peaks (Cu K.alpha. radiation) selected
from 13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
43. The method of claim 41, wherein the crystalline ansolvate of
the pharmaceutical composition is characterized by at least three
X-ray powder diffraction peaks (Cu K.alpha. radiation) selected
from 13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
44. The method of claim 41, wherein the crystalline ansolvate of
the pharmaceutical composition is characterized by X-ray powder
diffraction peaks (Cu K.alpha. radiation) of 13.37.degree.,
14.37.degree., 19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.).
45. The method of claim 41, wherein the crystalline ansolvate of
the pharmaceutical composition is substantially free of a solvated
polymorph of Compound 1.
46. The method of claim 41, wherein the crystalline ansolvate of
the pharmaceutical composition is characterized by X-ray powder
diffraction peaks (Cu K.alpha. radiation) of 13.37.degree.,
14.37.degree., 19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.), and less than about 25 mole %, 10 mole %,
or 5 mole % of one or more of crystalline Form I, Material N, or
amorphous forms of Compound 1.
47. A method of treating pulmonary disorder in a patient having a
pulmonary disorder comprising administering to the patient in need
thereof a crystalline ansolvate of Compound 1: ##STR00015## wherein
the crystalline ansolvate is characterized by at least one X-ray
powder diffraction peak (Cu K.alpha. radiation) selected from
13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
48. The method of claim 47, wherein the crystalline ansolvate is
characterized by at least two X-ray powder diffraction peaks (Cu
K.alpha. radiation) selected from 13.37.degree., 14.37.degree.,
19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.).
49. The method of claim 47, wherein the crystalline ansolvate is
characterized by at least three X-ray powder diffraction peaks (Cu
K.alpha. radiation) selected from 13.37.degree., 14.37.degree.,
19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.).
50. The method of claim 47, wherein the crystalline ansolvate is
characterized by X-ray powder diffraction peaks (Cu K.alpha.
radiation) of 13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
51. The method of claim 47, wherein the crystalline ansolvate is
substantially free of a solvated polymorph of Compound 1.
52. The method of claim 47, wherein the crystalline ansolvate is
characterized by X-ray powder diffraction peaks (Cu K.alpha.
radiation) of 13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.), and less than
about 25 mole %, 10 mole %, or 5 mole % of one or more of
crystalline Form I, Material N, or amorphous forms of Compound
1.
53. A method of treating pulmonary disorder in a patient having a
pulmonary disorder comprising administering to the patient in need
thereof a pharmaceutical composition comprising a crystalline
ansolvate of Compound 1: ##STR00016## wherein the crystalline
ansolvate is characterized by at least one X-ray powder diffraction
peak (Cu K.alpha. radiation) selected from 13.37.degree.,
14.37.degree., 19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.).
54. The method of claim 53, wherein the crystalline ansolvate of
the pharmaceutical composition is characterized by at least two
X-ray powder diffraction peaks (Cu K.alpha. radiation) selected
from 13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
55. The method of claim 53, wherein the crystalline ansolvate of
the pharmaceutical composition is characterized by at least three
X-ray powder diffraction peaks (Cu K.alpha. radiation) selected
from 13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
56. The method of claim 53, wherein the crystalline ansolvate of
the pharmaceutical composition is characterized by X-ray powder
diffraction peaks (Cu K.alpha. radiation) of 13.37.degree.,
14.37.degree., 19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.).
57. The method of claim 53, wherein the crystalline ansolvate of
the pharmaceutical composition is substantially free of a solvated
polymorph of Compound 1.
58. The method of claim 53, wherein the crystalline ansolvate of
the pharmaceutical composition is characterized by X-ray powder
diffraction peaks (Cu K.alpha. radiation) of 13.37.degree.,
14.37.degree., 19.95.degree. and 23.92.degree.2.theta. (each
.+-.0.2.degree.2.theta.), and less than about 25 mole %, 10 mole %,
or 5 mole % of one or more of crystalline Form I, Material N, or
amorphous forms of Compound 1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 61/937,393 filed Feb. 7, 2014, and U.S. Provisional
Application No. 61/937,404 filed Feb. 7, 2014, the contents of each
of which is incorporated herein in its entirety by reference
BACKGROUND
[0002]
2-Hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)b-
enzaldehyde is a compound having the formula:
##STR00001##
[0003] Sickle cell disease is a disorder of the red blood cells,
found particularly among those of African and Mediterranean
descent. The basis for sickle cell disease is found in sickle
hemoglobin (HbS), which contains a point mutation relative to the
prevalent peptide sequence of hemoglobin (Hb).
[0004] Hemoglobin (Hb) transports oxygen molecules from the lungs
to various tissues and organs throughout the body. Hemoglobin binds
and releases oxygen through conformational changes. Sickle
hemoglobin (HbS) contains a point mutation where glutamic acid is
replaced with valine, allowing HbS to become susceptible to
polymerization to give the HbS containing red blood cells their
characteristic sickle shape. The sickled cells are also more rigid
than normal red blood cells, and their lack of flexibility can lead
to blockage of blood vessels. A need exists for therapeutics that
can treat disorders that are mediated by Hb or by abnormal Hb such
as HbS, such as
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzald-
ehyde.
[0005] When used for treating humans, it is important that a
crystalline form of a therapeutic agent, like
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzald-
ehyde, or a salt thereof, retains its polymorphic and chemical
stability, solubility, and other physicochemical properties over
time and among various manufactured batches of the agent. If the
physicochemical properties vary with time and among batches, the
administration of a therapeutically effective dose becomes
problematic and may lead to toxic side effects or to ineffective
therapy, particularly if a given polymorph decomposes prior to use,
to a less active, inactive, or toxic compound. Therefore, it is
important to choose a form of the crystalline agent that is stable,
is manufactured reproducibly, and has physicochemical properties
favorable for its use as a therapeutic agent.
[0006] However, the art remains unable to predict which crystalline
form of an agent will have a combination of the desired properties
and will be suitable for human administration, and how to make the
agent in such a crystalline form.
SUMMARY
Ansolvates
[0007] This invention arises in part out the discovery that an HCl
salt of Compound 1 disproportionates or loses HCl, and a
disproportionation of the HCl salt of Compound 1 in water generates
the free base and disproportionation was facile upon exposure to
elevated humidity, with wet milling, and in direct contact with
water (e.g. slurry). The sulfate salt of Compound 1 also
disproportionates from certain solvents such as dimethyl sulfoxide
and methanol when precipitated with water. The volatilization of
HCl was evident within hours of exposure to drying conditions. For
example, partial conversion to the free base was observed within 12
hours at 30.degree. C. Accordingly, the free base of Compound 1
provides a stabler chemical entity compared to the corresponding
HCl or sulfate and such other salt.
[0008] It has now been discovered that
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzald-
ehyde (or Compound 1) i.e., the free base of Compound 1, can be
obtained as one or more crystalline ansolvate forms, several of
which are referred to here as crystalline Form I, Form II and
Material N. In preferred embodiments, the free base of Compound 1
is a crystalline ansolvate, such as a crystalline anhydrous form.
The free base of Compound 1, can be obtained from its corresponding
salt form, such as the HCl salt of Compound 1.
[0009] Three anhydrous crystalline forms of the free base were
identified, termed Free Base Forms I, II, and Material N. It has
been discovered that nucleation of Free Base Form I generally
occurs first from a slurry. Extending the slurry time can induce
the transformation of Free Base Form I to Free Base Form II, a
thermodynamically more stable phase relative to Form I. It has
further been discovered that Free Base Material N can be stable
relative to Forms I and II, at room temperature.
[0010] Free Base Material N was found to be enantiotropically
related to Form II, and will transform reversibly at a specific
transition temperature (estimated herein near 40-42.degree. C.).
Above the transition temperature, Free Base Form II appears to be
the most stable form, relative to Form I and Material N. Thus,
under operating temperatures below 40.degree. C., e.g., at
30.degree. C., the free base of Compound 1 exists primarily as
Material N, which may have some residual Form II. Thus, at
operating temperatures above 40.degree. C., e.g., at 50.degree. C.,
the free base of Compound 1 exists primarily as Form II, which may
have some residual Material N. At 40.degree. C. little appreciable
conversion is seen between Material N and Form II. This is
contemplated to be true for slurries of the free base in certain
solvents and in the solid state. In one embodiment, the one or more
crystalline free base forms of Compound 1 do not undergo
polymorphic transformation under conditions suitable for
manufacturing and storing the crystalline forms.
Form I
[0011] In one embodiment, the crystalline free base of Compound 1
comprises crystalline Form I, which is characterized by an
endothermic peak at (97.+-.2) C as measured by differential
scanning calorimetry. In another embodiment, the crystalline Form I
of the free base of crystalline Compound 1 is characterized by the
substantial absence of thermal events at temperatures below the
endothermic peak at (97.+-.2.degree. C. as measured by differential
scanning calorimetry. In another embodiment, the crystalline Form I
of the free base of crystalline Compound 1 is characterized by an
X-ray powder diffraction peak (Cu K.alpha. radiation at one or more
of 12.82.degree., 15.74.degree., 16.03.degree., 16.63.degree.,
17.60.degree., 25.14.degree., 25.82.degree. and
26.44.degree..+-.0.2.degree.2.theta.. In another embodiment, the
crystalline Form I of the free base of crystalline Compound 1 is
characterized by an X-ray powder diffraction pattern (Cu K.alpha.
radiation) substantially similar to that of FIG. 3.
[0012] In another embodiment, the crystalline Form I of the free
base of crystalline Compound 1 is characterized by at least one
X-ray powder diffraction peak (Cu K.alpha. radiation) selected from
12.82.degree., 15.74.degree., 16.03.degree., 16.63.degree.,
17.60.degree., 25.14.degree., 25.82.degree. and 26.44.degree. (each
.+-.0.2.degree.2.theta.). In another embodiment, the crystalline
Form I of the free base of crystalline Compound 1 is characterized
by at least two X-ray powder diffraction peaks (Cu K.alpha.
radiation) selected from 12.82.degree., 15.74.degree.,
16.03.degree., 16.63.degree., 17.60.degree., 25.14.degree.,
25.82.degree. and 26.44.degree. (each .+-.0.2.degree.2.theta.). In
another embodiment, the crystalline Form I of the free base of
crystalline Compound 1 is characterized by at least three X-ray
powder diffraction peaks (Cu K.alpha. radiation) selected from
12.82.degree., 15.74.degree., 16.03.degree., 16.63.degree.,
17.60.degree., 25.14.degree., 25.82.degree. and 26.44.degree. (each
.+-.0.2.degree.2.theta.).
[0013] In another embodiment, Form I is characterized by 1, 2, 3,
4, or more peaks as tabulated below.
TABLE-US-00001 Observed peaks for Form I, XRPD file 609973.
.degree.2.theta. d space (.ANG.) Intensity (%) 5.52 .+-. 0.20
16.021 .+-. 0.602 68 12.82 .+-. 0.20 6.906 .+-. 0.109 74 15.03 .+-.
0.20 5.897 .+-. 0.079 38 15.74 .+-. 0.20 5.629 .+-. 0.072 46 16.03
.+-. 0.20 5.530 .+-. 0.069 46 16.63 .+-. 0.20 5.331 .+-. 0.064 61
17.60 .+-. 0.20 5.040 .+-. 0.057 100 18.74 .+-. 0.20 4.736 .+-.
0.051 24 19.07 .+-. 0.20 4.654 .+-. 0.049 17 19.35 .+-. 0.20 4.587
.+-. 0.047 23 20.32 .+-. 0.20 4.370 .+-. 0.043 18 21.64 .+-. 0.20
4.106 .+-. 0.038 23 22.80 .+-. 0.20 3.901 .+-. 0.034 26 23.28 .+-.
0.20 3.821 .+-. 0.033 34 25.14 .+-. 0.20 3.543 .+-. 0.028 52 25.82
.+-. 0.20 3.451 .+-. 0.026 81 26.44 .+-. 0.20 3.371 .+-. 0.025 51
27.91 .+-. 0.20 3.197 .+-. 0.023 17 28.19 .+-. 0.20 3.165 .+-.
0.022 26
Form II
[0014] In another embodiment, the crystalline Compound 1 free base
comprises crystalline Form II, which is characterized by an
endothermic peak at (97.+-.2) C as measured by differential
scanning calorimetry. In another embodiment, the crystalline Form
II of the free base of crystalline Compound 1 is characterized by
the substantial absence of thermal events at temperatures below the
endothermic peak at (97.+-.2.degree. C. as measured by differential
scanning calorimetry. In another embodiment, the crystalline Form
II of the free base of crystalline Compound 1 is characterized by
an X-ray powder diffraction peak (Cu K.alpha. radiation at one or
more of 13.37.degree., 14.37.degree., 19.95.degree. or
23.92.degree.2.theta.. In another embodiment, the crystalline Form
II of the free base of crystalline Compound 1 is characterized by
an X-ray powder diffraction pattern (Cu K.alpha. radiation)
substantially similar to that of FIG. 5.
[0015] In another embodiment, the crystalline Form II of the free
base of crystalline Compound 1 is characterized by at least one
X-ray powder diffraction peak (Cu K.alpha. radiation) selected from
13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.). In another
embodiment, the crystalline Form II of the free base of crystalline
Compound 1 is characterized by at least two X-ray powder
diffraction peaks (Cu K.alpha. radiation) selected from
13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.). In another
embodiment, the crystalline Form II of the free base of crystalline
Compound 1 is characterized by at least three X-ray powder
diffraction peaks (Cu K.alpha. radiation) selected from
13.37.degree., 14.37.degree., 19.95.degree. and
23.92.degree.2.theta. (each .+-.0.2.degree.2.theta.).
[0016] In another embodiment, Form II is characterized by 1, 2, 3,
4, or more peaks as tabulated below.
TABLE-US-00002 Observed peaks for Form II, XRPD file 613881.
.degree.2.theta. d space (.ANG.) Intensity (%) 5.62 .+-. 0.20
15.735 .+-. 0.581 24 12.85 .+-. 0.20 6.888 .+-. 0.108 22 12.97 .+-.
0.20 6.826 .+-. 0.106 21 13.37 .+-. 0.20 6.622 .+-. 0.100 100 14.37
.+-. 0.20 6.162 .+-. 0.087 56 15.31 .+-. 0.20 5.788 .+-. 0.076 21
16.09 .+-. 0.20 5.507 .+-. 0.069 23 16.45 .+-. 0.20 5.390 .+-.
0.066 69 16.75 .+-. 0.20 5.294 .+-. 0.064 32 16.96 .+-. 0.20 5.227
.+-. 0.062 53 19.95 .+-. 0.20 4.450 .+-. 0.045 39 20.22 .+-. 0.20
4.391 .+-. 0.043 20 23.18 .+-. 0.20 3.837 .+-. 0.033 38 23.92 .+-.
0.20 3.721 .+-. 0.031 41 24.40 .+-. 0.20 3.648 .+-. 0.030 44 24.73
.+-. 0.20 3.600 .+-. 0.029 22 24.99 .+-. 0.20 3.564 .+-. 0.028 50
25.12 .+-. 0.20 3.545 .+-. 0.028 28 25.39 .+-. 0.20 3.509 .+-.
0.027 51 25.70 .+-. 0.20 3.466 .+-. 0.027 21 26.19 .+-. 0.20 3.403
.+-. 0.026 27 26.72 .+-. 0.20 3.336 .+-. 0.025 30 27.02 .+-. 0.20
3.300 .+-. 0.024 25 27.34 .+-. 0.20 3.262 .+-. 0.024 23 28.44 .+-.
