U.S. patent number RE48,923 [Application Number 15/830,544] was granted by the patent office on 2022-02-08 for crystal forms.
This patent grant is currently assigned to AbbVie Inc.. The grantee listed for this patent is AbbVie Inc.. Invention is credited to Jean-Christophe Califano, Michael G. Fickes, Lars Fredrik Nordstroem.
United States Patent |
RE48,923 |
Califano , et al. |
February 8, 2022 |
Crystal forms
Abstract
The present invention features crystalline forms of Compound I.
In one embodiment, a crystalline form of Compound I has
characteristic peaks in the PXRD pattern as shown in one of FIGS.
1-10.
Inventors: |
Califano; Jean-Christophe
(Whitefish Bay, WI), Fickes; Michael G. (Lake Bluff, IL),
Nordstroem; Lars Fredrik (Evanston, IL) |
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Assignee: |
AbbVie Inc. (North Chicago,
IL)
|
Family
ID: |
53284512 |
Appl.
No.: |
15/830,544 |
Filed: |
December 4, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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61991242 |
May 9, 2014 |
|
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Reissue of: |
14707433 |
May 8, 2015 |
9593078 |
Mar 14, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D
413/14 (20130101); C07D 519/00 (20130101); A61K
31/4178 (20130101); C07D 401/10 (20130101); A61P
31/14 (20180101); C07D 405/14 (20130101); C07D
417/14 (20130101); C07D 207/16 (20130101); C07D
401/14 (20130101); C07D 403/14 (20130101); A61K
38/05 (20130101); A61P 1/16 (20180101); A61P
43/00 (20180101) |
Current International
Class: |
C07D
401/14 (20060101); C07D 519/00 (20060101); C07D
417/14 (20060101); C07D 405/14 (20060101); C07D
207/16 (20060101); C07D 413/14 (20060101); A61K
38/05 (20060101); C07D 403/14 (20060101); C07D
401/10 (20060101); A61K 31/4178 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2283822 |
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Feb 2011 |
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EP |
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2013539791 |
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Oct 2013 |
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JP |
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2017515897 |
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Jun 2017 |
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JP |
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WO-2012051361 |
|
Apr 2012 |
|
WO |
|
WO-2013025449 |
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Feb 2013 |
|
WO |
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Other References
Braga D., et al., "Crystal Polymorphism and Multiple Crystal
Forms," Structure and Bonding, Feb. 2009, vol. 132, pp. 25-50.
cited by applicant .
Caira M.R., "Crystalline Polymorphism of Organic Compounds," Topics
in Current Chemistry,1998, vol. 198, pp. 163-208. cited by
applicant .
Hilfiker R., et al., "Relevance of Solid-state Properties for
Pharmaceutical Products," Polymorphism: in the Pharmaceutical
Industry, 2006, pp. 1-19. cited by applicant .
Office Action dated Mar. 19, 2019 for Mexican Patent Application
No. MX/a/2016/014459, 8 pages (with English translation). cited by
applicant .
Masakuni Matsuoka, "Kesshoutakei no kiso to ouyou" (Fundamentals
and applications of crystalline polymorphism), CMC Publishing Co.,
Ltd., Oct. 22, 2010, a popular edition, first copy, pp. 105-117,
pp. 181-191. cited by applicant .
Brandrup J., et al., Polymer Handbook, 2nd Edition, John Wiley
& Sons, 1975, Table of Contents. cited by applicant .
Fiedler., "Encyclopedia of Excipients for Pharmaceuticals,
Cosmetics and related Areas," 5th Edition, Hoepfner E. M., et al.,
eds., Editio Cantor Verlag Aulendorf, 2002, Table of Contents.
cited by applicant .
Masters K., "Spray Drying Handbook" 4th Edition, John Wiley &
Sons, 1985, Table of Contents. cited by applicant .
Sperling L. H., "Introduction to Physical Polymer Science," 2nd
Edition, John Wiley & Sons, Inc., 1992, Table of Contents, 18
pages. cited by applicant .
International Search Report for PCT/US2015/029842, 3 pages. Sep.
16, 2015. cited by applicant.
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Primary Examiner: Jones; Dwayne C.
Claims
What is claimed is:
1. A process for making a pharmaceutical composition comprising
Compound I ##STR00002## comprising .[.dissolving.]. .Iadd.combining
.Iaddend.a crystalline form of Compound I .[.in a solvent.].
.Iadd.with a hydrophilic polymer.Iaddend., .[.wherein said
crystalline form has characteristic peaks in PXRD pattern as
described in one of Tables 1-10 when tested using a diffractometer
that is operated with a copper anode tube at 40 kV and 30 mA and a
germanium monochromator to provide monochromatic Cu-K.sub..alpha.
radiation with a wavelength of 1.54178 .ANG..]. .Iadd.wherein the
crystalline form has a powder X-ray diffraction pattern comprising
a two theta (.degree. 2.theta.) peak at about 17.62.+-.0.2.degree.
2.theta. when tested using a diffractometer that is operated with a
copper anode tube at 40 kV and 30 mA and a germanium monochromator
to provide monochromatic Cu-K.sub..alpha. radiation with a
wavelength of 1.54178 .ANG..Iaddend..
2. The process of claim 1, wherein .[.said solvent is a volatile
solvent, and said.]. .Iadd.the .Iaddend.process further comprises
.Iadd.dissolving Compound I and the polymer in a solvent, and
.Iaddend.spray drying the .[.dissolved Compound I.].
.Iadd.resulting solution .Iaddend.to remove the solvent, thereby
creating a solid dispersion comprising amorphous Compound I
.Iadd.and the polymer.Iaddend..
3. The process of claim 1, wherein .[.said solvent.]. .Iadd.the
polymer .Iaddend.is a molten or rubbery polymer .Iadd.in which the
crystalline form of Compound I dissolves.Iaddend., and .[.said.].
.Iadd.the .Iaddend.process further comprises cooling and
solidifying the dissolved Compound I, thereby creating a solid
dispersion comprising amorphous Compound I and .[.said polymer.].
.Iadd.the polymer.Iaddend..
.[.4. The process of claim 1, wherein said characteristic peaks in
PXRD pattern are as described in Table 9..].
.[.5. The process of claim 2, wherein said characteristic peaks in
PXRD pattern are as described in Table 9..].
.[.6. The process of claim 3, wherein said characteristic peaks in
PXRD pattern are as described in Table 9..].
.[.7. A process for making a pharmaceutical composition comprising
Compound I, ##STR00003## comprising dissolving a crystalline form
of Compound I in a solvent, wherein said crystalline form has
characteristic peaks in PXRD pattern as described in one of FIGS.
1-10 when tested using a diffractometer that is operated with a
copper anode tube at 40 kV and 30 mA and a germanium monochromator
to provide monochromatic Cu-K.sub..alpha. radiation with a
wavelength of 1.54178 .ANG...].
.[.8. The process of claim 7, wherein said solvent is a volatile
solvent, and said process further comprises spray drying the
dissolved Compound I to remove the solvent, thereby creating a
solid dispersion comprising amorphous Compound I..].
.[.9. The process of claim 7, wherein said solvent is a molten or
rubbery polymer, and said process further comprises cooling and
solidifying the dissolved Compound I, thereby creating a solid
dispersion comprising amorphous Compound I and said polymer..].
.[.10. The process of claim 7, wherein said characteristic peaks in
PXRD pattern are as described in FIG. 9..].
.[.11. The process of claim 8, wherein said characteristic peaks in
PXRD pattern are as described in FIG. 9..].
.[.12. The process of claim 9, wherein said characteristic peaks in
PXRD pattern are as described in FIG. 9..].
.[.13. A process for making a pharmaceutical composition comprising
Compound I, ##STR00004## comprising dissolving a crystalline form
of Compound I in a solvent, wherein said crystalline form has
characteristic peaks in PXRD pattern at values of two theta
(.degree. 2.theta.) of 5.31, 11.11, 12.60, 13.75, 15.29, 15.96,
17.62, 19.71, 21.30, and 22.88 when tested using a diffractometer
that is operated with a copper anode tube at 40 kV and 30 mA and a
germanium monochromator to provide monochromatic Cu-K.sub..alpha.
radiation with a wavelength of 1.54178 .ANG...].
.[.14. The process of claim 13, wherein said solvent is a volatile
solvent, and said process further comprises spray drying the
dissolved Compound I to remove the solvent, thereby creating a
solid dispersion comprising amorphous Compound I..].
.[.15. The process of claim 13, wherein said solvent is a molten or
rubbery polymer, and said process further comprises cooling and
solidifying the dissolved Compound I, thereby creating a solid
dispersion comprising amorphous Compound I and said polymer..].
.[.16. A process for making a pharmaceutical composition comprising
Compound I, ##STR00005## comprising dissolving a crystalline form
of Compound I in a solvent, wherein said crystalline form has
characteristic peaks in PXRD pattern at values of two theta
(.degree. 2.theta.) of 5.31, 10.16, 10.62, 11.11, 12.60, 13.75,
15.29, 15.96, 17.62, 18.19, 19.16, 19.71, 20.58, 21.30, 22.40,
22.88, 23.66, 26.40, 26.74, and 33.46 when tested using a
diffractometer that is operated with a copper anode tube at 40 kV
and 30 mA and a germanium monochromator to provide monochromatic
Cu-K.sub..alpha. radiation with a wavelength of 1.54178
.ANG...].
.[.17. The process of claim 16, wherein said solvent is a volatile
solvent, and said process further comprises spray drying the
dissolved Compound I to remove the solvent, thereby creating a
solid dispersion comprising amorphous Compound I..].
.[.18. The process of claim 16, wherein said solvent is a molten or
rubbery polymer, and said process further comprises cooling and
solidifying the dissolved Compound I, thereby creating a solid
dispersion comprising amorphous Compound I and said polymer..].
.[.19. A process for making a pharmaceutical composition comprising
Compound I, ##STR00006## comprising dissolving a crystalline form
of Compound I in a solvent, wherein said crystalline form has
characteristic peaks in PXRD pattern at values of two theta
(.degree. 2.theta.) of 5.31, 10.16, 10.62, 11.11, 12.60, 13.75,
15.29, 15.96, 17.62, 18.19, 19.16, 19.71, 20.58, 21.30, 22.40,
22.88, 23.66, 26.40, 26.74, 28.12, 31.62, and 33.46 when tested
using a diffractometer that is operated with a copper anode tube at
40 kV and 30 mA and a germanium monochromator to provide
monochromatic Cu-K.sub..alpha. radiation with a wavelength of
1.54178 .ANG...].
.[.20. The process of claim 19, wherein said solvent is a volatile
solvent, and said process further comprises spray drying the
dissolved Compound I to remove the solvent, thereby creating a
solid dispersion comprising amorphous Compound I..].
.[.21. The process of claim 19, wherein said solvent is a molten or
rubbery polymer, and said process further comprises cooling and
solidifying the dissolved Compound I, thereby creating a solid
dispersion comprising amorphous Compound I and said polymer..].
.Iadd.22. The process of claim 1, wherein the crystalline form has
a powder X-ray diffraction pattern further comprising a two theta
(.degree. 2.theta.) peak at about 13.75.+-.0.2.degree. 2.theta.
when tested using a diffractometer that is operated with a copper
anode tube at 40 kV and 30 mA and a germanium monochromator to
provide monochromatic Cu-K.sub..alpha. radiation with a wavelength
of 1.54178 .ANG.. .Iaddend.
.Iadd.23. The process of claim 22 wherein the crystalline form has
a powder X-ray diffraction pattern further comprising a two theta
(.degree. 2.theta.) peak at about 11.11.+-.0.2.degree. 2.theta.
when tested using a diffractometer that is operated with a copper
anode tube at 40 kV and 30 mA and a germanium monochromator to
provide monochromatic Cu-K.sub..alpha. radiation with a wavelength
of 1.54178 .ANG.. .Iaddend.
.Iadd.24. A process for making a pharmaceutical composition
comprising Compound I ##STR00007## comprising combining a
crystalline form of Compound I with a hydrophilic polymer wherein
the crystalline form has a powder X-ray diffraction pattern
comprising a two theta (.degree. 2.theta.) peak at about
10.16.+-.0.2.degree. 2.theta. when tested using a diffractometer
that is operated with a copper anode tube at 40 kV and 30 mA and a
germanium monochromator to provide monochromatic Cu-K.sub..alpha.
radiation with a wavelength of 1.54178 .ANG., wherein the
crystalline form is anhydrous. .Iaddend.
