U.S. patent application number 10/218985 was filed with the patent office on 2003-04-10 for crystals including a malic acid salt of a 3-pyrrole substituted 2-indolinone, and compositions thereof.
This patent application is currently assigned to PHARMACIA & UPJOHN COMPANY. Invention is credited to Fleck, Thomas J., Hawley, Michael, Maloney, Mark T., Prescott, Stephen P..
Application Number | 20030069298 10/218985 |
Document ID | / |
Family ID | 23211067 |
Filed Date | 2003-04-10 |
United States Patent
Application |
20030069298 |
Kind Code |
A1 |
Hawley, Michael ; et
al. |
April 10, 2003 |
Crystals including a malic acid salt of a 3-pyrrole substituted
2-indolinone, and compositions thereof
Abstract
The present invention provides crystals, and compositions
thereof, wherein the crystals include a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-
-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrro-
le-3-carboxamide. Methods of preparing such crystals are also
disclosed.
Inventors: |
Hawley, Michael; (Kalamazoo,
MI) ; Fleck, Thomas J.; (Scotts, MI) ;
Prescott, Stephen P.; (Schoolcraft, MI) ; Maloney,
Mark T.; (Kalamazoo, MI) |
Correspondence
Address: |
MUETING, RAASCH & GEBHARDT, P.A.
P.O. BOX 581415
MINNEAPOLIS
MN
55458
US
|
Assignee: |
PHARMACIA & UPJOHN
COMPANY
Kalamazoo
MI
|
Family ID: |
23211067 |
Appl. No.: |
10/218985 |
Filed: |
August 13, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60312353 |
Aug 15, 2001 |
|
|
|
Current U.S.
Class: |
514/414 ;
548/465 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
35/02 20180101; A61P 17/06 20180101; C07D 403/06 20130101; A61P
35/00 20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/414 ;
548/465 |
International
Class: |
A61K 031/404; C07D
43/02 |
Claims
What is claimed is:
1. An anhydrous crystal comprisng a malic acid salt of a compound
having the structure: 3
2. The crystal of claim 1, wherein the malic acid is L-malic
acid.
3. An anhydrous crystal comprising a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide.
4. A crystal comprising a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[-
(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyr-
role-3-carboxamide, wherein the crystal has characteristic
diffraction peaks at about 13.2 and 24.2 degrees two-theta in a
powder X-ray diffraction pattern.
5. The crystal of claim 4 having characteristic diffraction peaks
at about 13.2, 19.4, 24.2, and 25.5 degrees two-theta in a powder
X-ray diffraction pattern.
6. The crystal of claim 5 having characteristic diffraction peaks
in a powder X-ray diffraction pattern as listed in Table 1 for
Crystal Form I.
7. The crystal of claim 4 further comprising at most about 2% by
weight water.
8. The crystal of claim 7 comprising at most about 0.5% by weight
water.
9. The crystal of claim 8 comprising at most about 0.2% by weight
water.
10. A crystal comprising a malic acid salt of
N-[2-(diethylamino)ethyl]-5--
[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-py-
rrole-3-carboxamide, wherein the crystal has a melting point of at
least about 190.degree. C.
11. The crystal of claim 10 having a melting point of at least
about 195.degree. C.
12. The crystal of claim 10 further comprising at most about 2% by
weight water.
13. The crystal of claim 12 comprising at most about 0.5% by weight
water.
14. The crystal of claim 13 comprising at most about 0.2% by weight
water.
15. A crystal comprising a malic acid salt of
N-[2-(diethylamino)ethyl]-5--
[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-py-
rrole-3-carboxamide, wherein the crystal has characteristic
diffraction peaks at about 3.0 and 27.7 degrees two-theta in a
powder X-ray diffraction pattern.
16. The crystal of claim 15 having characteristic diffraction peaks
at about 3.0, 12.1, 14.5, and 27.7 degrees two-theta in a powder
X-ray diffraction pattern.
17. The crystal of claim 16 having characteristic diffraction peaks
in a powder X-ray diffraction pattern as listed in Table 1 for
Crystal Form II.
18. The crystal of claim 15, wherein the crystal absorbs at least
about 5% by weight water upon exposure to 80% relative
humidity.
19. A crystal comprising a malic acid salt of
N-[2-(diethylamino)ethyl]-5--
[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-py-
rrole-3-carboxamide, wherein the crystal has a melting point of at
most about 185.degree. C.
20. The crystal of claim 19, wherein the crystal absorbs at least
about 5% by weight water upon exposure to 80% relative
humidity.
21. A method of preparing an anhydrous crystal comprising a malic
acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-
-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, the
method comprising: combining malic acid;
N-[2-(diethylamino)ethyl]-5-[(5-fluoro--
1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-car-
boxamide; and a solvent; and inducing the salt to crystallize under
crystallization conditions comprising one or more factors
comprising: a difference between the initial and final temperatures
of the crystallization solution of at most about 100.degree. C.; a
rate of cooling of at most about 50.degree. C. per hour; no
seeding; a supersaturation ratio of at most about 10; no
precipitant; and/or combinations thereof.
22. The method of claim 21, wherein the malic acid is L-malic
acid.
23. The method of claim 21, wherein the one or more factors
comprise: a difference between the initial and final temperatures
of the crystallization solution of at most about 50.degree. C.; a
rate of cooling of at most about 20.degree. C. per hour; a
supersaturation ratio of at most about 5; and/or combinations
thereof.
24. The method of claim 23, wherein the one or more factors
comprise: a difference between the initial and final temperatures
of the crystallization solution of at most about 25.degree. C.; a
rate of cooling of at most about 2.degree. C. per hour; a
supersaturation ratio of at most about 1.5; and/or combinations
thereof.
25. The method of claim 24, wherein the initial and final
temperatures of the crystallization solution are the same.
26. The method of claim 21, wherein the solvent is selected from
the group consisting of acetonitrile, methanol, ethanol,
isopropanol, toluene, n-butanol, tetrahydrofuran,
N,N-dimethylformamide, acetone, water, and combinations
thereof.
27. The method of claim 21, wherein the anhydrous crystal has
characteristic diffraction peaks at about 13.2 and 24.2 degrees
two-theta in a powder X-ray diffraction pattern.
28. The crystal of claim 27 having characteristic diffraction peaks
at about 13.2, 19.4, 24.2, and 25.5 degrees two-theta in a powder
X-ray diffraction pattern.
29. The crystal of claim 28 having characteristic diffraction peaks
in a powder X-ray diffraction pattern as listed in Table 1 for
Crystal Form I.
30. A method of preparing an anhydrous crystal comprising a malic
acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-
-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, the
method comprising contacting a crystal comprising a malic acid salt
of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide with a solvent in
which the contacting crystal has substantial solubility, wherein
the contacting crystal has characteristic diffraction peaks at
about 3.0 and 27.7 degrees two-theta in a powder X-ray diffraction
pattern.
31. The method of claim 30, wherein the contacting crystal has
characteristic diffraction peaks at about 3.0, 12.1, 14.5, and 27.7
degrees two-theta in a powder X-ray diffraction pattern.
32. The method of claim 3 1, wherein the contacting crystal has
characteristic diffraction peaks in a powder X-ray diffraction
pattern as listed in Table 1 for Crystal Form II.