0.20 3.138 .+-. 0.022 20
[0017] In some embodiments, the free base of crystalline Compound 1
comprises the crystalline Form II. In some preferred embodiments,
the free base of crystalline Compound 1 comprises the crystalline
Form II and less than 25 mole %, 10 mole % or 5 mole % of
crystalline Form I, crystalline Material N or amorphous forms of
Compound 1.
[0018] In a preferred embodiment, the crystalline Form II is
prepared from a slurry comprising the free base of Compound 1 in
heptane, from which the crystalline Form II is formed and filtered.
Thus, in some embodiments, the crystalline Form II comprises
residual (1-500 ppm) heptane. In another preferred embodiment, the
crystalline Form II is prepared from a slurry comprising the free
base of Compound 1 in water, from which the crystalline Form II is
formed and filtered.
[0019] There are several advantages of crystalline Form II relative
to crystalline Form I or Material N. For example, the crystalline
Form II can be prepared from a slurry comprising the free base of
Compound 1 in heptane, which is suitable for good manufacturing
practices (GMP) protocols. Further, in a most preferred embodiment,
the crystalline Form II can be prepared from a slurry comprising
the free base of Compound 1 in water or the HCl salt of Compound 1
in water, thus reducing or eliminating the need for solvent during
recrystallization. Thus, in some embodiments, crystalline Form II
of Compound 1 comprises less than 500 ppm, 100 ppm, less than 50
ppm or less than 10 ppm organic solvent. Also, Form II has less of
a propensity than Material N to agglomerate upon size reduction,
e.g., upon milling. As such, Form II has greater flowability than
Material N. Certain illustrative and non-limiting advantages of
Form II over Material N (i.e., Form N) are shown in the table
below.
TABLE-US-00003 DATA/EXPERIMENT RESULTS/STATUS Identify suitable
solvent Form N: for scale-up Limited number of suitable solvents
compared to Form II MTBE identified (suitable for GMP; Class III
solvent) Scale-up results look good Form II: More solvent options
than Form N, including H.sub.2O Current solvent is heptane
(suitable for GMP; Class III solvent) produced on 5 kg scale
Formation time faster than N (could translate to 2-3 day saving in
production time) Better recovery than N Size/Morphology of N
Acicular morphology observed for form N; material and II composed
of small and large particles Agglomerates are an issue for Form N
relative to Form II (less agglomeration seen with energy-reduced
method) PK Comparison of N and Oral administrations of GBT440 Forms
N and II to rats II resulted in comparable exposure at 100 &
500 mg/kg
Material N
[0020] In another embodiment, the crystalline Compound 1 free base
comprises crystalline Material N, which is characterized by an
endothermic peak at (95.+-.2) C as measured by differential
scanning calorimetry. The terms "Material N", "form N" and
"polymorphic form N" are used interchangeably herein. In another
embodiment, the crystalline Material N of the free base of
crystalline Compound 1 is characterized by the substantial absence
of thermal events at temperatures below the endothermic peak at
(95.+-.2.degree. C. as measured by differential scanning
calorimetry. In another embodiment, the crystalline Material N of
the free base of crystalline Compound 1 is characterized by an
X-ray powder diffraction peak (Cu K.alpha. radiation at one or more
of 11.65.degree., 11.85.degree., 12.08.degree., 16.70.degree.,
19.65.degree. or 23.48.degree.2.theta.. In another embodiment, the
crystalline Material N of the free base of crystalline Compound 1
is characterized by an X-ray powder diffraction pattern (Cu
K.alpha. radiation) substantially similar to that of FIG. 7.
[0021] In another embodiment, the crystalline Material N of the
free base of crystalline Compound 1 is characterized by at least
one X-ray powder diffraction peak (Cu K.alpha. radiation) selected
from 11.65.degree., 11.85.degree., 12.08.degree., 16.70.degree.,
19.65.degree. and 23.48.degree.2.theta. (each
.+-.0.2.degree.2.theta.). In another embodiment, the crystalline
Material N of the free base of crystalline Compound 1 is
characterized by at least two X-ray powder diffraction peaks (Cu
K.alpha. radiation) selected from 11.65.degree., 11.85.degree.,
12.08.degree., 16.70.degree., 19.65.degree. and
23.48.degree.2.theta. (each .+-.0.2.degree.2.theta.). In another
embodiment, the crystalline Material N of the free base of
crystalline Compound 1 is characterized by at least three X-ray
powder diffraction peaks (Cu K.alpha. radiation) selected from
11.65.degree., 11.85.degree., 12.08.degree., 16.70.degree.,
19.65.degree. and 23.48.degree.2.theta. (each
.+-.0.2.degree.2.theta.).
[0022] In another embodiment, Material N is characterized by 1, 2,
3, 4, or more peaks as tabulated below.
TABLE-US-00004 Observed peaks for Material N, XRPD file 615765.
.degree.2.theta. d space (.ANG.) Intensity (%) 5.55 .+-. 0.20
15.924 .+-. 0.595 54 11.65 .+-. 0.20 7.597 .+-. 0.132 31 11.85 .+-.
0.20 7.468 .+-. 0.128 50 12.08 .+-. 0.20 7.324 .+-. 0.123 31 12.67
.+-. 0.20 6.987 .+-. 0.112 29 13.12 .+-. 0.20 6.748 .+-. 0.104 83
14.94 .+-. 0.20 5.929 .+-. 0.080 34 15.19 .+-. 0.20 5.832 .+-.
0.077 56 15.76 .+-. 0.20 5.623 .+-. 0.072 20 16.70 .+-. 0.20 5.310
.+-. 0.064 100 17.35 .+-. 0.20 5.112 .+-. 0.059 52 19.65 .+-. 0.20
4.517 .+-. 0.046 60 23.48 .+-. 0.20 3.789 .+-. 0.032 72 23.68 .+-.
0.20 3.757 .+-. 0.032 29 25.25 .+-. 0.20 3.527 .+-. 0.028 20 25.47
.+-. 0.20 3.497 .+-. 0.027 20 25.70 .+-. 0.20 3.466 .+-. 0.027 85
26.04 .+-. 0.20 3.422 .+-. 0.026 35 26.37 .+-. 0.20 3.380 .+-.
0.025 55
[0023] In some embodiments, the free base of crystalline Compound 1
comprises the crystalline Material N and less than 25 mole %, 10
mole % or 5 mole % of crystalline Forms I or II or amorphous forms
of Compound 1.
[0024] In another embodiment, the crystalline Material N is
prepared from a slurry comprising the free base of Compound 1 in
methyl tertiary butyl ether (MTBE), from which the
crystalline-Material N is formed and filtered. Thus, in some
embodiments, the crystalline Material N comprises residual (1-500
ppm) MTBE.
[0025] There are several advantages of crystalline Material N
relative to crystalline Forms I or II. For example, the crystalline
Material N can be prepared from a slurry comprising the free base
of Compound 1 in MTBE, which is suitable for good manufacturing
practices (GMP) protocols.
[0026] In some embodiments, the crystalline ansolvate forms are
stable to contact with water, heptane, iso propyl ether (IPE),
MTBE, and toluene, and such other solvents.
[0027] In another of its composition embodiments, this invention
provides for a pharmaceutical composition comprising a
pharmaceutically acceptable excipient and a crystalline Compound 1
free base, comprising one or more of Form I, Form II or Material
N.
[0028] In one of its method embodiments, this invention provides a
method of preparing the solid crystalline free base of Compound 1
comprising, e.g., Form I, Form II and/or Material N.
[0029] In yet another of its method embodiments, there are provided
methods for increasing oxygen affinity of hemoglobin S in a
subject, the method comprising administering to a subject in need
thereof a therapeutically effective amount of a crystalline free
base of Compound 1, comprising, e.g., Form I, Form II and/or
Material N.
[0030] In yet another of its method embodiments, there are provided
methods for treating oxygen deficiency associated with sickle cell
anemia in a subject, the method comprising administering to a
subject in need thereof a therapeutically effective amount of a
crystalline free base of Compound 1, comprising, e.g., Form I, Form
II and/or Material N.
[0031] In all of such treatments, the effective amount of free base
of Compound 1, comprising e.g., Form I, Form II and/or Material N
to the treated patient is already disclosed in the art.
Solvates
[0032] This invention arises in part out of the discovery that
ansolvate polymorphs of the free base of Compound 1 form solvate
polymorphs with a variety of solvents, preferably other than
certain hydrocarbon solvents, water and ethers.
[0033] Solvates of the crystalline free base of Compound 1 (e.g.,
from acetone, acetonitrile, dichloromethane, dioxane, ethanol,
ethyl acetate, isopropyl alcohol, methyl ethyl ketone (MEK) and
tetrahydrofuran) are also contemplated to be used e.g., as
intermediates to regenerate the free base crystalline ansolvate of
Compound 1. Such methods can include, without limitation,
subjecting the solvate to vacuum conditions; and/or generating a
salt and disproportionating it in water to form the ansolvate;
and/or slurrying or washing the solvate with a solvent less prone
to solvate formation such as heptane, di-isopropyl ether (IPE),
tert-methyl butyl ether (MTBE) and toluene.
[0034] In another of its composition embodiments, this invention
provides for a pharmaceutical composition comprising a
pharmaceutically acceptable excipient and one or more of the
solvated crystal forms provided herein.
[0035] In one of its method embodiments, this invention provides a
method of preparing the solvated crystal forms provided herein.
[0036] In yet another of its method embodiments, there are provided
methods for increasing oxygen affinity of hemoglobin S in a
subject, the method comprising administering to a subject in need
thereof a therapeutically effective amount of one or more of the
solvated crystal forms provided herein.
[0037] In yet another of its method embodiments, there are provided
methods for treating oxygen deficiency associated with sickle cell
anemia in a subject, the method comprising administering to a
subject in need thereof a therapeutically effective amount of one
or more of the solvated crystal forms provided herein.
[0038] In all of such treatments, the effective amount of the free
base of Compound 1, to the treated patient is already disclosed in
the art.
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] FIG. 1 is a XRPD profile of the crystalline HCl salt before
(top) and after (bottom) 5 minutes slurried in water.
[0040] FIG. 2 is a XRPD profile of the free base Form I (top), Form
II (middle), and Material N (bottom).
[0041] FIG. 3 is a XRPD profile and contemplated indexing for free
base Form I.
[0042] FIG. 4 is a thermal characterization for free base Form
I.
[0043] FIG. 5 is a XRPD profile and contemplated indexing for free
base Form II.
[0044] FIG. 6 is a thermal characterization for free base Form
II.
[0045] FIG. 7 is a XRPD profile for free base Material N.
[0046] FIG. 8 is a thermal characterization for free base Material
N.
[0047] FIG. 9 depicts an Energy-Temperature Diagram between the
Free Base Forms I, II, and Material N. The enthalpy (H) and free
energy (G) isobars for each form are depicted as a function of
temperature. .DELTA.H.sub.f is the heat of fusion; T is transition
temperature; m is melt temperature; superscripts I, II, and N refer
to the polymorphs. *Under the test conditions, not enough
information was available to graphically represent the free energy
isobar of Form I below 6.degree. C. and above the estimated
transition temperature T.sup.N-II; the isobar likely intersects
G.sub.L at a temperature below m.sup.II, allowing the possibility
that Form I may be enantiotropic with Form II (where T.sup.I-II
occurs below 6.degree. C.) and/or Material N (where either
T.sup.I-N occurs below T.sup.I-II or T.sup.N-I occurs above
T.sup.N-II, but not both). Free energy isobars can only intersect
each other once.
[0048] FIG. 10 depicts .sup.13C Solid State NMR spectra for Free
Base Forms I (bottom), II (middle), and Material N (top). Form I
contains one molecule per asymmetric unit. Material N contains four
molecules per asymmetric unit. As observed by .sup.13C Solid State
NMR spectra, Forms II and N did not undergo a transition over 250 K
to 340 K. Chemical shifts change slightly with temperature (not
illustrated graphically).
[0049] FIG. 11 depicts .sup.15N Solid State NMR spectra for Free
Base Forms I (bottom), II (middle), and Material N (top).
[0050] FIG. 12 depicts a differential scanning calorimetry (DSC)
curve for Free Base Material N.
[0051] FIG. 13 depicts a DSC curve for Free Base Form II.
[0052] FIG. 14 depicts a DSC curve for Free Base Form I.
[0053] FIG. 15 depicts a XRPD profile of maturation experiments for
the free base of Compound 1 at multiple temperatures.
[0054] FIG. 16 depicts a contemplated XRPD profile for solvated
Material E.
[0055] FIG. 17 depicts a contemplated XRPD profile for solvated
Material F.
[0056] FIG. 18 depicts a contemplated XRPD profile for solvated
Material G.
[0057] FIG. 19 depicts a contemplated XRPD profile for solvated
Material H.
[0058] FIG. 20 depicts a contemplated XRPD profile for solvated
Material J.
[0059] FIG. 21 depicts a contemplated XRPD profile for solvated
Material K.
[0060] FIG. 22 depicts a contemplated XRPD profile for solvated
Material L.
[0061] FIG. 23 depicts a contemplated XRPD profile for solvated
Material M.
[0062] FIG. 24 depicts a contemplated XRPD profile for solvated
Material O.
[0063] FIG. 25 depicts an XRPD profile comparison of contemplated
isostructural solvates of the free base of Compound 1. From top to
bottom: Material E from acetone; Material F from ACN; Material G
from DCM; Material H from dioxane; Material J from EtOH; Material K
from IPA/water (also obtained from IPA); and Material L from THF,
Material M from MEK.
DETAILED DESCRIPTION
[0064] As noted above, this invention is directed, in part, to a
stable free base of Compound 1 and, in particular, the free base
Form I, Form II or Material N. However, prior to discussing this
invention in further detail, the following terms will be
defined.
DEFINITIONS
[0065] As used herein, the following terms have the following
meanings.
[0066] The singular forms "a," "an," and "the" and the like include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a compound" includes both a single
compound and a plurality of different compounds.
[0067] The term "about" when used before a numerical designation,
e.g., temperature, time, amount, and concentration, including a
range, indicates approximations which may vary by .+-.10%, .+-.5%
or .+-.1%.
[0068] "Administration" refers to introducing an agent into a
patient. A therapeutic amount can be administered, which can be
determined by the treating physician or the like. An oral route of
administration is preferred. The related terms and phrases
administering" and "administration of", when used in connection
with a compound or pharmaceutical composition (and grammatical
equivalents) refer both to direct administration, which may be
administration to a patient by a medical professional or by
self-administration by the patient, and/or to indirect
administration, which may be the act of prescribing a drug. For
example, a physician who instructs a patient to self-administer a
drug and/or provides a patient with a prescription for a drug is
administering the drug to the patient. In any event, administration
entails delivery to the patient of the drug.
[0069] The "crystalline ansolvate" of Compound 1 is a crystalline
solid form of the free base of
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzald-
ehyde, such as, e.g., crystalline Form I, Form II or Material N as
disclosed herein. Each of the Form I, Form II or Material N crystal
lattices is substantially free of solvents of crystallization.
However, any solvent present is not included in the crystal lattice
and is randomly distributed outside the crystal lattice. Therefore,
Form I, Form II or Material N crystals in bulk may contain, outside
the crystal lattice, small amounts of one or more solvents, such as
the solvents used in its synthesis or crystallization. As used
above, "substantially free of" and "small amounts," refers to the
presence of solvents preferably less that 10,000 parts per million
(ppm), or more preferably, less than 500 ppm.