.Iadd.25. The process of claim 24 wherein the process further
comprises dissolving Compound I and the polymer in a solvent, and
spray drying the resulting solution to remove the solvent, thereby
creating a solid dispersion comprising amorphous Compound I and the
polymer. .Iaddend.
.Iadd.26. The process of claim 24, wherein the polymer is a molten
or rubbery polymer in which the crystalline form of Compound I
dissolves, and the process further comprises cooling and
solidifying the dissolved Compound I, thereby creating a solid
dispersion comprising amorphous Compound I and the polymer.
.Iaddend.
.Iadd.27. The process of claim 24, wherein the crystalline form is
anhydrous. .Iaddend.
.Iadd.28. The process of claim 24, wherein the crystalline form has
a powder X-ray diffraction pattern further comprising a two theta
(.degree. 2.theta.) peak at about 21.30.+-.0.2.degree. 2.theta. and
about 23.66.+-.0.2.degree. 2.theta. when tested using a
diffractometer that is operated with a copper anode tube at 40 kV
and 30 mA and a germanium monochromator to provide monochromatic
Cu-K.sub..alpha. radiation with a wavelength of 1.54178 .ANG..
.Iaddend.
.Iadd.29. The process of claim 24, wherein the crystalline form has
a powder X-ray diffraction pattern further comprising a two theta
(.degree. 2.theta.) peak at about 5.31.+-.0.2.degree. 2.theta.,
11.11.+-.0.2.degree. 2.theta., 12.60.+-.0.2.degree. 2.theta.,
13.75.+-.0.2.degree. 2.theta., 15.29.+-.0.2.degree. 2.theta.,
15.96.+-.0.2.degree. 2.theta., 19.71.+-.0.2.degree. 2.theta.,
21.30.+-.0.2.degree. 2.theta., and 22.88.+-.0.2.degree. 2.theta.
when tested using a diffractometer that is operated with a copper
anode tube at 40 kV and 30 mA and a germanium monochromator to
provide monochromatic Cu-K.sub..alpha. radiation with a wavelength
of 1.54178 .ANG.. .Iaddend.
.Iadd.30. The process of claim 24, wherein the crystalline form has
a powder X-ray diffraction pattern further comprising a two theta
(.degree. 2.theta.) peak at about 5.31.+-.0.2.degree. 2.theta.,
10.62.+-.0.2.degree. 2.theta., 11.11.+-.0.2.degree. 2.theta.,
12.60.+-.0.2.degree. 2.theta., 13.75.+-.0.2.degree. 2.theta.,
15.29.+-.0.2.degree. 2.theta., 15.96.+-.0.2.degree. 2.theta.,
17.62.+-.0.2.degree. 2.theta., 18.19.+-.0.2.degree. 2.theta.,
19.16.+-.0.2.degree. 2.theta., 19.71.+-.0.2.degree. 2.theta.,
20.58.+-.0.2.degree.2.theta., 21.30.+-.0.2.degree. 2.theta.,
22.40.+-.0.2.degree. 2.theta., 22.88.+-.0.2.degree. 2.theta.,
23.66.+-.0.2.degree. 2.theta., 26.40.+-.0.2.degree. 2.theta.,
26.74.+-.0.2.degree. 2.theta. and 33.46.+-.0.2.degree. 2.theta.,
when tested using a diffractometer that is operated with a copper
anode tube at 40 kV and 30 mA and a germanium monochromator to
provide monochromatic Cu-K.sub..alpha. radiation with a wavelength
of 1.54178 .ANG.. .Iaddend.
.Iadd.31. The process of claim 24, wherein the crystalline form has
a powder X-ray diffraction pattern of Pattern G. .Iaddend.
.Iadd.32. A crystalline form of Compound I, ##STR00008## wherein
the crystalline form has a powder X-ray diffraction pattern
comprising a two theta (.degree. 2.theta.) peak at about
17.62.+-.0.2.degree. 2.theta. when tested using a diffractometer
that is operated with a copper anode tube at 40 kV and 30 mA and a
germanium monochromator to provide monochromatic Cu-K.sub..alpha.
radiation with a wavelength of 1.54178 .ANG.. .Iaddend.
.Iadd.33. The crystalline form of claim 32, wherein the crystalline
form has a powder X-ray diffraction pattern further comprising a
two theta (.degree. 2.theta.) peak at about 13.75.+-.0.2.degree.
2.theta.. .Iaddend.
.Iadd.34. The crystalline form of claim 33, wherein the crystalline
form has a powder X-ray diffraction pattern further comprising a
two theta (.degree. 2.theta.) peak at about 11.11.+-.0.2.degree.
2.theta.. .Iaddend.
.Iadd.35. A crystalline form of Compound I, ##STR00009## wherein
the crystalline form has a powder X-ray diffraction pattern
comprising a two theta (.degree. 2.theta.) peak at about
10.16.+-.0.2.degree. 2.theta. when tested using a diffractometer
that is operated with a copper anode tube at 40 kV and 30 mA and a
germanium monochromator to provide monochromatic Cu-K.sub..alpha.
radiation with a wavelength of 1.54178 .ANG.. .Iaddend.
.Iadd.36. The process of claim 35, wherein the crystalline form is
anhydrous. .Iaddend.
.Iadd.37. The crystalline form of claim 35, wherein the crystalline
form has a powder X-ray diffraction pattern further comprising a
two theta (.degree. 2.theta.) peak at about 21.30.+-.0.2.degree.
2.theta. and about 23.66.+-.0.2.degree. 2.theta. when tested using
a diffractometer that is operated with a copper anode tube at 40 kV
and 30 mA and a germanium monochromator to provide monochromatic
Cu-K.sub..alpha. radiation with a wavelength of 1.54178 .ANG..
.Iaddend.
.Iadd.38. The crystalline form of claim 35, wherein the crystalline
form has a powder X-ray diffraction pattern further comprising a
two theta (.degree. 2.theta.) peak at about 5.31.+-.0.2.degree.
2.theta., 11.11.+-.0.2.degree. 2.theta., 12.60.+-.0.2.degree.
2.theta., 13.75.+-.0.2.degree. 2.theta., 15.29.+-.0.2.degree.
2.theta., 15.96.+-.0.2.degree. 2.theta., 19.71.+-.0.2.degree.
2.theta., 21.30.+-.0.2.degree. 2.theta., and 22.88.+-.0.2.degree.
2.theta. when tested using a diffractometer that is operated with a
copper anode tube at 40 kV and 30 mA and a germanium monochromator
to provide monochromatic Cu-K.sub..alpha. radiation with a
wavelength of 1.54178 .ANG.. .Iaddend.
.Iadd.39. The crystalline form of claim 35, wherein the crystalline
form has a powder X-ray diffraction pattern further comprising a
two theta (.degree. 2.theta.) peak at about 5.31.+-.0.2.degree.
2.theta., 10.62.+-.0.2.degree. 2.theta., 11.11.+-.0.2.degree.
2.theta., 12.60.+-.0.2.degree. 2.theta., 13.75.+-.0.2.degree.
2.theta., 15.29.+-.0.2.degree. 2.theta., 15.96.+-.0.2.degree.
2.theta., 17.62.+-.0.2.degree. 2.theta., 18.19.+-.0.2.degree.
2.theta., 19.16.+-.0.2.degree. 2.theta., 19.71.+-.0.2.degree.
2.theta., 20.58.+-.0.2.degree. 2.theta., 21.30.+-.0.2.degree.
2.theta., 22.40.+-.0.2.degree. 2.theta., 22.88.+-.0.2.degree.
2.theta., 23.66.+-.0.2.degree. 2.theta., 26.40.+-.0.2.degree.
2.theta., 26.74.+-.0.2.degree. 2.theta. and 33.46.+-.0.2.degree.
2.theta., when tested using a diffractometer that is operated with
a copper anode tube at 40 kV and 30 mA and a germanium
monochromator to provide monochromatic Cu-K.sub..alpha. radiation
with a wavelength of 1.54178 .ANG.. .Iaddend.
.Iadd.40. The crystalline form of claim 35, wherein the crystalline
form has a powder X-ray diffraction pattern of Pattern G. .Iaddend.
Description
RELATED APPLICATION
This application .Iadd.is a reissue application of U.S. Pat. No.
9,593,078, which issued on Mar. 14, 2017 from U.S. Utility
application Ser. No. 14/707,433, which was filed on May 8, 2015 and
.Iaddend.claims the benefit of U.S. Provisional Application Ser.
No. 61/991,242, filed May 9, 2014, the contents of which are
incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to crystalline polymorphs of Compound
I, pharmaceutical compositions comprising the same, and methods of
using the same to prepare pharmaceutical compositions.
BACKGROUND
The hepatitis C virus (HCV) is an RNA virus belonging to the
Hepacivirus genus in the Flaviviridae family. The enveloped HCV
virion contains a positive stranded RNA genome encoding all known
virus-specific proteins in a single, uninterrupted, open reading
frame. The open reading frame comprises approximately 9500
nucleotides and encodes a single large polyprotein of about 3000
amino acids. The polyprotein comprises a core protein, envelope
proteins E1 and E2, a membrane bound protein p7, and the
non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.
HCV infection is associated with progressive liver pathology,
including cirrhosis and hepatocellular carcinoma. Chronic hepatitis
C may be treated with peginterferon-alpha in combination with
ribavirin. Substantial limitations to efficacy and tolerability
remain as many users suffer from side effects, and viral
elimination from the body is often inadequate. Therefore, there is
a need for new drugs to treat HCV infection.
BRIEF DESCRIPTION OF THE DRAWINGS
The drawings are provided for illustration, not limitation.
FIG. 1 shows experimental PXRD patterns of Compound I
n-butylamine-H2O solvate (Pattern A or Form I).
FIG. 2 depicts experimental PXRD pattern of Compound I Pattern
B.
FIG. 3 describes experimental PXRD of Compound I Pattern B
(MeOH-Diethyl ether solvate).
FIG. 4 shows experimental PXRD of Compound I Pattern C
(anhydrate).
FIG. 5 illustrates experimental PXRD of Compound I Pattern C (MTBE
solvate).
FIG. 6 depicts experimental PXRD of Compound I Pattern D (from
EtOH/H.sub.2O).
FIG. 7 shows experimental PXRD of Compound I Pattern E
(hydrate).
FIG. 8 describes experimental PXRD of Compound I ACN solvate
(Pattern F or Form II).
FIG. 9 shows experimental PXRD of Compound I anhydrate (Pattern G
or Form III).
FIG. 10 depicts experimental PXRD of Compound I di-n-butyl ether
solvate (Pattern H).
DETAILED DESCRIPTION
The present invention features crystalline polymorphs of methyl
{(2S,3R)-1- [(2S)-2
-{5-[(2R,5R)-1-{3,5-difluoro-4[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-
-(6-fluoro-2{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2--
yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}py-
rrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate
##STR00001## herein "Compound I"). Compound I is a potent HCV NS5A
inhibitor and is described in U.S. Patent Application Publication
No. 2012/0004196, which is incorporated herein by reference in its
entirety.
Compound I was found to be very difficult to crystallize during
early development. Crystalline Compound I was not readily obtained
despite months of development work. Even if a crystalline form of
Compound I had been known to exit, the precise crystal structure of
the crystalline form would generally not have been predictable.
A crystalline form of Compound I was unexpectedly obtained using a
highly unconventional solvent system--namely, n-butylamine.
Additional crystalline forms were subsequently identified. Prior to
the isolation and characterization of these crystalline forms, the
existence and identity of these particular polymorphs had not been
expected. These crystalline forms can be used to improve
formulation (e.g., via hot melt extrusion), allow for purification
via crystallization as well as manufacturing at scale, and enable
improved stability, handling and bulk properties among others.
In one aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern as shown in FIG. 1.
In another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) as shown in Table 1.