33. The method of claim 30, wherein the solvent is selected from
the group consisting of acetonitrile, ethanol, methanol, and
combinations thereof.
34. The method of claim 30, wherein contacting the crystal with the
solvent forms a slurry.
35. The method of claim 34 further comprising stirring the
slurry.
36. The method of claim 34 further comprising heating the
slurry.
37. The method of claim 34 further comprising removing the
anhydrous crystal from the slurry.
38. The method of claim 30, wherein the anhydrous crystal has
characteristic diffraction peaks at about 13.2 and 24.2 degrees
two-theta in a powder X-ray diffraction pattern.
39. The method of claim 38, wherein the anhydrous crystal has
characteristic diffraction peaks at about 13.2, 19.4, 24.2, and
25.5 degrees two-theta in a powder X-ray diffraction pattern.
40. The method of claim 39, wherein the anhydrous crystal has
characteristic diffraction peaks in a powder X-ray diffraction
pattern as listed in Table 1 for Crystal Form I.
41. A method of preparing a crystal comprising a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, the method
comprising: combining malic acid;
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro--
2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide;
and a solvent; and inducing the salt to crystallize under
crystallization conditions comprising one or more factors
comprising: a difference between the initial and final temperatures
of the crystallization solution of at least about 25.degree. C.; a
rate of cooling of at least about 25.degree. C. per hour; seeding;
a supersaturation ratio of at least about 2; presence of a
precipitant; and/or combinations thereof.
42. The method of claim 41, wherein the malic acid is L-malic
acid.
43. The method of claim 41, wherein the one or more factors
comprise: a difference between the initial and final temperatures
of the crystallization solution of at least about 50.degree. C.; a
rate of cooling of at least about 100.degree. C. per hour; a
supersaturation ratio of at least about 5; and/or combinations
thereof.
44. The method of claim 43, wherein the one or more factors
comprise: a difference between the initial and final temperatures
of the crystallization solution of at least about 100.degree. C.; a
rate of cooling of at least about 300.degree. C. per hour; a
supersaturation ratio of at least about 10; and/or combinations
thereof.
45. The method of claim 41, wherein the solvent is selected from
the group consisting of methanol, water, tetrahydrofuran/water
mixtures, and combinations thereof.
46. The method of claim 41, wherein the crystal has characteristic
diffraction peaks at about 3.0 and 27.7 degrees two-theta in a
powder X-ray diffraction pattern.
47. The method of claim 46, wherein the crystal has characteristic
diffraction peaks at about 3.0, 12.1, 14.5, and 27.7 degrees
two-theta in a powder X-ray diffraction pattern.
48. The method of claim 47, wherein the crystal has characteristic
diffraction peaks in a powder X-ray diffraction pattern as listed
in Table 1 for Crystal Form II.
49. A composition comprising anhydrous crystals comprising a malic
acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-
-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide.
50. The composition of claim 49 further comprising an
excipient.
51. A composition comprising crystals comprising a malic acid salt
of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the
crystals have characteristic diffraction peaks at about 13.2 and
24.2 degrees two-theta in a powder X-ray diffraction pattern.
52. A composition comprising crystals comprising a malic acid salt
of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the
crystals have a melting point of at least about 190.degree. C.
53. A composition comprising crystals comprising a malic acid salt
of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the
crystals have characteristic diffraction peaks at about 3.0 and
27.7 degrees two-theta in a powder X-ray diffraction pattern.
54. A composition comprising crystals comprising a malic acid salt
of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, wherein the
crystals have a melting point of at most about 185.degree. C.
Description
[0001] This application claims the benefit of the U.S. Provisional
Application Serial No. 60/312,353, filed Aug. 15, 2001, which is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to crystals, and compositions
thereof, wherein the crystals include a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide. The present
invention also relates to methods of preparing such crystals.
BACKGROUND
[0003] PKs are enzymes that catalyze the phosphorylation of hydroxy
groups on tyrosine, serine, and threonine residues of proteins. The
consequences of this seemingly simple activity are staggering: cell
growth, differentiation, and proliferation, i.e., virtually all
aspects of cell life in one way or another, depend on PK activity.
Furthermore, abnormal PK activity has been related to a host of
disorders, ranging from relatively non-life threatening diseases
such as psoriasis to extremely virulent diseases such as
glioblastoma (brain cancer). The PKs can be conveniently broken
down into two classes, the protein tyrosine kinases (PTKs) and the
serine-threonine kinases (STKs).
[0004] One of the prime aspects of PTK activity is their
involvement with growth factor receptors. Growth factor receptors
are cell-surface proteins. When bound by a growth factor ligand,
growth factor receptors are converted to an active form, which
interacts with proteins on the inner surface of a cell membrane.
This leads to phosphorylation on tyrosine residues of the receptor
and other proteins and to the formation inside the cell of
complexes with a variety of cytoplasmic signaling molecules that,
in turn, effect numerous cellular responses such as cell division
(proliferation), cell differentiation, cell growth, expression of
metabolic effects to the extracellular microenvironment, etc.
[0005] Small molecules that act as PK inhibitors have been
identified and include, for example, 3-pyrrole substituted
2-indolinone compounds as disclosed in PCT International
Publication No. WO 01/60814 (Tang et al.). 3-Pyrrole substituted
2-indolinone compounds include, for example,
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide as disclosed in
PCT International Publication No. WO 01/60814 (Tang et al.).
However, the disclosure is silent as to the preparation of and the
nature of specific crystal forms of salts of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihy-
dro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide-
. There exists a need for crystalline forms of such materials that
have superior chemical and/or physical properties that are useful
in drug delivery applications.
SUMMARY OF THE INVENTION
[0006] In one aspect, the present invention provides a crystal
including a malic acid salt of a compound having the structure:
1
[0007] The compound with the above structure is also known as
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide. The malic acid
salt may be a salt of D-malic acid; D,L-malic acid; L-malic acid;
or combinations thereof. Preferably, the malic acid salt is a salt
of L-malic acid. Preferably, the crystal is anhydrous. Preferably,
the crystal has characteristic diffraction peaks at about 13.2 and
24.2 degrees two-theta, and more preferably at about 13.2, 19.4,
24.2, and 25.5 degrees two-theta, and most preferably as listed in
Table 1 for Crystal Form I, in a powder X-ray diffraction pattern.
Preferably, the crystal includes at most about 2% by weight water,
more preferably at most about 0.5% by weight water, and most
preferably at most about 0.2% by weight water. Preferably, the
crystal has a melting point of at least about 190.degree. C., and
more preferably at least about 195.degree. C. Compositions
including the crystals described herein are also provided.
Preferably, the compositions include a therapeutically effective
amount of the crystals. Optionally, the compositions include an
excipient, preferably a pharmaceutically acceptable excipient.
[0008] In another aspect, the present invention provides a crystal
including a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-
-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbox-
amide, wherein the crystal has characteristic diffraction peaks at
about 3.0 and 27.7 degrees two-theta, more preferably at about 3.0,
12.1, 14.5, and 27.7 degrees two-theta, and most preferably as
listed in Table 1 for Crystal Form II, in a powder X-ray
diffraction pattern. Typically, the crystal absorbs at least about
5% by weight water upon exposure to 80% relative humidity and has a
melting point of at most about 185.degree. C. Compositions
including the crystals described herein are also provided.