[0070] The "crystalline solvate" of Compound 1 is a crystalline
solid form of the free base of
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzald-
ehyde, where the crystal lattices comprises one or more solvents of
crystallization.
[0071] "Characterization" refers to obtaining data which may be
used to identify a solid form of a compound, for example, to
identify whether the solid form is amorphous or crystalline and
whether it is unsolvated or solvated. The process by which solid
forms are characterized involves analyzing data collected on the
polymorphic forms so as to allow one of ordinary skill in the art
to distinguish one solid form from other solid forms containing the
same material. Chemical identity of solid forms can often be
determined with solution-state techniques such as .sup.13C NMR or
.sup.1H NMR. While these may help identify a material, and a
solvent molecule for a solvate, such solution-state techniques
themselves may not provide information about the solid state. There
are, however, solid-state analytical techniques that can be used to
provide information about solid-state structure and differentiate
among polymorphic solid forms, such as single crystal X-ray
diffraction, X-ray powder diffraction (XRPD), solid state nuclear
magnetic resonance (SS-NMR), and infrared and Raman spectroscopy,
and thermal techniques such as differential scanning calorimetry
(DSC), Solid state .sup.13C-NMR, thermogravimetry (TG), melting
point, and hot stage microscopy.
[0072] To "characterize" a solid form of a compound, one may, for
example, collect XRPD data on solid forms of the compound and
compare the XRPD peaks of the forms. For example, when only three
solid forms, e.g., Forms I and II and Material N, are compared and
the Form I pattern shows a peak at an angle where no peaks appear
in the Form II or Material N pattern, then that peak, for that
compound, distinguishes Form I from Form II and Material N and
further acts to characterize Form I. The collection of peaks which
distinguish e.g., Form I from the other known forms is a collection
of peaks which may be used to characterize Form I. Those of
ordinary skill in the art will recognize that there are often
multiple ways, including multiple ways using the same analytical
technique, to characterize solid forms. Additional peaks could also
be used, but are not necessary, to characterize the form up to and
including an entire diffraction pattern. Although all the peaks
within an entire XRPD pattern may be used to characterize such a
form, a subset of that data may, and typically is, used to
characterize the form.
[0073] An XRPD pattern is an x-y graph with diffraction angle
(typically .degree.2.theta.) on the x-axis and intensity on the
y-axis. The peaks within this pattern may be used to characterize a
crystalline solid form. As with any data measurement, there is
variability in XRPD data. The data are often represented solely by
the diffraction angle of the peaks rather than including the
intensity of the peaks because peak intensity can be particularly
sensitive to sample preparation (for example, particle size,
moisture content, solvent content, and preferred orientation
effects influence the sensitivity), so samples of the same material
prepared under different conditions may yield slightly different
patterns; this variability is usually greater than the variability
in diffraction angles. Diffraction angle variability may also be
sensitive to sample preparation. Other sources of variability come
from instrument parameters and processing of the raw X-ray data:
different X-ray instruments operate using different parameters and
these may lead to slightly different XRPD patterns from the same
solid form, and similarly different software packages process X-ray
data differently and this also leads to variability. These and
other sources of variability are known to those of ordinary skill
in the pharmaceutical arts. Due to such sources of variability, it
is usual to assign a variability of .+-.0.2.degree.2.theta. to
diffraction angles in XRPD patterns.
[0074] "Comprising" or "comprises" is intended to mean that the
compositions and methods include the recited elements, but not
exclude others. "Consisting essentially of" when used to define
compositions and methods, shall mean excluding other elements of
any essential significance to the combination for the stated
purpose. Thus, a composition consisting essentially of the elements
as defined herein would not exclude other materials or steps that
do not materially affect the basic and novel characteristic(s) of
the claimed invention. "Consisting of" shall mean excluding more
than trace elements of other ingredients and substantial method
steps. Embodiments defined by each of these transition terms are
within the scope of this invention.
[0075] Form II and Material N are enantiotropic at a transition
temperature (of approximately 42.degree. C.). Below this transition
temperature, Material N of the free base of Compound 1 is the
thermodynamically more stable form relative to Forms I and II.
Above this transition temperature, Form II of the free base of
Compound 1 is the thermodynamically more stable form relative to
Form I and Material N.
[0076] "Room temperature" refers to (22.+-.5).degree. C.
[0077] "Therapeutically effective amount" or "therapeutic amount"
refers to an amount of a drug or an agent that when administered to
a patient suffering from a condition, will have the intended
therapeutic effect, e.g., alleviation, amelioration, palliation or
elimination of one or more manifestations of the condition in the
patient. The therapeutically effective amount will vary depending
upon the subject and the condition being treated, the weight and
age of the subject, the severity of the condition, the particular
composition or excipient chosen, the dosing regimen to be followed,
timing of administration, the manner of administration and the
like, all of which can be determined readily by one of ordinary
skill in the art. The full therapeutic effect does not necessarily
occur by administration of one dose, and may occur only after
administration of a series of doses. Thus, a therapeutically
effective amount may be administered in one or more
administrations. For example, and without limitation, a
therapeutically effective amount of an agent, in the context of
treating disorders related to hemoglobin S, refers to an amount of
the agent that alleviates, ameliorates, palliates, or eliminates
one or more manifestations of the disorders related to hemoglobin S
in the patient.
[0078] "Treatment", "treating", and "treat" are defined as acting
upon a disease, disorder, or condition with an agent to reduce or
ameliorate the harmful or any other undesired effects of the
disease, disorder, or condition and/or its symptoms. Treatment, as
used herein, covers the treatment of a human patient, and includes:
(a) reducing the risk of occurrence of the condition in a patient
determined to be predisposed to the disease but not yet diagnosed
as having the condition, (b) impeding the development of the
condition, and/or (c) relieving the condition, i.e., causing
regression of the condition and/or relieving one or more symptoms
of the condition. For purposes of this invention, beneficial or
desired clinical results include, but are not limited to,
multilineage hematologic improvement, decrease in the number of
required blood transfusions, decrease in infections, decreased
bleeding, and the like.
Identifying Forms I, II and Material N
[0079] When the HCl salt of Compound 1 was subjected to various
stress conditions, disproportionation of the HCl salt in water was
observed to generate the free base. At least three anhydrous
crystalline forms of the free base were identified, termed Free
Base Forms I, II, and Material N. It was discovered that nucleation
of Free Base Form I generally occurs first and that extending the
slurry time induces the transformation of Free Base Form I to Free
Base Form II, a more thermodynamically stable phase relative to
Form I. It was further discovered that Free Base Material N appears
to be most stable form, relative to Forms I and II, at room
temperature. Free Base Material N was found to be enantiotropically
active relative to Form II, and will transform reversibly at a
specific transition temperature (estimated herein near 42.degree.
C.). Above the transition temperature, Free Base Form II appears to
be the most stable form, relative to Form I and Material N.
[0080] Based in part on solid-state nuclear magnetic resonance
data, all three forms are crystalline and are distinct polymorphic
forms. See FIGS. 10 and 11. Form I contains one molecule per
asymmetric unit, Form II contains two molecules per asymmetric unit
and Form N contains four molecules per asymmetric unit. See the
.sup.15N spectra in FIG. 11.
Ansolvates of Forms I, II and Material N
[0081] In one embodiment, this invention provides the free base
crystalline ansolvate of Compound 1. The free base crystalline
ansolvate of Compound 1 may include one or more of Form I, Form II
and/or Material N polymorphs. In some embodiments, the free base
crystalline ansolvate of Compound 1 may include the Form II
polymorph. Preferably, the free base crystalline ansolvate of
Compound 1 may include Form II and/or Material N polymorphs. More
preferably, the free base crystalline ansolvate of Compound 1 may
include the Material N polymorph. Yet more preferably, the free
base crystalline ansolvate of Compound 1 is substantially free of a
solvated polymorph of Compound 1 free base. Further yet more
preferably, the free base crystalline ansolvate of Compound 1 is
substantially free of other ansolavte polymorphs of Compound 1 free
base. "Substantially free" of a component as used herein refers to
contain up to about 5%, more preferably about 3%, and still more
preferably about 1% of that component. As used herein, solvate
includes a hydrate form as well.
Solvates of Compound 1
[0082] In one aspect, provided is a crystalline solvate of Compound
1:
##STR00002##
[0083] In some embodiments, the crystalline solvate is
substantially free of an ansolvated polymorph of Compound 1.
[0084] Many of the solubility and screen experiments with the free
base of Compound 1 resulted in precipitation of solids
characterized as solvate formation with some solvents. Under the
conditions, solvates were not observed from the free base of
Compound 1 with four solvents, including heptane, di-isopropyl
ether (IPE), tert-methyl butyl ether (MTBE) and toluene. Solvates
were observed from the free base of Compound 1 in nine solvents
including acetone (Material E), acetonitrile (Material F),
dichloromethane (Material G), dioxane (Material H), ethanol
(Material J), isopropyl alcohol or a mixture of water and isopropyl
alcohol (Material K), tetrahydrofuran (Material L), methyl ethyl
ketone "MEK" (Material M), ethyl acetate (Material O) and dimethyl
sulfoxide "DMSO" (Material P). The majority of the solvates (i.e.,
Materials E-H, J-M, O and P are contemplated to be isostructural.
In some embodiments, the crystalline solvate includes one or more
of Material E, Material F, Material G, Material H, Material J,
Material K, Material L, Material M, Material O or Material P.
[0085] Material E can be characterized by at least one X-ray powder
diffraction peak (Cu K.alpha. radiation) selected from 8.69, 11.73,
12.10, 15.26, 16.11, 17.45, 22.39, 22.55 and 23.70.+-.0.20.
Material F can be characterized by at least one X-ray powder
diffraction peak (Cu K.alpha. radiation) selected from 8.47, 8.81,
12.75, 13.17, 14.92, 15.63, 17.01 23.73, and 24.07.+-.0.20.
Material G can be characterized by at least one X-ray powder
diffraction peak (Cu K.alpha. radiation) selected from 8.47, 11.45,
12.62, 14.66, 15.69, 17.01, 18.47, 20.32, 22.61, 23.08, 23.43 and
23.70.+-.0.20. Material H can be characterized by at least one
X-ray powder diffraction peak (Cu K.alpha. radiation) selected from
8.61, 11.67, 15.33, 16.28, 17.28, 22.58, 23.51 and 25.77.+-.0.20.
Material J can be characterized by at least one X-ray powder
diffraction peak (Cu K.alpha. radiation) selected from 8.52, 8.88,
12.79, 15.04, 15.61, 17.11, 22.81, 23.87, 24.17, 24.62 and
26.44.+-.0.20. Material K can be characterized by at least one
X-ray powder diffraction peak (Cu K.alpha. radiation) selected from
8.52; 8.83, 11.35, 15.04, 15.74, 17.11, 23.46, 23.58, 24.08 and
25.99.+-.0.20. Material L can be characterized by at least one
X-ray powder diffraction peak (Cu K.alpha. radiation) selected from
8.61, 8.78, 11.67, 14.94, 15.28, 16.14, 17.30, 22.75, 23.71 and
26.05.+-.0.20; and Material M can be characterized by at least one
X-ray powder diffraction peak (Cu K.alpha. radiation) selected from
7.74, 10.05, 12.82, 15.33, 16.80, 20.82, 21.14, 25.80 and
26.97.+-.0.20.
[0086] The solvates (such as, of acetone, acetonitrile,
dichloromethane, dioxane, ethanol, ethyl acetate, isopropyl
alcohol, MEK, tetrahydrofuran or DMSO) could be used e.g., as
intermediates to regenerate the free base crystalline ansolvate of
Compound 1 by several methods including subjecting the solvate to
vacuum conditions; and/or regenerating the HCl salt and
disproportionating HCl; and/or washing the solvate with a solvent
less prone to solvate formation such as heptane, di-isopropyl ether
(IPE), tert-methyl butyl ether (MTBE) and toluene.
TABLE-US-00005 TABLE 1 Data Related to Solvates of the Free Base of
Compound 1 Estimated Volume Crystallization Volume Number of
Formula per Formula Unit* Indexing Identifier Solvent
(.ANG..sup.3/Cell) Units per Cell (.ANG..sup.3) Result Material E
acetone 968 2 484 FIG 1 Material F ACN 947 2 473 FIG 2 Material G
DCM 959 2 480 FIG 3 Material H dioxane 977 2 488 FIG 4 Material J
EtOH 943 2 472 FIG 5 Material K IPA 963 2 481 FIG 6 Material L THF
972 2 486 FIG 7 Material M MEK 3956 8 494 FIG 8 Material O EtOAc --
-- -- FIG 9 Material DMSO -- -- -- -- P** *The value is obtained by
dividing the volume of the cell, derived from the tentative
indexing solution, by the number of formula units within the cell.
**Material P was observed as a mixture with a "sulfate form I".
[0087] Certain contemplated peaks of the various solvates provided
herein are tabulated below. Certain peaks, which are preferably
non-overlapping, low-angle peaks, with strong intensity, were not
identified. The peaks were determined to the extent that the state
of preferred orientation in the samples were unknown.
TABLE-US-00006 TABLE 2 Observed peaks for Material E.
.degree.2.theta. d space (.ANG.) Intensity (%) 8.41 .+-. 0.20
10.517 .+-. 0.256 13 8.69 .+-. 0.20 10.174 .+-. 0.239 100 11.73
.+-. 0.20 7.543 .+-. 0.130 17 12.10 .+-. 0.20 7.314 .+-. 0.122 20
13.00 .+-. 0.20 6.809 .+-. 0.106 15 14.02 .+-. 0.20 6.316 .+-.
0.091 5 14.77 .+-. 0.20 5.996 .+-. 0.082 16 15.26 .+-. 0.20 5.807
.+-. 0.077 34 15.81 .+-. 0.20 5.605 .+-. 0.071 7 16.11 .+-. 0.20
5.501 .+-. 0.069 20 16.48 .+-. 0.20 5.379 .+-. 0.066 11 16.65 .+-.
0.20 5.326 .+-. 0.064 11 16.88 .+-. 0.20 5.253 .+-. 0.063 3 17.26
.+-. 0.20 5.136 .+-. 0.060 9 17.45 .+-. 0.20 5.083 .+-. 0.058 32
20.02 .+-. 0.20 4.435 .+-. 0.044 2 20.92 .+-. 0.20 4.246 .+-. 0.041
13 21.91 .+-. 0.20 4.057 .+-. 0.037 20 22.39 .+-. 0.20 3.970 .+-.
0.035 49 22.55 .+-. 0.20 3.944 .+-. 0.035 37 22.81 .+-. 0.20 3.898
.+-. 0.034 16 23.36 .+-. 0.20 3.807 .+-. 0.032 12 23.70 .+-. 0.20
3.755 .+-. 0.032 61 24.37 .+-. 0.20 3.653 .+-. 0.030 12 24.85 .+-.
0.20 3.583 .+-. 0.029 5 25.42 .+-. 0.20 3.504 .+-. 0.027 2 25.89
.+-. 0.20 3.442 .+-. 0.026 8 26.19 .+-. 0.20 3.403 .+-. 0.026 40
26.97 .+-. 0.20 3.306 .+-. 0.024 3 27.61 .+-. 0.20 3.231 .+-. 0.023
16 28.24 .+-. 0.20 3.160 .+-. 0.022 2 28.48 .+-. 0.20 3.134 .+-.
0.022 5 28.69 .+-. 0.20 3.111 .+-. 0.021 7 29.83 .+-. 0.20 2.995
.+-. 0.020 4
TABLE-US-00007 TABLE 3 Observed peaks for Material F.