The relative intensity, as well as the two theta value, of each
peak in Tables 1-10 and FIGS. 1-10 may change or shift under
certain conditions, although the crystalline form is the same. One
of ordinary skill in the art should be able to readily determine
whether a given crystalline form is the same crystalline form as
described in one of FIGS. 1-10 or Tables 1-10 by comparing their
PXRD profiles.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 3.78, 4.09, 8.19, 9.15, 10.42, 13.02, 13.50, 18.45,
19.48, and 20.86.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 3.78, 4.09, 6.92, 8.19, 9.15, 10.12, 10.42, 12.30,
13.02, 13.50, 14.77, 16.20, 16.97, 18.12, 18.45, 19.48, 20.86,
24.24, 24.79, and 25.97.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 3.78, 4.09, 6.72, 6.92, 8.19, 9.15, 9.84, 10.12,
10.42, 10.72, 11.66, 12.30, 13.02, 13.50, 14.77, 15.26, 15.62,
16.20, 16.97, 17.27, 17.55, 18.12, 18.45, 19.48, 19.90, 20.37,
20.61, 20.86, 21.99, 22.25, 22.72, 24.24, 24.79, 25.97, 26.88,
27.42, 27.81, and 30.23.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern as shown in FIG. 2.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) as shown in Table 2.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.70, 7.53, 10.51, 11.43, 11.80, 15.85, 17.23, 19.11,
21.37, and 23.00.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.23, 5.70, 7.53, 8.24, 8.97, 10.51, 11.43, 11.80,
12.05, 12.69, 13.23, 14.97, 15.85, 17.23, 19.11, 20.20, 21.37,
21.99, 22.22, and 23.00.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.23, 5.70, 7.53, 8.24, 8.97, 10.51, 11.43, 11.80,
12.05, 12.69, 13.23, 13.99, 14.97, 15.85, 17.23, 18.45, 19.11,
19.76, 20.20, 21.37, 21.99, 22.22, 23.00, 25.17, 25.43, 26.73, and
32.46.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern as shown in FIG. 3.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) as shown in Table 3.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.22, 5.69, 7.55, 10.49, 11.38, 11.84, 15.99, 17.23,
19.18, and 21.41.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.22, 5.69, 7.55, 8.21, 9.40, 10.49, 11.38, 11.84,
12.04, 12.67, 13.24, 15.99, 17.23, 19.18, 20.15, 21.41, 22.10,
22.53, 23.02, and 25.19.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.22, 5.69, 7.55, 8.21, 8.99, 9.40, 10.49, 11.07,
11.38, 11.84, 12.04, 12.67, 13.24, 13.99, 14.96, 15.99, 17.23,
18.10, 18.47, 19.18, 20.15, 21.41, 22.10, 22.53, 23.02, 25.19,
25.69, 26.57, 26.98, 30.09, and 32.45.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern as shown in FIG. 4.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) as shown in Table 4.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.43, 6.24, 7.53, 10.91, 12.34, 12.57, 13.67, 13.94,
17.44, and 19.30.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.43, 6.24, 7.53, 8.68, 10.58, 10.91, 12.34, 12.57,
13.67, 13.94, 14.71, 15.40, 15.99, 16.64, 17.44, 19.30, 19.70,
21.10, 21.33, and 21.72.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.43, 6.24, 7.53, 8.68, 9.28, 10.58, 10.91, 11.65,
12.34, 12.57, 13.67, 13.94, 14.71, 15.40, 15.99, 16.64, 17.44,
19.30, 19.70, 21.10, 21.33, 21.72, and 22.78.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern as shown in FIG. 5.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) as shown in Table 5.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.57, 6.19, 7.50, 10.86, 11.46, 12.42, 13.59, 15.28,
16.66, and 19.44.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.57, 6.19, 7.50, 8.75, 10.86, 11.08, 11.46, 12.42,
13.59, 15.28, 16.26, 16.66, 17.25, 17.87, 19.44, 20.80, 21.13,
21.39, 22.15, and 27.12.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.57, 6.19, 7.50, 8.75, 10.86, 11.08, 11.46, 12.42,
12.84, 13.59, 15.28, 16.26, 16.66, 17.25, 17.87, 19.44, 20.80,
21.13, 21.39, 22.15, 23.17, 24.15, and 27.12.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern as shown in FIG. 6.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) as shown in Table 6.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 4.35, 4.68, 7.33, 12.01, 13.13, 13.35, 16.54, 17.96,
18.26, and 21.21.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 4.35, 4.68, 6.41, 7.33, 9.54, 10.26, 11.13, 11.34,
12.01, 13.13, 13.35, 14.33, 16.54, 17.96, 18.26, 18.60, 19.77,
21.21, 21.75, and 24.19.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 4.35, 4.68, 6.41, 6.92, 7.33, 9.25, 9.54, 10.26,
11.13, 11.34, 12.01, 13.13, 13.35, 14.33, 14.65, 15.36, 16.54,
17.96, 18.26, 18.60, 19.05, 19.77, 21.21, 21.75, and 24.19.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern as shown in FIG. 7.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) as shown in Table 7.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.36, 8.81, 10.09, 10.69, 11.43, 12.95, 14.14, 17.96,
18.28, and 22.88.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 3.50, 5.36, 8.81, 10.09, 10.69, 11.43, 12.19, 12.95,
14.14, 14.72, 15.18, 17.53, 17.96, 18.28, 18.86, 21.36, 22.01,
22.88, 26.54, and 28.04.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 3.50, 4.61, 5.36, 5.79, 7.61, 8.81, 10.09, 10.69,
11.43, 12.19, 12.95, 14.14, 14.72, 15.18, 15.64, 16.87, 17.53,
17.96, 18.28, 18.86, 19.76, 21.36, 22.01, 22.88, 24.42, 25.20,
26.54, 28.04, and 28.65.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern as shown in FIG. 8.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) as shown in Table 8.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.08, 10.81, 12.05, 13.47, 13.68, 17.68, 19.02, 19.48,
21.73, and 25.53.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.08, 7.82, 10.27, 10.81, 12.05, 13.47, 13.68, 14.95,
16.81, 17.68, 19.02, 19.48, 20.36, 21.73, 22.24, 23.48, 25.53,
26.93, 32.01, and 33.12.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.08, 7.82, 10.27, 10.81, 11.11, 12.05, 13.47, 13.68,
14.95, 15.57, 16.28, 16.81, 17.68, 19.02, 19.48, 20.36, 21.73,
22.24, 23.48, 24.16, 25.53, 26.93, 28.26, 30.41, 31.07, 32.01,
33.12, and 35.04.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern as shown in FIG. 9.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) as shown in Table 9.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.31, 11.11, 12.60, 13.75, 15.29, 15.96, 17.62, 19.71,
21.30, and 22.88.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.31, 10.16, 10.62, 11.11, 12.60, 13.75, 15.29, 15.96,
17.62, 18.19, 19.16, 19.71, 20.58, 21.30, 22.40, 22.88, 23.66,
26.40, 26.74, and 33.46.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.31, 10.16, 10.62, 11.11, 12.60, 13.75, 15.29, 15.96,
17.62, 18.19, 19.16, 19.71, 20.58, 21.30, 22.40, 22.88, 23.66,
26.40, 26.74, 28.12, 31.62, and 33.46.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern as shown in FIG. 10.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) as shown in Table 10.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 7.42, 10.57, 11.84, 13.74, 15.72, 17.36, 19.38, 21.34,
22.07, and 23.36.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.28, 5.65, 7.42, 9.26, 10.57, 10.90, 11.31, 11.84,
12.15, 12.73, 13.74, 15.72, 17.36, 18.04, 19.38, 21.34, 22.07,
22.90, 23.36, and 26.49.
In yet another aspect, the invention features a crystalline form of
Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.28, 5.65, 7.42, 8.02, 8.94, 9.26, 10.57, 10.90,
11.31, 11.84, 12.15, 12.73, 13.14, 13.74, 14.78, 15.72, 16.32,
16.95, 17.36, 18.04, 18.81, 19.38, 21.34, 22.07, 22.90, 23.36,
24.50, 25.13, 25.59, 26.49, 32.24, and 32.93.
As used herein, PXRD data can be collected using a G3000
diffractometer (Inel Corp., Artenay, France) equipped with a curved
position-sensitive detector and parallel-beam optics. The
diffractometer is operated with a copper anode tube (1.5 kW fine
focus) at 40 kV and 30 mA. An incident-beam germanium monochromator
provides monochromatic Cu-K.sub..alpha. radiation, which has a
wavelength of 1.54178 .ANG.. The diffractometer is calibrated using
the attenuated direct beam at one-degree intervals. Calibration is
checked using a silicon powder line position reference standard
(NIST 640c). The instrument is computer-controlled using Symphonix
software (Inel Corp., Artenay, France) and the data are analyzed
using Jade software (version 6.5, Materials Data, Inc., Livermore,
Calif.). The sample can be loaded onto an aluminum sample holder
and leveled with a glass slide. PXRD peak position measurements are
typically .+-.0.2 degrees two-theta (.degree. 2.theta.).
In another aspect, the present invention features a crystalline
form described above which is substantially pure. As used herein,
the term "substantially pure", when used in reference to a given
crystalline form, refers to the crystalline form which is at least
about 90% pure. This means that the crystalline form does not
contain more than about 10% of any other form of Compound I. More
preferably, the term "substantially pure" refers to a crystalline
form of Compound I which is at least about 95% pure. This means
that the crystalline form of Compound I does not contain more than
about 5% of any other form of Compound I. Even more preferably, the
term "substantially pure" refers to a crystalline form of Compound
I which is at least about 97% pure. This means that the crystalline
form of Compound I does not to contain more than about 3% of any
other form of Compound I.