Preferably, the compositions include a therapeutically effective
amount of the crystals. Optionally, the compositions include an
excipient, preferably a pharmaceutically acceptable excipient.
[0009] In another aspect, the present invention provides methods of
preparing an anhydrous crystal including a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (e.g., Crystal
Form I). In one embodiment, the method includes: combining malic
acid;
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide; and a solvent;
and inducing the salt to crystallize under crystallization
conditions (e.g., Crystal Form I crystallization conditions)
including one or more factors including: a difference between the
initial and final temperatures of the crystallization solution of
at most about 100.degree. C.; a rate of cooling of at most about
50.degree. C. per hour; no seeding; a supersaturation ratio of at
most about 10; no precipitant; and/or combinations thereof.
Preferably, the malic acid is L-malic acid. Preferably, the solvent
includes one or more solvents including, for example, acetonitrile,
methanol, ethanol, isopropanol, toluene, n-butanol,
tetrahydrofuran, N,N-dimethylformamide, acetone, water, and
combinations thereof.
[0010] In another embodiment, the method of preparing an anhydrous
crystal including a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-
-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbox-
amide (e.g., Crystal Form I) includes: contacting a crystal
including a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-o-
xo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
with a solvent in which the contacting crystal has substantial
solubility, wherein the contacting crystal (e.g., Crystal Form II)
has characteristic diffraction peaks at about 3.0 and 27.7 degrees
two-theta in a powder X-ray diffraction pattern. Preferably, the
solvent includes one or more solvents including, for example,
acetonitrile, ethanol, methanol, and combinations thereof.
Preferably, contacting the crystal with the solvent forms a slurry,
and the slurry is preferably stirred and/or heated. Optionally, the
anhydrous crystal may be removed from the slurry.
[0011] In another aspect, the present invention provides a method
of preparing a crystal including a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (e.g., Crystal
Form II). The method includes: combining malic acid;
N-[2-(diethylamino)ethyl]-5-[(-
5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrr-
ole-3-carboxamide; and a solvent; and inducing the salt to
crystallize under crystallization conditions (e.g., Crystal Form II
crystallization conditions) including one or more factors
including: a difference between the initial and final temperatures
of the crystallization solution of at least about 25.degree. C.; a
rate of cooling of at least about 25.degree. C. per hour; seeding;
a supersaturation ratio of at least about 2; presence of a
precipitant; and/or combinations thereof. Preferably, the malic
acid is L-malic acid. Preferably, the solvent includes one or more
solvents including, for example, methanol, water,
tetrahydrofuran/water mixtures, and combinations thereof.
Preferably, the crystal has characteristic diffraction peaks at
about 3.0 and 27.7 degrees two-theta in a powder X-ray diffraction
pattern.
[0012] The anhydrous Crystal Form I is advantageous over Crystal
Form II for many applications because the properties that Crystal
Form I offers preferably include, for example, greater
thermodynamic stability, higher crystallinity, and lower
hygroscopicity than the respective properties of Crystal Form
II.
[0013] Numerous factors effect crystallization conditions, and they
are well known to one of skill in the art. Such factors include,
for example: the concentration of the salt in the crystallization
solution; the difference, if any, between the initial and final
temperatures of the crystallization solution; the rate of cooling,
if any; the solvent vaporization rate, if any; seeding;
supersaturation ratio; and presence of a precipitant. With guidance
from the disclosure provided herein, one of skill in the art,
without undue experimentation, may select and/or adjust one or more
appropriate factors to arrive at crystallization conditions to
provide Crystal Form I and/or Crystal Form II.
[0014] Definitions
[0015] As used herein, "supersaturation ratio" refers to the ratio
of the concentration of the material in solution to the
concentration of the material in a saturated solution at the
crystallization temperature.
[0016] As used herein, "seeding" refers to the technique of adding
a "seed" crystal to the crystallization solution to promote the
formation of crystals. Preferably, the composition of the seed
crystal is the same as the composition of the crystals being
formed.
[0017] As used herein, "precipitant" means a substance that tends
to induce crystallization when added to a crystallization solution.
Useful precipitants include, for example, non-solvents for the salt
and solutions including excess counterions. As used herein, a
non-solvent is a solvent in which the salt preferably has a
solubility of at most about 1% by weight, more preferably at most
about 0.1% by weight, and most preferably at most about 0.01% by
weight.
[0018] As used herein, "anhydrous crystal" means a crystal in which
water is not specifically bound. Anhydrous crystals preferably do
not include substantial amounts of water. The water content can be
determined by methods known in the art including, for example, Karl
Fischer titrations. Preferably an anhydrous crystal includes at
most about 2% by weight water, more preferably at most about 0.5%
by weight water, and most preferably at most about 0.2% by weight
water.
[0019] As used herein, "crystalline" means a material that has an
ordered, long range molecular structure. The degree of
crystallinity of a crystal form can be determined by many
techniques including, for example, powder X-ray diffraction,
moisture sorption, differential scanning calorimetry, solution
calorimetry, and dissolution properties.
[0020] As used herein, "more crystalline" means that a material has
a higher degree of crystallinity than the material to which it is
being compared. Materials with higher degrees of crystallinity
generally have highly ordered, long range molecular structure with
fewer defects in the crystal structure than materials with lower
degrees of crystallinity. The higher degree of crystallinity can be
assessed relative to the other form by techniques including, for
example, sharper reflections in the powder X-ray diffraction
pattern, lower moisture sorption for similar sized particles at a
specified relative humidity, lower heat of solution, higher heat of
fusion, slower dissolution rate, and combinations thereof.
[0021] As used herein, "less crystalline" means that a material has
a lower degree of crystallinity than the material to which it is
being compared. Materials with lower degrees of crystallinity
generally have less long range order and more defects in the
crystal structure than materials with higher degrees of
crystallinity. The lower degree of crystallinity can be assessed
relative to the other form by techniques including, for example,
broader and/or fewer reflections in the powder X-ray diffraction
pattern, higher moisture sorption for similar sized particles at a
specified relative humidity, higher heat of solution, lower heat of
fusion, faster dissolution rate, and combinations thereof.
[0022] As referred to in the present application, "stable" in bulk
drug stability tests means that at least about 97% by weight,
preferably at least about 98% by weight, and more preferably at
least about 99% by weight of the bulk drug remains unchanged after
storage under the indicated conditions for the indicated time.
BRIEF DESCRIPTION OF THE FIGURES
[0023] FIG. 1 is an illustration of the powder X-ray diffraction
(PXRD) data for Crystal Form I of the L-malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide. The pattern is
distinct from other crystal forms of the salt and the free base,
and is more crystalline than Crystal Form II (e.g., FIG. 2).
[0024] FIG. 2 is an illustration of the powder X-ray diffraction
(PXRD) data for Crystal Form II of the L-malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide. The pattern is
distinct from other crystal forms of the salt and the free base,
and is less crystalline than Crystal Form I as evidenced by the
broader reflections in the powder X-ray diffraction pattern (e.g.,
FIG. 1).