.degree.2.theta. d space (.ANG.) Intensity (%) 8.47 .+-. 0.20
10.434 .+-. 0.252 100 8.81 .+-. 0.20 10.039 .+-. 0.233 49 11.42
.+-. 0.20 7.752 .+-. 0.138 15 12.75 .+-. 0.20 6.942 .+-. 0.110 27
13.17 .+-. 0.20 6.723 .+-. 0.103 21 13.87 .+-. 0.20 6.384 .+-.
0.093 7 14.61 .+-. 0.20 6.064 .+-. 0.084 13 14.92 .+-. 0.20 5.936
.+-. 0.080 43 15.51 .+-. 0.20 5.713 .+-. 0.074 24 15.63 .+-. 0.20
5.671 .+-. 0.073 43 15.96 .+-. 0.20 5.553 .+-. 0.070 15 17.01 .+-.
0.20 5.212 .+-. 0.062 31 17.26 .+-. 0.20 5.136 .+-. 0.060 4 17.70
.+-. 0.20 5.011 .+-. 0.057 9 18.17 .+-. 0.20 4.883 .+-. 0.054 4
18.79 .+-. 0.20 4.724 .+-. 0.050 10 19.35 .+-. 0.20 4.587 .+-.
0.047 4 19.49 .+-. 0.20 4.555 .+-. 0.047 3 20.02 .+-. 0.20 4.435
.+-. 0.044 4 20.29 .+-. 0.20 4.377 .+-. 0.043 9 21.06 .+-. 0.20
4.219 .+-. 0.040 11 21.33 .+-. 0.20 4.167 .+-. 0.039 4 22.71 .+-.
0.20 3.915 .+-. 0.034 27 23.11 .+-. 0.20 3.848 .+-. 0.033 15 23.73
.+-. 0.20 3.749 .+-. 0.031 42 24.07 .+-. 0.20 3.698 .+-. 0.031 59
24.65 .+-. 0.20 3.612 .+-. 0.029 87 24.95 .+-. 0.20 3.569 .+-.
0.028 6 25.20 .+-. 0.20 3.534 .+-. 0.028 5 25.69 .+-. 0.20 3.468
.+-. 0.027 15 26.52 .+-. 0.20 3.361 .+-. 0.025 61 26.79 .+-. 0.20
3.328 .+-. 0.025 10 27.02 .+-. 0.20 3.300 .+-. 0.024 9
TABLE-US-00008 TABLE 4 Observed peaks for Material G.
.degree.2.theta. d space (.ANG.) Intensity (%) 8.47 .+-. 0.20
10.434 .+-. 0.252 45 8.76 .+-. 0.20 10.096 .+-. 0.235 12 11.45 .+-.
0.20 7.729 .+-. 0.137 76 12.62 .+-. 0.20 7.015 .+-. 0.113 36 13.09
.+-. 0.20 6.765 .+-. 0.105 10 13.87 .+-. 0.20 6.384 .+-. 0.093 5
14.66 .+-. 0.20 6.044 .+-. 0.083 39 14.92 .+-. 0.20 5.936 .+-.
0.080 26 15.33 .+-. 0.20 5.782 .+-. 0.076 7 15.69 .+-. 0.20 5.647
.+-. 0.072 88 16.01 .+-. 0.20 5.536 .+-. 0.070 8 16.76 .+-. 0.20
5.289 .+-. 0.063 15 17.01 .+-. 0.20 5.212 .+-. 0.062 29 17.50 .+-.
0.20 5.068 .+-. 0.058 5 17.60 .+-. 0.20 5.040 .+-. 0.057 4 18.13
.+-. 0.20 4.892 .+-. 0.054 5 18.47 .+-. 0.20 4.804 .+-. 0.052 21
19.55 .+-. 0.20 4.540 .+-. 0.046 4 20.01 .+-. 0.20 4.439 .+-. 0.044
5 20.32 .+-. 0.20 4.370 .+-. 0.043 20 21.11 .+-. 0.20 4.209 .+-.
0.040 15 22.61 .+-. 0.20 3.932 .+-. 0.035 42 22.88 .+-. 0.20 3.887
.+-. 0.034 9 23.08 .+-. 0.20 3.854 .+-. 0.033 28 23.43 .+-. 0.20
3.797 .+-. 0.032 56 23.70 .+-. 0.20 3.755 .+-. 0.032 48 24.12 .+-.
0.20 3.690 .+-. 0.030 13 24.42 .+-. 0.20 3.646 .+-. 0.030 100 25.05
.+-. 0.20 3.555 .+-. 0.028 7 25.40 .+-. 0.20 3.506 .+-. 0.027 26
26.36 .+-. 0.20 3.382 .+-. 0.025 50 26.57 .+-. 0.20 3.355 .+-.
0.025 7 26.82 .+-. 0.20 3.324 .+-. 0.025 27 27.07 .+-. 0.20 3.294
.+-. 0.024 10
TABLE-US-00009 TABLE 5 Observed peaks for Material H.
.degree.2.theta. d space (.ANG.) Intensity (%) 8.61 .+-. 0.20
10.273 .+-. 0.244 48 8.81 .+-. 0.20 10.039 .+-. 0.233 20 11.67 .+-.
0.20 7.586 .+-. 0.132 32 12.10 .+-. 0.20 7.314 .+-. 0.122 11 12.79
.+-. 0.20 6.924 .+-. 0.110 9 14.56 .+-. 0.20 6.085 .+-. 0.084 4
14.87 .+-. 0.20 5.956 .+-. 0.081 22 15.33 .+-. 0.20 5.782 .+-.
0.076 42 15.76 .+-. 0.20 5.623 .+-. 0.072 18 16.28 .+-. 0.20 5.445
.+-. 0.067 51 16.73 .+-. 0.20 5.299 .+-. 0.064 9 17.28 .+-. 0.20
5.132 .+-. 0.060 61 17.68 .+-. 0.20 5.016 .+-. 0.057 3 20.47 .+-.
0.20 4.338 .+-. 0.042 12 21.38 .+-. 0.20 4.157 .+-. 0.039 7 21.83
.+-. 0.20 4.072 .+-. 0.037 4 22.23 .+-. 0.20 3.999 .+-. 0.036 9
22.58 .+-. 0.20 3.938 .+-. 0.035 100 22.95 .+-. 0.20 3.876 .+-.
0.034 6 23.11 .+-. 0.20 3.848 .+-. 0.033 14 23.51 .+-. 0.20 3.783
.+-. 0.032 88 24.37 .+-. 0.20 3.653 .+-. 0.030 13 24.65 .+-. 0.20
3.612 .+-. 0.029 10 25.77 .+-. 0.20 3.457 .+-. 0.027 41 26.67 .+-.
0.20 3.342 .+-. 0.025 7 26.97 .+-. 0.20 3.306 .+-. 0.024 5 27.66
.+-. 0.20 3.225 .+-. 0.023 3 28.11 .+-. 0.20 3.174 .+-. 0.022 4
28.61 .+-. 0.20 3.120 .+-. 0.022 6 28.96 .+-. 0.20 3.083 .+-. 0.021
4 29.23 .+-. 0.20 3.055 .+-. 0.021 3 29.63 .+-. 0.20 3.015 .+-.
0.020 3
TABLE-US-00010 TABLE 6 Observed peaks for Material J.
.degree.2.theta. d space (.ANG.) Intensity (%) 8.52 .+-. 0.20
10.373 .+-. 0.249 100 8.88 .+-. 0.20 9.964 .+-. 0.229 39 11.33 .+-.
0.20 7.809 .+-. 0.140 22 12.79 .+-. 0.20 6.924 .+-. 0.110 25 13.12
.+-. 0.20 6.748 .+-. 0.104 24 13.94 .+-. 0.20 6.354 .+-. 0.092 4
14.47 .+-. 0.20 6.120 .+-. 0.085 14 15.04 .+-. 0.20 5.890 .+-.
0.079 42 15.61 .+-. 0.20 5.677 .+-. 0.073 56 15.84 .+-. 0.20 5.594
.+-. 0.071 16 17.11 .+-. 0.20 5.181 .+-. 0.061 33 17.40 .+-. 0.20
5.097 .+-. 0.059 4 17.82 .+-. 0.20 4.979 .+-. 0.056 8 18.12 .+-.
0.20 4.897 .+-. 0.054 3 18.90 .+-. 0.20 4.695 .+-. 0.050 11 19.39
.+-. 0.20 4.579 .+-. 0.047 5 19.62 .+-. 0.20 4.525 .+-. 0.046 4
20.16 .+-. 0.20 4.406 .+-. 0.044 8 20.96 .+-. 0.20 4.239 .+-. 0.040
12 22.81 .+-. 0.20 3.898 .+-. 0.034 27 23.15 .+-. 0.20 3.843 .+-.
0.033 9 23.28 .+-. 0.20 3.821 .+-. 0.033 7 23.87 .+-. 0.20 3.729
.+-. 0.031 34 24.17 .+-. 0.20 3.683 .+-. 0.030 52 24.62 .+-. 0.20
3.616 .+-. 0.029 95 25.20 .+-. 0.20 3.534 .+-. 0.028 5 25.77 .+-.
0.20 3.457 .+-. 0.027 13 26.44 .+-. 0.20 3.371 .+-. 0.025 70 26.71
.+-. 0.20 3.338 .+-. 0.025 10 27.21 .+-. 0.20 3.278 .+-. 0.024
7
TABLE-US-00011 TABLE 7 Observed peaks for GBT000440, Material K.
.degree.2.theta. d space (.ANG.) Intensity (%) 8.52 .+-. 0.20
10.373 .+-. 0.249 75 8.83 .+-. 0.20 10.020 .+-. 0.232 33 11.35 .+-.
0.20 7.797 .+-. 0.139 29 12.52 .+-. 0.20 7.071 .+-. 0.114 21 12.90
.+-. 0.20 6.861 .+-. 0.108 24 13.92 .+-. 0.20 6.361 .+-. 0.092 4
14.49 .+-. 0.20 6.113 .+-. 0.085 18 15.04 .+-. 0.20 5.890 .+-.
0.079 41 15.34 .+-. 0.20 5.775 .+-. 0.076 17 15.74 .+-. 0.20 5.629
.+-. 0.072 57 15.93 .+-. 0.20 5.564 .+-. 0.070 13 16.61 .+-. 0.20
5.336 .+-. 0.065 7 17.11 .+-. 0.20 5.181 .+-. 0.061 33 17.70 .+-.
0.20 5.011 .+-. 0.057 7 18.00 .+-. 0.20 4.928 .+-. 0.055 4 18.38
.+-. 0.20 4.826 .+-. 0.053 13 19.04 .+-. 0.20 4.662 .+-. 0.049 4
19.74 .+-. 0.20 4.498 .+-. 0.046 5 20.21 .+-. 0.20 4.395 .+-. 0.043
11 20.99 .+-. 0.20 4.232 .+-. 0.040 12 22.70 .+-. 0.20 3.918 .+-.
0.034 22 22.90 .+-. 0.20 3.884 .+-. 0.034 17 23.46 .+-. 0.20 3.791
.+-. 0.032 45 23.58 .+-. 0.20 3.773 .+-. 0.032 70 24.08 .+-. 0.20
3.695 .+-. 0.030 100 24.75 .+-. 0.20 3.597 .+-. 0.029 6 25.19 .+-.
0.20 3.536 .+-. 0.028 21 25.99 .+-. 0.20 3.429 .+-. 0.026 71 26.71
.+-. 0.20 3.338 .+-. 0.025 11 27.36 .+-. 0.20 3.260 .+-. 0.024 9
28.11 .+-. 0.20 3.174 .+-. 0.022 4 28.69 .+-. 0.20 3.111 .+-. 0.021
9
TABLE-US-00012 TABLE 8 Observed peaks for Material L.
.degree.2.theta. d space (.ANG.) Intensity (%) 8.61 .+-. 0.20
10.273 .+-. 0.244 79 8.78 .+-. 0.20 10.077 .+-. 0.235 38 11.67 .+-.
0.20 7.586 .+-. 0.132 35 12.17 .+-. 0.20 7.274 .+-. 0.121 19 12.94
.+-. 0.20 6.844 .+-. 0.107 14 14.07 .+-. 0.20 6.293 .+-. 0.090 3
14.62 .+-. 0.20 6.057 .+-. 0.084 5 14.94 .+-. 0.20 5.929 .+-. 0.080
25 15.28 .+-. 0.20 5.800 .+-. 0.076 50 15.93 .+-. 0.20 5.564 .+-.
0.070 18 16.14 .+-. 0.20 5.490 .+-. 0.068 49 16.33 .+-. 0.20 5.429
.+-. 0.067 9 16.70 .+-. 0.20 5.310 .+-. 0.064 9 16.85 .+-. 0.20
5.263 .+-. 0.063 6 17.30 .+-. 0.20 5.127 .+-. 0.060 52 17.63 .+-.
0.20 5.030 .+-. 0.057 6 18.37 .+-. 0.20 4.830 .+-. 0.053 3 20.14
.+-. 0.20 4.409 .+-. 0.044 5 20.59 .+-. 0.20 4.314 .+-. 0.042 14
21.53 .+-. 0.20 4.128 .+-. 0.038 11 22.01 .+-. 0.20 4.038 .+-.
0.037 3 22.44 .+-. 0.20 3.961 .+-. 0.035 27 22.75 .+-. 0.20 3.910
.+-. 0.034 72 23.10 .+-. 0.20 3.851 .+-. 0.033 20 23.31 .+-. 0.20
3.816 .+-. 0.033 19 23.48 .+-. 0.20 3.789 .+-. 0.032 12 23.71 .+-.
0.20 3.752 .+-. 0.031 100 24.48 .+-. 0.20 3.636 .+-. 0.029 20 24.70
.+-. 0.20 3.604 .+-. 0.029 4 24.93 .+-. 0.20 3.571 .+-. 0.028 3
25.59 .+-. 0.20 3.482 .+-. 0.027 5 25.72 .+-. 0.20 3.464 .+-. 0.027
5 26.05 .+-. 0.20 3.420 .+-. 0.026 62 26.59 .+-. 0.20 3.352 .+-.
0.025 6 27.14 .+-. 0.20 3.286 .+-. 0.024 8 27.83 .+-. 0.20 3.206
.+-. 0.023 8 28.38 .+-. 0.20 3.145 .+-. 0.022 3 28.78 .+-. 0.20
3.102 .+-. 0.021 8 29.05 .+-. 0.20 3.074 .+-. 0.021 4 29.36 .+-.
0.20 3.042 .+-. 0.020 3
TABLE-US-00013 TABLE 9 Observed peaks for Material M.
.degree.2.theta. d space (.ANG.) Intensity (%) 7.74 .+-. 0.20
11.424 .+-. 0.303 100 8.34 .+-. 0.20 10.601 .+-. 0.260 4 10.05 .+-.
0.20 8.806 .+-. 0.178 17 12.82 .+-. 0.20 6.906 .+-. 0.109 46 13.05
.+-. 0.20 6.783 .+-. 0.105 4 14.17 .+-. 0.20 6.249 .+-. 0.089 2
14.54 .+-. 0.20 6.092 .+-. 0.085 6 14.99 .+-. 0.20 5.910 .+-. 0.079
16 15.33 .+-. 0.20 5.782 .+-. 0.076 47 15.53 .+-. 0.20 5.707 .+-.
0.074 21 16.80 .+-. 0.20 5.278 .+-. 0.063 27 18.33 .+-. 0.20 4.839
.+-. 0.053 3 19.17 .+-. 0.20 4.630 .+-. 0.048 22 20.19 .+-. 0.20
4.399 .+-. 0.044 23 20.82 .+-. 0.20 4.266 .+-. 0.041 32 21.14 .+-.