In one embodiment, the present invention feature a crystalline form
of Compound I which has characteristic peaks in the powder X-ray
diffraction (PXRD) pattern as shown in FIG. 1 and which is
substantially pure. For example the crystalline form can be at
least 90% pure, preferably at least 95% pure, or more preferably at
least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) as shown in Table 1 and which is substantially pure. For
example the crystalline form can be at least 90% pure, preferably
at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 3.78, 4.09, 8.19, 9.15, 10.42, 13.02, 13.50, 18.45,
19.48, and 20.86, and which is substantially pure. For example the
crystalline form can be at least 90% pure, preferably at least 95%
pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 3.78, 4.09, 6.92, 8.19, 9.15, 10.12, 10.42, 12.30,
13.02, 13.50, 14.77, 16.20, 16.97, 18.12, 18.45, 19.48, 20.86,
24.24, 24.79, and 25.97, and which is substantially pure. For
example the crystalline form can be at least 90% pure, preferably
at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 3.78, 4.09, 6.72, 6.92, 8.19, 9.15, 9.84, 10.12,
10.42, 10.72, 11.66, 12.30, 13.02, 13.50, 14.77, 15.26, 15.62,
16.20, 16.97, 17.27, 17.55, 18.12, 18.45, 19.48, 19.90, 20.37,
20.61, 20.86, 21.99, 22.25, 22.72, 24.24, 24.79, 25.97, 26.88,
27.42, 27.81, and 30.23, and which is substantially pure. For
example the crystalline form can be at least 90% pure, preferably
at least 95% pure, or more preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern as shown in FIG. 2 and
which is substantially pure. For example the crystalline form can
be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern at values of two theta
(.degree. 2.theta.) as shown in Table 2 and which is substantially
pure. For example the crystalline form can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.70, 7.53, 10.51, 11.43, 11.80, 15.85, 17.23, 19.11,
21.37, and 23.00, and which is substantially pure. For example the
crystalline form can be at least 90% pure, preferably at least 95%
pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.23, 5.70, 7.53, 8.24, 8.97, 10.51, 11.43, 11.80,
12.05, 12.69, 13.23, 14.97, 15.85, 17.23, 19.11, 20.20, 21.37,
21.99, 22.22, and 23.00, and which is substantially pure. For
example the crystalline form can be at least 90% pure, preferably
at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.23, 5.70, 7.53, 8.24, 8.97, 10.51, 11.43, 11.80,
12.05, 12.69, 13.23, 13.99, 14.97, 15.85, 17.23, 18.45, 19.11,
19.76, 20.20, 21.37, 21.99, 22.22, 23.00, 25.17, 25.43, 26.73, and
32.46, and which is substantially pure. For example the crystalline
form can be at least 90% pure, preferably at least 95% pure, or
more preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern as shown in FIG. 3 and
which is substantially pure. For example the crystalline form can
be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern at values of two theta
(.degree. 2.theta.) as shown in Table 3 and which is substantially
pure. For example the crystalline form can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.22, 5.69, 7.55, 10.49, 11.38, 11.84, 15.99, 17.23,
19.18, and 21.41, and which is substantially pure. For example the
crystalline form can be at least 90% pure, preferably at least 95%
pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.22, 5.69, 7.55, 8.21, 9.40, 10.49, 11.38, 11.84,
12.04, 12.67, 13.24, 15.99, 17.23, 19.18, 20.15, 21.41, 22.10,
22.53, 23.02, and 25.19, and which is substantially pure. For
example the crystalline form can be at least 90% pure, preferably
at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.22, 5.69, 7.55, 8.21, 8.99, 9.40, 10.49, 11.07,
11.38, 11.84, 12.04, 12.67, 13.24, 13.99, 14.96, 15.99, 17.23,
18.10, 18.47, 19.18, 20.15, 21.41, 22.10, 22.53, 23.02, 25.19,
25.69, 26.57, 26.98, 30.09, and 32.45, and which is substantially
pure. For example the crystalline form can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern as shown in FIG. 4 and
which is substantially pure. For example the crystalline form can
be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern at values of two theta
(.degree. 2.theta.) as shown in Table 4 and which is substantially
pure. For example the crystalline form can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.43, 6.24, 7.53, 10.91, 12.34, 12.57, 13.67, 13.94,
17.44, and 19.30, and which is substantially pure. For example the
crystalline form can be at least 90% pure, preferably at least 95%
pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.43, 6.24, 7.53, 8.68, 10.58, 10.91, 12.34, 12.57,
13.67, 13.94, 14.71, 15.40, 15.99, 16.64, 17.44, 19.30, 19.70,
21.10, 21.33, and 21.72, and which is substantially pure. For
example the crystalline form can be at least 90% pure, preferably
at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.43, 6.24, 7.53, 8.68, 9.28, 10.58, 10.91, 11.65,
12.34, 12.57, 13.67, 13.94, 14.71, 15.40, 15.99, 16.64, 17.44,
19.30, 19.70, 21.10, 21.33, 21.72, and 22.78, and which is
substantially pure. For example the crystalline form can be at
least 90% pure, preferably at least 95% pure, or more preferably at
least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern as shown in FIG. 5 and
which is substantially pure. For example the crystalline form can
be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern at values of two theta
(.degree. 2.theta.) as shown in Table 5 and which is substantially
pure. For example the crystalline form can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.57, 6.19, 7.50, 10.86, 11.46, 12.42, 13.59, 15.28,
16.66, and 19.44, and which is substantially pure. For example the
crystalline form can be at least 90% pure, preferably at least 95%
pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.57, 6.19, 7.50, 8.75, 10.86, 11.08, 11.46, 12.42,
13.59, 15.28, 16.26, 16.66, 17.25, 17.87, 19.44, 20.80, 21.13,
21.39, 22.15, and 27.12, and which is substantially pure. For
example the crystalline form can be at least 90% pure, preferably
at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.57, 6.19, 7.50, 8.75, 10.86, 11.08, 11.46, 12.42,
12.84, 13.59, 15.28, 16.26, 16.66, 17.25, 17.87, 19.44, 20.80,
21.13, 21.39, 22.15, 23.17, 24.15, and 27.12, and which is
substantially pure. For example the crystalline form can be at
least 90% pure, preferably at least 95% pure, or more preferably at
least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern as shown in FIG. 6 and
which is substantially pure. For example the crystalline form can
be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern at values of two theta
(.degree. 2.theta.) as shown in Table 6 and which is substantially
pure. For example the crystalline form can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 4.35, 4.68, 7.33, 12.01, 13.13, 13.35, 16.54, 17.96,
18.26, and 21.21, and which is substantially pure. For example the
crystalline form can be at least 90% pure, preferably at least 95%
pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 4.35, 4.68, 6.41, 7.33, 9.54, 10.26, 11.13, 11.34,
12.01, 13.13, 13.35, 14.33, 16.54, 17.96, 18.26, 18.60, 19.77,
21.21, 21.75, and 24.19, and which is substantially pure. For
example the crystalline form can be at least 90% pure, preferably
at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 4.35, 4.68, 6.41, 6.92, 7.33, 9.25, 9.54, 10.26,
11.13, 11.34, 12.01, 13.13, 13.35, 14.33, 14.65, 15.36, 16.54,
17.96, 18.26, 18.60, 19.05, 19.77, 21.21, 21.75, and 24.19, and
which is substantially pure. For example the crystalline form can
be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern as shown in FIG. 7 and
which is substantially pure. For example the crystalline form can
be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern at values of two theta
(.degree. 2.theta.) as shown in Table 7 and which is substantially
pure. For example the crystalline form can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.36, 8.81, 10.09, 10.69, 11.43, 12.95, 14.14, 17.96,
18.28, and 22.88, and which is substantially pure. For example the
crystalline form can be at least 90% pure, preferably at least 95%
pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 3.50, 5.36, 8.81, 10.09, 10.69, 11.43, 12.19, 12.95,
14.14, 14.72, 15.18, 17.53, 17.96, 18.28, 18.86, 21.36, 22.01,
22.88, 26.54, and 28.04, and which is substantially pure. For
example the crystalline form can be at least 90% pure, preferably
at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 3.50, 4.61, 5.36, 5.79, 7.61, 8.81, 10.09, 10.69,
11.43, 12.19, 12.95, 14.14, 14.72, 15.18, 15.64, 16.87, 17.53,
17.96, 18.28, 18.86, 19.76, 21.36, 22.01, 22.88, 24.42, 25.20,
26.54, 28.04, and 28.65, and which is substantially pure. For
example the crystalline form can be at least 90% pure, preferably
at least 95% pure, or more preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern as shown in FIG. 8 and
which is substantially pure. For example the crystalline form can
be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern at values of two theta
(.degree. 2.theta.) as shown in Table 8 and which is substantially
pure. For example the crystalline form can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.08, 10.81, 12.05, 13.47, 13.68, 17.68, 19.02, 19.48,
21.73, and 25.53, and which is substantially pure. For example the
crystalline form can be at least 90% pure, preferably at least 95%
pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.08, 7.82, 10.27, 10.81, 12.05, 13.47, 13.68, 14.95,
16.81, 17.68, 19.02, 19.48, 20.36, 21.73, 22.24, 23.48, 25.53,
26.93, 32.01, and 33.12, and which is substantially pure. For
example the crystalline form can be at least 90% pure, preferably
at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.08, 7.82, 10.27, 10.81, 11.11, 12.05, 13.47, 13.68,
14.95, 15.57, 16.28, 16.81, 17.68, 19.02, 19.48, 20.36, 21.73,
22.24, 23.48, 24.16, 25.53, 26.93, 28.26, 30.41, 31.07, 32.01,
33.12, and 35.04, and which is substantially pure. For example the
crystalline form can be at least 90% pure, preferably at least 95%
pure, or more preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern as shown in FIG. 9 and
which is substantially pure. For example the crystalline form can
be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern at values of two theta
(.degree. 2.theta.) as shown in Table 9 and which is substantially
pure. For example the crystalline form can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.31, 11.11, 12.60, 13.75, 15.29, 15.96, 17.62, 19.71,
21.30, and 22.88, and which is substantially pure. For example the
crystalline form can be at least 90% pure, preferably at least 95%
pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.31, 10.16, 10.62, 11.11, 12.60, 13.75, 15.29, 15.96,
17.62, 18.19, 19.16, 19.71, 20.58, 21.30, 22.40, 22.88, 23.66,
26.40, 26.74, and 33.46, and which is substantially pure. For
example the crystalline form can be at least 90% pure, preferably
at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.31, 10.16, 10.62, 11.11, 12.60, 13.75, 15.29, 15.96,
17.62, 18.19, 19.16, 19.71, 20.58, 21.30, 22.40, 22.88, 23.66,
26.40, 26.74, 28.12, 31.62, and 33.46, and which is substantially
pure. For example the crystalline form can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern as shown in FIG. 10 and
which is substantially pure. For example the crystalline form can
be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In yet another embodiment, the present invention feature a
crystalline form of Compound I which has characteristic peaks in
the powder X-ray diffraction (PXRD) pattern at values of two theta
(.degree. 2.theta.) as shown in Table 10 and which is substantially
pure. For example the crystalline form can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 7.42, 10.57, 11.84, 13.74, 15.72, 17.36, 19.38, 21.34,
22.07, and 23.36, and which is substantially pure. For example the
crystalline form can be at least 90% pure, preferably at least 95%
pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.28, 5.65, 7.42, 9.26, 10.57, 10.90, 11.31, 11.84,
12.15, 12.73, 13.74, 15.72, 17.36, 18.04, 19.38, 21.34, 22.07,
22.90, 23.36, and 26.49, and which is substantially pure. For
example the crystalline form can be at least 90% pure, preferably
at least 95% pure, or more preferably at least 97%.
In another embodiment, the present invention feature a crystalline
form of Compound I which has characteristic peaks in the powder
X-ray diffraction (PXRD) pattern at values of two theta (.degree.
2.theta.) of 5.28, 5.65, 7.42, 8.02, 8.94, 9.26, 10.57, 10.90,
11.31, 11.84, 12.15, 12.73, 13.14, 13.74, 14.78, 15.72, 16.32,
16.95, 17.36, 18.04, 18.81, 19.38, 21.34, 22.07, 22.90, 23.36,
24.50, 25.13, 25.59, 26.49, 32.24, and 32.93, and which is
substantially pure. For example the crystalline form can be at
least 90% pure, preferably at least 95% pure, or more preferably at
least 97%.
In yet another aspect, the present invention features processes of
using a crystalline form of the invention to make a composition
comprising Compound I. The processes comprise dissolving a
crystalline form of the invention in a solvent.
Any crystalline form described herein, including any crystalline
form described in any aspect, embodiment or example of this
application, can be used in any process of the invention described
herein.
In one embodiment, the solvent is a volatile solvent such as
ethanol or methanol. A suitable excipient, such as a hydrophilic
polymer described below or a sugar alcohol, can also be dissolved
in the solvent. The solution thus produced can then be dried to
remove the solvent, such as via spray drying, freeze drying or
other solvent evaporization techniques, thereby creating a solid
dispersion that comprises Compound I and the excipient. Preferably,
Compound I is in an amorphous form in the solid dispersion. More
preferably, the solid dispersion is a solid solution or a glassy
solution. In many cases, a pharmaceutically acceptable surfactant
described below can also be added to the solution prior to solvent
removal; and as a result, the solid dispersion/solid solution/glass
solution produced according to this embodiment also comprises the
surfactant.
In another embodiment, the solvent is an excipient, such as a
hydrophilic polymer described below or a sugar alcohol, in a molten
or rubbery state. The crystalline form of Compound I dissolves in
the molten or rubbery excipient. Heating may be used to facilitate
the dissolving and mixing of the crystalline form of Compound I in
the molten or rubbery excipient. Preferably, melt extrusion is used
to dissolve and mix the crystalline form of Compound I in the
excipient. A solution or melt thus produced can be cooled and
solidified to form a solid dispersion that comprises Compound I and
the excipient. Preferably, Compound I is in an amorphous form in
the solid dispersion. More preferably, the solid dispersion is a
solid solution or a glassy solution. The solid dispersion, solid
solution or glassy solution can be milled, ground or granulated,
and then compressed into a tablet or another suitable solid dosage
form with or without other additives. The solid dispersion, solid
solution or glassy solution can also be directly shaped or
configured into a tablet or another suitable solid dosage form. In
many cases, a pharmaceutically acceptable surfactant described
below can be added to the solution or melt prior to solidification;
and as a result, the solid dispersion/solid solution/glassy
solution produced according to this embodiment also comprises the
surfactant.
In yet another embodiment, both heating and a volatile solvent are
used to dissolve a crystalline form of Compound I in a solution
comprising a suitable excipient.
As used herein, the term "solid dispersion" defines a system in a
solid state (as opposed to a liquid or gaseous state) comprising at
least two components, wherein one component is dispersed throughout
the other component or components. For example, an active
ingredient or a combination of active ingredients can be dispersed
in a matrix comprised of a pharmaceutically acceptable hydrophilic
polymer(s) and a pharmaceutically acceptable surfactant(s). The
term "solid dispersion" encompasses systems having small particles
of one phase dispersed in another phase. When a solid dispersion of
the components is such that the system is chemically and physically
uniform or homogenous throughout or consists of one phase (as
defined in thermodynamics), such a solid dispersion is called a
"solid solution." A glassy solution is a solid solution in which a
solute is dissolved in a glassy solvent.
Non-limiting examples of excipients suitable for use in a process
of the invention include numerous hydrophilic polymers. Preferably,
a hydrophilic polymer employed in a process of the invention has a
T.sub.g of at least 50.degree. C., more preferably at least
60.degree. C., and highly preferably at least 80.degree. C.
including, but not limited to from, 80.degree. C. to 180.degree.
C., or from 100.degree. C. to 150.degree. C. Methods for
determining T.sub.g values of organic polymers are described in
INTRODUCTION TO PHYSICAL POLYMER SCIENCE (2nd Edition by L. H.