[0025] FIG. 3 is an illustration of dynamic moisture sorption
gravimetry (DMSG) sorption isotherm for Moisture sorption profiles
for Crystal Form I & Crystal Form II of the L-malic acid salt
of N-[2-(diethylamino)ethyl]-
-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1
H-pyrrole-3-carboxamide. The more crystalline polymorph, Crystal
Form I is of low hygroscopicity, absorbing less than 0.5% water
across the 0-90% relative humidity range. The less crystalline
polymorph, Crystal Form II, is very hygroscopic, absorbing over 15%
water over the 0-90% relative humidity range.
[0026] FIG. 4 is an illustration of differential scanning
calorimetry (DSC) data showing DSC profiles for Crystal Form I
& Crystal Form II of the L-malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihyd-
ro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide.
Exothermic transitions are indicated in the up direction. Crystal
Form I melts at a higher temperature (about 196.degree. C.) with a
higher melt enthalpy (about 141 J/g) than Crystal Form II, which
melts at about 181.degree. C. with a melt enthalpy of about 105
J/g. This suggests the two crystal forms are monotropic, although
degradation occurs after the crystals melt. Monotropism is
confirmed by the conversion of Crystal Form II to Crystal Form I in
a room temperature slurry as described herein.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0027]
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-
-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide is a
3-pyrrole substituted 2-indolinone compound having the following
structure: 2
[0028]
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-
-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide can be
prepared as the free base by standard synthetic procedures
including, for example, those disclosed in PCT International
Publication No. WO 01/60814 (Tang et al.). Although the free base
may be crystallized as small particles, it is desirable in large
scale operations, for example, to have larger particle size
crystals for ease in filtration. To this end, the preparation of
salts of N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydr-
o-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
was undertaken for evaluation of the resulting properties related
to the processing of the salt and the preparation of oral
pharmaceutical compositions therefrom.
[0029] Crystalline forms of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dih-
ydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamid-
e including the free base and salts thereof (e.g., cyclamic acid,
maleic acid, hydrobromic acid, mandelic acid, tartaric acid,
fumaric acid, ascorbic acid, phosphoric acid, hydrochloric acid,
p-toluenesulfonic acid, cirtric acid, and malic acid salts) were
screened for properties related to the processing of the salt and
the preparation of oral pharmaceutical compositions therefrom,
including, for example, crystallinity (e.g., crystalline or
amorphous, degree of crystallinity, anhydrous or hydrated
crystals), toxicity, hygroscopicity, stability, and morphology.
Based on the above screening, a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide was determined to
provide the best balance of desired properties. Upon further study,
it was found that a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihy-
dro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
crystallized in multiple crystal forms.
[0030] The present invention provides methods for preparing crystal
forms including a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-
-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbox-
amide, and the identification of those crystal forms. The
preparation of anhydrous crystals including a malic acid salt is
described herein. The anhydrous Crystal Form I has superior
properties for many applications.
[0031] Crystal Form I
[0032] In one embodiment, a malic acid salt of
N-[2-(diethylamino)ethyl]-5-
-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-p-
yrrole-3-carboxamide has been prepared as anhydrous crystals (e.g.,
Crystal Form I). The anhydrous Crystal Form I is thermodynamically
more stable than other crystal forms (e.g., Crystal Form II). in
one method, Crystal Form I can be prepared, for example, by
inducing crystallization of a malic acid salt under Crystal Form I
crystallization conditions from a supersaturated solution.
[0033] As used herein, "Crystal Form I crystallization conditions"
refer to crystallization conditions that provide the thermodynamic
crystal form (e.g., Crystal Form I). Such conditions are commonly
called "slow" crystallization conditions. One of skill in the art
may select one or more factors including, for example: a difference
between the initial and final temperatures of the crystallization
solution of preferably at most about 100.degree. C., more
preferably at most about 50.degree. C., even more preferably at
most about 25.degree. C., and most preferably about 0.degree. C.; a
cooling rate of preferably at most about 50.degree. C. per hour,
more preferably at most about 20.degree. C. per hour, even more
preferably at most about 2.degree. C. per hour, and most preferably
about 0.degree. C. per hour; no seeding; a supersaturation ratio of
preferably at most about 10, more preferably at most about 5, and
most preferably at most about 1.5; no precipitant; and/or
combinations thereof to provide for Crystal Form I crystallization
conditions.
[0034] Useful solvents for preparing the crystallization solution
include, for example, acetonitrile, methanol, ethanol, isopropanol,
toluene, n-butanol, tetrahydrofuran, N,N-dimethylformamide,
acetone, water, and combinations thereof.
[0035] In another method, Crystal Form I can be prepared, for
example, by providing a slurry of Crystal Form II in solvents in
which Crystal Form II has substantial solubility. As used herein,
"substantial solubility" means that a crystal is preferably soluble
in the solvent in concentrations of at least about 0.1% by weight,
more preferably at least about 1% by weight, and most preferably at
least about 10% by weight, at about room temperature (e.g., about
15.degree. C. to about 30.degree. C.). Optionally, the crystal can
be dissolved in the solvent at the indicated concentration at room
temperature.
[0036] Such solvents include, for example, acetonitrile, ethanol,
methanol, and combinations thereof.
[0037] Crystal Form II
[0038] In another embodiment, a malic acid salt of
N-[2-(diethylamino)ethy-
l]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl--
1H-pyrrole-3-carboxamide has been prepared in another crystalline
form (e.g., Crystal Form II). Crystal Form II is useful, for
example, as an intermediate in the preparation of the anhydrous
Crystal Form I.
[0039] Crystal Form II can be prepared, for example, by inducing a
malic acid salt to crystallize under Crystal Form II
crystallization conditions from a supersaturated solution.
[0040] As used herein, "Crystal Form II crystallization conditions"
refer to crystallization conditions that provide a crystal form
other than the thermodynamic form. Such conditions are commonly
called "rapid" crystallization conditions. One of skill in the art
may select one or more factors including, for example: a difference
between the initial and final temperatures of the crystallization
solution of preferably at least about 25.degree. C., more
preferably at least about 50.degree. C., and most preferably at
least about 100.degree. C.; a rate of cooling of preferably at
least about 25.degree. C. per hour, more preferably at least about
100.degree. C. per hour, and most preferably at least about
300.degree. C. per hour; seeding; a supersaturation ratio of
preferably at least about 2, more preferably at least about 5, and
most preferably at least about 10; presence of a precipitant;
and/or combinations thereof to provide for Crystal Form II
crystallization conditions.
[0041] Useful solvents for the crystallization solution include,
for example, methanol, water, tetrahydrofuran/water mixtures, and
combinations thereof.
[0042] Powder X-ray Diffraction (PXRD)
[0043] Crystalline organic compounds consist of a large number of
atoms that are arranged in a periodic array in three-dimensional
space. The structural periodicity normally manifests distinct
physical properties, such as sharp, explicit spectral features by
most spectroscopic probes (e.g., X-ray diffraction, infrared and
solid state NMR). X-ray diffraction (XRD) is acknowledged to be one
of the most sensitive methods to determine the crystallinity of
solids. Crystals yield explicit diffraction maxima that arise at
specific angles consistent with the lattice interplanar spacings,
as predicted by Bragg's law. On the contrary, amorphous materials
do not possess long-range order. They often retain additional
volume between molecules, as in the liquid state. Amorphous solids
normally unveil a featureless XRD pattern with broad, diffuse halos
because of the absence of the long range order of repeating crystal
lattice.