0.20 4.202 .+-. 0.040 27 21.29 .+-. 0.20 4.173 .+-. 0.039 14 22.01
.+-. 0.20 4.038 .+-. 0.037 13 22.28 .+-. 0.20 3.991 .+-. 0.036 23
22.93 .+-. 0.20 3.879 .+-. 0.034 6 23.35 .+-. 0.20 3.810 .+-. 0.032
11 24.00 .+-. 0.20 3.708 .+-. 0.031 14 24.25 .+-. 0.20 3.670 .+-.
0.030 3 24.88 .+-. 0.20 3.578 .+-. 0.029 11 25.54 .+-. 0.20 3.488
.+-. 0.027 9 25.80 .+-. 0.20 3.453 .+-. 0.027 94 26.97 .+-. 0.20
3.306 .+-. 0.024 27 27.63 .+-. 0.20 3.229 .+-. 0.023 2 28.41 .+-.
0.20 3.142 .+-. 0.022 7 28.54 .+-. 0.20 3.127 .+-. 0.022 8 29.03
.+-. 0.20 3.076 .+-. 0.021 3 29.30 .+-. 0.20 3.049 .+-. 0.020 7
29.63 .+-. 0.20 3.015 .+-. 0.020 15
Pharmaceutical Compositions
[0088] In another of its composition embodiments, this invention
provides for a pharmaceutical composition comprising a
pharmaceutically acceptable excipient and crystalline free base
ansolvate of Compound 1, preferably including one or more of the
Form I, Form II and/or Material N polymorphs.
[0089] Such compositions can be formulated for different routes of
administration. Although compositions suitable for oral delivery
will probably be used most frequently, other routes that may be
used include intravenous, intraarterial, pulmonary, rectal, nasal,
vaginal, lingual, intramuscular, intraperitoneal, intracutaneous,
intracranial, subcutaneous and transdermal routes. Suitable dosage
forms for administering any of the compounds described herein
include tablets, capsules, pills, powders, aerosols, suppositories,
parenterals, and oral liquids, including suspensions, solutions and
emulsions. Sustained release dosage forms may also be used, for
example, in a transdermal patch form. All dosage forms may be
prepared using methods that are standard in the art (see e.g.,
Remington's Pharmaceutical Sciences, 16.sup.th ed., A. Oslo editor,
Easton Pa. 1980).
[0090] Pharmaceutically acceptable excipients are non-toxic, aid
administration, and do not adversely affect the therapeutic benefit
of the compound of this invention. Such excipients may be any
solid, liquid, semi-solid or, in the case of an aerosol
composition, gaseous excipient that is generally available to one
of skill in the art. Pharmaceutical compositions in accordance with
the invention are prepared by conventional means using methods
known in the art.
[0091] The compositions disclosed herein may be used in conjunction
with any of the vehicles and excipients commonly employed in
pharmaceutical preparations, e.g., talc, gum arabic, lactose,
starch, magnesium stearate, cocoa butter, aqueous or non-aqueous
solvents, oils, paraffin derivatives, glycols, etc. Coloring and
flavoring agents may also be added to preparations, particularly to
those for oral administration. Solutions can be prepared using
water or physiologically compatible organic solvents such as
ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide,
fatty alcohols, triglycerides, partial esters of glycerin and the
like.
[0092] Solid pharmaceutical excipients include starch, cellulose,
hydroxypropyl cellulose, talc, glucose, lactose, sucrose, gelatin,
malt, rice, flour, chalk, silica gel, magnesium stearate, sodium
stearate, glycerol monostearate, sodium chloride, dried skim milk
and the like. Liquid and semisolid excipients may be selected from
glycerol, propylene glycol, water, ethanol and various oils,
including those of petroleum, animal, vegetable or synthetic
origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil,
etc. In certain embodiments, the compositions provided herein
comprises one or more of .alpha.-tocopherol, gum arabic, and/or
hydroxypropyl cellulose.
[0093] In one embodiment, this invention provides sustained release
formulations such as drug depots or patches comprising an effective
amount of a compound provided herein. In another embodiment, the
patch further comprises gum Arabic or hydroxypropyl cellulose
separately or in combination, in the presence of alpha-tocopherol.
Preferably, the hydroxypropyl cellulose has an average MW of from
10,000 to 100,000. In a more preferred embodiment, the
hydroxypropyl cellulose has an average MW of from 5,000 to
50,000.
[0094] Compounds and pharmaceutical compositions of this invention
maybe used alone or in combination with other compounds. When
administered with another agent, the co-administration can be in
any manner in which the pharmacological effects of both are
manifest in the patient at the same time. Thus, co-administration
does not require that a single pharmaceutical composition, the same
dosage form, or even the same route of administration be used for
administration of both the compound of this invention and the other
agent or that the two agents be administered at precisely the same
time. However, co-administration will be accomplished most
conveniently by the same dosage form and the same route of
administration, at substantially the same time. Obviously, such
administration most advantageously proceeds by delivering both
active ingredients simultaneously in a novel pharmaceutical
composition in accordance with the present invention.
Preparative and Treatment Methods
Ansolvate
[0095] In another aspect, the present invention provides a method
of preparing the crystalline free base ansolvate of Compound 1. In
one embodiment, provided herein is a method of preparing the
crystalline free base of Compound 1 comprising slurrying or
contacting the HCl salt of the Compound 1 with water and allowing
dissociation of HCl to produce the free base of Compound 1. In one
embodiment, the crystalline free base ansolavte of Compound 1
prepared comprises one or more of Form I, Form II and Material
N.
[0096] In yet another of its method embodiments, there are provided
methods for increasing oxygen affinity of hemoglobin S in a
subject, the method comprising administering to a subject in need
thereof a therapeutically effective amount of a crystalline free
base of Compound 1. In some embodiments, the crystalline free base
of Compound 1 is an ansolvate. In one embodiment, the crystalline
free base of Compound 1 comprises one or more of Form I, Form II
and Material N.
[0097] In yet another of its method embodiments, there are provided
methods for treating oxygen deficiency associated with sickle cell
anemia in a subject, the method comprising administering to a
subject in need thereof a therapeutically effective amount of a
crystalline free base of Compound 1. In some embodiments, the
crystalline free base of Compound 1 is an ansolvate. In one
embodiment, the crystalline free base of Compound 1 comprises one
or more of Form I, Form II and Material N.
[0098] In further aspects of the invention, a method is provided
for treating sickle cell disease, the method comprising
administering to a subject in need thereof a therapeutically
effective amount of a crystalline free base of Compound 1. In some
embodiments, the crystalline free base of Compound 1 is an
ansolvate. In one embodiment, the crystalline free base of Compound
1 comprises one or more of Form I, Form II and Material N. In still
further aspects of the invention, a method is provided for treating
cancer, a pulmonary disorder, stroke, high altitude sickness, an
ulcer, a pressure sore, Alzheimer's disease, acute respiratory
disease syndrome, and a wound, the method comprising administering
to a subject in need thereof a therapeutically effective amount of
a crystalline free base of Compound 1. In some embodiments, the
crystalline free base of Compound 1 is an ansolvate. In one
embodiment, the crystalline free base of Compound 1 comprises one
or more of Form I, Form II and Material N.
[0099] In such treatments, the dosing of the crystalline free base
of Compound 1 to the treated patient is already disclosed in the
art.
Solvates
[0100] In another aspect, the present invention provides a method
of preparing the crystalline free base solvates of Compound 1. In
some embodiments, a free base ansolvate, as described herein (e.g,
as obtained by slurrying an HCl salt of Compound 1 in water) of
Compound 1 is contacted with a solvent as provided herein,
including a mixture of solvents, to prepare the solvate. the
solvent or the mixture of solvents. Thus, a solvent can be a single
solvent or substantially a single solvent or a mixture of solvents.
When a mixture of solvents is used, a solvate can be produced
having one or more of the individual constituent solvents of the
solvent mixture. In some embodiments, the solvent includes
alcoholic solvents such as mono di or higher alcohols or alkanols.
In some embodiments, the solvent includes chlorinated solvents such
as dichloromethane chloroform, et cetera. In some embodiments, the
solvent includes ketone solvents such as alkanones and
cycloalkanones. Certain solvents include without limitation,
methanol, ethanol, 2-propanol, 2-methyl-1-propanol, 1-butanol,
acetonitrile, acetone, dichloromethane, dioxane, or
tetrahydrofuran, or combinations thereof, optionally including
water.
[0101] In another aspect, a method is provided for increasing
oxygen affinity of hemoglobin S in a subject, the method comprising
administering to a subject in need thereof a therapeutically
effective amount of a crystalline solvate of Compound 1.
[0102] In another aspect, a method is provided for treating oxygen
deficiency associated with sickle cell anemia, the method
comprising administering to a subject in need thereof a
therapeutically effective amount of a crystalline solvate of
Compound 1.
EXAMPLES
[0103] The following examples describe the preparation,
characterization, and properties of the free base of Compound 1
Form I ansolvate. Unless otherwise stated, all temperatures are in
degrees Celcius (.degree. C.) and the following abbreviations have
the following definitions: [0104] DSC Differential scanning
calorimetry [0105] DVS Dynamic vapor sorption [0106] HPLC High
performance liquid chromatography [0107] NA Not applicable [0108]
ND Not determined [0109] Q Percent dissolved per unit time [0110]
RH Relative humidity [0111] RSD Residual standard deviation [0112]
RRT Relative retention time [0113] SS-NMR Solid state nuclear
magnetic resonance [0114] TGA Thermogravimetric analysis [0115]
TG-IR Thermogravimetric infra red analysis [0116] XRPD X-ray powder
diffraction [0117] VT-XRPD Variable temperature X-ray powder
diffraction
Synthetic Routes for Preparing Compound 1
[0118] The compound of formula (I) was synthesized as schematically
described below and elaborated thereafter.
##STR00003##
Example 1
Synthesis of Compound 15
##STR00004##
[0120] To a solution of 2-bromobenzene-1,3-diol (5 g, 26.45 mmol)
in DCM (50 ml) at 0.degree. C. was added DIPEA (11.54 mL, 66.13
mmol) and MOMCl (4.42 mL, 58.19 mmol). The mixture was stirred at
0.degree. C. for 1.5 h, and then warmed to room temperature. The
solution was diluted with DCM, washed with sat. NaHCO.sub.3, brine,
dried and concentrated to give crude product, which was purified by
column (hexanes/EtOAc=4:1) to give desired product 15.58 g
(90%).
Example 2
Synthesis of Compound 13 from 15
##STR00005##
[0122] To a solution of 2-bromo-1,3-bis(methoxymethoxy)benzene (15)
(19.9 g, 71.8 mmol) in THF (150 mL) at -78.degree. C. was added
BuLi (2.5 M, 31.6 mL, 79.0 mmol) dropwise. The solution was stirred
at -78.degree. C. for 25 min (resulting white cloudy mixture), then
it was warmed to 0.degree. C. and stirred for 25 min. The reaction
mixture slowly turns homogenous. To the solution was added DMF at
0.degree. C. After 25 min, HPLC showed reaction completed. The
mixture was quenched with sat. NH4Cl (150 mL), diluted with ether
(300 mL). The organic layer was separated, aq layer was further
extracted with ether (2.times.200 mL), and organic layer was
combined, washed with brine, dried and concentrated to give crude
product, which was triturated to give 14.6 g desired product. The
filtrate was then concentrated and purified by column to give
additional 0.7 g, total mass is 15.3 g.
Example 3
Synthesis of Compound 13 from Resorcinol 11
##STR00006##
[0124] A three-necked round-bottom flask equipped with mechanical
stirrer was charged with 0.22 mol of NaH (50% suspension in mineral
oil) under nitrogen atmosphere. NaH was washed with 2 portions (100
mL) of n-hexane and then with 300 mL of dry diethyl ether; then 80
mL of anhydrous DMF was added. Then 0.09 mol of resorcinol 11,
dissolved in 100 mL of diethyl ether was added dropwise and the
mixture was left under stirring at rt for 30 min. Then 0.18 mol of
MOMCl was slowly added. After 1 h under stirring at rt, 250 mL of
water was added and the organic layer was extracted with diethyl
ether. The extracts were washed with brine, dried
(Na.sub.2SO.sub.4), then concentrated to give the crude product
that was purified by silica gel chromatography to give compound 12
(93% yield).
[0125] A three-necked round-bottom flask was charged with 110 mL of
n-hexane, 0.79 mol of BuLi and 9.4 mL of tetramethylethylendiamine
(TMEDA) under nitrogen atmosphere. The mixture was cooled at
-10.degree. C. and 0.079 mol of bis-phenyl ether 12 was slowly
added. The resulting mixture was left under magnetic stirring at
-10.degree. C. for 2 h. Then the temperature was raised to
0.degree. C. and 0.067 mol of DMF was added dropwise. After 1 h,
aqueous HCl was added until the pH was acidic; the mixture was then
extracted with ethyl ether. The combined extracts were washed with
brine, dried (Na.sub.2SO.sub.4), and concentrated to give aldehyde
13 (84%).
[0126] 2,6-bis(methoxymethoxy)benzaldehyde (13): mp 58-59.degree.
C. (n-hexane); IR (KBr) n: 1685 (C.dbd.O) cm.sup.-1; .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. 3.51 (s, 6H, 2 OCH.sub.3), 5.28 (s,
4H, 2 OCH.sub.2O), 6.84 (d, 2H, J=8.40 Hz, H-3, H-5), 7.41 (t, 1H,
J=8.40 Hz, H-4), 10.55 (s, 1H, CHO); MS, m/e (relative intensity)
226 (M+, 3), 180 (4), 164 (14), 122 (2), 92 (2), 45 (100); Anal.
Calc'd. for C.sub.11H.sub.14O.sub.5: C, 58.40; H, 6.24. Found: C,
57.98; H, 6.20.
Example 4
The Synthesis of Compound 16
##STR00007##
[0128] To a solution of 2,6-bis(methoxymethoxy)benzaldehyde (13)
(15.3 g, 67.6 mmol) in THF (105 mL) (solvent was purged with
N.sub.2) was added conc. HCl (12N, 7 mL) under N.sub.2, then it was
further stirred under N.sub.2 for 1.5 h. To the solution was added
brine (100 mL) and ether (150 ml). The organic layer was separated
and the aqueous layer was further extracted with ether (2.times.200
mL). The organic layer was combined, washed with brine, dried and
concentrated to give crude product, which was purified by column
(300 g, hexanes/EtOAc=85:15) to give desired product 16 (9.9 g) as
yellow liquid.
Example 5
Synthesis of Compound 17
##STR00008##
[0130] To a solution of 2-hydroxy-6-(methoxymethoxy)benzaldehyde
(16) (10.88 g, 59.72 mmol) in DMF (120 mL) (DMF solution was purged
with N.sub.2 for 10 min) was added K.sub.2CO.sub.3 (32.05 g, 231.92
mmol) and 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine
hydrochloride (10) (15.78 g, 57.98 mmol). The mixture was heated at
65.degree. C. for 1.5 h, cooled to rt, poured into ice water (800
mL). The precipitated solids were isolated by filtration, dried and
concentrated to give desired product (17, 18 g).
Example 6
Synthesis of Compound (I)
##STR00009##
[0132] To a solution of
2-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-(methoxymethox-
y)benzaldehyde (17) (18 g, 47.19 mmol) in THF (135 mL, solution was
purged with N.sub.2) was added conc. HCl (12N, 20 mL). The solution
was stirred at rt for 3 h when HPLC showed the reaction complete.