Sperling, published by John Wiley & Sons, Inc., 1992). The
T.sub.g value can be calculated as the weighted sum of the T.sub.g
values for homopolymers derived from each of the individual
monomers, i.e., the polymer T.sub.g=.SIGMA.W.sub.iX.sub.i where
W.sub.i is the weight percent of monomer i in the organic polymer,
and X, is the T.sub.g value for the homopolymer derived from
monomer i. T.sub.g values for the homopolymers may be taken from
POLYMER HANDBOOK (2nd Edition by J. Brandrup and E. H. Immergut,
Editors, published by John Wiley & Sons, Inc., 1975).
Hydrophilic polymers with a T.sub.g as described above may allow
for the preparation of solid dispersions that are mechanically
stable and, within ordinary temperature ranges, sufficiently
temperature stable so that the solid dispersions may be used as
dosage forms without further processing or be compacted to tablets
with only a small amount of tabletting aids. Hydrophilic polymers
having a T.sub.g of below 50.degree. C. may also be used.
Preferably, a hydrophilic polymer employed in the present invention
is water-soluble. A solid composition of the present invention can
also comprise poorly water-soluble or water-insoluble polymer or
polymers, such as cross-linked polymers. A hydrophilic polymer
comprised in a solid composition of the present invention
preferably has an apparent viscosity, when dissolved at 20.degree.
C. in an aqueous solution at 2% (w/v), of 1 to 5000 mPas., and more
preferably of 1 to 700 mPas, and most preferably of 5 to 100
mPas.
Hydrophilic polymers suitable for use in a process of the invention
include, but are not limited to, homopolymers or copolymers of
N-vinyl lactams, such as homopolymers or copolymers of N-vinyl
pyrrolidone (e.g., polyvinylpyrrolidone (PVP), or copolymers of
N-vinyl pyrrolidone and vinyl acetate or vinyl propionate);
cellulose esters or cellulose ethers, such as alkylcelluloses
(e.g., methylcellulose or ethylcellulose), hydroxyalkylcelluloses
(e.g., hydroxypropylcellulose), hydroxyalkylalkylcelluloses (e.g.,
hydroxypropylmethylcellulose), and cellulose phthalates or
succinates (e.g., cellulose acetate phthalate and
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose succinate, or
hydroxypropylmethylcellulose acetate succinate); high molecular
polyalkylene oxides, such as polyethylene oxide, polypropylene
oxide, and copolymers of ethylene oxide and propylene oxide;
polyacrylates or polymethacrylates, such as methacrylic acid/ethyl
acrylate copolymers, methacrylic acid/methyl methacrylate
copolymers, butyl methacrylate/2-dimethylaminoethyl methacrylate
copolymers, poly(hydroxyalkyl acrylates), and poly(hydroxyalkyl
methacrylates); polyacrylamides; vinyl acetate polymers, such as
copolymers of vinyl acetate and crotonic acid, and partially
hydrolyzed polyvinyl acetate (also referred to as partially
saponified "polyvinyl alcohol"); polyvinyl alcohol; oligo- or
polysaccharides, such as carrageenans, galactomannans, and xanthan
gum; polyhydroxyalkylacrylates; polyhydroxyalkyl-methacrylates;
copolymers of methyl methacrylate and acrylic acid; polyethylene
glycols (PEGs); or any mixture thereof.
Non-limiting examples of preferred hydrophilic polymers for use in
a process of the invention include polyvinylpyrrolidone (PVP) K17,
PVP K25, PVP K30, PVP K90, hydroxypropyl methylcellulose (HPMC) E3,
HPMC E5, HPMC E6, HPMC E15, HPMC K3, HPMC A4, HPMC A15, HPMC
acetate succinate (AS) LF, HPMC AS MF, HPMC AS HF, HPMC AS LG, HPMC
AS MG, HPMC AS HG, HPMC phthalate (P) 50, HPMC P 55, Ethocel 4,
Ethocel 7, Ethocel 10, Ethocel 14, Ethocel 20, copovidone
(vinylpyrrolidone-vinyl acetate copolymer 60/40), polyvinyl
acetate, methacrylate/methacrylic acid copolymer (Eudragit)
L100-55, Eudragit L100, Eudragit S100, polyethylene glycol (PEG)
400, PEG 600, PEG 1450, PEG 3350, PEG 4000, PEG 6000, PEG 8000,
poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and
poloxamer 407.
Of these, homopolymers or copolymers of N-vinyl pyrrolidone, such
as copolymers of N-vinyl pyrrolidone and vinyl acetate, are
preferred. A non-limiting example of a preferred polymer is a
copolymer of 60% by weight of N-vinyl pyrrolidone and 40% by weight
of vinyl acetate. Other preferred polymers include, without
limitation, hydroxypropyl methylcellulose (HPMC, also known as
hypromellose in USP), such as hydroxypropyl methylcellulose grade
E5 (HPMC-E5); and hydroxypropyl methylcellulose acetate succinate
(HPMC-AS).
A pharmaceutically acceptable surfactant employed in a process of
the invention is preferably a non-ionic surfactant. More
preferably, the non-ionic surfactant has an HLB value of from 2-20.
The HLB system (Fiedler, H. B., ENCYLOPEDIA OF EXCIPIENTS, 5.sup.th
ed., Aulendorf: ECV-Editio-Cantor-Verlag (2002)) attributes numeric
values to surfactants, with lipophilic substances receiving lower
HLB values and hydrophilic substances receiving higher HLB
values.
Non-limiting examples of pharmaceutically acceptable surfactants
that are suitable for use in a process of the invention include
polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol
triricinoleate or polyoxyl 35 castor oil (Cremophor.RTM. EL; BASF
Corp.) or polyoxyethyleneglycerol oxystearate such as
polyethylenglycol 40 hydrogenated castor oil (Cremophor.RTM. RH 40,
also known as polyoxyl 40 hydrogenated castor oil or
macrogolglycerol hydroxystearate) or polyethylenglycol 60
hydrogenated castor oil (Cremophor.RTM. RH 60); or a mono fatty
acid ester of polyoxyethylene sorbitan, such as a mono fatty acid
ester of polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20)
sorbitan monooleate (Tween.RTM. 80), polyoxyethylene (20) sorbitan
monostearate (Tween.RTM. 60), polyoxyethylene (20) sorbitan
monopalmitate (Tween.RTM. 40), or polyoxyethylene (20) sorbitan
monolaurate (Tween.RTM. 20). Other non-limiting examples of
suitable surfactants include polyoxyethylene alkyl ethers, e.g.
polyoxyethylene (3) lauryl ether, polyoxyethylene (5) cetyl ether,
polyoxyethylene (2) stearyl ether, polyoxyethylene (5) stearyl
ether; polyoxyethylene alkylaryl ethers, e.g. polyoxyethylene (2)
nonylphenyl ether, polyoxyethylene (3) nonylphenyl ether,
polyoxyethylene (4) nonylphenyl ether, polyoxyethylene (3)
octylphenyl ether; polyethylene glycol fatty acid esters, e.g.
PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400
dilaurate, PEG-300 distearate, PEG-300 dioleate; alkylene glycol
fatty acid mono esters, e.g. propylene glycol monolaurate
(Lauroglycol.RTM.); sucrose fatty acid esters, e.g. sucrose
monostearate, sucrose distearate, sucrose monolaurate, sucrose
dilaurate; sorbitan fatty acid mono esters such as sorbitan mono
laurate (Span.RTM. 20), sorbitan monooleate, sorbitan monopalnitate
(Span.RTM. 40), or sorbitan stearate. Other suitable surfactants
include, but are not limited to, block copolymers of ethylene oxide
and propylene oxide, also known as polyoxyethylene polyoxypropylene
block copolymers or polyoxyethylene polypropyleneglycol, such as
Poloxamer.RTM. 124, Poloxamer.RTM. 188, Poloxamer.RTM. 237,
Poloxamer.RTM. 388, or Poloxamer.RTM. 407 (BASF Wyandotte
Corp.).
Non-limiting examples of preferred surfactants for use in a process
of the invention include polysorbate 20, polysorbate 40,
polysorbate 60, polysorbate 80, Cremophor RH 40, Cremophor EL,
Gelucire 44/14, Gelucire 50/13, D-alphatocopheryl polyethylene
glycol 1000 succinate (vitamin E TPGS), propylene glycol laurate,
sodium lauryl sulfate, and sorbitan monolaurate.
A pharmaceutically acceptable surfactant as used herein can be a
mixture of pharmaceutically acceptable surfactants, such as a
combination of a surfactant having an HLB value of below 10 and
another surfactant having an HLB value of no lees than 10.
In one embodiment, a surfactant having an HLB value of at least 10
is used in a process of the invention. In another embodiment, a
surfactant having an HLB value of below 10 is used in a process of
the invention. In yet another embodiment, a mixture of two or more
surfactants (e.g., a combination of one surfactant having an HLB
value of at least 10 and another surfactant having an HLB value of
below 10) is used in a process of the invention.
In one embodiment, a process of the invention comprises dissolving
a crystalline form of the invention, a hydrophilic polymer
described above, and a surfactant described above to form a
solution (e.g., a melt). The hydrophilic polymer can be selected,
for example, from the group consisting of homopolymer of N-vinyl
lactam, copolymer of N-vinyl lactam, cellulose ester, cellulose
ether, polyalkylene oxide, polyacrylate, polymethacrylate,
polyacrylamide, polyvinyl alcohol, vinyl acetate polymer,
oligosaccharide, and polysaccharide. As a non-limiting example, the
hydrophilic polymer is selected from the group consisting of
homopolymer of N-vinyl pyrrolidone, copolymer of N-vinyl
pyrrolidone, copolymer of N-vinyl pyrrolidone and vinyl acetate,
copolymer of N-vinyl pyrrolidone and vinyl propiovate,
polyvinylpyrrolidone, methylcellulose, ethylcellulose,
hydroxyalkylcelluloses, hydroxypropylcellulose,
hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, cellulose
phthalate, cellulose succinate, cellulose acetate phthalate,
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose succinate,
hydroxypropylmethylcellulose acetate succinate, polyethylene oxide,
polypropylene oxide, copolymer of ethylene oxide and propylene
oxide, methacrylic acid/ethyl acrylate copolymer, methacrylic
acid/methyl methacrylate copolymer, butyl
methacrylate/2-dimethylaminoethyl methacrylate copolymer,
poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate),
copolymer of vinyl acetate and crotonic acid, partially hydrolyzed
polyvinyl acetate, carrageenan, galactomannan, and xanthan gum.
Preferably, the hydrophilic polymer is selected from
polyvinylpyrrolidone (PVP) K17, PVP K25, PVP K30, PVP K90,
hydroxypropyl methylcellulose (HPMC) E3, HPMC E5, HPMC E6, HPMC
E15, HPMC K3, HPMC A4, HPMC A15, HPMC acetate succinate (AS) LF,
HPMC AS MF, HPMC AS HF, HPMC AS LG, HPMC AS MG, HPMC AS HG, HPMC
phthalate (P) 50, HPMC P 55, Ethocel 4, Ethocel 7, Ethocel 10,
Ethocel 14, Ethocel 20, copovidone (vinylpyrrolidone-vinyl acetate
copolymer 60/40), polyvinyl acetate, methacrylate/methacrylic acid
copolymer (Eudragit) L100-55, Eudragit L100, Eudragit S100,
polyethylene glycol (PEG) 400, PEG 600, PEG 1450, PEG 3350, PEG
4000, PEG 6000, PEG 8000, poloxamer 124, poloxamer 188, poloxamer
237, poloxamer 338, or poloxamer 407. More preferably, the
hydrophilic polymer is selected from homopolymers of
vinylpyrrolidone (e.g., PVP with Fikentscher K values of from 12 to
100, or PVP with Fikentscher K values of from 17 to 30), or
copolymers of 30 to 70% by weight of N-vinylpyrrolidone (VP) and 70
to 30% by weight of vinyl acetate (VA) (e.g., a copolymer of 60% by
weight VP and 40% by weight VA). The surfactant can be selected,
for example, from the group consisting of polyoxyethyleneglycerol
triricinoleate or polyoxyl 35 castor oil (Cremophor.RTM. EL; BASF
Corp.) or polyoxyethyleneglycerol oxystearate, mono fatty acid
ester of polyoxyethylene sorbitan, polyoxyethylene alkyl ether,
polyoxyethylene alkylaryl ether, polyethylene glycol fatty acid
ester, alkylene glycol fatty acid mono ester, sucrose fatty acid
ester, and sorbitan fatty acid mono ester. As a non-limited
example, the surfactant is selected from the group consisting of
polyethylenglycol 40 hydrogenated castor oil (Cremophor.RTM. RH 40,
also known as polyoxyl 40 hydrogenated castor oil or
macrogolglycerol hydroxystearate), polyethylenglycol 60
hydrogenated castor oil (Cremophor.RTM. RH 60), a mono fatty acid
ester of polyoxyethylene (20) sorbitan (e.g. polyoxyethylene (20)
sorbitan monooleate (Tween.RTM. 80), polyoxyethylene (20) sorbitan
monostearate (Tween.RTM. 60), polyoxyethylene (20) sorbitan
monopalmitate (Tween.RTM. 40), or polyoxyethylene (20) sorbitan
monolaurate (Tween.RTM. 20)), polyoxyethylene (3) lauryl ether,
polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether,
polyoxyethylene (5) stearyl ether, polyoxyethylene (2) nonylphenyl
ether, polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4)
nonylphenyl ether, polyoxyethylene (3) octylphenyl ether, PEG-200
monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400
dilaurate, PEG-300 distearate, PEG-300 dioleate, propylene glycol
monolaurate, sucrose monostearate, sucrose distearate, sucrose
monolaurate, sucrose dilaurate, sorbitan monolaurate, sorbitan
monooleate, sorbitan monopalnitate, and sorbitan stearate.