[0044] Powder X-ray diffraction has been reportedly been used to
characterize different crystal forms of organic compounds (e.g.,
compounds useful in pharmaceutical compositions). See, for example,
U.S. Pat. Nos. 5,504,216 (Holohan et al), 5,721,359 (Dunn et al.),
5,910,588 (Wangnick et al.), 6,066,647 (Douglas et al.), 6,225,474
(Matsumoto et al.), 6,239,141 (Allen et al.), 6,251,355 (Murata et
al.), 6,288,057 (Harkness), 6,316,672 (Stowell et al.), 6,329,364
(Groleau), and U.S. Pat. Application Publication Nos. 2001/0003752
(Talley et al.), 2002/0038021 (Barton et al.), and 2002/0045746
(Barton et al.).
[0045] Crystalline materials are preferred in many pharmaceutical
applications. Crystalline forms are generally thermodynamically
more stable than amorphous forms of the same substance. This
thermodynamic stability is preferably reflected in the lower
solubility and improved physical stability of the crystalline form.
The regular packing of the molecules in the crystalline solid
preferably denies the incorporation of chemical impurities. Hence
crystalline materials generally possess higher chemical purity than
their amorphous counterparts. The packing in the crystalline solid
generally constrains the molecules to well defined lattice
positions and reduces the molecular mobility that is the
prerequisite for chemical reactions. Hence, crystalline solids,
with very few notable exceptions, are chemically more stable than
amorphous solids of the same molecular composition. Preferably, the
crystalline forms of malic acid salts
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-
-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
disclosed in the present application possess one or more of the
advantageous chemical and/or physical properties disclosed
herein.
[0046] The crystalline forms of malic acid salts of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide disclosed in the
present application preferably have distinct powder X-ray
diffraction profiles. For example, the anhydrous crystals including
a malic acid salt of the
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide can preferably be
distinguished from the other crystal form including a malic acid
salt disclosed herein by the presence of characteristic diffraction
peaks. Characteristic diffraction peaks as used herein are peaks
selected from the most intense peaks of the observed diffraction
pattern. Preferably, the characteristic peaks are selected from
about 20 of the most intense peaks, more preferably from about 10
of the most intense peaks, and most preferably from about 5 of the
most intense peaks in the diffraction pattern.
[0047] FIGS. 1 and 2 show the powder X-ray diffraction patterns for
Crystal Forms I and II, respectively, of the L-malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide. Table 1 contains
the listing of the most intense peaks from each PXRD pattern
between 2 and 35 degrees two theta. The free base, Crystal Form I,
and Crystal Form II are all easily distinguished by their unique
PXRD patterns.
[0048] Preferably an anhydrous crystal including a malic acid salt
of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (e.g., Crystal
Form I) has characteristic diffraction peaks at about 13.2 and 24.2
degrees two-theta, more preferably at about 13.2, 19.4, 24.2, and
25.5 degrees two-theta, and most preferably has the characteristic
diffraction peaks as listed in Table 1 for Crystal Form I.
[0049] Preferably, Crystal Form II of a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide has characteristic
diffraction peaks at about 3.0 and 27.7 degrees two-theta, more
preferably at about 3.0, 12.1, 14.5, and 27.7 degrees two-theta,
and most preferably has the characteristic diffraction peaks as
listed in Table 1 for Crystal Form II.
1TABLE 1 Powder X-Ray Diffraction Peak Table for Crystal Forms I
and II Crystal Form I Crystal Form II Two Theta Relative Two Theta
Relative (deg.) Intensity (deg.) Intensity 11.39 7 3.02 100 11.90 7
5.93 12 13.16 82 7.61 18 15.92 27 9.26 7 16.79 25 12.08 32 17.18 24
14.54 42 19.40 76 17.54 19 20.30 20 19.46 28 21.26 31 23.36 54
21.68 28 24.77 28 22.13 48 27.71 80 22.91 21 24.17 100 25.46 79
26.06 23 26.96 26 27.56 28 32.27 13 32.93 17 34.43 23
[0050] Purity and Solid State Stability
[0051] The purity of Crystal Form I of a malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide was evaluated by
high pressure liquid chromatography (HPLC). The results showed
greater than about 98 area % purity with less than about 2 area %
impurities detected (Table 2).
[0052] A solid state stability study of Crystal Form I of the
L-malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-
-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide was also
conducted (Table 2). Four week data after aging at 60.degree.
C./ambient relative humidity, 60.degree. C./75% relative humidity,
and 80.degree. C./ambient relative humidity showed no significant
degradation. Powder X-ray diffraction on two-week samples also
indicated no change in crystal form.
2TABLE 2 Stability of Crystal Form I based on HPLC Analysis Purity
Total Impurities Condition (Area %) (Area %) Initial 99.7 1.5 2
weeks at 60.degree. C./ambient RH* 98.2 1.1 2 weeks at 60.degree.
C./75% RH 99.6 1.2 2 weeks at 80.degree. C./ambient RH 99.5 1.2 4
weeks at 60.degree. C./ambient RH 100.4 1.2 4 weeks at 60.degree.
C./75% RH 100.1 2.2 4 weeks at 80.degree. C./ambient RH 98.0 3.1
*relative humidity (RH)
[0053] Moisture Sorption Data
[0054] The moisture sorption data at 25.degree. C. for Crystal
Forms I and II of the L-malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-
-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carbox-
amide are shown in FIG. 3. The more crystalline polymorph, Crystal
Form I is of low hygroscopicity, absorbing less than 0.5% water
across the 0-90% relative humidity range. The less crystalline
polymorph, Crystal Form II, is very hygroscopic, absorbing over 15%
water over the 0-90% relative humidity range.
[0055] Thermal Data
[0056] The differential scanning calorimetry data is shown in FIG.
4. The anhydrous Crystal Form I of the L-malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide melts at about
196.degree. C., while Crystal Form II melts at about 181.degree. C.
The events observed after the initial melt suggest that there is
probably some decomposition associated with the melting. Therefore,
an accurate heat of fusion could not be readily measured.
[0057] The TGA data for Crystal Form I (not shown) showed no
significant weight loss up to the melting point, indicating the
lack of residual solvent and/or water retained in the crystals.
[0058] Administration and Pharmaceutical Compositions
[0059] Crystals of the present invention can be administered as
such to a human patient or can be administered in pharmaceutical
compositions in which the foregoing crystal is mixed with suitable
carriers or excipient(s). Techniques for formulation and
administration of drugs may be found in "Remington's
Pharmacological Sciences," Mack Publishing Co., Easton, Pa., latest
edition.
[0060] As used herein, "administer" or "administration" refers to
the delivery of a crystal of the present invention or a
pharmaceutical composition thereof to an organism for the purpose
of prevention or treatment of a PK-related disorder.