The mixture was added to a solution of NaHCO.sub.3 (15 g) in water
(1.2 L), and the resulting precipitate was collected by filtration,
dried to give crude solid, which was further purified by column
(DCM/EtOAc=60:40) to give pure product (15.3 g).
Example 7
Synthesis of Compound I (Free Base) and its HCl Salt Form
[0133] Compound (I) free base (40 g) was obtained from the coupling
of the alcohol intermediate 7 and 2,6-dihydroxybenzaldedhye 9 under
Mitsunobu conditions. A procedure is also provided below:
##STR00010##
Example 8
Synthesis of Compound (I) by Mitsunobu Coupling
[0134] Into a 2000-mL three neck round-bottom flask, which was
purged and maintained with an inert atmosphere of nitrogen, was
placed a solution of
[2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methanol (7) (70
g, 322.18 mmol, 1.00 equiv) in tetrahydrofuran (1000 mL).
2,6-Dihydroxybenzaldehyde (9) (49.2 g, 356.21 mmol, 1.10 equiv) and
PPh.sub.3 (101 g, 385.07 mmol, 1.20 equiv) were added to the
reaction mixture. This was followed by the addition of a solution
of DIAD (78.1 g, 386.23 mmol, 1.20 equiv) in tetrahydrofuran (200
ml) dropwise with stirring. The resulting solution was stirred
overnight at room temperature. The resulting solution was diluted
with 500 ml of H.sub.2O. The resulting solution was extracted with
3.times.500 ml of dichloromethane and the combined organic layers
were dried over sodium sulfate and concentrated under vacuum. The
residue was applied onto a silica gel column with EA:PE (1:50-1:3)
as eluent to yield the crude product. The crude product was
re-crystallized from i-propanol/H.sub.2O in the ratio of 1/1.5.
This resulted in 40 g (37%) of
2-hydroxy-6-([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]methoxy)ben-
zaldehyde as a light yellow solid. The compound exhibited a melting
point of 80-82.degree. C. MS (ES, m/z): 338.1 [M+1]. .sup.1H NMR
(300 MHz, DMSO-d6) .delta. 11.72 (s, 1H), 10.21 (s, 1H), 8.76 (d,
J=3.6 Hz, 1H), 8.24 (d, J=2.7 Hz, 1H), 7.55 (m, 3H), 6.55 (m, 3H),
5.21 (s, 2H), 4.65 (m, 1H), 1.37 (d, J=5.1 Hz, 6H). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 11.96 (s, 1H), 10.40 (s, 1H), 8.77
(dd, J=4.8, 1.5 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.63 (d, J=1.8 Hz,
1H), 7.49-7.34 (m, 2H), 6.59 (d, J=8.5 Hz, 1H), 6.37 (d, J=1.8 Hz,
1H), 6.29 (d, J=8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J=6.7 Hz,
1H), 1.50 (d, J=6.6 Hz, 6H).
[0135] In another approach, multiple batches of Compound (I) free
base are prepared in multi gram quantities (20 g). The advantage of
this route is the use of mono-protected 2,6-dihydroxybenzaldehyde
(16), which effectively eliminates the possibility of
bis-alkylation side product. The mono-MOM ether of
2,6-dihydroxybenzaldehyde (16) can be obtained from two starting
points, bromoresorcinol (14) or resorcinol (11) [procedures
described in the Journal of Organic Chemistry, 74(11), 4311-4317;
2009]. All steps and procedures are provided below. Due to the
presence of phenolic aldehyde group, precautions (i.e., carry out
all reactions under inert gas such as nitrogen) should be taken to
avoid oxidation of the phenol and/or aldehyde group.
[0136] Preparation of compound I HCl salt: A solution of compound I
(55.79 g, 165.55 mmol) in acetonitrile (275 mL) was flushed with
nitrogen for 10 min, then to this solution was added 3N aqueous HCl
(62 mL) at room temperature. The mixture was stirred for additional
10 min after the addition, most of the acetonitrile (about 200 mL)
was then removed by evaporation on a rotary evaporator at around
32.degree. C., the remaining solution was frozen by cooling in an
acetone-dry ice bath and lyophilized to afford compound I HCl salt
(59.4 g).
Example 9
Characterization of the HCl Salt of Compound 1
TABLE-US-00014 [0137] Technique Details Result XRPD indexed HCl
salt of Compound 1 Microscope -- pale yellow solids, thin
blades/tablets, birefringent .sup.1H NMR DMSO-d6 consistent with
structure, <0.01 moles MEK XRPD -- HCl salt of Compound 1 DVS --
0.03% gain upon equilibration at 5% RH 0.10% gain from 5 to 95% RH
0.09% loss from 95 to 5% RH post XRPD HCl I + Free Base Form I
Example 10
Physical Stability of the HCl Salt of Compound 1 Exposed to
Water
TABLE-US-00015 [0138] Time (all times Condition are approximated)
Observation XRPD Result contacted w/ -- sheet formation after --
water 5 min water slurry about 5 min Floating yellow Free base (FB)
solids convert to I (indexed) white solids upon isolation vacuum
dried about 1 day Remain FB I water slurry about 6 days white, thin
blades, FB I + FB II birefringent (B)
Example 11
Physical Stability of the HCl Salt of Compound 1 with Grinding
TABLE-US-00016 [0139] Condition Time Observation XRPD Result
grinding, dry 30 min off white/pale yellow HCl I grinding, wet 30
min off white/pale yellow paste HCl I + FB I
Example 12
Physical Stability of the HCl Salt of Compound 1 Exposed to
Elevated Temperature and/or Vacuum
TABLE-US-00017 [0140] Condition Time Observation XRPD Result RT
vacuum 6 days pale yellow, blades/plates, B HCl I + FB I 30.degree.
C. 6 hrs pale yellow, blades/tablets, B HCl I 12 hrs pale yellow,
blades/tablets, B HCl I + FB I 24 hrs pale yellow, blades/tablets,
B HCl I + FB I 40.degree. C. 6 hrs pale yellow, blades/tablets, B
HCl I + FB I 12 hrs pale yellow, blades/tablets, B HCl I + FB I 24
hrs pale yellow, blades/tablets, B HCl I + FB I 40.degree. C. 6 hrs
pale yellow, blades/tablets, B HCl I + FB I vacuum 12 hrs pale
yellow, blades/tablets, B HCl I + FB I 24 hrs pale yellow,
blades/tablets, B HCl I + FB I 60.degree. C. 6 days pale yellow
blades, B HCl I + FB I 60.degree. C. 6 days pale yellow, blades, B;
HCl I + FB I + vacuum irregular residue other free base form 100 to
20 min pH paper above sample HCl I + FB I + 125.degree. C. indicate
acidic volatiles other free base form
Example 13
Generation of the Free Base of Compound 1 from the
Disproportionation of the HCl Salt of Compound 1 in Water (the
Starting Material is the HCl Salt of Compound 1)
TABLE-US-00018 [0141] Method Observation XRPD Result 1. contacted
with water 1. pale yellow, FB I 2. sonicated wets poorly 3.
filtered and rinsed with water 2. white 4. dried under N.sub.2 for
10 minutes 3. -- 5. vacuum RT, overnight 4. -- 5. -- 1. contacted
with water 1. -- FB I + other 2. sonicated for 5 minutes 2. pale
yellow, free base form 3. slurried for 10 minutes turned white 4.
filtered, rinsed with water 3. -- 5. dried under N.sub.2 for 10
minutes 4. -- 6. vacuum RT, overnight 5. white 7. stored in freezer
6. -- 7. -- 1. slurry in water, RT, 8 days; 1. thick white FB II
seeded with FB II slurry 2. filtered, rinsed with water 2. -- 3.
vacuum RT, overnight 3. -- 2. sub sample of slurry 2. -- FB II
(indexed) 3. rinsed with water 3. --
Example 14
Characterization Form I of the Free Base of Compound 1
TABLE-US-00019 [0142] Technique Details Result XRPD indexed Free
Base Form I XRPD -- Free Base Form I TGA 25 to 0.2% weight loss up
to 100.degree. C. 350.degree. C. DSC 25 to endothermic event with
onset near 97.degree. C. 350.degree. C. Hot Stage 22.7.degree. C.
initial, fines, birefringent Microscopy 91.2.degree. C. increase in
particle size and birefringence 94.2.degree. C. increase in
particle size and birefringence 95.7.degree. C. melt onset, larger
particles from initial heating 96.1.degree. C. melt continuation
96.3.degree. C. melt complete, no crystallization upon melting
68.7.degree. C. fresh preparation, larger magnification
91.1.degree. C. increase in birefringence 94.8.degree. C. melt
onset, larger particles, birefringent 95.4.degree. C. melt
continuation 95.9.degree. C. only few crystals remain, cooled to
92.6.degree. C. 92.6.degree. C. held for 2 to 3 minutes crystal
growth to larger blades, - began heating 96.3.degree. C. complete
melt .sup.1H NMR DMSO-d6 consistent with structure DVS -- 0.02%
loss upon equilibration at 5% RH 0.22% gain from 5 to 95% RH 0.22%
loss from 95 to 5% RH post XRPD Free Base Form I + other Free Base
Material
Example 15
Characterization of Form II of the Free Base of Compound 1
TABLE-US-00020 [0143] Technique Details Result XRPD indexed Free
Base Form II XRPD initial Free Base Form II after 7 days Free Base
Form II TGA 25 to 350.degree. C. 0.1% weight loss up to 100.degree.
C. DSC 25 to 350.degree. C. endothermic event with onset near
97.degree. C. .sup.1H NMR DMSO-d6 consistent with structure
Example 16
Characterization of Material N of the Free Base of Compound 1
TABLE-US-00021 [0144] Technique Details Result XRPD -- Free Base
Material N TGA 25 to 350.degree. C. 0.2% weight loss up to
100.degree. C. DSC 25 to 350.degree. C. endothermic event with
onset near 94.degree. C. .sup.1H NMR DMSO-d6 consistent with
structure, no residual reaction solvent observed
Example 17
Competitive Interconversion Slurries Between Free Base Forms I and
II
TABLE-US-00022 [0145] Conditions Solvent Observation XRPD Result
6.degree. C., 6 days water white FB II 6.degree. C., 6 days heptane
white FB II 6.degree. C., 6 days IPE faint pale yellow FB N RT, 6
days water white FB II RT, 6 days heptane off white FB II RT, 6
days IPE pale yellow FB N.sup.Error! Bookmark not defined. RT, 6
days toluene pale yellow FB N 57.degree. C., 2 days water fines,
off white, B FB II + FB I 57.degree. C., heptane blades and FB II
overnight tablets, B 57.degree. C., IPE blades, laminated, FB II
overnight pale yellow, B
Example 18
Competitive Interconversion Slurries Between Free Base Form II and
Material N
TABLE-US-00023 [0146] Conditions 35.degree. C., 3 days heptane pale
yellow fines, B FB N 57.degree. C., 3 days heptane larger blades,
and rosettes of blades, B FB II
Example 19
Selected Experimental Methods
[0147] Indexing:
[0148] XRPD patterns are indexed by using proprietary SSCI
software. Agreement between the allowed peak positions, marked with
red bars within the figures, and the observed peaks indicates a
consistent unit cell determination. Indexing and structure
refinement are computational studies which are performed under the
"Procedures for SSCI Non-cGMP Activities." To confirm the tentative
indexing solution, the molecular packing motifs within the
crystallographic unit cells must be determined. No attempts at
molecular packing were performed.
[0149] Differential Scanning Calorimetry (DSC):
[0150] DSC was performed using a TA Instruments Q2000 differential
scanning calorimeter. Temperature calibration was performed using
NIST-traceable indium metal. The sample was placed into an aluminum
DSC pan, covered with a lid, and the weight was accurately
recorded. A weighed aluminum pan configured as the sample pan was
placed on the reference side of the cell. The data acquisition
parameters and pan configuration for each thermogram are displayed
in the image in the Data section of this report. The method code on
the thermogram is an abbreviation for the start and end temperature
as well as the heating rate; e.g., -30-250-10 means "from
-30.degree. C. to 250.degree. C., at 10.degree. C./min". The
following summarizes the abbreviations used in each image for pan
configurations: Tzero crimped pan (TOC); and Lid not crimped
(NC).
[0151] Dynamic Vapor Sorption (DVS):
[0152] Dynamic vapor sorption (DVS) data were collected on a VTI
SGA-100 Vapor Sorption Analyzer. NaCl and PVP were used as
calibration standards. Samples were not dried prior to analysis.
Adsorption and desorption data were collected over a range from 5
to 95% RH at 10% RH increments under a nitrogen purge. The
equilibrium criterion used for analysis was less than 0.0100%
weight change in 5 minutes with a maximum equilibration time of 3
hours. Data were not corrected for the initial moisture content of
the samples.
Microscopy
[0153] Hot Stage Microscopy:
[0154] Hot stage microscopy was performed using a Linkam hot stage
(FTIR 600) mounted on a Leica DM LP microscope equipped with a SPOT
Insight.TM. color digital camera. Temperature calibrations were
performed using USP melting point standards. Samples were placed on
a cover glass, and a second cover glass was placed on top of the
sample. As the stage was heated, each sample was visually observed
using a 20.times.0.40 N.A. long working distance objective with
crossed polarizers and a first order red compensator. Images were
captured using SPOT software (v. 4.5.9).
[0155] Polarized Light Microscopy:
[0156] During the course of experimentation generated samples were
viewed utilizing a microscope with cross polarized light to observe
morphology and birefringence. Samples were visually observed at
40.times. magnification.
.sup.1H Solution Nuclear Magnetic Resonance (.sup.1H NMR)
[0157] SSCI:
[0158] Samples were prepared for NMR spectroscopy as .about.5-50 mg
solutions in the appropriate deuterated solvent. The specific
acquisition parameters are listed on the plot of the first full
spectrum of each sample in the data section for samples run at
SSCI.
[0159] Spectral Data Solutions:
[0160] For samples run using Spectral Data Solutions
(subcontractor), the solution .sup.1H NMR spectra were acquired at
ambient temperature on a Varian .sup.UNITYINOVA-400 spectrometer
(.sup.1H Larmor Frequency=399.8 MHz). The specific acquisition
parameters are listed on the spectral data sheet and on each data
plot of the spectrum of the sample.
Thermogravimetric Analysis (TGA)
[0161] TG analyses were performed using a TA Instruments 2950
thermogravimetric analyzer. Temperature calibration was performed
using nickel and Alumel.TM.. Each sample was placed in an aluminum
pan and inserted into the TG furnace. The furnace was heated under
a nitrogen purge. The data acquisition parameters are displayed
above each thermogram in the Data section of this report. The
method code on the thermogram is an abbreviation for the start and
end temperature as well as the heating rate; e.g., 25-350-10 means
"from 25.degree. C. to 350.degree. C., at 10.degree. C./min". The
use of 0 as the initial temperature indicates sample run initiated
from ambient.
XRPD Analysis
[0162] INEL:
[0163] XRPD patterns were collected with an Inel XRG-3000
diffractometer. An incident beam of Cu K.alpha. radiation was
produced using a fine-focus tube and a parabolically graded
multilayer mirror. Prior to the analysis, a silicon standard (NIST
SRM 640d) was analyzed to verify the Si 111 peak position. A
specimen of the sample was packed into a thin-walled glass
capillary, and a beam-stop was used to minimize the background from
air. Diffraction patterns were collected in transmission geometry
using Windif v. 6.6 software and a curved position-sensitive
Equinox detector with a 2.theta. range of 120.degree.. The
data-acquisition parameters for each pattern are displayed above
the image in the Data section of this report.