Preferably, the surfactant is selected from polysorbate 20,
polysorbate 40, polysorbate 60, polysorbate 80, Cremophor RH 40,
Cremophor EL, Gelucire 44/14, Gelucire 50/13, D-alpha-tocopheryl
polyethylene glycol 1000 succinate (vitamin E TPGS), propylene
glycol laurate, sodium lauryl sulfate, or sorbitan monolaurate.
More preferably, the surfactant is selected from sorbitan
monolaurate or D-alpha-tocopheryl polyethylene glycol 1000
succinate.
In another embodiment, a process of the invention comprises
dissolving a crystalline form of the invention, a hydrophilic
polymer described above, and a surfactant described above to form a
solution (e.g., a melt). The hydrophilic polymer is a homopolymer
or copolymer of N-vinyl pyrrolidone (e.g., copovidone). The
pharmaceutically acceptable surfactant can be, e.g., vitamin E
TPGS, or sorbitan monolaurate.
A melt-extrusion process of the invention typically comprises
preparing a melt from (1) a crystalline form of the invention, (2)
a hydrophilic polymer described above (or another suitable binder),
and (3) preferably a surfactant described above. The melt can then
be cooled until it solidifies. The crystalline form of Compound I
initially used will disappear upon the formation of the melt. The
melt may also include other additives. "Melting" means a transition
into a liquid or rubbery state in which it is possible for one
component to get embedded, preferably homogeneously embedded, in
the other component or components. In many cases, the polymer
component will melt and the other components including the
crystalline form of Compound I and the surfactant will dissolve in
the melt thereby forming a solution. Melting usually involves
heating above the softening point of the polymer. The preparation
of the melt can take place in a variety of ways. The mixing of the
components can take place before, during or after the formation of
the melt. For example, the components can be mixed first and then
melted or be simultaneously mixed and melted. The melt can also be
homogenized in order to disperse Compound I efficiently. In
addition, it may be convenient first to melt the polymer and then
to mix in and homogenize Compound I. In one example, all materials
except the surfactant are blended and fed into an extruder, while
the surfactant is molten externally and pumped in during
extrusion.
In another example, the melt comprises Compound I and a hydrophilic
polymer described above, and the melt temperature is in the range
of from 100 to 170.degree. C., preferably from 120 to 150.degree.
C., and highly preferably from 135 to 140.degree. C. The melt can
also include a pharmaceutically acceptable surfactant described
above.
In still another example, the melt comprises Compound I, at least
another anti-HCV agent (e.g., a HCV polymerase inhibitor, or a NS5A
inhibitor, or a combination of a HCV polymerase inhibitor and a
NS5A inhibitor), and a hydrophilic polymer described above. The
melt can also include a pharmaceutically acceptable surfactant
described above.
To start a melt-extrusion process, Compound I is employed in a
crystalline form of the invention, e.g., any crystalline form
described in any aspect, embodiment or example of this application.
A crystalline form of the invention may also be first dissolved in
a suitable liquid solvent such as alcohols, aliphatic hydrocarbons,
esters or, in some cases, liquid carbon dioxide; the solvent can be
removed, e.g., evaporated, upon preparation of the melt.
Various additives can also be included in the melt, for example,
flow regulators (e.g., colloidal silica), lubricants, fillers,
disintegrants, plasticizers, colorants, or stabilizers (e.g.,
antioxidants, light stabilizers, radical scavengers, and
stabilizers against microbial attack).
The melting and/or mixing can take place in an apparatus customary
for this purpose. Particularly suitable ones are extruders or
kneaders. Suitable extruders include single screw extruders,
intermeshing screw extruders or multiscrew extruders, preferably
twin screw extruders, which can be corotating or counterrotating
and, optionally, be equipped with kneading disks. It will be
appreciated that the working temperatures will be determined by the
kind of extruder or the kind of configuration within the extruder
that is used. Part of the energy needed to melt, mix and dissolve
the components in the extruder can be provided by heating elements.
However, the friction and shearing of the material in the extruder
may also provide a substantial amount of energy to the mixture and
aid in the formation of a homogeneous melt of the components.
The melt can range from thin to pasty to viscous. Shaping of the
extrudate can be conveniently carried out by a calender with two
counter-rotating rollers with mutually matching depressions on
their surface. The extrudate can be cooled and allow to solidify.
The extrudate can also be cut into pieces, either before (hot-cut)
or after solidification (cold-cut).
The solidified extrusion product can be further milled, ground or
otherwise reduced to granules. The solidified extrudate, as well as
each granule produced, comprises a solid dispersion, preferably a
solid solution, of Compound I in a matrix comprised of the
hydrophilic polymer and optionally the pharmaceutically acceptable
surfactant. Where the granules do not contain any surfactant, a
pharmaceutically acceptable surfactant described above can be added
to and blended with the granules. The extrusion product can also be
blended with other active ingredient(s) (e.g., ritonavir) and/or
additive(s) before being milled or ground to granules. The granules
can be further processed into suitable solid oral dosage forms.
In one example, copovidone and a surfactant described above are
mixed and granulated, followed by the addition of aerosil and a
crystalline form of Compound I of the invention. The mixture can
also contain ritonavir. The mixture, which may contain for example
5% by weight of Compound I, is then milled. The mixture is then
subject to extrusion, and the extrudate thus produced can be milled
and sieved for further processing to make capsules or tablets. The
surfactant employed in this example can also be added through
liquid dosing during extrusion.
The approach of solvent evaporation, e.g., via spray-drying,
provides the advantage of allowing for processability at lower
temperatures, if needed, and allows for other modifications to the
process in order to further improve powder properties. The
spray-dried powder can then be formulated further, if needed, and
final drug product is flexible with regards to whether capsule,
tablet or any other solid dosage form is desired.
Exemplary spray-drying processes and spray-drying equipment are
described in K. Masters, SPRAY DRYING HANDBOOK (Halstead Press, New
York, 4.sup.th ed., 1985). Non-limiting examples of spray-drying
devices that are suitable for the present invention include spray
dryers manufactured by Niro Inc. or GEA Process Engineering Inc.,
Buchi Labortechnik AG, and Spray Drying Systems, Inc. A
spray-drying process generally involves breaking up a liquid
mixture into small droplets and rapidly removing solvent from the
droplets in a container (spray drying apparatus) where there is a
strong driving force for evaporation of solvent from the droplets.
Atomization techniques include, for example, two-fluid or pressure
nozzles, or rotary atomizers. The strong driving force for solvent
evaporation can be provided, for example, by maintaining the
partial pressure of solvent in the spray drying apparatus well
below the vapor pressure of the solvent at the temperatures of the
drying droplets. This may be accomplished by either (1) maintaining
the pressure in the spray drying apparatus at a partial vacuum; (2)
mixing the liquid droplets with a warm drying gas (e.g., heated
nitrogen); or (3) both.
The temperature and flow rate of the drying gas, as well as the
spray dryer design, can be selected so that the droplets are dry
enough by the time they reach the wall of the apparatus. This help
to ensure that the dried droplets are essentially solid and can
form a fine powder and do not stick to the apparatus wall. The
spray-dried product can be collected by removing the material
manually, pneumatically, mechanically or by other suitable means.
The actual length of time to achieve the preferred level of dryness
depends on the size of the droplets, the formulation, and spray
dryer operation. Following the solidification, the solid powder may
stay in the spray drying chamber for additional time (e.g., 5-60
seconds) to further evaporate solvent from the solid powder. The
final solvent content in the solid dispersion as it exits the dryer
is preferably at a sufficiently low level so as to improve the
stability of the final product. For instance, the residual solvent
content of the spray-dried powder can be less than 2% by weight.
Highly preferably, the residual solvent content is within the
limits set forth in the International Conference on Harmonization
(ICH) Guidelines. In addition, it may be useful to subject the
spray-dried composition to further drying to lower the residual
solvent to even lower levels. Methods to further lower solvent
levels include, but are not limited to, fluid bed drying, infra-red
drying, tumble drying, vacuum drying, and combinations of these and
other processes.
Like the solid extrudate described above, the spray dried product
contains a solid dispersion, preferably a solid solution, of
Compound I in a matrix comprised of a hydrophilic polymer described
above and optionally a pharmaceutically acceptable surfactant
described above. Where the spray dried product does not contain any
surfactant, a pharmaceutically acceptable surfactant described
above can be added to and blended with the spray-dried product
before further processing.
Before feeding into a spray dryer, a crystalline form of Compound I
of the invention, a hydrophilic polymer described above, as well as
other optional active ingredients or excipients such as a
pharmaceutically acceptable surfactant described above, can be
dissolved in a solvent. Suitable solvents include, but are not
limited to, alkanols (e.g., methanol, ethanol, 1-propanol,
2-propanol or mixtures thereof), acetone, acetone/water,
alkanol/water mixtures (e.g., ethanol/water mixtures), or
combinations thereof. The solution can also be preheated before
being fed into the spray dryer. In many cases, ritonavir is
dissolved together with the crystalline form of Compound I.
The solid dispersion produced by melt-extrusion, spray-drying or
other techniques can be prepared into any suitable solid oral
dosage forms. In one embodiment, the solid dispersion prepared by
melt-extrusion, spray-drying or other techniques (e.g., the
extrudate or the spray-dried powder) can be compressed into
tablets. The solid dispersion can be either directly compressed, or
milled or ground to granules or powders before compression.
Compression can be done in a tablet press, such as in a steel die
between two moving punches. When a solid composition comprises
Compound I and another anti-HCV agent, it is possible to separately
prepare solid dispersions of each individual active ingredient and
then blend the optionally milled or ground solid dispersions before
compacting. Compound I and another antiHCV agent can also be
prepared in the same solid dispersion, optionally milled and/or
blended with other additives, and then compressed into tablets.
Likewise, when a solid composition comprises Compound I and
ritonavir, it is possible to separately prepare solid dispersions
of each individual active ingredient and then blend the optionally
milled or ground solid dispersions before compacting. Compound I
and ritonavir can also be prepared in the same solid dispersion,
optionally milled and/or blended with other additives, and then
compressed into tablets.
At least one additive, such as one selected from flow regulators,
lubricants, fillers, disintegrants or plasticizers, may be used in
compressing the solid dispersion. These additives can be mixed with
ground or milled solid dispersion before compacting. Disintegrants
promote a rapid disintegration of the compact in the stomach and
keeps the liberated granules separate from one another.
Non-limiting examples of suitable disintegrants are cross-linked
polymers such as cross-linked polyvinyl pyrrolidone, cross-linked
sodium carboxymethylcellulose or sodium croscarmellose.
Non-limiting examples of suitable fillers (also referred to as
bulking agents) are lactose monohydrate, calcium hydrogenphosphate,
microcrystalline cellulose (e.g., Avicell), silicates, in
particular silicium dioxide, magnesium oxide, talc, potato or corn
starch, isomalt, or polyvinyl alcohol. Non-limiting examples of
suitable flow regulators include highly dispersed silica (e.g.,
colloidal silica such as Aerosil), and animal or vegetable fats or
waxes. Non-limiting examples of suitable lubricants include
polyethylene glycol (e.g., having a molecular weight of from 1000
to 6000), magnesium and calcium stearates, sodium stearyl fumarate,
and the like.
Various other additives may also be used in preparing a solid
composition prepared according to a process of the invention, for
example dyes such as azo dyes, organic or inorganic pigments such
as aluminium oxide or titanium dioxide, or dyes of natural origin;
stabilizers such as antioxidants, light stabilizers, radical
scavengers, stabilizers against microbial attack.