[0061] Suitable routes of administration may include, without
limitation, oral, rectal, transmucosal or intestinal administration
or intramuscular, subcutaneous, intramedullary, intrathecal, direct
intraventricular, intravenous, intravitreal, intraperitoneal,
intranasal, or intraocular injections. The preferred routes of
administration are oral and parenteral.
[0062] Alternatively, one may administer the crystal of the present
invention or a pharmaceutical composition thereof in a local rather
than systemic manner, for example, via injection of the crystal of
the present invention or a pharmaceutical composition thereof
directly into a solid tumor, often in a depot or sustained release
formulation.
[0063] Furthermore, one may administer the drug in a targeted drug
delivery system, for example, in a liposome coated with
tumor-specific antibody. The liposomes will be targeted to and
taken up selectively by the tumor.
[0064] Pharmaceutical compositions of the present invention may be
manufactured by processes well known in the art, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or lyophilizing
processes.
[0065] Pharmaceutical compositions for use in accordance with the
present invention may be formulated in conventional manner using
one or more physiologically acceptable carriers including
excipients and auxiliaries that facilitate processing of crystals
of the present invention into preparations that can be used
pharmaceutically. Proper formulation is dependent upon the route of
administration chosen.
[0066] For injection, a crystal of the present invention or a
pharmaceutical composition thereof may be formulated in aqueous
solutions, preferably in physiologically compatible buffers such as
Hanks' solution, Ringer's solution, or physiological saline buffer.
For transmucosal administration, penetrants appropriate to the
barrier to be permeated are used in the formulation. Such
penetrants are generally known in the art.
[0067] For oral administration, a crystal of the present invention
or a pharmaceutical composition thereof can be formulated by
combining a crystal of the present invention with pharmaceutically
acceptable carriers well known in the art. Such carriers enable
crystals of the present invention to be formulated as tablets,
pills, lozenges, dragees, capsules, liquids, gels, syrups,
slurries, suspensions and the like, for oral ingestion by a
patient. Pharmaceutical preparations for oral use can be made using
a solid excipient, optionally grinding the resulting mixture, and
processing the mixture of granules, after adding other suitable
auxiliaries if desired, to obtain tablets or dragee cores. Useful
excipients are, in particular, fillers such as sugars, including
lactose, sucrose, mannitol, or sorbitol, cellulose preparations
such as, for example, maize starch, wheat starch, rice starch and
potato starch and other materials such as gelatin, gum tragacanth,
methyl cellulose, hydroxypropylmethyl- cellulose, sodium
carboxymethylcellulose, and/or polyvinyl- pyrrolidone (PVP). If
desired, disintegrating agents may be added, such as cross-linked
polyvinyl pyrrolidone, agar, or alginic acid. A salt such as sodium
alginate may also be used.
[0068] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used which may
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active doses.
[0069] Pharmaceutical compositions that can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with a filler such as lactose, a binder such as starch,
and/or a lubricant such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, crystals of the present
invention may be dissolved or suspended in suitable liquids, such
as fatty oils, liquid paraffin, or liquid polyethylene glycols.
Stabilizers may be added in these formulations, also.
[0070] The capsules may be packaged into brown glass or plastic
bottles to protect crystals of the present invention or
pharmaceutical compositions thereof from light. The containers
containing the active capsule formulation must be stored at
controlled room temperature (e.g., about 15.degree. C. to about
30.degree. C.).
[0071] For administration by inhalation, a crystal of the present
invention or a pharmaceutical composition thereof is conveniently
delivered in the form of an aerosol spray using a pressurized pack
or a nebulizer and a suitable propellant, e.g., without limitation,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethan- e or carbon dioxide. In the case of a
pressurized aerosol, the dosage unit may be controlled by providing
a valve to deliver a metered amount. Capsules and cartridges of,
for example, gelatin for use in an inhaler or insufflator may be
formulated containing a powder mix of a crystal of the present
invention or a pharmaceutical composition thereof, and a suitable
powder base such as lactose or starch.
[0072] A crystal of the present invention or a pharmaceutical
composition thereof may also be formulated for parenteral
administration, e.g., by bolus injection or continuous infusion.
Formulations for injection may be presented in unit dosage form,
e.g., in ampoules or in multi-dose containers, with an added
preservative. The compositions may take such forms as suspensions,
solutions, or emulsions in oily or aqueous vehicles, and may
contain formulating materials such as suspending, stabilizing,
and/or dispersing agents.
[0073] Pharmaceutical compositions for parenteral administration
include aqueous solutions of a water soluble form of a crystal of
the present invention or pharmaceutical composition thereof.
Additionally, suspensions of crystals of the present invention or
pharmaceutical compositions thereof may be prepared in a lipophilic
vehicle. Suitable lipophilic vehicles include fatty oils such as
sesame oil, synthetic fatty acid esters such as ethyl oleate and
triglycerides, or materials such as liposomes. Aqueous injection
suspensions may contain substances that increase the viscosity of
the suspension, such as sodium carboxymethyl cellulose, sorbitol,
or dextran. Optionally, the suspension may also contain suitable
stabilizers and/or agents that increase the solubility of the
crystals of the present invention or a pharmaceutical composition
thereof to allow for the preparation of highly concentrated
solutions.
[0074] Alternatively, the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g., sterile,
pyrogen-free water, before use.
[0075] A crystal of the present invention or a pharmaceutical
composition thereof may also be formulated in rectal compositions
such as suppositories or retention enemas, using, e.g.,
conventional suppository bases such as cocoa butter or other
glycerides.
[0076] In addition to the formulations described previously, a
crystal of the present invention or a pharmaceutical composition
thereof may also be formulated as depot preparations. Such long
acting formulations may be administered by implantation (for
example, subcutaneously or intramuscularly) or by intramuscular
injection. A crystal of the present invention or a pharmaceutical
composition thereof may be formulated for this route of
administration with suitable polymeric or hydrophobic materials
(for instance, in an emulsion with a pharamcologically acceptable
oil), with ion exchange resins, or as a sparingly soluble
derivative.
[0077] Additionally, a crystal of the present invention or a
pharmaceutical composition thereof may be delivered using a
sustained-release system, such as semipermeable matrices of solid
hydrophobic polymers containing the therapeutic agent. Various
sustained-release materials have been established and are well
known by those skilled in the art. Sustained-release capsules may,
depending on their chemical nature, release a salt or a
pharmaceutical composition thereof for a few weeks up to over 100
days. Depending on the chemical nature and the biological stability
of the therapeutic reagent, additional strategies for protein
stabilization may be employed.
[0078] The pharmaceutical compositions herein also may include
suitable solid or gel phase carriers or excipients. Examples of
such carriers or excipients include, but are not limited to,
calcium carbonate, calcium phosphate, various sugars, starches,
cellulose derivatives, gelatin, and polymers such as polyethylene
glycols.
[0079] Pharmaceutical compositions suitable for use in the present
invention include compositions wherein the active ingredients are
contained in an amount sufficient to achieve the intended purpose,
e.g., the modulation of PK activity or the treatment or prevention
of a PK-related disorder.
[0080] More specifically, a therapeutically effective amount means
an amount of crystals of the present invention or pharmaceutical
compositions thereof effective to prevent, alleviate or ameliorate
symptoms of disease or prolong the survival of the subject being
treated.