[0164] PANalytical Transmission:
[0165] XRPD patterns were collected with a PANalytical X'Pert PRO
MPD diffractometer using an incident beam of Cu radiation produced
using an Optix long, fine-focus source. An elliptically graded
multilayer mirror was used to focus Cu K.alpha. X-rays through the
specimen and onto the detector. Prior to the analysis, a silicon
specimen (NIST SRM 640d) was analyzed to verify the Si 111 peak
position. A specimen of the sample was sandwiched between 3 .mu.m
thick films and analyzed in transmission geometry. A beam-stop,
short antiscatter extension, and an antiscatter knife edge were
used to minimize the background generated by air. Soller slits for
the incident and diffracted beams were used to minimize broadening
from axial divergence. Diffraction patterns were collected using a
scanning position-sensitive detector (X'Celerator) located 240 mm
from the specimen and Data Collector software v. 2.2b. The
data-acquisition parameters for each pattern are displayed above
the image in the Data section of this report including the
divergence slit (DS) before the mirror and the incident-beam
antiscatter slit (SS).
[0166] PANalytical Reflection:
[0167] XRPD patterns were collected with a PANalytical X'Pert PRO
MPD diffractometer using an incident beam of Cu K.alpha. radiation
produced using a long, fine-focus source and a nickel filter. The
diffractometer was configured using the symmetric Bragg-Brentano
geometry. Prior to the analysis, a silicon specimen (NIST SRM 640d)
was analyzed to verify the observed position of the Si 111 peak is
consistent with the NIST-certified position. A specimen of the
sample was prepared as a thin, circular layer centered on a silicon
zero-background substrate. Antiscatter slits (SS) were used to
minimize the background generated by air. Soller slits for the
incident and diffracted beams were used to minimize broadening from
axial divergence. Diffraction patterns were collected using a
scanning position-sensitive detector (X'Celerator) located 240 mm
from the sample and Data Collector software v. 2.2b. The data
acquisition parameters for each pattern are displayed above the
image in the Data section of this report including the divergence
slit (DS) and the incident-beam SS.
[0168] Approximate Solubility:
[0169] A weighed sample was treated with aliquots of the test
solvent at room temperature. The mixture was sonicated between
additions to facilitate dissolution. Complete dissolution of the
test material was determined by visual inspection. Solubility was
estimated based on the total solvent used to provide complete
dissolution. Some samples were then heated and observed visually
for complete dissolution. The actual solubility may be greater than
the value calculated because of the use of solvent aliquots that
were too large or due to a slow rate of dissolution. The solubility
is expressed as "less than" if dissolution did not occur during the
experiment. If complete dissolution was achieved as a result of
only one aliquot addition, the solubility is expressed as "greater
than".
[0170] Anti-Solvent Additions: Compound 1/organic solvent solutions
were contacted with solvents that Compound 1 was determined to be
poorly soluble or insoluble in. These anti solvent additions were
added to help lower the solubility of the solvent system and induce
crystallization.
[0171] Cooling and Slow Cools:
[0172] Solutions were prepared in the selected solvent or
solvent/anti-solvent system. These solutions were chilled below
room temperature within a refrigerator for varying lengths of time
in an attempt to induce nucleation. The presence or absence of
solids was noted. Upon observation of solids, in quantities
sufficient for analysis, isolation of material was conduction. If
insufficient quantities were present further cooling was performed
in a freezer. Samples were either isolated for analysis wet or as
dry powders.
[0173] Compression:
[0174] Selected samples were compressed utilizing a KBr die and a
Carver hydraulic press. An applied load of 10000 lbs was applied to
the die shaft for approximately 20 minutes.
[0175] Crystallization from Solution:
[0176] Saturated solutions were generated at ambient and then
capped. Nucleation was observed to occur from these systems during
evaluation of the Free Base of Compound 1.
[0177] Fast Evaporation:
[0178] Solutions were prepared in selected solvents and agitated
between aliquot additions to assist in dissolution. Once a mixture
reached complete dissolution, as judged by visual observation, the
solution was allowed to evaporate at ambient temperature in an
uncapped vial or at ambient under nitrogen. The solids that formed
were isolated for evaluation.
[0179] Milling:
[0180] Selected material was milled utilizing a Reitch Mill. The
material was loaded into an agate lined milling vessel followed by
the addition of an agate ball. The vessel was then placed on to the
mill and milled for approximately 30 minutes at frequency of 1/30
seconds. The milling was stopped approximately every 10 minutes and
material scraped from the wall before further milling.
[0181] Slurry:
[0182] Solutions were prepared by adding enough solids to a given
solvent so that excess solids were present. The mixture was then
agitated in a sealed vial at either ambient or an elevated
temperature. After a given amount of time, the solids were isolated
for analysis.
[0183] Temperature and Relative Humidity Stress:
[0184] Selected materials were stressed at elevated related
humidity and/or temperature. Relative humidity jars (saturated salt
solutions used to generate desired relative humidity) were utilized
to store selected samples. The following relative humidity jars
were utilized during evaluation: 75% RH (NaCl) and 60% (NaBr), to
investigate the effects of humidity. Temperatures utilized were
ambient, 30, 40, 60, and 100-125.degree. C.
[0185] Vacuum:
[0186] Selected materials were stressed under reduced pressure for
a set time period. Initial stressing was conducted with the
in-house vacuum system with absolute pressure readings <500
mTorr, typically 30 to 50 mTorr (0.030 to 0.05 mm Hg). Additional
vacuum stressing was conducted at 48 mmHg utilizing a portable lab
vacuum and bleed to simulate conditions similar to those expected
during process.
Example 20
Disproportionation of the HCl Salt
[0187] The disproportionation of the HCl salt in water was utilized
to generate free base. The nucleation of Free Base Form I occurs
first. Extending the slurry time induces the transformation to a
more thermodynamically stable phase relative to Form I, Free Base
Form II.
[0188] Three anhydrous materials of the free base were identified;
Free Base Forms I, II, and Material N. Free Base Material N appears
to be most stable form, relative to Forms I and II, at room
temperature. Free Base Material N is enantiotropic relative to Form
II, and will transform reversibly at a specific transition
temperature (estimated near 42.degree. C.). Above the transition
temperature, Free Base Form II appears to be the most stable form,
relative to Form I and Material N.
[0189] The HCl salt (termed "HCl Form I") was subjected to various
stress conditions and monitored by XRPD to evaluate physical
stability. As discussed, disproportionation occurred during the DVS
experiment of the HCl salt, indicating instability upon exposure to
elevated humidity. Disproportionation is further evident with wet
milling or in direct contact with water (e.g. slurry) as shown by
the presence of Free Base Forms I or II, identified by XRPD. The
volatilization and loss of HCl upon heating and/or vacuum is shown
by the presence of Free Base Form I, identified by XRPD, and also
indicates instability at these conditions. [0190] Contact with
water resulted in a visual color change of the material from pale
yellow to white; physical changes were also observed
microscopically. Immediate disproportionation occurs. XRPD analysis
identified the resulting material from a water slurry (.about.5
minutes) as Free Base Form I. Free Base Form II also becomes
evident if the amount of time in the slurry is extended. [0191] The
volatilization of HCl was evident within hours of exposure to
drying conditions. Conversion to Free Base Form I was observed by
XRPD at 30.degree. C. (after 12 hrs), 40.degree. C. (after 6 hrs),
and at 40.degree. C./48 mmHg (after 6 hrs). [0192] Free Base
Material C becomes evident at more extreme conditions involving
elevated temperatures. Heating HCl Form I up to 125.degree. C.
induces the loss of acidic volatiles (judged visually by use of pH
paper held above sample). XRPD analysis identifies the resulting
sample as a mixture of HCl Form I, Free Base Form I, and Free Base
Material C. Exposing the HCl salt to 60.degree. C. under vacuum for
6 days provides the same result. The nature of Material C is not
established
[0193] The HCl salt was shown to disproportionate immediately in
water. This phenomenon was utilized to generate free base. The
nucleation of Free Base Form I occurs first. Extending the slurry
time induces the transformation to a more thermodynamically stable
phase relative to Form I, Free Base Form II. [0194] A 20 ml vial
was charged with 266.4 mg of HCl Form I and contacted with 10 ml of
water. The sample was sonicated until the pale yellow material
changed color to white. The resulting solids were collected by
filtration (water aspirated) and rinsed with 10 ml of water. A
nitrogen purge was blown over the sample for approximately 10
minutes prior to exposure to vacuum at ambient temperature to dry
overnight. The resulting material was analyzed by XRPD and
determined to be Free Base Form I. [0195] A 250 ml Erlenmeyer flask
was charged with 6.0250 grams of HCl Form I and contacted with 220
mL of water. The sample was sonicated for approximately 5 minutes
to disperse the material. The yellow material changed color to
white during sonication. A stir bar was added and the sample was
stirred at 700 RPM for approximately 10 minutes. The solids were
collected by filtration and rinsed with 220 ml of water followed by
a nitrogen purge over the sample for approximately 10 minutes prior
to exposure to vacuum at ambient temperature. The sample was dried
at this condition for approximately 24 hours yielding 5.1834 grams
of material. The resulting material was analyzed by XRPD and
determined to be a mixture of Free Base Form I and Free Base
Material D. (The nature of Material D is not established.)
[0196] The procedure used to generate Free Base Form II is
described below. [0197] A 20 ml vial was charged with 477.5 mg of
HCl Form I lot 20 and contacted with 20 ml of water. The sample was
sonicated until the pale yellow material changed color to white. A
small amount of sample (mixture of Free Base Forms I and II) was
added as seeds. A stir bar was added and the sample was stirred at
200 RPM for 8 days. The resulting solids were collected by
filtration (water aspirated) and rinsed with 15 ml of water. The
sample was exposed to vacuum at ambient temperature to dry
overnight. The resulting material was analyzed by XRPD and
determined to be Free Base Form II.
Example 21
Additional Procedures for the Preparation of the Free Base of Form
I, Form II, and From N
Conversion of the Free Base of Compound 1 to the HCl Salt
[0198] General Procedure:
[0199] Slowly treat a solution of the free base of Compound 1 in
MEK (5 vol) with cone HCl (1.5 eq). Cool the resulting slurry to
0-5.degree. C. for 1 h and filter. Wash solids with MEK (1 vol).
Dry under vacuum at 30-35.degree. C.
[0200] Preparation A:
[0201] Following the general procedure above, 35 g of crude
Compound 1 was processed to provide the HCl salt as a pale yellow
solid (32.4 g, 82% yield, 99.8% purity by HPLC).
Preparation of the Free Base Form I from the HCl Salt of Compound
1
[0202] General Procedure:
[0203] Vigorously stir a slurry of the HCl salt of Compound 1 in
DIW (10 vol) for 5 min to 2 h. Filter the slurry, wash with DIW
(2.times.1 vol), dry on funnel, then further dry under vacuum at
30-35.degree. C.
[0204] Preparation A:
[0205] Following the general procedure above, after stirring for 1
h, 32 g of the HCl salt of Compound 1 was processed to provide the
free base as a pale yellow solid (27.3 g, 95% yield, 99.8% purity
by HPLC; DSC indicates Form I).
[0206] Preparation B:
[0207] Following the general procedure above, after stirring for 1
h, 39 g of the HCl salt of Compound 1 was processed to provide the
free base as a pale yellow solid (31.8 g, 90% yield, >99.9%
purity by HPLC)).
[0208] Preparation C:
[0209] Thus, the HCl salt of Compound 1 (134 g) was vigorously
stirred in water (10 vol) until the material appeared as a finely
dispersed white slurry. After filtration and drying, a white
crystalline solid (116 g, 96% recovery, >99.9% purity by HPLC)
was isolated.
[0210] Preparation D:
[0211] The purpose of this experiment was to prepare the free base
from Compound 1, HCl. Thus, the HCl salt of Compound 1 (65.3 g) was
vigorously stirred in water (10 vol) until the material appeared as
a finely dispersed white slurry. After filtration and drying, a
white crystalline solid (57.5 g, 97.6% recovery, >99.9% purity
by HPLC) was isolated.
Preparation of GBT000440 Free Base Form II from GBT000440 Free Base
Form I
[0212] General Procedure:
[0213] Stir a slurry of the free base of Compound 1 Form I in an
appreciate solvent (e.g. heptane or water) (10 vol) for 1-7 days.
Filter the slurry, wash with DIW (2.times.1 vol), dry on funnel,
then further dry under vacuum at 30-35.degree. C.
[0214] Preparation A:
[0215] Thus, the free base of Compound 1, Form I (114 g) was
stirred in n-heptane (10 vol) at 35.degree. C. After 4 days, XRPD
indicated the material was Form II. The slurry was filtered and
dried to provide 110 g off white solid.
[0216] Preparation B:
[0217] the free base of Compound 1 (5 g) was slurried in heptanes
(10 vol 50 mlL) at room temperature. After 4 days, the slurry was
filtered to provide an off-white solid.
[0218] Preparation C:
[0219] the free base of Compound 1 (5.8 kg) was slurried in
heptanes (10 vol) at room temperature. After 2 days, the slurry was
filtered and washed with 2.times.2 vol n-heptane to provide 4.745
kg of Form II as an off-white solid.
[0220] Preparation D:
[0221] the free base of Compound 1 (5 g) was slurried in water.
After 4 days, the slurry was filtered to provide an off-white
solid. Preparation of GBT000440 free base Form N from GBT000440
free base Form I or Form II
[0222] General Procedure:
[0223] Stir a slurry of the free base of Compound 1, Form I in MTBE
(4 vol) at room temperature for at least 4 days. After 4 days,
filter the slurry to provide an off-white solid. Obtain XRPD to
confirm polymorph as Material N.
[0224] Preparation A:
[0225] Following the general procedure above, 27 g of the free base
of Compound 1, Form I (48TRS079) was stirred in MTBE at
18-23.degree. C. for 4 days. DSC indicated it should be Material N.
Isolated 22.2 g cream colored solid (82% recovery, 99.9 purity by
HPLC). XRPD analysis planned.
[0226] Preparation B:
[0227] Following the general procedure above, 31 g of the free base
of Compound 1, Form I was stirred in 3 vol MTBE at 18-23.degree. C.
for 4 days.
[0228] Preparation C:
[0229] the free base of Compound 1, Form I (13KWB023, 1 g) was
slurried in MTBE (5 vol) at room temperature. Slurry was seeded
with Material N (50 mg). After 4 days, the slurry was filtered to
provide a off-white solid. DSC indicated the melting point was the
same as Material N.
[0230] Preparation D:
[0231] The purpose of this experiment was to convert the free base
of Compound 1, Form II to Material N. Thus, the free base of
Compound 1 (0.5 g) was stirred in 5 vol of di-n-propyl ether at
18-23.degree. C. After 2 days, DSC corresponded to the pattern
observed for Material N. XRPD analysis confirmed Material N had
been formed.
[0232] Preparation E:
[0233] To the free base of Compound 1, Form II (5 g) was added
diisopropyl ether (5 vol, 25 mL) at room temperature. After 4 days,
the slurry was filtered to provide a off-white solid. DSC indicates
Material N.
Example 22
Preliminary Solvent-Based Screens
[0234] Rapid, solvent-based screens were conducted in an attempt to
determine the most stable form of the free base of Compound 1. The
study also provides a preliminary assessment of the propensity of
these materials to exist in various crystal forms. Generated solids
were observed by polarized light microscopy (PLM) and/or analyzed
by X-ray powder diffraction (XRPD), comparing the resulting XRPD
patterns to known patterns of Compound 1.