In one embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
as shown in FIG. 1 and which is substantially pure. For example,
the crystalline form used can be at least 90% pure, preferably at
least 95% pure, or more preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) as shown in Table 1 and
which is substantially pure. For example, the crystalline form used
can be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 3.78, 4.09, 8.19,
9.15, 10.42, 13.02, 13.50, 18.45, 19.48, and 20.86, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 3.78, 4.09, 6.92,
8.19, 9.15, 10.12, 10.42, 12.30, 13.02, 13.50, 14.77, 16.20, 16.97,
18.12, 18.45, 19.48, 20.86, 24.24, 24.79, and 25.97, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 3.78, 4.09, 6.72,
6.92, 8.19, 9.15, 9.84, 10.12, 10.42, 10.72, 11.66, 12.30, 13.02,
13.50, 14.77, 15.26, 15.62, 16.20, 16.97, 17.27, 17.55, 18.12,
18.45, 19.48, 19.90, 20.37, 20.61, 20.86, 21.99, 22.25, 22.72,
24.24, 24.79, 25.97, 26.88, 27.42, 27.81, and 30.23, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern as shown in FIG. 2 and which is substantially pure. For
example, the crystalline form used can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern at values of two theta (.degree. 2.theta.) as shown in
Table 2 and which is substantially pure. For example, the
crystalline form used can be at least 90% pure, preferably at least
95% pure, or more preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.70, 7.53, 10.51,
11.43, 11.80, 15.85, 17.23, 19.11, 21.37, and 23.00, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.23, 5.70, 7.53,
8.24, 8.97, 10.51, 11.43, 11.80, 12.05, 12.69, 13.23, 14.97, 15.85,
17.23, 19.11, 20.20, 21.37, 21.99, 22.22, and 23.00, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.23, 5.70, 7.53,
8.24, 8.97, 10.51, 11.43, 11.80, 12.05, 12.69, 13.23, 13.99, 14.97,
15.85, 17.23, 18.45, 19.11, 19.76, 20.20, 21.37, 21.99, 22.22,
23.00, 25.17, 25.43, 26.73, and 32.46, and which is substantially
pure. For example, the crystalline form used can be at least 90%
pure, preferably at least 95% pure, or more preferably at least
97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern as shown in FIG. 3 and which is substantially pure. For
example, the crystalline form used can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern at values of two theta (.degree. 2.theta.) as shown in
Table 3 and which is substantially pure. For example, the
crystalline form used can be at least 90% pure, preferably at least
95% pure, or more preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree.2.theta.) of 5.22, 5.69, 7.55,
10.49, 11.38, 11.84, 15.99, 17.23, 19.18, and 21.41, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree.2.theta.) of 5.22, 5.69, 7.55,
8.21, 9.40, 10.49, 11.38, 11.84, 12.04, 12.67, 13.24, 15.99, 17.23,
19.18, 20.15, 21.41, 22.10, 22.53, 23.02, and 25.19, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.22, 5.69, 7.55,
8.21, 8.99, 9.40, 10.49, 11.07, 11.38, 11.84, 12.04, 12.67, 13.24,
13.99, 14.96, 15.99, 17.23, 18.10, 18.47, 19.18, 20.15, 21.41,
22.10, 22.53, 23.02, 25.19, 25.69, 26.57, 26.98, 30.09, and 32.45,
and which is substantially pure. For example, the crystalline form
used can be at least 90% pure, preferably at least 95% pure, or
more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern as shown in FIG. 4 and which is substantially pure. For
example, the crystalline form used can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern at values of two theta (.degree. 2.theta.) as shown in
Table 4 and which is substantially pure. For example, the
crystalline form used can be at least 90% pure, preferably at least
95% pure, or more preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.43, 6.24, 7.53,
10.91, 12.34, 12.57, 13.67, 13.94, 17.44, and 19.30, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.43, 6.24, 7.53,
8.68, 10.58, 10.91, 12.34, 12.57, 13.67, 13.94, 14.71, 15.40,
15.99, 16.64, 17.44, 19.30, 19.70, 21.10, 21.33, and 21.72, and
which is substantially pure. For example, the crystalline form used
can be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.43, 6.24, 7.53,
8.68, 9.28, 10.58, 10.91, 11.65, 12.34, 12.57, 13.67, 13.94, 14.71,
15.40, 15.99, 16.64, 17.44, 19.30, 19.70, 21.10, 21.33, 21.72, and
22.78, and which is substantially pure. For example, the
crystalline form used can be at least 90% pure, preferably at least
95% pure, or more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern as shown in FIG. 5 and which is substantially pure. For
example, the crystalline form used can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern at values of two theta (.degree. 2.theta.) as shown in
Table 5 and which is substantially pure. For example, the
crystalline form used can be at least 90% pure, preferably at least
95% pure, or more preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.57, 6.19, 7.50,
10.86, 11.46, 12.42, 13.59, 15.28, 16.66, and 19.44, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.57, 6.19, 7.50,
8.75, 10.86, 11.08, 11.46, 12.42, 13.59, 15.28, 16.26, 16.66,
17.25, 17.87, 19.44, 20.80, 21.13, 21.39, 22.15, and 27.12, and
which is substantially pure. For example, the crystalline form used
can be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.57, 6.19, 7.50,
8.75, 10.86, 11.08, 11.46, 12.42, 12.84, 13.59, 15.28, 16.26,
16.66, 17.25, 17.87, 19.44, 20.80, 21.13, 21.39, 22.15, 23.17,
24.15, and 27.12, and which is substantially pure. For example, the
crystalline form used can be at least 90% pure, preferably at least
95% pure, or more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern as shown in FIG. 6 and which is substantially pure. For
example, the crystalline form used can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern at values of two theta (.degree. 2.theta.) as shown in
Table 6 and which is substantially pure. For example, the
crystalline form used can be at least 90% pure, preferably at least
95% pure, or more preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 4.35, 4.68, 7.33,
12.01, 13.13, 13.35, 16.54, 17.96, 18.26, and 21.21, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 4.35, 4.68, 6.41,
7.33, 9.54, 10.26, 11.13, 11.34, 12.01, 13.13, 13.35, 14.33, 16.54,
17.96, 18.26, 18.60, 19.77, 21.21, 21.75, and 24.19, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 4.35, 4.68, 6.41,
6.92, 7.33, 9.25, 9.54, 10.26, 11.13, 11.34, 12.01, 13.13, 13.35,
14.33, 14.65, 15.36, 16.54, 17.96, 18.26, 18.60, 19.05, 19.77,
21.21, 21.75, and 24.19, and which is substantially pure. For
example, the crystalline form used can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern as shown in FIG. 7 and which is substantially pure. For
example, the crystalline form used can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern at values of two theta (.degree. 2.theta.) as shown in
Table 7 and which is substantially pure. For example, the
crystalline form used can be at least 90% pure, preferably at least
95% pure, or more preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.36, 8.81, 10.09,
10.69, 11.43, 12.95, 14.14, 17.96, 18.28, and 22.88, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 3.50, 5.36, 8.81,
10.09, 10.69, 11.43, 12.19, 12.95, 14.14, 14.72, 15.18, 17.53,
17.96, 18.28, 18.86, 21.36, 22.01, 22.88, 26.54, and 28.04, and
which is substantially pure. For example, the crystalline form used
can be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 3.50, 4.61, 5.36,
5.79, 7.61, 8.81, 10.09, 10.69, 11.43, 12.19, 12.95, 14.14, 14.72,
15.18, 15.64, 16.87, 17.53, 17.96, 18.28, 18.86, 19.76, 21.36,
22.01, 22.88, 24.42, 25.20, 26.54, 28.04, and 28.65, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern as shown in FIG. 8 and which is substantially pure. For
example, the crystalline form used can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern at values of two theta (.degree. 2.theta.) as shown in
Table 8 and which is substantially pure. For example, the
crystalline form used can be at least 90% pure, preferably at least
95% pure, or more preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.08, 10.81, 12.05,
13.47, 13.68, 17.68, 19.02, 19.48, 21.73, and 25.53, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.08, 7.82, 10.27,
10.81, 12.05, 13.47, 13.68, 14.95, 16.81, 17.68, 19.02, 19.48,
20.36, 21.73, 22.24, 23.48, 25.53, 26.93, 32.01, and 33.12, and
which is substantially pure. For example, the crystalline form used
can be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.08, 7.82, 10.27,
10.81, 11.11, 12.05, 13.47, 13.68, 14.95, 15.57, 16.28, 16.81,
17.68, 19.02, 19.48, 20.36, 21.73, 22.24, 23.48, 24.16, 25.53,
26.93, 28.26, 30.41, 31.07, 32.01, 33.12, and 35.04, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern as shown in FIG. 9 and which is substantially pure. For
example, the crystalline form used can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern at values of two theta (.degree. 2.theta.) as shown in
Table 9 and which is substantially pure. For example, the
crystalline form used can be at least 90% pure, preferably at least
95% pure, or more preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.31, 11.11, 12.60,
13.75, 15.29, 15.96, 17.62, 19.71, 21.30, and 22.88, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.31, 10.16, 10.62,
11.11, 12.60, 13.75, 15.29, 15.96, 17.62, 18.19, 19.16, 19.71,
20.58, 21.30, 22.40, 22.88, 23.66, 26.40, 26.74, and 33.46, and
which is substantially pure. For example, the crystalline form used
can be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.31, 10.16, 10.62,
11.11, 12.60, 13.75, 15.29, 15.96, 17.62, 18.19, 19.16, 19.71,
20.58, 21.30, 22.40, 22.88, 23.66, 26.40, 26.74, 28.12, 31.62, and
33.46, and which is substantially pure. For example, the
crystalline form used can be at least 90% pure, preferably at least
95% pure, or more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern as shown in FIG. 10 and which is substantially pure. For
example, the crystalline form used can be at least 90% pure,
preferably at least 95% pure, or more preferably at least 97%.
In yet another embodiment, a process of the invention described
above (including any process described in any aspect, embodiment,
example or preference) uses a crystalline form of Compound I which
has characteristic peaks in the powder X-ray diffraction (PXRD)
pattern at values of two theta (.degree. 2.theta.) as shown in
Table 10 and which is substantially pure. For example, the
crystalline form used can be at least 90% pure, preferably at least
95% pure, or more preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 7.42, 10.57, 11.84,
13.74, 15.72, 17.36, 19.38, 21.34, 22.07, and 23.36, and which is
substantially pure. For example, the crystalline form used can be
at least 90% pure, preferably at least 95% pure, or more preferably
at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the powder X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.28, 5.65, 7.42,
9.26, 10.57, 10.90, 11.31, 11.84, 12.15, 12.73, 13.74, 15.72,
17.36, 18.04, 19.38, 21.34, 22.07, 22.90, 23.36, and 26.49, and
which is substantially pure. For example, the crystalline form used
can be at least 90% pure, preferably at least 95% pure, or more
preferably at least 97%.
In another embodiment, a process of the invention described above
(including any process described in any aspect, embodiment, example
or preference) uses a crystalline form of Compound I which has
characteristic peaks in the power X-ray diffraction (PXRD) pattern
at values of two theta (.degree. 2.theta.) of 5.28, 5.65, 7.42,
8.02, 8.94, 9.26, 10.57, 10.90, 11.31, 11.84, 12.15, 12.73, 13.14,
13.74, 14.78, 15.72, 16.32, 16.95, 17.36, 18.04, 18.81, 19.38,
21.34, 22.07, 22.90, 23.36, 24.50, 25.13, 25.59, 26.49, 32.24, and
32.93, and which is substantially pure. For example, the
crystalline form used can be at least 90% pure, preferably at least
95% pure, or more preferably at least 97%.
In yet another aspect, the present invention features compositions
comprising a crystalline form of Compound I of the invention. Any
crystalline form described herein (including any crystalline form
described in any aspect, embodiment or example) can be used to make
a composition of the invention. Preferably, the crystalline form is
substantially pure, such as at least 90% pure, preferably at least
95% pure, or more preferably at least 97% pure. In one embodiment,
a composition of the invention comprises at least 5% by weight of a
substantially pure crystalline form of the invention. In another
embodiment, the composition of the invention comprises at least 10%
by weight of a substantially pure crystalline form of the
invention. In still another embodiment, a composition of the
invention comprises at least 5% by weight of one or more
crystalline forms of the invention. In yet another embodiment, a
composition of the invention comprises at least 10% by weight of
one or more crystalline forms of the invention.