[0081] Determination of a therapeutically effective amount is well
within the capability of those skilled in the art, especially in
light of the detailed disclosure provided herein.
[0082] For any crystals of the present invention or pharmaceutical
compositions thereof used in the methods of the invention, the
therapeutically effective amount or dose can be estimated initially
from cell culture assays. Then, the dosage can be formulated for
use in animal models so as to achieve a circulating concentration
range that includes the IC.sub.50 as determined in cell culture
(i.e., the concentration of the crystals of the present invention
or pharmaceutical compositions thereof which achieves a
half-maximal inhibition of the PK activity). Such information can
then be used to more accurately determine useful doses in
humans.
[0083] Toxicity and therapeutic efficacy of a crystal of the
present invention or a pharmaceutical composition thereof can be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., by determining the IC.sub.50 and the
LD.sub.50 (both of which are discussed elsewhere herein) for a
subject crystal of the present invention or a pharmaceutical
composition thereof. The data obtained from these cell culture
assays and animal studies can be used in formulating a range of
dosage for use in humans. The dosage may vary depending upon the
dosage form employed and the route of administration utilized. The
exact formulation, route of administration and dosage can be chosen
by the individual physician in view of the patient's condition.
(See e.g., Fingl, et al., 1975, in "The Pharmacological Basis of
Therapeutics", Ch. 1 p.1).
[0084] Dosage amount and interval may be adjusted individually to
provide plasma levels of the active species that are sufficient to
maintain the kinase modulating effects. These plasma levels are
referred to as minimal effective concentrations (MECs). The MEC
will vary for each crystal of the present invention or a
pharmaceutical composition thereof but can be estimated from in
vitro data, e.g., the concentration necessary to achieve 50-90%
inhibition of a kinase may be ascertained using the assays
described herein. Dosages necessary to achieve the MEC will depend
on individual characteristics and route of administration. HPLC
assays or bioassays can be used to determine plasma
concentrations.
[0085] Dosage intervals can also be determined using MEC value. A
crystal of the present invention or a pharmaceutical composition
thereof should be administered using a regimen that maintains
plasma levels above the MEC for 10-90% of the time, preferably
between 30-90% and most preferably between 50-90%.
[0086] In cases of local administration or selective uptake, the
effective local concentration of the drug may not be related to
plasma concentration and other procedures known in the art may be
employed to determine the correct dosage amount and interval.
[0087] The amount of a composition administered will, of course, be
dependent on the subject being treated, the severity of the
affliction, the manner of administration, the judgment of the
prescribing physician, etc.
[0088] The compositions may, if desired, be presented in a pack or
dispenser device, such as an FDA approved kit, which may contain
one or more unit dosage forms containing the active ingredient. The
pack may for example include metal or plastic foil, such as a
blister pack. The pack or dispenser device may be accompanied by
instructions for administration. The pack or dispenser may also be
accompanied by a notice associated with the container in a form
prescribed by a governmental agency regulating the manufacture, use
or sale of pharmaceuticals, which notice is reflective of approval
by the agency of the form of the compositions or of human or
veterinary administration. Such notice, for example, may be of the
labeling approved by the U.S. Food and Drug Administration for
prescription drugs or of an approved product insert. Compositions
including a crystal of the present invention formulated in a
compatible pharmaceutical carrier may also be prepared, placed in
an appropriate container, and labeled for treatment of an indicated
condition. Suitable conditions indicated on the label may include
treatment of a tumor, inhibition of angiogenesis, treatment of
fibrosis, diabetes, and the like.
[0089] It is also an aspect of this invention that a crystal of the
present invention or a pharmaceutical composition thereof, might be
combined with other chemotherapeutic agents for the treatment of
the diseases and disorders discussed above. For instance, a crystal
of the present invention or a pharmaceutical composition thereof,
might be combined with alkylating agents such as fluorouracil
(5-FU) alone or in further combination with leukovorin; or other
alkylating agents such as, without limitation, other pyrimidine
analogs such as UFT, capecitabine, gemcitabine and cytarabine, the
alkyl sulfonates, e.g., busulfan (used in the treatment of chronic
granulocytic leukemia), improsulfan and piposulfan; aziridines,
e.g., benzodepa, carboquone, meturedepa and uredepa; ethyleneimines
and methylmelamines, e.g., altretamine, triethylenemelamine,
triethylenephosphoramide, triethylenethiophosphorami- de and
trimethylolmelamine; and the nitrogen mustards, e.g., chlorambucil
(used in the treatment of chronic lymphocytic leukemia, primary
macroglobulinemia and non-Hodgkin's lymphoma), cyclophosphamide
(used in the treatment of Hodgkin's disease, multiple myeloma,
neuroblastoma, breast cancer, ovarian cancer, lung cancer, Wilm's
tumor and rhabdomyosarcoma), estramustine, ifosfamide,
novembrichin, prednimustine and uracil mustard (used in the
treatment of primary thrombocytosis, non-Hodgkin's lymphoma,
Hodgkin's disease and ovarian cancer); and triazines, e.g.,
dacarbazine (used in the treatment of soft tissue sarcoma).
[0090] A crystal of the present invention or a pharmaceutical
composition thereof, can also be used in combination with other
antimetabolite chemotherapeutic agents such as, without limitation,
folic acid analogs, e.g. methotrexate (used in the treatment of
acute lymphocytic leukemia, choriocarcinoma, mycosis fungiodes
breast cancer, head and neck cancer and osteogenic sarcoma) and
pteropterin; and the purine analogs such as mercaptopurine and
thioguanine which find use in the treatment of acute granulocytic,
acute lymphocytic and chronic granulocytic leukemias.
[0091] It is contemplated that a crystal of the present invention
or a pharmaceutical composition thereof can also be used in
combination with natural product based chemotherapeutic agents such
as, without limitation, the vinca alkaloids, e.g., vinblastin (used
in the treatment of breast and testicular cancer), vincristine and
vindesine; the epipodophylotoxins, e.g., etoposide and teniposide,
both of which are useful in the treatment of testicular cancer and
Kaposi's sarcoma; the antibiotic chemotherapeutic agents, e.g.,
daunorubicin, doxorubicin, epirubicin, mitomycin (used to treat
stomach, cervix, colon, breast, bladder and pancreatic cancer),
dactinomycin, temozolomide, plicamycin, bleomycin (used in the
treatment of skin, esophagus and genitourinary tract cancer); and
the enzymatic chemotherapeutic agents such as L-asparaginase.
[0092] In addition to the above, a crystal of the present invention
or a pharmaceutical composition thereof could also be used in
combination with the platinum coordination complexes (cisplatin,
etc.); substituted ureas such as hydroxyurea; methylhydrazine
derivatives, e.g., procarbazine; adrenocortical suppressants, e.g.,
mitotane, aminoglutethimide; and hormone and hormone antagonists
such as the adrenocorticosteriods (e.g., prednisone), progestins
(e.g., hydroxyprogesterone caproate); estrogens (e.g.,
diethylstilbesterol); antiestrogens such as tamoxifen; androgens,
e.g., testosterone propionate; and aromatase inhibitors such as
anastrozole.