[0235] If possible, XRPD patterns were indexed. Indexing is the
process of determining the size and shape of the crystallographic
unit cell given the peak positions in a diffraction pattern. The
term gets its name from the assignment of Miller index labels to
individual peaks. XRPD indexing serves several purposes. If all of
the peaks in a pattern are indexed by a single unit cell, this is
strong evidence that the sample contains a single crystalline
phase. Given the indexing solution, the unit cell volume may be
calculated directly and can be useful to determine their solvation
states. Indexing is also a robust description of a crystalline form
and provides a concise summary of all available peak positions for
that phase at a particular thermodynamic state point.
[0236] Materials exhibiting unique crystalline XRPD patterns, based
on visual inspection of peaks associated with these materials, were
given letter designations. The letter designation is tentatively
associated with the word `Material` if insufficient
characterization data is available. The nomenclature is used only
to aid in the identification of unique XRPD patterns and does not
imply that the stoichiometry, crystalline phase purity, or chemical
purity of the material is known. Materials are further designated
as forms with Roman numeral designations (i.e., Free Base Material
A=Free Base Form I), when phase purity (obtained through indexing
of the XRPD pattern or single crystal structure elucidation) and
chemical identity/purity (obtained through proton NMR spectroscopy)
of the material is determined.
[0237] Three anhydrous materials were identified: Forms I, II, and
Material N. Material N appears to be most stable form, relative to
Forms I and II, at room temperature. Material N is enantiotropic
relative to Form II, and will transform reversibly at a specific
transition temperature (estimated near 42.degree. C.). Above the
transition temperature, Form II appears to be the most stable form,
relative to Form I and Material N.
[0238] Materials C and D are used to identify a few additional, low
intensity peaks observed in XRPD patterns which were predominantly
composed of the Free Base Form I of Compound 1 or mixtures of the
HCl Form I and Free Base Form I of Compound 1.
Example 23
Anhydrous Ansolvate Forms
Form I
[0239] Free Base Form I is a metastable, anhydrous phase of the
free base that is formed immediately from the disproportionation of
the HCl salt in water. A representative XRPD pattern of Form I was
successfully indexed and the unit cell volume is consistent with
anhydrous free base. Visual comparison of the XRPD pattern to the
historical pattern of the free base provided indicates the material
may be similar; however, the historical pattern appears to exhibit
additional peaks from a potential mixture.
[0240] The .sup.1H NMR spectrum is consistent with the chemical
structure of Compound 1. The chemical shift at approximately 2.5
ppm is assigned to DMSO (due to residual protons in the NMR
solvent). Peaks that could be associated with residual solvents
were not visible, consistent with the anhydrous unit cell volume
determined from the indexing solution above and the negligible wt %
loss observed by TGA discussed below.
[0241] Thermograms (TG) data shows negligible weight loss, 0.2%, up
to 100.degree. C., consistent with an anhydrous form. The DSC
exhibits a single endotherm with an onset near 97.degree. C.
(similar to what is observed for Form II). The endotherm is
consistent with a melt by hot stage microscopy. However, changes in
particle size and birefringence were evident prior to the melt; a
possible phase change occurred. Consequently, if a phase change
occurred and an endotherm similar to that of Free Base Form II was
observed, it can be inferred that the observed melt is truly not of
Form I but of the resulting phase, most likely Form II.
[0242] The DVS isotherm indicates Form I is not hygroscopic.
Negligible weight gain and loss, 0.2%, was observed through
sorption/desorption. By XRPD, the material recovered from the DVS
experiment was predominately Free Base Form I with a few additional
peaks. The additional peaks were termed Free Base Material D. The
nature of Material D is unknown; however, the appearance of another
phase(s) indicates that Form I is not likely physically stable at
elevated humidity conditions (at ambient temperature).
Form II
[0243] Free Base Form II is an anhydrous phase of the free base.
Form II is enantiotropically related to Material N, where it is the
thermodynamically stable form above an estimated transition
temperature of 42.degree. C. Form II can be generated in solvents
that do not form known solvates; such as heptane, IPE, MTBE, or
toluene; through short-term slurry conversions of Form I (where the
crystallization kinetics delay the nucleation of the more stable
form) or elevated temperature slurries (above 42.degree. C.). A
representative XRPD pattern of Form II was successfully indexed and
the unit cell volume is consistent with anhydrous free base of
Compound 1.
[0244] The .sup.1H NMR spectrum is consistent with the chemical
structure of Compound 1. The chemical shift at approximately 2.5
ppm is assigned to DMSO (due to residual protons in the NMR
solvent). Peaks that could be associated with residual solvents
were not visible, consistent with the anhydrous unit cell volume
determined from the indexing solution above and the negligible wt %
loss observed by TGA discussed below.
[0245] Thermograms (TG) data show negligible weight loss, 0.1%, up
to 100.degree. C., consistent with an anhydrous form. The DSC
exhibits a single endotherm (80.1 J/g) with an onset near
97.degree. C.
[0246] Form II remained unchanged after 7 days at ambient storage,
through reanalysis by XRPD. The form is known to be
thermodynamically metastable, relative to Material N, at this
condition; however, the kinetics of polymorph conversion may be
slow at ambient conditions in the solid state.
Material N
[0247] Free Base Material N is an anhydrous phase of the free base.
Material N is enantiotropically related to Form II, where it is the
thermodynamically stable form below an estimated transition
temperature of 42.degree. C. Given the opportunity, Material N can
be generated through slurries in solvents that do not form known
solvates; such as heptane, IPE, MTBE, or toluene; at temperatures
below 42.degree. C. The following is an example of a laboratory
scale procedure used to generate Free Base Material N. [0248] 53.0
mg of Free Base Form I was contacted with 2 ml of an IPE/free base
solution (concentration 13 mg/ml). A stir bar was added and the
sample was slurried for 7 days at ambient. The solution was
decanted from the sample and the remaining solids briefly dried
under nitrogen. Characterization Data indicates Material N is a
unique crystalline phase.
[0249] The .sup.1H NMR spectrum is consistent with the chemical
structure of Compound 1. The chemical shift at approximately 2.5
ppm is assigned to DMSO (due to residual protons in the NMR
solvent). Peaks that could be associated with residual solvents
were not visible, consistent with the negligible wt % loss observed
by TGA discussed below.
[0250] Thermograms (TG) data show negligible weight loss, 0.2%, up
to 100.degree. C., consistent with an anhydrous form. The DSC
exhibits a single endotherm (82.8 J/g) with an onset at 94.degree.
C.
[0251] Tentative Determination of the Thermodynamic Relationship
between Free Base Forms I, II, and Material N
[0252] Characterization data indicates that Forms I, II, and
Material N are unique crystalline phases; however, only the XRPD
patterns of Forms I and II were successfully indexed to confirm
phase purity. Therefore, any proposed thermodynamic relationship
between these materials is a working hypothesis, where the phase
purity of Material N is assumed.
[0253] Phase transitions of solids can be thermodynamically
reversible or irreversible. Crystalline forms which transform
reversibly at a specific transition temperature (T.sub.p) are
called enantiotropic polymorphs. If the crystalline forms are not
interconvertable under these conditions, the system is monotropic
(one thermodynamically stable form). Several rules have been
developed to predict the relative thermodynamic stability of
polymorphs and whether the relationship between the polymorphs is
enantiotropic or monotropic. The heat of fusion rule is applied
within this study. The heat of fusion rule states that if the
higher melting form has the lower heat of fusion then the two forms
are enantiotropic, otherwise they are monotropic.
[0254] Material N appears to be most stable form, relative to Forms
I and II, at room temperature. Based on the heats of fusion and
melts determined by DSC, Material N is enantiotropic relative to
Form II, and will transform reversibly at a specific transition
temperature (T.sup.N-II). Due to a possible phase change of Form I
to Form II that occurred prior to the observed endotherm in the
DSC, the relationship of Form I with either Material N or Form II
cannot be conclusively determined through the heat of fusion rule.
However, through various interconversion slurries, it was shown
that Form I is the least thermodynamically stable form between
6.degree. C. and T.sup.N-II. In addition, assuming that Form I
spontaneously converted to Form II in the DSC at elevated
temperatures (prior to the observed melt), it must follow that Form
II is also more stable than Form I above T.sup.N-II.
Example 24
Estimated Transition Temperature
[0255] The estimated transition temperature between two
enantiotropically related forms can be calculated from their melt
onsets and heats of fusion based on the equation shown below.
T p = .DELTA. H f , 2 - .DELTA. H f , 1 + ( C p , liq - C p , 1 ) (
T f , 1 - T f , 2 ) .DELTA. H f , 2 T f , 2 - .DELTA. H f , 1 T f ,
1 + ( C p , liq - C p , 1 ) ln ( T f , 1 T f , 2 ) ##EQU00001##
Where , ( C p , liq - C p , 1 ) = k .DELTA. H f , 1 ##EQU00001.2##
and ##EQU00001.3## k = 0.005 ##EQU00001.4##
[0256] Between Material N and Form II, the equation estimates a
transition temperature of 42.degree. C. To summarize, the relative
stability of the forms from most to least stable is shown
below.
TABLE-US-00024 Temperature Relative Range* Stability Comments Below
6.degree. C. N > II Relationships to Form I are not established
below this temp Between 6.degree. C. and N > II > I --
T.sup.N-II Above T.sup.N-II (II > N) and Relationship between
Form (II > I) I and Material N is not established above this
temp *T.sup.N-II is estimated to be near 42.degree. C.
Example 25
Energy-Temperature Diagram
[0257] The Energy-Temperature Diagram of FIG. 17 is a
semi-quantitative graphical solution of the Gibbs-Helmholtz
equation, where the enthalpy (H) and free energy (G) isobars for
each form are depicted as a function of temperature.
Example 26
Competitive Interconversion Slurry Experiments
[0258] Interconversion experiments were performed to support the
thermodynamic relationship between polymorphs illustrated by the
Energy-Temperature Diagram above. Interconversion or competitive
slurry experiments are a solution-mediated process that provides a
pathway for the less soluble (more stable) crystal to grow at the
expense of the more soluble crystal form. Outside the formation of
a solvate or degradation, the resulting more stable polymorph from
an interconversion experiment is contemplated to be independent of
the solvent used because the more thermodynamically stable
polymorph has a lower energy and therefore lower solubility. The
choice of solvent affects the kinetics of polymorph conversion and
not the thermodynamic relationship between polymorphic forms.
[0259] The results of the interconversion studies are consistent
with the tentative Energy-Temperature Diagram shown herein. Binary
slurries were prepared at ambient, 6, and 57.degree. C. using Forms
I and II. Form II resulted from the majority of these experiments,
confirming that Form II is more stable relative to Form I within
this temperature range.
[0260] A few of the experiments conducted at ambient and 6.degree.
C. resulted in Material N. Although this does not provide specific
clarification between Forms I and II, it does provide evidence that
Material N is the most stable form relative to both Forms I and II
at these temperatures (which were conducted below the estimated
transition temperature of 42.degree. C.). Additional
interconversion slurries between Form II and Material N were
conducted at temperatures which bracket this estimated transition
temperature and confirm that Form II and Material N are
enantiotropically related.
Example 27
Solid-State Nuclear Magnetic Resonance
[0261] .sup.13C and .sup.15N spectra acquired for the three
polymorphic forms I, II and Material N. See FIGS. 10 and 11.
Spectra were acquired at 253K to prevent any low temperature
transitions occurring during measurement and acquisition parameters
optimised for each polymorphic form.
[0262] Based on solid-state nuclear magnetic resonance, all three
forms are crystalline and are distinct polymorphic forms. Form I
contains one molecule per asymmetric unit, Form II contains two
molecules per asymmetric unit and Form N contains four molecules
per asymmetric unit. See the .sup.15N spectra in FIG. 11.
Example 28
Chemical and Physical Stability Evaluation of the Free Base Form I
of Compound 1
[0263] A mixture predominately composed of Free Base Form I (with
Free Base Material D) were exposed to stability conditions to
assess physical and chemical stability. Three conditions were used;
open to 25.degree. C./60% RH, open to 40.degree. C./75% RH, and
closed to 60.degree. C. Physical stability was evaluated by XRPD.
Chemical stability was determined through UPLC and .sup.1H NMR,
when applicable. Materials were tested after 1, 7, and 14 days of
exposure.
Chemical Stability of Free Base Form I
[0264] For the free base stability sample, UPLC showed very low
levels of impurities present. The level of impurities did not rise
significantly after 14 days of age. This would seem to indicate
good chemical stability against the conditions used for stability
assessment. The .sup.1H NMR spectra of samples exposed to
60.degree. C. (14 days) were also consistent with this
conclusion.
Physical Stability of Free Base Form I
[0265] The free base of Compound 1 remained unchanged, by XRPD, at
25.degree. C./60% RH. However, differences were observed at the
other two conditions. The few, minor peaks attributed to Free Base
Material D were no longer observed, indicating that Material D is
metastable and is not sustained at elevated temperatures. In
addition, Free Base Form II was observed after 7 days of age. This
is consistent with the conclusions discussed herein, where Free
Base Form II is more stable relative to Free Base Form I at these
temperatures.
Example 29
Physical Stability Evaluation of the Free Base Form II and Material
N (Form N) of Compound 1
[0266] DSC was modulated at low underlying heating rate, followed
by X-ray powder diffraction. A low underlying heating rate was used
of 0.02.degree. C. mid'. The temperature was 80.degree. C. for form
N and 90.degree. C. for form II. Exposure was essentially
isothermal, covering a temperature range with sensitivity to detect
changes in physical form. The resultant materials were examined by
X-ray powder diffraction. No changes in physical form were observed
for either polymorphic form II or polymorphic form N (i.e.,
material N).
[0267] Forms II and N were exposed to 40.degree. C./75% relative
humidity (RH), 80.degree. C., 80.degree. C./80% RH for 9 days
followed by X-ray powder diffraction. No changes in physical form
were observed for either polymorphic form II or polymorphic form
N.
[0268] The thermodynamic barrier for inter-conversion between
polymorphic form II and form N is high, and physical stability is
good for both forms. Thermally induced inter-conversion between
form II and form N is unlikely to occur.
Example 30
The Relative Thermodynamic Stability of Polymorphic Forms II and
N
[0269] Extended solvent mediated maturation studies were conducted
with 1:1 w/w mixtures of polymorphic form II and form N. Hexane
provided a good medium for solvent assessments. The temperatures
used include -20.degree. C., -10.degree. C., 0.degree. C.,
10.degree. C., 20.degree. C., 30.degree. C., 40.degree. C. and
50.degree. C. Significantly increased solubility was observed at
30.degree. C., 40.degree. C. and 50.degree. C. Solids derived from
maturation at -20.degree. C., -10.degree. C., 0.degree. C.,
10.degree. C., 20.degree. C. were analyzed by X-ray powder
diffraction. In each case, significant conversion to Form N was
observed.
[0270] Form N is thermodynamically more stable than form II at
temperatures of 20.degree. C. and lower. An enantiotropic
relationship between the two forms is likely to exhibit equivalence
in thermodynamic stability at ca. 30-40.degree. C.
Example 31
Morphology of Form N
[0271] Initial examination of a batch of polymorphic form N
indicates an acicular morphology.
[0272] While this invention has been described in conjunction with
specific embodiments and examples, it will be apparent to a person
of ordinary skill in the art, having regard to that skill and this
disclosure, that equivalents of the specifically disclosed
materials and methods will also be applicable to this invention;
and such equivalents are intended to be included within the
following claims.
* * * * *