Example 1
Preparation of n-Butylamine-H.sub.2O Solvate (Compound I Pattern
A)
Amorphous Compound I was suspended in n-butylamine at ambient
temperature. Solids were isolated after crystallization and left at
ambient conditions for a short period of time prior to
characterization.
The crystal structure has been resolved by Single-Crystal XRD. The
asymmetric unit contains 4 molecules of n-butylamine, 2 molecules
of water and 2 molecules of Compound I. The experimental powder
X-ray diffraction patterns (PXRD) are shown in FIG. 1. Peak listing
of the experi mental PXRD pattern with relative intensities is
given in Table 1.
Several isostructural crystal forms have been obtained from other
solvents (e.g., propylamine/H2O, amylamine, n-hexylamine,
sec-butylamine/H2O, isobutylamine/H2O, n-butanol/Heptane,
2-butanol/Heptane, n-pentanol/Heptane, EtOH/Pentane, and
n-propanol/Pentane) exhibiting very similar experimental PXRD
patterns. These crystal forms are labeled "Pattern A" or "Form I"
according to their PXRD patterns.
Compound I was initially found to be very difficult to crystallize
during early development. Of all the numerous solvent systems
investigated, it was unexpected found that only the n-alkylamines
(4-6 carbons) led to significant crystallization.
TABLE-US-00001 TABLE 1 PXRD Peak Listing of Compound I Pattern A
(n-Butylamine-H2O Solvate) Peak Position (.degree. 2.theta.)
Relative Intensity 3.775 64.6 4.087 31 6.718 11.5 6.921 24.2 8.19
100 9.151 35.7 9.836 12.3 10.118 22.4 10.419 60.6 10.724 12.4
11.658 12.9 12.304 20.3 13.019 39.7 13.502 37.3 14.772 23.2 15.255
11.7 15.622 7.6 16.196 20.9 16.974 19.1 17.271 12.5 17.548 18.4
18.122 19.7 18.445 50.5 19.478 46.5 19.896 11.4 20.371 11.1 20.609
18.3 20.861 41.4 21.993 18 22.248 9.2 22.724 8.4 24.242 26.5 24.792
26.6 25.967 24.1 26.884 6.3 27.415 6.3 27.812 7 30.226 9.5
Example 2
Compound I Pattern B Isolated from MEK/Heptane
Amorphous Compound I was dissolved in methyl ethyl ketone (MEK) at
ambient temperature and heptane was added. A seed mixture was
prepared from different crystalline solids of Compound I including
Form I (n-butylamine-H2O solvate) and other Pattern A forms
isolated from alkylamines. Solids were isolated after
crystallization and left at ambient conditions for a short period
of time prior to characterization.
Powder X-ray diffraction pattern and peak listing with relative
intensities are shown in FIG. 2 and Table 2, respectively.
TABLE-US-00002 TABLE 2 PXRD Peak Listing of Compound I Pattern B
(MEK-Heptane Solvate) Peak Position (.degree. 2.theta.) Relative
Intensity 5.228 34.9 5.7 48.7 7.525 62 8.236 32.7 8.97 27.6 10.514
53.8 11.43 51.9 11.801 51.1 12.053 41.1 12.689 33.6 13.227 20.6
13.988 20.5 14.973 23.8 15.847 47.1 17.228 64.2 18.449 15.6 19.114
45.4 19.755 13.8 20.195 34.3 21.367 100 21.988 25.8 22.217 28
23.003 43.5 25.165 19.7 25.432 13.5 26.726 20 32.455 11.6
Example 3
Compound I Pattern B Isolated from MeOH/Diethyl Ether
Amorphous Compound I was dissolved in methanol at ambient
temperature and diethyl ether was added. Pattern B seeds were added
to the solution. Solids were isolated after crystallization and
left at ambient conditions for a short period of time prior to
characterization.
Powder X-ray diffraction pattern and peak listing with relative
intensities are shown in FIG. 3 and Table 3, respectively.
TABLE-US-00003 TABLE 3 PXRD Peak Listing of Compound I Pattern B
(MeOH-Diethyl Ether Solvate) Peak Position (.degree. 2.theta.)
Relative Intensity 5.219 55.1 5.686 82.8 7.545 63.4 8.213 51.9 8.99
18.9 9.399 19 10.491 100 11.068 15.6 11.384 77.3 11.841 59.3 12.044
34.4 12.671 35.4 13.243 25.1 13.987 18.3 14.955 16 15.985 67.5
17.226 78.1 18.098 11.1 18.47 17.3 19.176 61.2 20.147 37 21.409
71.1 22.1 24 22.525 19.8 23.021 41.6 25.188 27.8 25.687 10.6 26.568
13.9 26.978 18.1 30.091 12.9 32.453 11.7
Several other isostructural Pattern B solvates have also been
obtained from >15 solvent systems, which have similar PXRD
patterns.
Example 4
Compound 1 Anhydrate (Pattern C)
Compound I Pattern B solvate isolated from methanol and diethyl
ether was dried under vacuum at 50.degree. C. for two weeks. Solids
were equilibrated a short time prior to characterization. Powder
X-ray diffraction pattern and peak listing with relative
intensities are shown in FIG. 4 and Table 4, respectively.
TABLE-US-00004 TABLE 4 PXRD Peak Listing of Compound I Anhydrate
(Pattern C) Peak Position (.degree. 2.theta.) Relative Intensity
5.433 100 6.239 81.8 7.525 52.2 8.684 35.7 9.283 15.3 10.582 27.4
10.914 38.5 11.648 20.1 12.34 47.1 12.568 48.6 13.674 78.4 13.942
43 14.711 20.6 15.398 30.4 15.993 27.5 16.637 36.4 17.44 37.8
19.304 53.3 19.698 28.8 21.102 32.5 21.332 36.7 21.715 33.2 22.776
17.1
Example 5
Compound I MTBE Solvate (Pattern C)
Compound I Pattern B MTBE solvate was dried under vacuum at
70.degree. C. for two days. Solids were equilibrated a short time
prior to characterization. Powder X-ray diffraction pattern and
peak listing with relative intensities are shown in FIG. 5 and
Table 5, respectively.
TABLE-US-00005 TABLE 5 PXRD Peak Listing of Compound I MTBE Solvate
(Pattern C) Peak Position (.degree. 2.theta.) Relative Intensity
5.571 98 6.19 100 7.498 34 8.746 22 10.861 32.1 11.083 22.4 11.458
41.3 12.419 57.2 12.839 11.4 13.59 33.5 15.275 56 16.261 28 16.655
33 17.25 13.2 17.867 16.9 19.435 76.3 20.796 19.4 21.134 21.7 21.39
23.4 22.147 15.9 23.165 12.1 24.147 10.4 27.12 14.2
Example 6
Pattern D
Compound I Pattern B MTBE solvate and Pattern C MTBE solvate were
combined and suspended in 20 w % ethanol in H.sub.2O at ambient
temperature for approximately three weeks. Solids were analyzed by
PXRD while still wet. Powder X-ray diffraction pattern and peak
listing with relative intensities are shown in FIG. 6 and Table 6,
respectively.
TABLE-US-00006 TABLE 6 PXRD peak Listing of Compound I Pattern D
(from EtOH/H.sub.2O) Peak Position (.degree. 2.theta.) Relative
Intensity 4.347 63.4 4.684 85.5 6.413 24.0 6.917 15.3 7.331 43.2
9.246 14.9 9.539 17.1 10.261 18.7 11.127 23.1 11.337 27.3 12.006 60
13.131 79.8 13.354 35.3 14.325 34.3 14.653 16 15.359 13.7 16.536
41.1 17.961 100 18.26 37.3 18.604 22.0 19.054 11.4 19.774 16.4
21.208 49.6 21.754 22.5 24.19 31.3
Example 7
Compound I Hydrate (Pattern E)
Compound I Pattern D was air dried for approximately 2 h. Powder
X-ray diffraction pattern and peak listing with relative
intensities are shown in FIG. 7 and Table 7, respectively.
TABLE-US-00007 TABLE 7 PXRD Peak Listing of Compound I Hydrate
(Pattern E) Peak Position (.degree. 2.theta.) Relative Intensity
3.495 22.7 4.611 6.6 5.356 75.5 5.786 14.3 7.609 8.6 8.806 42.6
10.091 40.1 10.691 40.2 11.428 54.3 12.193 27.6 12.945 40.8 14.143
52.6 14.715 20.7 15.179 30.8 15.643 8.2 16.873 13.8 17.525 26.1
17.957 100 18.284 41.2 18.86 25.3 19.757 11.5 21.363 19.6 22.006
23.7 22.883 34.6 24.423 13.2 25.203 13.9 26.542 21.5 28.035 15.4
28.654 11.7
Example 8
Compound I ACN Solvate (Pattern F or Form II)
Compound I Pattern B MTBE solvate was suspended in acetonitrile at
ambient temperature over four days. Solids were analyzed by PXRD
while still wet. Powder X-ray diffraction pattern and peak listing
with relative intensities are shown in FIG. 8 and Table 8,
respectively.
TABLE-US-00008 TABLE 8 PXRD Peak Listing of Compound I ACN solvate
(Form II) Peak Position (.degree. 2.theta.) Relative Intensity
5.081 100 7.815 5.6 10.274 7.6 10.812 18.3 11.108 4.2 12.052 43.6
13.473 17.7 13.683 13.3 14.948 7.1 15.57 2.9 16.282 3 16.812 8.4
17.684 14.1 19.017 13.9 19.48 17.5 20.358 11.8 21.733 47.8 22.237
12 23.483 11.4 24.155 3.3 25.529 27.4 26.933 8.9 28.264 2.7 30.406
2.8 31.074 1.8 32.013 4.8 33.119 4.6 35.037 2.1
Example 9
Compound I ACN Solvate (Pattern F or Form II)
Compound I was dissolved in acetonitrile at 40.degree. C.
Di-n-butyl ether was charged to prepare a 60% di-n-butyl
ether/acetonitrile composition, and the solution was seeded with
Form III. The mixture was charged with di-n-butyl ether to a
composition of 83% di-n-butyl ether/acetonitrile and cooled to
25.degree. C. Solids were analyzed by PXRD while still wet.
Example 10
Compound I Anhydrate (Pattern G or Form III)
Compound I ACN solvate (Form II) was air dried at ambient
temperature for a few minutes. Powder X-ray diffraction pattern and
peak listing with relative intensities are shown in FIG. 9 and
Table 9, respectively.
TABLE-US-00009 TABLE 9 PXRD Peak Listing of Compound I Anhydrate
(Pattern G or Form III) Peak Position (.degree. 2.theta.) Relative
Intensity 5.313 100 10.162 6.2 10.623 6.5 11.108 9 12.603 34.4
13.753 13.7 15.291 6.7 15.961 9.5 17.618 15.8 18.192 6.7 19.16 3.2
19.71 9 20.579 5.2 21.296 13.5 22.395 4.1 22.884 7.6 23.662 3.9
26.402 6.7 26.743 5.3 28.124 2.1 31.621 2.2 33.461 3.2
Example 11
Compound I di-n-Butyl Ether Solvate (Pattern H)
Compound I Pattern G (Form III) and Pattern C solids in an
.about.1:1 ratio were suspended in di-n-butyl ether at 25.degree.
C. for about 3 months. Solids were analyzed by PXRD after a short
equilibration time at ambient temperature. Powder X-ray diffraction
pattern and peak listing with relative intensities are shown in
FIG. 10 and Table 10, respectively.
TABLE-US-00010 TABLE 10 PXRD Peak Listing of Compound I di-n-Butyl
Ether Solvate (Pattern H) Peak Position (.degree. 2.theta.)
Relative Intensity 5.28 32.5 5.649 28.6 7.421 75.9 8.017 15.9 8.944
15.8 9.259 31.4 10.574 73.4 10.896 31.1 11.309 30.2 11.837 52.3
12.154 42.4 12.734 34.1 13.144 22.9 13.742 47.8 14.778 18.4 15.721
100 16.32 22.1 16.947 19.1 17.359 63.2 18.044 26 18.806 22 19.382
54.8 21.335 84.6 22.072 45.3 22.9 28.8 23.358 49.9 24.504 9.4
25.126 17.3 25.591 19.1 26.49 26.2 32.237 10.7 32.934 8.8
The foregoing description of the present invention provides
illustration and description, but is not intended to be exhaustive
or to limit the invention to the precise one disclosed.
Modifications and variations are possible in light of the above
teachings or may be acquired from practice of the invention. Thus,
it is noted that the scope of the invention is defined by the
claims and their equivalents.
* * * * *