[0093] Finally, it is also contemplated that the combination of a
crystal of the present invention or a pharmaceutical composition
thereof will be effective in combination with mitoxantrone or
paclitaxel for the treatment of solid tumor cancers or leukemias
such as, without limitation, acute myclogenous (non-lymphocytic)
leukemia.
[0094] The present invention is illustrated by the following
examples. It is to be understood that the particular examples,
materials, amounts, and procedures are to be interpreted broadly in
accordance with the scope and spirit of the invention as set forth
herein.
EXAMPLES
[0095] X-ray diffraction (XRD) patterns were measured on a Scintag
X2 diffractometer (Thermo ARL, Ecublens, Switzerland) equipped with
a theta-theta goniometer. Melting points were determined using a TA
Instruments 2920 differential scanning calorimeter (TA Instruments,
New Castle, Del.) with standard crimped pans and a heating rate of
10.degree. C./minute. Hygroscopicity was assessed by dynamic
moisture sorption gravimetry (DMSG) using a Controlled Atmosphere
Microbalance (Pharmacia Corp., Kalamazoo, Mich.). All chemicals
used are available from Aldrich Chemical Co., Milwaukee, Wis.,
unless otherwise specified.
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide was prepared as
the free base by a procedure similar to that described in Example
80 of PCT International Publication No. WO 01/60814 (Tang et
al.).
[0096] Methods
[0097] Powder X-Ray Diffraction (XRD). Powder X-Ray diffraction was
performed using a Scintag X2 Advanced Diffraction System operating
under Scintag DMS/NT 1.30a and Microsoft Windows NT 4.0 software.
The system uses a Copper X-Ray source maintained at 45 kV and 40 MA
to provide CuK(.alpha..sub.1 emission of 1.5406 .ANG. and a
solid-state Peltier cooled detector. The beam aperture was
controlled using tube divergence and anti-scatter slits of 2 and 4
mm and detector anti-scatter and receiving slits of 0.5 and 0.2 mm
width. Data was collected from 2 to 35.degree. two-theta using a
step scan of 0.03.degree./point with a one second per step counting
time. Scintag round, top loading stainless steel sample cups with
12 mm diameter inserts were utilized for the experiments. Bulk drug
was sampled as-is and placed into the sample tray without any
preparation. Some specific samples were also hand-ground in a
mortar and pestle before they were run. Data analysis was completed
using Origin 6.0 (Microcal Software, Northampton Mass.).
[0098] Dynamic Moisture Sorption Gravimetry (DMSG). DMSG isotherms
were collected on the variable temperature controlled atmosphere
microbalance. Approximately 10 mg samples were used in the balance.
Samples were run as received. The humidity was sequentially set
between 0 and 90% relative humidity (RH) in 3% RH steps. The mass
was then measured every two minutes. The RH was changed to the next
value when the mass of the sample was stable to within 0.5
microgram in 480 seconds. A Visual Basic program was used to
control the data collection and export the information to an Excel
spreadsheet.
[0099] Thermal Analysis. Differential Scanning Calorimetry (DSC)
data was obtained by crimping the powdered sample into an aluminum
DSC pan. Samples were run as received, sizes were about 1 mg.
Temperatures were typically scanned to 320.degree. C. at a scan
rate of 10.degree. C. per minute. The DSC was a TA Instruments 2920
calorimeter. The data analysis software used was TA's Universal
Analysis V 1.1 OB.
[0100] Thermogravimetric Analysis (TGA) data was obtained on a TA
instruments TGA 2950. Samples were equilibrated in the TGA at
25.degree. C., with a 20.degree. C. dew point for 30 minutes before
the temperature program began. The temperature ramp was at
10.degree. C./minute, but was scanned under TA's proprietary
high-resolution conditions. This technique slows the scan rate when
a transition is occurring, improving the ability of the instrument
to resolve independent weight loss events.
Example 1
[0101] Preparation of the Anhydrous Crystal Form I of the L-Malic
Acid Salt of
N-[2-(Diethylamino)ethyl]-5-[(5fluoro-1,2-dihydro-2-oxo-3H-indol--
3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide.
[0102] Preparation A:
N-[2-(Diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-
-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
(130 mg, 0.326 mMol) was added to 20 mL methanol, and the mixture
was stirred. L-malic acid (47.2 mg, 0.352 mMol) was added,
resulting in rapid dissolution of all the solids. The methanol was
removed under reduced pressure to produce a poorly crystalline
orange solid. Acetonitrile (5 mL) was added, and the slurry was
stirred and heated for about 10 minutes. Stirring was continued
while the slurry was allowed to cool to room temperature. The
crystals were filtered and dried, resulting in 149 mg of solids
(86% yield) of Crystal Form I.
[0103] Preparation B:
N-[2-(Diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-
-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
may be purified by an aqueous pH=11 wash prior to formation of the
L-malic acid salt. A solution of the free base in a mixture of
80:20 n-butanol:water (v:v) was prepared at 80.degree. C. After
cooling to 20.degree. C. and stirring for 1 hour, significant
crystallization was observed. A sample was analyzed by PXRD and
found to be Crystal Form I. Filtration, drying, and co-milling of
the crystals resulted in 99% yield.
Example 2
[0104] Preparation of Crystal Form II of the L-Malic Acid Salt of
N-[2-(Diethylamino)ethyl]-5-[(5fluoro-1,2-dihydro-2-oxo-3H-indol-3-yliden-
e)methyl]-2,4-dimethyl-]H-pyrrole-3-carboxamide.
[0105] Crystals of Crystal Form I of the L-malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (25 mg) were added
to tetrahydrofuran (2 mL), followed by the addition of water (250
microliters). The mixture was heated to dissolve the crystals. The
solvent was allowed to evaporate overnight, resulting in crystals
of Crystal Form II.
Example 3
[0106] Preparation of the Anhydrous Crystal Form I of the L-Malic
Acid Salt of
N-[2-(Diethylamino)ethyl]-5-[(5fluoro-1,2-dihydro-2-oxo-3H-indol--
3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide from
Crystal Form II.
[0107] Acetonitrile (approximately 5 mL) was added to Crystal Form
II (150 mg). The slurry was stirred and heated for about 10
minutes. Stirring was continued while the slurry was allowed to
cool to room temperature. The crystals were filtered and dried,
resulting in crystals of Crystal Form I.
Example 4
[0108] Solubility of Crystal Form I of the L-Malic Acid Salt of
N-[2-(Diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-]H-pyrrole-3-carboxamide
[0109] The solubility of Crystal Form I of the L-malic acid salt of
N-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylide-
ne)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide was determined to
be 5 mg/mL in water at 25.degree. C. This indicates that solubility
should not be a limiting factor in bioavailablity of the
material.
[0110] The complete disclosure of all patents, patent applications,
and publications, and electronically available material (e.g.,
GenBank amino acid and nucleotide sequence submissions; and protein
data bank (pdb) submissions) cited herein are incorporated by
reference. The foregoing detailed description and examples have
been given for clarity of understanding only. No unnecessary
limitations are to be understood therefrom. The invention is not
limited to the exact details shown and described, for variations
obvious to one skilled in the art will be included within the
invention defined by the claims.
* * * * *